9
ORTHO BULLETS
Volume
Nine
Basic Science
2017
Collected By : Dr AbdulRahman AbdulNasser
drxabdulrahman@gmail.com
OrthoBullets 2017
OrthoBullets 2017
Preface
Orthobullets.com is an educational resource for
orthopaedic surgeons designed to improve
training through the communal efforts of those
who use it as a learning resource. It is a simple but
powerful concept. All of our topics, technique
guides, cases, and user-generated videos are
free, and will stay that way.
The site was collected to PDF files, to make it
easy to navigate through topics, a well-organized
index is included in table of contents at the
beginning of each volume, another way for e-book
users is bookmarks function of your favorite PDF
viewer, it easily accessed through PC or any
smart device, and easily can reach to any topic in
the e-book.
To be easy to study, all trauma topics collected
in one volume , in volume one you find adult trauma
topics including spine trauma, hand trauma, foot
and ankle trauma, and pediatric trauma, also
chapter of infections (adult osteomyelitis, septic
arthritis , wound & hardware infections, necrotizing
fasciitis and Gas gangrene) all these topics moved
from trauma to pathology volume eight.
In other volumes you will find a note about any
topics that moved to trauma volume.
Also any text that copied from another source than orthobullets.com formatted in a red box like this.
Dr, AbdulRahman AbdulNasser
OrthoBullets 2017
Table of Contents
I.
Musculoskeletal biology ..................................................................................................... 0
A.
Bone Basic Science ....................................................................................................... 1
1. Types of Bone ................................................................................................................. 1
2. Bone Cells ...................................................................................................................... 3
3. Bone Matrix .................................................................................................................... 8
4. Bone Marrow .................................................................................................................. 9
5. Bone Circulation ........................................................................................................... 10
6. Bone Signaling & RANKL .............................................................................................. 12
7. Normal Bone Metabolism .............................................................................................. 14
B.
Bone Formation & Healing ........................................................................................... 19
1. Embryology .................................................................................................................. 19
2. Endochondral Bone Formation ..................................................................................... 25
3. Intramembranous Bone Formation ............................................................................... 28
4. Bone Remodeling ......................................................................................................... 29
5. Fracture Healing .......................................................................................................... 30
6. Nonunion ...................................................................................................................... 34
7. Bone Growth Factors.................................................................................................... 36
8. Bone Grafting ............................................................................................................... 39
9. PTH & Vit D Physiology ................................................................................................. 44
C.
Biologic Tissues .......................................................................................................... 46
1. Muscle Biology & Physiology ........................................................................................ 46
2. Ligaments..................................................................................................................... 49
3. Tendons ....................................................................................................................... 53
4. Articular Cartilage ........................................................................................................ 56
5. Cartilage ...................................................................................................................... 61
6. Synovium & Synovial Fluid ............................................................................................ 63
7. Collagen ....................................................................................................................... 65
D.
Molecular Biology ........................................................................................................ 68
1. Molecular Biology Basics.............................................................................................. 68
2. Immunology .................................................................................................................. 70
3. Inheritance Patterns of Orthopaedic Syndromes .......................................................... 72
4. Genetic Pearls .............................................................................................................. 74
OrthoBullets 2017
E.
Material Science .......................................................................................................... 77
1. Material Properties ....................................................................................................... 77
2. Structural Properties .................................................................................................... 84
3. Orthopaedic Implants ................................................................................................... 84
4. Bioabsorbable Materials ............................................................................................... 89
5. Rehab & Prosthetics ..................................................................................................... 92
II.
Systemic Disease ............................................................................................................100
A.
Metabolic Bone Disease..............................................................................................101
1. Osteopenia & Osteoporosis .........................................................................................101
2. Renal Osteodystrophy .................................................................................................110
3. Rickets ........................................................................................................................113
4. Osteomalacia ..............................................................................................................116
5. Oncogenic Osteomalacia ............................................................................................118
B.
Joint Diseases ............................................................................................................120
1. Gout ............................................................................................................................120
2. Pseudogout (CPPD) .....................................................................................................122
3. Hemochromatosis .......................................................................................................123
4. Neuropathic (Charcot) Joint of Shoulder & Elbow........................................................125
5. Ochronosis ..................................................................................................................129
6. Reiter's ........................................................................................................................129
7. Psoriatic Arthritis ........................................................................................................131
8. Hemophilic Arthropathy ..............................................................................................133
C.
Blood Conditions ........................................................................................................137
1. Fat Embolism Syndrome ..............................................................................................137
2. Thromboembolism (PE & DVT).....................................................................................138
3. Anticoagulation ...........................................................................................................142
D.
Neurologic Diseases ...................................................................................................146
1. Stroke .........................................................................................................................146
2. Multiple Sclerosis ........................................................................................................148
3. Amyotrophic Lateral Sclerosis (ALS) ...........................................................................151
4. Complex Regional Pain Syndrome (CRPS) ...................................................................152
E.
Systemic Diseases ......................................................................................................155
1. Rheumatoid Arthritis ...................................................................................................155
2. Systemic Lupus Erythematosus (SLE) .........................................................................165
OrthoBullets 2017
3. Pustulosis palmoplantaris............................................................................................166
4. Acute Rheumatic Fever ...............................................................................................168
F.
Metabolic Disease ......................................................................................................169
1. Hypercalcemia ............................................................................................................169
2. Hypocalcemia..............................................................................................................170
3. Hypoparathyroidism ....................................................................................................172
4. Hyperparathyroidism...................................................................................................173
5. Hypophosphatasia .......................................................................................................175
6. Pseudohypoparathyroidism .........................................................................................177
7. Scurvy .........................................................................................................................179
III.
A.
Medications & Toxicity ...................................................................................................182
Medications ................................................................................................................183
1. Bisphosphonates .........................................................................................................183
2. Prophylaxis Antibiotics ................................................................................................185
3. Antibiotic Classification & Mechanism .........................................................................187
4. Anti-inflammatory Medications ....................................................................................194
5. Analgesic Medications.................................................................................................196
6. Anesthesia ..................................................................................................................200
7. Platelet-Rich Plasma ....................................................................................................208
B.
Toxicology ..................................................................................................................209
1. Lead Toxicity ...............................................................................................................209
IV.
A.
Clinical Science .............................................................................................................210
Clinical Studies ...........................................................................................................211
1. Statistic Definitions .....................................................................................................211
2. Level of Evidence ........................................................................................................218
3. Clinical Trial Design .....................................................................................................220
4. Outcome Measure Tools ..............................................................................................223
B.
Healthcare Worplace ..................................................................................................228
1. Occupational Health ....................................................................................................228
2. Legal and Ethics ..........................................................................................................229
OrthoBullets2017
| Bone Basic Science
ORTHO BULLETS
I.Musculoskeletal biology
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
A. Bone Basic Science
1. Types of Bone
Introduction
 Bone can be classified based on both anatomy and structure
o anatomic
 long bones
 flat bones
o structure
 macroscopic level
 cortical
 cancellous
 microscopic level
 lamellar
 woven bone
Anatomic classification
 Long bones
o e.g. femur, humerus, tibia, forearm bones
o three anatomic regions in long bones
 diaphysis
 thick cortical bone surrounding a central canal of cancellous bone
 outer region covered by periosteum
 metaphysis
 thin cortical bone surrounding loose trabecular bone
 epiphysis
 end of bone that forms the articular surface
 contains the physis and the subchondral region under the articular cartilage
 Flat bones
o e.g. skull, pelvis, scapula
o varied structure of either purely cortical bone or cortical bone with a thin central trabecular
region
Macroscopic structural classification
 Cortical
o 80% of skeleton
o metabolism
 characterized by slow turnover rate and high Young's modulus
o structure
 made of packed osteons or Haversian systems
 osteons
‎I:1 In this image we see mature,
 outer border defined by cement lines
lamellar cortical bone. 1 - A new
Haversian system or osteon 2  vascular canals
Haversian canal 3 - Interstitial region
 contain arterioles, venules, capillaries, and nerves
between osteons
 if oriented along long axis of bone: Haversian canals
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OrthoBullets2017
Musculoskeletal biology | Bone Basic Science
 if oriented transversely to long axis of bone: Volkmann canals
interstitial lamellae
 the region between osteons
Cancellous bone (spongy or trabecular bone)
o metabolism
 lower Young's modulus and more elastic
 high turnover to remodel according to stress across the bone
o structure
 boney struts organized into a loose network
 each strut is approximately 200 micrometers in diameter
I‎:2 Cancellous bone is a trabecular
 30-90% of bone is porous and contains bone marrow
framework of bone which is highly
porous. The porous region of the bone
 increased porosity in osteoporosis


contains bone marrow. Metaphyseal
regions have larger amounts of cancellous
bone and subsequently better healing
potential than diaphyseal regions.
Microscopic structural classification
 Woven bone
o immature or pathologic bone that is woven and random and is not stress oriented
o compared to lamellar bone, woven bone has:
 more osteocytes per unit of volume
 higher rate of turnover
o weaker and more flexible than lamellar bone
 Lamellar bone
o secondary bone created by remodeling woven bone
o organized and stress oriented
o stronger and less flexible than woven bone
I‎ :4 In this image the woven bone is not organized and is simply
calcified. The bone is also thin and no osteons are seen
indicating an immature bone. Diffuse inflammatory cells are
also seen suggestive of a healing or inflammed area.
- 2 -
I‎ :3 The organized structure of this bone is
consistent with organized lamellar bone.
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
2. Bone Cells
Osteoblasts
 Origin
o derived from undifferentiated mesenchymal cells
o mesenchymal cells then differentiate into osteoprogenitor cells
 Structure
o contain increased amounts of endoplasmic reticulum, Golgi apparatus, and mitochondria than
other cells
o allows for synthesis and secretion of bone matrix
 Function
o form bone by producing non-mineralized matrix
 alkaline phosphatase
 type I collagen
 osteonectin
 osteocalcin
 stimulated by 1,25 dihydroxyvitamin D
o regulate osteoclast function
 Signaling
o osteoblastic differentiation
 BMP stimulates mesenchymal cells to become osteoprogenitor cells
 core binding factor alpha-1 (cbf alpha -1: RUNX2)
 stable beta-catenin plays a major role in inducing cells to form osteoblasts with resulting
intramembranous bone formation
 platelet derived growth factor (PDGF) induces osteoblast differentiation
 insulin derived growth factor (IDGF) induces osteoblast differentiation
o osteoblast bone production
 PTH receptor
 stimulates alkaline phosphatase and type I collagen production
 1,25 dihydroxyvitamin D receptor
 stimulates matrix and alkaline phosphatase synthesis
 production of bone specific proteins (osteocalcin)
 estrogen inhibits bone resorption and stimulates bone production by inhibiting adenylyl
cyclase
 glucocorticoids inhibit collagen and bone matrix production
 prostaglandins stimulate bone resorption by activating adenylyl cyclase
o osteoclast signaling
 interconnected signaling allows coupling of bone resorption and formation
 osteoclast activation
 PTH receptors on osteoblast bind to PTH which when leads to expression of RANKL
 RANKL binds to RANK receptor on osteoclast and bone resorption
 osteoclast inhibition
 osteoblasts can secrete OPG (osteoprotegrin)
 OPG binds to RANKL on the osteoblast, preventing RANK activation
 inhibits osteoclast activity
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OrthoBullets2017

Musculoskeletal biology | Bone Basic Science
Location
o more metabolically active cells at the bone surface
o less active cells in more central bone
 activated by disruption of the more peripheral osteoblasts
Osteoclasts
 Function
o reabsorb bone
 osteoblasts regulate osteoclast bone reabsorbtion (see above)
 steps in resorption cycle
 migration to resorption site
 bone attachment
 polarization (formation of membrane domains)
 dissolution of hydroxyapatite
 degradation of organic matrix
 removal of degradation products from resorption lacuna
 apoptosis of the osteoclasts or return to the non-resorbing stage.
 Origin
o originate from hematopoietic cells from macrophage cell lineage
o monocyte progenitors fuse together to form mature multinuclear cells
 Cellular biology
o cellular anatomy
 multinucleated giant cells
o cellular physiology
 bone reabsorbtion occurs at ruffled border
 Howship's lacunae
 are site of bone resorption where ruffled border meets bone surface
 tartrate resistant acid phosphate
 secreted by osteoclasts to lowers the Ph (utilizing carbonic anhydrase) and increases
the solubility of hydroxyapatite crystals
 deficiency of carbonic anhydrase prevents bone resorption
 proteolytic digestion
 the organic matrix is then removed by proteolytic digestion
 cathepsin K
 is one major proteolytic enzyme that degests organic matrix at ruffled border
 bisphosphonates mechanism
 prevents osteoclasts from forming ruffled border and producing acid hydrolases
 Molecular biology
o osteoclast-bone attachment
 osteoclast attaches to bone matrix at sealing zone
 attach to bone surfaces via integrins on osteoclast surface
 integrins include αVβ3, αVβ5, α2β1, αVβ1
 αVβ3 (on osteoclast) is a receptor for vitronectin (on bone surface)
 Arg-Gly-Asp (RGD) sequence of extracellular bone proteins directly allows binding
to integrins
 antibodies to αVβ3 and RGD inhibit bone resorption
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
- 5 -
OrthoBullets2017
Musculoskeletal biology | Bone Basic Science
- 6 -
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
o osteoclast
polarization
contain specialized membrane domains
 ruffled border (RB)
 functional secretory domain (FSD)
 basolateral membrane (BL)
o mineralized bone matrix degradation
 hydroxyapatite crystals dissolved by HCl secreted through ruffled border into resorption
lacuna (RL)
 RL is an extracelllular space between RB and bone matrix, sealed from ECF by sealing
zone
 uses ATP-consuming proton pumps in RB and in intracellular vacuoles
 H+ come from carbonic anhydrase II
 RB has high number of chloride channels (maintain electroneutrality)
o organic bone matrix degradation
 lysosomal cysteine proteinases
 matrix metaloproteinases (MMPs), esp MMP-9
 cathepsin K : mutation in cathepsin K gene leads to pycnodysostosis
o removal of degradation products
 by transcystosis to FSD, where they are secreted into ECF
 tartrate-resistant acid phosphatase (TRAP) is localized in transcytotic vesicles, generates
reactive O2 species that destroys collagen
o osteoclast-osteoblast signaling
 osteoblasts upregulate and downregulate osteoclast activity
 osteoclast activation
 RANKL (NF-kB ligand)
 expressed by osteoblasts and tumor cells to activate osteoclasts
 IL-1
 found adjacent to loose total joint implants and known to activate osteoclasts
 osteoclast inhibition
 calcitonin
 IL-10

Osteocytes
 Origin
o are former osteoblasts trapped in the matrix they produced
o account for 90% of cells in the mature skeleton
 Structure
o high nucleus to cytoplasm ratio
o have long cellular processes which communicate with other cells via canalculi in the bone
 Function
o maintain bone and cellular matrix
o important in regulation of calcium and phosphorous concentrations in bone
o do not express alkaline phosphatase
 Signaling
o stimulated by calcitonin
o inhibited by PTH
o communicate with adjacent osteocytes via gap junctions in canaliculi
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OrthoBullets2017
Musculoskeletal biology | Bone Basic Science
Osteoprogenitor Cells
 Origin
o originate from mesenchymal stem cells
o environment will determine their function
 Function
o become osteoblasts under low strain and high oxygen tension
o become cartilage under intermediate strain and low oxygen tension
o become fibrous tissue under high strain
3. Bone Matrix
Introduction
 Bone is made up of
o organic component
 40% of dry weight
o inorganic component
 60% of dry weight
Organic component
 Components include
o collagen
 90% of organic component
 primarily type I collagen
 provides tensile strength
 it is a triple helix composed of one alpha-2 and two alpha-1 chains
o proteoglycans
 responsible for compressive strength
 inhibit mineralization
 composed of glycosaminoglycan-protein complexes
o matrix proteins
 includes noncollagenous proteins
 function to promote mineralization and bone formation
 three main types of proteins involved in bone matrix
 osteocalcin
 most abundant non-collagenous protein in the matrix (10%-20% of total)
 produced by mature osteoblasts
 function
 promotes mineralization and formation of bone
 directly involved in regulation of bone density
 attracts osteoclasts
 signaling
 stimulated by 1,25 dihydroxyvitamin D3
 inhibited by PTH
 clinical application
 marker of bone turnover
 can be measured in urine or serum
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
osteonectin
 secreted by platelets and osteoblasts
 function
 believed to have a role in regulating calcium or organizing mineral in matrix
 osteopontin
 function : cell-binding protein
o cytokine and growth factors
 small amounts present in matrix
 aid in bone cell differentiation, activation, growth, and turnover
 include
 IL-1, IL-6, IGF, TGF-beta, BMPs

Inorganic component
 Components include
o calcium hydroxyapatite (Ca10(PO4)6(OH)2
 provides compressive strength
o osteocalcium phosphate (brushite)
4. Bone Marrow
Introduction
 Gelatinous tissue found in the inner spaces of bone that contains progenitor cells and stromal cells
 Types of bone marrow
o red marrow
 hematopoietic tissue
 composition
 40% water
 40% fat
 20% protein
o yellow marrow
 fatty tissue
 composition
 15% water
 80% fat
 5% protein
 Function
o primary function of hematopoiesis
o controls the inner diameter of bone
Red Bone Marrow
 Location
o most commonly found in flat bones
 ribs, ilium, sternum, vertebrae, skull
 epiphysis/metaphysis of long bone (children only)
 Function
o contains mesenchymal stem cells and hematopoietic stem cells
o red marrow slowly changes to yellow marrow with age
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OrthoBullets2017
Musculoskeletal biology | Bone Basic Science
Yellow Bone Marrow
 Location
o most commonly found in diaphysis or shaft of long bones
 femur, humerus, tibia
 Function
o contains mostly fat cells
o may revert to red bone marrow if there is an increased demand for red blood cells (e.g. trauma)
Bone Marrow Examination
 Biopsy
o location
 anterior or posterior iliac crest
 sternum
 tibia
o indications
 malignancies (most common)
 multiple myeloma, lymphoma, leukemia, metastatic disease
 infection
 TB (rare)
o technique
 needle/trochar biopsy
 open surgical biopsy
Clinical Aspects of Cell Therapy
 Bone Marrow Aspirate
o applications in orthopedic surgery
 fracture union/non-union
 osteonecrosis
 mesenchymal tissue engineering (e.g., bone, ligaments, cartilage)
5. Bone Circulation
Introduction
 Bone receives 5-10% of cardiac output
 Bones that receive tenuous blood supply
o scaphoid
o talus
o femoral head
o odontoid
 Blood supply to long bone comes from three sources
o nutrient artery system
o metaphyseal-epiphyseal system
o periosteal system
Nutrient Artery System
 High pressure system that branches from major systemic arteries
 Enter the cortex through the nutrient foramen and enter the medullary canal
- 10 -
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
o then

branch into ascending and descending branches
then branch into arterioles and supply the inner 2/3 of mature bone via the haversion system
Metaphyseal epiphyseal system
 Arteries arise from periarticular vascular plexus
o e.g. geniculate arteries
Periosteal System
 Low pressure system that supplies the outer 1/3 of bone
o connected by
 Volkman's artery (perpendicular to long axis)
 Haversion system (parallel to long axis)
Intracortical Vascularization
 Intracortical vessels travel within canals
o Primary Haversian canals
o Secondary Volkmann canals
Direction of Arterial Flow
 Normal intraosseous blood flow rate is 5-20ml/min/100g of bone
 Mature bone
o flow is centrifugal (inside to outside)
 because of high pressure nutrient artery system and low pressure periosteal system
 Immature bone
o flow is centripetal (outside to inside)
 because low pressure periosteal system predominates
 Factors increasing blood flow
o hypoxia
o hypercapnia
o sympathectomy
Direction of Venous Flow
 Mature bone
o flow is centripetal (outside to inside)
 cortical capillaries drain to venous sinusoids, which drain to the emissary venous system
Growth Plate
 Perichondrial artery is the major source of nutrition of the growth plate
Pathoanatomy
 Fractures
o patterns of blood flow following fracture
 immediate phase
 initial decrease in blood flow after fracture
 flow is centripetal (outside to inside)
 because high pressure nutrient artery system is disrupted
 low pressure periosteal system predominates
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OrthoBullets2017
Musculoskeletal biology | Bone Basic Science
o hours
to days
increase in blood flow (regional acceleratory phenomenon)
 peaks at 2 weeks and returns to normal in 3-5 months
 Intramedullary nails
o unreamed intramedullary nails preserve endosteal blood supply
o reaming devascularizes inner 50-80% of the cortex and delays revascularization of endosteal
blood supply
o loose fitting nails spare cortical perfusion and allow more rapid reperfusion
o tight fitting nails compromise cortical perfusion and reperfusion is slow

6. Bone Signaling & RANKL
Introduction
 Bone metabolism is a dynamic process that balances bone formation and bone resorption
o bone resorption
 performed by active osteoclast
 stimulated by RANKL in normal process
 stimulated by PTH in pathologic process (metastatic disease)
o bone formation
 performed by inhibiting osteoclasts and stimulating osteoblasts
 OPG inhibits osteoclasts
Osteoclast Activation
 Osteoclast activation stimulates bone resorption
 Molecules that stimulate bone resorption
- 12 -
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
o RANKL
RANKL (ligand) is secreted by osteoblasts and binds to the RANK receptor on osteoclast
precursor and mature osteoclast cells
o PTH (secreted by many cancer cells)
 activation of its receptor stimulates adenylyl cyclase
 binds to cell-surface receptors on osteoblasts to stimulate production of RANKL and M-CSF
o interleukin 1 (IL-1)
 stimulates osteoclast differentiation and thus bone resorption
o 1,25 dihydroxy vitamin D
 stimulates RANKL expression
o prostaglandin E2
 activates adenylyl cyclase and stimulates resorption
o IL-6 (myeloma)
o MIP-1A (myeloma)

Osteoclast Inhibition
 Osteoclast Inhibition decreases bone resorption
 Molecules that inhibit bone resorption
o osteoprotegerin (OPG)
 decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters
RANKL
 inhibits osteoclast differentiation, fusion, and activation
o calcitonin
 interacts directly with the osteoclast via cell-surface receptors
o estrogen (via decrease in RANKL)
 stimulates bone production (anabolic) and prevents resorption
 inhibits activation of adenylyl cyclase
o transforming growth factor beta (via increase in OPG)
o interleukin 10 (IL-10) : suppresses osteoclasts
Clinical Implications
 Osteopetrosis
o condition caused by a genetic defect resulting in absence of osteoclastic bone resorption
o a mouse RANKL knockout model creates a osteopetrosis-like condition
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OrthoBullets2017

Musculoskeletal biology | Bone Basic Science
Osteoyltic bone metastasis
o found to be mediated by the RANK and RANKL pathway
o RANKL is produced directly by the cancer cells
o blocking of RANKL by OPG results in decreased skeletal metastasis in animal models
o bisphosphonates decrease skeletal events in cancer metastasis
7. Normal Bone Metabolism
Introduction
 Normal bone metabolism is the complex sequence of bone turnover (osteoclastogenesis) and bone
formation (osteoblastogenesis)
o Physiology of bone metabolism
 bone has structural and metabolic functions
 metabolic functions of bone largely involve the homeostasis of calcium and phosphate
 release of calcium, or absorption of calcium, by bone is largely regulated by hormones and,
less so, by steroids
o Regulators of bone metabolism
 Hormones
 PTH
 Calcitonin
 Sex Hormones (eg. estrogen, androgens)
 Growth Hormone
 Thyroid Hormones
 Steroids
 Vitamin D
 Glucocorticosteroids
o Properties of bone metabolism
 Bone mass
 bone mass is the measure of bone tissue present at the end of skeletal maturity
 represents both its volume and size, as well as the density of the mineralized tissue
 peak bone mass occurs between ages 16 and 25
 greater in men and African Americans
 Bone loss
 bone mass decreases by 0.3 to 0.5% per year after skeletal maturity
 further decreases by 2-3% per year for untreated women during the 6th-10th years after
menopause
 rate of bone loss can be modulated by structural and metabolic factors
Calcium
 Location
o bone (99%)
o blood and extracellular fluid (0.1%)
o intracellular (1%)
 Function
o calcium has a wide range of function including
 muscle cell contraction
 nerve conduction
- 14 -
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
 clotting mechanisms
Forms of calcium
o bone
 majority is hydroxyapatite
o serum
 Ca++ bound to protein (45%)
 free-ionized Ca++ (45%)
 bound to various anions, eg. citrate, bicarbonate (10%)
 Regulation
o absorption from the digestive tract
o resorption from bone
o resorption in the kidneys
 Dietary requirements
o 2000 mg/day for lactating women
o 1500 mg/day for pregnant women, postmenopausal woman, and patients with a healing bone
fracture
o 1300 mg/day for adolescents and young adults
o 750 mg/day for adults
o 600 mg/day for children
 Dysfunction
o hypercalcemia
o hypocalcemia

Phosphate
 Location
o bone (86%)
o blood and extracelluar fluid (0.08%)
o intracellular (14%)
 Function
o key component of bone mineral
o important in enzyme systems and molecular interactions
 Forms of phosphate
o bone
 majority is hydroxyapatite
o serum
 mostly inorganic phosphate (H2PO4-)
 Regulation
o plasma phosphate is mostly unbound and reabsorbed by the kidney
o may be excreted in urine
o elevated serum phosphate can lead to increased release of PTH and bone resorption
 Dietary intake
o 1000-1500 mg/day
PTH
 Structure
o 84 amino acid peptide
 Origin
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Musculoskeletal biology | Bone Basic Science
o synthesized and secreted from chief cells in the four parathyroid glands
Net effect
o increases serum calcium
o decreases serum phosphate
 Mechanism
o bone
 PTH stimulates osteoblasts to secrete IL-1, IL-6 and other cytokines to activate osteoclasts
and increase resorption of bone
 Increases osteoblast production of M-CSF (macrophage colony-stimulating factor) and
RANKL, which increases number of osteoclasts.
 Paradoxically, osteoclasts do not express receptor for PTH
o kidney
 stimulates enzymatic conversion of 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin
D3 (active hormone form) which:
 increases resorption of Ca++ in kidney (increasing serum Ca++)
 increases excretion of PO4- from kidney (decreasing serum phosphate)
o intestine
 no direct action
 indirectly increase Ca++ absorption by activating 1,25-(OH)2-vitamin D3
 Dysfunction
o PTH-related protein and its receptor have been implicated in metaphyseal dysplasia
 Parathyroid hormone-related protein (PTHrP) has related effects to PTH as it binds to the same
receptors on osteoblasts and renal cells to increase serum calcium

Calcitonin
 Structure
o 32 amino-acid peptide hormone
 Origin
o produced by clear cells in the parafollicles of the thyroid gland (C cells)
 Net effect
o limited role in calcium homeostasis
o inhibit number and activity of osteoclasts
 Function
o bone
 inhibits osteoclastic bone resorption by decreasing number and activity of osteoclasts
 osteoclast have receptor for calcitonin
 Inc. serum Ca > secretion of calcitonin > inhibition of osteoclasts > dec. Ca (transiently)
 Dysfunction
o secreted by medullary thyroid tumors and mulitple endocrine neoplasia type II tumors
o Recombinant calcitonin used to treat Paget disease, osteoporosis, and hypercalcemia in
malignancy
Vitamin D
 Structure
o fat soluble secosteroid (steroid with a 'broken ring')
 Origin
o produced by skin when exposed to sunlight (UV B-generated Vitamin D)
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Basic Science
o dietary
intake (lipid-soluble vitamin D3)
metabolite 1,25-(OH)2-vitamin D3 formed by two hydroxylations in the liver and kidney,
respectively
 Net effect
o maintains normal serum calcium levels by activating osteoclasts for bone resorption and
increasing intestinal absorption of calcium (increase serum Ca++)
o promotes the mineralization of osteoid matrix
 Function
o liver
 activated-vitamin D3 converted to 25-(OH)-vitamin D3
o kidney
 25-(OH)-vitamin D3 converted to 1,25-(OH)2-vitamin D3 (active hormone form)
 activated by
 increased levels of PTH
 decreased levels of serum Ca++, P
 1,25-(OH)2-vitamin D3 (active hormone form)can be inactivated to 24,25-(OH)2-vitamin D3
 inactivity occurs with:
 decreased levels of PTH
 increased levels of serum Ca++, P
 vitamin D parallels that of PTH by increasing reabsorption of Ca in the kidneys
o bone
 1,25-(OH)2-vitamin D3 stimulates terminal differentiation of osteoclasts
 when osteoclasts mature they do not respond to 1,25-(OH)2-vitamin D3 and respond mostly
to cytokines released by osteoblasts
 1,25-(OH)2-vitamin D3 promotes the mineralization of osteoid matrix produced by
osteoblasts
 Dysfunction
o Vitamin D deficiency causes osteomalacia and rickets
o phenytoin (dilantin) causes impaired metabolism of vitamin D
o active
Estrogen
 Structure
o D ring steroid hormone
 Origin
o predominantly in the ovaries
o synthetic forms available
 Net effect
o prevents bone loss by decreasing the frequency of bone resorption and remodeling
 Function
o alone, because bone formation and resorption are coupled, it also indirectly decreases bone
formation
o leads to an increase in bone density of the femoral neck and reduces the risk of hip fracture
o most
important sex-steroid for peak bone mass attainment in both men and women
 Therapeutic estrogen
o outcomes
 decreases bone loss if started within 5-10 years after onset of menopause
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OrthoBullets2017
Musculoskeletal biology | Bone Basic Science
significant side effects so risk/benefit ratio must be evaluated
gains in bone mass usually limited to an annual increase of 2-4% for the first 2 years of
therapy
o secondary effects
 increases risk of
 heart disease
 breast cancer
 decreases risk of
 hip fracture
 endometrial cancer (if combined with cyclic progestin)
o laboratory
 will see a decreases in
 urinary pyridoline
 serum alkaline phosphatase


Thyroid Hormone
 Function
o regulates skeletal growth at the physis by stimulating
 chondrocyte growth
 type X collagen synthesis
 alkaline phosphatase activity
o thyroid hormones increase bone resorption and can lead to osteoporosis
 large doses of therapeutic thyroxine can mimic this process and cause osteoporosis
Growth Hormone
 Function
o increases serum calcium by
 increased absorption in intestine
 decreasing urinary excretion
o function is interdependent with insulin, somatomedins, and growth factors (TGF-B, PDGF,
mono/lyphokines)
 Gigantism
o oversecretion or increased response to growth hormone effecting the proliferative zone of the
growth plate
Steroids
 Function
o increase bone loss by
 decreasing Ca++ absorption in intestine through a decrease in binding proteins
 decreasing bone formation (cancellous more so than cortical bone) by
 decreasing collagen synthesis
 inhibiting osteoblast activity
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
B. Bone Formation & Healing
1. Embryology
Limb Development
 Overview
o the appendicular system forms between the 4-8 weeks of gestation
o limb bud development
 appears to be under the control of fibroblast growth factors (FGF)
 enlargement of the limb bud is due to the interaction between the apical ectodermal ridge
(AER) and the mesodermal cells in the progress zone.
 Steps of limb development
o notochord expresses Shh
o Shh regulates limb bud formation
 limb bud is combination of lateral plate mesoderm and somatic mesoderm
 growing outwards into ectoderm (called apical ectodermal ridge)
 limb bud formed at embryonic stage 12 (26 days after fertilization)
o mesenchyme condenses into preskeletal blastemal at core of limb bud
o chondrification occurs where mesenchyme differentiates into chondrocytes
 All upper limb bones are endochondral except distal parts of distal phalanges (membranous)
 From proximal (humerus, 36 days after fertilization) to distal (distal phalanges, 50 days)
 Factors required for chondrification
 transcription factors – Sox-5, Sox-6, Sox-9
 transforming growth factor superfamily – TGF-b, BMP-2
 FGF family
 receptor mutation leads to acrocephalosyndactyly (Apert syndrome)
 patients with severe craniofacial features have mild hand syndactyly (gain of function
in FGFR2c affinity for FGF2 expressed in craniofacial area )
 patients with mild craniofacial features have severe hand syndactyly (loss of function
in FGFR2c specificity for FGF2, and is now able to bind FGF10, more expressed in
hands)
 retinoids
 hedgehog gene products
 PTHrP
 cadherins
 WNT5a and WNT7a
o Formation of joints requires repression of chondrogenesis at sites of future joints
 proteins involved – WNT4, WNT14, growth and differentiation factor 5 (also known as
cartilage-derived morphogenetic protein 1)
 shoulder interzone appears at 36 days, hand interzones appear at 47 days
o Finger separation
 digital rays are evident within hand paddle at stage 17 (41 days)
 interdigital mesenchyme cells undergo programmed cell death (stage 19 to 22)( days 47-54)
 transcription factor Msx2 is expressed in interdigital mesenchyme, regulates BMP4-mediated
programmed cell death pathway
 transcription factor Hox-7 also expressed in interdigital zones
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OrthoBullets2017
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Musculoskeletal biology | Bone Formation & Healing
Limb patterning
o Proximodistal
 first signaling center to appear is AER
 controls proximal to distal growth
 forms under FGF10 stimulation
 removal /defect in AER results in proximal limb truncation
 example is central deficiency (cleft hand)
 another example is radial clubhand (radial dysplasia, absence of radius)
 FGFs expressed in AER include FGF4, FGF8, FGF9, and FGF 17
 FGF8 expressed earliest and is obligatory for normal limb development
 FGF4, 9 and 17 are redundant
 disrupted FGF signalling leads to arrested limb development
o Anteroposterior (radioulnar) limb growth (nomenclature: ulnar=posterior, radius=anterior)
 second signaling center to appear is ZPA (zone of polarizing activity), along posterior limb
bud
 grafting ZPA on anterior limb margin leads to mirror-image digit duplication (ulnar
dimelia, or mirror hand)
 signaling molecule is Shh compound (dose dependent)
 normal
 high concentration of Shh on posterior (ulnar) side for small finger development
 low concentration of Shh on anterior (radial) side for thumb development
 posterior/ulnar side abnormalities
 abnormal upregulation of Shh in the ZPA results in polydactly on the ulnar (posterior)
side
 extent of duplication is dose dependent (higher dose = more replication)
 downregulation of Shh (on the posterior/ulnar side) leads to loss of ulnar digits
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
anterior/radial side abnormalities
 abnormal upregulation of Shh in the anterior aspect of the limb bud (where Shh
concentration is supposed to be low) leads to loss of thumb
 timing
 posterior elements (little finger/ulna) are formed EARLY prior to anterior elements
which are formed LATE (radius/thumb)
 disruption of AP patterning will result in loss of later forming elements
(radius/thumb)
o Dorsoventral axis
 third signaling center is non-AER limb ectoderm /Wnt signalling center (progress zone, PZ)
 dorsal limb ectoderm expresses WNT7a
 activates Lmx1b (LIM-homeodomain factor) to regulate dorsal patterning
 WNT7a is responsible for all dorsal features (including nails)
 ventral ectoderm expresses en-1 (engrailed-1 protein, antagonistic to WNT7a)
 inhibits WNT7a (and restricts it to dorsal ectoderm)
 allows ventral limb development

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OrthoBullets2017
Musculoskeletal biology | Bone Formation & Healing

Key Genes
o Sonic Hedgehog (Shh) genes
 secreted by ZPA
 involved with HOX gene expression
 anterior-posterior (radioulnar) growth
 anterior (radial) mesoderm expresses ALX4
 posterior (ulnar) mesoderm expresses Hox8
 concentration gradient dictates formation of digits
 little finger develops where there is highest Shh concentration
 thumb develops where there is lowest Shh concentration
 activates Gremlin
 Gremlin inhibits BMPs that would otherwise block FGF expression in the AER
o Hox genes
 anterior-posterior (radioulnar) patterning
 together with Shh
 regulate somatization of the axial skeleton, essentially patterning digit formation
o Wnt genes (Wnt7a)
 expressed in dorsal (non-AER) ectoderm (Wnt signalling center)
 dorsal-ventral growth
 Mutations
o removal of AER
 truncated limb
o duplication of ZPA
 mirror-image duplication of the limb
mirror-image duplication of the limb
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
Key Genes/Regions
Gene/Region
Expresses
Regulates
Apical ectodermal ridge (AER)
FGF8 is dominant (also FGF 4, Proximal to distal growth and
9, 17, which are redundant)
interdigital necrosis
Zone of polarizing activity (ZPA) Shh
Anterior-posterior (radio-ulnar)
growth
Non-AER limb ectoderm (dorsal) Dorsal ectoderm expresses
Dorso-ventral growth
WNT7a, that activates Lmx1b
(regulates dorsal patterning)
Non-AER limb ectoderm (ventral) Ventral ectoderm expresses en- Dorso-ventral growth
1, antagonistic to WNT7a
(regulates ventral patterning)
Spine and Spinal Cord Development
 Somites
o the spinal column originates from pairs of mesodermal structures known as somites
o somites develop in a cranial to caudal direction on either side of the notochord and neural tube
 this process is dependent on the presence of the paraxis gene
o somite layers
 sclerotome
 layer will become the vertebral bodies and annulus fibrosus
 myotome
 will lead to myoblasts
 dermatome
 becomes skin
 Dorso-vental patterning
o dorso-vental patterning of the neural tube determined by counteracting activities of
 Sonic Hedgehog (Shh)
 in the floor plate and notochord (ventral)
 canonical Wnt/β-catenin
 in the roof plate (dorsal)
 Metameric shift phenomenon
o the phenomenon of how the spinal nerves, which originally ran in the center of the sclerotome,
exit between the two vertebral bodies at each level.
 Progression
o neural crest
 forms PNS, pia mater, spinal ganglia, sympathetic trunk
o neural tube : forms spinal cord
o notochord
 forms anterior vertebral bodies and nucleus pulposus
 Ossification centers
o vertebrae have 3 primary ossification centers
 centrum (anterior vertebral body)
 neural arch (posterior elements, pedicles, small portion of anterior vertebra)
 costal element (anterior part of lateral mass, transverse process, or rib)
 Intervertebral disc
o nucleus pulposus forms from notochord
o annulus fibrosus forms from sclerotome
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OrthoBullets2017
Musculoskeletal biology | Bone Formation & Healing
‎I:6 Formation of neural tube and neural crest
I‎ :7 Sclerotome forms vertebral bodies and annulus fibrosus. Notochord
forms nucleus pulposus.
‎I:5 Wnt (dorsal) and Shh (ventral) gradients in neural tube
development.
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
2. Endochondral Bone Formation
Introduction
 Enchondral bone formation occurs in
o longitudinal physeal growth
o embryonic long bone formation
o non-rigid fracture healing (secondary healing)
 Cell biology
o enchondral bone formation occurs with
a cartilage model
 chondrocytes produce cartilage which is
absorbed by osteoclasts
 osteoblasts lay down bone on cartilaginous
framework (bone replaces cartilage, cartilage
is not converted to bone)
 forms primary trabecular bone
 bone deposition occurs on metaphyseal side
‎I:8 blood supply of the physis
 type X collagen associated with enchondral ossification
 Molecular biology
o chondrocytes play a critical role in endochondral bone formation throughout the formation of the
cartilage intermediate
o transcription factors involved in regulation of chondrocytes include
 Sox-9
 considered a major regulator of chondrogenesis, regulates several cartilage-specific genes
during endochondral ossification, including collagen types II, IV, and XI and aggrecan
 PTHrP
 delays differentiation of chondrocytes in the zone of hypertrophy
 Biomechanics
o variables that affect growth across the physis
 Hueter-Volkmann Law
 compression across the growth plate slows longitudinal growth
 tension accerelates longitudinal growth
Anatomy
 Blood supply
o perichondrial artery
 You have not been
heard from for a while.
 major source of
nutrition to physis
Longitudinal Physeal Growth
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OrthoBullets2017
Musculoskeletal biology | Bone Formation & Healing
Physeal Growth Plate
(letters on left correspond to histology in top right)
Reserve Zone
Proliferative
Zone
 Cells store lipids, glycogen, and proteoglycan 
aggregates for later growth and matrix

production

 Low oxygen tension

Gaucher's
diastrophic dysplasia
Kneist*
Pseudoachondroplasia*
 Proliferation of chondrocytes with longitudinal  Achondroplasia
growth and stacking of chondrocytes.
 Gigantism
 Highest rate of extracellular matrix production  MHE
 Increased oxygen tension in surroundings
inhibits calcification
Hypertrophic
Zone
 Zone of chondrocyte maturation, chondrocyte 
hypertrophy, and chondrocyte calcification.

 Three phases occur in the hypertrophic zone 
o Maturation zone: preparation of matrix 
for calcification, chondrocyte growth

o Degenerative zone: further preparation 
of matrix for calcification, further

chondrocyte growth in size (5x)

o Provisional calcification zone:

chondrocyte death allows calcium

release, allowing calcification of matrix

 Chondrocyte maturation regulated by local
growth factors (parathyroid related peptides,
expession regulated by Indian hedgehog
gene)
 Type X collagen produced by hypertrophic
chondrocytes important for mineralization
Primary Spongiosa
(metaphysis)
SCFE (not renal)
Rickets (provisional calcification zone)
Enchondromas
Mucopolysarcharide disease
acromegaly
SED
MED
Schmids
Kneist*
Pseudoachondroplasia*
Fractures most commonly occur
through the zone of provisional
calcification, specifically Salter-Harris I
fractures
 Vascular invasion and resportion of
 Metaphyseal "corner fracture" in child
transverse septa.
abuse
 Osteoblasts align on cartilage bars produced  Scurvy
by physeal expansion.
 Primary spongiosa mineralized to form woven
bone and then remodels to become
secondary spongiosa (below)
Secondary spongiosa  Internal remodeling (removal of cartilage
 Renal SCFE
(metaphysis)
bars, replacement of fiber bone with lamellar
bone)
 External remodeling (funnelization)
Physis Periphery
Groove of Ranvier
 During the first year of life, the zone spreads
over the adjacent metaphysis to form a
fibrous circumferential ring bridging from the
epiphysis to the diaphysis.
 This ring increases the mechanical strength
of the physis and is responsible for
appositional bone growths
o supplies chondrocytes to periphery
Perichondrial
fibrous ring of La
Croix
 Dense fibrous tissue that is the primary
limiting membrane that anchors and supports
the physis through peripheral stability
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 Osteochondroma
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
‎I:9 Illustration of relationship of the perichondrial ring of La Croix providing peripheral stability.
‎I:10 Illustration: Cartilage model showing process of enchondral bone formation.
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OrthoBullets2017
Musculoskeletal biology | Bone Formation & Healing
Embryonic Long Bone Formation
 Overview
o allows growth in width and length
o formed from mesenchymal anlage around 6th week in utero.
 Steps of formation include
o vascularization
 vascular buds invade the mesenchymal model
o primary ossification centers form
 (at ~ 8 weeks) osteoprogenitor cells migrate through vascular buds and differentiate into
osteoblasts forming the primary ossification centers
o cartilage model forms
 grows through appositional (width) and interstitial (length) growth
o marrow forms
 marrow is formed by resorption of central portion of the cartilage anlage by myeloid
precursor cells that migrate in through the vascular buds
o secondary ossification centers form
 develop at bone ends and lead to epiphyseal ossification center (growth plate)
Non-Rigid Fracture Healing
 Overview
o mechanism of bone formation is similar to physeal enchondral ossification
 Cell biology
o soft callus is the cartilage intermediate
o bone replaces callus via same chondrocyte proliferation, chondrocyte hypertrophy, and finally
chondrocyte calcification
 Examples include
o casting and bracing
o intramedullary nailing
 allows for motion at the fracture site, which promotes bone formation both directly
(intramembranous ossification) and through a cartilage intermediate (endochondral
ossification)
3. Intramembranous Bone Formation
Introduction
 One of the two essential processes during
o fetal development bone formation
o fracture healing
o also commonly known as contact healing, and Haversian remodeling
 Physiology
o occurs without a cartilage model (unlike enchondral ossification)
 Examples of intramembranous ossification
o embryonic flat bone formation (skull, maxilla, mandible, pelvis, clavicle, subperiosteal surface of
long bone)
o distraction osteogenesis bone formation
o blastem bone (occurs in children with amputations)
o fracture healing with rigid fixation (compression plate)
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By Dr, AbdulRahman AbdulNasser

Musculoskeletal biology | Bone Formation & Healing
o one component of healing with intramedullary nailing
Associated conditions
o conditions with defects in intramembranous ossification
 cleidocranial dysplasia
 caused by defect in intramembranous ossification
 caused by mutation in CBFA1 (also know as Runx2)
located on chromosome 6
Mechanism
 Steps of intramembranous bone formation
o aggregation of undifferentiated mesenchymal cells
o osteoblast differentiation
o organic matrix deposition
 Regulation and signaling
o controlled by pathway called canonical Wnt and Hedgehog signaling
 beta-catenin enters cells and induces cells to form osteoblasts which then proceed with
intramembranous bone formation
 important transcription factors include CBFA1 (also know as Runx2) and osterix (OSX)
 sclerostin, created by the SOST gene, decreases bone mass by inhibiting the Wnt pathway
4. Bone Remodeling
Introduction
 Wolff's Law
o bone remodels in response to mechanical stress
 Piezoelectic charges
o bone remodels is response to electric charges
o compression side is electronegative and stimulates osteoblast formation
o tension side is electropostive and stimulates osteoclasts
 Hueter-Volkmann Law
o theory that bone remodels in small packets of cells known as
Basic Multicellular Units (BMUs)
o theory suggest that mechanical forces influence longitudinal
growth
o compressive forces inhibit growth
o may play role in scoliosis
Remodeling Mechanism
 Cortical bone
o remodels by osteoclastic tunneling (cutting cone)
 osteoclastic resorption > layering of osteoblasts > layering of lamellae > cement line laid
down
 osteoclast make up head of cutting cone, followed by capillaries and then osteoblasts which
lay down the osteoid to fill the cutting cone
 sclerostin inhibits osteoblastogenenesis to decrease bone formation
o cortical bone continues to change over time
 cortical area decreases as age increases
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Musculoskeletal biology | Bone Formation & Healing
 linked to increase fracture risk
medullary canal volume increases as age increases
 Cancellous bone remodels by
o osteoclastic resorption
o osteoblastic deposition of layers of lamellae

5. Fracture Healing
Introduction
 Fracture healing involves a complex and sequential set of events to restore injured bone to prefracture condition
o stem cells are crucial to the fracture repair process
 the periosteum and endosteum are the two major sources
 Fracture stability dictates the type of healing that will occur
o the mechanical stability governs the mechanical strain
o when the strain is below 2%, primary bone healing will occur
o when the strain is between 2% and 10%, secondary bone healing will occur
 Modes of bone healing
o primary bone healing (strain is < 2%)
 intramembranous healing
 occurs via Haversian remodeling
 occurs with absolute stability constructs
o secondary bone healing (strain is between 2%-10%)
 involves responses in the periosteum and external soft tissues.
 enchondral healing
 occurs with non-rigid fixation, as fracture braces, external fixation, bridge plating,
intramedullary nailing, etc.
o bone healing may occur as a combination of the above two process depending on the stability
throughout the construct
Type of Fracture Healing with Treatment Technique
Cast treatment
Secondary: enchondral ossification
External fixation
Secondary: enchondral ossification
IM nailing
Secondary: enchondral ossification
Compression plate
Primary: Haversian remodeling
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
Secondary Bone Healing
Stages of Fracture Healing
Inflammation  Hematoma forms and provides source of hemopoieitic cells capable of secreting growth factors.
 Macrophages, neutrophils and platelets release several cytokines
o this includes PDGF, TNF-Alpha, TGF-Beta, IL-1,6, 10,12
o they may be detected as early as 24 hours post injury
o lack of TNF-Alpha (ie. HIV) results in delay of both enchondral/intramembranous
ossification
 Fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around
fracture ends
o during fracture healing granulation tissue tolerates the greatest strain before failure
 Osteoblasts and fibroblasts proliferate
o inhibition of COX-2 (ie NSAIDs) causes repression of runx-2/osterix, which are critical for
differentiation of osteoblastic cells
Repair
 Primary callus forms within two weeks. If the bone ends are not touching, then bridging soft
callus forms.
o the mechanical environment drives differentiation of either osteoblastic (stable enviroment)
or chondryocytic (unstable environment) lineages of cells
 Enchondral ossification converts soft callus to hard callus (woven bone). Medullary callus also
supplements the bridging soft callus
o cytokines drive chondocytic differentiation.
o cartilage production provides provisional stabilization
 Type II collagen (cartilage) is produced early in fracture healing and then followed by type I
collagen (bone) expression
 Amount of callus is inversely proportional to extent of immobilization
o primary cortical healing occurs with rigid immobilization (ie. compression plating)
o enchondral healing with periosteal bridging occurs with closed treatment
Remodeling  Begins in middle of repair phase and continues long after clinical union
o chondrocytes undergo terminal differentiation
 complex interplay of signaling pathways including, indian hedgehog (Ihh), parathyroid
hormone related peptide (PTHrP), FGF and BMP
 these molecules are also involved in terminal differentiation of the appendicular
skeleton
o type X collagen types is expressed by hypertrophic chondrocytes as the extraarticular
matrix undergoes calcification
o proteases degrade the extracellular matrix
o cartilaginous calcification takes place at the junction between the maturing chondrocytes
and newly forming bone
 multiple factors are expressed as bone is formed including BMPs, TGF-Betas, IGFs,
osteocalcin, collagen I, V and XI
o subsequently, chondrocytes become apoptotic and VEGF production leads to new vessel
invasion
o newly formed bone (woven bone) is remodeling via organized osteoblastic/osteoclastic
activity
 Shaped through
o Wolff's law: bone remodels in response to mechanical stress
o piezoelectic charges : bone remodels is response to electric charges: compression side is
electronegative and stimulates osteoblast formation, tension side is electropostive and
simulates osteoclasts
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OrthoBullets2017
Musculoskeletal biology | Bone Formation & Healing
Variables that Influence Fracture Healing
 Internal variables
o blood supply (most important)
 initially the blood flow decreases with vascular disruption
 after few hours to days, the blood flow increases
 this peaks at 2 weeks and normalizes at 3-5 months
 un-reamed nails maintain the endosteal blood supply
 reaming compromises of the inner 50-80% of the cortex
 looser fitting nails allow more quick reperfusion of the endosteal blood supply versus
canal filling nails
o head injury may increase osteogenic response
o mechanical factors
 bony soft tissue attachments
 mechanical stability/strain
 location of injury
 degree of bone loss
 pattern (segmental or fractures with butterfly fragments)
 increased risk of nonunion likely secondary to compromise of the blood supply to the
intercalary segement
 External variables
o Low Intensity Pulsed Ultrasound (LIPUS)
 exact mechanism for enhancement of fracture healing is not clear
 alteration of protein expression
 elevation of vascularity
 development of mechanical strain gradient
 accelerates fracture healing and increases mechanical strength of callus (including torque and
stiffness)
 the beneficial ultrasound signal is 30 mW/cm2 pulsed-wave
 healing rates for delayed unions/nonunions has been reported to be close to 80%
o bone stimulators
 four main delivery modes of electrical stimulation
 direct current
 decrease osteoclast activity and increase osteoblast activity by reducing oxygen
concentration and increasing local tissue pH
 capacitively coupled electrical fields (alternating current, AC)
 affect synthesis of cAMP, collagen and calcification of carilage
 pulsed electromagnetic fields
 cause calcification of fibrocartilage
 combined magnetic fields
 they lead to elevated concentrations of TGF-Beta and BMP
o COX-2
 promotes fracture healing by causing mesenchymal stem cells to differentiate into osteoblasts
o radiation (high dose)
 long term changes within the remodeling systems
 cellularity is diminished
 Patient factors
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Musculoskeletal biology | Bone Formation & Healing
o diet
nutritional deficiencies
 vitamin D and calcium
 as high as 84% of patients with nonunion were found to have metabolic issues
 greater than 66% of these patients had vitamin D deficiencies
 in a rat fracture model
 protein malnourishment decreases fracture callus strength
 amino acid supplementation increases muscle protein content and fracture callus
mineralization
 gastric bypass patients
 calcium absorption is affected because of duodenal bypass with Roux-en-Y procedure
 leads to decreased Ca/Vit D levels, hyperparathyroidism (secondary) & increased Ca
resportion from bone
 treat these patients with Ca/Vit D supplementation
 gastric banding does not lead to these abnormalities because the duodenum is not
bypassed
o diabetes mellitus
 affects the repair and remodeling of bone
 decreased cellularity of the fracture callus
 delayed enchondral ossification
 diminished strength of the fracture callus
 fracture healing takes 1.6 times longer in diabetic patients versus non-diabetic patients
o nicotine
 decreases rate of fracture healing
 inhibits growth of new blood vessels as bone is remodeled
 increase risk of nonunion (increases risk of pseudoarthrosis in spine fusion by 500%)
 decreased strength of fracture callus
 smokers can take ~70% longer to heal open tibial shaft fractures versus non-smokers
o HIV
 higher prevalence of fragility fractures with associated delayed healing
 contributing factors
 anti-retroviral medication
 poor intraosseous circulation
 TNF-Alpha deficiency
 poor nutritional intake
o medications affecting healing
 bisphosphonates are recognized as a cause of osteoporotic fractures with long term usage
 recent studies demonstrated longer healing times for surgically treated wrist fractures in
patients on bisphosphonates
 long term usage may be associated with atypical subtrochanteric/femoral shaft fractures
 systemic corticosteroids
 studies have shown a 6.5% higher rate of intertrochanteric fracture non unions
 NSAIDs
 prolonged healing time becaue of COX enzyme inhbition
 quinolones
 toxic to chondrocytes and diminishes fracture repair

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6. Nonunion
Introduction
 A nonunion is an arrest in the fracture repair process
o progressive evidence of non healing of a fracture of a bone
o a delayed union is generally defined as a failure to reach bony union by 6 months post-injury
 this also includes fractures that are taking longer than expected to heal (ie. distal radial
fractures)
o large segmental defects
 should be considered functional non-unions
 Pathophysiology
o multifactorial
 most commonly, inadequate fracture stabilization and poor blood supply lead to nonunion
 infection
 eradication needs to occur along with the achieving fracture union
 location
 scaphoid, distal tibia, base of the 5th metatarsal are at higher risk for nonunion because
blood supply in these areas
 pattern
 segmental fractures and those with butterfly fragments
 increased risk of nonunion like because of compromise of the blood supply to the
intercalary segment
Classification
 Types of nonunion
o septic nonunion
o pseudoarthrosis
o hypertrophic nonunion
 caused by inadequate immobilization with adequate blood supply
 type 2 collagen is elevated
 typically heal once mechanical stability is improved
o atrophic nonunion
 caused by inadequate immobilization and inadequate blood supply
o oligotrophic nonunion
 produced by inadequate reduction with fracture fragment displacement
Presentation
 Symptoms
o important to discern injury mechanisms, non operative interventions, baseline metabolic,
nutritional or immunologic statuses and use of NSAIDs and/or nicotine containing products
o assess pain levels with axial loading of involved extremity
 Physical exam
o important to complete a thorough neurovascular exam, including the status of the soft tissue
envelope
o assess mobility of the nonunion
o assess extremity for the presence of deformity
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
Imaging
 Radiographs
o plain radiographs are the cornerstone for evaluation of fracture healing; four views should be
included
o full length weight bearing films should obtained if a limb length discrepancy is present
 CT
o if the status of union is in question, a CT scan should be obtained; hardware artifact may limit
utility of the CT scan
Treatment
 Nonoperative
o fracture brace immobilization
o bone stimulators
 contraindications include synovial pseudoarthroses, nonunions
that move and greater than 1 cm between fracture ends
 Operative
o infected nonunion
 often associated with pseudoarthrosis
 chance of fracture healing is low if infection isn't eradicated
 staged approach often important
 modalities
 need to remove all infected/devitalized soft tissue
 use antibiotic beads, VAC dressings to manage the wound
 with significant bone loss, bone transport may be an option
 muscle flaps can be critical in wound management with soft tissue loss
o pseudoarthrosis
 may be found in association with infection
 joint capsule may be encountered with operative exposure
 modalities
 removal of atrophic, non-viable bone ends
 internal fixation with mechanical stability
 maintenance of viable soft tissue envelope
o hypertrophic nonunions
 often have biologically viable bone ends
 issue with fixation, not the biology
 modalities
 internal fixation with application of appropriate mechanical stability
o oligotrophic nonunions
 often have biologically viable bone ends
 may require biological stimulation
 modalities
 internal fixation
o atrophic nonunions
 often have dysvascular bone ends
 mobile
 modalities
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Musculoskeletal biology | Bone Formation & Healing
need to ensure biologically viable bony ends are apposed
fixation needs to be mechanically stable
 bone grafting
 autologous iliac crest (osteoinductive) is gold standard
 BMPs
 osteoconductive agents (ie. crushed cancellous chips, DBM)
 establishment of healthy soft tissue flap/envelope


Techniques
 Bone stimulators
o four main delivery modes of electrical stimulation
 direct current
 decrease osteoclast activity and increase osteoblast activity by reducing oxygen
concentration and increasing local tissue pH
 capacitively coupled electrical fields (alternating current, AC)
 affect synthesis of cAMP, collagen and calcification of carilage
 pulsed electromagnetic fields
 cause calcification of fibrocartilage
 combined magnetic fields
o bone simulators work through induction coupling, which stimulates bone growth through the
following direct effects
 increasing expression of BMP7
 increasing expression of BMP7
 increasing expression of BMP2
 increasing expression of TGF-beta1
 increasing expression of osteoblasts proliferation
 increasing expression of BMP2
 increasing expression of TGF-beta1
 increasing expression of osteoblasts proliferation
7. Bone Growth Factors
Factor
Source
TGF-B
Platelets, bone ECM,
cartilage matrix
BMP
Osteoprogenitor cells,
osteoblasts, bone ECM
FGF
Macrophages,
mesenchymal cells,
chondrocytes, osteoblasts
Bone matrix, osteoblasts,
chondrocytes
Platelets, osteoblasts
IGF
PDGF
Overview of Growth Factors
Receptor Class
Function
Seronine threonine sulfate Pleiotropic growth factor stimulates
undifferentiated mensenchymal cell proliferation
.
Seronine threonine sulfate Promotes differentiation of mesenchymal cells
into chondrocytes and osteoblasts.
Promotes differentiation of osteoprogenitors into
osteoblasts, influences skeletal pattern
formation.
Tyrosine kinase
Mitogenic for mesenchymal cells, chondrocytes,
and osteoblasts.
Tyrosine kinase
Tyrosine kinase
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Promotes proliferation and differentiation of
osteoprogenitor cells.
Mitogen for mesenchymal cells and osteoblasts;
macrophage chemotaxis.
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
Bone Morphogenetic Protein (BMP) & SMADs
 Overview
o BMPs belong to the TGF-B superfamily
o BMP 2,4,6, and 7 all exhibit osteoinductive activity
o BMP 3 does not exhibit osteoinductive activity
o Mutations in BMP-4 are associated with Fibrodysplasia ossificans progressiva
 Mechanism
o osteoinductive
 leads to bone formation
 activates mesenchymal cells to transform into osteoblasts and produce bone
 Signaling Pathways and Cellular Targets
o BMP targets undifferentiated perivascular mesenchymal cells
o activates a transmembrane serine/threonine kinase receptor that leads to the activation of
intracellular signaling molecules called SMADs
 SMADS are primary intracellular signaling mediators
 currently eight known SMADs, and the activation of different SMADs within a cell leads to
different cellular responses.

Clinical applications
o FDA-approved uses
 rhBMP-2
 single-level ALIF from L2 to S1 levels in degenerative disc disease together with the
lumbar tapered fusion device (LT Cage; Medtronic)
 open tibial shaft fractures stabilized with an IM nail and treated within 14 days of the
initial injury
 rhBMP-7
 as an alternative to autograft in recalcitrant long bone nonunions where use of autograft is
unfeasible and alternative treatments have failed
 as an alternative to autograft in compromised patients (with osteoporosis, smoking or
diabetes) requiring revision posterolateral/intertransverse lumbar fusion for whom
autologous bone and bone marrow harvest are not feasible or are not expected to promote
fusion
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Musculoskeletal biology | Bone Formation & Healing
o contraindications
pregnancy
 allergy to bovine type I collagen or recombinant human rhBMP-2
 infection
 tumor
 skeletal immaturity

Transforming Growth Factor-B (TGF-B)
 Mechanism
o secreted in a paracrine fashion
o both osteoblast and osteoclasts synthesize and respond to TGF-B
o found in fracture hematomas and believed to regulate cartilage and bone formation in fracture
callus
o stimulates production of Type II collagen and proteoglycans by mesenchymal cells.
o induces osteoblasts to synthesize collagen
 Signal Pathway & Cellular Targets
o signal mechanism involves transmembrane serine/threonine kinase receptors
 Clinical applications
o TGF-B is used to coat porous coated implants to promote bone ingrowth
Insulin-like Growth Factor 1 (IGF-1)
 Overview
o IGF-1, formerly known as somatomedin-C, possibly acts by both paracrine and endocrine
hormone pathways
o most abundant growth factor in bone
 Mechanism
o the products of the GH-IGF-1 system induce proliferation without maturation of the growth plate
and thus induce linear skeletal growth.
o the action of the thyroid hormone axis is via an active metabolite that enters target cells and
signals a nuclear receptor to stimulate both proliferation and maturation of the growth plate.
Increased amounts of the active steroid hormone metabolite promote proliferation and maturation
of the growth plate
o IGF-1 may have a role in enhancing bone formation in defects that heal via intramembranous
ossification
 Signal Pathway & Cellular Targets
o signal mechanism involves tyrosine kinase receptors
Insulin-like Growth Factor 2 (IGF-2)
 Overview
o more potent than IGF-1
 Mechanism
o stimulates type I collagen production
o stimulates cartilage matrix synthesis
o stimulates cellular proliferation
o stimulates bone formation
 Signal Pathway & Cellular Targets
o signal mechanism involves tyrosine kinase receptors
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
Fibroblast Growth Factor (FGF)
 Overview
o FGF-1 and FGF-2 are most abundant
o promote growth and differentiation of a variety of cells
 epithelial cells
 myocytes
 osteoblasts
 chondrocytes
 Mechanism
o binds to membrane spanning tyrosine kinase
o associated with angiogenesis and chondrocyte and osteoblast activation
o involved in early stages of fracture healing
Platelet-derived growth factor (PDGF)
 Mechanism
o released from platelets and signals inflammatory cells to migrate to fracture site
o role in fracture healing and bone repair has not been clearly defined
 Signal Pathway & Cellular Targets : signal mechanism involves tyrosine kinase receptors
Peroxisome proliferator-activated receptor gamma (PPAR-gamma or PPARG)
 Overview
o key factor demonstrated in adipogenic differentiation of mesenchymal precursor cells in vitro
 Signal Pathway & Cellular Targets
o a nuclear binding receptor that binds to DNA and regulates transcription of target genes
 Clinical and research applications
o utilized for adipogenic differentiation in vitro
o agonists are being utilized to attempt treatment of hyperglycemia and hyperlipidemia
o targeted by thiazolidinediones for treatment of diabetes
8. Bone Grafting
Introduction
 A material with either osteoconductive, osteoinductive, and/or osteogenic properties
o autografts
o allografts
o demineralized bone matrix (DBM)
o synthetics
o bone morphogenetic protein (BMP)
o stem cells
 Epidemiology
o incidence
 almost 1 million bone grafting procedures performed in US each year, with a growth of
almost 13% per year
 Indications
o assist in healing of fractures, delayed unions, or nonunions
o assist in arthrodeses and spinal fusions
o replace bone defects from trauma or tumor
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
Resorption rates
o relative resorption rates of bone graft substitutes
 fastest to slowest
 calcium sulfate > tricalcium phosphate > hydroxyapatite
 Outcomes
o allograft retrieval
 retrieval studies are helpful in understanding the body's response to allografts
 5 years after implantation, allograft articular cartilage is completely acellular - no donor or
recipient chondrocytes will be present
Properties
 Bone graft has aspects of one or more of these three properties
o osteoconductive
 material acts as a structural framework for bone growth
 demineralized bone matrices (DBMs)
 the various three-dimensional makeups of the material dictate the conductive properties
o osteoinductive
 material contains factors that stimulate bone growth and induction of stem cells down a boneforming lineage
 bone morphogenetic protein (BMP) is most common from the transforming growth factor
beta (TGF-B) superfamily
o osteogenic
 material directly provides cells that will produce bone including primitive mesenchymal stem
cells, osteoblasts, and osteocytes
 mesenchymal stem cells can potentially differentiate down any cell line
 osteoprogenitor cells differentiate to osteoblasts and then osteocytes
 cancellous bone has a greater ability than cortical bone to form new bone due to its larger
surface area
 autologous bone graft (fresh autograft and bone marrow aspirate) is the only bone graft
material that contains live mensenchymal precursor cells
Antigenicity
 Allograft is a composite material and therefore has many potential antigens (cell surface
glycoproteins)
o Class I and Class II antigens on graft are recognized by host T lymphocytes and elicit an immune
response
o immunogenic cells are marrow-based, endothelium, and retinacular-activating cells
 bone marrow cells elicit the greatest immune response
 extracellular matrix also acts as an antigen
 type I collagen stimulates both humoral and cell-mediated responses
 noncollagenous matrix (proteoglycans, osteocalcin)
o hydroxyapatite has not been shown to elicit an immune response
 primary rejection is cell-mediated related to the major histocompatibility complex (MHC)
incompatibility
Overview
See table next page
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
Types of Bone Graft
Autograft
Cancellous
- Less structural support
- Greater osteoconduction
- Rapid incorporation via creeping substitution
Cortical
- Slower incorporation due to need to remodel existing Haversion canals
- Interstitial lamellae preserved
- Provides more structural support
- 25% of massive grafts sustain insufficiency fractures
Vascularized bone - Technically challenging with quicker union and cell preservation
graft
- Examples include: free fibula strut graft (peroneal artery), free iliac crest (deep
circumflex iliac arteries), distal radius used for scaphoid fx (1-2 intercompartmental
superretinacular artery branch of radial artery)
Allograft
Fresh
Fresh frozen
Freeze dried
(croutons)
- Highest risk of disease transmission and immunogenicity
- BMP preserved and therefore osteoinductive
- Less immunogenicity than fresh
- BMP preserved and therefore osteoinductive
- Least immunogenic
- Least structural integrity
- BMP depleted (purely osteoconductive)
- Lowest likelihood of viral transmission
Demineralized Bone Matrix
Grafton DBM
- Osteoinductive and osteoconductive
- Contains: collagen, bone morphogenetic proteins, transforming growth factorbeta, residual calcium
- Does NOT contain mesenchymal precursor cells
Synthetics
Silicate based
grafts
Aluminum oxide
Calcium
phosphate grafts
Alumina ceramic bonds bind to bone in response to stress and strain
- Osteoconduction and osteointegration
- Biodegrade very slowly
- Highest compressive strength
- Many prepared as ceramics (heated to fuse into crystals)
- Examples include: tricalcium phosphate, Norian (Synthes), hydroxyapatitie (tradename
Collagraft by Zimmer)
Calcium sulfate
- Osteoconductive
- Quick resorption
- Examples include: OsteoSet (Wright medical)
Coralline
- Calcium carbonate skeleton is converted to calcium phosphate via a thermoexchange
hydroxyapatine
process (Interpore)
Calcium carbonate - Chemically unaltered marine coral
- Osteoconductive
- Examples include: Biocora (Inoteb, france)
Bone Growth Factors
BMP
TGF-B
IGF-II
PDGF
see Rank-L and Bone Growth Factors
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Autograft
 Bone graft transferred from one body site to another in the same patient
 Indications
o gold standard
 Properties
o osteogenic, osteoinductive, and osteoconductive
o least immunogenic
o cortical, cancellous, or corticocancellous
o vascular or nonvascular
 Donor sites
o bone marrow aspirate
 source of osteogenic mesenchymal precursor cells
 iliac crest and vertebral body most common sites
 variable number of cells depending on patient age
o iliac crest is the most common site for autograft
 provides both cancellous and cortical graft
 higher complication rate with anterior versus posterior harvesting
 2% to 36% complication rate
 blood loss and hematoma
 injury to lateral femoral cutaneous or cluneal nerves
 hernia formation
 infection
 fracture
 cosmetic defect
 chronic pain
o fibula and ribs are most common sources of vascularized autografts
o tibial metaphysis
Allograft
 Bone graft obtained from a cadaver and inserted after processing
 Most commonly used bone substitute
 Properties
o osteoconductive only due to lack of viable cells
 the degree of osteoconduction available depends on the processing method (fresh, frozen, or
freeze-dried) and type of graft (cortical or cancellous)
o cortical, cancellous, corticocancellous, and osteoarticular (tumor surgery)
 Osteoarticular allograft
o immunogenic
o preserved with glycerol or dimethyl sulfoxide (DMSO)
o cryogenically preserved (few viable chondrocytes remain)
o tissue-matched (syngeneic) grafts decrease immunogenicity
 Processing methods
o debridement of soft tissue, wash with ethanol (remove live cells), gamma irradiation
(sterilization)
 dose-dependent higher doses of irradiation kills bacteria and viruses but may impair
biomechanical properties
o fresh allograft
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
cleansing and processing removes cells and decreases the immune response improving
incorporation
 indications
 rarely used due to disease transmission and immune response of recipient
o frozen or freeze-dried
 reduces immunogenicity while maintaining osteoconductive properties
 reduces osteoinductive capabilities
 shelf life
 one year for fresh frozen stored at -20 degrees C
 five years for fresh frozen stored at -70 degrees C
 indefinite for freeze-dried

Demineralized bone matrix (DBM)
 Acidic extraction of bone matrix from allograft
o removes the minerals and leaves the collagenous and
noncollagenous structure and proteins
 Properties
‎I:11 Demineralized bone matrix (DBM)
o osteoconductive without structural support
o minimally osteoinductive despite preservation of osteoinductive molecules
o interproduct and interlot variability is common
 Synthetics
 Alternative to autografts and allografts
 Various compositions available (see summary above)
 Made in powder, pellet, or putty form
 Properties : osteoconductive only
 Outcomes
o Level I evidence shows that calcium-phosphate bone substitutes allow for bone defect filling,
early rehabilitation, and prevention of articular subsidence in distal radius and tibial plateau
fractures
Bone morphogenetic proteins (BMP)
 Osteoinductive properties
o stimulates undifferentiated perivascular mesenchymal cells to differentiate into osteoblasts
through serine-threonine kinase receptors
 rhBMP-2 and rhBMP-7 are FDA-approved for application in long bones and spine
 Complications
o under or overproduction of bone
o inflammatory responses
o early bone resorption
Reamer Aspirator Irrigator
 Provides large volume of bone graft from intramedullary source
o femur (most common)
o tibia
 Possible iatrogenic complications
o femoral shaft fracture due to eccentric reaming
o insertion site pain (hip abductors)
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Musculoskeletal biology | Bone Formation & Healing
Graft Healing
Stages of Graft Healing
Stage
1. Inflammation
2. Osteoblast differentiation
3. Osteoinduction
4. Osteoconduction
5. Remodeling
Characteristics
Necrotic debris stimulates chemotaxis
Differentiates from mesenchymal precursor cells
Stimulation of osteoblast and osteoclast function
Bone forms around the new scaffold
Continual process for years
Risks & Complications
 Disease Transmission
o hepatitis B
 risk of hepatitis B disease transmission in musculoskeletal fresh-frozen allograft
transplantation is 1 in 63,000
o hepatitis C
 risk of hepatitis C disease transmission in musculoskeletal fresh-frozen allograft
transplantation is 1 in 100,000
o HIV
 risk of transmission of HIV in fresh-frozen allograft bone is 1 in 1,000,000
o allografts are tested for HIV, HBV, HCV, HTLV-1, and syphilis
 Serous wound drainage
o calcium sulfate bone graft substitute associated with increased serous wound drainage
9. PTH & Vit D Physiology
Introduction
 Vitamin D and PTH play an important role in calcium homeostasis
o skin, liver, parathyroid gland, kidney, bone, and small intestine all play a role
o increased PTH and Vitamin D leads to increase serum calcium levels
Vitamin D Physiology
 Overview
o Vitamin D and PTH play an important role in calcium homeostasis
 skin, liver, parathyroid gland, kidney, bone, and small intestine all play a role
 Increased PTH and Vitamin D leads to increase serum calcium levels
 Synthesis
o 7-Dehydrocholesterol
 precursor to calcitriol is stored in the skin where UV exposure converts it to previtamin D3.
o cholecalciferol (Vitamin D3)
 Previtamin D3 is then bound to vitamin-D binding protein (DBP) where it is carried to the
liver and metabolized to 25-hydroxyvitamin D3
o 25-hyrdoxyvitamin D3
 when calcium is low, parathyroid hormone (PTH) levels become elevated which activates 1alpha-hydroxylase in the kidney
 1-alpha-hydroxylase converts 25-hydroxyvitamin D to the active Vitamin D (calcitriol)
 laboratory study of choice to determine Vitamin D deficiency
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Bone Formation & Healing
o 1,25-dihydroxyvitamin
D3 (Vitamin D, calcitriol)
active form that controls calcium homeostasis in body by targeting intestines and bones (see
function below)
 Function
2+
o ↑ serum Ca and phosphate via
 ↑ absorption of calcium and phosphate from the intestine
2+
 ↑ bone resorption of Ca and phosphate
2+
o recall PTH functions to ↑ serum Ca but ↓ serum phosphate
 Regulation
o PTH stimulates 1,25-(OH)2 vitamin D production
o hypocalcemia/hypophoshatemia stimulates 1,25-(OH)2 vitamin D production
o 1,25-(OH)2 vitamin D feedback negatively on itself

PTH Physiology
 Synthesis
o secreted by the chief cells of parathyroid
 Function
2+
o ↑ serum Ca and ↓ serum phosphate in response to hypocalcemia/hypomagnesemia via
 ↑ bone resorption of calcium and phosphate (bone is destroyed)
 PTH receptor is on the osteoblasts which secretes IL-1 to activated osteoclasts
 ↑ kidney resorption of calcium in distal convoluted tubule
 ↓ kidney resorption of phosphate
 ↑ 1,25-(OH)2 vitamin D production
Clinical Conditions
 Conditions related to PTH
o hypoparathyrodism
o pseudohypoparathyroidism
o renal osteodystrophy
 Conditions related to Vitamin D
o Rickets
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OrthoBullets2017
Musculoskeletal biology | Biologic Tissues
C. Biologic Tissues
1. Muscle Biology & Physiology
Overview
 Key topics of this chapter include
o Gross anatomy
o Muscle contraction
o Muscles type
o Muscle metabolism
o Types of contraction
o Muscle training
o Nutritional training
o Muscle injury
Gross Anatomy
 Myotendinous junction
o weak link in muscle and often site of tears (especially with eccentric contraction)
o involution of muscles cells maximized surface area for attachment
 Noncontractile elements
o Epimysium surrounds muscle bundles
o Perimysium surrounds muscle fascicles
o Endomysium surrounds individual fibers
Muscle Contraction
 Contractile elements
o derived from myoblasts
o the muscles fiber (an elongated cell) is the basic unit of contraction
o a myofibril is a collection of sarcomeres
 Sarcomere composition
o filaments
 thick myosin filaments
 thin actin filaments
o bands
 H band is myosin only
 I band is actin only
 A band is both actin and myosin
 Z line flanks each sarcomere and acts as site of attachment for actin filament
 during muscle contraction
 A band stays the same length
 I band reduces in length
 H zone reduces in length
 Action stimulation
o nerve cell body delivers electrical signal to motor endplate (junction between muscle and nerve)
 nerve action potentials are started with passage of sodium ions through voltage gated
channels
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
o Ach
is released and diffuses across synaptic cleft to bind to Ach receptor
myasthenia gravis patient has shortage of Ach receptors
 botox blocks release of Ach from end plate
o Ach binding triggers depolarization of sarcoplasmic reticulum and release of calcium into
muscles cytoplasm
o excitation-contraction coupling
 in low calcium environment
 tropomyosin blocks myosin-binding sites on actin
 in high calcium environment
 calcium binds to troponin (on thin filaments) leading to a configuration change of
tropomyosin (on thin filaments)
 exposing myosin-binding sites on actin filament
 actin forms cross-bridges to myosin, and the ATP breakdown, the two fibers contract past
one another
 Types of muscle contraction
o isometric
 muscle contracts with constant length (e.g. pushing against an immovable object)
o isokinetic
 muscle contracts with constant speed (requires specific equipment like cybex machines)
o plyometric
 rapid lengthening followed by contraction of muscle groups (e.g. jumping up and down on
boxes)
o isotonic - muscle contract with constant tension
 concentric
 muscle shortens during contraction (e.g. biceps curl)
 eccentric
 muscle lengthens during contraction (e.g. "negative" of a biceps curl)
 Force generation
o force generated is most dependent on muscle cross-sectional area
o muscle fiber size increases with strength conditioning
 Contraction speed
o duration and speed of contraction is most dependent on fiber type

Muscle Types
Metabolism
Energy
source
Exercise
duration
Note
Type I muscle
(slow twich - ST)
"slow red ox muscles"
• aerobic / oxidative
• Aerobic system (oxidative
phosphorolation via Krebs cycle)
• endurance (distance running)
• low strength of contraction
• low speed of contraction
• first to atrophy with deconditoning
• high yield ATP
• requires O2 and thus more vascular
• increase mitochondria in cells
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Type II muscle
(fast twitch - FT)
• anaerobic / glycolytic
• ATP-CP system
• high strength of contraction
• high speed of contraction (large force
generation per cross sectional area)
• fatigue rapidly
• sprinting is example
• high yield ATP (increased ATPase)
• low intramuscular triglycerine stores
OrthoBullets2017
Musculoskeletal biology | Biologic Tissues
Metabolic Systems
 Three systems are used to generate energy for muscles
o ATP-CP anaerobic system
 (adenosine triphosphate-creatinine phosphate system, "phosphagen system")
 basis for creatine phosphate supplementation (main side effect: muscle cramping)
 used for intense metabolic exercise lasting less than 20 seconds (e.g., 100 meter sprint)
 converts carbohydrates stored within muscle into energy
 anaerobic (does not use oxygen and does not produce lactate)
 formulas
 ATP –» ADP + P + energy
 ADP –» AMP + P + energy
o lactic anaerobic system (lactic acid metabolims)
 intense muscle activity lasting 20 to 120 seconds (e.g., 400 meter sprint)
 involves hydrolysis of one glucose molecule
 formula
 glucose –» lactic acid + energy
o aerobic system
 used in longer duration and lower intensity exercises
 Krebs cycle generates ATP from glucose and fatty acids through oxidative phosphorylation
Muscle Injury
 Muscles soreness
o caused by edema and inflammation in the connective tissue
 neutrophils are the most abundant cells early on after acute injury
 generates free radicals that possibly increase muscle damage
o worse with unaccustomed eccentric exercise
o peaks at 24-48 hours
o elevated CK levels seen in serum
 Muscles strain
o occur at myotendinous junction (off during eccentric contraction which produces highest forces
in skeletal muscle)
o pathoanatomy in inflammation followed by fibrosis
 Muscle atrophy
o caused by disuse or nerve injury
o leads to fatty infiltration and increased fatigability
o muscles crossing a single joint atrophy faster
o loss of cross-sectional area leads to decreased force generation
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
2. Ligaments
Introduction
 Ligaments function to
o restrict joint motion
o stabilize joint
o have mechanoreceptors and free nerve endings that help with joint proprioception
Composition
 Extracellular components consist of
o water
o Type I collagen (70% of dry weight)
o elastin
 higher elastin content than tendons
o lipids
o proteoglycans
o epiligament coat
 present in some ligaments, not all
 analogous to epitenon of tendons
 Cellular component
o the main cell type in both tendons and ligaments is the fibroblast
o both tendons and ligaments have low vascularity and cellularity
 Ligaments vs. tendons
o composition
 compared to tendons, ligaments have
 lower percentage of collagen
 higher percentage of proteoglycans and water
 less organized collagen fibers
 rounder fibroblasts
Bone insertion
 Two types of ligament bone insertion
o indirect (fibrous insertion)
 most common form of bone insertion
 superficial fibers insert into the periosteum
 deep fibers insert directly into bone via perforating collagen fibers called Sharpey fibers
 at insertion, endotenon becomes continuous with periosteum
 examples
 MCL inserting into proximal tibia
o direct (fibrocartilaginous insertion)
 has both deep and superficial fiber insertion
 deep fibers
 have four transitional zones of increasing stiffness that allow for force dissipation and
reduce stress concentration
 Zone 1 (tendon or ligament proper)
 consists of well aligned type I collagen fibers with small amounts of proteoglycan
decorin
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Zone 2 (fibrocartilage)
 consists of types II and III collagen, with small amoutns of type I, IX and X
collagen, and proteoglycans aggrecan and decorin
 Zone 3 (mineralized fibrocartilage)
 consists of type II collagen, with significant amounts of type X collagen and
aggrecan
 Zone 4 (bone)
 is made up of type I collagen, with high mineral content
 examples : supraspinatus insertion

Blood Supply
 Origin
o receives blood supply at insertion site (different from tendons)
 ACL (and PCL) receives blood supply from middle geniculate artery
o have uniform microvascularity within ligament
Biomechanical Properties
Stress relaxation
Creep
Hysteresis

Stress-strain
Stress relaxation
o decreased stress with time under constant deformation
 Creep
o increased deformation with time under constant load
 Hysteresis (energy dissipation)
o when tissue is loaded and unloaded, the unloading curve will not follow the loading curve
o the difference between the 2 curves is the energy that is dissipated
 Stress-strain (load-elongation) curve
o toe region
 significant deformation for given load
 in this region, the crimped and relaxed fibers of the ligament straighted to take up load
o linear region
 fibers oriented longitudinal and parallel to load
 constant load-elongation
 stiffness = slope of load-elongation curve in this region
 Young's modulus of elasticity
o yield and failure region
 nonlinear
 yield point
 transition from elastic (reversible) to plastic (irreversible) deformation
 ultimate failure
 point before steep decline in load-deformation curve
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By Dr, AbdulRahman AbdulNasser

Musculoskeletal biology | Biologic Tissues
Ligament vs. tendons
o stress-strain differences between tendons and ligaments
 tendons carry higher loads, recruit fibers quickly
 smaller toe region
 ligaments recruit fibers gradually
 elongated toe region
Ligament Failure
 Mechanism
o rupture of sequential series of collagen fibers
o ligaments do not plastically deform
 Failure site
o usually midsubstance in adults
o usally at bony insertion in children
 ligament avulsion
 occurs at junction of mineralized and unmineralized fibrocartilage layers
 Classification
o ligament injuries are classified into 3 grades
 Grade I
 corresponds to mild sprain
 Grade II
 corresponds to moderate sprain/partial tear
 Grade III
 corresponds to complete tear
Ligament Healing
 Phases
o inflammatory phase
 occurs at 1-7days
 influx of neutrophyils and macrophages
 production of type III collagen
 growth factors involved
 TGF-β1
 IGF
 PDGF
 BMPs -12 and -13
 bFGF
o proliferation phase
 occurs at 7-21 days
 gradually replaced by type I collagen
 tendons and ligaments are weakest at day 5-21
o remodeling phase
 occurs at >14 days
o maturation phase
 up to 18 months
 Factors that impair ligament healing
o intra-articular
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extra-articular ligaments (e.g. knee MCL) have a greater capacity to heal compared with
intra-articular ligaments (e.g. knee ACL)
o increasing age
o immobilization
 reduces strength of both intact and repaired ligament
o smoking
o NSAIDS
 including indocin, celcoxib, parecoxib
o diabetes
o alcohol intake
o decreased growth factors
 bFGF, NGF, and IGF-1
o decreased expression of genes involved with tendon and ligament healing
 examples include
 procollagen I
 cartilage oligomeric matrix protein (COMP)
 tenascin-C
 tenomodulin
 scleraxis
 Factors that improve ligament healing (experimental)
o extra-articular
 extra-articular ligaments (e.g. knee MCL) have a greater capacity to heal compared with
intra-articular ligaments (e.g. knee ACL)
o compromised immune response
 CD44 (receptor for lymphocyte activation) knockout mice have faster patellar tendon healing
 Interleukin 10 (anti-inflammatory cytokine) improves patellar tendon healing in mice
 Interleukin 1 (inflammatory mediator) receptor antagonist inhibits loss of mechanial
properties in patellar tendons in rabbits
 depletion of macrophages (source of TGF-β1 that stimulates fibrosis) improves ACL graft
healing in mice (less scar, more fibrocartilage)
o mesenchymal stem cells
 improved healing of tendon graft in bone tunnel in rabbits and rats
 promote healing of partial tears of digital flexor tendons in horses
 insufficient for rat rotator cuff repair (shear stresses too high)
o growth factors
 PDGF-BB
 increases cellular proliferation and limits adhesions in dog flexor tendon repairs, but
provides no improvement in tensile strength
 GCSF
 improves tendon incorporation into bone tunnels in ACL reconstruction in dogs
 BMP-2 and -12
 improves healing in animal rotator cuff models
o scaffolds to help primary ligament healing (instead of reconstruction)
 collagen-platelet-rich plasma hydrogel helps primary ACL repair
 but still inferior to native ACL strength
o neuropeptides

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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
denervation degrades tendons and ligaments
calcitonin gene-related peptide improves MCL healing in rabbits
 Scarring
o tendons and ligaments heal with scar tissue that
 reduces ultimate strength
 causes adhesions


3. Tendons
Introduction
 Function
o transfer forces from muscle to bone to produce joint motion
o tendons orient themselves along stress
 Types
o paratenon covered tendons
 e.g., patellar, achilles tendons
 have rich vascular supply and thus heal better
 often injured due to trauma and most often fail at the
 musculotendinous junction
 tendon-bone junction
o sheathed tendons
 e.g., hand flexor tendons
 less vascularized and have avascular areas that receive nutrition by diffusion
 often injured due to laceration and at risk for adhesions
Anatomy
 Composition
o groups of collagen bundles (fascicles) separated by endotenon and surrounded by epitenon
o composed of
 water
 tendons primarily composed of water
 collagen
 Type I collagen makes up 85% of dry weight of tendons
 Type III collagen make up 0-5% of dry weight of tendons
 proteoglycans
 make up 0-5% of dry weight of tendons
 decorin
 is the most predominant proteoglycan in tendon
 regulates collagen fiber diameter (length of 300nm, diameter of 1.5nm)
 forms cross-links between collagen fibers and transfers loads between collagen fibers
 aggrecan
 is proteoglycan found in areas of tendon compression
 Structure
o has a highly ordered hierarchical structure
o microfibrils<subfibrils<fibrils<fascicles<tendon unit
o insert into bone via 4 transitional tissues of increasing modulus)
 tendon
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 type I and III collagen, elastin, proteoglycans, tendon fibroblasts
uncalcified fibrocartilage
 aggrecan, types I, II and III collagen, fibrochondrocytes
 tidemark - straight, basophilic line separating uncalcified and calcified fibrocartilage, a
mechanical boundary between soft-hard tissue
 calcified fibrocartilage (separated from fibrocartilage by tidemark)
 type II collagen, aggrecan, types I and X collagen, fibrochondrocytes
 irregular boundary, with interlocking of calcified fibrocartilage zone with bone
 bone
 osteocytes, osteoclasts, osteoblasts, type I collagen, apatite

Tendon inserts into bone via 4 transitional tissues of increasing modulus
Structure of tendon: microfibrils<subfibrils<fibrils<fascicles<tendon unit
 Blood supply
o the musculotendinous junction
o the osseotendinous junction
o vessels from various surrounding connective tissue (such as the paratenon, mesotenon and
vincula)
 FDS and FDP tendons have 2 vincula each (vincula longa and vincula brevia)
 Cell biology
o fibroblasts are predominant cell type
 spindle shaped and arranged in parallel rows in direction of muscle loading
 produce mostly type I collagen (85% of dry weight of tendons)
 produce small amount of type III collagen (5% of dry weight)
 responsible for healing process
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
Fibrous Enthesis (Indirect Attachment)
Attachment
Metaphysis and diaphysis of long bones
Composition
Perforating mineralized collagen fibers
Angle of Insertion
Example
Insertion angle changes slightly during
motion
Deltoid-humerus attachment, adductor
magnus-linea aspera attachment, pronator
teres attachment
Fibrocartilaginous Enthesis (Direct
Attachment)
Epiphysis and apophysis
4 distinct zones (tendon, fibrocartilage,
calcified fibrocartilage, and bone)
Insertion angle changes greatly during
motion (thus prone to overuse injury)
Rotator cuff, Achilles tendon
Material Properties
 Characteristics
o tendons contain more collagen and are less viscoelastic than ligaments
o viscoelastic behavior with nonlinear elasticity
 the rate at which tendon sees force can influence the mechanical property
o biomechanical effects
 exercise has positive effect
 immobilization has detrimental effect
 age dependent
 increase in strength from birth to maturity
 decrease in strength after maturity
 laser/heat causes tendons to shrink
 vary with exposure to hydration, temperature, pH
I‎:12 Load-elongation or stress tendons should be tested under physiologic relevant conditions
strain curve
 Advantages
o strong in tension (can withstand 5-10% as opposed to 1-4% in bone)
 Disadvantages
o buckle in compression
o demonstrate creep and stress relaxation
 Load-elongation or stress-strain curve
o toe region
 initial nonlinear segment of curve during low loads due to tendons being "crimped"
o linear region
 intermediate loads
o failure region : high loads
Tendon Healing
 Stages of tendon healing
Hemostasis
Inflammation
Organogenesis
Remodeling
Stages of Soft Tissue Healing (including tendons)
Platelets initiate coagulation cascade
Fibrin clot and fibronectin interaction leading to
chemotaxis to stabilize torn tendon edges
Fibroblasts produce type III collagen
macrophages help initiate healing and remodeling
Tissue modeling via large amounts of disorganized
collagen and angiogenesis
Tissue remodeling replacing type III collagen to type I
collagen
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5-15 minutes
1-7 days
7-21 days
up to 18 mos.
OrthoBullets2017
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Tendon Surgical Repair
 Strength following repair
o tendon repairs are weakest at 7-10 days
o most of strength by 21-28 days
o maximum strength at 6 months
 final strength only reaches 2/3 of normal even years after repair
 Early mobilization
o allows earlier ROM but decreased tendon repair strength
o beneficial for flexor tendon healing to prevent adhesion formation
4. Articular Cartilage
Introduction
 Articular cartilage is one of five forms of cartilage
o hyaline or articular cartilage
o fibroelastic cartilage (meniscus)
o fibrocartilage (at tendon and ligament insertion into bone)
o elastic cartilage (trachea)
o physeal cartilage (growth plate)
Articular (hyaline) Cartilage Components
 Function
o decreases friction and distributes loads
o cartilage exhibits stress-shielding of the solid matrix components due to its high water content,
the incompressibility of water, and the structural organization of the proteoglycan and collagen
molecules
 Composition
o includes
 extracellular matrix (water, 90% type II collagen, proteoglycans)
 cells (chondrocytes)
o % by weight
 water > collagen > proteoglycan > noncollagenous protein > cells
 Extracellular matrix
o water
 makes up 65% to 80% of mass of the cartilage
 accounts for 80% of the weight near the surface
 65% at the deep zone
 water content
 decreases with normal aging
 increases with osteoarthritis
 increased water content leads to
 increased permeability
 decreased strength
 decreased Young Modulus of elasticity
o collagen
 makes up 10 to 20% of total cartilage mass
 type II collagen accounting for 90% to 95% of the total collagen content.
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
 functions to provide cartilagenous framework and tensile strength
small amounts of types V, VI, IX, X, and XI collagen are also present
o proteoglycans
 make up 10 to 15% of cartilage
 function to provide compressive strength and attract water
 aggrecan is most responsible for hydrophilic behavior
 produced by chondrocytes
 proteoglycans composed of GAG subunits
 chondroitin sulfate
 keratin sulfate
o noncollagenous protein
 Cells
o chondrocytes
 produce collagen, proteoglycans, and enzymes
 derive from chondroblasts that are trapped in lacunae and become chondrocytes
 chondrocyte metabolism responds to both mechanical (mechanical load, hydrostatic pressure
change) and chemical stimuli (growth factors, cytokines)
 immature articular cartilage has stem cells (mature articular cartilage does not)

Layers of Articular Cartilage
 Normal articular cartilage is composed of three zones and the tidemark
o zones based on the shape of the chondrocytes and the orientation of the type II collagen.
Zones of Articular Cartilage
Superficial zone • Type II collagen orientation is parallel to joint
(tangential
• Has flattened chondrocytes, condensed collagen fibers, and
zone)
sparse proteoglycans
• only zone where articular cartilage progenitor cells have been found
Intermediate
• Type II collagen has an oblique or random organization
zone
• Is the thickest layer with round chondrocytes, and abundant proteoglycan
content
Deep layer
• Type II collagen is perpendicular to joint and crosses tidemark; has the
(basal layer)
highest concentration of proteoglycans
• Round chondrocytes arranged in columns
Tidemark
• Is deep to the basal layer and separates the true articular cartilage from
the deeper cartilage that is a remnant of the cartilage anlage, which
participated in endochondral ossification during longitudinal growth in
childhood.
• The tidemark divides
- the superficial, uncalcified cartilage from the deeper, calcified cartilage
- division between nutritional sources for the chondrocytes
• The tidemark is found only in joints
• Most prominently in the adult and nongrowing joint
Subchondral
Bone
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Zones of Articular Cartilage
Growth Factors
 PDGF
o thought to be involved with healing of articular cartilage lacerations
o effects extrapolated from PRP (which contains it)
o no adverse effects in normal joints
 TGF-B
o stimulates proteoglycan and ECM synthesis
o decreases catabolic activity of IL-1 and MMPs
o causes synovial proliferation and fibrosis
o induces osteophyte formation
 b-FGF (Basic Fibroblastic Growth Factor)
o stimulates DNA synthesis in articular chondrocytes
 IGF-1 (Insulin growth factor -1)
o stimulates DNA and cartilage matrix synthesis in adult articular cartilage
o stimulates ECM synthesis
o decreaes synovial thickening and chronic synovial inflammation
o additive when combined with TGF-b
Nourishment and Metabolism
 Cartilage is avascular
 Nourished by
o synovial fluid at the surface
o subchondral bone at the base
 Relies on glycolysis for ATP production
Mechanical Stress Response
 Physiologic stress stimulates matrix synthesis and inhibits chondrolysis
o cyclic stress (1-5 MPa)
o moderate frequency (0.1-1 Hz)
o low rates (<1000 MPa/s)
 Excess stress suppresses matrix synthesis and promotes chondrolysis
o excess stress (>5 MPa)
o static load (<0.01 Hz)
o high rates (>1000 MPa/s)
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By Dr, AbdulRahman AbdulNasser

Musculoskeletal biology | Biologic Tissues
Cellular responses
o primary cilia act as a mechanosensory organ on chondrocytes and osteoblasts
o transduction of mechanical signals involves integrins
 Repetitive loading
o moderate running increases cartilage thickness and proteoglycan content
o strenuous loading leads to cartilage thinning and proteoglycan loss
o immobilization leads to cartilage thinning, softening and proteoglycan loss
Wear Mechanics
 Forms of lubrication
o elastohydrodynamic
 main mechanism during dynamic joint function
 elastic deformation of articular surfaces
 thin films of lubricant separate the surfaces
 a fully congruent joint will not allow a fluid film to form
o boundary (slippery surfaces)
 bearing surface is non-deformable
 lubricant only partially separates surfaces
 superficial zone proteins have a role in this lubrication mechanism
o boosted (fluid entrapment)
 concentration of lubricating fluid in pools
 trapped by regions of bearing surfaces that are making contact
o hydrodynamic
 fluid separates surfaces when one surface is sliding on the other
o weeping
 fluid shifts out of articular cartilage in response to load
 surfaces separated by hydrostatic pressure
 Mechanisms of wear
o adhesion
o abrasion
o transfer
o fatigue
o third body
Aging in Articular Cartilage
 With age changes in articular cartilage include
o increases in
 chondrocytes size
 protein content
 stiffness (passive glycation leads to increased stiffness of collagen)
 increase in ratio of proteoglycan keratin sulfate to chondroitin sulfate
o decrease in
 absolute number of cells (becomes hypocellular, despite the fact that individual chondrocytes
are increasing in size)
 water content (differentiates from osteoarthritis where water content actually increases)
 solubility
 proteoglycan size
 elasticity
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Musculoskeletal biology | Biologic Tissues
Advanced glycosylation end-products (AGEs)
o from spontaneous nonenzymatic glycation of proteins when sugars (glucose, fructose, ribose)
react with lysine or arginine residues
o because of the low turnover, articular cartilage is susceptible to AGEs accumulation.
o accumulation of AGEs has been thought to play a role in the development of OA of the knee and
ankle.
o effects of AGEs formation
 modification of type II collagen by cross-linking of collagen molecules
 increasing stiffness and brittleness
 increasing susceptibility to fatigue failure
Factor
Water
Modulus/stiffness
Chondrocytes
Glycosaminoglycans
Proteoglycans
Collagen
Advanced Glycosylation End
products (AGE)
Aging
Osteoarthritis
Decreased
Increased
Increased (less elastic)
Decreased (more elastic)
Fewer but increased size
Cells cluster (late stage)
Increased keratan
Increased chondroitin 4
sulfate:chondroitin 4 sulfate ratio,
sulfate:keratan sulfate ratio
constant chondroitin 6 sulfate
Increased decorin, decreased
Proteoglycans unbound
proteoglycan size
from hyaluronate
Increased collagen
Collagen disorganized
crosslinking/brittleness
(increased collagenase)
Accumulation of AGE
Increased
thought to lead to OA knee
and ankle
Healing in Articular Cartilage
 Deep lacerations (through tidemark)
o leads to fibrocartilage healing
o occurs when laceration travels through tidemark and penetrates subchondral bone
o fibrocartilage produced by undifferentiated marrow mesenchymal stem cells
o a healing response is initiated with hematoma, stem cell migration, and vascular ingrowth.
o This response produces type I collagen and resultant fibrous cartilage rather than desired hyaline
cartilage as produced by chondrocytes.
o This repair cartilage has diminished resiliency, stiffness, poor wear characteristics, and the
predilection for arthritis.
 Superficial laceration (not through tidemark)
o leads to chondrocytes proliferation but no healing takes place because of avascular nature of
cartilage
Clinical Conditions
 Articular Defects of the Knee (Adults)
 Osteocondritis dissecans
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
5. Cartilage
Introduction
 Main types of cartilage include
o articular (hyaline) cartilage
o fibrocartilage (tendon/ligament junction with bone) and fibroelastic cartilage (menisci)
o elastic cartilage (trachea)
o epiphyseal cartilage (growth plates)
 Cartilage contents (avascular, aneural, and alymphatic)
o cells
 chondrocytes
o extracellular matrix
 water
 collagen
 proteoglycans
 noncollagenous proteins
 Cell differentiation
o cartilage is formed from mesenchymal stem cells designated towards the cartilagenous lineage
 multi-step process involving activation and migration of cells to necessary sites
 SOX-9 is a key transcription factor involved in the differentiation of cells towards the
cartilage lineage
 Metabolism
o regulated through mechanical stimulation
o pH of cartilage is 7.4
 disruption in pH can lead to an abnormal cartilage structure
 Nutrition
o oxygen and other nutrients supplied to cartilage from synovial fluid diffusion
 Loading
o physiologic loading is chondroprotective
o underloading leads to cartilage thinning, tissue softening, and reduced proteoglycan content,
leading to cartilage fibrillation, ulceration and erosion
o overloading leads to cartilage damage (in vitro only)
 has not been shown in clinical setting
Articular (Hyaline) cartilage
 Complete Topic
 Location
o articular surfaces
o ribs
o nasal septum
 Composition
o water > collagen > proteoglycan > noncollagenous protein > cells
 water = 65% to 80% of mass of the cartilage
 Type II collagen = provides cartilagenous framework and tensile strength
 proteoglycans = function to provide compressive strength and attract water
 chondrocytes = produce collagen, proteoglycans, and enzymes
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Function
o decreases friction and distributes loads
o cartilage exhibits stress-shielding of the solid matrix components due to its high water content,
the incompressibility of water, and the structural organization of the proteoglycan and collagen
molecules
Fibrocartilage
 Location
o tendon/ligament junction with bone
o pubic symphysis
o annulus fibrosis of the intervertebral disc
o menisci
 Composition
o fibrous cartilage
 Type I collagen (predominantly)
 extracellular matrix
 proteoglycans
 chondrocytes
 water
o fibroelastic cartilage
 fewer proteoglycans and glycoproteins compared to
hyaline cartilage
 Function
o healing response to injury of articular cartilage including
 chondroplasty microfracture
 drilling
 abrasion arthroplasty
o compressive strength
Elastic Cartilage
 Location
o auricle of external ear
o epiglottis
o auditory tube
 Composition
o chondrocytes surrounded by a thin collagenous network
 Type II collagen (predominantly)
 elastin fiber network
 extracellular matrix
 proteoglycans and glycoproteins
 chondrocytes
 water
 Function
o highly elastic
o designed to tolerate repetitive deformation
‎I:15 Epiphyseal cartilage
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‎I:13 Fibrocartilage
‎I:14 Elastic cartilage
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
Epiphyseal cartilage
 Location
o also known as the epiphyseal plate or epiphyseal ossification center
o between the epiphysis and metaphysis at each end of long bones
 Composition
o stacked chondrocytes are divided into different zones of maturation
o proteoglycans and growth factor (e.g.BMP-2) are found in the extracellular matrix between
chondrocytes
o progressive chondrocyte maturation and calcification of the extracellular matirix
o infiltration of osteoprogenitor cells to produce osteoblasts and osteoid
 Histology of Epiphyseal cartilage
o Reserve zone
o Proliferative zone
o Hypertrophic zone
o Primary spongiosa
o Secondary spongiosa
 Function
o linear growth via endochondral ossification
o can allow extensive bone deformity remodeling potential
6. Synovium & Synovial Fluid
Synovium
 Function
o mediates nutrient exchange between blood and joint fluid
 Composition
o vascularized connective tissue is porous and lacks basement
membrane
o cell types
 type A cells
 derived from macrophages
 non-fixed cells with antigen presenting ability
 located in superficial layer
 important in phagocytosis
 type B cells
 fibroblast like cells
 rich rough endoplasmic reticulum and dendritic processes that reach out to the joint
surface
 located at various depths, frequently in deeper layer
 produce synovial fluid
 produce hyaluronic acid, fibronectin, collagen
 type C cells
 intermediate cell type
 unknown function and origin
 may serve as multi-potent precursor to either type A or B synovial cells
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Synovial Fluid
 Function
o lubricates articular cartilage and provides nourishment through diffusion
 Origin
o made from a ultrafiltrate of blood plasma
 regulated by synovium
 healthy knee contains ~2mL of synovial fluid
 Consists of
o hyaluronin
 uridine diphosphoglucose dehydrogenase enzyme critical for its synthesis
o lubricin
 a key lubricating glycoprotein
o proteinase
o collagenases
o prostaglandins
 Biomechanics
o synovial fluid exhibits non-Newtonian flow characteristics
 the viscosity coefficient is not a constant
 the fluid is not linearly viscous
 viscosity increases as the shear rate decreases
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Biologic Tissues
7. Collagen
Overview
 Collagen is a naturally occurring family of proteins
o over 25 types of collagen have been described
 Makes up the most abundant type of protein found in humans
o ~25% of the whole-body protein content is composed of some type of collagen
o found in multiple tissues like cartilage, tendon, bone, ligament, skin (see table below)
o multiple different forms of collagen exist, each with different biomechanical properties suited to
the environment in which that form is expressed
 Collagen is made of elongated fibrils formed by fibroblast cells
o synthesis of collagen is unique in that it occurs both inside and outside the cell
Biochemisty
 Composition
o collagen is composed of a triple helix of
 two alpha1 chains
 one alpha2 chain
o several common amino acid sequences are found in collagen including
 Glycine-X-Hydroxyproline
 Glycine-Proline-X
 Formation of collagen fibers
o alpha chains
 three alpha chains (two alpha1 and one alpha 2) are formed
o procollagen
 two alpha1 and one alpha2 combine to form procollagen
o tropocollagen
 procollagen is processed by extracellular protein modification into a tropocollagen molecule
after being expressed from the golgi apparatus
o collagen fibril
 aldehyde formation on tropocollagen lysine and hydroxylysine allow for covalent bonding
between tropocollagen molecules forming the collagen fibril
o collagen fiber
 multiple collagen fibrils aggregate to form a collagen fiber
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OrthoBullets2017
Musculoskeletal biology | Biologic Tissues
Types of Collagen
Type
Location
Bone
Ligament
Tendon
Meniscus
Disc - Annulus
Disc - Pulposus
Cartilage - Articular
Cartilage - Basement Membrane
Cartilage - Deep calcified layer
Cartilage - Reparative(fibrocartilage)
Skin
Blood Vessels
Epithelial Basement Membrane
Collagen lattice
I
o
o
o
o
o
II
III
IV
o
o
V
VI
o
o
VII
VIII
IX
X
XI
o
o
o
o
o
o
o
o
o
o
o
o

Type I Collagen
o accounts for more than 90% of the total collagen content in the body
o found in
 bone
 ligament
 tendon
 meniscus
 annulus of intervertebral disks
 skin
 healed cartilage
 scar tissue
 nerves
o related clinical conditions
 osteogenesis imperfecta
 Ehlers-Danlos syndrome
 Type II Collagen
o is found
 articular (hyaline) cartilage
 nucleus pulposus of intervertebral disks
o type II collagen has a very long half life
 Type III Collagen
o found in skin and blood vessels
o related clinical conditions
 Ehlers-Danlos syndrome
 Dupuytren's contracture
 Type IV Collagen
o found in basement membranes
o related clinical conditions
 renal diseases like Goodpasture's and Alport syndromes
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Molecular Biology

Type V, VI, IX Collagen
o occur in small amounts in articular cartilage
o type IX collagen gene deletion linked to development of OA in women and in knockout mice
o mutations in COL9A1, COL9A2, COL9A3 linked to multiple epiphyseal dysplasia (MED)
 however 70% of MED is associated with COMP
 fragmented ossific centers
 coxa vara hips
 genu valgum
 shortened, stunted metacarpals
 Type VII and VIII Collagen
o basement membrane (epithelial)
 Type X Collagen
o is found in the deep calcified layer of cartilage
o produced only by hypertrophic chondrocytes during enchondral ossification (growth plate,
fracture callus, heterotopic ossification)
 associated with calcification of cartilage in the deep zone of articular cartilage
o increased in early arthritis
o related clinical conditions
 Schmid metaphyseal chondrodysplasia
 Type XI Collagen
o an adhesive with the function of holding the collagen lattice together in cartilage
Coxa vara hip
Shortened, stunted metacarpals
Genu valgum
Genu valgum
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OrthoBullets2017
Musculoskeletal biology | Molecular Biology
D. Molecular Biology
1. Molecular Biology Basics
Nuclear structures
 Chromosomes
o 46 in humans (23 pairs)
 22 pairs of autosomes, 1 pair of sex chromosomes
o contains DNA and RNA
 Deoxyribonucleic acid (DNA)
o Thymine, adenine, guanine, and cytosine
 adenine linked to thymine (A-T)
 guanine linked to cytosine (G-C)
o double stranded
o strands linked together by phosphate groups
o 2' hydrogen group
o regulates cell division
o mRNA is produced from DNA
 an exon is portion of gene that codes for
mRNA
 exon is expressed
 Gene
o segment of DNA that contains the information needed to synthesize a protein
o determines the unique biologic qualities of a cell
o exon
 coding information
o intron
 does not code for mRNA
 Ribonucleic acid (RNA)
o usually single stranded but can be double stranded
 double stranded RNA found in some viruses
 certain interactions between single stranded RNA in human cells can form double stranded
RNA
o has ribose sugar
o Uracil, adenine, guanine, and cytosine (no thymine)
o less stable than DNA
o 2' hydroxyl group
o can be located in either the nucleus or cytoplasm
o messenger RNA (mRNA)
 translates DNA information into protein
o ribosomal RNA (rRNA)
 major part of ribosome, which helps synthesize a protein
o transfer RNA (tRNA)
 transfers amino acids to mRNA
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Molecular Biology
Genetic Terms
 Nucleotides
o thymine, adenine, guanine, and cytosine
 Codon
o sequence of three nucleotides
o each codon correlates to one of the 20 amino acids
o linking of the amino acids create a protein
 Gene promotor
o regulatory portion of DNA that controls initiation of transcription
 Gene enhancers
o site on DNA that transcription factors bind to
o regulate transcription
 Transcription
o DNA => mRNA
 Translation
o mRNA => protein
 Haploid
o Haploid is the amount of DNA in a human egg or sperm cell (half the amount of DNA in a
normal cell)
Cell Cycle
 Phases
o G0
 represents a "stable" phase
 cells are diploid (2N) in the G0 and G1 phases
o G1
 initial growth phase
 cells are diploid (2N) in the G0 and G1 phases
oS
 DNA replication/synthesis phase
 cells become tetraploid (4N) at the end of S and
for the entire G2 phases
o G2
 gap phase
 cells become tetraploid (4N) at the end of S and for the entire G2 phases
oM
 mitosis phase
Apoptosis
 Defined as programmed cell death
 Requires a series of intracellular signaling events
 Different from cell lysis - where a cell releases its contents into the surrounding area
 One hallmark of cancer is the cell's loss of apoptosis
Research techniques
 Agarose gel electrophoresis
o separates DNA based on size
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o DNA
is negatively charged
exposed to electric field
o smaller pieces moves through gel faster
 Southern blotting
o restriction enzymes cut up DNA
o separate on agarose gel
o identifies DNA sequence
 Northern blotting
o restriction enzymes cut up RNA
o separate on agarose gel
o identifies RNA sequence
 Western blotting
o SDS-PAGE gel
o identifies protein
 DNA ligation
o combining different DNA fragments not found together naturally to create recombinant DNA
 Plasmid vector
o an extrachromosomal element, often circular, that can replicate and be transferred independently
of the host chromosome
o one example of the function of a plasmid is antibiotic resistance
o can be introduced into bacteria in the process of transformation
 Polymerase chain reaction (PCR)
o DNA => DNA
o a molecular biology tool used to generate many copies of a DNA sequence
o uses "primers" specific to a segment of DNA
o requires temperature-mediated enzyme DNA polymerase
 Reverse transcription polymerase chain reaction (RT-PCR)
o RNA => DNA
o variant of polymerase chain reaction (PCR) used in molecular biology to generate many copies
of a DNA sequence from fragments of RNA
o RNA strand is first reverse transcribed into its DNA complement
o amplification of the resulting DNA proceeds using polymerase chain reaction
o gel
2. Immunology
Introduction
 Types of Immune Responses
o innate response
 not specific to a type of immunological challenge
 represents the immune response which does not have memory
 e.g., anatomic barriers (skin), inflammation, complement cascade
 recognizes structures common to multiple microbes
 found in nearly all forms of life
 cells include
 natural killer cells
 mast cells
 eosinophils
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Molecular Biology
basophils
phagocytic cells (macrophages, neutrophils, and dendritic cells)
o acquired response
 portion of immune response which has memory
 occurs in a pathogen and antigen specific mechanism
 requires antigen processing and presentation
 performed by antigen presentation cells (APC)
 B cells and dendritic cells are two examples of APCs
 the APC breaks down the protein antigen in a multitude of enzymatic reactions and
presents key peptide sequences via the major histocompatibility complex (MHC)
receptors
 once presented on the surface of the APC, the T-cell receptor recognizes the
MHC/antigen complex prior to T-cell activation
 cells include
 CD8+ T lymphocytes
 T helper cells
 delta gamma T cells
 B cells and plasma cells


Types of Immunological Reactions
 Type I: Immediate anaphylactic reaction
o associated with allergy
o mediated by IgE antibody activation of mast cells and basophils
 Type II: Antibody dependent (aka cytotoxic) hypersensitivity
o mediated by IgG and IgM antibodies
 Type III: Immune complex (antigen bound to antibody) deposition type of hypersensitivity
o mediated by IgG and IgM antibodies which when bound to antigen get deposited in various
tissues
 Type IV: Delayed-type or cell-mediated hypersensitivity
o mediated by T cells, monocytes and macrophages
o take several days to develop
o examples include
 tuberculosis skin test
 the immune response to metallic orthopaedic implants is typically a Type IV (delayed-type
hypersensitivity reaction)
Immunoglobulins
 Immunoglobulin types
o IgG
 the most abundant immunoglobulin
o IgM
 the first class of antibody to appear in our serum after exposure to an antigen
o IgA
 the major class of antibody in external secretions (e.g. intestinal mucus, bronchial mucus,
saliva, and tears)
o IgE
 important in conferring protection against parasites and allergic reactions
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Immunologic Variations
 Benign Ethnic Neutropenia
o Most common neutropenia in the world
o Approximately 25%-50% of people of African descent and some sub-groups in the Middle East
found to have low ANC without increased infection risk
o ANC < 1.5 x 10(9) cells/L considered "abnormally low" without clear clinical relevance.
 4.5% African Americans, 0.79% white Americans, 0.38% Mexican-Americans below this
ANC
o Also more common in males vs females, athlete vs non-athlete, and children under age 5
3. Inheritance Patterns of Orthopaedic Syndromes
Introduction
 Allows for specific patterns of inheritance controlled by a single gene pair (“monogenic”)
o 4 different types of patterns
 autosomal dominant
 autosomal recessive
 x-linked dominant
 x-linked recessive
o additional inheritance effects include
 imprinting
 anticipation
Pedigree Analysis
 A pedigree chart displays a family tree and the members of the family affected by a genetic trait
 Use
o a pedigree chart can be used to determine the mode of transmission
o dominance
 whether the trait is dominant or recessive
o linkage : whether the trait is X-linked or autosomal
 Key
o shapes
 circles represent females
 squares represent males
o color
 a black circle/square represents an individual affected by the genetic trait
 a white circle/square represents an individual that is not affected by the trait
o lines
 horizontal
 a male and female connected by a horizontal line have mated and have children
 vertical
 vertical lines connect parents to their children
Autosomal Dominant
 Description
o only need to get the abnormal gene from one parent in order for you to inherit the disease.
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By Dr, AbdulRahman AbdulNasser

Musculoskeletal biology | Molecular Biology
Examples
o Syndactyly
o Polydactyly
o Marfan's syndrome
o Cleidocranial Dysostosis
o Hereditary Multiple Exostosis
o Achondroplasia
o MED |( Multiple Epiphyseal Dysplasia)
o Metaphyseal chondrodysplasia (Schmid and Jansen types)
o Kniest dysplasia
o Malignant hyperthermia
o Ehlers-Danlos syndrome
o Osteogenesis imperfecta (types I and IV)
o Osteochondromatosis/Multiple Hereditary Exostosis
o Osteopetrosis (tarda, mild form)
Autosomal Recessive
 Description
o an autosomal recessive disorder means two copies of an abnormal gene must be present in order
for the disease or trait to develop.
 Examples
o Diastrophic Dysplasia
o Friedreich's Ataxia
o Gaucher disease
o Spinal muscular atrophy
o Sickle cell anemia
o Osteogenesis imperfecta (II and III)
o Hypophosphatasia
o Osteopetrosis (infantile, malignant form)
Sex-linked Recessive (males only)
 Description
o X-linked diseases usually occur in males. Males have only one X chromosome. A single
recessive gene on that X chromosome will cause the disease.
 Examples
o Duchenne muscular dystrophy
o Becker's muscular dystrophy
o Hunter's syndrome
o Hemophilia
o SED tarda (Spondyloepiphyseal Dysplasia)
Sex-linked Dominant
 Examples
o Hypophosphatemic rickets
o Leri-Weill dyschondrosteosis (bilateral Madelung's deformity)
Multiple inheritance patterns
 Examples
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Musculoskeletal biology | Molecular Biology
o Charcot-Marie-Tooth
(AD, AR, Xlink)
(AD, AR)
o Osteogenesis Imperfecta (AR, AD)
o Neurofibromatosis (AD, AR)
o Spondyloepiphyseal Dysplasia (AD, Xlink)
o Osteopetrosis
Miscellaneous Genetic Inheritance
 Imprinting
o a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific
manner
o Examples
 Angelman Syndrome
 Prader-Willi Syndrome
 Anticipation
o a phenotype occurs earlier (and typically worse) in each subsequent generation
o common in trinucleotide repeat disorders
4. Genetic Pearls
Pediatric Dwarfisms
Achondroplasia
Apert Syndrome
CMT (80-90%) *
Pseudoachondroplasia
SED congenital **
Kniest's Syndrome
MED - Type I ***
MED - Type II ***
Jansen's metaphyseal
chondrodysplasia
Schmid's metaphyseal
chondrodysplasia
Cleidocranial dysplasia
Osteogenesis Imperfecta
(Type I, IV)
Diastophic dysplasia
Friedreich's Ataxia
Osteo. Imperfecta
(Type II, III)
McKusick metaphyseal
Genetic Pearls of Skeletal Dysplasia
Autosomal Dominant
FGFR-3
Inhibition of chondrocytes proliferation
FGFR-2
Inhibition of chondrocytes proliferation
PMP22
Nerve demyelination
COMP
Abnormal cartilage formation
COL2A1 / Type II collagen
Defect in cartilage matrix formation
Type II collagen
Type II collagen
COMP
Type IX collagen
PTHrP
Type II collagen
Type X Collagen
Defect in cartilage matrix formation
CBFA-1
COL1A1/COL1A2
Impaired intramembranous ossification
Type I collagen
Functional defect in parathyroid hormone
Autosomal Recessive
DTD (Sulfate Transport Protein)
Defect in sulfaction of proteoglycan
Frataxin
COL1A1/COL1A2
Type I collagen
Unknown
X Linked Recessive
SED tarda **
COL2A1
Type II collagen
CMT (10-20%) *
connexin gene
Nerve demyelination
* CMT = Charcot-Marie-Tooth Disease (peroneal muscular atrophy)
See these topics in Pediatrics.
** SED congenita = Spondyloepiphyseal Dysplasia ***MED = Multiple Epiphyseal Dysplasia
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Molecular Biology
Epigenetics
 Overview
o epigenetic changes include inheritable genetic alteration (developmental or environmental cues)
that do NOT involve DNA mutation
o DNA methylation, histone modification, nucleosome location, or noncoding RNA are
components of epigenetics
o osteoarthritis is thought to have epigenetic mechanisms that influence the disease process
Translocations
 Overview
o translocations allow expression of genes (oncogenes) that are usually not active.
o cytogenetic analysis allows for the detection of gene translocations by evaluating the size and
number of chromosomes isolated from the cell nucleus.
 Examples
o present in up to 95% of sarcomas.
Disease
Ewing's sarcoma
Rhabdomyosarcoma
Myxoid liposarcoma
Synovial sarcoma
Clear cell sarcoma
Chondrosarcoma (Myxoid Variant)
Translocation
t (11:22)
t (2:13)
t (12:16)
t (X:18)
t (12:22)
t (9:22)
Gene
Fusion protein (EWS-FLI1)
Pax3-FKHR
TLS-CHOP
SYT-SSX1, 2, or 4 fusion protein
Fusion protein EWS-ATF1
Fusion protein EWS-CHN
Tumor Suppressor Genes
 Definition
o inhibit cell proliferation
o therefore a mutation interfering with normal function causes leads to uncontrolled cell growth
 Examples
o retinoblastoma protein (pRB-1)
 acts as a regulator of gene expression
 recessive suppressor
 both alleles must be mutated to have uncontrolled growth
 Rb mutation in
 100% of retinoblastomas
 35% of osteosarcomas
 abnormal state is phosphorylated and unable to bind to DNA to regulate
o p53
 normal protein prevents entrance into S-phase of cell cycle when DNA is damaged
 dominant suppressor
 single allele must be mutated to have uncontrolled growth
 mutation in this gene found in
 50% of all tumors
 osteosarcoma (20-65%)
 chondrosarcoma
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Musculoskeletal biology | Molecular Biology
Oncogenes
 Definition
o induce uncontrolled growth
o normal function causes leads to uncontrolled cell
 Examples
o FAK
 focal adhesion kinase)
o Erb-2
 epidermal growth factor variant
Tumor Antigens
 Definition
o tumor antigens are used in the diagnosis, monitoring of treatment response, and are being
researched for treatment options as anti-cancer vaccines
 Examples
o carcinoembryonic antigen (CEA)
 colorectal carcinoma
o carbohydrate antigen 19-9 (CA-19-9)
 pancreatic cancer
o carbohydrate antigen 125 (CA-125)
 ovarian cancer
o cancer antigen 15-3 (CA-15-3)
 breast cancer
o alpha fetoprotein (AFP)
 can be seen in many cancers, but is most commonly seen in hepatocellular carcinomas
Assays
 Western blot
o detects protein
 Southern blot
o detects DNA
 Northern blot
o detects RNA
 Southwestern blot
o detects DNA binding proteins
 RT-PCR
o reverse transcription PCR
o highly sensitive, detects low copy number of RNA
o reversed transcribed into complimentary DNA (cDNA)
o may be used together with Northern blot
 siRNA
o blocks translation of mRNA
o useful for loss-of-function experiment designs
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
E. Material Science
1. Material Properties
Introduction
 Biomaterials encompasses all synthetic and natural materials used during orthopaedic procedures
 Basic definitions
o load : a force that acts on a body
o stress
 definition : intensity of an internal force
 calculation : force / area
 units : Pascal's (Pa) or N/m2
o strain
 definition : relative measure of the deformation of an
object
 calculation : change in length / original length
 units : none
 Mechanical property definitions
o elastic deformation
 reversible changes in shape to a material due to a load
 material returns to original shape when load is removed
o plastic deformation
 irreversible changes in shape to a material due to a load
 material DOES NOT return to original shape when load is removed
o toughness
 definition : amount of energy per volume a material can absorb before failure (fracture)
 calculation : area under the stress/strain curve
 units : joules per meter cubed, J/m3
o creep : increased load deformation with time under constant load
o load relaxation : decrease in applied stress under conditions of constant strain
Elastic deformation is the
REVERSIBLE change due to a load.
Plastic deformation is the
IRREVERSIBLE change in shape
due to a load
Toughness is calculated by
measuring the area under each
materials stress/strain curve.
Brittle materials are easily
fractured while ductile materials
are not.
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Hysteresis is a characteristic of
viseoelastic materials where the load
and unload curves are not the same.
The area inbetween these two curves is
the energy dissipated. The loading and
unloading curves of 4 different materials
are shown
OrthoBullets2017
Musculoskeletal biology | Material Science
o hysteresis
(energy dissipation)
characteristic of viseoelastic materials where the loading curve does not follow the unloading
curve
 the difference between the two curves is the energy that is dissipated
o finite element analysis
 breaking up a complex shape into triangular or quadrilateral forms and balancing the forces
and moments of each form to match it with its neighbor

Material Strength: Stress vs Strain Curve
 Derived from axially loading an object and plotting the stress verses strain curve
 Elastic zone
o the zone where a material will return to its original shape
for a given amount of stress
o "toe region" see graph below
 applies to a ligaments stress/strain curve
 represents straightening of the crimped ligament
fibrils
 Yield point
o the transition point between elastic and plastic
deformation
 Yield strength
o the amount of stress necessary to produce a specific amount of permanent deformation
 Plastic zone
o the zone where a material will not return to its orginal shape for a given amount of stress
 Breaking point
o the object fails and breaks
 Ultimate (Tensile) strength
o defined as the load to failure
 Hooke's law
o when a material is loaded in the elastic zone, the stress is proportional to the strain
 Young's modulus of elasticity
o measure of the stiffness (ability to resist deformation) of a material in the elastic zone
o calculated by measuring the slope of the stress/strain curve in the elastic zone
o a higher modulus of elasticity indicates a stiffer material
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
Young's Modulus of Metals and Biologics
 Relative values of Young's modulus of elasticity (numbers correspond to numbers on illustration to
right)
o Ceramic (Al2O3)
o Alloy (Co-Cr-Mo)
o Stainless steel
o Titanium
o Cortical bone
o Matrix polymers
o PMMA
o Polyethylene
o Cancellous bone
o Tendon / ligament
o Cartilage
Material Descriptions
 Brittle material
o a material that exhibits linear stress stain relationship up until the point of failure
o undergoes elastic deformation only, and little to no plastic deformation
o examples
 PMMA
 ceramics
 Ductile Material
o undergoes large amount of plastic deformation before
failure
o example
 metal
 Viscoelastic material
o a material that exhibits a stress-strain relationship that is
dependent on duration of applied load and the rate by
which the load is applied (strain rate)
 a function of the internal friction of a material
 examples
 ligaments
 bone
 Isotropic materials
o possess the same mechanical properties in all directions
 example
 golf ball
 Anisotropic materials
o possess different mechanical properties depending on the direction of the applied load
o examples
 ligaments
 bone
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Metal Characteristics
 Fatigue failure
o failure at a point below the ultimate tensile strength secondary to repetitive loading
 depends on magnitude of stress and number of cycles
 Endurance limit
o defined as the maximal stress under which an object is immune to fatigue failure regardless of
the number of cycles
 Creep
o phenomenon of progressive deformation of metal in response to a constant force over an
extended period of time
 Corrosion
o refers to the chemical dissolving of metal. Types include
 galvanic corrosion
 dissimilar metals leads to electrochemical destruction
 mixing metals 316L stainless steel and cobalt chromium (Co-Cr) has highest risk of
galvanic corrosion
 can be reduced by using similar metal
 crevice corrosion
 occurs in fatigue cracks due to differences in oxygen tension
 316L stainless steel most prone to crevice corrosion
 fretting corrosion
 description
 a mode of destruction at the contact site from the relative micromotion of two
materials or two components
 clinical significance
 common at the head-neck junction in hip arthroplasty
 most common cause of mid-stem failure in modular revision type stems
 arthroplasty involving modular implants are at risk for fretting corrosion and
failure between the components of the final implant
 increased risk with the increased number of interfaces between the various
components
Galvanic corrosion is due to an
electrical contact with a more noble
metal or a non-metallic conductor in a
conductive environment. The galvanic
corrosion is very dependent of the
cathode reaction and which metals
are in contact which each other.
Localized corrosion on a
cemented Ti–6Al–4V stem
region due to crevice
attack.
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In the first picture, fretting
corrosion has occured between
the stem and the cement
interface. In the second picture,
corrosion has occured between
the modular head-neck
interface.
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
Specific Metals
 Titanium
o uses
 fracture plates
 screws
 intramedullary nails
 some femoral stems
o advantages
 very biocompatable
 forms adherent oxide coating through self passivation
 corrosion resistant
 low modulus of elasticity makes it more similar to biologic materials as cortical bone
o disadvantages
 poor resistance to wear (notch sensitivity) (do not use as a femoral head prosthesis)
 generates more metal debris than cobalt chrome
 Stainless Steel (316L)
o components
 primarily iron-carbon alloy with lesser elements of
 chromium
 molybdenum
 manganese
 nickel
o advantages
 very stiff
 fracture resistant
o disadvantages
 susceptible to corrosion
 stress shielding of bone due to superior stiffness
 Cobalt alloy
o components
 cobalt
 chromium
 molybdenum
o advantages
 very strong
 better resistance to corrosion than stainless steel
Specific Non-Metals
 Ultra-high-molecular-weight polyethylene
o advantages
 tough
 ductile
 resilient
 resistant to wear
o disadvantages
 susceptible to abrasion
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 wear usually caused by third body inclusions
thermoplastic (may be altered by extreme temperatures)
 weaker than bone in tension
o other
 gamma irradiation
 increases polymer chain cross-linking which improves wear characteristics
 decreases fatigue and fracture resistance
 Polymethylmethacrylate (PMMA, bone cement)
o functions
 used for fixation and load distribution in conjunction with orthopaedic implants
 functions by interlocking with bone
 may be used to fill tumor defects and minimize local recurrence
o properties
 2 component material
 powder
 polymer
 benzoyl peroxide (initiator)
 barium sulfate (radio-opacifier)
 coloring agent (green chlorophyll or blue cobalt)
 liquid
 monomer
 DMPT (N,N-Dimethyl para-toluidine, accelerator)
 hydroquinone (stabilizer)
o advantages
 reaches ultimate strength at 24 hours
 strongest in compression
 Young's modulus between cortical and cancellous bone
o disadvantages
 poor tensile and shear strength
 insertion can lead to dangerous drop in blood pressure
 failure often caused by microfracture and fragmentation
 Silicones
o polymers that are often used for replacement in non-weight bearing joints
o disadvantages
 poor strength and wear capability responsible for frequent synovitis
 Ceramics
o advantages
 best wear characteristics with PE
 high compressive strength
o disadvantages
 typically brittle, low fracture toughness
 high Young's modulus
 low tensile strength
 poor crack resistance characteristics

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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
Bone
 Bone composition
o composed of collagen and hydroxyapatite
o collagen
 low Young's modulus
 good tensile strength
 poor compressive strength
o hydroxyapatite
 stiff and brittle
 good compressive strength
 Mechanical properties
o advantages
 strongest in compression
 a dynamic structure
 remodels geometry to increase inner and outer cortex to alter the moment of inertia and
minimize bending stresses
o disadvantages
 weakest in shear
 Failure (fracture)
o tension
 usually leads to transverse fracture secondary to muscle pull
o compression
 due to axial loading
 leading to a crush type fracture
 bone is strongest in resisting compression
o bending
 leads to butterfly fragment
o torsion
 leads to spiral fracture
 the longer the bone the greater the stresses on the outer cortex under torsion
Ligaments & Tendons
 Characteristics
o viscoelastic with nonlinear elasticity
o displays hysteresis (see definition above)
 Advantages
o strong in tension (can withstand 5-10% as opposed to 1-4% in bone)
 Disadvantages
o demonstrate creep and stress relaxation
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2. Structural Properties
Introduction
 Charateristics of orthopaedic implants depend
o structural properties (this topic)
o material properties
 Structural characteristic differs from strength characteristic
o not only depends on the material, but also the structural
configuation of the object (cylinder, rectangle)
o the stuctural properties can also be demonstrated in a stress
vs. strain curve
Bending Rigidity (stiffness)
 Definitions
o defined as the slope of the curve in the elastic range on a structure stress-strain curve
o stress shielding of proximal bone in THA is related to implant stem stiffness
 Solid Cylinder
o proportional to the radius to 4th power for a solid cylinder
o cylinder A has great rigidity than cyliner B on illustration above (and thus has greater radius)
 Hollow Cylinder
o proportional to the radius to the 3rd power for a hollow cylinder
 Rectangular Object
o proportional to the (base x height) to the 3rd power
Area Moment of Inertia (I)
 Closely related to bending rigidity
o area moment of inertia is a function of: structure width, thickness, and polar moment of inertia
(J)
 polar moment of inertia represents an object resistance to torsion
Deflection
 Proportional to: (applied force/elastic modulus)(area moment of inertia)
3. Orthopaedic Implants
Introduction
 Characteristics of orthopaedic implants depends on
o material properties
o structural properties
Screws
 Definitions
o pitch : distance between threads
o lead : distance advanced with one revolution
o screw working distance (length)
Cancellous screw
 defined as the length of bone traversed by the screw
o outer diameter
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Cortical screw
By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
o root
(inner) diameter
strength is proportionate to inner (minor) diameter^3
o pullout strength is proportionate to outer (major) diameter^2
 maximized by
 large outer diameter difference
Locking screw
 fine pitch
 pedicle screw pullout most affected by quality of bone (degree of osteoporosis)
 Types of screws
o cortical screws
o cancellous screws
o locking screws
o bending
Plate Properties
 Overview & definitions
o a load-bearing devic
o e that is most effective when placed on the tension side
o plate working distance
 the length between the 2 screws closest to the fracture on each end of the fracture.
 decreasing the working distance increases the stiffness of the fixation construct
 Structural properties
o bending rigidity proportional to thickness to the 3rd power
o titanium has Young's modulus of elasticity that most closely approximates cortical bone
 Biomechanics
o absolute stability
 constructs heal with primary (Haversian) healing
 must eliminate micromotion with lag screw fixation
 must be low strain at fracture site with high fixation stiffness
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o relative
stability
constructs heal with enchondral healing
 strain rates must be <10%, or fibrous union will predominate

Plate Variations
 Concave plates
o placing a concave bend on a plate is useful in transverse fractures to ensure compressive forces
occur on both the far and near cortices of the fracture
 Compression plates
o compression plates work by placing a cortical screw eccentrically into an oval hole in the plate
 Locking plates
o advantages of locking plates
 locked plate/screw constructs compared to non-locked plate/screw constructs result in less
angulation in comminuted metaphyseal fractures
o indications for locking plate technology
 indirect fracture reduction
 diaphyseal/metaphyseal fractures in osteoporotic bone
 bridging severely comminuted fractures
 plating of fractures where anatomical constraints prevent plating on
the tension side of the bone (e.g. short segment fixation).
o locking plate screw biomechanics
 bicortical locking screws have significantly more resistance to all
applied forces, with resistance to torsion increased the most (versus
unicortical)
 unicortical locking screws have less torsion fixation strength than
non-locking bicortical constructs
o percutaneous locking plates
 application has less soft-tissue stripping but higher chance malunion
o hybrid locked plates
 utilize locking and nonlocking screws in order to assist with fracture
reduction (nonlocking screws) as well as provide a fixed angle
construct (locking screws).
‎I:16 Radiograph: Example
o locking plate construct stability increases with:
of compression plating of a
midshaft humerus fracture
 bicortical locking screws
 increased number of screws
 screw divergence from screw hole < 5 degrees
 longer plate
 Bridging plates
o provides relative stability, relative length and alignment
o preserves the blood supply to the fracture fragments as the fracture site is undisturbed during the
operative procedure
 this theoretically improves secondary bone healing
o allows some motion at fracture site; relative stability leads to callus formation
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By Dr, AbdulRahman AbdulNasser
Illustration: Example of a hybrid
plate. Locking hole is threaded
and left empty, while this screw is
placed in the eccentrically
located compression slot hole.
Musculoskeletal biology | Material Science
AP Radiograph: Example of distal
femoral locking plate. This fixed
angle construct was utilized for
bridging across the fracture site.
AP and lateral views
after plate fixation of
both bone forearm
fractures. Bridge plate
fixation of radius was
utilized due to amount
of comminution
AP Radiograph: Bending
rigidity of hollowed femoral
nail proportional to 3rd
power, while torsional
rigidity proportional to 4th
power.
Intramedullary nails
 Overview
o a load-sharing device
 Structural Properties
o stiffness
 torsional rigidity
 defined as amount of torque needed to produce torsional (rotational) deformation
 proportional to the radius to the 4th power
 depends on
 shear modulus
 polar moment of inertia
 increased by reaming
 decreased by slotting of nail
 bending rigidity
 proportional to the radius to the 4th power for a solid nail


area moment of inertia of a solid cylinder
proportional to the radius to the 3rd power (approximately) for a hollow nail

area moment of inertia of a hollow cylinder
where r1 is inner radius and r2 is outer radius
 for thin cylinders
 depends on
 material properties
 Young modulus of elasticity of material
 structural properties
 area moment of inertia
 length

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
Radius of curvature
o intramedullary nail radius of curvature is greater
(straighter) than the radius of curvature of the femur
 Interlocking options
o dynamic locking-->axially and rotationally stable fractures
o static locking-->axially and rotationally unstable fractures
o secondary dynamization for nonunion
 remove proximal interlocking screw or move proximal
interlocking screw from the static to dynamic slot
‎I:17 Larger radius of curvature of nail in
comparison to femur bone can cause anterior
perforation at anterior distal femur.
External fixators
 Factors that increase stability of conventional external fixators
o contact of ends of fracture
o larger diameter pins (most important)
o additional pins
o decreased bone to rod distance
o pins in different planes
o increasing size or stacking rods
o rods in different planes
o increased spacing between pins
 Factors that increase stability of circular (Ilizarov) external fixators
o larger diameter wires
o decreased ring diameter
o olive wires
o extra wires
o wires cross perpendicular to each other
o increased wire tension
o placement of two central rings close to fracture
o increased number of rings
‎I:18 External Fixator
Total Hip Implants
 Structural Properties
‎I:19 Total hip
implant
o rigidity depends on length and radius of femoral stem
‎I:20 Ilizarov
 Biomechanics
o place femoral component in neutral or slight valgus to reduce moment arm and stress on cement
o increasing femoral offset does the following
 advantages
 moves abductor moment away from center of rotation
 increase abductor moment arm
 reduces abductor force required for normal gait
 disadvantages
 increased strain on implant
 increases strain on medial cement mantle
‎I:21 Illustration shows intimate relationship
between changing femoral neck offset vs hip
abductor muscle tension.
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
4. Bioabsorbable Materials
Introduction
 Bioabsorbable materials were invented to address issues with synthetic implants including
o migration
o growth disturbance
o rigidity
o radioopacity
o infection
o need for implant removal operations
 Indications include but are not limited to
o pediatric orthopaedics
 transphyseal SR PLGA 80/20 screws only cause temporary growth arrest in rabbits (unlike
nonbioabsorbable implants)
o osteomyelitis
 antibiotic eluting PLA
o carriers for growth factors
 rhBMP2 and rhBMP7
o augmentation of bone healing at iliac crest bone harvest site
Types of Bioabsorbable Materials
 Polyglycolic acid (PGA)
o hydrophilic, crystallic
o glass transition temperature 36degC
 becomes malleable if this temperature is exceeded
o disadvantages
 early degradation and strength loss
 potential postop complications
 intraoperatively, must be heated to adapt to implantation surface, and cooled
 increased intraoperative time consumption
 Polylactic acid (PLA)
o more hydrophobic than PGA
 L-isomer or poly-L-lactic acid (PLLA)
 hydrophobic and crystallic
 has prolonged degradation time (several years)
 late adverse reactions in the final stages of polymer degradation
 glass transition temperature 57degC
 D-isomer
 amorphous, less stable
 useful for building co-polymers
 Co-polymers
o P(L/D)LA copolymers
 mixture of D- and L-isomers of PLA
 hydrophobic and crystallic
 resistant to hydrolysis and degradation
 adding D-isomers results in less tightly packed polymer chains
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 less crystallic and more rapidly degraded than PLLA alone
example is P(L/D)LA 70/30 in oral-maxillofacial surgery
 simple and self-reinforced forms
o PLGA copolymers
 combination of PLA and PGA
 low crystallinity
 used in oral-maxillofacial surgery
 simple and self-reinforced forms
 Self reinforcing (SR)
o composite structure made from partially crystalline/amorphous material made of orientated
fibers/fibrils and binding matrix
o better biomechanical properties
 improved rigidity and strength along longitudinal axis
 malleable at room temperature
 no need for heating-cooling
 can withstand 4 times bending
 minimal "memory" (tendency to return to previous shape after bending)
 can be sterilized by gamma irradiation
 gamma irradiation cannot be used with non-reinforced materials
 will reduce its molecular weight and adversely affect the mechanical properties of the
implant

Absorption Time
>5-6 years
>5 years
2-3 years
1-2 years
2 years
0.5-1 years
2 months
1-2 months
Material
SR PLLA
PLLA
P(D/L)LA 70/30
PLA/PGA (PLGA) 80/20
P(D/L)LA 96/4
SR PGA
PDS
PGA
Biodegradation
 Primary mechanisms of biodegradation
o poly-hydroxy-acid degradation
 breakdown is by random hydrolysis of ester bonds, which leads to
 reduction of molecular weight
 loss of mechanical properties
 final products are CO2, H2O, and products of TCA (tricarboxylic acid, Krebs) cycle
o kidney excretion
 PDS and PGA products can be excreted by the kidney
o enzyme breakdown
 enzymes are involved with PLA and PGA degradation
o lowered pH
 polymer breakage produces products that lower pH
 accelerating the breakdown
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
o material
crystallinity
determines hydrophobicity and degradation speed
 amorphous and hydrophillic materials degrade faster
 more contact with water molecules
 crystalline and hydrophobic
materials degrade slower
 less contact with water molecules
 Additional variable that affect degradation
o chemical composition and molecular weight
o fiber orientation (SR or simple)
o monomer concentration (in polymers)
o stereoisomerism and conformation
o pores and surface area/volume ratio
o pores and surface area/volume ratio
o sterilization method (gamma irradiation vs others)Degradation method (enzymatic vs hydrolysis)

Histopathology
 Granulomatous inflammation
o cellular reactions around bioabsorbale implants are characterized by
 T lymphocytes (CD4>CD8)
 plasma cells
 endothelial cells
 birefringent polymer debris
 thin macrophage layer
 multinucleated giant cells
 Capsule formation
o a capsule forms around implants that consists of
 internal cell layer
 2-3 cells thick
 type III collagen predominance
 external fibrous layer
 few spindle shaped cells
 type I collagen predominance
 Stages
o begins with infiltration of neutrophils
 tissue reaction to trauma
o followed by CD4 T lymphocytes infiltration
o macrophages infiltration is last
Adverse Tissue Reactions
 Incidence
o 3% in pediatrics
o up to 60% in adults (more common in adults)
 Presentation
o symptoms
 fluid accumulation, fluctuant papules
 when implant degradation exceeds debris removal rate, fluid accumulates
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Musculoskeletal biology | Material Science
symptoms appear late in materials with low degradation rate
 e.g. PLLA at 5 years postop
o physical exam
 synovitis
 discharging sinus
 Labs
o fluid cultures are sterile
 unless there is secondary bacterial infection after bursting
 Radiography
o osteolysis is seen in up to 60% of cases
 Treatment
o nonoperative
 observation
 healing without active treatment
o operative
 aspiration and/or surgical debridement
 implant removal
 indicated if there is sterile implant failure
 or if there is secondary bacterial infection
 arthrodesis
 if there is severe osteoarthritis

5. Rehab & Prosthetics
Gait
 Antalgic gait describes any gait abnormality resulting from pain
o antalgic
gait associated with knee arthritis
 knee is maintained in flexion
 shortened stride length
 compensatory toe walking
 Gait pattern of ambulation with an assistive device
o 3-point
 both the crutch and the injured limb move forward together with weightbearing on the
crutches followed by all of the weight on the uninjured limb
o 4-point
o swing-to
o swing-through
 Crutch walking
o requires more energy than walking with a prosthesis
o muscles that need strengthening in preparation for crutch walking
 latissimus dorsi
 triceps and biceps
 quads
 hip extensors
 hip abductors
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
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OrthoBullets2017
Musculoskeletal biology | Material Science

Wheelchair propulsion
o 9% increase in energy expenditure compared to ambulation in normal subjects
 Ambulation assistive devices
o cane
o axillary crutch
 2 axillary crutches are required for proper gait if lower extremity is non-weightbearing or toetouch weightbearing
 Patient specific factors need to be considered when identifying the correct prosthesis for a patient
 Low demand patients may not require a prosthesis for activities of daily living
 Pearls for prosthetic gait abnormalities
Upper Extremity Prosthesis
 Timing of prosthetic fitting
o as soon as possible, even before wound healing has completed
 transradial prosthesis outcomes depend on timing of fitting
 70% to 85% when fitted within 30 days of amputation
 <30% when fitted later than 30 days of amputation
 Myoelectric prostheses
o transmits electrical activity to surface electrodes on residual limb muscles
o types of units
 2-site/2-function device
 separate electrodes for flexion and extension
 1-site/2-function device
 one electrode for flexion and extension
 indications
 best candidate is a patient with a transradial amputation
 best for sedentary work
‎I:22 Myoelectric
 can be used for overhead activities
prostheses
o advantages
 better cosmesis
 allows more proximal coverage
o disadvantages
 heavier and more expensive prosthesis
 less sensory feedback
 requires more maintenance
I‎:23 Body-powered prothesis
 Body-powered prostheses
o indications :best for heavy labor with less maintenance needed
o techniques
 activate terminal device with shoulder flexion and abduction
 center the harness ring just off the midline of C7 towards the non-amputated side
o advantages
 moderate cost and weight
 most durable prosthesis
 higher sensory feedback
o disadvatnages
 poorer cosmesis
 requires more gross upper limb movement for proper function
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By Dr, AbdulRahman AbdulNasser

Musculoskeletal biology | Material Science
Components
o Terminal device
 passive terminal device
 more cosmetic but less functional than active terminal devices
 active terminal device
 more functional, but less cosmetic than passive terminal devices
 either hooks and prosthetic hands with cables or myoelectric devices
 grips
 precision grip (pincer-type)
 tripod grip (palmar grip, 3-jaw chuck pinch)
 lateral pinch (key pinch)
 hook power grip
 spherical grip
 prehension devices
 handlike device
 thumb, index, and long finger components
 may be covered with a glove for better cosmesis
 good choice for office worker
 non-hand prehension device
 hook or two-finger pincer with parallel surfaces
 may attach task-specific tools with quick release mechanism
 good for physical labor
 myoelectric devices
 can only be used in an environment clean from dirt, dust, water, grease, or solvents
 mechanisms
 voluntary opening
 device is closed at rest and opens with contraction of proximal muscles
 more common than voluntary closing
 voluntary closing
 device is open at rest and residual forearm flexors grip the desired object
 heavier and less durable than voluntary opening
o wrist units
 quick disconnect wrist
 allows easy swapping of devices with specialized function
 locking wrist unit
 prevents rotation during grasping and lifting
 wrist flexion unit
 used in bilateral upper extremity amputees
 placed on longer residual limb to allow midline activities (shaving, buttoning)
o elbow units
 rigid elbow hinge
 indications
 short trans-radial amputation with inability to pronate or supinate with maintenance of
elbow flexion
 flexible elbow hinge
 indications
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OrthoBullets2017
Musculoskeletal biology | Material Science
wrist disarticulation or long transradial amputation with sufficient pronation,
supination, and elbow flexion and extension
o shoulder units
 due to increased energy expenditure and weight of prosthesis many choose to use a purely
cosmetic prosthesis
 indications
 forequarter or shoulder level amputation

Knee Prosthesis
 Knee prostheses provide controlled knee motion
 Indications
o transfemoral and knee disarticulation amputations
 Technique
o the prosthesis needs to be in line with the weightbearing axis of the patient's knee
o errors in technique
 slightly posterior knee center of rotation allows better control of stance phase with more
difficult flexion
 slightly anterior knee center of rotation flexion is easier with less control
 Socket
o the connection between the stump and the prosthesis
o protects the stump and transmits forces
o preparatory socket may need to be adjusted several time as edema resolves
o patellar tendon-bearing prosthesis is most common
 Suspension systems
o attaches prosthesis to residual limb using belts, wedges, straps, and suction
o suction suspension
 standard suction
 form-fitting rigid or semi-rigid socket which fits onto residual limb
 silicon suction
 silicon-based sock fits over the stump and is then inserted into the socket
 silicon provides an airtight seal between prosthesis and amputated stump
 Knee joint
o polycentric (four-bar linkage) knee
 indications
 transfemoral amputation
 knee disarticulations
 bilateral amputations
 techniques
 variable knee center of rotation
 controlled flexion
 ability to walk at a moderately fast pace
 supports increased weight compared to constant friction
‎I:24 Polycentric knee
knee
o stance-phase control (weight-activated) knee
 indications
 older patients with proximal amputations
 patients walking on uneven terrain
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
techniques
 acts like a constant-friction knee in swing phase
 weightbearing through the prosthesis locks up through the high-friction housing
o fluid-control (hydraulic and pneumatic) knee
 indications
 active patients willing to sacrifice a heavier prosthesis for more utility and variability
 techniques
 allows for variable cadence via a piston mechanism
 prevents excess flexion
 extends earlier in the gait cycle
o constant friction (single axis) knee
 indications
 general use
 patients walking on uneven terrain
 most common pediatric prosthesis
I‎:25 Constant friction knee
 not recommended for older or weaker patients
 technique
 hinge that uses a screw or rubber pad to apply friction to the knee to decrease knee swing
 only allows a single speed of walking
 relies on alignment for stance phase stability
o variable-friction (cadence control)
 technique
 multiple friction pads increase knee flexion resistance as the knee extends
 variable walking speeds are allowed
 not very durable
o manual locking knee
 technique
 constant friction knee hinge with an extension lock
 extension lock can be unlocked to allow knee to act like a constant-friction knee
 Pylon
o simple tube or shell that attaches the socket to the terminal device
o newer styles allow axial rotation and absorb, store, and release energy
o exoskeleton
 soft foam contoured to match other limb with hard outer shell
o endoskeleton
 internal metal frame with cosmetic soft covering
 Terminal device
o Most commonly a foot, but may take other forms

Foot Prosthesis
 Single axis foot
o ankle hinge allows dorsiflexion and plantar flexion
o disadvantages
 poor durability
 poor cosmesis
 SACH (solid ankle cushioned heel) foot
o indications
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‎I:26 SACH foot
OrthoBullets2017
Musculoskeletal biology | Material Science
general use in patients with low activity levels
use is being phased out
o disadvantages
 overloads the nonamputated foot
 Dynamic response (energy-storing) foot
o indications
 general use for most normal activities
 patients who regularly ambulate over uneven surfaces likely benefit from multi-axial
articulated protheses
o articulating and non-articulating dynamic-response foot prostheses are available
 articulating
 allows inversion, eversion, and rotation of the
‎I:27 Dynamic response foot
foot
 indications
 patients walking on uneven surfaces
 advantages
 allows inversion, eversion, and foot
rotation
 absorbs loads and decreases shear forces
 flexible keels
 acts as a spring to decrease
contralateral loading, allow dorsiflexion, and provide a spring-like push-off
 posterior projection from keel gives a smooth transition from heel-strike
 sagittal split allows for inversion and eversion
 non-articulating
 have short or long keels
 shorter keels are not as responsive and are indicated for moderate-activitiy patients
 longer keels are indicated for high-demand patients
 different feet for running and lower-demand activities available


Prosthetic Complications
 General issues
o choke syndrome
 caused by obstructed venous outflow due to a socket that is too snug
 acute phase
 red, indurated skin with orange-peel appearance
 chronic phase
 hemosiderin deposits and venous stasis ulcers
o skin problems
 contact dermatitis
 most commonly caused by liner, socks, and suspension mechanism
 treatment
 remove the offending item with symptomatic treatment
 cysts and excess sweating
 signs of excess shear forces and improperly fitted components
 scar
 massage and lubricate the scar for a well-healed incision
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By Dr, AbdulRahman AbdulNasser
Musculoskeletal biology | Material Science
o painful
residual limb
possible causes include heterotopic ossification, bony prominences, poorly fitting prostheses,
neuroma formation, and insufficient soft tissue coverage
 Transtibial prostheses
o swing-phase pistoning
 ineffective suspension system
o stance-phase pistoning
 poor socket fit
 stump volume changes (stump sock may need to be changed)
o foot alignment abnormalities
 inset foot
 varus strain, circumduction and pain
 outset foot
 valgus strain, broad-based gait and pain
 anterior foot placement
 stable increased knee extension with patellar pain
 posterior foot placement
 unstable increased knee flexion
 dorsiflexed foot
 increased patellar pressure
 plantar-flexed foot
 drop-off and increased patellar pressure
o pain or redness related to pressure
o prosthetic foot abnormalities
 heel is too soft
 leads to excessive knee extension
 heel is too hard
 leads to excessive knee flexion and lateral rotation of toes

Collected By : Dr AbdulRahman
AbdulNasser
drxabdulrahman@gmail.com
In June 2017
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OrthoBullets2017
Systemic Disease | Material Science
ORTHO BULLETS
II. Systemic Disease
- 100 -
By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease
A. Metabolic Bone Disease
1. Osteopenia & Osteoporosis
Introduction
 Definition (main characteristics common to both osteopenia and osteoporosis)
o age-related decrease in bone mass secondary to uncoupling of osteoclast-osteoblast activity
o disrupted microarchitecture
o WHO definition (see table below)
 Epidemiology
o incidence
 10 million Americans and 200 million people worldwide have osteoporosis
 34 million Americans have osteopenia
 1.5 million osteoporotic fractures occur each year
 700,000 are vertebral fractures
 300,000 are hip fractures
 200,000 are wrist fractures
o demographics
 male: female ratio is 1:4
 men have a higher prevalence of secondary osteoporosis (60%) including
 hypogonadism
 glucocorticoid excess
 alcoholism
 age bracket
 osteoporosis
 postmenopausal osteoporosis is highest in women aged 50-70 years
 senile osteoporosis begins after 70 years
 secondary osteoporosis begins at any age
 fractures
 wrist fractures occur most commonly at age 50-60 years
 vertebral fractures occur most commonly at age 60-70 years
 hip fractures occur most commonly at age 70-80 years
o location of fractures
 vertebral body > hip > wrist fractures
o risk factors : table of risk factors next page
 Pathophysiology
o quantitative, not qualitative, disorder of bone mineralization
o factors
 failure to build peak bone mass as a young adult
 bone loss in later life
 Associated conditions
o fragility fractures
 direct relationship between degree of bone loss and fractures
 kyphotic deformity can arise from verteberal body fractures
 pelvic ring insufficiency fractures most often treated with bed rest and analgesia
 total hip arthroplasty with constrained components are a risk factor for fragility fractures
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Systemic Disease | Metabolic Bone Disease
Table of risk factors

Prognosis
o prior fragility fracture is the strongest predictor of a future fracture from low energy trauma
o vertebral fractures
 associated with 15% increase in 5-year mortality
 associated with increased morbidity
 back pain
 loss of height
 poor balance
 respiratory compromise
 restrictive lung disease
 pneumonia
 history of 1 vertebral fracture results in 5 fold increased risk of 2nd vertebral fracture and 5
fold increased risk of hip fracture
 history of 2 vertebral fractures is the strongest indicated for further compression fractures in
postmenopausal women
o hip fractures
 associated with 20% increase in mortality
 men have higher mortality rates following hip fractures than women
 associated with increased morbidity
 reduced quality of life
 only one third of patients with hip fractures return to their previous level of function
 history of 1 hip fracture results in up to 10 fold increased risk of 2nd hip fracture
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease
o FRAX
score
 WHO fracture risk assessment tool that calculates the 10-year risk of hip fracture and 10-year
risk of major osteoporosis-related fracture
 factors include age, sex, personal history of fracture, low BMI, oral steroid use, secondary
osteoporosis, parental history of hip fracture, smoking status and alcohol intake.
Classification
Type I (Post menopausal)
Type II (Senile)
Age group
Post menopausal (highest incidence in 50-70 years
old)
>70 years old
Bone affected
Almost exclusively trabecular
Trabecular > cortical
Bones fractured
Distal radius and vertebral
Hip and pelvis
Net negative change in calcium levels because of
Effect on calcium decreased intestinal absorption and increased urinary
excretion of calcium.
Effect on Vit D
Poor calcium absorption
Reduced circulating levels of total (but not free) 1,25
dihydroxyvitamin D.
Labs
 25 hydroxyvitamin D level
o low 25 hydroxy cholecalciferol levels (25 hydroxy vit D) in patients sustaining low energy
fractures
Imaging
 Radiographs
o indications
 suspicion of fracture
 loss of height
 pain in thoracic or lumbar spine
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o recommended
views
lateral spine radiograph
 AP pelvis or hip
o findings
 thinned cortices
 loss of trabecular bone
 kyphosis
 codfish vertebra
o sensitivity and specificity
 usually not helpful unless > 30% bone loss
 Dexa Scan (Dual Energy Xray Absorptiometry)
o usually performed in
 lumbar spine: measures BMD from L2 to L4 and compiles scores
 hip: measure BMD from femoral neck, trochanter, and intertrochanter region and compiles
scores
o sensitivity and specificity
 most accurate with the least radiation exposure

The blue areas on the graph show the usual bone mass for
women of different ages. As illustrated, the bone mass is lower
among elderly women. A 70-year-old woman's bone mass is
indicated by a cross in the figure. It is estimated that 95 per cent
of the population belong within the blue areas. Those in the dark
blue area have a bone mass above average in relation to age,
while people belonging to the light blue area are below average
in relation to their age. The curve for men is similar but is higher
placed on the chart and shows a smaller decline with age. In
this example I believe we are looking at the graph for the Neck
region of the hip only. The dexa scan of her neck shows a BMD
is 0.543 as demonstrated by the cross on the graph. This gives
her a T score of -3.52 for the femoral neck. Based on the fact
that she falls in the blue, I believe her BMD is normal in the
neck. However, the diagnosis of osteoporosis is based on the
Central Dexa Scan, which includes the total hip which includes
the neck, troch, and intertroch region. Her total score is 0.664.
DEXA Scan: This graph plots Bone Mineral Density
(BMD), going up the left edge against age along the
bottom. The blue band across the graph shows the
range of normal BMD across the span of a lifetime. You
can see that bone density is highest between ages 20 to
45, then decreases. The little white square stands for the
patient's estimated BMD (1.036) at her current age (55).
The DEXA scanner puts the box at the lower end of the
normal blue zone for her age.
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease
DEXA Scan Report: The Z Score: This DEXA scan report says that this patient's lumbar spine density compared to women
her age is 0.7 standard deviations below average. The T-Score: This number compares this patient's bone density with a
twenty-year old female and shows that she is 1.4 standard deviations below mean. Impression: The patient is 2.6 times as
likely as other women her age to suffer a compression fracture of a vertebral body.
Term
Definition
BMD
absolute, patient-specific score determined from certain anatomic areas
T score
BMD relative to normal young matched controls (30-year-old women)
Z score
BMD relative to similar aged patients
Osteopenia
L2-4 lumbar density of 1 to 2.5 standard of deviations (T score -1 to -2.5) below
the peak bone mass of a 25 year old individual
Osteoporosis
L2-4 lumbar density > 2.5 standard of deviations (T score <-2.5) below the peak
bone mass of a 25 year old individual
Studies
 Biopsy
o after tetracycline labeling
o indications
 may be helpful to rule out osteomalacia
 Histology
o thinned trabeculae
o decreased osteon size
o enlarged haversian and marrow spaces
o osteoclast ruffled border
 Increases osteoclast ruffled border seen with
 PTH
 1,25 dihydroxy Vit D3
 Prostaglandin E
 flattened ruffled border seen with
 Bisphosphonates
 Calcitonin
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I‎ I:1 Slide demonstrating loss of interconnected trabecular
bone (stained with Masson's trichrome)
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Differential
Osteoporosis
Osteomalacia
Definition
Reduced bone mass, normal
mineralization
Bone mass variable, reduced mineralization
Age
Post menopausal (Type I)
or elderly (Type II)
Any age
Etiology
Vit D deficiency or abnormal vit D pathway,
Endocrine abnormality, age, idiopathic,
hypophosphatemia, hypophosphatasia, renal
inactivity, alcohol, calcium deficiency
tubular acidosis
Symptoms
and signs
Pain and tenderness at fracture site
Generalized bone pain and tenderness
Xray
Axial fracture predominance
Appendicular fracture predominance, symmetric,
includes pseudofractures (Looser zones)
Serum Ca
Normal
Low or normal
Serum PO4
Normal
Low or normal
ALP
Normal
Elevated (except hypophosphatasia)
Urinary Ca
High or normal
Normal or low (high in hypophosphatasia)
Bone biopsy Tetracycline labeling normal
Tetracycline labeling abnormal
Treatment
 Nonoperative
o lifestyle modification & vitamins
 indications
 calcium and Vitamin D
o pharmacologic treatment
 indications
 2008 National Osteoporosis Foundation Guidelines for Pharmacologic Treatment of
Osteoporosis suggests that pharmacologic treatment be considered for
 postmenopausal women and men >= 50yrs old with:
 hip/vertebral fracture
 T score between -1.0 and -2.5 at the femoral neck/spine and
 10-year risk of hip fracture ≥ 3% or
 10-year risk of major osteoporosis-related fracture ≥ 20% by FRAX calculation
 T score -2.5 or less at the femoral neck/spine.
 pharmacologic agents
 calcium and Vitamin D
 bisphosphonates
 Conjugated Estrogen-progestin hormone replacement (HRT)
 Estrogen-only replacement (ERT)
 Salmon calcitonin (Fortical or Miacalcin)
 Raloxifene (Evista)
 Teriparatide (Forteo)
 Operative
o osteoporotic vertebral compression fracture
o femoral neck fracture
o distal radius fracture
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease
Pharmacologic Agents
 Bisphosphonates
o 1st line therapy
o indications for pharmacologic treatment
 hip or vertebral fracture
 T-score <2.5 at the femoral neck or spine (after exclusion of secondary causes)
 low bone mass (T-score between -1.0 and -2.5) and
 10-year probability of a hip fracture ≥ 3% or greater or
 10-year probability of a major osteoporosis-related fracture ≥ 20% based on WHO
algorithm
o mechanism
 accumulate at sites of bone remodeling and are incorporated into bone matrix
 are released into acid environment once bone is resorbed, and are then taken up by
osteoclasts
 decrease osteoclastic bone resorption, flattening of osteoclast ruffled border and increased
osteoclast apoptosis
 renal excretion without undergoing metabolism
 exact mechanism depends on presence of nitrogen on alkyl chain (see table below)
o technique
 improved rates of treatment when coordinated by treating orthopedic surgeon and referral to
osteoporosis clinic is made
 DEXA scan and referral to endocrinologist
o outcomes
 alendronate reduces the rate of hip, spine and wrist fractures by 50%
 risedronate reduces vertebral and nonvertebral fractures by 40% (each) over 3 years
 IV zolendronic acid reduces the rate of spine fractures by 70% and hip fractures by 40% over
3 years
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Drug
Systemic Disease | Metabolic Bone Disease
Indications
Mechanism
Effects
Characteristics
Contraindications/
Adverse Effects
Calcium reduces
fracture risk by
34%.
daily calcium and
Vitamin D
requirements are as
follows:
 Age 1-3yrs 500mg/d
 Age 4-8yrs 800mg/d
 Age 9-18yrs - 1000
to 1500mg/d
High dose vitamin
 Age >50 yrs- 1200
D (median,
to 1500 mg/d calcium
800IU/d) reduces
 800-1,000 IUs Vit.
hip fractures by
D
24% and
nonvertebral
fractures by 30%.
Vit D
supplementation
reduces hip
fracture risk by
10% and
nonvertebral
fracture risk by
7%.
prophylactic in all
Calcium & Vit D patients, best for
Type II (senile)
Esophagitis,
dysphagia, gastric
ulcers, osteonecrosis
etidronate, clodronate,
of the jaw (ONJ),
tiludronate
atypical
subtrochanteric
fractures
T score <-2.5SD,
Non-nitrogen
fragility fracture of Produce toxic ATP
containing
the hip, in both men analog,
Bisphosphonates
and women
Alendronate
reduces vertebral
fractures by 48%
and nonvertebral
fractures by 47%.
Inhibit farnesyl
T score <-2.5SD,
pyrophosphate
Nitrogen
fragility fracture of
synthase
containing
the hip, in both men
(mevalonate
bisphosphonates
and women
pathway)
Risedronate
reduces vertebral
fractures by 65%
and nonvertebral
fractures by 39%.
Ibrandronate
reduces
vetebralfracture
risk by 77%, hip
fractures by 41%
and nonvertebral
fractures by 15%.
pamidronate,
Esophagitis,
alendronate
dysphagia, gastric
(Fosamax), risedronate
ulcers, ONJ, atypical
(Actonel),
subtrochanteric
zolendronate (Reclast),
fractures
ibandronate (Boniva)
Decreased the risk of
hip fracture, but it also
led to small increases
in a woman's risk
of breast cancer, CAD
and heart
attack, stroke, PE,
DVT, and Alzheimer's
disease
Conjugated
Estrogen-progestin in women with
hormone
Type I (within 6
replacement
years of menopause)
(HRT)
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By Dr, AbdulRahman AbdulNasser
Drug
Indications
Systemic Disease | Metabolic Bone Disease
Mechanism
Effects
indicated for women
Estrogen-only
with prior
replacement (ERT) hysterectomy
Men with low levels
of testosterone
Women >5y
postmenopause,
Binds membrane
Salmon calcitonin decreases pain in
receptors on
(Fortical or
acute vertebral
osteoclasts to
Miacalcin)
compression
inhibit resorption
fractures (acts as
neurotransmitter)
Testosterone
Women
Agonist on estrogen
receptors in bone
(reduce osteoclast
resorption).
Antagonizes
estrogen receptor in
breast, reducing
breast cancer risk.
Teriparatide
(Forteo)
Severe
osteoporosis/high
fracture risk
Receptors on
osteoblasts
(activates
osteoblasts) and
renal tubule cells,
also stimulates
intestinal absorption
Ca and PO4
Denosumab
(Prolia)
Monoclonal Ig2
against RANKL
Postmenopausal
(inhibits binding of
women at high risk
RANKL to RANK,
of fracture
like
osteoprotegerin)
Raloxifene
(Evista)
Reduced vertebral
fractures by 68%,
hip fractures by
40%, nonvertebral
fractures by 20%.
Contraindications/
Adverse Effects
Taking unconjugated
estrogen
Estrogen receptors are
(alone) increases the
present on osteoblasts
risk of endometrial
and osteoclasts
hyperplasia / uterine
cancer)
Not yet approved by
FDA for osteoporosis
Characteristics
Injection or nasal
spray (destroyed by
gastric acid)
Intranasal - Transient
rhinitis. Injectable nausea, vomiting,
flushing,
hypersensitivity
reactions
Selective estrogen
receptor modulator
(SERM), slows bone
resorption and mild
increase in bone
thickness. Reduces
risk of vertebral
fractures only (not
non-vertebral
fractures).
Hot flashes, leg
cramps.
Contraindicated in
patients with VTE
Transient
1-34 amino terminal hypercalcemia,
residues of parathyroid dizziness, nausea,
hormone (1-84) ; given headache.
by daily subcutaneous
injections (continuous Contraindicated in
infusion leads to bone Paget's disease due to
resorption)
potential
osteosarcoma risk
Arthralgia,
nasopharyngitis,
SC injection to arm, back pain.
thigh, abdomen
Contraindicated in
severe hypocalcemia
Complications
 Osteonecrosis of the jaw (ONJ) is associated with IV bisphosphonates (but not oral bisphosphonates)
o incidence : rare
o treatment : stop bisphosphonates
 Atypical subtrochanteric transverse stress fractures (in patients on long-term bisphosphonates)
o incidence : rare
o mechanism
 extremely low bone turnover rates
 shown by reduced markers of bone resorption (e.g. urinary collagen type 1 cross-linked Ntelopeptide, NTx)
o treatment : operative fixation with intramedullary nail and stop bisphosphonates
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2. Renal Osteodystrophy
Introduction
 Definition
o a spectrum of disease seen in patients with chronic renal disease.
o characterized by bone mineralization deficiency due to electrolyte and endocrine abnormalities
o common cause of hypocalcemia
 Pathophysiology
o hypocalcemia
 due to the inability of the damaged kidney to convert vitamin D3 to calcitrol (the active form)
 because of phosphate retention (hyperphosphatemia)
o hyperparathyroidism and secondary hyperphosphatemia
 caused by hypocalcemia and lack of phosphate excretion by damaged kidney
o uremia related phosphate retention
 is a key pathological step
 Associated conditions
o orthopaedic manifestations
 osteomalacia (adults) and growth retardation (children)
 AVN
 tendinitis and tendon rupture
 carpal tunnel syndrome
 deposition of amyloid (β2 microglobulin)
 pathologic fracture
 from brown tumors (hyperparathyroidism) or amyloid deposits
I‎I:2 Pathologic fracture
 osteomyelitis and septic arthritis
Classification
 High-turnover renal bone disease (high PTH disease)
o chronically elevated phosphate leads to secondary hyperparathyroidism
 hyperphosphatemia lowers serum Ca, stimulating PTH
 phosphorus impairs renal 1α-hydroxylase, reducing 1,25(OH)2 vitamin D3 production
 phosphorus retention directly stimultes PTH production
 hyperplasia of chief cells of parathyroid gland
o associated lab values
 decreased calcium, increased serum phosphate, increased alkaline phosphate, increased
parathyroid hormone
 Low turnover renal bone disease (normal PTH disease)
o characterized by lack of secondary hyperparathyroidism
o normal levels of PTH with characteristic bone lesions marked by low levels of bone formation
o excess deposition of aluminium into bone affects bone mineralization
 impairs differentiation of precursors into osteoblasts, and osteoblast proliferation
 impairs PTH release from parathyroid gland
 disrupts mineralization
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease
Presentation
 Symptom
o weakness
o bone pain
o pathological fracture
 commonest complication
o skeletal deformity
o symptoms of hypocalcemia
 abdominal pain
 muscle cramps
 dyspnea
 convulsions/seizures
 mental status changes
 Physical exam
o provocative tests for tetany
 Trousseau's Sign
 carpalpedal spasm after blood pressure readings
 Chvostek's Sign
 facial muscle contractions after tapping on the facial nerve
Imaging
 Radiographs
o findings
 Looser's zones
 brown tumor
 osteosclerosis
 from mineralization of osteomalacic bone
 rugger jersey spine
 widened growth plate and zone of provisional calcification (children)
 varus deformity of the femurs (children)
 fracture
 soft-tissue calcification
 osteopenia
 CT
o osseous resorption
Looser zone in the femoral
neck of an adult
Looser zone in the distal
fibula of a child
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brown tumor
OrthoBullets2017
Osteosclerosis & varus
deformity
Tumoral calcinosis
Systemic Disease | Metabolic Bone Disease
rugger jersey spine
CT showing osseous resorption
Patella tendon calcification
soft-tissue calcification
Evaluation
 Histology
o thinned trabeculae
o amyloid stains pink on Congo red stain
 Labs
o decreased serum calcium
o increased serum phos
o increased PTH
Treatment
 Nonoperative
o treat underlying renal condition or relieve urologic obstruction
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Chondrocalcinosis
By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease
3. Rickets
Introduction
 A defect in mineralization of osteoid matrix caused by inadequate calcium and phosphate
o prior to closure of physis known as rickets
o after physeal closure called osteomalacia
 Pathophysiology
o disruption of calcium/phosphate homeostasis
o poor calcification of cartilage matrix of growing long bones
o occurs at zone of provisional calcification
o leads to increased physeal width and cortical thinning and bowing
o Vitamin D and PTH play an important role in calcium homeostasis
 Associated conditions
o orthopaedic manifestations include
 brittle bones with physeal cupping/widening
 bowing of long bones
 ligamentous laxity
 flattening of skull
 enlargement of costal cartilage (rachitic rosary)
 kyphosis (cat back)
Classification
 Types include
o familial hypophosphatemic (vitamin D-resistant) (see below)
o vitamin D-deficient (Nutritional)
o vitamin D-dependent (type I & type II)
o renal osteodystrophy
o hypophosphatasia
Imaging
 Radiographs
o recommended views
 AP and lateral of affected bone
o findings
 physeal widening
 metaphyseal cupping
 Looser's zones (pseudofracture on the compression side of bone)
 decreased bone density
 prominence of rib heads at the osteochondral junction (rachitic rosary)
 bowing (often genu varum)
Studies
 Laboratory studies
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
Systemic Disease | Metabolic Bone Disease
Histology
o zone of proliferation is disordered and elongated in growthplate
o widened osteoid seams
o swiss cheese trabeculae
o poorly defined zone of provisional calcification
Familial Hypophosphatemic Rickets (Vitamin D resistant Rickets)
 Also known as
o Vitamin D resistant Rickets
o X-linked hypophosphatemic
 Most common form of heritable rickets
o caused by inability of renal tubules to absorb phosphate
o GFR is normal
o impaired vitamin D3 response
 Genetics
o X-linked dominant
 Presentation
o tibial bowing as result of widened proximal tibia physis
 Labs
o low serum phosphorous
o elevated alkaline phosphatase
o serum calcium is usually normal or low normal
 Treatment
o medical treatment
 Calcitriol
 indications : is standard therapy
‎II:3 tibial bowing
 phosphate replacement
 indications
 controversial and counter-intuitive
 physiology would suggest that phosphate replacement would be beneficial and
treatment of 1-3 grams phosphate daily was recommended
 recent research evaluated the addition of phosphate to the standard vitamin D therapy
and found no additional benefit with phosphate therapy
o surgical treatment
 corrective surgery
 indications
 to correct tibial bowing in severe deformity
Vitamin D-Deficiency Rickets (Nutritional)
 Nutritional rickets is associated with decreased dietary intake of Vitamin D
o rare now that Vitamin D is added to milk
o still seen in
 premature infants
 black children >6 months who are still breastfed
 patients with malabsorption syndromes (celiac sprue) or chronic parenteral nutrition
 Asian immigrants
 patients with unusual dietary choices
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease

Physiology
o low Vitamin D levels lead to decreased intestinal absorption of calcium
o low calcium levels leads to a compensatory increase in PTH and bone resorption
o bone resorption leads to increased alkaline phosphatase levels
 Clinical findings
o rachitic rosary (enlargement of costochondral junction)
o bowing of knees
o codfish vertebrae
o retarded bone growth (widened osteoid seams, physeal cupping)
o muscle hypotonia
o dental disease
o pathologic fractures
o waddling gate
 Laboratory values
o low to normal serum calcium
o low serum phosphate
o elevated alkaline phosphatase
o elevated parathyroid hormone
o low vitamin D
 Treatment
o Vitamin D (5000 IU daily)
 indications
 resolves most deformities
‎II:4 Codfish vertebrae
Hereditary Vitamin D-Dependent Rickets (Type I and II)

Rare disorder
 Clinical features similar to Vitamin D-Deficient Rickets but more severe
 Clinical characteristics
o Type I
 joint pain/deformity, hypotonia, muscle weakness, growth failure, and hypocalcemic seizures
or fractures in early infancy
o Type II
 bone pain, muscle weakness, hypotonia, hypocalcemic convulsions, growth retardation,
severe dental caries or teeth hypoplasia
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
Pathophysiology
o Type I
 caused by defect in renal 25-(OH)-vitamin D1 alpha-hydroxylase
 prevents conversion of inactive form of vitamin D to active form
 responsible gene 12q14
o Type II
 caused by a defect in intracellular receptor for 1,25-(OH)2-vitamin D
 Genetics
o type II
 autosomal recessive
 Laboratory values
o type II is distinguished from type I by markedly elevated levels of 1,25-(OH)2-Vitamin D
 Treatment
o physiologic doses (1-2 micrograms/day) of 1,25-(OH)2-Vit D
 indications
 type I
o daily high dose Vitamin D + elemental calcium
 indications
 type II
4. Osteomalacia
Introduction
 A metabolic bone disease where defective mineralization results in a large amount or unmineralized
osteoid
o qualitative defect as opposed to a quanitative defect like osteoporosis
o rickets and osteomalacia are manifestations of the same pathologic process
 Epidemiology
o incidence
 rare in the US (approximately 1 in 1000)
 much less common than osteoporosis
 because of adequate exposure to sunlight and dairy products fortified with vitamin D
o demographics
 rickets is found in children (open physis)
 osteomalacia is found in adults (closed physis)
o risk factors
 the following conditions predispose a patient to osteomalacia
 vitamin-D deficient diets
 malabsorption e.g. celiac disease
 renal osteodystrophy
 hypophosphatemia
 chronic alcoholism
 tumors (tumor-induced osteomalacia)
 drugs
 drugs associated with vitamin D deficiency
 phenytoin
 phenobarbital
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease
rifampin
cholestyramine
 cadmium
 glucocorticoids
 drugs affecting phosphate homeostasis
 aluminium-containing phosphate-binding antacid
 ifosfamide
 drugs affecting bone mineralization
 aluminium
 etidronate
 fluoride


Presentation
 Symptoms
o generalized bone and muscle pain
o fractures of long bones, ribs and vertebrae
o proximal muscle weakness weakness
o fatigue
 Physical exam
o inspection
 waddling gait
 from hip pain and thigh weakness
 difficulty rising from chair and climbing stairs
‎II:5 Looser's zones
‎II:6 Protrusio acetabuli
Imaging
 Radiographs
o findings
 Looser's zones (insufficiency fractures)
 medial femoral cortex
 pubic ramus
 scapula
 fractures (especially in the proximal femur/femoral neck)
 biconcave vertebral bodies
 trefoil pelvis
 protrusio acetabuli
 Bone scan
o findings
 increased activity
o Studies
 Labs
Osteomalacia
Osteoporosis
Tumor induced
osteomalacia
Osteopetrosis
‎II:7 Proximal femoral neck
fracture associated with
osteomalacia
low
normal
1,25-(OH)
vit D
low
normal
Urinary
Ca
low
normal
low
low
low
low
normal
normal
normal
normal
Serum Ca
Serum P
Alk phos
PTH
25-(OH)vit D
low
normal
low
normal
high
variable
high
normal
low
very low
low
normal
normal
high
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
Histology
o requires transiliac biopsy for definitive diagnosis
o Histology
 Characteristic histology includes
o technique
 requires transiliac biopsy for definitive diagnosis
o findings
 widely separated osteoid seams
 greater amounts of unmineralized osteoid than normal
o Treatment
 Nonoperative
o large doses of oral vitamin D (1000IU/day), treat underlying cause
 indications
 most patients
o technique
 specific subgroups of patients
 on long-term anticonvulsant therapy
 supplement with 400-800IU/day of vitamin D
 with hepatobiliary disease
 supplement with 25(OH)-vit D
 with renal disease
 supplement with 1,25(OH)2 vit D
5. Oncogenic Osteomalacia
Introduction
 Definition
o paraneoplastic syndrome of renal phosphate wasting
o caused by bone tumor or soft tissue tumor
 Epidemiology
o demographics
 age bracket
 age of onset is late childhood to early adulthood
 Pathophysiology
o the tumor secretes a humoral factor ("phosphatonin") that affects the proximal renal tubules
o reduces calcitriol production in the kidney and inhibits phosphate transport
o leads to increased renal phosphate excretion, hypophosphatemia and osteomalacia
o types of tumors that cause oncologic osteomalacia (known as phosphaturic mesenchymal tumor)
 benign tumors (more common)
 phosphaturic mesenchymal tumors (mixed connective tissue variant) e.g.
hemangiopericytoma (commonest cause)
 osteoblastoma-like tumors
 ossifying fibrous tumors
 nonossifying fibrous tumors
 malignant causes (rare)
 osteosarcoma
 fibrosarcoma
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Bone Disease

Genetics
o mutations
 phosphatonin gene is FGF23
 Associated conditions
o orthopaedic manifestations
 pathological fractures of long bones and vertebrae
Presentation
 Symptoms
o generalized bone and muscle pain
o fractures of long bones, ribs and vertebrae
o proximal muscle weakness
o fatigue
‎II:8 Bilateral superior and inferior pubic ramus
Looser's zones (also note right transcervical fracture
and diffuse osteopenia)
Imaging
 Radiographs
o findings
 diffuse osteopenia
 Looser's zones (pseudofractures)
 Octrotide scans (radiolabeled somatostatin analog)
o gallium-68 DOTA-octreotate PET scan
o indium-111 pentetreotide SPECT/CT
o indications
 to identify primary tumors when TIO is suspected
 will only identify tumors expressing somatostatin receptors
Studies
Serum Ca Serum P
Alk phos
PTH
25-(OH)vit
D
1,25(OH)vit D
Urinary
Ca
Osteomalacia
low
low
high
high
low
low
low
Osteoporosis
normal
normal
variable
normal
normal
normal
normal
Tumor induced
osteomalacia
low
very low
low
low
low
low
low
Osteopetrosis
normal
normal
high
normal
normal
normal
normal
Treatment
 Nonoperative
o phosphate supplementation with 1,25-dihydroxyvitamin D
 Operative
o tumor removal
 outcomes
 resolution of hypophosphatemia and low vitamin D levels within hours of resection
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B. Joint Diseases
1. Gout
Introduction
 A monosodium urate crystal deposition disorder
o primary gout
 an idiopathic disorder of nucleic acid metabolism that leads to hyperuricemia and deposition
of monosodium urate crystals in joints (a purine breakdown product)
o secondary gout
 is associated with a disease with high metabolic turnover (psoriasis, hemolytic anemia,
leukemia, chemotherapy)
 Epidemiology
o demographics
 recurrent attacks seen in men from ages 40-60 years
o location
 usually seen in lower limb
 podagra (arthritis attacks of great toe)
 crystal deposition as tophi
 ear helix, eyelid olecranon, Achilles tendon
o risk factors
 chemotherapy
 Pathophysiology
o dysfunctional nucleic acid metabolism causing hyperuricemia
o deposition of monosodium urate crystals in synovium of joint
o crystals lead to an inflammatory response activating
 proteases
 prostaglandins
 leukotriene B4
 free oxygen radicals
 Associated conditions
o renal stones
o septic arthritis
 the presence of uric acid crystals does not exclude septic arthritis
Presentation
 Symptoms
o pain in joint
o can resemble septic arthritis
o symptoms of renal stones
 Physical exam
o may have decreased range of motion due to pain
o white toothpaste-like appearance of tophus aspirate
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Joint Diseases
Imaging
 Radiographs
o recommended views
 AP and lateral of affected joint
o findings
 may see punched out periarticular erosion with sclerotic overhanging borders
 may see soft tissue crystal deposition (tophi)
Studies
 Labs
o serum uric acid
 elevated uric acid is not diagnostic (80% of people with an elevated uric acid will never have
a gout attack)
 Crystal analysis
o diagnosis made by joint aspiration and crystal analysis
o monosodium urate (MSU) crystals are
 thin, tapered, needle-shaped intracellular crystals
 yellow when aligned parallel to red compensator
 blue when aligned across the direction of polarization
 strongly negatively birefringent
Treatment
 Acute gout
o indomethacin vs. colchicine
 indications
 first line of treatment
 medications
 indomethacin (indocin) 50mg tid
 NSAID
 inhibits phagocytosis
 colchicine
 indicated in acute attacks if patient has a history of peptic ulcers
 inhibits inflammatory mediators
 can be given intravenously
o oral, intraarticular or IV glucocorticoid
 indication
 patient unable to take NSAID or colchicine
 Chronic gout
o allopurinol
 indications
 first line of treatment for chronic gout attack
 medications
 allopurinol is an xanthine oxidase inhibitor
o colchicine
 indications
 for prophylaxis after recurrent attacks
 up to 85% effective
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2. Pseudogout (CPPD)
Introduction
 A metabolic disease resulting in deposition of calcium pyrophosphate dihydrate (CPPD) crystals
within the joint space
o characterized by recurrent monoarticular arthritis
 Epidemiology
o commonly affects the elderly
o rarely affects younger patients, unless occurring in conjunction with other disease
 Associated conditions
o hemochromatosis
o hyperparathyroidism
o SLE
o gout
o RA
o Wilson's disease
o hemophilia
o long term hemodialysis can cause a pyrophosphate like deposition disorder
o chondrocalcinosis is present in 7% of patients
 Mimics gout except
o affects older patients > 60 years old
o affects more proximal joints
o positively-birefringent crystal
Presentation
 Symptoms
o acute, onset joint tenderness
o warm, erythematous joint
o commonly on knee and wrist joints
 Physical exam
o erythematous, monoarticular arthritis
o joints tender to palpation
o may observe superficial mineral deposits under the skin at affected joints
Imaging
 Radiographs
o may see calcification of fibrocartilage structures
(chondrocalcinosis)
 TFCC in wrist
 meniscus in the knee
Evaluation
 Joint aspiration crystal analysis
o weakly positively birefringent rhomboid-shaped crystals
Treatment
 Acute pseudogout
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Systemic Disease | Joint Diseases
o nonoperative
NSAIDS
 splint
 intra-articular steroids
 splints for comfort
 Chronic pseudogout
o nonoperative
 intraarticular yttrium-90 injections
 colchicine ( 0.6 mg PO bid for recurrent cases)
 prophylactic colchine can help to prevent recurrence

Complications
 Can result in permanent damage to the joints and renal disease
3. Hemochromatosis
Introduction
 A chronic and often silent disorder that results from inappropriate levels of iron in the blood and
tissue
 Epidemiology
o prevalence
 1 in 200 people of northern European extraction
o demographics
 usually presents in 4th-5th decade of life
 women usually present later than men due to the protective effect of iron loss during menses
and pregnancy
o location
 multi-system disease
 hypogonadism
 diabetes
 liver cirrhosis
 cardiomyopathy
 arthritis
 may be unilateral or bilateral
 may affect one or multiple joints
 Pathophysiology
o increased dietary iron absorption and/or increased iron release from cell
o leading to inappropriate levels of iron into organs and tissues
 Genetics
o inheritance
 autosomal recessive
o mutations
 C282Y allele is most common
 Prognosis
o produces arthritis and chondrocalcinosis in > 50% of patients
o treatment returns life expectancy to normal if patient non cirrhotic and no diabetic
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Presentation
 Symptoms
o classically presents with non-specific symptoms
 fatigue
 lethargy
 joint or muscle pain
o may present with systemic symptoms
 impotence
 diabetes
 skin hyperpigmentation
 Examination
o arthropathy
 most often in PIPJ, MCPJ of index and middle finger
 larger joints may also be affected
 highly suspicious with bilateral ankle OA
Imaging
 Radiographs
o may identify arthritis of the joints
o chonrocalcinosis presents in >50% of patients
Studies
 Labs
o serum ferritin levels
o serum iron levels (>30 µmol/L)
o total iron-binding capacity
o TSH
o lipid profile
 Liver Biopsy (gold standard)
o hemosiderin in parenchymal cells
Treatment
 Nonoperative
o decrease iron intake
 indications
 standard of treatment to reduce iron overload
 methods
 reduced consumption of red meat
 avoid raw shellfish
 limit supplemental vitamin C
 avoid excessive alcohol (secondary liver damage)
o phlebotomy regime
 indications
 weekly blood letting sessions to reduce serum ferritin levels
 contraindications
 severe anemia
 congestive heart failure
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
Systemic Disease | Joint Diseases
Operative
o total joint arthroplasty
 indications
 large joint involvement
Orthopaedic Manifestations
 Bilateral ankle arthritis
o hemochromatosis should be suspected when symmetrical ankle arthropathy occurs in young men
4. Neuropathic (Charcot) Joint of Shoulder & Elbow
Introduction
 Chronic and progressive joint disease following loss of protective sensation
o leads to destruction of joints and surrounding bony structures
 Epidemiology
o incidence
 rare condition in the upper extremity
o location of neuropathic joints
 shoulder & elbow (this topic)
 foot & ankle (see diabetic Charcot foot)
 Pathophysiology
o neurotrauma
 loss of peripheral sensation and proprioception leads to repetitive microtrauma to the joint
 poor fine motor control generates unnatural pressure on certain joints leading to additional
microtrauma
o neurovascular
 neuropathic patients have dysregulated reflexes and desensitized joints that receive
significantly greater blood flow
 the resulting hyperemia leads to increased osteoclastic resorption of bone
 Genetics
o molecular biology
 RANK/RANKL/OPG triad pathway is thought to be involved
 Associated conditions
o shoulder
 syringomyelia
 most common etiology of neuropathic arthropathy of the upper extremity
 25% of Charcot joints are a result of syringomyelia
 monoarticular (shoulder > elbow)
 Hansen's disease (leprosy)
 second most common cause of upper extremity neuropathic arthropathy
 syphilis
 usually affects the knee
 can be polyarticular
 diabetes
 most common cause of foot and ankle neuropathic joints
 Arnold-Chiari malformation
 cervical spondylosis
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adhesive arachnoiditis and TB arachnoiditis
posttraumatic syringomyelia
 alcoholism
o elbow
 syringomyelia
 syphilis
 congenital insensitivity to pain
 diabetes
 Charcot-Marie-Tooth


Classification
Eichenholtz Classification
Stage 0
• Joint edema
• Radiographs are negative
• Bone scan may be positive in all stages
Stage 1
• Joint edema
• Radiographs show osseous fragmentation with joint dislocation
Stage 2
• Decreased local edema
• Radiographs show coalescence of fragments and absorption of fine bone debris
Stage 3
• No local edema
• Radiographs show consolidation and remodeling of fracture fragments
Stage 0 - hot foot, normal
x-rays; MR shows bone
edema and fractures
Stage 1 - fragmentation,
bone resorption,
dislocations, fractures
Stage 2 - coalescence,
sclerosis, fracture healing,
debris resorption
Presentation
 Symptoms
o swollen shoulder or elbow
o 50% have pain, 50% are painless
o loss of function
 Physical exam
o inspection
 swollen, warm, erythematous joint
 mimics infection
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Stage 3 - Remodelling
By Dr, AbdulRahman AbdulNasser
Systemic Disease | Joint Diseases
o motion
joint may be mechanically unstable
 loss of active motion, but passive motion is maintained
o neurovascular
 a neurologic evaluation is essential

Imaging
 Radiographs
o recommended views
 standard views of affected joint
 AP and scapula Y of the shoulder
 AP and lateral of the elbow
‎II:9 Neuropathic shoulder joint due to
syringomyelia. Characteristic radiographic
o findings
findings include obliteration of joint space,
 early changes
fragmentation of both articular surfaces of a
joint leading to subluxation or dislocation.
 degenerative changes may mimic osteoarthritis
and surrounding soft tissue edema.
 late changes
 obliteration of joint space
 fragmentation of both articular surfaces of a joint leading
to subluxation or dislocation
 scattered "chunks" of bone in fibrous tissue
 joint distention by fluid
 surrounding soft tissue edema
 heterotopic ossification
 fracture
 MRI
o indications
 MRI of cervical spine to rule out syrinx when neuropathic
shoulder arthropathy is present
‎II:10 A sagittal MRI of the
cervical spine reveals a syrinx
 Bone scan
or fluid-filled cavity within
o technetium bone scan
the spinal cord.
 findings
 may be positive (hot) for neuropathic joints and osteomyelitis
o indium WBC scan
 findings
 will be negative (cold) for neuropathic joints and positive (hot) for osteomyelitis
 useful to differentiate from osteomyelitis
Shoulder with Charcot arthropathy
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Elbow with Charcot arthropathy
Studies
 Labs
o ESR and WBC can be elevated making it difficult to differentiate from osteomyelitis
 Histology
o synovial hypertrophy
o detritic synovitis (cartilage and bone distributed in synovium)
Differential
 Osteomyelitis/septic joint
o difficult to distinguish from osteomyelitis based on radiographs and physical exam
 common findings in both conditions
 swelling, warmth
 elevated WBC and ESR
 technetium bone scan is "hot"
 unique to Charcot joint disease
 indium leukocyte scan will be "cold" (negative)
 will be "hot" (positive) for osteomyelitis
Treatment
 Nonoperative
o rest, elevation, protected immobilization with a sling, and restriction of activity
 indications : neuropathic shoulder joint
o functional bracing
 indications : neuropathic elbow joint
 technique : should allow flexion-extension, but neutralizes varus-valgus stresses
 Operative
o arthrodesis
 do not attempt during acute inflammatory stage (Eichenholtz 0-2) because of continued bone
erosion
 only perform during quiescent stage (Eichenholtz 3)
 requires long periods of immobilization
o total joint replacement
 indications
 Charcot joint is a contraindication to total joint replacement
 due to poor bone stock, prosthetic loosening, instability, and soft-tissue compromise
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Systemic Disease | Joint Diseases
5. Ochronosis
Introduction
 Degenerative arthritis that results from alkaptonuria
 Pathophysiology
o excess homogentistic acid is deposited in the joints
o acid polymerizes in joint and leads to early joint arthritis
 Genetics
o rare inborn defect in homogentisic acid oxidase enzyme system
 Associated conditions
o orthopaedic manifestations
 ochronotic spondylitis
 commonly occurs in fourth decade
 progressive degenerative changes in spine
 calcification
 narrowing of disc spaces
Presentation
 Symptoms
o may complain of black urine
 caused by polymerization of homogentistic acid
Imaging
 Radiographs
o spine
 findings
 irregular calcification
 narrowing of intervertebral discs
Treatment
 Nonoperative
o no current medical treatment available
6. Reiter's
Introduction
 A seronegative spondyloarthropathy characterized by:
o urethritis
o conjunctivitis or uveitis
o arthritis
 Epidemiology
o incidence
 rare
o demographics
 occurs most commonly in young man (<40 years of age)
 rarely occurs in children, but sometimes appears in adolescents
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o location
arthritis
 may be unilateral or bilateral
 may affect one or multiple joints
 Pathophysiology
o associated infections
 mycoplasma
 yersinia
 salmonella
 shigella
 chlamydia
 campylobacter
 Genetics
o may be genetic component making certain individuals more susceptible
 Prognosis
o most cases resolve within weeks, but can last up to months
o recurrence occurs in up to half of cases over period of several years

Presentation
 Symptoms
o urinary discomfort or pain
 usually appears within days or weeks of infection
o inflammation or dryness of the eye
o joint pain
 may develop within weeks of initial infection and urinary symptoms
o other non-specific pain symptoms including
 heel pain (Achilles tendon pain)
 low back pain
 Physical exam
o nongonococcal urethritis
o conjunctivitis or uveitis
o arthritis
o skin lesions on palms/soles
 may resemble psoriasis
 genital skin lesions
o low-grade fever
Imaging
 Radiographs : may identify arthritis of the joints
Studies
 Diagnosis is based primarily on symptoms and presentation
 Labs
o HLA-B27 positive in 75% of cases
o CRP elevated
o ESR elevated
 Urinalysis : may identify signs of active infection
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Joint Diseases
Treatment
 Nonoperative
o antibiotics, symptomatic treatment, observation
 indications : standard of treatment in most cases
 medications
 direct antibiotics at underlying infection
 azithromycin and doxycycline indicated for Chlamydia
 NSAIDs for pain and inflammation
o systemic steroids
 indications : severe or recalcitrant cases
Complications
 Aortic insufficiency
 Arrhythmia
7. Psoriatic Arthritis
Introduction
 A seronegative spondyloarthropathy that presents with the following orthopaedic manifestations
o 5 patterns of arthritis
 asymmetric oligo/monoarticular arthritis affecting DIPJ, PIPJ, MCPJ
 DIP-predominant arthritis
 arthritis mutilans
 symmetric, RF-negative polyarthritis
 psoriatic spondyloarthropathy
 Epidemiology
o incidence : affect up to 5-20% of patients with psoriasis
o demographics : equally affects men and women
 Genetics
o HLAB27 found in 50%
Presentation
 Symptoms
o arthritic symptoms in hands
 Physical exam
o rash with silvery plaques over extensor surfaces (elbows, knees)
 typically precede joint involvement by several years (80-85% of time)
o hands
 dactylitis (sausage digit)
 onychodystrophy (nail pitting)
 onycholysis (lifting of nail plate starting distally)
 arthritis mutilans
 opera glass hands (la main en lorgnette)
 excess skin from the shortening of the phalanx bones becomes folded transversely, as
if retracted into one another like opera glasses
o chronic uveitis
o entheses such as achilles tendonitis, posterior tibial tendonitis, and plantar fasciitis
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‎II:11
Rash with silvery plaques
Systemic Disease | Joint Diseases
‎II:12 Sausage digit
‎II:13 Nail pitting
Imaging
 Radiographs
o hands
 distal phalanx acrolysis
 DIP arthritis
 classic finding is "pencil-in-cup" deformity
 simultaneous destruction of the head of the middle
phalanx and expansion of the base of the distal
phalanx
 different than DJD by presence of centripetal erosions
which cause joint space widening)
 small joint erosions or fusions (PIP, MCP, and wrist
commonly involved)
 fluffy periostitis (caused by periosteal ossification)
 acroosteolysis (resorption of the distal phalanx tuft)
 flail digits
o spine in axial disease
 sacroiliitis
 syndesmophytes
 paravertebral ossification
 destructive discovertebral lesions
DIP joint erosion and acrolysis in a patient with psoriatic arthritis
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pencil-in-cup deformity
By Dr, AbdulRahman AbdulNasser
Systemic Disease | Joint Diseases
Studies
 HLAB27 found in 50%
 RA and ANA tests are usually negative
Treatment
 Nonoperative
o NSAIDS, methotrexate, sulfasalazine, cyclosporine,TNF-alpha inhibitors
 indications : mainstay of treatment , similar to RA
 Operative
o digit fusion vs resection arthroplasty
 indications : advanced joint diseas
8. Hemophilic Arthropathy
Introduction
 A condition characterized by repetitive hemarthroses and ultimately joint deformation in patients
with bleeding disorders
 Epidemiology
o incidence
 has decreased significantly due to home factor treatment
o demographics
 young males
 affects patients between 3-15 years old
o location
 knee is most commonly affected
 elbow, ankle, shoulder and spine are also involved
 Pathophysiology
o mechanism of injury
 persistent minor trauma
o root bleeding disorder may be
 hemophilia A
 X-linked recessive
 decrease factor VIII
 hemophilia B - Christmas disease
 X-linked recessive
 decreased factor IX
 von Willebrand's disease
 rare cause of joint bleeds
 more commonly mucosal bleeding
 autosomal dominant
 abnormal factor VIII with platelet dysfunction
o pathoanatomy
 synovitis -> cartilage destruction (enzyme based) -> joint deformity
 Associated conditions
o orthopaedic manifestations
 hemarthrosis
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intramuscular hematoma (pseudotumor)
 may lead to nerve compression
 femoral nerve palsy may be caused by iliacus hematomas
 leg length discrepancy
 due to epiphyseal overgrowth
 fractures
 due to generalized osteopenia
 normal healing chronology
o medical conditions and comorbidities
 HIV
 prevalence up to 90% in hemophiliacs
 Prognosis
o prognostic variables
 degree of factor deficiency
 determines severity of disease
 mild: 5-25%
 moderate: 1-5%
 severe: 0-1%
 presence of factor VIII inhibitors (including IgG antibodies)
 IgG antibody inhibits response of therapeutic factor treatment (monocolonal recombinant
factor VIII)
 found in 5-25% of hemophiliac patients
 is a relative contraindication for surgical interventions
 should be screened for preoperatively

Classification
Arnold-Hilgartner Staging
Stage 1
• Shows swelling of the soft tissues
Stage 2
• Shows osteoporotic changes
Stage 3
• Shows development of subchondral cysts
• Joint is grossly intact
Stage 4
• Shows cartilage loss with narrowing of the joint
Stage 5
• Demonstrates severe arthritis of affected joint
Stage 1
Stage 2
Stage 4
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Stage 5
By Dr, AbdulRahman AbdulNasser
Systemic Disease | Joint Diseases
Presentation
 Symptoms
o painful range of motion of joints
o hemarthrosis
 the knee is most commonly affected
 acute
 presentation will show a painful and tense joint effusion
 subacute
 occurs after two prior bleeds
 chronic
 presentation will demonstrate contractures or arthritis
o paresthesias
 in the L4 distribution
 caused by iliacus hematoma that compress femoral nerve
Imaging
 Radiographs
o knee
 squaring of patella and femoral condyles (Jordan's sign)
 ballooning of distal femur
 widening of intercondylar notch
 joint space narrowing
 patella appear long and thin on
lateral
o ankle
 joint arthritis
o elbow
 joint arthritis
o epiphyseal overgrowth
o generalized osteopenia
o fractures
 MRI
o can be used to identify early
degeneratve joint disease
‎II:15 widening of the intercondylar notch
and ballooning of the distal femur
 Ultrasound
o often helpful to follow intramuscular
hematomas
I‎ I:14 Coronal MRI of a patient
with hemophilic arthropathy of the
ankle. Note the cartilaginous
destruction of the talus.
Studies
 Labs
o screening for factor VIII inhibitors (including IgG antibodies)
 indicated prior to surgery as presence will negate effects of factor treatment
 Histology
o hypertrophy and hyperplastic changes to the synovium
Differential
 Septic arthritis : concomitant infection should be ruled out by physical exam and joint aspiration
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Treatment
 Nonoperative
o compressive dressings, analgesics, short term immobilization followed by rehabilitation
 indications : joint pain
 modalities
 steroids for to help reduce inflammation
 splints and braces
 physical therapy to prevent contracture development
o factor administration
 indications
 vigorous physical therapy
 increase factor VIII to 20%
 acute hematomas (including intramuscular hematomas)
 increase factor VIII to 30%
 acute hemarthrosis and soft tissue surgery
 increase factor VIII to 40-50%
 skeletal surgery
 increase factor VIII to 100% for first week following surgery then maintain at > 50%
for second week following surgery
 modalities
 home transfusion therapy
 has reduced the severity of arthropathies
o desmopressin
 indications : mild or moderate hemophillia A
 Operative
o synovectomy
 indications : recurrent hemarthroses recalcitrant to medical management
 techniques : increase factor VIII to 40-50%
 outcomes
 decreases incidence of recurrent hemarthroses
 limits pain and swelling
o synoviorthesis
 indications : chronic hemophiliac synovitis that is recalcitrant to medical management
 technique
 destruction of synovial tissue with intra-articular injection of radioactive agent
 colloidal phosphorus-32 chromic phosphate
o total joint arthroplasties
 indications : end stage arthropathy
 perioperative care
 increase factor VIII to 100% for first week postoperatively then maintain at > 50% for
second week postoperatively
o arthrodesis
 indications : arthropathy of the ankle
 perioperative care
 increase factor VIII to 100% for first week postoperatively then maintain at > 50% for
second week postoperatively
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Blood Conditions
C. Blood Conditions
1. Fat Embolism Syndrome
Introduction
 A syndrome caused by an inflammatory response to embolized fat globules
o characterized by
 hypoxia
 CNS depression
 pulmonary edema
 petechial rash
 Epidemiology
o incidence
 3-4% with isolated long bone trauma
 10-15% with polytrauma
 Pathophysiology
o fat and marrow elements are embolized into the bloodstream during
 acute long bone fractures
 intramedullary instrumentation
 intramedullary nailing
 hip & knee arthroplasty
o pathophysiology
 two theories regarding the causes of fat embolism include
 mechanical theory
 embolism is caused by droplets of bone marrow fat released into venous system
 metabolic theory
 stress from trauma causes changes in chylomicrons which result in formation of fat
emboli
 Prognosis
o fatal in up to 15% of patients
Diagnosis Criteria
 Major (1)
o hypoxemia (PaO2 < 60)
o CNS depression (changes in mental status)
o petechial rash
o pulmonary edema
 Minor (4)
o tachycardia
o pyrexia
o retinal emboli
o fat in urine or sputum
o thrombocytopenia
o decreased HCT
 Additional
o PCO2 > 55
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o pH
< 7.3
> 35
o dyspnea
o anxiety
o RR
Presentation
 History
o symptoms usually present within 24 hours of inciting event
 Symptoms
o patient complains of feeling "short of breath"
o patient appears confused
 Physical exam
o tachycardia
o tachypnea
o petechiae
 axillary region
 conjunctivae
 oral mucosa
Studies
 ABG
o hypoxemia (PaO2 < 60 mmHg)
Treatment
 Nonoperative
o mechanical ventilation with high levels of PEEP (positive end expiratory pressure)
 indications : acute fat emboli syndrome
 Prevention
o early fracture stabilization
 indications
 early fracture stabilization (within 24 hours) of long bone fracture is most important
factor in prevention of FES
 techniques to reduce the risk of fat emboli
 overreaming of the femoral canal during a TKA
 use of reamers with decreased shaft width reduces the risk during femoral reaming for
intramedullary fixation
 use of external fixation for definitive fixation of long bone fractures in medically unstable
patients decreases the risk
2. Thromboembolism (PE & DVT)
Introduction
 Incidence
o DVT
o pulmonary embolism
 700,000 symptomatic PE/yr in USA
 of these 200,000 are fatal
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
Systemic Disease | Blood Conditions
Risk factors for thromboembolism
o Virchow's triad
 venous stasis
 hypercoagulable state
 intimal injury
o primary hypercoagulopathies (inherited)
 MTHFR/C677T/TT gene mutation carries highest risk
 factor V Leiden mutation
 antithrombin III deficiency
 protein C deficiency
 protein S deficiency
 activated protein C resistance
o secondary factors (acquired)
 malignancy
 recently been associated with up to 20% of all new diagnoses of VTE
 elevated hormone conditions
 recombinant erythropoeitin
 hormone replacement
 oral contraceptive therapy
 late pregnancy
 elevated antiphospholipid antibody conditions
 lupus anticoagulant
 anticardiolipin antibody
 history of thromboembolism
 obesity
 aging
 CHF
 varicose veins
 smoking
 general anesthetics (vs. epidural and spinal)
 immobilization
 increased blood viscosity
Pathophysiology
 Mechanism of clot formation
o stasis
o fibrin formation
 thromboplastin (aka Tissue Factor (TF), platelet tissue factor, factor III, or CD142) is
released during dissection which leads to activation of the extrinsic pathway and fibrin
formation
o clot retraction
o propagation
Prophylaxis
 Overview
o prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) is most important
factor in decreasing morbidity and mortality
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o prophylaxis
treatment should be determined by weighing risk of bleeding vs risk of pulmonary
embolus
 AAOS risk factors for major bleeding
 bleeding disorders
 history of a recent gastrointestinal bleed
 history of a recent hemorrhagic stroke
 AAOS risk factors for pulmonary embolus
 hypercoagulable state
 previous documented pulmonary embolism
 Prophylaxis in hip & knee replacement
o mechanical prophylaxis
 compressive stockings recommended
 pneumatic compression devices are recommended by the AAOS across all risk (low to high
risk of either bleeding or pulmonary embolism) groups undergoing total hip or total knee
arthroplasty
 increase venous return and endothelial-derived fibrinolysis
 decrease venous compliance and venous stasis
o medical treatment
 see anticoagulation section below
Deep Venous Thrombosis
 Introduction
o procedures associated with greater frequency of DVT
 spine fracture with paralysis
 elective total knee arthroplasty
 2-3X greater rate of DVT than THA
 elective total hip arthroplasty
 hip fracture
 polytrauma
o based on AAOS review, the rate of DVT does not correlate with PE or death following THA or
TKA
 Physical exam
o often more helpful than imaging
 pain and swelling
 Homan's sign is not very specific
 Imaging
o venography is gold standard
o for proximal DVTs (proximal to trifurcation)
 venous duplex ultrasound is 96% sensitive, 98% specific
 plethysmography is 75% sensitive, 90% specific
 CT is 90% sensitive, 95% specific
 Treatment
o heparin therapy followed by long term coumadin
 indications
 postoperative DVT above knee
 treatment for DVT below knee is controversial
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Systemic Disease | Blood Conditions
o vena

cava filter placement
indications
 preoperative identification of DVT in a patient with lower extremity or pelvic trauma who
is high risk for DVT development
 see anticoagulation
Pulmonary Embolism
 Introduction
o 700,000 asymptomatic PE/yr in USA
 of these 200,000 are fatal
o procedures associated with pulmonary embolism
 hip fracture
 elective total hip arthroplasty
 the greatest risk of activation of the clotting cascade during total hip arthroplasty occurs
during insertion of the femoral component
 elective total knee arthroplasty
 spine fracture with paralysis
o early diagnosis and treatment is most important factor for survival
 Presentation
o PE should be suspected in postoperative patients with
 acute onset pleuritic pain and dyspnea
 tachypnea
 tachycardia
 Evaluation
o EKG
o ABG
 Imaging
o CXR
o nuclear medicine ventilation-perfusion scan (V/Q)
o pulmonary angiography
 is gold standard
o helical chest CT
 widely considered first line imaging modality
 Treatment
o continuous IV heparin infusion followed by warfarin therapy
 indications
 in most cases as first line treatment
 technique
 continuous IV heparin infusion typically given for 7-10 days
 warfarin therapy typically given for 3 months
 monitor heparin therapy with PTT (partial thromboplastin time)
 monitor coumadin therapy with INR (international normalized ratio)
o thrombolytics
 indications
 in specific cases
 technique
 see anticoagulation
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3. Anticoagulation
Introduction
 The coagulation cascade comprises a series of reactions that lead to formation of fibrin, which leads
to platelet activiation and clot formation
o an imbalance of the coagulation cascade can cause thromboembolism and DVT
 Virchow's triad describes risk factors for thromboembolism and DVT and includes
o venous stasis
o endothelial damage
o hypercoagulable state
 Orthopaedic surgery predisposes high risk of thromboembolism and certain procedures may require
anticoagulation
o there are many choices of anticoagulants, each has advantages and disadvantages
Overview of Anticoagulants (details below)
Method
Mechanism
Advantage
Disadvantage
Compression stocking Mechanical
no bleeding risk compliance
ASA
Inhibits the production of
prostaglandins and
thromboxanes
convenience
IV heparin
Enhances ability of Antithrombin reversible
III to inhibit factors IIa, III, Xa
limited efficacy
IV administration
Unfractionated heparin Enhances ability of ATIII to inhibit reversible
(subcutaneous)
factors IIa, III, Xa
bleeding
LMWH (Lovenox)
Enhancing ability of ATIII to
fixed dose, no
inhibit factors IIa (thrombin) and lab monitoring
Xa
required
bleeding
Fondaparinux
Indirect Xa inhibitor (works
through ATIII)
no lab monitoring
required
Coumadin
Affects Vit K metabolism in the
liver, limiting production of
clotting factors II, VII, IX, X
most effective
difficult to reverse
Dextran
Dilutional
efficacy
fluid overload
Rivaroxaban (Xarelto),
Apixaban (Eliquis),
Direct Xa inhibitor
Edoxaban (Savaysa)
Dabigatran (Pradaxa),
Direct thrombin inhibitor
Compression Stocking
 Mechanism
o increases fibrinolytic system
o decreases venous stasis
 Evidence : literature supports efficacy in TKA
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Systemic Disease | Blood Conditions
ASA (acetylsalicylic acid)
 Introduction
o thromboxane function
 under normal conditions thromboxane is responsible for the aggregation of platelets that
form blood clots
o prostaglandins function
 prostaglandins are local hormones produced in the body and have diverse effects including
 the transmission of pain information to the brain
 modulation of the hypothalamic thermostat
 inflammation
 Mechanism of ASA
o inhibits the production of prostaglandins and thromboxanes through irreversible inactivation of
the cyclooxygenase enzyme
 acts as an acetylating agent where an acetyl group is covalently and irreversibly attached to
a serine residue in the active site of the cyclooxygenase enzyme.
 this differentiates aspirin different from other NSAIDs which are reversible inhibitors
 Metabolism
o renal
Unfractionated Heparin (SQ)
 Mechanism
o binds and enhances ability of antithrombin III to inhibit factors IIa, III, Xa
 Reversal
o protamine sulfate
 Metabolism
o hepatic
 Risk
o bleeding
o HIT (heparin induced thrombocytopenia)
Low Molecular Weight Heparin
 Overview
o molecular name: enoxaparin
o trade name: Lovenox, Clexane
o has advantage of not requiring lab value monitoring
 Mechanism
o LMWH acts in several sites of the coagulation cascade, with its principal action being inhibition
of factor Xa.
o reversed by protamine
 Metabolism
o renal
 Risk : bleeding
Fondaparinux
 Overview
o trade name: Arixtra
o has advantage of not requiring lab value monitoring
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
Mechanism
o indirect factor Xa inhibitor (acts through antithrombin III)
 Metabolism
o renal
 Evidence
o studies show decreased incidence of DVT when compared to enoxaparin in hip fx and TKA
patients
 Risk
o highest bleeding complications
 not to be used in conjunction with epidurals
Warfarin
 Mechanism of anticoagulation
o inhibits vitamin K 2,3-epoxide reductase
 prevents reduction of vitamin K epoxide back to active vitamin K
o vitamin K is needed for gamma-carboxylation of glutamic acid for factors
 II (prothrombin), VII (first affected), IX, X
 protein C, protein S
 Monitoring
o target level of INR (international normalized ratio) is 2-3 for orthopaedic patients
o not achieved for 3 days after initiation
 Reversal
o vitamin K (takes up to 3 days)
o fresh frozen plasma (acts immediately)
 Risk
o difficult to dose requires the frequent need for INR lab monitoring
o can have adverse reaction with other drugs including
 rifampin
 phenobarbital
 diuretics
 cholestyramine
Rivaroxaban (Xarelto)
 Overview
o others in the same class include apixaban (Eliquis) and edoxaban (Savaysa or Lixiana)
o Mechanism of action of these drugs can be deduced from the name.
 Rivaro(Identifier)-xa(FactorXa)-ban(inhibitor)
 Mechanism
o direct Xa inhibitor
 Metabolism
o liver
 Antidote
o no current antidote
o andexanet alpha being investigated
 Risk
o Bleeding
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Systemic Disease | Neurologic Diseases
Dabigatran (Pradaxa)
 Mechanism
o reversible direct thrombin (factor IIa) inhibitor
 Metabolism : renal
 Antidote : idarucizumab (FDA approved Oct 2015)
 Risk
o GI upset
o bleeding
Tranexamic acid (TXA)
 Overview
o an antifibrinolytic that promotes and stabilizes clot formation
o studies have shown that TXA reduce perioperative blood loss and transfusion in THA and TKA
 Mechanism
o synthetic derivative of the amino acid lysine
o competitively inhibits the activation of plasminogen by binding to the lysine binding site
o at high concentrations, is a non-competitive inhibitor of plasmin
o has roughly 8-10 times the antifibrinolytic activity of ε-aminocaproic acid
 Dosing
o intravenous
 10-20 mg/kg initial bolus dose followed by repeated doses of the initial TXA dose every 3
hours for 1-4 doses
 10-20mg initial bolus followed either by an infusion of 1-10 mg/kg/hr for 4-30 hours
o topical application is as effective as IV
 sprayed onto open wound at completion of procedure
 no detectable TXA in the bloodstream after topical application
 Metabolism
o <5% of the drug is metabolized
o biological half-life in joint fluid is 3h, present in tissues for up to 17h
 Risks
o systematic review shows no increase in thromboembolic events
o relatively few adverse reactions have been reported in the arthroplasty literature
Herbal Supplements
 Increased bleeding
o gingko, ginsing, and garlic have been found to increase the rate of bleeding
o related to effect on platelets
o proper history taking can avoid complications
 Increased warfarin effect (increase INR)
o omega-3 fish oil
 affects platelet aggregation and vitamin K dependent coagulation factors
 Reduced warfarin effect (reduces INR)
o coenzyme Q10
o green tea
 direct warfarin antagonist (reduces INR)
o St John's wort
 increases catabolism of warfarin (reduces INR)
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D. Neurologic Diseases
1. Stroke
Introduction
 Acute onset of focal neurologic deficits resulting from
o diminished blood flow (ischemic stroke)
o hemorrhage (hemorrhagic stroke)
 Epidemiology
o incidence
o risk factors include
 diabetes
 smoking
 atrial fibrillation
 cocaine
 Pathophysiology
o etiology include
 35% - atherosclerosis of the extracranial vessels (carotid atheroma)
 30% -cardiac and fat emboli, endocarditis
 15% - lacunar
 occur in areas supplied by small perforating vessels and result from
 atherosclerosis
 hypertension
 diabetes
 10% - parenchymal hemorrhage
 10% - subarachnoid hemorrhage
 Watershed occurs at areas at border of two arterial supplies
o often follow prolonged hypotension
 TIA is charcaterized by transient neurologic deficits for less than 24 hours (usually less than 1 hr.)
Presentation
 Edema occurs 2-4 days post-infarct.
 Watch for symptoms
o decorticate (cortical lesion): flexion of arms
o decerebrate (midbrain or lower lesion): extension of arms
Carotid/Ophthalmic Amaurosis fugax (monocular blind)
MCA
Aphasia, neglect, hemiparesis, gaze
preference, homonymous hemianopsia.
ACA
Leg paresis, hemiplegia, urinary incontinence
PCA
homonynmous hemianopsia
Basilar Art
Coma, cranial nerve palsies, apnea, drop
attach, vertigo
Lacunar stroke
Silent, pure motor or sensory stroke,
dysarthria (clusy hand syndrome), ataxic
hemiparesis.
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Systemic Disease | Neurologic Diseases
Other stroke syndromes
o lateral medullary infarct (Wallenburg syndrome)
 loss of pain and temp on ipsilateral face and contralateral body, vestibulocerebellar
impairment, Horner's syndrome
Imaging
 CT without contrast
o indicated for acute presentation
o important to diagnose as ischemic or hemorrhagic
 MRI
o indicated for subacute
o vascular studies of intra and extracranial vessels
Studies
 Labs
o should include coagulation studies
o lumbar puncture to r/o encephalitis
 Echo
o to check for mural thrombus, rule out endocarditis
 EEG to rule out seizure
Differential
 Brain tumor, epi / subdural bleeds, brain abscess, endocarditis, multiple sclerosis, metabolic
(hypoglycemia), neurosyphillis
Treatment
 Nonoperative
o thrombolytics
 indications : for occlusive disease
 modalities
 give IV tPA if within 3-4.5 hours
 can consider intra-arterial thrombolysis in select patients (major MCA occlusion) up to 6
hours after onset of symptoms
o warfarin/aspirin therapy
 indications
 for embolic disease and hypercoagulable states give warfarin / aspirin once the
hemorrhagic stroke has been ruled out
o anti-hypertensive medications
 Do not overtreat hypertension. Allow BP to rise to 200/100 to maintain perfusion
 Operative
o thrombectomy
 indications
 Within 6 hours in an ischemic stroke with a proximal cerebral arterial occlusion,
compared to alteplase alone, improved reperfusion, early neurological recovery, and
functional outcome.
o endarterectomy
 indications
 if corotid > 70% occluded
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Prognosis, Prevention, and Complications
 Less than 1/3 achieve full recovery
 For embolic disease give warfarin / aspirin for prophylaxis
 Carotid endarterectomy if stenosis is > 70%. Contraindicated if vessel is 100% occluded.
 Manage hypertension
2. Multiple Sclerosis
Introduction
 A chronic inflammatory disease that causes demyelination and widespread axonal injury in the
central nervous system, leading to motor and sensory dysfunction
 Epidemiology
o incidence
 5 per 100,000 people in the US
o demographics
 20-40 years old
 women>men
 northern latitude
o risk factors
 genetic
 not considered a hereditary disease
 environment
 stress
 smoking
 decreased sunlight/low vitamin D exposure
 Pathophysiology
o pathophysiology
 believed to be caused by a combination of genetic, environmental and infectious factors
 recent research suggests a T-cell mediated autoimmune mechanism
 Associated conditions
o orthopaedic
 increased fracture risk
 relating to increased risk of falling and decreased bone mineral density
 osteoporosis
 relating to physical inactivity, vitamin D deficiency, immunomodulatory medication
 gait abnormalities
 muscle paralysis causing foot drop, etc
 muscle and joint spasticity
 Prognosis
o patterns of disease progression
 remitting-relapsing (most common)
 primary progressive
 secondary progressive
 progressive relapsing
o life expectancy
 5 to 10 years lower than that of unaffected people
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Systemic Disease | Neurologic Diseases
Presentation
 History
o clinically defined by two or more episodes of neurological dysfunction (brain, spinal cord or
optic nerves) that are separated in time and space
 Symptoms
o symptoms of disease are based on the systems involved
 psych
 fatigue, depression, mood disorders
 central nervous system
 optic neuritis, diplopia, nystagmus
 ENT
 dysarthria, dysphagia
 MSK
 weakness, loss of balance and coordination, spasms, ataxia, falls
 neuro
 parasthesis, hypoesthesia, peculiar sensory phenomena's (e.g. sensation of wetness)
 GI
 incontinence, diarrhea, constipation
 urology
 incontinence, frequency, retention
 Physical exam
o inspection
 assess for gait abnormalities (e.g. wide-based gait, limb ataxia, slapping foot)
 joint or muscle contractures
o neurological examination
 muscle spasticity
 increased deep tendon reflexes
 muscle weakness
 Babinski positive
o special tests
 fundoscopy
 MLF syndrome (Internuclear Ophthalmoplegia)
 Lhermitte's sign
Evaluation
 Laboratory studies
o CBC, lytes, TSH, comprehensive metabolic panel
 used to exclude concomitant illnesses
 usually normal
o CSF analysis
 Mononucleur pleocytosis (25%)
 elevated CSF IgG (80%)
 oligoclonal bands on electrophoresis
 Imaging studies
o MRI
 indications : obtain MRI with gadolinium of brain and spinal cord
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findings
 multiple focal demyelination scattered in brain and spinal cord
 asymmetric periventricular plaques
Differential
 Cervical myelopathy, CNS mass lesion, vitamin B12 deficiency, sarcoidosis, CNS infections
Treatment
 Nonoperative
o immunomodulators
 indications
 treatment attempt to return function after an attack, prevent new attacks, and prevent
disability
 modalities
 corticosteroids
 indicated for acute exacerbations
 prophylactic immunosuppresants (interferon beta)
 may decrease the number and severity of relapses
 has been shown to decrease the progression of relapsing remitting multiple sclerosis
o antispasticity agents
 indications
 increased muscle tone with spasms
 modalities
 oral agents
 baclofen, gabapentin, clonazapem
 botox injections
o physiotherapy
 indications
 improve gait and balance
 modalities
 gentle stretching exercises for spasticity
 progressive resistant-training
o osteoporosis management
Complications
 Increased fracture risk
o relating to increased risk of falling and decreased bone mineral density
 Osteoporosis
o relating to physical inactivity, vitamin D deficiency, immunomodulatory medication
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Systemic Disease | Neurologic Diseases
3. Amyotrophic Lateral Sclerosis (ALS)
Introduction
 Also referred to as Lou Gehrig's disease.
 A progressive motor neuron disorder characterized by involvement of anterior horn cells of spinal
cord.
 Pathologic features
o lower motor neuron signs
 loss of motor neurons within the anterior horns of the spinal cord and motor cranial nerve
nuclei
o upper motor neuron signs
 degeneration with loss of myelinating fibers in the corticospinal and corticobulbar pathways
o abnormal motor conduction, normal sensory conduction
 Genetics
o cause is mostly unknown
o small percentage (~5%) of patients have familial form of the disease
 some map to gene for superoxide dismutase on chromosome 21
Presentation
 Symptoms
o painless weakness in one extremity that extends to the other extremities
o fasciculations
o impaired speech or swallowing
o reduced head control
o breathing difficulty
o muscle cramping
o urinary frequency or incontinence (late findings)
o sensory remains normal
 Physical exam
o neck ptosis (neck drop) due to neck extensor weakness
o manual muscle testing elicits muscle cramping
o upper motor neuron (UMN) signs
 spasticity
 hyperreflexia
 (+) Hoffman's
 (+) Babinski's
 spastic dysarthria
o lower motor neuron (LMN) signs
 muscular atrophy
 weakness
 clinical fasciculations
 clumsiness
Evaluation
 Diagnosis
o dependent on demonstration of both UMN and LMN involvement
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o combination
of UMN and LMN in the same extremity, in the absence of pain or sensory
symptoms, and cranial nerve findings is highly indicative of ALS
o often misdiagnosed as cervical myelopathy or radiculopathy
 Laboratory diagnosis
o there are currently no laboratory tests that confirm the diagnosis
 EMG / NCS - shows denervation + reinnervation
o widespread decreased amplitude of CMAP and slowed motor conduction velocity
o denervation (fibrillations and positive waves) + decreased recruitment in ≥ 3 extremities
o reinnervation
o abnormal spontaneous fibrillation & fasciculation potentials
o normal sensory studies (SNAP, sensory nerve action potentials)
Differentials
 Peripheral compressive neuropathy
o hyperreflexia and other UMN signs (Babinski, Hoffman) are present in ALS (which can present
in a single extremity mimicking cubital/carpal tunnel syndrome), but absent in peripheral
neuropathy
o ALS has normal sensory studies on EMG/NCS
Treatment
 Nonoperative
o currently no cure or effective treatment
 goals of treatment
 provide supportive care
 prevent progression
 maintain independent patient function and comfort
o riluzole
 indications
 modest benefits only
 prolongs life by 2-3 months
 mechanism
 blocks tetrodotoxin-sensitive sodium channels associated with damaged neurons
 delays onset of ventilator-dependence and may prolong survival
4. Complex Regional Pain Syndrome (CRPS)
Introduction
 Sustained sympathetic activity in a perpetuated reflex arc characterized by pain out of proportion to
physical exam findings
o also known as complex regional pain syndrome (CRPS)
o known as causalgia when associated with defined nerve
 Pathophysiology
o trauma from an exagerrated response to injury
 most common reason for a poor outcome following a crush injury to the foot
o surgery
o prolonged immobilization
o possible malingering
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
Prevention
o vitamin C 500 mg daily x 50 days in distal radius fractures treated conservatively
 200mg daily x 50 days if impaired renal function
o vitamin C also has been shown to decrease the incidence of CRPS (type I) following foot and
ankle surgery
o avoid tight dressings and prolonged immobilization
 Prognosis
o responds poorly to conservative and surgical treatments
Classification
Stage
Acute
Subacute
Chronic

Lankford and Evans Stages of RSD
Onset
Exam
Imaging
Pain, swelling, warmth, redness, decreased
Normal x-rays, positive three0-3 months
ROM, hyperhidrosis
phase bone scan
3 to 12
Worse pain, cyanosis, dry skin, stiffness, skin
Osteopenia on x-ray
mos
atrophy
> 12
Dimished pain, fibrosis, glossy skin, joint
Extreme osteopenia on x-ray
months
contractures
International Association for the Study of Pain Classification
o type I
 CRPS without demonstrable nerve lesions
 most common
 from trauma, cast or tight bandage
o type II
 CRPS with evidence of identifiable nerve damage
 minimal positive response with sympathetic blocks
Presentation
 Cardinal signs
o exaggerated pain
o swelling
o stiffness
o skin discoloration
 Physical exam
o vasomotor disturbance
o trophic skin changes
o hyperhidrosis
o "flamingo gait" if the knee is involved
Imaging
 Radiographs
o patella osteopenia if the knee is involved
 Three-phase bone scan
o indications
 to rule out CRPS type I (has high negative predictive value)
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o findings
RSD shows positive phase III that does not correlate with positive phase I and phase II
 phase background
 phase I (2 minutes) : shows an extremity arteriogram
 phase II (5-10 minutes) : shows cellulitis and synovial inflammation
 phase III (2-3 hours) : shows bone images
 phase IV (24 hours) : can differentiate osteomyelitis from adjacent cellulitis
 Thermography
o questionable utility
 EMG/NCV
o may show slowing in known nerve distribution e.g. slowing of median nerve conduction for
CRPS type II in forearm

Studies
 Diagnosis
o diagnosis is clinical, but can be confirmed by pain relief with sympathetic block
o early diagnosis is critical for a successful outcome
Treatment
 Nonoperative
o physical therapy and pharmacologic treatment
 indications : indicated as first line of treatment
 modalities
 gentle physiotherapy
 tactile discrimination training
 graded motor imagery
 medications
 NSAIDs
 alpha blocking agents (phenoxybenzamine)
 antidepressants
 anticonvulsants
 calcium channel blockers
 GABA agonists
o nerve stimulation
 indications : symptoms present mainly in the distribution of one major peripheral nerve
 programmable stimulators placed on affected nerves
o chemical sympathectomy
 indications
 acts as another option when physical therapy and less aggressive nonoperative
management fails
 Operative
o surgical sympathectomy
 indications : failed nonoperative management, including chemical block
o surgical decompression
 indications : CRPS type II with known nerve involvement e.g. carpal tunnel release if median
nerve involved
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Systemic Diseases
E. Systemic Diseases
1. Rheumatoid Arthritis
Introduction
 A chronic systemic autoimmune disease with a genetic predisposition
 Epidemiology
o incidence : most common form of inflammatory arthritis
o demographics : affects 3% of women and 1% of men
 Pathophysiology
o immunology
 cell-mediated (T cell-MHC type II) immune response against soft tissues (early), cartilage
(later), and bone (later)
 rheumatoid factor
 an IgM antibody against native IgG antibodies
 immune complex is then deposited in end tissues like the kidney as part of the
pathophysiology
 mononuclear cells
 are the primary cellular mediator of tissue destruction in RA
 IL-1, TNF-alpha
 are part of cascade that leads to joint damage
 immune response thought be related to
 infectious etiology or
 HLA locus
o pathoanatomy
 cascade of events includes
 antigen-antibody and antibody-antibody reactions >
 microvascular proliferation and obstruction >
 synovial pannus formation (histology shows prominent intimal hyperplasia) >
 joint subluxation, chondrocyte death/joint destruction, and deformity >
 tendon tenosynovitis and rupture
 Genetics
o associated with specific HLA loci (HLA-DR4 & HLA DW4)
o ~15% rate of concordance amongst monozygotic twins
 Associated conditions
o orthopaedic manifestations
 see below
o medical conditions & comorbidities
 rheumatoid vasculitis
 pericarditis
 pulmonary disease
 Felty's syndrome (RA with splenomegaly and leukopenia)
 Still's disease (acute onset RA with fever, rash and splenomegaly)
 Sjogren's syndrome (autoimmune condition affecting exocrine glands)
 Decreased secretions from salivary and tear duct glands
 Lymphoid tissue proliferation
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Prognosis
o significant advances in pharmacologic management have led to a decrease in surgical
intervention
Presentation
 Symptoms
o insidious onset of morning stiffness and polyarthropathy
o usually affects hands and feet
 DIP joint of hand is usually spared
 may also affect knees, cervical spine, elbows, ankle and shoulder
 Physical exam
o subcutaneous nodules in 20% (strong association with positive serum RF)
o ulnar deviation with metacarpophalangeal (MCP) subluxation, swan neck deformity
o hallux valgus, claw toes, metatarsophlanageal (MTP) subluxation
o joints become affected at later stage in disease process
Imaging
 Radiographs
o periarticular erosions and osteopenia
o protrusio acetabuli
 medial migration of femoral head past the radiographic teardrop
 Also seen in Marfan's syndrome, Paget's disease, Otto's pelvis and other metabolic bone
conditions
o joint space narrowing
o central glenoid erosion
Studies
 Labs
o anti-CCP (cyclic citrullinated peptide, most sensitive and specific test)
o anti-MCV (mutated citrullinated vimentin)
o elevated ESR
o elevated CRP
o positive RF titer (most commonly IgM)
 targets the Fc portion of IgG
 elevated in 75-80% of patients with RA
o joint fluid testing
 decreased complement
 may have elevated RF levels
Diagnostic Criteria (1987 Revised Criteria for Diagnosis of RA)
 Morning stiffness ≥ 1h
 Swelling in ≥ 3 joints
 Rheumatoid nodules
 Radiographic changes of the hand including bony erosions and decalcification
 Symmetric arthritis
 Serum rheumatoid factor
 Arthritis of the hand (MCP, PIP) and wrist
o have ≥4 of 7 criteria for a 6 week period
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Systemic Diseases
Treatment
 Nonoperative
o pharmacologic treatment
 indications
 mainstay of treatment
 medications (see table below)
 first line includes NSAIDS, antimalarials, remittent drugs (gold, sulfasalazine,
methotrexate), steroids, cytotoxic drugs
 more aggressive approach with DMARDs is now favored over pyramid approach
 outcomes
 significant advances in pharmacologic management have significantly changes prognosis
of disease
 Operative
o operative treatment dictated by specific condition
 significant advances in pharmocologic management have led to a decrease in surgical
intervention
o important to obtain preoperative cervical spine radiographs
Pharmacologic Management of RA
1st Line:
Low dose steroids
Corticosteroids
2nd Line:
Disease modifying anti-rheumatic drugs (DMARDs)
Methotrexate
a folate analogue with anti-inflammatory properties linked to inhibition of
neovascularization
therapeutic effects increased when combined with tetracyclines due to anticollagenase properties
Leflunomide
an inhibitor of pyrimidine synthesis
Sulfasalazine
exact mechanism unknown, but associated with a decrease in ESR and CRP
Hydroxychloroquine
blocks the activation of toll-like receptors (TLR), which decreases the activity of
dendritic cells, thus mitigating the inflammatory process
Others
D-penicillamine
3rd Line:
DMARDS / Biologic Agents / TNF antagonists
Etanercept (Enbrel)
TNF-alpha receptor fusion protein (TNF type II receptor fused to IgG1: Fc portion)
that binds to TNF-alpha
Infliximab (Remicade)
human mouse chimeric anti-TNF-alpha monoclonal antibody
Adalimumab (Humira)
human anti-TNF-alpha monoclonal antibody
Golimumab (Simponi)
human anti-TNF-alpha monoclonal antibody
Certolizumab (Cimzia)
pegylated human anti-TNF-alpha monoclonal antibody
4th Line:
DMARDS / Biologic Agents / IL-1 antagonists
Anakinra (Kineret)
recombinant IL1 receptor antogonist
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Biologic Agents: Other
Rituximab (Rituxan)
monoclonal antibody to CD20 antigen (inhibits B cells)
Abatacept (Orencia)
selective costimulation modulator that binds to CD80 and CD86 (inhibits T cells)
Tocilizumab (Actemra)
IL6 receptor inhibitor (2nd line treatment for poor response to TNF-antagonist
therapy)
When to Stop/Restart
Perioperative Medication
NSAIDS
Stop 5 half lives before surgery (stop ASA 7-10days before)
Steroids
Dosing depends on level of potential surgical stress
Methotrexate (MTX)
Continue
Leflunomide
Continue for minor procedures. Stop 1-2days before major
procedures, restart 1-2wks after
Sulfasalazine
Continue
Hydroxychloroquine
Continue
TNF antagonists (etanercept,
infliximab, adalimumab)
IL-1 antagonist (anakinra)
Continue for minor procedures. Stop etanercept 1wk before for
major procedures. Plan surgery at the end of dosing interval for
adalimumab and infliximab. Restart all 10-14days after.
Continue for minor procedures. Stop 1-2 days before for major
procedures. Restart 10 days after.
Cervical Spondylitis
 Cervical spondylitis includes
o atlantoaxial subluxation
o basilar invagination
o subaxial subluxation
Finger Conditions
 Rheumatoid nodules
o epidemiology
 most common extra-articular manifestation of RA
 seen in 25% of patients with RA and associated with aggressive disease
 an extraarticular process found over IP joints, over olecranon, and over ulnar border of the
forearm
o prognosis
 erosion through skin may lead to formation of sinus tract
o presentation
 patients complain of pain and cosmetic concerns
o treatment
 non operative
 steroid injection
 operative
 surgical excision
 indications
 cosmetic concerns, pain relief, diagnostic biopsy
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Systemic Diseases

Arthritis Mutilans
o seen in patients with RA or psoriatic arthritis
o digits develop gross instability with bone loss (pencil in cup deformity, wind chime fingers)
o treated with interposition bone grafting and fusion
 Ulnar drift at MCP joint
o introduction
 volar subluxation associated with ulnar drifting of digits
 pathoanatomy
 joint synovitits >
 radial hood sagittal fiber stretching >
 concomitant volar plate stretching
 extrinsic extensor tendons subluxate ulnarly >
 lax collateral ligaments allow ulnar deviation deformity >
 ulnar intrinsics contract further worsening the deformity >
 wrist radial deviation further worsens >
 flexor tendon eventually drifts ulnar
o presentation
 extensor lag at level of MCP joint
o treatment
 operative
 synovectomy, extensor tendon centralization,
and intrinsic release
 indications
 early disease
 MCP arthroplasty
 silicone MCP arthroplasty is most common
 indications
 late disease
 thumb MCP involvement + thumb IP involvment
 techniques
 important to correct wrist deformity at same time if it is radially deviated
 synovectomy, volar capsular resection, ulnar collateral ligament release, radial
collateral ligament repair/reconstruction, extensor tendon realignment, intrinsic
tendon release
 outcomes
 ultimate function is less predictable
 overall patient satisfaction of 70%
 1 year followup shows improved ulnar drift and extensor lag
 complications
 infection
 implant failure
 deformity recurrence
 MCP fusion
 indications
 thumb MCP involvement without IP involvement
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
Boutonniere deformity
o pathoanatomy
 synovitis of PIP leads to central slip and dorsal capsule attenuation
 increasing PIP flexion
 lateral bands subluxate volar to axis of rotation of PIP
 oblique retinacular ligament contracture causes extension contracture of DIP
o treatment
 splinting
 for flexible PIP
 extensor reconstruction (central slip imbrication or
Fowler distal tenotomy)
 for moderate deformity
 PIP arthrodesis or arthroplasty
 for rigid contractures
 Swan neck deformity
o pathoanatomy
 terminal tendon rupture from DIP synovitis leads to DIP flexion/PIP hyperextension
 FDS, volar plate and collateral ligament attenuation from synovitis leads to decreased volar
support of PIP, and hyperextension deformity
 lateral band subluxate dorsal to PIP axis of rotation
 contracture of triangular ligament, attenuation of transverse retinacular ligament
o treatment
 splinting
 for flexible PIP (prevent hyperextension)
 FDS tenodesis or proximal Fowler tenotomy
 for flexible PIP and failed splinting
 dorsal capsule release, lateral band mobilization, collateral ligament and intrinsic
release, extensor tenolysis
 for rigid deformities
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Systemic Diseases
Thumb Conditions
Nalebuff Classification of Rheumatoid Thumb Deformities
Type
Description
Treatment
Type 1
Boutonniere (most common deformity, MCP
flexion and IP extension)
Stage 1: Synovectomy with extensor hood
reconstruction
Stage 2: MCP fusion or arthroplasty
Stage 3: IP and MCP fusion (if CMC is normal).
IP fusion and MCP arthroplasty (if CMC is
diseased)
Type 2
Boutonniere with CMC subluxation
(uncommon, deformity primarily at CMC)
Same as Type 1 and 3
Type 3
Swan neck deformity (MCP hyperextension, IP Stage 1:splinting vs CMC arthroplasty
flexion)
Stage 2: MCP fusion
Stage 3: MCP fusion with first web release
Type 4
Gamekeeper deformity (metacarpal adduction, Stage 1 (passively correctable): synovectomy,
radial deviation of P1 with lax volar plate and UCL reconstruction, and adductor fascia release
UCL)
Stage 2 (fixed deformity) MP arthroplasty or
fusion
Type 5
Swan neck with MCP disease (MCP volar
plate laxity)
Type 6
Skeletal collapse (arthritis mutilans)
(MCP volar plate laxity)
MP stabilized in flexion by volar capsulodesis
Combination of arthrodesis
Flexor Tendon Conditions
 Triggering
o treatment is synovectomy + resection of FDS
 Mannerfelt syndrome
o introduction
 rupture of FPL (most common flexor rupture) in carpal tunnel due to scaphoid spur
o treatment options
 FDS4 to FPL tendon transfer + excision of scaphoid spurs (may also lead to rupture
index FDP2)
 tendon graft + spur excision
 IPJ fusion (for advanced disease)
 FDP rupture
o treatment is synovectomy + DIP fusion
 FDS rupture
o treatment is observation
Extensor Tendon Conditions
 Extensor Tendon Rupture
o epidemiology
 frequency EDM > EDC (ring) > EDC (small) > EPL
o treatment
 tendon transfer, interposition graft, or Darrach's procedure
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
Radial sagittal band failure
o extensor tendons migrate slip into ulnar gutter and volar to center of rotation of MCP joint
o physical exam
 lose active extension
 if MCP placed in extension actively then patient can hold extended
o treatment
 sagittal band reconstruction (extensor hood reconstruction)
 Vaughan-Jackson syndrome
o introduction
 rupture of digital extensor tendons from ulnar to radial
o pathoanatomy
 DRUJ instability + volar carpal subluxation results in dorsal ulnar head prominence and
attritional rupture of the extensor tendons
 EDM is the first extensor ruptured
o treatment
 EIP to EDC transfer and distal ulna resection
 Differentials for loss of digital extension
o PIN neuropathy
o extensor tendon rupture
o extensor tendon subluxation (torn radial sagittal band)
o MCP volar subluxation
Common Tendon Transfers in RA
Ruptured Tendon
Tendon Transfer
EPL
EIP to EPL
EDQM
leave alone
EDQM and EDC5
EDQM, EDC5, EDC4
EIP to EDC5
or EDQM to EDC piggyback transfer
EIP to EDQM and EDC4 side to side to EDC3
Multiple tendon rupture
Use palmaris graft and FDS
Wrist Conditions
 Caput-ulna syndrome
o pathoanatomy
 synovitis in the DRUJ > ECU subsheath stretching > ECU subluxation > supination of the
carpal bones away from the head of the ulna > volar carpal subluxation > increased pressure
over the extensor compartments > tendon rupture
 distinguish from extensor lag caused by PIN compression neuropathy (seen in RA due to
elbow synovitis)
o treatment
 Darrach distal ulna resection
 must also relocate ECU dorsally with a retinacular flap or perform ECU stabilization of
ulna
 ulnar hemiresection
 Sauvé-Kapandji (ulnar pseudoarthrosis)
 has advantage of preserving the TFCC
 good option for younger patients
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By Dr, AbdulRahman AbdulNasser

Systemic Disease | Systemic Diseases
Radiocarpal Destruction
o pathoanatomy
 synovitis and capsular distension leads to supination, radial deviation (angulation) of carpus
 ulnar and volar translocation of the carpus on the radius
 with scaphoid flexion, radiolunate widening, lunate translocation (ulnarwards)
 secondary radioscaphoid arthrosis
 ulnar deviation of the fingers at the MP joints creating the classic zigzag deformity
o treatment
 synovectomy
 indications
 early disease
 technique
 transfer of ECRL to ECU to diminish deforming forces (Clayton's procedure)
 radiolunate fusion (Chamay) or radioscapholunate fusion
 indications
 intermediate disease with preserved midcarpal joint
 wrist fusion
 indications
 advanced disease, poor bone stock
 remains gold standard
 often combined with Darrach
 total wrist arthroplasty
 indications
 sedentary patients with good bone stock
 advantages over fusion is motion and best in patients with reasonable motion preop
Elbow Conditions
 Rheumatoid elbow
o nonoperative
 rheumatoid elbow is mainly managed with medical management and cortisone injections
o operative
 synovectomy and radial head excision
 indications
 focus of degeneration is in radiohumeral joint
 posterior interosseous nerve compression secondary to radial head synovitis
 technique
 performed through lateral approach to elbow
 interposition arthroplasy
 indications
 young active patients who are not candidates of TEA
 technique
 resection and contouring of humeral surface
 cover humeral surface with cutis autograft, Achilles tendon, fascia, or dermal allograft
 some use distraction external fixator to unload membrane and enhance its bonding to
bone and improve motion
 results less predictable than TEA, but avoids prosthetic complications
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total elbow arthoplasty
 indications
 pain
 loss of motion
 instability
 technique
 semiconstrained device has best results
 outcomes
 reliable procedure for advanced RA of elbow
 5 lb single arm weight lifting restriction
Shoulder Conditions
 Introduction
o RA is most prevalent form of inflammatory process affecting the shoulder with >90% developing
shoulder symptoms
o commonly associated with rotator cuff tears
 Evaluation
o classic radiographic findings include
 central glenoid wear
 periarticular osteopenia
 cysts
Hip Conditions
 Protrusio acetabuli
Knee Conditions
‎II:16 Protrusio acetabuli
 Operative
o synovectomy of knee
 decreases pain and swelling but does not alter prevent radiographic progression and does not
prevent the need for TKA in the future
 normal synovium reforms, but degenerates to rheumatoid synovium over time
 range of motion is not improved
o total knee arthroplasty
 rheumatoid arthritis is considered an indication for resurfacing of the patella during total knee
arthroplasty
Foot & Toe Conditions
 Introduction
o usually bilateral and symmetric
o forefoot joints are the first to be affected
o human leukocyte antigen (HLA)-DR4 positive
 Toe hyperextension deformity
o the earliest manifestation of rheumatoid arthritis of the forefoot is synovitis of the MTP joints
with eventual hyperextension deformity of the MTP joints including distal migration of the
forefoot pad, painful plantar callosities and skin ulcerations over bony prominences.
o treatment
 arthrodesis of the 1st MTP joint and lesser MTP joint resections
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By Dr, AbdulRahman AbdulNasser

Systemic Disease | Systemic Diseases
Talonavicular arthritis
o common to have degenerative changes
o treat with fusion
Cervical Conditions
 Present in 90% of patients with RA
o diagnosis often missed
 Cervical rheumatoid spondylitis includes three main patterns of instability
o atlantoaxial subluxation
 most common form of instability
o basilar invagination
o subaxial subluxation
Complications
 Postoperative infection
o history of prior surgical site infection (SSI)
 is the most significant risk factor for development of another SSI
o immunosuppressive therapy
 the literature is controversial whether RA patients on immunosuppressive therapy have
significantly increased infection rates for orthopaedic procedures
 pharmacologic therapy may need to be changed prior to surgical interventions
 surgery should be performed when immunosuppressive agents are at their lowest levels
 etanercept should be discontinued 3 days prior to surgical procedures
 adalimumab should be discontinued 10 days prior to surgery
 the lowest level of infliximab is found 2 weeks prior to the next scheduled infusion
2. Systemic Lupus Erythematosus (SLE)
Introduction
 Chronic autoimmune disorder of unknown origin
o leads to accumulation of autoimmune complexes in joints, skin, kidneys, lungs, heart, blood
vessels, and nervous system
 Genetic & epidemiology
o common in 15-25 year old African-American women
o multiple genes involved
o multiple HLAs involved
 HLA class II, HLA class III, HLA-DR, HLA-DQ
 Systemic manifestations
o Joint involvement is most common feature (75%)
o pancytopenia
o pericarditis
o kidney disease is most common cause of mortality
o hip osteonecrosis is common in patients taking glucocorticoids
o Raynaud's phenomenon
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Presentation
 Symptoms
o fever
o pain in multiple joints : hip pain (osteonecrosis)
 Physical exam
o butterfly malar rash
o large joint swelling and synovitis
o hand and wrist manifestation are common (90%)
 swelling and synovitis of PIPs, MCPs, and carpus
 ligamentous laxity
 Raynaud's phenomenon
 dorsal subluxation of ulna at DRUJ
Imaging Studies
 Radiographs
o usually no evidence of joint destruction
o osteonecrosis of hips is common
Labs
 Usually positive for
o ANA (95%)
o anti-DNA antibodies
o HLA-DR3
o few are RF positive
Treatment
 Nonoperative
o NSAIDS, methotrexate, sulfasalazine, cyclosporine, antimalarials, DMARDs
 treatment is similar to RA
 Operative
o digit fusion vs resection arthroplasty for hand
 indicated in advanced joint disease
 soft tissue procedures have high failure rates
 arthrodesis is treatment of choice for PIP or DIP deformities
3. Pustulosis palmoplantaris
Introduction
 Crops of sterile pustules that occur on one or both hands and feet, also known as pustular psoriasis
 Introduction
o demographics : more common in middle-aged men than in women
 rare in children
o risk factors
 the majority of patients are smokers (65–90%)
 increased stress
 infection (i.e acute or chronic tonsillitis)
 drugs (i.e.TNF-alpha inhibitors)
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Systemic Diseases

Pathophysiology
o unknown
 therories
 activated nicotine receptors in the sweat glands cause an inflammatory process
 Associated conditions
o orthopaedic conditions
 chronic recurrent multifocal osteomyelitis
 synovitis–acne–pustulosis–hyperostosis–osteomyelitis (SAPHO) syndrome
 rare presentations of arthropathy
o medical conditions & comorbidities
 autoimmune diseases
 gluten sensitive enteropathy (celiac disease)
 thyroid disease
 type 1 diabetes
 Prognosis
o not contagious
o varies in severity and can persist for many years
o little effect on general health
Presentation
 Symptoms
o pruritis, bruning sensation and occasionally pain
o worsend by pressure, rubbing and friction
o may have discomfort walking
o significant psychologic effect
 Physical exam
o inspection
 1 to 10 mm sterile pustules on palms +/- soles of feet
 surrounding erythema and fissures
 usually bilateral
o motion
 joint pain suggestive of SAPHO
Studies
 Labs
o no serological tests are specific for disease
o laboratory tests for bacterial infection are negative
 Biopsy and diagnositc injections
o skin biopsy may be helpful but is rarely necessary
Treatment
 Non-operative
o general measures
 smoking cessation
 skin moiturization
 avoidance of irritants
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o topical
corticosteroids, oral retinoid, photochemotherapy
indications
 first-line therapy
 outcomes
 low-risk for adverse effects with topical corticosteriod therapy

4. Acute Rheumatic Fever
Introduction
 Although once the most common cause of childhood arthritis, it is now rare
o may follow untreated group A beta-hemolytic strep infections (2-6 wk latent period)
 Characterized by migratory arthritis that involves multiple large joints
 Systemic manifestations
o carditis
o erythema marginatum (painless macules usually on abdomen, but never on the face)
o subcutaneous nodules (on upper extremity extensor surfaces)
o chorea
 Diagnosis based on Jones criteria
o preceding strep infection with 2 major criteria or 1 major criteria and 2 minor criteria
 major criteria
 carditis
 polyarthralgia
 chorea
 erythema marginatum
 subcutaneous nodules
 minor criteria
 fever
 arthralgia
 prior rhematic fever
 increased ESR
 prolonged PR interval
Presentation
 Symptoms
o extremely painful joints; usually knees and ankles
 Physical exam
o red and tender joints with effusions
Imaging
 Radiographs
Labs
 Antistreptolysin O titers elevated in 80%
 Synovial Fluid Analysis
Condition
Normal
Effusion from trauma
Toxic synovitis
Acute rheumatic fever
JRA
Septic arthritis
Treatment
 Nonoperative
o penicillin (250,000 U orally BID) and salicylates
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WBC (cells/mL)
<200
<5,000
5,000-15,000
10,000-15,000
15,000-80,000
>50,000
PMNs (%)
<25%
<25%
<25%
50%
75%
>75%
By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Disease
F. Metabolic Disease
1. Hypercalcemia
Introduction
 Causes of hypercalcemia include
o malignancy
o hypercalcemia in malignancy caused by parathyroid-related hormone protein (PTHrP)
o characterized by:
 hypercalcemia, hypophosphatemia, low PTH
 examples of malignancies:
 Paget's Disease
 Multiple Myeloma
 Squamous cell cancer of the lung
 ectopic production of PTH
 Multiple endocrine neoplasia (type I and II)
 Pituitary adenoma
o medical conditions
 primary hyperparathyroidism
 sarcoidosis
 Familial hypocalciuric hypercalcemia
 hyperthyroidism
 Addison's disease
 Zollinger-Ellison syndrome
o drugs
 thiazide diuretics
o dietary
 calcium ingestion (milk-alkali syndrome)
 hypervitaminosis D
 hypervitaminosis A
Presentation
 Symptoms
o CNS
 confusion
 stupor
 weakness
o gastrointestinal
 constipation
 anorexia
 nausea
 vomiting
o kidney
 polyuria
 kidney stones
 polydipsia
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Treatment
 Hydration
o saline diuresis
 Drug therapies
o loop diuretics
o bisphosphonates
o mithramycin
o calcitonin
o galium nitrate
 Dialysis (severe)
2. Hypocalcemia
Introduction
 Causes of hypocalcemia include
o decreased PTH that can be caused by
 hypoparathyrodism
 pseudohypoparathyroidism
 renal osteodystrophy
o decreased vitamin D3
Presentation
 Symptom
o symptoms of hypocalcemia
 paresthesia
 fingertip, toes, perioral
 abdominal pain, biliary colic
 muscle cramps, tetany
 dyspnea (laryngospasm, bronchospasm)
 convulsions
 mental status changes
 anxiety, fatigue, mood swings
 Physical exam
o findings of tetany
 Trousseau's Sign
 carpopedal spasm after blood pressure readings
 inflate BP cuff 20mmHg above systolic BP x 3-5min
 hand adopts a MCP flexed, DIP and PIP extended position
 more sensitive than Chvostek's sign
 Chvostek's Sign
 facial muscle contractions after tapping on the facial nerve
o dermatologic
 fungal nail infections
 hair loss
 blotchy skin
 pigment loss, vitiligo
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Disease
Radiographs
 Basal ganglia calcification
o comprises striatum, globus pallidus, substantia nigra, subthalamic nucleus
Evaluation
 Serum calcium, phosphate, vit D, PTH
 Serum albumin
o low serum albumin (low protein) leads to low total calcium
 but ionized calcium levels will be normal
 pH
o alkalosis increases albumin binding to ionized calcium
 leads to hypocalcemia
 EKG
o prolonged QT interval
Serum Serum
Ca
Phos
PTH
Common Cause
Hyperparathyroidism
Hypoparathyroidism
↑
↓
↓
↑
↑
↓
adenoma
parathyroidectomy
Ectopic PTH
↑
↓
↓
Vit D malabsorption
↓
↓
↑
Hypo vit D with no phosphate excretion
from the kidney.
↓
↑
↑
malignancy
celiac disease, other GI
isease
renal failure, pseudo
hypoparathyroidism
Treatment
 Nonoperative
o calcium gluconate infusion
 with cardiac monitoring to prevent hypercalcemia)
o activated vitamin D (calcitriol)
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3. Hypoparathyroidism
Introduction
 Decreased production of parathyroid hormone (PTH) by chief cells of the parathyroid gland
resulting in
o decreased plasma calcium levels
o increased plasma phosphate levels
o decreased 1,25(OH)2 Vitamin D levels
 Etiology
o Iatrogenic : thyroidectomy most common cause
 Pathophysiology
o decreased PTH levels cause
 decreased urinary excretion of phosphate at kidneys
 serum phosphate levels increase
 decreased conversion of inactive form of vitamin D to active form
 1,25(OH)2-vitamin levels decrease
 Prognosis
o no current hormone replacement therapy available
o treatment is aimed at supplementing vitamin D and calcium levels
Presentation
 Symptoms
o hypocalcemia
 more common in hypoparathyroidism
 neuromuscular irritability
 Chvostek's sign
 seizures
 tetany
 cataracts
 fungal infections of the nail
 hair loss
 skin changes
 vitiligo
 blotchiness of skin
Imaging
 Radiographs
o skull
 basal ganglia calcification
Evaluation
 Labs
o decreased
 PTH
 calcium
 1,25-Vit D
 urinary calcium
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Disease
o increased
serum phosphate
o normal
 alkaline phosphatase
 pH
o alkalosis increases albumin binding to ionized calcium
 leads to hypocalcemia
 EKG
o prolonged QT interval

Serum Serum
Ca
Phos
PTH
Hyperparathyroidism
↑
↓
↑
Hypoparathyroidism
↓
↑
↓
Ectopic PTH
Vit D malabsorption
hypo vit D with no phosphate excretion from
the kidney
↑
↓
↓
↓
↓
↑
↓
↑
↑
Common Cause
adenoma
thyroidectomy (including
parathyroid)
malignancy
celiac disease, other GI disease
renal failure, pseudo
hypoparathyroidism
Treatment
 Nonoperative
o calcium and vitamin D supplementation
 indications
 decreased serum calcium level
 decreased levels of vitamin D
 outcomes
 must monitor labs on a regular basis
4. Hyperparathyroidism
Introduction
 Increased parathyroid hormone (PTH) production that may be of primary, secondary or tertiary
causes
 Epidemiology
o incidence
 occurs in 0.1% of the population
 90% result form a single adenoma
 remaining 10% from parathyroid hyperplasia
o demographics
 more common in women
 hyperparathyroidism and maligncacy make up the majority of patients with hypercalcemia
 Pathophysiology
o PTH indirectly stimulates osteoclasts by binding to its receptor on osteoblasts, inducing RANKL and M-CSF synthesis
o Excessive PTH leads to over-stimulation of bone resorption
 cortical bone affected more than cancellous
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
Systemic Disease | Metabolic Disease
Associated conditions
o Brown tumor
 Resembles a giant cell tumor of bone relating to focal demineralization of bone in the setting
of hyperparathyroidism.
Classification
 Primary
o typically the result of hypersecretion of PTH by a parathyroid adenoma/hyperplasia
o may result in osteitis fibrosa cystica
 breakdown of bone, predominently subperiosteal bone
 commonly involves the jaw
 Secondary
o secondary parathyroid hyperplasia as compensation from hypocalcemia or hyperphosphatemia
2+
 ↓ gut Ca absorption
 ↑ phosphorous
o associated conditions
 chronic renal disease
 renal disease causes hypovitaminosis D
2+
 leads to ↓ Ca absorption
 renal osteodystrophy
 bone leisons due to secondary hyperparathyroidism
 Tertiary
o parathyroid glands become dysregulated after secondary hyperparathyroidism
2+
 secrete PTH regardless of Ca level
Primary
Secondary
Tertiary
Serum Ca
↑
normal or ↓
↑
Presentation
 Symptoms
o often asymptomatic
o weakness
o kidney stones ("stones")
o bone pain ("bones")
o constipations ("groans")
o uncommon cause of secondary hypertension
Evaluation
 Serology
o primary
 hypercalcemia
 ↑ PTH
o secondary
 hypocalcemia/normocalcemia
 ↑ PTH
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Serum Phos
↓
↑
↑
Serum PTH
↑
↑
↑
By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Disease
o malignancy
↓ PTH
o ↑ alkaline phosphatase
o normal anion gap metabolic acidosis
 ↓ renal reclamation of bicarbonate
 Urinalysis
o primary
 hypercalciuria (renal stones)
 ↑ cAMP
 Radiograph
o cystic bone spaces ("salt and pepper")
 often in the skull
o loss of phalange bone mass
 ↑ concavity (see key image of this topic)
 EKG
o shortened QT

Treatment
 Acute hypercalcemia
o IV fluids
o Loop diuretics
 Symptomatic hypercalcemia is treated surgically
o treat with parathyroidectoy
o complications include post-op hypocalcemia
o manifests as numbness, tingling, and muscle cramps
o should be treated with IV calcium gluconate
Complications
 Peptic ulcer disease
2+
o ↑ gastrin production stimulated by ↑ Ca
 Acute pancreatitis
2+
o ↑ lipase activity stimulated by ↑ Ca
 CNS dysfunction
o anxiety, confusion, coma
o result of metastatic calcification of the brain
 Osteoporsis
o Bone loss occurs as result of bone resorption due to excess PTH
5. Hypophosphatasia
Introduction
 Metabolic bone disease characterized by a generalized impairment of bone mineralization
 Incidence
o estimated to be 1 in 100,000
 Pathophysiology
o low levels of alkaline phosphate result in decreased synthesis of inorganic phosphate necessary
for bone matrix formation
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o osteoid
that forms in the hypertrophic zone of the growth plate fails to mineralize
zone of provisional calcification never forms and growth is inhibited
 Genetics
o inheritance pattern
 autosomal recessive
o caused by a mutation in the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP)
 Associated conditions
o orthopaedic manifestations
 similar to rickets
 bow legs
 short stature
o non-orthopaedic manifestations
 abnormal tooth formation
 loss of teeth
o the
Presentation
 Clinical findings
o presentation similar to rickets
 genu varum
 short stature
o abnormal dentition
Imaging
 Radiographs
o recommended : AP and lateral of affected bone
o findings
 abnormal bone formation
 "deossification of bone" adjacent to growth plate
 physeal widening
Evaluation
 Labs
o serum
 decreased serum alkaline phosphatase
o urine
 phosphoethanolamine in the urine diagnostic for hypophosphatasia
Treatment
 Nonoperative
o no approved therapies
 phosphate therapy under investigation but not utilized at this time
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Disease
6. Pseudohypoparathyroidism
Introduction
 Rare genetic disorder
 Mechanism
o PTH resistance
 decreased target cell response to PTH
Classification
 Type 1a - Albright hereditary osteodystrophy
o defect in GNAS1 (Gsα protein)
 defective gene from mother
 upstream defect
 proximal to formation of cAMP
o skeletal defects
 short 4th, and 5th metacarpals and metatarsals or short 4th metacarpal only
 "knuckle, knuckle, dimple, dimple" sign on closed fist
 differentials
 Turner syndrome
 short 4th metacarpal only
 "knuckle, knuckle, dimple, knuckle"
 Down syndrome
 short middle phalanx
 brachydactyly
 exostoses
o round facies
o obesity
o short stature
o diminished intelligence
 Type 1b
o defect in GNAS1 (Gsα protein)
o normal appearance
 Type 2
o unknown gene defect
o downstream defect
 distal to formation of cAMP
o normal appearance
Presentation
 Symptom
o symptoms of hypocalcemia
 paresthesia : fingertip, toes, perioral
 abdominal pain, biliary coli
 muscle cramps, tetany
 dyspnea (laryngospasm, bronchospasm)
 convulsions
 mental status changes : anxiety, fatigue, mood swings
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Systemic Disease | Metabolic Disease
Physical exam
o findings of tetany
 Trousseau's Sign
 carpopedal spasm after blood pressure readings
 inflate BP cuff 20mmHg above systolic BP x 3-5min
 hand adopts a MCP flexed, DIP and PIP extended position
 more sensitive than Chvostek's sign
 Chvostek's Sign
 facial muscle contractions after tapping on the facial nerve
o dermatologic
 fungal nail infections
 hair loss
 blotchy skin : pigment loss, vitiligo
Evaluation
 Laboratory
o high PTH
o low calcium
o high phosphate
o low vit D
 Ellsworth-Howard test
o method to differentiate type 1 and type 2 by administering exogenous PTH
 Type 1
 will show no increase in urinary cAMP and phosphate
 Type 2
 will show increased excretion of urinary cAMP and phosphate
Differential
 Causes of hypocalcemia
o renal osteodystrophy (low Ca, high PTH, high phosphate, high ALP)
o hypoparathyrodism (low Ca, low PTH, high phosphate)
o pseudopseuodohypoparathyroidism
 mechanism
 no PTH resistance
 normal target cell response to PTH
 genetics
 defect in GNAS1 (Gsα protein)
 defective gene from father
 skeletal defects
 also has short 4th metacarpal and metatarsal
 metastatic calcification
 laboratory
 normal PTH
 normal calcium
 normal phosphate
 normal vit D
o decreased vitamin D3
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By Dr, AbdulRahman AbdulNasser
Type
Systemic Disease | Metabolic Disease
Response to
Appearance PTH Calcium Phos Vit D PTH
administration
Hypoparathyroidism
Normal
↓
↓
↑
↓
Pseudohypoparathyroidism Type
1a
Skeletal
defects
↑
↓
↑
↓
Pseudohypoparathyroidism Type
1b
Normal
↑
↓
↑
↓
Pseudohypoparathyroidism Type 2 Normal
↑
↓
↑
↓
N
N
N
N
Pseudopseudohypoparathyroidism
Skeletal
defects
Genetics
no increase in
GNAS1 (maternal
urinary cAMP
defect, upstream)
or phosphate
GNAS1 and
STX16
increased
GNAS1
urinary cAMP
(downstream)
and phosphate
GNAS1 (paternal
defect)
Treatment
 Nonoperative
o oral calcium and 1alpha-hydroxylated vitamin D metabolites
 indications
 all patient with pseudohypoparathyroidism
o IV calcium replacement
 indications : patients with severe symptoms of hypocalcemia
7. Scurvy
Introduction
 Definition
o Vitamin C (ascorbic acid) deficiency
 Epidemiology
o incidence
 8% of men and 6% of women in the US have vitamin C deficiency
o demographics
 male: female ratio is 4:3
o bimodal age bracket
 infants 5-10months
 uncommon in infants <7mths who are being breast fed as breast milk has vitamin C
 men >60 years
o location
 wrists, knees, sternal ends of ribs
 areas of rapid growth in children
o risk factors
 elderly, especially men who live alone
 chronic malnutrition
 overcooking destroys vitamin C
 alcoholic
 smokers
 malabsorptive conditions (Whipple's disease, inflammatory bowel disease, cancer
chemotherapy)
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
Pathophysiology
o humans are unable to synthesize L-ascorbic acid because the enzyme L-gluconolactone oxidase
is nonfunctional
o Vitamin C deficiency leads to decrease in chondroitin sulfate and collagen synthesis and repair
o impaired intracellular hydroxylation of collagen peptides
o net effect is altered bone formatin with the greatest effect occuring in the metaphysis
o defect in spongiosa of the metaphysis at the growth plate
o because the demand for type I collagen is greatest during new bone formation
 Prognosis : excellent prognosis if treated early
Presentation
 History
o infant diet consisting of evaporated or
condensed milk
o "tea and toast" diet in elderly
 Symptoms
o malaise and fatigue
o pain
 bone pain
 myalgia, because of reduced carnitine production
o bleeding
 gum bleeding and loosening of teeth
 hematuria
 hematemesis
 hemorrhage
 iron deficiency
 Physical exam
o petechiae and ecchymosis
o joint effusions
o swelling over long bones because of subperiosteal hemorrhage
o scorbutic rosary (costochondral separation)
 angular step-off deformity in children
 differentiated from rachitic rosary, which is rounded and nodular
Imaging
 Radiographs
o recommended views
 wrist radiographs
 knee
 sternal ends of ribs
o findings
 the white line of Frankel
 widened zone of provisional calcification
 between epiphysis and metaphysis
 Trummerfeld zone
 transvese radiolucent band in the metaphysis adjacent to the Frankel line
 also known as the scurvy line
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By Dr, AbdulRahman AbdulNasser
Systemic Disease | Metabolic Disease
Wimberger ring
 ring of increased density surrounding epiphysis
 Pelkin spur and fracture
 metaphyseal spurs and fractures
 corner sign of Park
 metaphyseal clefts
 thin cortices ("pencil-point" cortex)
 decreased trabeculae with ground-glass osteopenia
 subperiosteal elevation
 epiphyseal separation
 fractures and dislocations

Studies
 The diagnosis is usually made based on history, clinical and radiological picture, and resolution of
symptoms following vitamin C administration. Lab tests are usually not helpful.
 Labs
o fasting serum ascorbic acid level is low
 Histology
o replacement of primary trabeculae with granulation tissue
o areas of hemorhage
o widening zone of provisional calcification of the physis
Treatment
 Nonoperative
o vitamin C replacement
o indications
 signs and symptoms of scurvy
 chronic malnutrition
o techniques
 oral vitamin C at 250mg qid x 1 week in adults
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‎II:17 Pencil-point cortices characteristic of
scurvy, Ground glass osteopenia
characteristic of scurvy.
OrthoBullets2017
Medications & Toxicity | Metabolic Disease
ORTHO BULLETS
III.Medications &
Toxicity
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By Dr, AbdulRahman AbdulNasser
Medications & Toxicity | Medications
A. Medications
1. Bisphosphonates
Introduction
 Overview
o class of drugs that prevent bone mass loss by inhibiting osteoclast resorption
 prevent formation of osteoclast ruffled borders microtubules, causing apoptosis
 inhibition of osteoclasts also infereres with normal bone healing and remodeling
o there are two types of bisphosphonates
 non-nitrogen containing
 tiludronate
 clodronate
 etidronate
 nitrogen containing
 alendronate
 risedronate
 pamidronate
 zolendronate
 zoledronic acid - relatively new and appealing to patients, due to IV adminstration
every 12 months
 Indications
o osteoporosis
o metastatic bone disease
o multiple myeloma
o paget's disease
o polyostotic fibrous dysplasia
o total joint arthroplasty to prevent osteolysis
o early stage avascular necrosis
o osteogenesis imperfecta
o metastatic hypercalcemia
 Contraindications
o severe renal disease
 primary mode of excretion is renal
o following lumbar fusion
 decreased spinal fusion rates in lab animal models (increased fusion mass size, but decreases
the actual fusion rate)
Mechanism
 Delivery
o bisphophonates accumulate in high concentration in bone due to binding affinity to calcium
o bisphosphonates are ingested by osteoclasts and work by two different methods depending on
presence of nitrogen atom on the alkyl chain
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
Nitrogen containing bisphosphonates mechanism
o inhibits osteoclast farnesyl pyrophosphate synthase enzyme, required in mevalonate (cholesterol
pathway)
 inhibits GTPase formation
 Non-nitrogen containing bisphosphonates (simple) mechanism
o induce osteoclasts to undergo premature death and apoptosis
 does so by forming a toxic adenosine triphosphate (ATP) analogue
Treatment
 Vertebral Compression Fractures
o indications
 vertebral compression fracture in osteoporotic patient
 bone mineral density 2.5 or more standard deviations below that of young healthy adults
(T score < 2.5 SD)
o outcomes
 1 year of treatment with a pharmacologic antiosteoporotic medication, the risk of vertebral
fracture decreases by 50-60%
 Non-vertebral Fragility fractures
o indications
 fragility fracture in osteoporotic patient
o outcomes
 effective in reducing the risk of multiple fractures
 Osteogenesis imperfecta
o cyclical IV pamidronate administration
I‎II:1 Complications: Jaw osteonecrosis
 reduces bone pain and fracture incidence
 increases level of ambulation and bone density
 Multiple myeloma
o indications
 diagnosis of multiple myeloma
o outcomes
 reduced incidence of skeletal events in multiple myeloma
 Avascular necrosis
o indications
 early, precollapse AVN
o outcomes
I‎II:2 Complicatios : Atypical
subtrochanteric and femoral stress
 still considered investigational
fractures
 randomized clinical trial showed that bisphosphonate
treatment was more effective at preventing head collapse than placebo at 2 years
(bisphosphonate collapse 6.9% vs placebo collapse 76%)
Side Effects & Complications
 Jaw osteonecrosis
 Atypical subtrochanteric and femoral stress fractures
 Radiographic changes consistent with osteopetrosis
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By Dr, AbdulRahman AbdulNasser
Medications & Toxicity | Medications
2. Prophylaxis Antibiotics
Perioperative Abx Overview
 Includes preoperative and postoperative antibiotics
o 25-50% of all antibiotics used are for prophylaxis
 Indications
o routine adminstration of prophylactic antibiotics is accepted in
 patients who will have a foreign body implanted
 bone grafting procedures
 large dissection resulting in significant dead space or hematoma
 expecting significant blood loss
o orthopaedics procedures that do not require prophylactic antibiotics
 carpal tunnel surgery
 diagnostic arthroscopy is more controversial
 Most likely pathogens to cause infection in orthopaedic procedures includes
o S aureus
o S epidermidis
o aerobic streptococci
o anaerobic cocci
Perioperative Prophylaxis in Total Joint Replacement (AAOS Recommendations)
 Choice of antibiotics
o if no beta-lactam allergy
 cefazolin or
 cefuroxime
o if beta-lactam allergy
 vancomycin or
 clindamycin
o if history of MRSA infection
 vancomycin
 use judiciously - increased risk of vancomycin-resistant enterococcus (VRE)
 Administration
o always administer abx prior to tourniquet inflation
o be cognizant of length of procedure and re-dose appropriately
o cefazolin
 administer within 1 hour of incision
 double amount of cefazolin administered if above 80kg
o vancomycin
 administer within 2 hours of incision
 Duration
o prophylactic antibiotics should NOT exceed 24 hours after surgery
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Dental Procedure Abx Prophylaxis in TJR Patients (AAOS & ADA)
 Indications
o TJA patients at increased risk of hematogenous seeding should be given prophylactic antibiotics
prior to dental procedures. This includes
 all patients for the first two years after TJA
 immunocompromised patients
 drug induced immunosuppression
 radiation induced immunosuppression
 inflammatory arthropathies including SLE and RA
 comorbidities including
 previous prosthetic joint infection
 Type I (insulin-dependent) diabetes
 malnourishment
 hemophilia
 HIV
 malignancy
o evidence to support recommendations
 AAOS and ADA recognizes there is limited or inconclusive evidence to support the
recommendations above and practitioners should use clinical judgment
 Administration
o antibiotics is given 1 hour before dental procedure
o patients NOT allergic to penicillin should be given
 amoxicillin or cephalexin 2 grams orally
 if unable to take oral medications than 1 gram cefazolin or 2 gram ampicillin IV or IM
o if allergic to penicillin
 clindamycin 600 mg orally
 if unable to take oral medications than clindamycin 600 mg IV
Splenectomy Patients Prophylaxis
 Indications in splenectomized patients
o pneumococcal immunization
 indicated in all splenectomized patients and those with functional hyposplenism
o haemophilus influenza type B vaccine
 indicated in all patients not previously immunized
o meningococcal group C conjugate vaccine
 indicated in all patients not previously immunized
o influenza immunization
 should be given annually
o lifelong prophylactic antibiotics (oral phenoxymethylpenicillin or erythromycin)
 indicated in all splenectomized patients
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By Dr, AbdulRahman AbdulNasser
Medications & Toxicity | Medications
3. Antibiotic Classification & Mechanism
Overview of By Mechanism
PENICILLINS
Natrual
First generation
Penicillin G
Penicillin-VK
Cephalothin
Cefazolin (Ancef,
Kefzol)
Cephapririn
Cephalexin (Keflex)
other
Penicillinase
Resistant
Methicillin
Nafcillin
Oxacillin
other
Ciprofloxacin (Cipro)
Levofloxacin (Levaguin)
Moxifloxacin (Avelox)
Norfloxacin
AMINOGLYCOSIDES
Amikacin
Gentamicin
Kanamycin
Neomycin
Tobramycin
MONOBACTAMS
Aztreonam
CARBAPENEMS
Ertapenem
Imienem
Meropenem
Second
Generation
Cefacor
Cefotetan (Cefotan)
other
Aminopenicillins
Ampicillin
CEPHALOSPORINS FLUOROQUINOLONES
Third Generation
Ceftriaxone
(Rocephin)
other
Fourth Generation
Cefpirome
Cefepime
Antibiotic Grouping By Mechanism
Cell Wall Synthesis
Penicillins
Cephalosporins
Vancomycin
Beta-lactamase Inhibitors
Carbapenems
Aztreonam
Polymycin
Bacitracin
Protein Synthesis Inhibitors
Inhibit 30s Subunit
Aminoglycosides (gentamicin)
Tetracyclines
Inhibit 50s Subunit
Macrolides
Chloramphenicol
Clindamycin
Linezolid
Streptogramins
Fluoroquinolones
Metronidazole
DNA Synthesis Inhibitors
RNA synthesis Inhibitors
Rifampin
Mycolic Acid synthesis inhibitors
Isoniazid
Folic Acid synthesis inhibitors
Sulfonamides
Trimethoprim
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MACROLIDES
Azithromycin
Clarithromycin
Dirithromycin
Erythromycin
Clindamycin
OTHER
Vancomycin
Rifampin
Doxycycline
Linezolid
Tetracycline
Trimethoprim/
sulfamethoxacole
OrthoBullets2017
Medications & Toxicity | Medications
Antibiotic Classification & Indications
Inhibits Cell Wall Synthesis
Penicillins
(bactericidal: blocks cross linking via competitive inhibition of the transpeptidase enzyme)
Class/Mechanism
Drugs
Indications (**Drug of
Choice)
Toxicity
Penicillin
Penicillin G
Aqueous penicillin G
Procaine penicillin G
Benzathine penicillin G
Penicillin V
Strep. pyogenes (Grp.A)** Hypersensitivity reaction
Step. agalactiae (Grp.B)** Hemolytic anemia
C. perfringens(Bacilli)**
Aminopenicillins
Ampicillin
Amoxicillin
Penicillinase-resistantpenicillins
Methicillin
Nafcillin
Oxacillin
Cloxacillin
Dicloxacillin
Above +
↑ Gram-negative:
E. faecalis**
E. Coli**
Above +
PCNase-producingStaph.
aureus
Antipseudomonal
penicillins
Carbenicillin
Ticarcillin
Piperacillin
Above +
Pseudomonas
aeruginosa**
Above
Above +
Interstitial nephritis
Above
Cephalosporins
(bactericidal: inhibits bacterial cell wall synthesis via competitive inhibition of the transpeptidase enzyme)
1st generation
Cefazolin
Cephalexin
Staph. aureus**
Staph. epidermidis**
Some Gram-negatives:
E. Coli
Klebsiella
Allergic reaction
Coombs-positive
anemia (3%)
2nd generation
Cefoxitin
Cefaclor
Cefuroxime
Above +
↑ Gram-negative
Allergic Reaction
ETOH Disulfiram
reaction
3rd generation
Ceftriaxone
Cefotaxime
Ceftazidime
Cefepime (4th generation)
Above +
↑ Gram-negative
Pseudomonas
Allergic Reaction
ETOH Disulfiram
reaction
Other Cell Wall Inhibitors
Vancomycin
(bactericidal: disrupts
peptioglycan cross-linkage)
Vancomycin
MRSA**
PCN/Ceph allegies**
S. aureus
S. epidermidis
Beta-lactamase Inhibitors
(bactericidal: blocking cross
linking)
Clavulanic Acid
Sulbactam
Tazobactam
Carbapenems
Imipenem (+ cilastatin)
Meropenem
Doripenem
Ertapenem
S aureus**
Hypersensitivity
S epidermis**
Reaction
E.Coli**
Hemolytic anemia
Klebsiella**
Broadest activity of any
antibiotic
(except MRSA, Mycoplasma)
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Nephrotoxicity
Ototoxicity
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Medications & Toxicity | Medications
Aztreonam
Aztreonam
Gram-negative rods
Aerobes
Hospital-acquired infections
Polymyxins
Polymyxin B
Polymyxin E
Topical Gram-negative
infections
Bacitracin
Bacitracin
Topical Gram-positive
infections
Protein Synthesis Inhibition
Anti-30S ribosomal subunit
Aminoglycosides
(bactericidal: irreversible
binding to 30S)
Gentamicin
Neomycin
Amikacin
Tobramycin
Streptomycin
Tetracyclines
Tetracycline
(bacteriostatic: blocks tRNA) Doxycycline
Minocycline
Demeclocycline
Aerobic Gram-negatives
Enterobacteriaceae
Pseudomonas
Nephrotoxicity
Ototoxicity
Rickettsia
Mycoplasma
Spirochetes (Lyme's
disease)
Hepatotoxicity
Tooth discoloration
Impaired growth
Avoid in children < 12
years of age
Anti-50S ribosomal subunit
Macrolides
(bacteriostatic: reversibly
binds 50S)
Erythromycin
Azithromycin
Clarithromycin
Streptococcus
H. influenzae
Mycoplamsa pneumonia
Coumadin Interaction
(cytochrome P450)
Chloramphenicol
(bacteriostatic)
Chloramphenicol
H influenzae
Bacterial Meningitis
Brain absces
Aplastic Anemia
Gray Baby Syndrome
Lincosamide
(bacteriostatic: inhibits
peptidyl transferase by
interfering with amino acyltRNA complex)
Clindamycin
Bacteroides fragilis
S aureus
Coagulase-negative
Staph & Strep
Excellent Bone Penetration
Pseudomembranous
colitis
Hypersensitivity
Reaction
Linezolid
(variable)
Linezolid
Resistant Gram-positives
Streptogramins
Quinupristin
Dalfopristin
VRE
GAS and S. aureus skin
infections
DNA Synthesis Inhibitors
Fluoroquinolones
(bactericidal: inhibit DNA gyrase enzyme, inhibiting DNA synthesis)
1st generation
Nalidixic acid
Steptococcus
Mycoplasma
Aerobic Gram +
2nd generation
Ciprofloxacin
Norfloxacin
Enoxacin
Ofloxacin
Levofloxacin
As Above +Pseudomonas
Phototoxicity
Achilles tendon rupture
Impaired fracture
healing
as above
3rd generation
Gatifloxacin
As above + Gram-positives
as above
4th generation
Moxifloxacin
Gemifloxacin
As above + Gram-positives + as above
anaerobes
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Other DNA Inhibitors
Metronidazole
(bacteridical: metabolic
biproducts disrupt DNA)
Metronidazole (Flagyl)
Anaerobics
Seizures
Crebelar dysfunction
ETOH disulfram
reaction
RNA Synthesis Inhibitors
Rifampin
(bactericidal: inhibits RNA
transcription by inhibiting
RNA polymerase)
Rifampin
Staphylococcus
Mycobacterium (TB)
Body fluid discoloration
Hepatoxicity (with INH)
Mycolic Acids Synthesis Inhibitors
Isoniazid
Isoniazidz
TB
Latent TB
Folic acid Synthesis Inhibitors
Trimethoprim/Sulfonamides Trimethoprim/Sulfamethoxazole UTI organisms
(bacteriostatic: inhibition with (SMX)
Proteus
PABA)
Sulfisoxazole
Enterobacter
Sulfadiazine
Pyrimethamine
Pyrimethamine
Malaria
T. gondii
Bacteria Overview
Gram Postive Cocci
Staphylococcus
Staph. aureus
MSSA
MRSA
Staph. epidermis
Staph saprophyticus
Streptococcus
Strep pneumoniae
Strep pyogenes (Group A)
Strep agalacticae (Group B)
Strep viridans
Strep Bovis (Group D)
Enterococci
E. faecalis (Group D strep)
Gram Positive Bacilli
Spore Forming
Non-Spore Forming
Bacillus anthracis
Bacillus cereus
Clostridium tetani
Clostridium botulinum
Clostridium perfringens
Clostridium difficile
Corynebacterium diphtheriae
Listeria monocytogenes
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Thrombocytopenia
Avoid in third trimester
of pregnancy
By Dr, AbdulRahman AbdulNasser
Medications & Toxicity | Medications
Gram Negative Cocci
Neisseria
Neisseria meningitidis
Neisseria gonorrhoeae
Gram Negative Bacilli
Enterics
Escherichia coli
Salmonella typhi
Salmonella enteridis
Shigella dysenteriae
Klebsiella pneumoniae
Serratia
Proteus
Campylobacter jejuni
Vibrio cholerae
Vibrio parahaemolyticus/vulnificus
Helicobacter pylori
Pseudomonas aeruginosa
Bacteroides fragilis
Respiratory bacilli
Haemophilus influenzae
Haemophilius ducreyi
Bordatella pertussis
Zoonotic bacilli
Yersinia enterocolitica
Yersinia pestis
Brucella
Francisella tularensis
Pasteurella multocida
Bartonella henselae
Other
Gardnerella vaginalis
Other Bacteria
Mycobacteria
Mycobacterium tuberculosis
Mycobacterium leprae
MOTTS
Spirochetes
Borrelia burgdorferi
Leptospira interrogans
Treponema pallidum
Chlamydiaceae
Chlamydia trachomatis
Chlamydophila
Rickettsia
Ehrlichia
Mycoplasmataceae
Mycoplasma pneumoniae
Ureaplasma urealyticum
Fungus-like Bacteria
Actinomyces israelii
Nocardia
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Antibiotic Resistance Mechanisms
 Bacteria develop ability to hydrolyze these drugs using β lactamase
o confers resistance to penicillin
o e.g. E. coli, Staph epidermidis, Pseudomonas aeruginosa, Klebsiella pneumoniae
o add β lactamase inhibitor e.g. clavulanic acid in amoxicillin-clavulanate (Augmentin)
 Genetic mutation of mecA
o carried by Staphylococcal cassette chromosome (SCCmec) mobile genetic unit
o a bacterial gene encoding a penicillin-binding protein (PBP2a).
 PBP2a has reduced affinity for antibiotics
 confers resistance to methicillin, oxacillin, nafcillin
 e.g. MRSA
 SCCmec type IV has less genetic elements and is specific to CA-MRSA, making CAMRSA less multi-drug resistant
 Altered cell wall permeability
o confers resistance to tetracyclines, quinolones, trimethoprim and β lactam antibiotics
 Creation of biofilm barrier
o provides an environment where offending bacteria can multiply safe from the hoste immune
system
 Salmonella
 Staph epidermidis
 Active efflux pumps
o confers resistance to erythromycin and tetracycline
o e.g. msrA gene in Staph
 Altered peptidoglycan subunit (altered D-alanyl-D-alanine
of NAM/NAG-peptide)
o confers resistance to vancomycin
o e.g. vancomycin resistant enterococcus (VRE)
I‎II:3 D zone test
 Ribosome alteration
o erm gene confer inducible resistance to MLS (macrolide lincosamide streptogranin) agents via
methylation of 23s rRNA
o demonstrate using D zone test
 for inducible clindamycin resistance in Staph and beta hemolytic Strep
‎III:4 TOP: Negative D zone test. Discs contain either 15 μg
erythromycin (E) or 2 μg clindamycin (C) on an agar plate
with S. aureus. Lack of a zone of inhibition around E disc
indicates bacterial resistance to macrolides. Large zone of
inhibition around the
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Penicillins
 Mechanism
o interfer with bacterial cell wall synthesis
 Subclassification and tested examples
o natural
 penicillin G
o penicillinase-resistant
 methicillin (Staphcillin)
o aminopenicillins
 ampicillin (Omnipen, Polycillin)
Cephalosporins
 Overview
o bactericidal
 Mechanism
o disrupts the synthesis of the peptidoglycan layer of bacterial cell walls
 does so through competitive inhibition on PCB (penicllin binding proteins)
 peptidoglycan layer is important for cell wall structural integrity.
o same mechanicsm of action as beta-lactam antibiotics (such as penicillins)
 Subclassification and tested examples
o first generation
 cefazolin (Ancef, Kefzol)
o second generation
 cefaclor (Ceclor)
o third generation
 cefriazone (Rocephin)
o fourth generation
 cefepime (Maxipime)
Fluoroquinolones
 Mechanism
o blocks DNA replication via inhibition of DNA gyrase
 Side effects
o inhibit early fracture healing through toxic effects on chondrocytes
o Increased rates of tendinitis, with special predilection for the Achilles tendon.
 Tenocytes in the Achilles tendon have exhibited degenerative changes when viewed
microscopically after fluoroquinolone administration.
 Recent clinical studies have shown an increased relative risk of Achilles tendon rupture of
3.7.
 Subclassification and tested examples
o ciprofloxacin (Cipro)
o levofloxacin (Levaquin)
Aminoglycosides
 Mechanism
o bactericidal
o inhibition of bacterial protein synthesis
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work by binding to the 30s ribosome subunit, leading to the misreading of mRNA. This
misreading results in the synthesis of abnormal peptides that accumulate intracellularly and
eventually lead to cell death. These antibiotics arebactericidal.
 Subclassification and tested examples : gentamicin (Garamycin)

Vancomycin
 Coverage : gram-positive bacteria
 Mechanism
o bactericidal
o an inhibitor of cell wall synthesis
 Resistance
o increasing emergence of vancomycin-resistant enterococci has resulted in the development of
guidelines for use by the (CDC)
o indications for vancomycin
 serious allergies to penicillins or beta-lactam antimicrobials
 serious infections caused by susceptible organisms resistant to penicillins (MRSA, MRSE)
 surgical prophylaxis for major procedures involving implantation of prostheses in institutions
with a high rate of MRSA or MRSE
Rifampin
 Most effective against intracellular phagocytized Staphylococcus aureus in macrophages
Linezolid
 Linezolid binds to the 23S portion of the 50S subunit and acts by preventing the formation of
the initiation complex between the the 30S and 50S subunits of the ribosome.
Splenectomy
 Splenectomy patients or patients with functional hyposplenism require the following vaccines and/or
antibiotics
o Pneumococcal immunization
o Haemophilus influenza type B vaccine
o Meningococcal group C conjugate vaccine
o Influenza immunization
o Lifelong prophylactic antibiotics (oral phenoxymethylpenicillin or erythromycin)
4. Anti-inflammatory Medications
Introduction
 Non-steroidal anti-inflammatory drugs (NSAIDS) have the following effects
o anti-inflammatory
o antipyretic
o analgesic
o antiplatelet
 Mechanism
o inhibit the COX (cyclooxygenase) enzymes ultimately inhibiting the synthesis and release of
prostaglandins
 COX enzymes catalyze the formation of prostaglandins and thromboxane from arachidonic
acid
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o There
are two different COX enzymes targeted
 COX inhibitors
 target both COX-1 and COX-2
 COX-2 specific inhibitors
 target COX-2 alone and do not affect COX-1 function
 Indications
o pain
o heterotopic ossfication prophylaxis
 Contraindications
o severe renal disease
o gastric ulcers
COX Inhibitors
 NSAIDS inhibit both COX-1 and COX-2
o Aspirin (ASA)
 salicylate that irreversibly binds a serine COX enzyme residue
 half life >1 week
 binds to COX and blocks active site
 inhibits thromboxane A2 blocking platelet aggregation
o ibuprofen
 reversible competitive COX inhibitor
o indomethacin
 acts on the lipoxygenase side of the arachidonic metabolic pathway
 inhibibits leukotriene inflammatory mediators
COX-2 Specific Inhibitors
 Introduction
o selectively target COX-2 enzymes and do not affect COX-1 function
 examples
 celecoxib (Celebrex)
 rofecoxib (Vioxx)
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
Benefits
o selective inhibition of COX-2 results in anti-inflammatory action without disrupting the
beneficial effects of COX-1 (maintaining gastric mucosa, regulating renal blood flow,
influencing platelet aggregation)
o can be used in the perioperative period because they do not affect platelet function
o no more efficacious in treating osteoarthritis than non-specific COX inhibitors
 Side effects : cardiac toxicity
Side Effects
 Renal dysfunction
 Gastrointestinal side effects
o pain and dyspepsia
o peptic ulcer perforation, bleeding, or obstruction
 2% to 4% occurence in chronic users
o risk factors
 concurrent anticoagulant use (most important)
 age >60 years
 history of previous gastrointestinal disorder
 Delayed fracture healing
o animal fracture models have shown decreased endochondral ossification in the absence of a
COX-2 enzyme
 Platelet dysfunction
 Cardiac Toxicity
Corticosteroids (Systemic)
 Steroid Dose Pack
o efficacy
o side effects
Corticosteroid Intra-articular-Injections
 Efficacy
 Side Effects
o Local flare
o Fat atrophy
o Skin pigmentation changes
o Facial flushing
5. Analgesic Medications
Introduction
 Definitions
o acute pain
 implies presence of tissue damage
o chronic pain (3-6 months)
 no implication of tissue damage necessary
o pathologic pain
 pain from abnormal nervous system functioning (neuropathic)
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
Pathophysiology
o afferent pain pathways
 nociceptors
 transduce signal through various substances
 Substance P
 a sensory neurotransmitter that plays an important role in pain
 depletion of substance P increases the threshold to painful stimuli
 Capsaicin is thought to function by decreasing Substance P
 peripheral nerves
 nociceptors transmit pain to type A and C peripheral nerve fibers
 spinal cord
 peripheral nerves transmit the pain signal via the dorsal column and spinothalamic tract
 brainstem
 spinal cord transmits the pain signal to the thalamus
 site of pain modulation with endogenous opiates
 Agents (details below)
o Acetaminophen
o NSAIDS
o Opiates
o Gaba synthesis agents
o Adjunctive agents
Indications & Special Consideratoins
 Pediatric patients
o follow specific dosing guidelines for children which have been tested and recommended by the
American Academy of Pediatrics
 Geriatric patients
o may have increased sensitivity to opioid pain medicines with higher rates of side effects
 decreased total body mass with increased body fat percentage
 potentially decreased hepatic and renal function
 Obese patients
o achieving adequate peri-operative pain control in the morbidly obese can be difficult
o the most accurate method to control pain and avoid respiratory depression should include patient
controlled analgesia (PCA), which is based on the patient's ideal weight
o intramuscular injections should be avoided due to the difficulty of avoiding injection into muscle
and the poor vascularity of the subcutaneous adipose tissue
 Red-haired patients
o often require more anaesthesia to maintain MAC levels and higher opioid dosages
postoperatively compared to other hair types
 Chronic regional pain syndrome
o Vitamin C has been shown to possibly prevent CRPS specifically related to distal radius
fractures
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Acetaminophen
 Mechanism
o not fully understood
o inhibits prostaglandin synthesis
o minimal antinflammatory effects
 As effective for pain control as aspirin
 Toxicity
o overdose leads to hepatic disfunction
o contraindicated in the setting of pre-existing hepatic dysfunction
NSAIDs
 Mechanism : decrease transduction of pain
 See anti-inflammatory medications
Local anesthetics
 Mechanism
o decrease transduction of pain
o interfere with nerve conduction to provide a reversible loss of sensation in a specific location
 affects the depolarization phase of action potentials (cells fail to depolarize enough to fire
after excitation leading to a blocked action potential)
 Examples
o amide family
 lidocaine (Xylocaine)
 bupivacaine (Marcaine)
o esters of p-aminobenzoic acid
 procaine (Novocain)
 butethamine (Monocaine)
o esters of meta-aminobenzoic acid
 cyclomethycaine (Surfacaine)
 metabutoxycaine (Primacaine)
o esters of benzoic acid
 cocaine
 ethyl aminobenzoate (Benzocaine)
 Adverse effects
o FDA warning on the administration of continuous intra-articular infusion of local anesthetics for
pain control
 Some patients have been noted to have chondrolysis following infusion
Opiates
 Overview
o useful in chronic nociceptive pain
 Mechanism
o perispinal method affects modulation of pain
o systemic opiates change the perception and modulation of pain
 Administration
o oral, IV, intraspinal
o oral administration preferred (more convenient and less costly)
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bony procedures require more analgesia than soft tissue procedures
compliance can improve with long-acting preparations that providue more uniform serum
drug levels
o implantable systems are available for intrathecal administration
 Prescription dosing guide for upper extremity surgery
o no narcotics
 trigger finger release, nonop Dupuytren's release, small lumps/bumps
o 10 narcotic tablets
 mucous cyst, carpal tunnel, deQuervain‟s, Dupuytren‟s releases and small joint fusion
o 20 narcotic tablets
 wrist ganglion cysts, hand fracture ORIF, LRTI and tendon transfers
o 40 narcotic tablets
 large trauma, wrist fusion, open carpal surgery and DRUJ reconstruction
 Chronic use
o addiction occurs in a minority of patients
o chronic opiates should be prescribed by pain management specialists
o written contracts should be obtained
o prescriptions should always be refilled in person

o patient
Methadone
 Synthetic diphenylheptaine-derivative opioid receptor agonist
 High bioavailability (three times as much as morphine), effective, and inexpensive
 Metabolism
o cytochrome P450 system
 Rapid distribution phase (2-3 hours) and prolonged elimination phase (15-60 hours)
 Caution
o can accumulate to high levels with repeated dosing
o rates of elimination vary considerably
o risk of respiratory depression, cardiac toxicity (torsades de pointes)
o consult with a qualified pain specialist when prescribing for the first-time
GABA agents
 Agents
o Pregabalin (Lyrica)
o Gabapentin (Neurontin)
 Mechanism
o decrease transduction of pain
 Reduce hyper-excitability of voltage dependent Ca2+ channels in activated neurons.
 Gabapentin is an anticonvulsant also used to treat neuropathic pain
o binds presynaptic calcium channels to inhibit release of neurotransmitters
 Efficacy
o evidence of effectiveness primarily for postherpetic neuralgia, diabetic nueropathy, and
fibromyalgia
o little evidence for other uses, though often prescribed for other forms of chronic neuropathic pain
(such as complex regional pain syndrome, CRPS)
o gabapentin has been shown to be as effective and less expensive than pregabalin
 Discontinuation requires a tapering dose
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Muscle relaxants
 Overview : Useful to treat pain secondary to muscle spasms
 Agents
o Cyclobenzaprine (Flexeril)
 mechnism of action not fully understood
 centrally acting
 potentiates norepinephrine and binds serotonin receptors
 Use
o may decrease pain during first two weeks after an injury
o no proven benefit after first two weeks
o may be effective for fibromyalgia
o not effective to reduce spasticity secondary to neuromuscular disorders
 Toxicity
o overdose rare
o may interact with other substances
 MAOIs
 alcohol
Adjuvant agents
 Heterogeneous class of medications the provide additive analgesic effect to traditional NSAIDs and
opioids
o anticonvulsants
o antidepressants
o antihistamines
o psychostimulants
o anti-spasmodics
6. Anesthesia
Anesthesia
 Components of anesthesia
o amnesia
o anxiolysis
o analgesia
o akinesia
o attenuation of autonomic repsonses to noxious stimuli
General Anesthesia
 Pharmacologically induced, reversible loss of conciousness, irrespective of airway management
o inhalational anesthesia
 by volatile liquids vaporized in a carrier gas including
 isoflurane
 sevoflurane
 desflurane
 nitrous oxide
 associated with increased gaseous abdominal distension
 leads to increased difficulty with fluoroscopic identification during pelvic and spinal
procedures
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o intravenous
anesthesia
non-opioids
 propofol
 etomidate
 benzodiazepines
 dexmedetomidine
 ketamine
 opioids
 fentanyl, alfentanil, sufentanil, remifentanil
 morphine
 hydromorphone
 neuromuscular blocking agents
 depolarizing agents
 bind to, depolarize, and transiently block ACh receptor
 short-acting: succinylcholine
 no intermediate or long-acting agents
 non-depolarizing agetns
 bind to and transiently block ACh receptor, but do not depolarize
 no short-acting agents
 intermediate-acting: rocuronium, vecuronium, atracurium, cisatracurium
 long-acting: pancuronium

Local Anesthesia - Upper Extremity
 Interscalene regional block
o indications
 commonly used for shoulder/upper arm/elbow surgery
o technique
 performed by injecting local anesthetic to the nerves of the brachial plexus as it passes
through the groove between the anterior and middle scalene muscles at the level of the
cricoid cartilage
o complications
 sensory neuropathy is most common complication
 Supraclavicular block
o indications
 ideal for operations involving the arm and forearm, from the lower humerus down to the
hand.
o technique
 targets brachial plexus superior to the clavicle
o complications
 nerve injury and intravascular injection
 pneumothorax, dyspnea damage to the subclavian artery
 Infraclavicular block
o indications
 ideal for operations involving the arm and forearm, from the lower humerus down to the
hand.
o technique
 targets brachial plexus inferior to the clavicle
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‎III:5 Location of an infraclavicular block, which is used for operations involving the arm and forearm,
from the lower humerus down to the hand
‎III:6 Axillary block

Axillary block
o indications
 postoperative analgesia for surgery to the elbow, forearm, wrist and hand
 Bier block
o indications
 short (< 60 mins) operative procedures (i.e., carpal tunnel release) in the hand and forearm
o technique
 Esmarch exsanguination and tourniquet inflation
 inject lidocaine through a small, distal (hand) intravenous catheter on the surgical side
 deflate tourniquet after a minimum of 30 minutes to avoid venous release of local anesthetic
and potential local anesthetic systemtic toxicity (LAST)
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Local Anesthesia - Spinal
 Spinal
o indications
 often used for knee and hip arthroplasty
o technique
 a single injection with a small 24 or 27-gauge needle
 combination of morphine and bupivacain is often used
o complications
 spinal headache (decreased with small gauge needle), hematoma and opioid side effects
(nausea, vomiting, purities, respiratory depression)
 Epidural
o indication
 often used for knee and hip arthroplasty
o technique
 similar to spinal anesthesia, except an indwelling catheter is placed
 combination of opioid and local anesthetic
o complications
 postoperative hypotension and motor impairment
 spinal headache, hematoma and opioid side effects (nausea, vomiting, pruritus, respiratory
depression)
 Combined spinal epidural
o indications
 often used for knee and hip arthroplasty
o technique
 an epidural needle is placed into the epidural space and spinal anesthesia is administered
through a spinal needle followed by placing an epidural catheter
o complications
 postoperative hypotension and motor impairment
 spinal headache, hematoma and opioid side effects (nausea, vomiting, purities, respiratory
depression)
Local Anesthesia - Lower Extremity
 Lumbar plexus/ psoas compartment nerve block
o indications
 surgeries involving the hip, anterior thigh and knee
 a sciatic block can be given concomitantly to provide pain relief to the entire lower extremity
o technique
 targets the lumbar plexus (L1 to L4 spinal nerves) which form the obturator nerve, lateral
femoral cutaneous nerve, and femoral nerve
 the injection is usually placed 3-5 cm lateral to the spinous process of L4 and is often guided
by ultrasound and nerve stimulators
o complications
 nerve damage and intravascular injection
 epidural diffusion, retroperitoneal hematomas, intrathecal injections and an increased risk of
falls
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
Femoral nerve block
o indications
 surgeries around the knee
 concomitant sciatic nerve block can be done to increase analgesia around the knee
o technique
 targets the femoral nerve (L2-L4)
 the injection occurs just lateral to the femoral artery and on a line connecting the anterior
superior iliac spine to the pubic symphysis
o complications
 nerve damage and intravascular injection
 increased risk of falls, prolonged quadriceps weakness and infections
 Sciatic nerve block
o indications
 surgeries involving the leg, ankle and foot
 can be combined with the femoral or lumbar plexus block to provide analgesia to the entire
lower extremity
o technique
 targets the sciatic nerve providing analgesia to the common peroneal and tibial nerves
 multiple techniques have been described
 lines are drawn between the greater trochanter and the posterior superior iliac spine
(PSIS), and the greater trochanter and the sacral hiatus
 halfway between the greater trochanter and the PSIS a perpendicular line is drawn, and
the injection is placed where the perpendicular line crosses the line between the greater
trochanter and the sacral hiatus
 complications
 nerve damage and intravascular injection
 vascular injury, heel ulcers and a delay in diagnosis of nerve injuries after surgery
 Obturator nerve block
o indications
 adductor muscle spasm, severe hip pain from osteoarthritis
 adjuvant pain management for knee surgeries
o technique
 targets the anterior and posterior branch of the obturator nerve
 blocking the anterior branch leads to decreased sensation at the hip joint and inner thigh,
where blocking the posterior branch decreases sensation around the knee
 injection site is usually 2 cm inferior
and 2 cm lateral to the pubic tubercle
o complications
 nerve injury and intravascular
injection
 damage to structures in the pelvic
cavity
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
Popliteal nerve block
o indications
 used for surgery around the foot and ankle
 often used in conjunction with the saphenous nerve block
o technique
 targets the sciatic nerve prior to its bifurcation
 injection site is often 10 cm proximal to the popliteal crease
o complications
 nerve injury and intravascular injection
 hematoma, persistent foot drop and pressure sores
 Saphenous nerve block
o indications
 procedures around the medial aspect of the knee, leg and ankle
o technique
 targets the saphenous nerve
 multiple different techniques, but it is often blocked behind the sartorius muscle
o complications
 nerve injury and intravascular injection
 hematoma and infection
Blood Management
 Risks of transfusion
o transfusion errors
o allergic reaction
o infection
o down-modulation of immune system
 Ways to reduce postop anemia and need for allogeneic transfusion
o surgical
 hemostasis
 meticulous dissection
o transfusion triggers
 example of strict transfusion triggers based on hemoglobin levels
 average patient, 8.1g/dl
 young (<60yr) patients without co-morbidity, 6.5g/dl
 compromised patients, 9.7g/dl
o subcutaneous epoetin injections
 used preop for patients with low Hb (10-13g/dl)
 able to bring up Hb by 1.9d/dl
 administer with supplementary PO iron
 dosing
 long interval to surgery
 600IU/kg once weekly x 3wk before surgery
 short interval to surgery
 300IU/KG daily x 2wk
o autologous blood donation (ABD) and acute normovolemic hemodilution (ANH)
 ABD
 donate 1-2 units preoperatively
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ANH
 collect 2-3 units at 1 hour preoperatively
 receive crystalloid/colloid intraoperatively
 re-infuse ABD blood postoperatively
o COX2 inhibitors analgesia (instead of COX1 NSAIDS)
 Avoids antiplatelet effects of
o anti-coagulation management
 stop anticoagulation a few days preoperatively
 restart just before surgery
o platelet rich plasma (PRP), fibrin sealants, anti-fibrinolytics
 PRP
 apply PRP to wounds might reduce capsule/subcutaneous bleeding
 fibrin sealants
 very low risk of infection from microbial/viral contamination during processing
 antifibrinolytics
 aprotinin
 tranexamic acid (TXA)
 topical
 IV
o hypotensive epidural anesthesia (HEA)
 epidural dermatomal block from T2 distal
 blocks cardio-accelerator fibers of sympathetic chain
 causes bradycardia which is treated with low-dose epinephrine
 lowers MAP to 50mmHg
 keeps normal heart rate, CVP, stroke volume, cardiac output
 can be used in high risk patients with
 hypertension
 poor cardiac function
 chronic kidney disease
o cell saver
 expensive
 intraoperative
 washed vs unwashed (filtered)
 indications
 revision surgery
 high EBL
 contraindications
 infection
 malignancy
 EBL <500ml
 postoperative
 filtering of shed blood (trap clots and debris)
 within 6h of end of surgery to avoid bacterial contamination, febrile reaction
 after 6h, converted to vacuum drain (not retransfused)

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Medications & Toxicity | Medications
Complications
 Malignant hyperthemia
o rare (1:15,000 to 1:50,000) life-threatening condition
o autosomal dominant transmission
 abnormalities in the ryanodine receptor (RYR1) gene
o triggers
 volatile inhalational anesthetic agents
 succinylcholine
o symptoms
 hypermetabolic state
 increased skeletal muscle contraction and metabolism
 rigidity
 masseter spasm
 rapid oxygen depletion
 increased carbon dioxide concentration (EtCO2) and body temperature
o outcome
 if untreated, leads to circulatory collapse and death
o treatment
 provide antidote
 active cooling
o antidote
 dantrolene (calcium blocker)
 Local anesthetic systemic toxicity (LAST)
o intravascular bupivicaine
 effect
 CNS
 seizures, coma, respiratory arrest
 CVS
 asystole, ventricular fibrillation, cardiac arrest
 antidote
 intravenous 20% lipid emulsion
 Bone cement implanation syndrome
o associated with use of bone cement during joint arthroplasty procedures
o symptoms
 hypotension
 hypoxemia
o treatment
 intravenous fluids
 vasopressors
 100% inspired oxygen
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7. Platelet-Rich Plasma
Introduction
 Platelet rich plasma (PRP) consists of plasma sample from one's own blood enriched with
autologous platelets
o indications
 controversially used in orthopaedics for possible stimulation of bone and soft tissue healing
o preparation technique
 PRP is created by centrifugation of blood to separate platelet rich plasma layer from a sample
of whole blood
 calcium chloride used to initiate platelet activation in the prepared sample of PRP
o optimal concentration
 3-5x that of whole blood
 >5x inhibits healing
 Platelet function
o plays an important role in the inflammatory cascade response after injury
o growth factors released from platelets include
 PDGF
 TGF-B
 VEGF
 IGF-1
 EGF (epidermal growth factor)
 CTGF (connective tissue growth factor)
 FGF-2
 Proposed function of PRP
o increase ECM deposition
o reduce pro-apoptotic signals
o minimize joint inflammation
Clinical Application
 PRP efficacy is controversial due to small amount of high level studies in literature
o soft tissue injury healing
 no consensus for acute ligamentous, tendon and muscle injuries or chronic tendonopathies
o osteoarthritis
 no consensus in evidence, lack of studies with long term followup
o fracture healing / fusion
 limited evidence for bone formation (some studies show detrimental effects)
o ACL reconstruction
 literature does NOT support PRP for ligamentization/graft maturation, patient reported
outcomes
 direct application to patellar and tibial plug donor sites (BPTB) linked to improved patientreported outcomes of knee function and decreased patellar tendon gap
o meniscal repair
 no clear evidence to support use in meniscal repair
o rotator cuff repair
 no benefit in augmenting RC repair (possible detrimental effects)
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Medications & Toxicity | Toxicology
o tendon
healing
lateral epicondylar tendinosis (tennis elbow)
 potential benefit (improved patient reported outcomes and pain scores)
 midsubstance/insertional Achilles tendinopathy
 current literature does NOT support

Summary
 Potential benefits for BPTB donor sites and tennis elbow
B. Toxicology
1. Lead Toxicity
Lead Toxicity
 Lead toxicity inhibits parathyroid hormone-related peptide (PTHrP) and may affect bone mineral
density
 Imaging
o radiographs can reveal radiodense metaphyseal bands
‎III:7 Lead toxicity
Collected By : Dr AbdulRahman
AbdulNasser
drxabdulrahman@gmail.com
In June 2017
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ORTHO BULLETS
IV. Clinical Science
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By Dr, AbdulRahman AbdulNasser
Clinical Science | Clinical Studies
A. Clinical Studies
1. Statistic Definitions
Introduction
 This topic covers the following statistical principles
o Measures of Central Tendency
o Sensitivity
o Specificity
o False Positive Rate
o False Negative Rate
o Positive Predictive Value
o Negative Predictive Value
o Likelihood Ratio
o Incidence
o Prevalence
o Relative Risk
o Odds Ratio
o Number Needed to Treat
o Post-test Odds of Disease
o Power
o Effect Size
o Variance
o Type II (beta) Error
o Type I (alpha) Error
o Confidence Interval
o Statistical Inference
o Funnel plot
Measures of Central Tendency
 Mode
o defined as the value that occurs most often
o best for nominal data
o not very descriptive
o does not use all data values
o some distributions are multimodal
 Median
o defined as the value that occurs at the middle of all values of the variable (half are greater, half
are less)
o not affected by extreme values
o always exists
o easy to compute
o good for all levels of measurement except nominal data
o expecially good for skewed distributions
o does not use all data values
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Mean
o defined as arithmetic average
o the most frequently used measure of central tendency
o uses all values of data
o highly sensitive to extreme values (especially skewed distributions)
Sensitivity
 Definition
o probability that test results will be positive in patients with disease
 Equation
o sensitivity = a / (a + c) or
o sensitivity = TP / (TP + FN)
 Relevance
o sensitive tests are useful for screening since they are unlikely to miss a patient with disease
 Example
o a new test is developed to quickly diagnose HIV. There are 10 patients in the study group with
the disease. Upon testing of all 10 patients, only 6 results return positive. What is the sensitivity
of the new test?
o solution
 sensitivity = a / (a + c)
 sensitivity = 6 / 10
 sensitivity = 60%
disease pos
disease neg
test pos
true positive
a (6)
false positive
b
test neg
false negative
c (4)
true negative
d
TOTAL
10
b+d
Specificity
 Definition
o probability test result will be negative in patients without disease
 Equation
o specificity= d / (b + d) or
o specificity = TN / (FP + TN)
 Relevance
o specific tests are useful for confirmation as they don't result in treatment of an unaffected
individual
 Example
o in a population of 90 patients who are disease free, a test incorrectly diagnoses 5 patients with
disease. What is the specificity of this test?
o solution
 specificity = d / (b + d)
 specificity = 85 / 90
 specificity = 94.4%
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Clinical Science | Clinical Studies
disease pos
disease neg
test pos
true positive
a
false positive
b (5)
test neg
false negative
c
true negative
d (85)
TOTAL
a+c
b + d (90)
False Positive Rate
 Definition
o patients without the disease who have a positive test result
 Equation
o false positive rate = b / (b + d)
disease pos
disease neg
test pos
true positive
a
false positive
b
test neg
false negative
c
true negative
d
False Negative Rate
 Definition
o patients with disease who have a negative test result
 Equation
o false negative rate = c / (a + c)
disease pos
disease neg
test pos
true positive
a
false positive
b
test neg
false negative
c
true negative
d
Positive Predictive Value
 Definition
o probability patient with a positive test actually has the disease
o dependent on prevalence of disease
 Equation
o PPV = a / (a + b) or
o PPV = TP / (TP + FP)
 Example
o you are evaluating a new serum diagnostic test for Lyme disease that claims sensitivity 90% and
specificity 0f 95%. The prevalence of Lyme disease is known to be 10% in late spring in the
study of patients who present with fever, arthralgias, and rash.
o solution
 using sensitivity, specificity, and prevalence to calculate the quadrants
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disease pos
disease neg
test pos
true positive
a (9)
false positive
b (4.5)
test neg
false negative
c (1)
true negative
d (85.5)
TOTAL
a+c (10)
b+d (90)
PPV = a / (a + b)
 PPV = 9 / (9 + 4.5)
 PPV = 67%

Negative Predictive Value
 Definition
o probability patient with a negative test actually has no disease
o dependent on prevalence of disease
 Equation
o NPV = d / (c + d) or
o NPV = TN / (FN + TN)
 Example
o 200 patients are enrolled in a study to evaluate the accuracy of a ELISA-based test for the
diagnosis of influenza. 100 patients were diagnosed by the gold-standard method. 80 of the
patients with influenza had a positive ELISA-based test as did 5 of the patients without
influenza. What is the negative predictive value of this test?
o solution
 NPV = TN / (FN + TN)
 NPV = 95 / (20 + 95)
 NPV = 83%
disease pos
disease neg
test pos
true positive
a (80)
false positive
b (5)
test neg
false negative
c (20)
true negative
d (95)
Likelihood Ratio
 Definition
o likelihood that a given test result would be expected in a patient with the target disorder
compared to the likelihood that that same result would be expected in a patient without the target
disorder
 Classification
o positive likelihood ratio
 definition
 describe how the likelihood of a disease is changed by a positive test result
 equation : positive likelihood ratio = sensitivity / (1 - specificity)
o negative likelihood ratio
 definition
 describe how the likelihood of a disease is changed by a negative test result
 equation : negative likelihood ratio = (1 - sensitivity) / specificity
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Incidence
 Number of newly reported cases of a disease in specific time period per unit measurement of
population
Prevalence
 The total number of cases of a disease present in a location at any time point
Relative Risk
 Definition
o risk of developing disease for people with known exposure compared to risk of developing
disease without exposure
 obtained from cohort studies
 when RR > 1, the incidence of the outcome is greater in the exposed/treated group
 Equation
o incidence risk of YES = a / (a + b)
o incidence risk of NO =c / (c + d)
o relative risk = [(a / a + b)] / [(c / c + d)]
Disease Status

Risk
Present
Absent
Yes
a
b
No
c
d
Example
o a study is performed concerning the relationship between blood transfusions and the risk of
developing hepatitis C. A group of patients is studied for three years.
Disease Status
Transfused

Hepatitis C
Healthy
Yes
75
595
No
16
712
solution
o disease incidence in transfused
 "YES" = 75 / (75 + 595) = .112
o disease incidence in patients not transfued
 "NO" = 16 / (16 + 712) = .022
o relative risk (RR) = 0.112 / 0.022 = 5.09
Odds Ratio
 Definition
o probability of having a risk factor if one has a disease
 obtained from case control studies (retrospective)
 Equation
o OR = (odds of developing disease in exposed patients) / (odds of developing disease in
unexposed patients)
Number Needed to Treat
 Definition
o number of patients that must be treated in order to achieve one additional favorable outcome
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
Equation
o number needed to treat = (1 / absolute risk reduction)
 Example
o you learn the number-needed-to-screen with FOBT is nearly 1000 to prevent colon cancer. What
is the absolute risk reduction associated with FOBT?
o solution
 absolute risk reduction (ARR) = 1 / number needed to treat
 ARR = 1 / 1000
 ARR = .1%
Post-test Odds of Disease
 Equations
o post-test probability = (pretest probabililty) X (likelihood ratio)
 likelihood ratio = sensitivity / (1 - specificity)
 pre-test odds = pre-test probability / (1 - pre-test probability)
o post-test probability = post-test odds / (post-test odds + 1)
Power
 Definition
o an estimate of the probability a study will be able to detect a true effect of the intervention
 Equation
o power = 1 - (probability of a type-II, or beta error)
Effect size
 Definition
o magnitude of the difference in the means of the control and experimental groups in a study with
respect to the pooled standard deviation
Variance
 Definition
o an estimate of the variability of each individual data point from the mean
Type II Error (beta)
 Definition
o a false negative difference that can occur by
 detecting no difference when there is a difference or
 accepting a null hypothesis when it is false and should be rejected
 Equation
o power = 1 - (type-II error)
 Clinical significance
o a study that fails to find a difference may be because
 there actually is no difference or
 the study is not adequately powered
Type I Error (alpha)
 Definition
o null hypothesis is rejected even though it is true
 Clinical significance
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Clinical Science | Clinical Studies
o by
definition, alpha-error rate is set to .05, meaning there is a 1/20 chance a type-I error has
occurred
 Related principle
o Bonferroni correction
 post-hoc statistical correction made to P values when several dependent or independent
statistical tests are being performed simultaneously on a single data set
Confidence Interval
 Definition
o the interval that will include a specific parameter of interest, if the experiment is repeated
Statistical Inference
 Definition
o used to test specific hypotheses about associations or differences among groups of
subjects/sample data
 Classification
o parametric inferential statistics
 continuous data that is normally distributed
o nonparametric inferential statistics
 categorical data that is not normally distributed
 Study types
o when comparing two means
 student t-test
 used for parametric data
 mann-whitney or wilcoxon sum rank test
 used for non-parametric data and
o when comparing proportions or categorical data
 chi-square test
 used for two or more groups of categorical data
 fisher exact test
 used when sample sizes are small or
 number of occurrences in a group is low
Funnel Plot
‎IV:1 Funnel Plot ( clinical significance)
 Definition
o is a simple scatter plot of the intervention effect estimates from individual studies against some
measure of each study‟s size or precision and is used to detect publication bias in meta-analyses
 Clinical Significance
o this method is based on the fact that larger studies have smaller variability, whereas small
studies, which are more numerous, have larger variability. Thus the plot of a sample of studies
without publication bias will produce a symmetrical, inverted-funnel shaped scatter, whereas a
biased sample will result in a skewed plot.
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2. Level of Evidence
Introduction
 A method utilized in evidenced based medicine to determine the clinical value of a study
 See details of Clinical Design Trials
Different Levels of Evidence
Level 1
1. Randomized controlled trial (RCT)
o a study in which patients are randomly assigned to the treatment or
control group and are followed prospectively
2. Meta-analysis of randomized trials with homogeneous results
Level 2
1. Poorly designed RCT
o follow up less than 80%
2. Prospective cohort study (therapeutic)
o a study in which patient groups are separated non-randomly by
exposure or treatment, with exposure occurring after the initiation of
the study
3. Meta-analysis of Level 2 studies
Level 3
1. Retrospective cohort study
o a study in which patient groups are separated non-randomly by
exposure or treatment, with exposure occurring before the initiation
of the study
2. Case-control study
o a study in which patient groups are separated by the current
presence or absence of disease and examined for the prior exposure
of interest
3. Meta-analysis of Level 3 studies
Level 4
1. Case series
o a report of multiple patients with the same treatment, but no control
group or comparison group
Level 5
1. Case report (a report of a single case)
2. Expert opinion
3. Personal observation
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Clinical Science | Clinical Studies
JBJS LOE
AAOS Recommendations
AAOS Evidence-Based Practice Committee
Recommendations in Clinical Practice Guidelines
Strong
• Two or more HIGH quality studies
Moderate
• One HIGH or 2 MODERATE quality studies
Weak
• One MODERATE or 1 or more LOW quality studies
Consensus • Expert opinion (no studies)* Only used in one circumstance: It pertains to medical
interventions that potentially prevent loss of life or limb (catastrophic consequences).
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3. Clinical Trial Design
Introduction
 Clinical trial design impacts Level of Evidence
 Clinical trials may be either observational or experimental
o observational
 researchers observe patient groups without allocation of intervention
 may be either prospective or retrospective
 may be descriptive or analytic
 descriptive
 useful for obtaining background information for more advance studies
 examples
 case reports
 case series
 cross-sectional studies
 analytic
 explores the association between a given outcome and a potentially related variable
 examples
 case-control
 cohort
 meta-analysis
o experimental
 researchers allocate treatment
 allows the evaluation of efficacies of therapeutic interventions
 examples
 double-blinded, prospective, randomized clinical trial is the gold standard for evidence
based medicine
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Clinical Science | Clinical Studies
Randomized controlled trial
 Definition
o a study in which patients are randomly assigned to the treatment or control group and are
followed prospectively
o provides the most compelling evidence that the study treatment causes the expected effect on
human health
o randomization minimizes study bias
 Crossover design
o administration of two or more therapies, one after the other, in a random order
o susceptible to bias if washout period is inadequate
o single blinded study vs. double blinded study
 Analysis
o intent-to-treat analysis
 outcomes based on the group into which they were randomized, regardless of whether the
patient actually received the planned intervention
 minimizes non-responder bias
o per protocol
 excludes patients who were not compliant with the protocol guidelines
 Example
o you want to determine whether your new toothpaste prevents cavities better than your old
toothpaste. You randomly assign a large number of patients to either an intervention group,
which uses the new toothpaste, or to a control group, which uses the old toothpaste. You would
then measure the amount of cavities between the groups over time.
 Orthopaedic Literature Examples
o Surgical vs nonoperative treatment for lumbar disk herniation: the Spine Patient Outcomes
Research Trial (SPORT): a randomized trial. JAMA. 2006.
o Should insertion of intramedullary nails for tibial fractures be with or without reaming? A
prospective, randomized study with 3.8 years' follow-up. J Orthop Trauma. 2004.
o Nonoperative treatment compared with plate fixation of displaced midshaft clavicular fractures.
A multicenter, randomized clinical trial. J Bone Joint Surg Am. 2007.
Cohort study
 Definition
o a study in which patient groups are separated non-randomly by exposure or treatment, with
exposure occurring after (prospective), or before (retrospective), the initiation of the study
 Evidence
o Level II or III evidence
 Analysis
o results usually reported as relative-risk
 Example
o you want to determine if smoking is a risk factor for the development of lung cancer. You
identify a group of smokers and a group of non-smokers, and follow them over time measuring
the desired outcome, in this case, lung cancer.
 Orthopaedic Literature Examples
o A prospective cohort study of the effects of lower extremity orthopaedic surgery on outcome
measures in ambulatory children with cerebral palsy. J Pediatr Orthop. 2009.
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o Functional
outcomes following displaced talar neck fractures. J Orthop Trauma. 2004.
of revision for fixed versus mobile-bearing primary total knee replacements. J Bone Joint
Surg Am. 2012.
o Risk
Case-control study
 Definition
o a study in which patient groups are separated by the current presence (cases) or absence
(controls) of disease and examined for the prior exposure of interest
 Evidence
o Most are Level III evidence
 Analysis
o usually reported as odds-ratio
 Example
o you want to determine if smoking is a risk factor for the development of lung cancer. You
compare the smoking history of individuals with lung cancer (cases) and those without
(controls).
 Orthopaedic Literature Examples
o Fluoride in drinking water and risk of hip fracture in the UK: a case-control study. Lancet. 2000.
o Risk factors for retained instruments and sponges after surgery. N Engl J Med. 2003.
o Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care
setting in the United Kingdom. Arch Intern Med. 2007.
Meta-analysis
 Definition
o a systematic review that summarizes results of other studies
 Evidence
o may be used in increase the statistical power of several under-powered studies
 Example
o you want to determine if wearing sunscreen results in fewer cases of melanoma. You pool the
results of 9 randomized controlled studies and statistically analyze the data to determine the
effect of the relationship.
 Orthopaedic Literature Examples
o Internal fixation compared with arthroplasty for displaced fractures of the femoral neck. A metaanalysis. J Bone Joint Surg Am. 2003.
o Vertebroplasty and kyphoplasty: a systematic review of 69 clinical studies. Spine (Phila Pa
1976). 2006.
o Influence of osteoporosis on fracture fixation--a systematic literature review. Osteoporos Int.
2008.
Cross-sectional Study
 Definition
o study group is analyzed at a given time ("snapshot") with no follow-up
 Example
o you want to determine the prevalence of baseball injuries during the 2003 little-league season
 Orthopaedic Literature Examples
o Variability in the definition and perceived causes of delayed unions and nonunions: a crosssectional, multinational survey of orthopaedic surgeons. J Bone Joint Surg Am. 2012.
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Clinical Science | Clinical Studies
o Hypovitaminosis
D in patients scheduled to undergo orthopaedic surgery: a single-center
analysis. J Bone Joint Surg Am. 2010.
o Treatment preferences for displaced three- and four-part proximal humerus fractures. J Orthop
Trauma. 2010.
Case Series
 Definition
o a retrospective account of multiple patients with the same injury or treatment with no control or
comparison group
 useful for generating hypotheses for additional studies
 Evidence
o level IV evidence
 Example
o you have found that several of your patients who have used a new lipid lowering medication
have developed hemorrhagic cysts. You want to alert other members of the community of this
possible association.
 Orthopaedic Literature Examples
o Familial bilateral osteochondritis dissecans of the femoral head. J Bone Joint Surg Am. 2009.
o Familial osteofibrous dysplasia. A case series. J Bone Joint Surg Am. 2005.
o Treatment of posterior cruciate ligament tibial avulsion fractures through a modified open
posterior approach: operative technique and 12- to 48-month outcomes. J Orthop Trauma. 2008.
4. Outcome Measure Tools
SF-36
 Overview
o a generic, multi-purpose, short-form health survey consisting of 36 questions
o useful for
 surveys of general and specific populations
 comparing the relative burden of diseases
 differentiating the health benefits produced by a wide range of different treatment
o example
 polytrauma patients with foot injury have lower SF-36 scores than polytrauma patients
without foot injury
 SF-12 (shortened version with 12 questions)
 Self-rated preinjury pain-related disability is a predictor of moderate to severe pain 6
months after musculoskeletal injury as measured by SF-12
 Structure
o consists of 8 scaled scores, which are the weighted sums of the questions in their section
o each scale is directly transformed into a 0-100 scale on the assumption that each question carries
equal weight
o 8 scales include
1. vitality
5. physical role functioning
2. physical functioning
6. emotional role functioning
3. bodily pain
7. social role functioning
4. general health perceptions
8. mental health
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Clinical Science | Clinical Studies
Harris Hip Score

Tool for evaluating patient after total hip replacement
o scored 0-100
 score is reported as
 90-100: excellent
 80-90: good
 70-79: fair
 60-69: poor
 below 60: a failed result
 Four categories
o pain
 no pain given 44 points
o function
 no limp, walks without aid, and can walk more than six blocks given 33 points
o function activities
 no disabilities given 14 points
o physical exam
 based on range of motion with maximum score of 9
 Score does not allow for individual differences based on age, health, or other personal issues that
may affect the total score
Foot and Ankle Outcome Score
 Developed to assess the patients opinion about a variety of foot and ankle related problems
o commonly used in patients with
 lateral ankle instability
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By Dr, AbdulRahman AbdulNasser
Clinical Science | Clinical Studies
Achilles tendinosis
plantar fasciitis
 Consists of 5 subscales:
o pain
o other symptoms
o function in daily living (ADL)
o function in sport and recreation
o foot and ankle-related Quality of Life (QOL)
 Scoring
o last week is taken into consideration when answering the questionnaire
o each question gets a score from 0 to 4
 normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is
calculated for each subscale.
 the result can be plotted as an outcome profile


Constant Shoulder Outcome Score
 Scoring
o scored form 0-100
o consists of four variables that are used to assess
the function of the shoulder; right and left
shoulders are assessed separately
 4 variables include
o pain score
 subjective measurment, score for no pain is 15
o functional assessment
 subjective measurment, score for no
functional deficit is 20
o range of motion
 objective measurment, full range of motion
score is 40
o strength measures
 objective measurment, full strength score is
25
UCLA Shoulder Score
 Overview
o a shoulder scoring system
 Categories
o consists of 5 sections:
 pain
 function
 active forward flexion
 strength of forward flexion
 satisfaction of patient
 Scoring
o score of >27 indicates good or excellent results
o maximum score is 35
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Clinical Science | Clinical Studies
Disabilities of the Arm, Shoulder, and Hand (DASH) Score
 Overview
o 30-item, self-report questionnaire
o measures physical function and symptoms in people with musculoskeletal disorders of the upper
limb
 Scoring
o scored in two components
 disability/symptom section (30 items, scored 1-5)
 optional high performance sport/music or work section (4 items, scored 1-5)
o DASH disability/symptom score = [(sum of n responses/n) - 1] x 25
 n is equal to the number of completed responses
 a DASH score may not be calculated if there are greater than 3 missing items
o optional module scoring
 add up assigned values for each response; divide by 4 (number of items); subtract 1; multiply
by 25
 an optional module score may not be calculated if there are any missing items
Oswestry Disability Index
 Overview
o important tool that researchers and disability evaluators use to measure a patient's permanent
functional disability
o considered the „gold standard‟ of low back functional outcome tools
 Scoring
o consists of 10 sections, and for each section the total possible score is 5
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By Dr, AbdulRahman AbdulNasser
Clinical Science | Clinical Studies
o if
all 10 sections are completed the score is calculated as follows:
Example: 16 (total scored), 50 (total possible score) x 100 = 32%
o if one section is missed or not applicable the score is calculated:
 16 (total scored) 45 (total possible score) x 100 = 35.5%
o interpretation of scores

Survivorship Analysis
 Overview
o often used to measure success of joint replacements
o analyzes data from patients with different lengths of follow-up
 for analysis, it is assumed that all patients had their operation simultaneously
o chance of implant surviving for a particular length of time is calculated as the survival rate
 calculation method is either life table or product limit method
 LIfe table method
o number ofjoints being
 followed and the number of failures are determined for
 each year after operation (number of joints being followed and the number of failures
are determined foreach year after operation each year of follow-up, failure rate is
calculated from the number of failures and the „number at risk‟
o annual success rate, determined from the failure rate, is cumulated to give a survival rate for each
successive year, this can change only once per year
 Product limit method
o same as life table method, but the survival rate is recalculated each time a failure occurs
Minimal Clinically Important Difference (MCID)
 Difference in outcome measures that will have clinical relevance
 Difficult to study and measure, very few outcome tools have established and universally accepted
MCID
 Helps to reconcile statistical significance and clinical relevance of study results that use outcome
tools.
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OrthoBullets2017
Clinical Science | Healthcare Worplace
B. Healthcare Worplace
1. Occupational Health
Radiation Exposure and Fluoroscopy
 Factors which increase radiation exposure levels during use of fluoroscopy
o imaging large body parts
o positioning extremity closer to the x-ray source
o use of large c-arm rather than mini c-arm
 radiation exposure is minimal during routine use of mini-c-arm fluoroscopy unless the
surgical team is in the direct path of the radiation beam
 Factors to decrease radiation exposure to patient and surgeon
o maximizing the distance between the surgeon and the radiation beam
o minimizing exposure time
o manipulating the x-ray beam with collimation
o orienting the fluoroscopic beam in an inverted position relative to the patient
o strategic positioning of the surgeon within the operative field to avoid direct path of beam
o use of protective shielding during imaging
Risk of Transmission
 Risk of HIV transmission
o needlestick
 seroconversion from a contaminated needlestick is ~ 0.3%
 exposure to large quantities of blood increases risk
 seroconversion from exposure to HIV contaminated mucous membranes is ~0.09%
o frozen bone allograft
 risk of transmission is <1 per million
 donor screening is the most important factor in prevention
 no reported cases of transmission from frozen bone allograft since 2001
o blood transfusion
 risk of transmission from blood transfusion is 1/500,000 per unit transfused
 seronegative blood may still transmit virus due to delay between HIV infection and antibody
development
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By Dr, AbdulRahman AbdulNasser
Clinical Science | Healthcare Worplace

Risk of Hepatitis B transmission
o needlestick
 37% to 62% eventually seroconvert following needlestick
 22 to 31% develop clinical Hepatitis B infection following needlestick
 Risk of Hepatitis C transmission
o needlestick
 0.5 to 1.8% risk of transmission
Resident Surgeon Work Duty Hours
 ACGME has restricted work hours in order to address impaired performance by residents caused by
long duty hours
 Duty hours
o include
 clinical time
 academic hours
 administrative work
 time on call
 no more than 1 day per every 3 days in house
 must include a 10-hour period of "off-time" between
 clinics
 on-call
o restricted to 80 or less per week (averaged over a 4 week period)
o 10% increase allowed if justified by educational value
o 1 day in 7 must be a day off (averaged over 4 week period)
 Results of new duty hours
o early evaluations have caused concern over issues of
 patient safety
 continuity of care
 communication and transfers in care have been cited as sources of decreased continuity of
care as a sequelae of the 80-hour resident physician work week
2. Legal and Ethics
Informed Consent
 Health Information Portability and Accountability Act (HIPAA)
o Provider does not need consent from patient to communicate HIPAA protected information to
other treating providers
 Process for obtaining informed consent for patients included in clinical trials is mandated by the
Institutional Review Board (IRB)
 Elective procedures
o informed consent for an elective surgical procedure is best obtained by the physician in the
office/clinic setting a few days before the scheduled procedure
o must understand the important risks and benefits as well as the indications for and alternatives to
a procedure
o origin of surgical implants should be discussed with patients
 this may have implications for their use based on a patient's religious background
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in Hinduism, use of bovine derived implants should be discussed
 in Judaism and Islam, use of porcine derived implants should be discussed
 Emergent procedures in absence of legal consent
o confirm necessity of procedure
 in situation of required surgery for life threatening injury without available legal consent the
surgeon should confirm and document the necessity of care with a fellow orthopaedic
surgeon or colleague
 in non-life threatening injury, consent must be obtained prior to intervention (e.g. language
barrier, pediatric patient)

Physician errors
 Communication errors are the leading cause of wrong-side surgeries, medication errors, diagnostic
delays or loss to follow-up
 Wrong site surgery
o prevention
 involve the patient in identifying correct side
o response when performed
 address by immediate discussions with family revealing errors
 apologize and accept responsibility, but not blame
 Surgical "time-out"
o should include the following according to JCAHO
 identify correct side, site, and patient
 verify the correct procedure
 surgeon is most effective OR team member at reducing complications when using surgical
checklist and "time-out"
o all members of the team should be present for the time out; alternatively, it can be repeated
 Medication prescribing errors
o reduced when physicians use computerized order entry
o errors in medical documentation
 It is illegal to alter the medical record for any reason
o no one has the authority to authorize a physician to alter the medical record
o errors can be noted and addendums can be added
 Second opinions
o the second opinion surgeon is ethically required to disclose the effect of medical errors on patient
outcome
o the patient can only unilaterally decide to transfer care to the second surgeon; ethically, the
surgeon is not to seek out transfer of care of the patient
Litigation
 Overview
o medical liability lawsuits involving orthopaedic surgeons rose by 13 percent from 2003 to 2008
 thought to be related to aging population
o orthopaedic surgery has the seventh highest # of lawsuits compared to other specialties
o ~33% of all orthopaedic surgery claims results in payment to plaintiffs
o the average cost associated with defending orthopaedic surgery claims is ~ $47,000USD
 Procedures associated with lawsuits (as of 2008)
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By Dr, AbdulRahman AbdulNasser
Clinical Science | Healthcare Worplace
o "improper
performance" makes up 45% of lawsuits
most commonly associated procedures
1. operative procedures of joint structures (not including spinal fusion)
2. open reduction of dislocation
3. closed reduction of fractures
4. operative procedures on bones
5. operative procedures on cranial and peripheral nerves
Most common clinical diagnosis associated with orthopaedic lawsuits (as of 2008)
1. osteoarthritis (21%)
2. disorder of joint, not including arthritis
3. fracture of femur
o the

Legislation
 Patient Protection and Affordable Care Act - 2010
 Physician Payments Sunshine Act - 2010
o Requires collection and reporting of financial relationships between physicians / teaching
hospitals and businesses (manufacturers of drugs, devices, medical supplies)
o All payments beyond $10 must be reported to Centers for Medicare and Medicaid Services
Physician Impairment
 Impairment of a healthcare professional is the inability or impending inability to practice according
to accepted standards as a result of substance use, abuse, or dependency (addiction).
 A surgeon (resident, fellow or attending) who discovers chemical impairment, dependence, or
incompetence in a colleague or supervisor has the responsibility to ensure that the problem is
identified and treated.
Medical Negligence
 Negligence is the failure to provide the standard of health care resulting in medical injuries
 A second-opinion physician has an ethical obligation, but not legal obligation, to disclose if the
standard of care has been breached by a treating physician.
 A successful patient-plaintiff lawsuit for medical negligence against a physician requires that the
following FOUR elements be alleged and proven in a court of law
o duty
 the duty of the physician is to provide care equal to the same standard of care ordinarily
executed by surgeons in the same medical specialty.
o breach of duty
 breach of duty occurs when action or failure to act deviates from the standard of care.
o causation
 causation is present when it is demonstrated that failure to meet the standard of care was the
direct cause of the patient‟s injuries.
o damages
 damages are monies awarded as compensation for injuries sustained as the result of medical
negligence
Workers Compensation
 A Workers' Compensation patient is determined to reach maximum medical improvement
when further restoration of function is no longer anticipated and can then settle his/her claim.
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
Ability for worker's compensation patients to choose their own physician varies by the statutes of
each state.
 Legal definitions
o impairment
 loss of function resulting from an anatomic or physiologic derangement.
o disability
 limitation of an individual‟s capacity to meet certain personal social or occupational
demands.
Relations with Industry and Hospitals
 Acceptable Standards of professionalism
o practicing orthopaedic surgeons may accept tuition, travel, and modest hospitality (including
meals and receptions) to attend an industry sponsored non-CME course given at a local
convention center
o must disclose relationships with industry to patients, colleagues, and their institution
o can only receive gifts with a market value under $100
o no
direct kick-back can be given to a physician from industry or hospital systems
o physicians cannot refer patients to centers in which they have a financial interest (Stark II laws)
Patient Satisfaction & Complaints
 Patient complaints
o a formal written patient complaint regarding quality of care requires a letter of response to the
patient from the surgeon
 Communication
o when surveyed, patients and colleagues describe orthopaedic surgeons as "high tech but low
touch"
o orthopaedic surgeons are described as having poor communication skills and empathy for their
patients
o as communication issues are the number one cause of medical litigation, this is an area where
orthopaedic surgeons need to improve
o translation services can be provided by employees fluent in the languange, commercially
available telephonic services, professional interpreters, and volunteer translators
 inappropriate for family members to act as translator unless patient offers or agrees
Medical Innovation
 Royalties
o if an implant is used by which the surgeon is receiving royalties, this information must be
disclosed to the patient
Patient Transfer
 EMTALA
o all patients must be appropriately screened in the original emergency room/hospital
o risk of patient transfer must be less than the risk of keeping patient
o accepting hospital/center must know of, and accept patient
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By Dr, AbdulRahman AbdulNasser
Clinical Science | Healthcare Worplace
Physician Advertising
 Advertising by physicians becoming more commonplace
o AMA and AAOS can't prevent physicians from advertising services
o FTC, AAOS, state medical boards can sanction for false advertising
o things to avoid
 using terms such as "cure" if no cure truly exists
 using terms such as "painless" or "bloodless" to describe surgery
 overstating credentials such as "board certified in joint replacement" if no such qualification
exists
 using terms such as "world renowned"
Diversity
 Important to understand cultural differences
o patient-physician relationships are enhanced
o disparities in health care are eliminated
o access to orthopaedic care is optimized
 Important to understand your own implicit biases
o Implicit bias is present when your unconscious prejudices or stereotypes influence the care
delivered to the patient.
o Implicit bias is a determinant of health disparities.
Billing & Coding
 The AMA updates Current Procedural Terminology annually
 Evaluation & Management services have defined categories for patients
o new patient
 has not received professional services from the physician or any other providers in the same
practice group and specialty within the last 3 years
o established patient
 has received professional services from the physician or any other providers in the same
practice group and specialty within the last 3 years
o consultation
 service requested by another physician
 advice must be object of request, not transfer of care
 request must be documented in chart
 level of visit must be documented
 written response to requesting physician must be provided by consulting physician
 Access to healthcare
o type of health insurance has been shown to be a determinant of healthcare access in the pediatric
population
Surgical Safety Checklists
 WHO implementation of surgical safety checklists began in 2009
 Implementation has demonstrated measureable improvements in:
o surgical mortality
o in-hospital complications
o adherence to surgical plan in OR crisis situations (e.g., massive hemorrhage, cardiac arrest)
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