Pathology Ch26 -- Bone -- part pp1187-1194
Acquired Disorders of Bone and Cartilage
 Osteopenia and Osteoporosis
o Osteopenia = decreased bone mass
 1-2.5 standard deviations below T-score
o Osteoporosis = osteopenia that is severe enough to significantly increase risk of fractures
 >2.5 standard deviations below T-score
 Also signified by presence of atraumatic or vertebral compression fracture
 Primary: idiopathic, postemenopausal**, senile**
 Secondary:
 Endocrine disorders: Addison disease, diabetes I, hyperparathyroidism, hypothyroidism, pituitary
tumors, neoplasia, carcinomatosis, multiple myeloma
 GI: hepatic insufficiency, malabsorption, nutrition, vitamin C/D deficiencies
 Drugs: alcohol, anticoagulants, anticonvulsants, chemotherapy, corticosteroids
 Miscellaneous: anemia, homocystinuria, immobilization, osteogenesis imperfect, pulm. disease
o Pathogenesis:
 Peak bone mass in young adulthood > small defects occur w/ every reformation cycle > 0.7% loss per year
 Age-related changes:
 Osteoblasts from older individuals have reduced proliferative and biosynthesis
 Cellular response to growth factors bound to ECM becomes weakened in older individuals
 Leads to senile osteoporosis, categorized as a low-turnover variant
 Reduced physical activity:
 Mechanical forces stimulate normal bone remodeling
 Load magnitude influences bone density more than load cycles
 Muscle contraction is the dominant source of skeletal loading
 Resistance training better than endurance exercises
 Leads to senile osteoporosis
 Genetic factors:
 Top associated genes: RANKL, OPG, and RANK > encode key regulates of osteoclasts
 Also, HLA locus (effects of inflammation on Ca++ metabolism) and estrogen receptor gene
 Calcium nutritional state:
 Contributes to peak bone mass
 Deficiency (more common in girls) occurs during period of rapid bone growth
 Ca++ deficiency, increased PTH, and reduced vitamin D > senile osteoporosis
 Hormonal influences:
 Estrogen deficiency in postmenopausal women > yearly loss of 2% cortical/9% cancellous bone
 Women lose 35% cortical/50% cancellous bone by 30-40 years postmenopause
 Decreased estrogen > increase secretion of inflammatory cytokines such as IL-6, IL-1, and TNF-α >
stimulate osteoclast recruitment/activity by increasing RANKL and diminishing OPG
 Estrogen deficiency increases bone resorption and formation, but out of proportion
 Leads to high-turnover osteoporosis
o Morphology:
 Histologically normal bone that is decreased in quantity
 Entire skeleton is affected in postmenopausal and senile osteoporosis, but certain bones tend to be worse
 Postmenopausal: affects bones w/ increased surface area > trabecular plates become perforated, thinned,
and lose their interconnections > progressive microfractures and vertebral collapse
 Senile: cortex thinned by subperiosteal and endosteal resorption, while Haversian system widens
o Clinical Course:
 Cannot be detected in plain radiographs until 30-40% bone mass is lost
 Measurement of blood Ca++, phosphorus, and alkaline phosphatase are not diagnostic
 Best estimates of bone loss are from specialized radiographs (dual energy x-ray absorptiometry and
quantitative CT) that measure bone density
 Prevention and treatment: exercise, Ca++ and vitamin D intake, pharmacologic agents (bisphopshates reduce osteoclast activity and induce apoptosis)
 Hormone replacement therapy has complications (deep vein thrombosis, stroke)
 Denosumab (anti-RANKL antibody) > promising postmenopausal treatment
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Paget Disease (Osteitis Deformans)
o Disorder of increased, but disordered and structurally unsound bone mass
o (1) Initial osteolytic stage, (2) mixed osteoclastic-osteoblastic stage, (3) burned-out quiescent osteosclerotic stage
o Usually begins in late adulthood (~70 yo), prevalently in Anglo-Saxon countries
o Pathogenesis:
 Uncertain cause, possible genetic and environmental factors
 SQSTM1 mutation > increase NF-κB activity > increase osteoclast activity
 Activating RANK mutations + inactivating OPG mutations
 Chronic infections of osteoclast precursors by measles or other RNA viruses may play a role
o Morphology:
 Lytic phase: Waves of osteoclastic activity and numerous resorption pits
 Mixed phase: Bone surfaces now lined by osteoblasts. Adjacent marrow replaced by loose CT.
 Osteosclerotic phase: ***Mosaic pattern of lamellar bone*** Decrease in cell activity.
 Jigsaw puzzle-like appearance produced by unusually prominent cement lines
 Periosseous fibrovascular tissue recedes > replaced by normal marrow
 Ultimately: bone composed of coarsely thickened trabeculae and cortices that are soft and porous
o Clinical Course:
 Most cases are asymptomatic and discovered as incidental radiograph finding
 Axial skeleton or proximal femur involved in 80% of cases
 Localized pain is common, caused by microfractures or overgrowth that compresses nerve roots
 Enlargment of craniofacial skeleton = leontiasis ossea (lion face)
 Weakend pagetic bone may lead to invagination of skull base = platybasia
 Weight bearing causes anterior bowing of the femur and tibiae > secondary osteoarthritis
 Chalk stick-type fractures occur in long bones of lower extremities
 Hypervascularity of Pagetic bone warms the overlying skin
 Variety of tumor and tumor-like conditions develop in Pagetic bones
 Benign lesions = giant cell tumor, giant cell reparative granuloma, extra-osseous masses
 Sarcoma (osteosarcoma or fibrosarcoma) of long bones, pelvis, skull, or spine, <1% of individuals
 W/o malignant transformation, disease is usually mild and suppressed w/ calcitonin and bisphosphates
Rickets and Oteomalacia
o Manifestations of vitamin D deficiency or its abnormal metabolism
o Impairment of mineralization > accumulation of unmineralized matrix
o Rickets = childhood, Osteomalacia = adult counterpart
Hyperparathyroidism
o Autonomous parathyroid secretion (primary hyperparathyroidism)
o Underlying renal disease (secondary hyperparathyroidism)
o PTH plays central role in Ca++ homeostasis
 Osteoclast activation via RANKL expression > increased resorption > increased Ca++ mobilization
 Increased Ca++ resorption in renal tubules
 Increased urinary excretion of phosphates
 Increased synthesis of active vitamin D (calcitriol) by kidneys > enhances intestinal Ca++ absorption
o Hyperparathyroidism leads to significant skeletal changes related to unabated osteoclast activation
o Morphology:
 (1) Osteoporosis: most severe in phalanges, vertebrae, and proximal femur
 Dissecting osteitis = osteoclast tunnel along length of trabeculae > railroad track appearance
 (2) Brown tumors: bone loss > microfractures > secondary hemorrhages > influx of macrophages >
ingrowth of reparative fibrous tissue
 (3) Osteitis fibrosa cystica (von Recklinghausen disease): increased bone cell activity, peritrabecular
fibrosis, and cystic brown tumors
Renal Osteodystrophy
o Skeletal changes that occur in chronic renal disease, including dialysis
o (1) Osteopenia/osteoporosis, (2) osteomalacia, (3) secondary hyperparathyroidism, (4) growth retardation
o Histologic changes:
 High-turnover osteodystrophy: increased bone resorption and bone formation (more resorption)
 Low-turnover (aplastic) disease: adynamic bone (little osteoclast/blast activity) and osteomalacia
 Mixed pattern of disease: areas of high turnover and areas of low turnover
o Pathogenesis:
 (1) Tubular dysfunction: renal tubular acidosis > low pH dissolves hydroxyappatite > demineralization
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(2) Generalized renal failure: glomerular and tubular function >reduced phosphate excretion > chronic
hyperphosphatemia, hypocalcemia > secondary hyperparathyroidism
(3) Decreased production of secreted factors: kidney converts D to active form (calcitriol) and secrestse
BMP-7 and Klotho
Other factors: aluminum from dialysis, oral phosphate binders, iron deposition, and diabetes mellitus
Fractures
 Loss of bone integrity due to mechanical injury and/or diminished bone strength
1. Simple: overlying skin is intact
2. Compound: bone communicates w/ the skin surface
3. Comminuted: bone is fragmented
4. Displaced: ends of bone at the fracture site are not aligned
5. Stress: slowly developing fracture that follows a period of increased physical activity and repetitive load on the bone
6. "Greenstick": extending only partially through the bone, common in infants
7. Pathologic: involving bone weakened by underlying disease process (ex. tumor)
 Healing of Fractures
o (1) Immediately: rupture of blood vessels results in hematoma > fills fracture gap and surrounds the area
 Clotted blood provides fibrin mesh > seals off site
 Degranulated platelets and inflammatory cells release PDGF, TGF-β, FGF > stimulate osteoclast/blast
o (2) After 2 weeks: soft tissue callus transformed into a bony callus
 Osteoprogenitor cells deposit subperiosteal trabeculae of woven bone
 Bony callus reaches maximal girth at end of the 2nd or 3rd week > stabilizes fracture site
o (3) Early callus formation: excess fibrous tissue, cartilage, and woven bone produced
o (4) Callus maturation: portions not subject to weight-bearing forces are resorbed
o NOTE:" Sequence of events can be easily impeded or even blocked
 Displaced and comminuted fractures frequently result in deformity
 Inadequate immobilization permits movement of the callus > delayed union or nonunion
 If nonunion persists > callus undergoes cystic degeneration > luminal surface becomes lined by
synovial-like cells = false joint aka pseudoarthritis
 Infection at fracture site (especially in open fracture) is a serious obstacle to healing process
 Malnutrition and skeletal dysplasia also hinder fracture healing