BONE PHYSIOLOGY

M. DJAUHARI WIDJAJAKUSUMAH

BAGIAN FISIOLOGI
FAKULTAS KEDOKTERAN UNIVERSITAS ILAM NEGERI JAKARTA
Skeletal System
Bone Tissue
 Martini Fundamentals of
Skeletal Elements Anatomy and Physiology 9e,
2012

 Skeletal elements are more than just racks from which muscles hang; they have a
variety of vital functions.
 supporting the weight of the body
 work together with muscles to maintain body position
 to produce controlled, precise movements.

 Without the skeleton to pull against, contracting muscle fibers could not make us
sit, stand, walk, or run.

 The skeletal system includes:

➢ the bones of the skeleton
➢ the cartilages,
➢ ligaments and other connective tissues that stabilize or interconnect the
bones.
 Martini Fundamentals of
Primary Functions the Skeletal System Anatomy and Physiology 9e,
2012

1. Support.

2. Storage of Minerals and Lipids.

3. Blood Cell Production.

4. Protection.

5. Leverage.
 Martini Fundamentals of
Primary Functions the Skeletal System Anatomy and Physiology 9e,
2012

1. Support.
 The skeletal system provides structural support for the entire body.
 Individual bones or groups of bones provide a framework for the attachment
of soft tissues and organs.
2. Storage of Minerals and Lipids.
 Minerals are inorganic ions that contribute to the osmotic concentration of
body fluids.
 Minerals participate in various physiological processes, and several are
important as enzyme cofactors.
 Calcium is the most abundant mineral in the human body.

 The calcium salts of bone are a valuable mineral reserve that maintains normal
concentrations of calcium and phosphate ions in body fluids.
 The bones store energy reserves as lipids in areas filled with yellow bone
marrow.
 Martini Fundamentals of
Primary Functions the Skeletal System Anatomy and Physiology 9e,
2012

3. Blood Cell Production.

 Red blood cells, white blood cells, and other blood elements are produced in
red bone marrow, which fills the internal cavities of many bones.
4. Protection.
 Many soft tissues and organs are surrounded by skeletal structures.

 The ribs protect the heart and lungs, the skull encloses the brain, the
vertebrae shield the spinal cord, and the pelvis cradles digestive and
reproductive organs.
5. Leverage.
 Many bones function as levers that can change the magnitude and direction
of the forces generated by skeletal muscles.
 The movements produced range from the precise motion of a fingertip to
changes in the position of the entire body.
 Lever Systems

 Muscles operate by applying tension to their points of insertion into bones, and the
bones in turn form various types of lever systems.
2
3 Analysis of the lever systems
of the body depends on
knowledge of
1. the point of muscle
insertion
2. its distance from the
fulcrum of the lever,
3. the length of the lever
arm,
Figure 6-16. The 4. the position of the lever.
lever system
activated by the
biceps muscle. Guyton Textbook of Medical
1 Physiology 13e, 2016
 Robbins and Cotran Pathologic
Skeletal System - Bones Basis Of Disease 8e, 2010

 The skeletal system is vital during life. It has an

➢ essential role in mineral homeostasis,
➢ houses the hematopoietic elements,
➢ provides mechanical support for movement,
➢ protects viscera,
➢ determines body size and shape.

 Bones are largely made up of

➢ an organic matrix (osteoid)
➢ the mineral calcium hydroxyapatite, which gives the bones strength and
hardness.

 Bone is a dynamic tissue that is continuously resorbed, renewed, and

remodeled which are carried out by several different types of bone cells that
are regulated by a number of transcription factors, cytokines, and growth
factors.
 Robbins and Cotran Pathologic
Bones Basis Of Disease 8e, 2010

 The skeletal system is composed of 206 bones that vary in size and shape
(tubular, flat, cuboid).

 The bones are interconnected by a variety of joints that allow for a wide
range of movement while maintaining structural stability.

 Bone is a type of connective tissue, and it is unique because it is one of the

few tissues that normally undergo mineralization.

 Biochemically, it is defined by its distinctive admixture of inorganic elements (65%) and

organic matrix (35%).

 The inorganic component, calcium hydroxyapatite is the mineral that gives

bone strength and hardness, and is the storehouse for 99% of the body's
calcium, 85% of the body's phosphorus, and 65% of the body's sodium and
magnesium.
 Bone Structure

 The diaphysis is connected to each epiphysis at

a narrow zone known as the metaphysis
 The wall of the diaphysis consists of a layer of
compact bone, or dense bone.
 Compact bone, which is relatively solid, forms
a sturdy protective layer that surrounds a
central space called the medullary cavity.
 The epiphyses consist largely of spongy bone,
also called cancellous or trabecular bone.
 Spongy bone consists of an open network of
struts and plates that resembles latticework
with a thin covering, or cortex of compact bone.
This superficial layer covering spongy bone is
also known as cortical bone (compact bone).
Martini Fundamentals of Anatomy and
Physiology 9e, 2012
1. The diaphysis (growing between) is the
bone’s shaft or body—the long,
cylindrical, main portion of the bone.
2. The epiphyses (growing over; singular
is epiphysis) are the proximal and distal
ends of the bone.
3. The metaphyses (meta- = between) are
the regions between the diaphysis and
the epiphyses. In a growing bone, each
metaphysis contains an epiphyseal
(growth) plate, a layer of hyaline
cartilage that allows the diaphysis of
the bone to grow in length.
When a bone ceases to grow in length
at about ages 14–24, the cartilage in
the epiphyseal plate is replaced by
bone; the resulting bony structure is
known as the epiphyseal line.

Tortora Principles of Anatomy &

Physiology 15e - 2017
 1. The diaphysis (growing between) is
the bone’s shaft or body—the long,
cylindrical, main portion of the
bone.
2. The epiphyses (growing over;
singular is epiphysis) are the
proximal and distal ends of the
bone.
3. The metaphyses (meta- = between)
are the regions between the
diaphysis and the epiphyses. In a
growing bone, each metaphysis
contains an epiphyseal (growth)
plate, a layer of hyaline cartilage
that allows the diaphysis of the
bone to grow in length. When a
bone ceases to grow in length at
about ages 14–24, the cartilage in
the epiphyseal plate is replaced
bybone; the resulting bony
structure is known as the
epiphyseal line.
Tortora Principles of Anatomy &
Physiology 15e - 2017
4. The articular cartilage is a thin
layer of hyaline cartilage
covering the part of the
epiphysis where the bone forms
an articulation (joint) with
another bone. Articular cartilage
reduces friction and absorbs
shock at freely movable joints.
Because articular cartilage lacks
a perichondrium and lacks blood
vessels, repair of damage is
limited.

Tortora Principles of Anatomy &

Physiology 15e - 2017
5. The periosteum (peri- = around) is a
tough connective tissue sheath and its
associated blood supply that surrounds
the bone surface wherever it is not
covered by articular cartilage. It is
composed of an outer fibrous layer of
dense irregular connective tissue and
an inner osteogenic layer that consists
of cells. Some of the cells enable bone
to grow in thickness, but not in length.
The periosteum also protects the bone,
assists in fracture repair, helps nourish
bone tissue, and serves as an
attachment point for ligaments and
tendons. The periosteum is attached to
the underlying bone by perforating
fibers or Sharpey’s fibers, thick bundles
of collagen that extend from the
periosteum into the bone extracellular
matrix.
Tortora Principles of Anatomy &
Physiology 15e - 2017
 Bone

❑ Compact bone
• Outer layer of bone, surrounding trabecular bone
& bone marrow cavity
• Much denser, less active metabolically
• Compose 75% of bone in the body
• Nutrients are provided via Haversian canals blood
vessels
• Collagen arrangement around Haversian canals →
osteon cylinders (Haversian system)

❑ Trabecular bone
• Spongy bone: bone spicules separated by spaces
• Compose 25% of bone in the body
• Nutrients diffuse from bone ECF
 Bone

❑ ORGANIC MATRIX
• 30-35 % content of compact bone
• Collagen fibers: 90-95%
✓ Fibers extend primarily along the lines of tensional force; give the powerful tensile
strength
• Homogeneous gelatinous medium – ground substance: 5-10%
✓ Extracellular fluids + proteoglycans (chondroitin sulfate & hyaluronic acid)
✓ Help control the deposition of calcium salts

❑ BONE SALTS
• 65-70 % content of compact bone
• Crystalline salts (principally calcium & phosphate): hydroxyapatite, Ca/P ratio: 1.3-2.0;
long, flat shaped crystal plates; give the compressional strength
• Mg, Na, K, carbonate
❑ BONE CELLS
• Osteoblasts, Osteocytes, Osteoclasts
 Bone cells

o OSTEOBLASTS
✓ Bone forming cells
✓ Derived from bone marrow cell precursors
✓ Secrete large quantities of type I collagen + other matrix proteins
✓ Secrete growth factors IGF-1, secrete cytokines IL-1, IL-6
✓ Receptors for PTH, DHC, estrogens, GH, IGF-1
✓ Differentiate into osteocytes

o OSTEOCYTES
✓ Rounded cells surrounded by bone matrix
✓ Send long processes:
▪ into the canaliculi, contact and form ‘tight junctions’ with processes of other
osteocytes, ramify throughout the bone
▪ function in Ca++ exchange with the ECF
Bone cells

OSTEOBLASTS
 The osteoblasts secrete the organic matrix, which are dense collagen layers
that alternate parallel and orthogonal to the axis of stress loading.
 Into this matrix is deposited extremely dense hydroxyapatite-based mineral
driven by both active and passive transport and pH control.
 As the matrix matures, hydroxyapatite microcrystals are organized into a
sophisticated composite in the collagen layer by nucleation in the protein
lattice.
 With matrix growth, osteoblasts are reorganized and incorporated into the
matrix as living cells, osteocytes, which communicate with each other and
surface epithelium by cell processes within canaliculi in the matrix.

Blair HC et al: Osteoblast Differentiation and Bone Matrix Formation In Vivo and In Vitro ,
Tissue Eng Part B Rev.2017 Jun;23(3):268-280
Bone cells

 If osteoblasts become surrounded by newly deposited organic matrix, they

transform into osteocytes; alternatively, osteoblasts remaining on the bone
surface may become flattened and quiescent bone lining cells.

 PTH and IGF-1 synergistically enhance osteoblast-to-osteocyte transition

[Tao Qiu, Janet L.,Crane; Bone Research 6, Article nbr: 5 (2018)

 Osteocytes help to control calcium and phosphate levels in the

microenvironment, and detect mechanical forces and translate them into
biologic activity—a process called mechanotransduction.

Robbins and Cotran Pathologic Basis

Of Disease 8e, 2010
Bone cells

• OSTEOCLASTS

✓ Derived from hematopoietic stem cells through monocytes

✓ Erode and resorb previously formed bone:

▪ proton pump → acidify the matrix (→ pH 4) → dissolves
hiydroxyapatite → calcium and phosphate ion
▪ proteases dissolve collagen → amino acids
▪ shallow depression in the bone – bone-resorbing compartment
Bone cells

 Osteoclasts are the cells responsible for bone resorption.

 Derived from the same hematopoietic progenitor cells that also give rise to
monocytes and macrophages.

 The cytokines and growth factors that regulate human osteoclast

differentiation and maturation include macrophage colony-stimulating
factor (M-CSF), interleukin-1 (IL-1), and tumor necrosis factor (TNF).

 Mature multinucleated osteoclasts bind to the bone surface via integrins,

where they form an underlying resorption pit—a self-contained
extracellular space analogous to a secondary lysosome.

Robbins and Cotran Pathologic Basis Of Disease 8e, 2010

Bone cells

Osteoclasts

 The cell membrane overlying the resorption pit is thrown into numerous
folds (the ruffled border), increasing its surface area, while the adjacent cell
surface forms a tight seal with the bone that prevents leakage of digestion
products.

 The osteoclast removes the mineral by generating an acidic environment

utilizing a proton pump system and digests the organic component by
releasing proteases.

Robbins and Cotran Pathologic Basis Of Disease 8e, 2010

 Bone cells

 OSTEOPROGENITOR CELLS
 Pluripotent mesenchymal stem cells that are found in the vicinity of all bony
surfaces. [along the inner portion of the periosteum, in the endosteum, and in
the canals within bone that contain blood vessels. [Tortora Principles of
Anatomy & Physiology 15e – 2017]
 When appropriately stimulated by growth factors they produce offspring that
differentiate into osteoblasts,
 Osteoprogenitor cells are found along the inner portion of the periosteum, in
the endosteum, and in the canals within bone that contain blood vessels.
[Tortora Principles of Anatomy & Physiology 15e – 2017]

Robbins and Cotran Pathologic Basis Of Disease 8e, 2010

 Bone cells

 OSTEOBLASTS AND LINING CELLS

 Located on the surface of bones, they synthesize, transport, and arrange the
many proteins of matrix and initiate the process of mineralization.
 Have receptors that bind regulatory hormones (parathyroid hormone, vitamin
D, leptin, and estrogen), cytokines, growth factors, and extracellular matrix
proteins,
 Express several factors that regulate the differentiation and function of
osteoclasts

Robbins and Cotran Pathologic Basis Of Disease 8e, 2010

 OSTEOBLASTOGENESIS - OSTEOCLASTOGENESIS
Bone Marrow Culture
Fibroblast Colony- Granulocyte-Macrophag
Forming Unit Colony Forming Unit
(Osteoprogenitor cells) (Hematopoetic cells)
Osteoblast, Fibroblast Osteoclast, Monocytes
Chondrocytes, Adipocytes Macrophage Progenitors
Progenitors

PTH
Calcitriol RANK-L
(-)
GH Osteoblastic Early pre-osteoclast
precursor cells
(+)
Late pre-osteoclast
Estrogen
(+) (+) Androgen (+)
Osteoblast Osteoclast

(+)
IGF-1 GH M-CSF Bone Resorption

Bone Forming (RANK: receptor activator of nuclear factor kappa B) =

(ODF: osteoclast differentiation factor)
 RANK-L

FIGURE 26-1 Bone cells and their interrelated activities. Hormones, cytokines, growth
factors, and signal-transducing molecules are key in their formation and maturation, and
allow communication between osteoblasts and osteoclasts. Bone resorption and formation
in remodeling are coupled processes that are controlled by systemic factors and local
cytokines, some of which are deposited in the bone matrix. BMP, bone morphogenic protein;
LRP5/6, LDL receptor related proteins 5 and 6.
 Matrix-bound
growth factors

RANK-L GH
Calcitriol
PTH

IGF-1
 Osteoblast – Osteoclast Communication

osteoblast (& osteoblast precursors)

estrogens + - glucocorticoids + - estrogens

GH + PTH
osteoprotegerin (OPG) OPG-ligand
free-floating decoy receptor (RANK ligand)

osteoclast precursors osteoclast +

RANK receptor RANK receptor
+
osteoclast activity

RANK ligand bone resorption

(osteoblast) +
PTH, DHC (vit D3), IL 1- 4 - 6-11-17, TNF-alfa
 Paracrine molecular mechanisms that
regulate osteoclast formation and
function.
 Osteoclasts are derived from the same
stem cells that produce macrophages.
 Osteoblast/stromal cell membrane-
associated RANK ligand (RANKL) binds
to its receptor RANK located on the cell
surface of osteoclast precursors. This
interaction in the background of
macrophage colony-stimulating factor
(M-CSF) causes the precursor cells to
produce functional osteoclasts.
 Stromal cells also secrete
osteoprotegerin (OPG) which acts as a
decoy receptor for RANKL, preventing
it from binding the RANK receptor on
osteoclast precursors. Consequently
OPG prevents bone resorption by
inhibiting osteoclast differentiation.
 Figure 19-22 Role of
osteoblasts in governing
osteoclast development
and activity.

Sherwood Human
Physiology From Cells to
Systems 9e, 2016
 Figure 19-22 Role of
osteoblasts in governing
osteoclast development
and activity.

Sherwood Human
Physiology From Cells to
Systems 9e, 2016
Osteoblast
• Produces bone matrix
• Mediating osteoclast activity

parathormone (PTH)
osteobalstic + osteoprotegerin (OPG) ligand
precursor → osteoblast → bone formation
cells + + → soluble mediators

+
osteoclast bone resorption activity

release matrix growth factors

(transforming growth factor-β / TGF- β)
 Growh Hormone Effects on Osteoblast

 GH affects bone size and mass in part through stimulating IGF-1 production in
liver and bone.

 Whether GH acts independent of IGF-1 in bone remains unclear.

 However, IGF-1 receptor is required for anabolic effects of GH in osteoblasts

which is increasing number of osteoblasts lining trabecular bone, whereas
osteoblast numbers in mice lacking the IGF-1R in osteoblasts were not
significantly affected.

 IGF-1R is required for anabolic effects of GH in osteoblasts in vivo.

[Di Girolamo DJ, et al. J Bio Chem. 2007]

 hGH induced a dose-dependent secretion of insulin-like growth factor-1.

Morel G. et al 1983
 Effects of IGF-1 on Osteoblast Proliferation and
Differentiation

 Insulin and IGF-1 have been shown to be anabolic agents in osteoblasts and
bone development

 The IGF-1 receptor expression decreases whereas insulin receptor

expression increases during osteoblast differentiation.

 Subsequently, although both insulin and IGF-1 promote osteoblast

differentiation and mineralization in vitro, IGF-1 (+ PTH), but not insulin, can
induce osteoblast proliferation.

Zhang et al 2012. Effects of insulin and IGF-1 on Osteoblast Proliferation and Differentiation:
differential signalling via Akt and ERK, in Cell Biochem Funct. 2012 Jun;30(4):297-302
The effects of IGF-I and IGF-II on proliferation and differentiation
of human osteoblasts and interactions with growth hormone.

 IGF-I and IGF-II exerted proliferative effects on both HOB (Human

osteoblast-like cells (HOB) established from trabecular explants) and HMS
(human marrow stromal cells (HMS) from marrow).

 Co-stimulation with GH exhibited synergism in enhancing the proliferative

response.

 In HMS prestimulation improved the proliferative response significantly.

 The effects of the IGFs on differentiation are more complex and dependent
on cell maturation and of the IGF used.
 Growth hormone stimulates osteoprotegerin expression and
secretion

 It is presently thought that osteoprotegerin (OPG) is a cytokine involved in

the regulation of osteoblast/osteoclast crosstalk and maintenance of bone
mass.
 Recent studies showed that GH was able to induce a significant increase of
OPG in the plasma,
 E Mrak et al study [Journal of Endocrnology 2007] showed that GH exposure
was able to stimulate OPG secretion in a concentration-dependent manner.
 These results suggest that that GH is able to modulate bone remodeling by
directly influencing osteoblast–osteoclast crosstalk.

Mrak et al 2007 Growth hormone stimulates osteoprotegerin expression and secretion

in human osteoblast-like cells: Journal of Endocrinology 2007
Mechanisms of Bone Growth
 Bone Formation & Resorption
‘Bone Is Constantly Being Resorbed And Formed’

Modelling
o Processes involved in formation of the skeleton

o Most active during childhood and adolescence

o Ceases at maturity (age 18-20 yrs)

o Long bones increase in diameter, change shape and develop a marrow cavity
related to stresses and strains imposed on skeleton by gravity and other
factors
o Bone strength adjustment to heavy loads /mechanical forces changes in
bone shapes and thickness bone rearrangement for proper support
 Bone Formation & Resorption
Bone Is Constantly Being Resorbed And Formed

Remodelling
o Processes occurring at bone surfaces before and after adult development to maintain
the structural integrity of the bone that continues throughout adult life

o No net gain or loss of skeletal mass after longitudinal growth has ceased. Bone
resorption equally balanced by bone formation in a healthy skeleton
o Local process: bone-remodeling units osteoclasts resorb bone, osteoblasts form new
bone
o 100 day cycle (3-4 months; 3 weeks resorption by osteoclasts, deposition
afterwards by osteoblasts)
o 5% of bone mass is remodeled at any one time by + 2 million bone-remodeling
units; 4%/year for compact bone, 20%/year for trabecular bone
 Bone Formation & Resorption

Equilibrium Between Bone Deposition and Absorption

❖ In growing bones, the rate of bone deposition exceeds that of bone
absorption

❖ The epiphyses of long bones fuse, growth cease, maximal height

achieved (20-21 yrs), peak bone mass age (35 yrs): the rate of bone
deposition and bone absorption are equal / constant total bone mass /
plateau
❖ After 35 yrs: the rate of bone absorption exceeds that of bone
deposition → osteopenia → osteoporosis
 Growth In Thickness

 Growth in thickness of bone is achieved by adding new bone on top of the

outer surface of existing bone. (Periosteum inner osteogenic layer consists of
cells that enable bone to grow in thickness, but not in length; [Tortora])

 This growth is produced by osteoblasts within the periosteum, a connective

tissue sheath that covers the outer bone.

 As osteoblast activity deposits new bone on the external surface, other cells
within the bone, the osteoclasts (“bone breakers”), dissolve the bony tissue
on the inner surface next to the marrow cavity.

 In this way, the marrow cavity enlarges to keep pace with the increased
circumference of the bone shaft.
Sherwood Human
Physiology From Cells to
Systems 9e, 2016
FIGURE 6.8 Bone growth in thickness
As new bone is deposited on the outer surface of bone by osteoblasts,
the bone tissue lining the medullary cavity is destroyed by osteoclasts in
the endosteum.
Tortora Principles of Anatomy &
Physiology 15e - 2017
 Bone Growth
During growth
Epiphyseal plate

 Plate of actively proliferating cartilage

 Separates epiphyses of long bones from its shaft
 Lays down new bone on the end of the shaft, finely balanced cycle of cartilage
growth, matrix formation and calcification of cartilage
 Its width is proportionate to the rate of growth, affected by hormones, most
markedly by GH and IGF-1
 Linear bone growth ceases after the epiphyses unite with the shaft of the bone
(epiphysial closure):
Cartilage cells stop proliferating, hypertrophic,
vascularization, ossification.
Epiphysial closure of bones is an orderly temporal
sequence, “bone age” can be determined by x ray
 Growth In Length

 Growth in length of long bones is accomplished by a different mechanism.

 Bones lengthen as a result of activity of the cartilage cells, or chondrocytes, in

the epiphyseal plates.

 During growth, cartilage cells on the outer edge of the plate next to the epiphysis
divide and multiply.

 As new chondrocytes are formed on the epiphyseal border, the older cartilage
cells toward the diaphyseal border are enlarging.

 This combination of proliferation of new cartilage cells and hypertrophy of

maturing chondrocytes temporarily widens the epiphyseal plate.

 This thickening of the intervening cartilaginous plate pushes the bony epiphysis
farther away from the diaphysis.
Sherwood Human Physiology From Cells to Systems 9e, 2016
 Growth In Length

 Soon the matrix surrounding the oldest hypertrophied cartilage becomes

calcified.

 Because cartilage lacks its own capillary network, the survival of cartilage
cells depends on diffusion of nutrients and O2 through the matrix, a process
prevented by the deposition of calcium salts. As a result, the old nutrient-
deprived cartilage cells on the diaphyseal border die.

 As osteoclasts clear away dead chondrocytes and the calcified matrix that
imprisoned them, the area is invaded by osteoblasts, which swarm upward
from the diaphysis, trailing their capillary supply with them.

 These new tenants lay down bone around the persisting remnants of
disintegrating cartilage until bone entirely replaces the inner region of
cartilage on the diaphyseal side of the plate.
Sherwood Human
Physiology From Cells to
Systems 9e, 2016
 Growth In Length

 When this ossification (“bone formation”) is complete, the bone on the

diaphyseal side has lengthened and the epiphyseal plate has returned to its
original thickness.

 The cartilage that bone has replaced on the diaphyseal end of the plate is as
thick as the new cartilage on the epiphyseal end of the plate.

 Thus, bone growth is made possible by the growth and death of cartilage,
which acts like a “spacer” to push the epiphysis farther out while it provides
a framework for future bone formation on the end of the diaphysis

Sherwood Human
Physiology From Cells to
Systems 9e, 2016
 Sherwood Human
Physiology, From
Cells to Systems 9re
- 2016
 Sherwood Human
Physiology, From Cells
to Systems 9re - 2016
Silverthorn Human Physiology 5th ed, 2010
 Bone Growth

FIGURE 6.7 Epiphyseal (growth) plate

The epiphyseal (growth) plate allows the diaphysis of a bone to increase in length.

Tortora’s Physiology 15e

 The Epiphyseal (growth) Plate

The epiphyseal (growth) plate is a layer of hyaline cartilage in the metaphysis of a growing
bone that consists of four zones
1. Zone of resting cartilage. This layer is nearest the epiphysis and consists of small,
scattered chondrocytes. The term “resting” is used because the cells do not function in
bone growth. Rather, they anchor the epiphyseal plate to the epiphysis of the bone.
2. Zone of proliferating cartilage. Slightly larger chondrocytes in this zone are arranged like
stacks of coins. These chondrocytes undergo interstitial growth as they divide and secrete
extracellular matrix. The chondrocytes in this zone divide to replace those that die at the
diaphyseal side of the epiphyseal plate.
3. Zone of hypertrophic cartilage This layer consists of large, maturing chondrocytes
arranged in columns
4. Zone of calcified cartilage. The final zone of the epiphyseal plate is only a few cells thick
and consists mostly of chondrocytes that are dead because the extracellular matrix
around them has calcified.

Tortora’s Physiology 15e

 Ganong’s Review of
Medical Physiology 26e,
2019
Musculoskeletal Development in
Children
 Bone Formation
 Bone formation, which begins at about the sixth week of gestation, involves
two phases:
(1) the delivery of bone cell precursors to sites of bone formation and
(2) the aggregation of these cells at primary centers of ossification,
where they mature and begin to secrete osteoid).
 Some of the bone cell precursors are present in fetal connective tissues,
whereas others migrate in blood to sites of bone formation after blood
vessels have grown into the tissue.
 Cellular aggregation and maturation occur in two types of fetal tissue,
depending on which bones are being formed.
 The cranium, facial bones, clavicles, and parts of the jawbone (classically
called “flatbones”) arise from a fetal membrane termed the mesenchyme.

McCance Pathophysiology 6e -2010

 Intramembranous Formation of Bone.

 Bones that develop on or within the mesenchyme grow by the process of

intramembranous formation of bone.
 As the mesenchyme becomes vascularized, the immature bone cells
aggregate and mature into osteoblasts, which form the centers of
ossification.
 Osteoblasts secrete osteoid, which surrounds them and quickly ossifies,
forming the lacunae and canaliculi of compact bone.
 Spicules of bone radiate from the ossification centers to form the primary
trabeculae characteristic of spongy bone.
 Later, some of the spongy bone is replaced by compact bone.

McCance Pathophysiology 6e -2010

Langmans Medical Embriology 13e - 2015
 Endochondral formation of bone

 Endochondral formation of bone is the development of new bone from

cartilage
 First, mesenchymal tissue forms a cartilage anlage, which defines the shape of
the bone (by 6 weeks of gestation).
 Blood vessel invasion to the inside the anlage brings osteoprogenitor cells
leading to primary centers of calcification by 8 weeks.
 Endochondral bone formation begins in the outer layer of the cartilage model,
which consists of a layer of dense connective tissue called perichondrium.
 Endochondral bone formation progresses at the primary center of ossification
in the middle of the cartilage model and extends toward either end of the
developing bone.
 By the end of gestation secondary centers of ossification (i.e., the epiphyseal
centers) begin to lay down bone at both ends of the cartilage model.
 Once the osteoblasts begin to secrete osteoid, ossification spreads from the
secondary centers in all directions until all the cartilage within the model is
replaced by bone McCance Pathophysiology 6e -2010
 Endochondral formation of bone

 Two regions of cartilage remain at the ends of long bones:

(1) articular cartilage over the free ends of the bone and
(2) the physeal plate, a layer of cartilage between the metaphysis and
epiphysis.
 The physeal plate retains the ability to form and calcify new cartilage and
deposit bone until the skeleton matures roughly 1 year after sexual maturity
(11 to 15 years of age in females, 15 to 18 in males)

McCance Pathophysiology 6e -2010

 Bone Formation

McCance Pathophysiology 6e -2010

Figure 43-1 Stages of endochondral bone formation and centers of ossification in long bone.
 Langmans
Medical
Embriology 12e
- 2012
 Bone Growth

Fetal development

Enchondral bone formation

Most of the bones
Modeled in cartilage →transformed into bone / ossification

Intramembranous bone formation

Clavicles, mandibles, bones of the skull
Mesenchymal cells form bones
Hormonal Control Of Calcium & Phosphate
Metabolism
 Introduction

Three hormones are primarily concerned with the regulation of calcium

metabolism:

 1,25-Dihydroxycholecalciferol
o a steroid hormone formed from vitamin D
o increases calcium absorption from the intestine.
 Parathyroid hormone (PTH)
o mobilizes calcium from bone, increases urinary phosphate excretion.
 Calcitonin,
o secreted primarily by cells in the thyroid gland
o inhibits bone resorption

All three hormones operate in concert to maintain the constancy of the

Ca2+ level in the body fluids
 Calcium Homeostasis Control

• Control of intestinal Ca absorbtion

✓ 1,25 DHC: absorbtion → plasma Ca

• Control of renal Ca reabsorbtion

✓ PTH : reabsorbtion → plasma Ca
✓ 1,25 DHC : reabsorbtion → plasma Ca
✓ Calcitonin : reabsorbtion → plasma Ca

• Control of bone Ca
✓ PTH & 1,25 DHC: bone resorption → plasma Ca
✓ Calcitonin: bone resorption → plasma Ca
 Phosphate Homeostasis Control

• Control of intestinal phosphate absorbtion

✓ 1,25 DHC: absorbtion → plasma phosphate

• Control of renal phosphate reabsorbtion

✓ PTH : reabsorbtion → plasma phosphate
✓ 1,25 DHC : reabsorbtion → plasma phopsphate
✓ Calcitonin : reabsorbtion → plasma phosphate

• Control of bone phosphate

✓ PTH & 1,25 DHC: bone resorption → plasma phosphate
✓ Calcitonin: bone resorption → plasma phosphate
 Calcium Distribution
Total Calcium
1100 g – 1.5% BW

Bone Calcium Plasma Calcium

99% total 1% total
10 mg/dL-2.5 mmol/l

Diffusible Nondiffusible
1.34 mmol/l 1.16 mmol/l
59% plasma calcium 41% plasma calcium
(protein-bound)

Ionized (Ca++) Complexed to HCO3, citrate

1.18 mmol/l 0.16 mmol/l Bound to Bound to
50% plasma calcium 9% plasma calcium albumin globulin
0.92 mmol/l 0.24 mmol/l
Ganong’s Review of Medical Physiology, 23rd ed, 2010
TABLE 21–1 Distribution (mg/dL) of calcium
in normal human plasma.

It is the free, ionized calcium (Ca2+) in the body fluids that is a vital
second messenger and is necessary for blood coagulation, muscle
contraction, and nerve function.

Ganong’s Review of Medical

Physiology, 26e - 2019
 Calcium Metabolism In An Adult Human

INTESTINAL Ca++ ABSORBTION Ganong’s Review of Medical Physiology, 26e - 2019

o Ca2+ is transported across intestinal epithelial cells via transient receptor potential vanilloid
channels type 6 (TRPV6) → binds to an intracellular protein known as calbindin-D9k.

o Calbindin sequesters the absorbed calcium so that it does not disturb epithelial signaling
processes that involve calcium.

o The absorbed Ca2+ is transported into the bloodstream by either a sodium/calcium exchanger
(NCX1) or a calcium-dependent ATPase in the basolateral membrane of the epithelial cell

o Some intestinal calcium uptake persists even in the absence of TRPV6 and calbindin-D9k, →
additional pathways are likely also involved in this critical process.

o The overall transport process is regulated by 1,25-dihydroxycholecalciferol

▪ As Ca2+ uptake rises, 1,25-dihydroxycholecalciferol levels fall in response to increased
plasma Ca2+.
 Calcium metabolism
Ganong’s Review of Medical Physiology, 23rd ed, 2010

o The body of a young adult human contains about 1100 g (27.5 mol) of
calcium
o 99% of the calcium is in the skeleton
o The plasma calcium, normally about 10 mg/dL (5 meq/L, 2.5 mmol/L), is
partly bound to protein and partly diffusible
o Free, ionized calcium in the body fluids:
o a vital second messenger

o necessary for blood coagulation, muscle contraction, and nerve function

o The extent of Ca2+ binding by plasma proteins is proportionate to the

plasma protein level → it is important to know the plasma protein level
when evaluating the total plasma calcium.
o Other electrolytes and pH also affect the free Ca2+ level.
 Calcium in Bone
Ganong’s Review of Medical Physiology, 23rd ed, 2010

o The calcium in bone is of two types:

➢ a readily exchangeable reservoir and,
➢ a much larger pool of stable calcium that is only slowly exchangeable.

o Two independent but interacting homeostatic systems affect the calcium

in bone.

➢ The system that regulates plasma Ca2+, providing for the movement
about 500 mmol of Ca2+ per day into and out of the readily
exchangeable pool in the bone (Figure 23–1).

➢ The system that involves bone remodeling by the constant interplay of

bone resorption and deposition.

➢ The Ca2+ interchange between plasma and this stable pool of bone
calcium is only about 7.5 mmol/d.
Ganong’s Review of
Medical Physiology,
26e - 2019
 Calcium metabolism in an adult human

Robert M. Berne,
Matthew N. Levy,
Bruce M. Koeppen,
Bruce A. Stanton:
Physiology, 5th ed,
2007

Figure 42-1 Average daily calcium turnover in humans. Note both the external balance between
intake and excretion and the internal balance between entry into and exit from bone.
 Ca++ vital roles
1. Neuromuscular excitability
Ca++ → Em → muscular excitability
Ca++ → Em → muscular excitability
→ cardiac arrhythmia
2. Excitation-contraction coupling in cardiac & smooth muscle
Ca++ → myocardial, and smooth muscle contractility (particularly)
3. Stimulus-secretion coupling
Ca++ entry into secreting cells (endocrine cells, nerve cells) in response to
stimulation → secretory product (peptide hormones, catecholamines,
neurotransmitters) exocytosis
4. Blood clotting
5. Bone minerals
✓ Bone growth and maintenance
✓ Hydroxyapatite: Ca10(PO4)6(OH)2
6. Second messenger
✓ IP3 → endoplasmic reticulum → Ca ion → enzyme activation
 Peak bone
mass age Menopause

35 50 95

Fig 23-14. Total body calcium, an index of bone mass, at various ages in men and women.
Note the rapid increase to young adult levels (phase I) followed by the steady loss of bone
with advancing age in both sexes (phase III) and the superimposed rapid loss in women after
menopause (phase II).
Ganong’s Review of Medical Physiology, 23 rd ed, 2010
 Phosphorus Metabolism

Phosphate is found in ATP, cAMP, 2,3-diphosphoglycerate, many proteins, and

other vital compounds in the body.

Phosphorylation and dephosphorylation of proteins are involved in the

regulation of cell function

Phosphate metabolism is closely regulated.

➢ Total body phosphorus is 500 to 800 g (16.1–25.8 mol), 85–90% of which
is in the skeleton.
➢ Total plasma phosphorus is about 12 mg/dL, with two-thirds of this total
in organic compounds and the remaining inorganic phosphorus (Pi)
mostly in PO4 3–, HPO4 2–, and H2PO 4–.
➢ The amount of phosphorus normally entering bone is about 3 mg (97
mol)/kg/d, with an equal amount leaving via reabsorption.
Ganong’s Review of Medical Physiology, 23rd ed, 2010
 Phosphorus Metabolism

Intestinal phosphoprus absorbtion

• Pi is absorbed in the duodenum and small intestine.

• Uptake occurs by a transporter related to those in the kidney, NaPi-
IIb, that takes advantage of the low intracellular sodium
concentration established by the Na, K ATPase on the basolateral
membrane of intestinal epithelial cells to load Pi against its
concentration gradient.

• The pathway by which Pi exits into the bloodstream is not known.

➢ Many stimuli that increase Ca2+ absorption, including 1,25-
dihydroxycholecalciferol, also increase Pi absorption via increased
NaPi-IIb expression.
Ganong’s Review of Medical Physiology, 23rd ed, 2010
 Phosphorus Metabolism

Renal phosphoprus reabsorbtion

 Pi in the plasma is filtered in the glomeruli, and 85–90% of the filtered Pi is

reabsorbed.
 Active transport in the proximal tubule accounts for most of the
reabsorption and involves two related sodium-dependent Pi cotransporters,
NaPi-IIa and NaPi-IIc.

 NaPi-IIa is powerfully inhibited by parathyroid hormone, which causes its

internalization and degradation and thus a reduction in renal Pi
reabsorption.

Ganong’s Review of Medical Physiology, 23rd ed, 2010

 Phosphorus Metabolism

Robert M. Berne,
Matthew N. Levy,
Bruce M. Koeppen,
Brice A. Stanton:
Physiology, 5th ed, 2007

Figure 42-2 Average daily phosphate turnover in humans. Note both the external balance
between intake and excretion and the internal balance between entry into and exit from bone.
 Parathyroid Gland

Figure 21–9.

Humans usually have four parathyroid

glands: two embedded in the superior poles
of the thyroid and two in its inferior poles.
Figure 21–9.
The human parathyroid glands, viewed from behind.
Ganong’s Review of Medical Physiology, 23 rd ed, 2010
 PTH Actions

PTH acts directly on bone to increase bone resorption and mobilize Ca2+.

In addition to increasing the plasma Ca2+, PTH increases phosphate excretion in

the urine and thereby depresses plasma phosphate levels.

This phosphaturic action is due to a decrease in reabsorption of phosphate via

effects on NaPi-IIa in the proximal tubules.

PTH increases reabsorption of Ca2+ in the distal tubules

PTH increases the formation of 1,25-dihydroxycholecalciferol, and this increases

Ca2+ absorption from the intestine.

On a longer time scale, PTH stimulates both osteoblasts and osteoclasts.

Ganong’s Review of Medical Physiology, 23rd ed, 2010
 Vitamin D & the Hydroxycholecalciferols
Chemistry

o The active transport of Ca2+ and PO43– from the intestine is increased by a
metabolite of vitamin D

o Vitamin D3 (cholecalciferol) is produced in the skin of mammals from 7-

dehydrocholesterol by the action of sunlight

o Vitamin D3 is also ingested in the diet

o Vitamin D3 → 25-hydroxycholecalciferol (calcidiol, 25-OHD3) [in the liver] → the

more active metabolite 1,25-dihydroxy-cholecalciferol (calcitriol or 1,25-(OH)2D3) [in
the proximal tubules cells of the kidneys, in the placenta, in keratinocytes in the skin,
and in macrophages]

o The normal plasma level of 1,25-dihydroxycholecalciferol + 0.03 ng/mL (+ 100

pmol/L).
Ganong’s Review of Medical Physiology, 23rd ed, 2010
 Regulation of Synthesis

o The formation of 1,25-dihydroxycholecalciferol in the kidneys, catalyzed by the renal 1α -

hydroxylase, is regulated in a feedback fashion by plasma Ca2+ and PO43+.
o This effect of Ca2+ on production of 1,25-dihydroxycholecalciferol is the mechanism that
brings about adaptation of Ca2+ absorption from the intestine.
o Expression of 1α -hydroxylase is stimulated by PTH, and when the plasma Ca2+ level is low,
PTH secretion is increased.
o The production of 1,25-dihydroxycholecalciferol is also increased by low and inhibited by
high plasma PO43– levels, by a direct inhibitory effect of PO43– on the 1α -hydroxylase.
o Additional control
➢ a direct negative feedback effect of the metabolite on 1-hydroxylase,
➢ a positive feedback action on the formation of 24,25-dihydroxycholecalciferol,
➢ a direct action on the parathyroid gland to inhibit PTH expression.
Figure 23–2
Formation and hydroxylation of vitamin D3. 25-hydroxylation takes place in the liver, and the
other hydroxylations occur primarily in the kidneys. The formulas of 7-dehydrocholesterol,
vitamin D3, and 1,25-dihydroxycholecalciferol are also shown below.
Ganong’s Review of Medical Physiology, 23 rd ed, 2010
Figure 79–6
Activation of vitamin D3 to form 1,25-dihydroxycholecalciferol and the role of vitamin D in controlling the plasma
calcium concentration. Guyton & Hall: Textbook of Medical Physiology 11th ed
Feedback control of the formation of 1,25-dihydroxycholecalciferol (1,25-[OH]2D3) from 25-
hydroxycholecalciferol (25-OHD3) in the kidneys. Solid arrows indicate stimulation, and
dashed arrows indicate inhibition.

Ganong’s Review of Medical Physiology, 22 nd ed

Fig 23-3.
Effects of PTH and 1,25-dihydroxycholecalciferol on whole body calcium homeostasis. Note
that these hormones are also involved in the regulation of circulating phosphate levels.
Ganong’s Review of Medical Physiology, 23 rd ed, 2010
 Parathormone and 1.25 (OH)2Cholecalciferol
7-dehydrocholesterol →cholecalciferol (vit D3)

25(OH)D3 Prolactin
PTH
Calcitonin
24.25(OH)2D3 1.25(OH)2 D3

Intestine Ca++ absorption Bone resorption Kidney Ca++ Kidney PO4 ion
reabsorbtion reabsorption

plasma Ca++ plasma PO4 ion

+
--
Figure 79–8
Effect of plasma calcium concentration on the plasma concentration of 1,25-
dihydroxycholecalciferol. This figure shows that a slight decrease in calcium concentration
below normal causes increased formation of activated vitamin D, which in turn leads to greatly
increased absorption of calcium from the intestine.
Guyton & Hall: Textbook of Medical Physiology 11th ed
 Calcitonin

Control of secretion

Secreted by the parafollicular cells

▪ [plasma Ca] > 9.5 mg/dl → calcitonin

▪ Estrogen → calcitonin
▪ Glucagon → calcitonin
 Calcitonin
Effects
Kidneys
Calcitonin membrane receptors on renal tubules cells
▪ Calcium reabsorption
▪ Phosphate reabsorption
Bones
Calcitonin membrane receptors on osteoclast
▪ osteoclast activity
▪ bone resorption
▪ Ca and PO4 release
Blood
[Ca++]
[PO4]
 Calcitonin

Prevents bone resorption excess in pregnancy

estrogen prolactin
+

calcitonin 1.25 DHC

bone resorption

[Ca ++]
+
--
 Osteoporosis

 A decrease in bone density resulting from reduced deposition of the bone’s

organic matrix (see the accompanying figure),
 The condition is especially prevalent among women following menopause
(permanent cessation of menstruation), owing to the marked drop in bone-
preserving estrogen.
 30% of postmenopausal women have osteoporosis. Following menopause,
women start losing 1% or more bone density each year.
 Skeletons of elderly women are typically only 50% to 80% as dense as at
their peak at about age 35, whereas elderly men’s skeletons retain 80% to
90% of their youthful density.
 Similar to estrogen, testosterone also helps preserve bone density, but
unlike women’s programmed withdrawal of estrogen at menopause, men
do not experience a similar built-in loss of testosterone secretion
Sherwood Human
Physiology From Cells to
Systems 9e, 2016
 Osteoporosis

 Osteoporosis is responsible for the greater incidence of bone fractures

among women older than age 50 years than among the population at
large.

 One in three women with osteoporosis ends up with a fractured bone, most
commonly of the hip or spine, which may lead to permanent disability or
even death.

 Because bone mass is reduced, osteoporotic bones are more brittle and
more susceptible to fracture in response to a fall, blow, or lifting action that
normally would not strain stronger bones.

 For every 10% loss of bone mass, the risk of fracture doubles.

 Half of all American women have spinal pain and deformity by age 75.
Sherwood Human
Physiology From Cells to
Systems 9e, 2016
FIGURE 26-9 Pathophysiology of postmenopausal and senile osteoporosis

Robbins & Cotran Pathologic Basis of Disease 8th ed, 2010

 Sherwood Human
Comparison of normal and osteoporotic bone. Note the reduced Physiology From
density of osteoporotic trabecular bone compared to normal trabecular Cells to Systems
bone. 9e, 2016
 Robbins & Cotran Pathologic Basis
of Disease 8th ed, 2010

FIGURE 26-10 Osteoporotic vertebral body (right) shortened by compression fractures

compared with a normal vertebral body. Note that the osteoporotic vertebra has a
characteristic loss of horizontal trabeculae and thickened vertical trabeculae.
 Drug Therapy for Osteoporosis

 Ca2+ and vitamin D supplementation and a regular weight-bearing exercise

program are long-standing therapeutic approaches used to prevent or treat
osteoporosis.

 Estrogen replacement therapy

 Was used to treat osteoporosis in the past.

 Estrogen slows bone loss by promoting apoptosis (cell suicide) of

osteoclasts and by enhancing activity of osteoblasts.
 The Food and Drug Administration (FDA) no longer approves estrogen
therapy for treating osteoporosis because this drug has been linked to an
increased risk of breast cancer and cardiovascular disease.

Sherwood Human Physiology From

Cells to Systems 9e, 2016
 Drug Therapy for Osteoporosis

The following newer classes of drugs are already approved by the FDA or
are under investigation
 Alendronate (Fosamax),
 A bisphosphonate, was the first nonhormonal osteoporosis drug.

 Blocking osteoclasts’ bone destroying actions.

 Calcitonin (Miacalcin),
 The thyroid C-cell hormone that slows osteoclast activity,

 To treat advanced osteoporosis, but traditionally it had to be injected

daily, a deterrent to patient compliance.
 Now calcitonin is available in a more patient-friendly nasal spray
(Fortical).
Sherwood Human
Physiology From Cells to
Systems 9e, 2016
 Drug Therapy for Osteoporosis

 Raloxifene (Evista)

 Belongs to a new class of drugs known as selective estrogen receptor

modulators (SERMs).
 Raloxifene does not bind with estrogen receptors in reproductive organs,
but it does bind with estrogen receptors outside the reproductive
system, such as in bone.
 Raloxifene mimics estrogen’s beneficial effects on bone to provide
protection against osteoporosis by keeping osteoclasts in check while
avoiding estrogen’s potentially harmful effects on reproductive organs,
such as increased risk of breast cancer.

Sherwood Human Physiology From

Cells to Systems 9e, 2016
 Drug Therapy for Osteoporosis

 Teriparatide (Forteo)

 Was the first approved treatment that stimulates bone formation instead
of acting to prevent bone loss, as the other drugs do.

 Must be injected, is an active fragment of parathyroid hormone (PTH).

 Even though continuous exposure to PTH, as with hyperparathyroidism,

increases osteoclast activity and thereby promotes the breakdown of
bone, evidence suggests that, by contrast, intermittent administration of
PTH (or its active teriparatide fragment) increases osteoblast formation
and prolongs survival of these bone builders by blocking osteoblast
apoptosis.

Sherwood Human
Physiology From Cells to
Systems 9e, 2016
 Drug Therapy for Osteoporosis

 Denosumab (Prolia)

 Is the newest drug for treatment of osteoporosis., injectable drug

reduces destruction of bone by binding to and inhibiting RANKL, the
protein that promotes maturation, function, and survival of bone-
resorbing osteoclasts.
 Denosumab mimics the natural action of osteoprotegerin

Sherwood Human
Physiology From Cells to
Systems 9e, 2016
Bone Fracture
 Rubin's Pathology :
Bone Fracture Clinicopathologic Foundations of
Medicine, 5th Ed, 2008

❖ Defined as a discontinuity of the bone.

➢ A force perpendicular to the long axis of the bone results in a transverse
fracture.
➢ A force along the long axis of the bone yields a compression fracture.

➢ Torsional force results in spiral fractures, and combined tension and

compression shear forces cause angulation and displacement of the
fractured ends.
❖ A force powerful enough to fracture a bone also injures adjacent soft tissues.
➢ (1) extensive muscle necrosis;
➢ (2) hemorrhage because of shearing of capillary beds and larger vessels
of the soft tissues;
➢ (3) tearing of tendinous insertions and ligamentous attachments; and (4)
even nerve damage, caused by stretching or direct tearing of the nerve.
 Bone Fracture Classification

o Complete or incomplete;
o Closed (simple) when the overlying tissue is intact;
o Compound when the fracture site communicates with the skin surface;

o Comminuted when the bone is splintered;

o Displaced when the ends of the bone at the fracture site are not aligned.

o Pathologic fracture if the break occurs in bone already altered by a disease

process

o Stress fracture is a slowly developing fracture that follows a period of

increased physical activity in which the bone is subjected to new repetitive
loads—as in sports training or marching in military boot camp.
Robbins & Cotran Pathologic Basis of Disease 8th ed, 2010
FIGURE 26-16 A, Recent fracture of the fibula. B, Marked callus
formation 6 weeks later. (Courtesy of Dr. Barbara Weissman, Brigham
and Women's Hospital, Boston, MA.)

Robbins & Cotran

Pathologic Basis of
Disease 8th ed, 2010
Tortora’s Physiology 15e
Tortora’s Physiology 15e
 Fracture Healing

Repair of a fracture

▪ Maximal activation of all periosteal and intraosseous osteoblasts at

the fracture site

▪ Immediate formation of immense number of osteoblasts →

development of large bulge of new organic matrix followed by
calcium salts deposition → callus formation; then reshaped into
appropriate structure within months

Robbins & Cotran Pathologic Basis of Disease 8th ed, 2010

 Fracture Healing

o Divided into phases

✓ Inflammatory,
✓ Reparative, and
✓ Remodeling

o The duration of each phase depends on

✓ the patient's age,
✓ the site of fracture,
✓ the patient's overall health and nutritional status,
✓ the extent of soft tissue injury.
✓ local factors, such as vascular supply and mechanical forces at the site,
 Healing of a
fracture.

Rubin's Pathology :
Clinicopathologic
Foundations of
Medicine, 5th
Edition, 2008

FIGURE 26-15.
A. Soon after a fracture is sustained, an extensive blood clot forms in the
subperiosteal and soft tissue, as well as in the marrow cavity. The bone at the
fracture site is jagged.
B. The inflammatory phase of fracture healing is characterized by neovascularization
and beginning organization of the blood clot. Because the osteocytes in the
fracture site are dead, the lacunae are empty. The osteocytes of the cortex are
necrotic well beyond the fracture site, owing to the traumatic interruption of the
perforating arteries from the periosteum.
 Healing of a
fracture.

Rubin's Pathology :
Clinicopathologic
Foundations of
Medicine, 5th
Edition, 2008

FIGURE 26-15.
C. The reparative phase of fracture healing is characterized by the formation of a callus of
cartilage and woven bone near the fracture site. The jagged edges of the original cortex
have been remodeled and eroded by osteoclasts. The marrow space has been
revascularized and contains reactive woven bone, as does the periosteal area.
D. In the remodeling phase, during which the cortex is revitalized, the reactive bone may be
lamellar or woven. The new bone is organized along stress lines and mechanical forces.
Extensive osteoclastic and osteoblastic cellular activity is maintained.
FIGURE 6.9 Steps in repair of a bone fracture

Tortora Principels of Anatomy and

Physiology 15e - 2015
 FIGURE 6.9 Steps in repair of a bone fracture

 Reactive phase, an early inflammatory phase.

 Blood vessels crossing the fracture line are broken. As blood leaks from the
torn ends of the vessels, a mass of blood (usually clotted) forms around the
site of the fracture. This mass of blood, called a fracture hematoma, usually
forms 6 to 8 hours after the injury.
 Because the circulation of blood stops at the site where the fracture
hematoma forms, nearby bone cells die.
 Swelling and inflammation occur in response to dead bone cells, producing
additional cellular debris.
 Phagocytes (neutrophils and macrophages) and osteoclasts begin to remove
the dead or damaged tissue in and around the fracture hematoma. This
stage may last up to several weeks.
Tortora Principels of Anatomy and
Physiology 15e - 2015
 FIGURE 6.9 Steps in repair of a bone fracture

 Reparative phase: Fibrocartilaginous callus formation.

 The reparative phase is characterized by two events: the formation of a
fibrocartilaginous callus, and a bony callus to bridge the gap between the
broken ends of the bones.
 Blood vessels grow into the fracture hematoma and phagocytes begin to
clean up dead bone cells.
 Fibroblasts from the periosteum invade the fracture site and produce
collagen fibers.
 Cells from the periosteum develop into chondroblasts and begin to produce
fibrocartilage in this region.
 These events lead to the development of a fibrocartilaginous (soft) callus, a
mass of repair tissue consisting of collagen fibers and cartilage that bridges
the broken ends of the bone.
 Formation of the fibrocartilaginous callus takes about 3 weeks.
Tortora Principels of Anatomy and
Physiology 15e - 2015
 FIGURE 6.9 Steps in repair of a bone fracture

 Reparative phase: Bony callus formation.

 In areas closer to well-vascularized healthy bone tissue, osteoprogenitor
cells develop into osteoblasts, which begin to produce spongy bone
trabeculae.
 The trabeculae join living and dead portions of the original bone fragments.
 In time, the fibrocartilage is converted to spongy bone, and the callus is
then referred to as a bony (hard) callus. The bony callus lasts about 3 to 4
months

Tortora Principels of Anatomy and

Physiology 15e - 2015
 FIGURE 6.9 Steps in repair of a bone fracture

 Bone remodeling phase. The final phase of fracture repair is bone

remodeling of the callus.
 Dead portions of the original fragments of broken bone are gradually
resorbed by osteoclasts.
 Compact bone replaces spongy bone around the periphery of the fracture.
 Sometimes, the repair process is so thorough that the fracture line is
undetectable, even in a radiograph (x-ray).
 However, a thickened area on the surface of the bone remains as evidence
of a healed fracture.
Thank You