Chapter 6- Part II
• Bone Development
• Bone growth and hormonal
regulation of bone growth
• Bone remodeling
– Regulation of blood Ca2+
• Bone Repair
• Osteomalacia, Rickets,
Osteoporosis
– Causes and Treatments
Can you identify
all of these parts
of a bone?
What is the definition of
• Ossification
• Calcification
Formation of the Bony Skeleton
• Begins at week 8 of embryonic development
• Ossification
– Intramembranous ossification – bone develops from
a fibrous membrane
– Endochondral ossification – bone forms by replacing
hyaline cartilage
Endochondral and
Intramembranous ossification
• Both processes are more similar than they are
different
– Same cells participate and do similar things
• At biochemical and cellular level, many of the
same events occur
• Differences:
–
–
–
–
Site of activity
Organization of activity
Numbers of centers of ossification
What is replaced
Intramembranous ossification
– Also called dermal ossification
– Occurs in fibrous membrane of mesenchyme
– Flat bones of the skull, mandible, and clavicle
You lucky ducks don’t have to know the steps
of this process!
The Birth of Bone
• When new bone is born, either during
development or regeneration, it often starts
out as spongy bone (even if it will later be
remodeled into compact bone)
Endochondral Ossification
Note: you DO have to know this one
• Begins in the second month of development
• Uses hyaline cartilage “bones” as models for bone
construction then ossifies cartilage into bone
• Common, as most bones originate as hyaline
cartilage
• This is like a “trick” the body uses to allow long
bones to grow in length when bones can only
grow by appositional growth
Bone formation in a chick embryo
• Stained to represent
hardened bone (red)
and cartilage (blue)
•
: This image is the cover illustration from The Atlas of Chick
Development by Ruth Bellairs and Mark Osmond, published by
Academic Press (New York) in 1998
Bone formation in a human embryo
Endochondral Ossification
• Bone replaces a cartilaginous model (hyaline)
• Occurs in most bones
1. Cells of the perichondrium differentiate to osteoblasts and form a
bone collar around the outside (a periosteum)
2. Chondrocytes at center of model grow large, cause calcification to
happen all around themselves, and then they die, leaving behind big
spaces (fancy term= cavitation)
3. Spaces invaded by periosteal bud, (blood vessels, nerve, lymphatic
vessel, osteoclasts, osteoblasts)
• Osteoclasts and -blasts arrive. Set up primary ossification center, and
bone growth occurs (as spongy bone, trabeculae) spreads along shaft of
bone, toward ends.
4. Primary ossification center grows, and a medullary cavity is carved
out. Cartilage continues to grow at the epiphyseal side of the shaft.
5. At or after birth, the centers of each epiphysis also begin to be replaced
by bone, each end is a secondary ossification center
• At the epiphyseal plate (growth plate), as long as cartilage growth
outpaces replacement by bone, bone length continues.
Stages of Endochondral Ossification
Secondary
ossificaton
center
Deteriorating
cartilage
matrix
Epiphyseal
blood vessel
Articular
cartilage
Spongy
bone
Epiphyseal
plate
cartilage
Hyaline
cartilage
Primary
ossification
center
Medullary
cavity
Bone collar
1 Formation of
bone collar
around hyaline
cartilage model.
2 Cavitation of
the hyaline cartilage within the
cartilage model.
3 Invasion of
internal cavities
by the periosteal
bud and spongy
bone formation.
4
Formation of the
medullary cavity as
ossification continues;
appearance of secondary ossification
centers in the epiphyses in preparation
for stage 5.
5
Ossification of the
epiphyses; when
completed, hyaline
cartilage remains only
in the epiphyseal plates
and articular cartilages.
Endochondral Ossification
…and the race is on
When secondary ossification is
complete, where would you find hyaline
cartilage?
Endochondral
Ossification: Step 5 (Elongation)
• Epiphyses fill with spongy
bone but cartilage remains
at two sites:
– ends of bones within the
joint cavity = articular
cartilage
– cartilage at the metaphysis
= epiphyseal cartilage
(plate)
Figure 6–9 (Step 6)
What occurs at the epiphyseal plate, or
growth plate?
…and the race is on
Postnatal Bone Growth
• Growth in length of long bones
– Cartilage on the side of the epiphyseal plate
closest to the epiphysis is relatively inactive
– Cartilage abutting the shaft of the bone
organizes into a pattern that allows fast,
efficient growth
– Cells of the epiphyseal plate proximal to the
resting cartilage form three functionally
different zones: growth, transformation, and
osteogenic
Functional Zones in Long Bone
Growth
• Growth zone – cartilage cells undergo
mitosis, pushing the epiphysis away from
the diaphysis
• Transformation zone – older cells enlarge,
the matrix becomes calcified, cartilage cells
die, and the matrix begins to deteriorate
• Osteogenic zone – new bone formation
occurs
Growth in
Length of Long
Bone
Figure 6.9
Growth Plate
Epiphyseal cartilages undergo
ossification and become epiphyseal lines
More on Postnatal bone growth
• Remember that bone growth can only occur
from the outside (appositional growth). So
this type of endochondral growth is a way
for bones to grow from the inside and
lengthen because it is the cartilage that is
growing, not the bone
Key Concept
• As epiphyseal cartilage grows through the
division of chondrocytes it pushes the ends of
the bone outward in length.
• At the “inner” (shaft) side of the epiphyseal
plate, recently born cartilage gets turned into
bone, but as long as the cartilage divides and
extends as fast or faster than it gets turned into
bone, the bone will grow longer
Long Bone Growth and
Remodeling
• Growth in length – cartilage continually grows
and is replaced by bone as shown
• Remodeling – bone is resorbed and added by
appositional growth as shown
– compact bone thickens and strengthens long
bones with layers of circumferential lamellae
Long Bone Growth and Remodeling
Figure 6.10
Appositional Growth
Epiphyseal Lines
• When long bone stops growing, between the ages
of 18 – 25:
– epiphyseal cartilage disappears
– epiphyseal plate closes
– visible on X-rays as an epiphyseal line
• At this point, bone has replaced all the cartilage
and the bone can no longer grow in length
Bone growth during youth
• What is the most important hormone for bone
growth during infancy and childhood?
• Where in the body does this hormone have its
most critical effects?
• Thyroid hormone, and sex hormones also play a
role in bone growth
• Primary cause of gigantism? Dwarfism?
What do we need to grow healthy
bones?
Rickets
In the adult, bone remodeling occurs
constantly and also when we break a bone
• What does bone remodeling involve?
• Bone remodeling is a continual, life-long process
– 5% of our bone mass is recycled/week
– Spongy bone is replaced every 3-4 years
– “Old, not-remodeled” bone becomes brittle
– If removal is faster than deposition, bones get
weaker!
Bone deposition & bone resorption
• Osteoblasts build bone
– Lay down osteoid
– Osteoid calcifies when calcium and phosphate
reach specific concentrations and in the presence of
alkaline phosphatase
• Osteoclasts dissolve bone
– Release lysosomal enzymes and hydrocholric acid
– Phagocytose demineralized matrix, dead osteocytes
What regulates and controls bone
remodeling?
#1 BLOOD CALCIUM LEVELS!
• First, where/how does the body GET “new”calcium?
– From birth to age 10, children need 400-800 mg/day
– From ages 11-24 need 1200-1500 mg/day
• Second, why is it so critical that blood calcium
levels are maintained? Or, what physiological
processes are affected by changes in calcium?
• What hormones have the most important role in
calcium regulation?
Calcium homeostasis of blood: 9–11 mg/100 ml
Stimulus
Falling blood
Ca2+ levels
Thyroid
gland
Osteoclasts
degrade bone
matrix and
release Ca2+
into blood.
Parathyroid
glands
Parathyroid
glands release
parathyroid
hormone (PTH).
PTH
• Parathyroid Hormone (PTH) is released in response to LOW
blood Ca2+ levels
•What does PTH do once released? What cells of the body have
PTH receptors?
•Is this a negative or positive feedback loop?
PTH increases blood calcium levels
via VitD
• Stimulates osteoclasts
• Decreases Ca2+
excretion at kidneys
• Stimulates calcium
absorption at gut, via
calcitriol (Vit D)
Calcitonin and Ca2+ regulation
• Calcitonin is a hormone released by cells
(parafollicular cells) of the thyroid
• At physiological levels, calcitonin does not have an
important role in calcium regulation.
• Mixed results for calcitonin in treatment of
osteoporosis or hypercalcemia
CT
may
osteoclast
Bone remodeling
• #2- is also controlled by mechanical stress
• What causes stress on bones?
• Wolff’s law holds that a bone grows or remodels
in response to the demands placed on it
– Examples of Wolff’s law in action? Inaction?
Crosssectional
dimension of
the humerus
Serving arm
Added
bone matrix
counteracts
added stress
Nonserving arm
Bone remodeling is controlled by
mechanical stress
• How does Wolff’s law work?
• Deforming a bone (mechanical stress) produces a
small electrical current
– Osteocytes and/or collagen molecules act as
‘biosensors’
– In a frequently loaded or ‘pulled’ region of a
bone, growth is stimulated
– Can magnets or applied voltage increase bone
growth/healing?
Bone Fractures
•
•
•
•
Nondisplaced or displaced fracture
Incomplete or complete fracture
Linear or transverse fracture
Closed (simple) or open (compound) fracture
• How is a fracture treated?
Bone Repair
• When bones are fractured, blood vessels are broken
1. A large blood clot (hematoma) forms around the
injured area
2. Capillaries grow into hematoma and dead cells,
pathogens and debris are cleaned up by immune
cells.
• Fibroblasts, osteoblasts, -clasts migrate to area, start
to rebuild. Some fibroblasts differentitate into
chondrocytes. Fibrocartilage (soft) callus formed.
3. Over time, the cartilage is replaced by bone.
Bone callus- exists from 3-4 weeks after injury to 23 months later
4. Remodeling of the affected area may continue for
months to years.
How do fractures repair?
Hematoma
Internal
callus
(fibrous
tissue and
cartilage)
1 A hematoma forms.
External
callus
New
blood
vessels
Bony
callus of
spongy
bone
Healed
fracture
Spongy
bone
trabecula
2 Fibrocartilaginous
callus forms.
3 Bony callus forms.
4 Bone
remodeling
occurs.
The first x-ray was taken right after a fracture. The second was 2 months later,
showing some callus. Notice that the leg is now in a cast, so the entire bone
looks a little more dense and fuzzy. The last x-ray was 4 months after the
fracture, showing a good callus. The bone now can bear weight, but it will take
many months to remodel the area and complete the repair.
http://depts.washington.edu/bonebio/ASBMRed/growth.html
Clinical advances in bone repair
•
Electrical stimulation of fracture site.
– results in increased rapidity and completeness of bone healing
– electrical field may prevent parathyroid hormone from activating
osteoclasts at the fracture site thereby increasing formation of bone and
minimizing breakdown of bone,
• Ultrasound.
– Daily treatment results in decreased healing time of fracture by about
25% to 35% in broken arms and shinbones. Stimulates cartilage cells to
make bony callus.
• Free vascular fibular graft technique.
– Uses pieces of fibula to replace bone or splint two broken ends of a
bone. Fibula is a non-essential bone, meaning it does not play a role in
bearing weight; however, it does help stabilize the ankle.
• Bone substitutes.
– synthetic material or crushed bones from cadavers serve as bone fillers
(Can also use sea coral).
Imbalances that affect bone
•
•
•
•
Osteomalacia
Rickets
Paget’s disease
Osteoporosis
Notice what happens in
osteoporosis
Bone density changes with age
•This graph shows values
for bone mineral density
at the hip in Caucasian
men and women and
African-American men
and women.
•With aging, bone density
decreases in all groups.
This inevitable bone loss
is frequently the cause of
osteoporosis.
Data are from a study by Looker,
Osteoporosis International 1998
Osteoporosis
• What is it?
• What does it look like?
• What bones and parts of bones are most
strongly affected?
• Who is most likely affected?
• What are the treatments?
Osteoporosis
• In osteoporosis bone resorption outpaces bone deposit
– Which cells are more active, osteoblasts or osteoclasts?
• Osteoporosis- reduction in bone compromises normal
function
• In the U.S., 10 million individuals are estimated to
already have the disease and almost 34 million more are
estimated to have low bone mass, placing them at
increased risk for osteoporosis.
• Over age 45, occurs in ~30% of women, ~18% men
• Risk factors?
• Osteoporotic fractures cost $18 billion per year in 2002
dollars
• Are all bones and parts of bones affected equally?
Osteoporosis
• Epiphyses, vertebrae, and the jaw
lose more mass than other sites
• How does this explain loss of height?
Loss of teeth, and fragile limbs?
Osteoporosis
Osteoporosis
• Animation of bone remodeling
•
http://courses.washington.edu/bonephys/opmovies.html
http://courses.washington.edu/bonephys/opmovies.html
• Treatments? Risks?
–
–
–
–
Calcium, Vit D, moderate exercise
Estrogens at menopause (HRT)?
Alendronate (Bisphosphonates)
SERMs- Selective Estrogen Receptor
Modulators
– Statins