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Further, based on the pattern of collagen form- within the matrix. During life, the bones undergo
ing the osteoid, two types of bone are identified: processes of longitudinal and radial growth, mod-
woven bone, which is characterized by a haphaz- eling (reshaping), and remodeling (Clarke 2008).
ard organization of collagen fibers (Eriksen et al. Longitudinal growth occurs at the growth plates,
1994), and lamellar bone, which is characterized where cartilage proliferates in the epiphyseal and
by a regular parallel alignment of collagen into metaphyseal areas of long bones, before subse-
sheets (lamellae) (Fig. 2.1). Lamellar bone, as a quently undergoing mineralization to form pri-
result of the alternating orientations of collagen mary new bone.
fibrils, has a significant mechanical strength sim-
ilar to plywood. This normal lamellar pattern is
absent in woven bone, in which the collagen 2.2.1 Bone Formation
fibrils are laid down in a disorganized manner.
Hence, the woven bone is weaker than lamellar Ossification (or osteogenesis) is the process of for-
bone. Woven bone is produced when osteoblasts mation of new bone by cells called osteoblasts.
produce osteoid rapidly. This occurs initially in These cells and the bone matrix are the two
all fetal bones and in fracture healing, but the most crucial elements involved in the formation
resulting woven bone is replaced by a process of bone. This process of formation of normal
called remodeling by the deposition of more healthy bone is carried out by two important pro-
resilient lamellar bone. Virtually all the bone in cesses, namely:
the healthy mature adult is lamellar bone. 1. Intramembranous ossification characterized
by laying down of bone into the primitive
connective tissue (mesenchyme) resulting in
2.2 Physiology of Bone Formation the formation of bones (skull, clavicle, man-
dible). It is also seen in the healing process of
Bone is composed of support cells, namely, fractures (compound fractures) treated by
osteoblasts and osteocytes; remodeling cells, open reduction and stabilization by metal
namely, osteoclasts; and non-mineral matrix of plate and screws.
collagen and noncollagenous proteins called 2. Endochondral ossification where a cartilage
osteoid, with inorganic mineral salts deposited model acts as a precursor (e.g., femur, tibia,
2 Physiology of Bone Formation, Remodeling, and Metabolism 31
salt in the osteoid matrix, which is a crystalline important mediators of calcium regulation, and
complex of calcium and phosphate (hydroxyapa- vitamin D deficiency or hyperparathyroidism will
tite). Calcified bone contains about 25 % organic lead to depletion of the bone minerals.
matrix, 5 % water, and 70 % inorganic mineral
(hydroxyapatite). Collagen 1 constitutes 9095 %
of the organic matrix of bone. Osteoblasts synthe- 2.2.5 Osteocytes
size and lay down precursors of collagen 1
(Brodsky and Persikov 2005). They also produce Osteocytes represent terminally differentiated
osteocalcin, which is the most abundant noncol- osteoblasts and function within syncytial net-
lagenous protein of bone matrix, and the proteo- works to support bone structure and metabolism.
glycans of ground substance. The collagen 1 Osteocytes maintain connection with each other
formed by osteoblasts is deposited in parallel or and the bone surface via their multiple filipodial
concentric layers to produce mature (lamellar) cellular processes. Osteocytes are linked meta-
bone. When bone is rapidly formed, as in the bolically and electrically through gap junctions
fetus or certain pathological conditions (e.g., composed primarily of connexin (Bonewald
fracture callus, fibrous dysplasia, hyperparathy- 1999; Plotkin et al. 2002). The presence of empty
roidism), the collagen is not deposited in a paral- lacunae in aging bone suggests that osteocytes
lel array but in a basket-like weave resulting in may undergo apoptosis, probably caused by dis-
woven, immature, or primitive bone (Fig. 2.1). ruption of their intercellular gap junctions or cell-
Osteoblasts also synthesize and secrete non- matrix interactions. Osteocyte apoptosis in
collagenous protein, such as proteoglycans, gly- response to estrogen deficiency or glucocorticoid
cosylated proteins, glycosylated proteins with treatment is harmful to bone structure. Estrogen
potential cell-attachment activities, and g-carbox- and bisphosphonate therapy and physiologic
ylated (gla) proteins. The main glycosylated pro- loading of bone may help prevent osteoblast and
tein present in bone is alkaline phosphatase, osteocyte apoptosis (Plotkin et al. 2005; Xing
which plays an as-yet-undefined role in mineral- and Boyce 2005).
ization of bone (Whyte 1994).
2.2.6 Intramembranous
2.2.4 Bone Minerals (Mesenchymal) Ossication
Fig. 2.3 Intramembranous ossification showing: (a) stem cell transform to osteoblasts which synthesize
Aggregates of osteoprogenotor cells. (b) Amorphous osteoid in the center of the aggregate. (d) A rudimentary
ground substance and collagen meshwork formed in the bone tissue formed by the osteoblasts and some of these
center and in between the cells. (c) The mesenchymal get incorporated within the osteoid to become osteocytes
The important cell in the creation of bone tissue by As these changes are proceeding in the ossification
membrane ossification is a mesenchymal stem center, the surrounding mesenchyme condenses
cell. Mesenchymal stem cells (MSCs) within as a fibrovascular periosteum around its edges and
human mesenchyme or the medullary cavity of a surfaces. The periosteum is thus formed, and bone
bone fracture initiate the process of intramembra- growth continues at the surface of trabeculae.
nous ossification. An MSC is an unspecialized cell Much like spicules, the increasing growth of tra-
whose morphology undergoes characteristic beculae results in interconnection, and this net-
changes as it develops into an osteoblast. The pro- work is called woven bone. Eventually, woven
cess of membranous ossification, which is essen- bone is replaced by lamellar bone. Extension of
tially the direct mineralization of a highly vascular the ossification process occurs through the agency
connective tissue, commences at certain constant of stem cells derived from the deeper layers of the
points known as centers of ossification. At such a periosteum.
center, the mesenchymal cells (osteoprogenitor
cells) proliferate and condense around a profuse
capillary network. Between the cells and around 2.2.7 Intracartilaginous
the vessels is amorphous ground substance (Endochondral) Ossication
(Fig. 2.3) with a fine meshwork of collagen fibers.
The osteoprogenitor cells differentiate (spe- Endochondral ossification (Greek: endon, within,
cialize) into osteoblasts, which create osteoid in chondros, cartilage) occurs in long bones and
the center of the aggregate. The osteoblasts pro- most of the rest of the bones in the body; it involves
duce bone matrix and get surrounded by collagen an initial hyaline cartilage which continues to
fibers and become osteocytes. At this point, the grow. It is also an essential process during the
osteoid becomes mineralized, resulting in a nidus growth of the length of long bones and the natural
consisting of mineralized osteoid that contains healing of bone fractures (Brighton and Hunt
osteocytes and is lined by active osteoblasts. The 1986; Netter 1987; Brighton et al. 1973).
nidus that began as a diffuse collection of MSCs The steps in endochondral ossification
has become rudimentary bone tissue. This process (Figs. 2.4, 2.5, and 2.6) are:
of entrapping of osteoblasts proceeds, the trabec- 1. Development of cartilage model
ulae gradually thicken, and the intervening vascu- 2. Growth of cartilage model
lar spaces (spongy layer) become progressively 3. Development of the primary ossification center
narrowed. Where the bone persists as cancellous 4. Development of the secondary ossification
bone, however, the process slows down, and the center
spaces later become occupied by hemopoietic 5. Formation of articular cartilage and epiphy-
tissue (Netter 1987; Brighton and Hunt 1991). seal plate
34 U. Kini and B.N. Nandeesh
Secondary
ossification
center
Chondrocyte
hypertrophy
Bone
collar
a b c d e
Fig. 2.4 Intracartilaginous ossification showing: (a) center of ossification (e) bone with medullary cavity and
aggregates of osteoprogenitor cells (b) model of hyaline epiphyseal ends (f) highlighting feeding blood vessels
cartilage (c) primary center of ossification (d) secondary
Endochondral ossification begins with points in foreshadowing that of the early bone (e.g., car-
the cartilage called primary ossification cen- pal bones are preceded by appropriately shaped
ters. They mostly appear during fetal develop- cartilaginous models). The cartilaginous
ment, though a few short bones begin their model is surrounded by a highly vascular con-
primary ossification after birth. They are respon- densed mesenchyme or perichondrium, similar
sible for the formation of the diaphyses of long in every way to that which precedes and sur-
bones, short bones, and certain parts of irregular rounds intramembranous ossification centers
bones. Secondary ossification occurs after birth with its deeper layers containing osteoprogeni-
and forms the epiphyses of long bones and the tor cells.
extremities of irregular and flat bones. The dia-
physis and both epiphyses of a long bone are 2.2.7.2 Growth of the Cartilage Model
separated by a growing zone of cartilage (the The cartilage model will grow in length by
epiphyseal plate). When the child reaches skele- continuous cell division of chondrocytes,
tal maturity (1825 years of age), all of the carti- which is accompanied by further secretion of
lage is replaced by bone, fusing the diaphysis extracellular matrix. This is called interstitial
and both epiphyses together (epiphyseal growth. The process of appositional growth
closure). occurs when the cartilage model would also
grow in thickness which is due to the addition
2.2.7.1 Development of Cartilage Model of more extracellular matrix on the periphery
Each long bone is represented in early fetal life cartilage surface, which is accompanied by
by a rod of hyaline cartilage which replaces new chondroblasts that develop from the
a rod of condensed mesenchyme, its shape perichondrium.
2 Physiology of Bone Formation, Remodeling, and Metabolism 35
Fig. 2.5 Microphotographs to show primary centers of mesenchyme which carries with it hemopoietic cells and
ossification: (a) first stage where the chondrocytes at the osteoprogenitor cells (f) showing trabeculae formation by
center of ossification undergo apoptosis/death (be) osteoblasts differentiated from the osteoprogenitor cells
showing invasion of this ossification center by vascular and the hemopoietic cells forming the bone marrow
Formation of Bone Collar. The osteoblasts Osteoclasts, formed from macrophages, break
secrete osteoid against the shaft of the carti- down spongy bone to form the medullary
lage model (appositional growth). This serves (bone marrow) cavity.
as support for the new bone.
Calcification of Matrix. Chondrocytes in the 2.2.7.4 Secondary Center of Ossication
primary center of ossification begin to grow About the time of birth, a secondary ossification
(hyperplasia) (Fig. 2.6). They stop secreting center appears in each end (epiphysis) of long
collagen and other proteoglycans and begin bones. Periosteal buds carry mesenchyme and
secreting alkaline phosphatase, an enzyme blood vessels in, and the process is similar to that
essential for mineral deposition. Then, occurring in a primary ossification center. The
calcification of the matrix occurs, and apopto- cartilage between the primary and secondary
sis of the hypertrophic chondrocytes occurs. ossification centers is called the epiphyseal plate,
This creates cavities within the bone. and it continues to form new cartilage, which is
Invasion of Periosteal Bud. The hypertrophic replaced by bone, a process that results in an
chondrocytes (before apoptosis) secrete vascu- increase in length of the bone. Growth continues
lar endothelial cell growth factor that induces until the individual is about 21 years old or until
the sprouting of blood vessels from the per- the cartilage in the plate is replaced by bone. The
ichondrium. Blood vessels forming the point of union of the primary and secondary
periosteal bud invade the cavity left by the ossification centers is called the epiphyseal line.
chondrocytes and branch in opposite directions Appositional Bone Growth. The growth in diam-
along the length of the shaft. The blood vessels eter of bones around the diaphysis occurs by depo-
carry hemopoietic cells, osteoprogenitor cells, sition of bone beneath the periosteum. Osteoclasts
and other cells inside the cavity. The hemopoi- in the interior cavity continue to degrade bone until
etic cells will later form the bone marrow. its ultimate thickness is achieved, at which point
Formation of Trabeculae. Osteoblasts, differ- the rate of formation on the outside and degrada-
entiated from the osteoprogenitor cells that tion from the inside is constant. The cartilaginous
entered the cavity via the periosteal bud, use the extremity (where an epiphysis usually forms) con-
calcified matrix as a scaffold and begin to secrete tinues to grow in pace with the rest of the bone by
osteoid, which forms the bone trabecula. appositional and interstitial mechanisms.
2 Physiology of Bone Formation, Remodeling, and Metabolism 37
When the whole bone is reaching maturity, gradual adjustment of the skeleton to the forces that
epiphyseal and metaphyseal ossification gradu- it encounters. Bones may widen or change axis by
ally encroach upon this growth plate, and final removal or addition of bone to the appropriate sur-
bony fusion occurs with cessation of growth. faces by independent action of osteoblasts and
osteoclasts in response to biomechanical forces.
Bones normally widen with aging in response to
2.2.8 Biological Factors Involved periosteal apposition of new bone and endosteal
in Normal Bone Formation resorption of old bone. Wolffs law describes the
and Its Regulation observation that long bones change shape to accom-
modate stresses placed on them. Bone modeling is
There is a rapid formation of bone mass in the less frequent than remodeling in adults (Kobayashi
fetus and infant. This slows somewhat during et al. 2003). Modeling may be increased in
childhood until age 11 in females and a year or so hypoparathyroidism (Ubara et al. 2005), renal
later in boys. During the growth spurt that accom- osteodystrophy (Ubara et al. 2003), or treatment
panies adolescence, tremendous bone formation with anabolic agents (Lindsay et al. 2006).
occurs. The vast majority of adult levels of bone
mass are achieved by age 18 or so, with only a
small amount added until about 28 years old. 2.2.10 Determinants of Bone Strength
2.2.8.1 Environmental Factors Inuencing Bone strength depends on bone mass, geometry
Normal Bone Formation and composition, material properties, and micro-
Physical activity and good nutrition are the most structure. Bone mass accounts for 5070 % of
important of these environmental factors. People bone strength (Pocock et al. 1987). Bone geom-
who are affected by any of these factors will likely etry and composition are important, however,
have a lower bone mineral density (BMD) than their because larger bones are stronger than smaller
healthier peers. Poor activity levels and nutrition bones, even with equivalent bone mineral den-
during the years of bone formation may prevent the sity. As bone diameter expands radially, the
normal growth of bones, which may cause them to strength of bone increases by the radius of the
be less dense. Smoking during these years may also involved bone raised to the fourth power. The
decrease the amount of bone formed. A significant amount and proportion of trabecular and cortical
illness during the teenage years that causes pro- bone at a given skeletal site affect bone strength
longed bed rest and lack of exercise will also pre- independently. Bone material properties are
vent the complete acquisition of bone density. important for bone strength. Some patients with
osteoporosis have abnormal bone matrix.
2.2.8.2 Hormones Mutations in certain proteins may cause bone
There are a number of hormones that are impor- weakness (e.g., collagen defects cause decreased
tant to this rapid formation of bone during the bone strength in osteogenesis imperfecta,
first two decades of life. These hormones include impaired g-carboxylation of gla proteins). Bone
estrogen in females, testosterone in males, growth strength can be affected by osteomalacia, fluoride
hormone, and others. They are discussed in detail therapy, or hypermineralization states. Bone
in Sect. 2.3.2. microstructure affects bone strength also. In some
pathological conditions, the thickness and extent
of the osteoid layer may be increased (hyperos-
2.2.9 Bone Modeling teoidosis) or decreased. Hyperosteoidosis may be
caused by conditions of delayed bone mineraliza-
Modeling (reshaping) is the process by which bones tion (as in osteomalacia/rickets, vitamin D
change their overall shape in response to physio- deficiency) or of increased bone formation (as in
logic influences or mechanical forces, leading to fracture callus, Pagets disease of bone, etc.).
38 U. Kini and B.N. Nandeesh
25-(OH)D3
Ca
1,25-(OH)2D3
PTH PTH
Ca2+ Ca2+
Calcium
PTH
1,25-(OH)2D3
Gut
PTH
PO4
Fig. 2.7 Figure to show a close interlink between calcium, phosphate, and parathyroid hormone with vitamin D in
bone metabolism
and can provide minute-to-minute exchanges of into the skeleton through the process of mineral-
minerals from bone matrix. ization of the organic matrix of bone, osteoid.
Skeletal calcium is controlled through the ECF calcium is also filtered by the kidney at a
regulatory pathways of the gastrointestinal (GI) rate of about 6 g/day, where up to 98 % of it is
tract and the kidney, and this regulation is medi- reabsorbed.
ated in bone by osteoblast and osteoclast. The various regulators playing an important
Calcium reaches the skeleton by being absorbed role in skeletal metabolism are:
from the diet in the GI tract. Unabsorbed cal- Calcitropic hormones
cium passes into the feces, which also contains Parathyroid hormone (PTH)
the small amount of calcium secreted into the GI Calcitonin (CT)
tract. Minor losses occur through perspiration Vitamin D [1,25(OH2)D]
and cell sloughing. In pregnancy, substantial PTHrP
losses can occur across the placenta to the devel- Other hormones
oping fetus and through breast milk. Absorbed Gonadal and adrenal steroids
dietary calcium then enters the extracellular Thyroid hormones
fluid (ECF) space and becomes incorporated Growth factors and cytokines
40 U. Kini and B.N. Nandeesh
UV rays
7,dehydroxy cholesterol
Provitamin D3
Skin
Vitamin D3
25 hydroxycholecalciferol
7 dehydroxy (25 OH D3)
cholesterol
Liver
Cholesterol
Plasma 25 hydroxycholecalciferol
Blood Plasma cholesterol
vessel
25 OH D3
Kidney
Bone
1,25 dihydroxycholecalciferol
Gut
Fig. 2.8 Synthesis and sources of vitamin D3 and its hydroxylation to form the hormone 1,25-dihydroxycholecalciferol
with its main sites of action being highlighted
1998; Suda et al. 1999; Theill et al. 2002; Yasuda osteoblasts communicate with each other through
et al. 1998) (see Sect. 2.4.1.4). the release of various signaling molecules.
Osteoblast precursors express a molecule Osteoclasts are apparently activated by sig-
called TRANCE, or osteoclast differentiation nals from osteoblasts. For example, osteoblasts
factor, which can activate cells of the osteoclast have receptors for PTH, whereas osteoclasts do
lineage by interacting with a receptor called not, and PTH-induced osteoclastic bone resorp-
RANK (Horwood et al. 1998; Yasuda et al. tion is said not to occur in the absence of osteo-
1998). blasts. The action of osteoblasts and osteoclasts
is controlled by a number of chemical factors
2.4.1.4 Osteoprotegerin which either promote or inhibit the activity of the
Osteoprotegerin (OPG), also known as osteoclast bone remodeling cells, controlling the rate at
inhibiting factor (OCIF) or osteoclast binding fac- which bone is made, destroyed, or changed in
tor (OBF), is a key factor inhibiting the differen- shape. The cells also use paracrine signaling to
tiation and activation of osteoclasts, and is, control the activity of each other, described in
therefore, essential for bone resorption. Sect. 2.4.3.
Osteoprotegerin is a dimeric glycoprotein belong-
ing to the TNF receptor family. Osteoprotegerin
inhibits the binding of RANK to RANKL and thus 2.4.2 Remodeling Phases
inhibits the recruitment, proliferation, and activa-
tion of osteoclasts. Abnormalties in the balance of Bone remodeling can be divided into the follow-
OPGL/RANK/OPG system lead to the increased ing six phases (Fig. 2.9), namely, quiescent, acti-
bone resorption that underlies the bone damage of vation, resorption, reversal, formation, and
postmenopausal osteoporosis, Pagets disease, mineralization. Activation precedes resorption
bone loss in metastatic cancers, and rheumatoid which precedes reversal, with mineralization as
arthritis. Bone resorption depends on osteoclast the last step. These occur at remodeling sites
secretion of hydrogen ions and cathepsin K which are distributed randomly but also are tar-
enzyme. H+ ions acidify the resorption compart- geted to areas that require repair (Burr 2002;
ment beneath osteoclasts to dissolve the mineral Fernndez-Tresguerres-Hernndez-Gil et al.
component of bone matrix, whereas cathepsin K 2006; Parfitt 2002).
digests the proteinaceous matrix, which is mostly 1. Quiescent Phase. It is the state/phase of the
composed of type I collagen (Boyle et al. 2003). bone when at rest. The factors that initiate the
Osteoclasts bind to bone matrix via integrin recep- remodeling process remain unknown.
tors in the osteoclast membrane linking to bone 2. Activation Phase. The first phenomenon that
matrix peptides. They digest the organic matrix, occurs is the activation of the bone surface
resulting in formation of saucer-shaped Howships prior to resorption, through the retraction of
lacunae on the surface of trabecular bone and the bone lining cells (elongated mature osteo-
Haversian canals in cortical bone. The resorption blasts existing on the endosteal surface) and
is completed by mononuclear cells after the multi- the digestion of the endosteal membrane by
nucleated osteoclasts undergo apoptosis (Eriksen collagenase action. The initial activation
1986; Reddy 2004; Teitelbaum et al. 1995; stage involves recruitment and activation of
Vaananen et al. 2000). mononuclear monocyte-macrophage osteo-
The boundary between the old and new bone clast precursors from the circulation
is distinguished in an hematoxylin and eosin sec- (Bruzzaniti and Baron 2007; Roodman et al.
tion by a blue (basophilic) line called a cement 1992), resulting in interaction of osteoclast
line or reversal line. and osteoblast precursor cells. This leads to
the differentiation, migration, and fusion of
2.4.1.5 Paracrine Cell Signaling the large multinucleated osteoclasts. These
At various stages throughout this process of cells attach to the mineralized bone surface
remodeling, the precursors, osteoclasts, and and initiate resorption by the secretion of
2 Physiology of Bone Formation, Remodeling, and Metabolism 45
f
b
e c
Fig. 2.9 Phases of bone remodeling: (a) quiescent phase (d) shows formation phase where the osteoclasts are
where flat bone lining cells are seen lining the endosteal replaced by osteoblasts with underlying new osteoid
membrane (b) showing activation phase characterized by matrix (e) shows mineralization of osteoid matrix (f)
cell retraction with resultant membrane resorption (c) shows formation of bone structure unit with progression
shows activated osteoclasts resorbing the underlying bone to quiescent phase
hydrogen ions and lysosomal enzymes, par- 4. Reversal Phase. During the reversal phase,
ticularly cathepsin K, which can degrade all bone resorption transitions to bone formation.
the components of bone matrix, including At the completion of bone resorption, resorp-
collagen, at low pH. tion cavities contain a variety of mononuclear
3. Resorption Phase (Fig. 2.10). The osteoclasts cells, including monocytes, osteocytes
then begin to dissolve the mineral matrix and released from bone matrix, and preosteo-
decompose the osteoid matrix. This process is blasts, recruited to begin new bone formation.
completed by the macrophages and permits The coupling signals linking the end of bone
the release of the growth factors contained resorption to the beginning of bone formation
within the matrix, fundamentally transforming are as yet unknown, but proposed coupling
growth factor-b (TGF-b), platelet-derived signal candidates include bone matrix-derived
growth factor (PDGF), and insulin-like growth factors such as TGF-/3, IGF-1, IGF-2, bone
factor I and II (IGF-I and II). Osteoclastic morphogenetic proteins, PDGF, or fibroblast
resorption produces irregular scalloped cavi- growth factor (Bonewald and Mundy 1990;
ties on the trabecular bone surface, called Hock et al. 2004; Locklin et al. 1999).
Howships lacunae, or cylindrical Haversian 5. Formation Phase. Once osteoclasts have
canals in cortical bone. Osteoclast-mediated resorbed a cavity of bone, they detach from
bone resorption takes only approximately the bone surface and are replaced by cells of
24 weeks during each remodeling cycle. the osteoblast lineage which in turn initiate
46 U. Kini and B.N. Nandeesh
Osteocytes
Calcified bone
matrix
New bone
bone formation. The preosteoblast grouping When the cycle is completed, the amount of
phenomenon is produced and attracted by the bone formed should equal the amount of bone
growth factors liberated from the matrix resorbed.
which act as chemotactics and in addition
stimulate their proliferation (Lind et al.
1995). The preosteoblasts synthesize a 2.4.3 Regulatory Factors in Bone
cementing substance upon which the new tis- Remodeling
sue is attached and express bone morphogenic
proteins (BMP) responsible for differentia- The balance between bone resorption and forma-
tion (refer Sect 2.4.3.2). A few days later, the tion is influenced by such interrelated factors as
already differentiated osteoblasts synthesize genetic, mechanical, vascular, nutritional, hor-
the osteoid matrix which fills the (resorption monal, and local.
cavity) perforated areas (Lind et al. 1995).
The remaining osteoblasts continue to syn- 2.4.3.1 Systemic Regulation of Bone
thesize bone until they eventually stop and Remodeling
transform to quiescent lining cells that com- 1. Genetic Factors
pletely cover the newly formed bone surface These are important in determining the maxi-
and connect with the osteocytes in the bone mum bone mass, since between 60 and 80 % of
matrix through a network of canaliculi. this bone mass is genetically determined. Thus,
6. Mineralization Phase. The process begins Negroes have a greater bone mass than Whites,
30 days after deposition of the osteoid, ending who in turn have a higher mass than Asians.
at 90 days in the trabecular and at 130 days in Bone mass is a characteristic transmitted from
the cortical bone. The quiescent or at rest parents to children, which is why daughters of
phase then begins again. mothers with osteoporosis are more predisposed
2 Physiology of Bone Formation, Remodeling, and Metabolism 47
to having this condition themselves(Grant and in the decreased bone density in de-nerved
Ralston 1997; Pocock et al. 1987). mandibles.
2. Mechanical Factors 4. Nutritional Factors
Remodeling is regulated by mechanical load- A minimum amount of calcium is needed for
ing, allowing bone to adapt its structure in mineralization, which the majority of authors
response to the mechanical demands. Physical put at 1,200 mg/day to the age of 25, not less
activity is essential for the correct develop- than 1 g/day from 25 to 45, and following
ment of bone. It is believed that muscular menopause should be at least 1,500 mg/day.
action transmits tension to the bone, which is Likewise, it is known that toxic habits such as
detected by the osteocyte network within the smoking, caffeine, alcohol, and excess salt
osseous fluid. On the other hand, the absence constitute risk factors for osteopenia.
of muscular activity, rest, or weightlessness 5. Hormonal Factors
has an adverse effect on bone, accelerating Normal development of the skeleton is condi-
resorption. It is well-known that trabeculae tioned by the correct functioning of the endo-
tend to align with maximum stresses in many crine system. The most important hormones
bones. Mechanical stress improves bone in bone remodeling are:
strength by influencing collagen alignment as (a) Thyroid Hormones. Thyroid hormones can
new bone is being formed. Cortical bone tis- also stimulate bone resorption and formation
sue located in regions subject to predomi- (possess two opposing actions on bone) and
nantly tensile stresses has a higher percentage are critical for maintenance of normal bone
of collagen fibers aligned along the bone long remodeling (Kawaguchi et al. 1994). In the
axis. In regions of predominant compressive first place, they stimulate the synthesis of the
stresses, fibers are more likely to be aligned osteoid matrix by the osteoblasts and its min-
transverse to the long axis. eralization, favoring the synthesis of IGF-I.
3. Vascular/Nerve Factors For this reason, in congenital hypothyroidism
Vascularization is fundamental for normal (cretinism), short stature is produced by the
bone development, supplying blood cells, alteration in bone formation. In the second
oxygen, minerals, ions, glucose, hormones, place, a contrary effect is produced, stimulat-
and growth factors. Vascularization consti- ing resorption with the increase in number
tutes the first phase in ossification: the blood and function of the osteoclasts. The clinical
vessels invade the cartilage and later produce manifestation of this effect is the appearance
resorption via the osteoclasts originating from of bone loss in hyperthyroidism.
the nearby vessels. In the same way, vascular (b) Parathyroid Hormone (PTH). It controls the
neoformation is the first event in the repair of homeostasis of calcium by direct action on
fractures or bone regeneration (Trueta 1963). the bone and the kidneys and indirectly on the
Innervation is necessary for normal bone intestine. It is produced by the parathyroid
physiology. The bone is innervated by the glands in response to hypocalcemia. Continual
autonomous nervous system and by sensorial supply of PTH would stimulate bone resorp-
nerve fibers. Autonomous fibers have been tion through the synthesis of a factor favoring
found in periosteum, endosteum, and cortical osteoclastogenesis (RANKL) on the part of
bone and associated with the blood vessels of the osteoblastic cells, while at intermittent
the Volkmann conduit, and likewise neuro- doses it would stimulate the formation of
peptides and their receptors in bone (Wheeless bone, associated with an increase of the
2011). Examples of the importance of inner- above-mentioned growth factors and with a
vation in bone physiology are found in decrease in the apoptosis of the osteoblasts.
osteopenia and the bone fragility present in PTH regulates serum calcium concentration.
patients with neurological disorders, and also It is a potent stimulator of bone resorption and
48 U. Kini and B.N. Nandeesh
has biphasic effects on bone formation. There muscle mass at older age. Androgens protect
is an acute inhibition of collagen synthesis men against osteoporosis via maintenance of
with high concentrations of PTH, but pro- cancellous bone mass and expansion of corti-
longed intermittent administration of this hor- cal bone.
mone produces increased bone formation, a (f) Estrogens. Estrogens are essential for the clo-
property for which it is being explored clini- sure of the growth plates and have an impor-
cally as an anabolic agent (Dempster et al. tant role in the development of the skeleton.
1993). Plasma PTH tends to increase with Estrogens have a dual effect on bone metabo-
age, and this may produce an increase in bone lism: on the one hand, they favor bone forma-
turnover and a loss of bone mass, particularly tion, increasing the number and function of
of cortical bone (see Sect. 2.3.2.1). the osteoblasts, and on the other, they reduce
(c) Calcitonin. Produced by the parafollicular C resorption. Estrogen receptors have been
cells of the thyroid, it is an inhibitor of bone described in human osteoblasts, osteocytes,
resorption, reducing the number and activity and osteoclasts. Recent investigations have
of the osteoclasts (see Sect. 2.3.2.1). However, found that estrogens can increase the levels of
this is a transitory action, since the osteoclasts osteoprotegerin (OPG), a protein produced by
seem to become impermeable to calcitonin osteoblasts that inhibits resorption, so they
within a few days. may play an important role in the regulation
(d) 1,25(OH)2 Vitamin D3 or Calcitriol. A steroid of osteoclastogenesis (Hofbauer et al. 1999).
hormone, by favoring the intestinal absorp- Alternatively, estrogen may inhibit local fac-
tion of calcium and phosphate, favors bone tors that impair bone formation or enhance
mineralization. It is necessary for normal local factors that stimulate bone formation.
growth of the skeleton. Some authors believe For this reason, estrogen deficiency during
it may be produced by lymphocytic or mono- menopause constitutes the most important
cytic bone cells, playing an important role as pathogenic factor in bone loss associated with
a local regulator of osteoclast differentiation osteoporosis. Loss of estrogens or androgens
(Raisz 1993). increases the rate of bone remodeling by
(e) Androgens. Androgens have an anabolic removing restraining effects on osteoblasto-
effect on bone through the stimulation of the genesis and osteoclastogenesis and also
osteoblast receptors. Likewise, they act as causes a focal imbalance between resorption
mediators of the growth hormone in puberty. and formation by prolonging the lifespan of
While androgen deficiency is associated with osteoclasts and shortening the lifespan of
lower bone density, the administration of tes- osteoblasts.
tosterone in young people before the closure (g) Progesterone. Progesterone also has an ana-
of the epiphyses increases bone mass. In the bolic effect on bone, either directly, through
same way, women with an excess of andro- the osteoblasts which possess hormone recep-
gens present higher bone densities. Androgens tors, or indirectly, through competition for the
increase cortical bone size via stimulation of osteoblastic receptors of the glucocorticoids.
both longitudinal and radial growth. First, (h) Insulin. Insulin stimulates matrix synthesis
androgens, like estrogens, have a biphasic effect both directly and indirectly, increasing the
on endochondral bone formation: at the start of hepatic synthesis of IGF-I (insulin-like growth
puberty, sex steroids stimulate endochondral factor) (see Sect. 2.4.3.2).
bone formation, whereas they induce epiphy- (i) Glucocorticoids. Glucocorticoids are neces-
seal closure at the end of puberty. This effect of sary for bone cell differentiation during devel-
androgens may be important because bone opment, but their greatest postnatal effect is to
strength in males seems to be determined by inhibit bone formation (at high doses, they
relatively higher periosteal bone formation and, have a catabolic effect on bone), since they
therefore, greater bone dimensions, relative to inhibit the synthesis of IGF-I by the osteoblasts
2 Physiology of Bone Formation, Remodeling, and Metabolism 49
and directly suppress BMP-2, critical factors an important role in the production of prostaglan-
in osteoblastogenesis. This is the major patho- dins and nitric oxide, as well as cytokines and
genetic mechanism in glucocorticoid-induced growth factors.
osteoporosis. Indirect effects of glucocorti- The important local factors acting on the skel-
coids on calcium absorption and sex hormone eton are as follows and are tabulated in Table 2.1:
production may, however, increase bone
resorption (Lukert and Kream 1996; Growth Factors
Manolagas 2000). Bone contains a large number of growth factors.
(j) Growth Hormone. Growth hormone acts both These are polypeptides produced by the bone
directly and indirectly on bone. Growth hor- cells themselves or in extra-osseous tissue and
mone acts directly on the osteoblasts with act as modulators of the cellular functions, fun-
hormone receptors, stimulating their activity, damentally growth, differentiation, and prolif-
thus increasing the synthesis of collagen, eration. Among the most abundant are the IGFs,
osteocalcin, and alkaline phosphate. The indi- which, with their associated binding proteins,
rect action is produced through an increase in may be important modulators of local bone
synthesis of IGF-I and II by the osteoblasts. remodeling (Fraher 1993; Hakeda et al. 1996;
These factors stimulate the proliferation and Rosen and Donahue 1998). Transforming
differentiation of the osteoblasts, increasing growth factor-b and the related family of bone
their number and function (Harvey and Hull morphogenetic proteins are present in the skel-
1998; Rosen and Donahue 1998). eton and have important functions not only in
Thus, the hormones that regulate bone metab- remodeling but also in skeletal development.
olism are as follows: Other growth factors, such as platelet-derived
Decrease bone resorption growth factor, PTH-related protein, and
Calcitonin fibroblast growth factor, may play an important
Estrogens role in physiologic remodeling and an even
Increase bone resorption more important role in the remodeling associ-
PTH/PTHrP ated with skeletal repair.
Glucocorticoids (a) IGF-I and II (Insulin-Like Growth Factor I
Thyroid hormones and II). These are polypeptides similar to
High-dose vitamin D insulin; they are synthesized by the liver and
Increase bone formation osteoblasts and found in high concentrations
Growth hormone in the osteoid matrix (Cohick and Clemmons
Vitamin D metabolites 1993). They increase the number and function
Androgens of the osteoblasts, stimulating collagen syn-
Insulin thesis. They circulate linked to IGF-binding
Low-dose PTH/PTHrP proteins (IGFBP), which in turn can exercise
Progestogens stimulatory or inhibitory effects on bone
Decrease bone formation (Conover 2008). IGF synthesis is regulated
Glucocorticoids by local growth factors and hormones; thus,
growth hormone, estrogens, and progesterone
2.4.3.2 Local Regulators of Bone increase their production, while the glucocor-
Remodeling ticoids inhibit it. They also mediate in the
Bone remodeling is also regulated by local fac- osteoblast-osteoclast interaction and actively
tors, among which principally growth factors and participate in bone remodeling (Hill et al.
cytokines, and recently, the bone matrix proteins 1995). IGF-II is the most abundant factor in
have been implicated as modulators of other local the bone matrix and is important during
factors (Raisz 1999; Fernndez-Tresguerres- embryogenesis (Canalis et al. 1989; Mohan
Hernndez-Gil et al. 2006). Bone cells also play and Baylink 1991).
50 U. Kini and B.N. Nandeesh
(b) Transforming growth factor-b (TGF-b) is a muscle cells, neovascularization, and colla-
superfamily of proteins highly abundant in gen synthesis, therefore favoring scarring
bone tissue (second after IGF). They are (Nash et al. 1994).
latently present in the matrix and activate dur- (e) Fibroblastic growth factor (FGF) has an ana-
ing osteoclastic resorption. TGF-b is a potent bolic effect on bone, as it is a mitogen of
stimulator of bone formation, promoting osteoblasts, vascular endothelial cells, and
osteoblastic differentiation and the synthesis fibroblasts. As a practical example of the
of the osteoid matrix and inhibiting the syn- effect of FGF, it is known that mutations in its
thesis of the proteases, especially the matrix receptors produce alterations in the craniofa-
metalloproteinase (MMP), an enzyme which cial skeleton, such as achondroplasia, Aperts
degrades it (Bonewald and Dallas 1994). syndrome, and Crouzons syndrome, among
TGF-b inhibits resorption on reducing the for- others (Marie 2003).
mation and differentiation of the osteoclasts, (f) Epidermal growth factor (EGF) is a powerful
as well as mature osteoclast activity, and stim- mitogen of cells of mesodermic or ectodermic
ulating their apoptosis (Baylink et al. 1993). origin. It has dual formative and destructive
(c) Bone morphogenetic proteins (BMP) are action, although the latter is the most well
included in the TGF-b family. They form a known.
group of 15 proteins able to achieve the trans- (g) Vascular endothelial growth factor (VEGF)
formation of connective tissue into bone tis- induces angiogenesis and vascular endothe-
sue, for which they are considered lial proliferation. It produces vasodilation and
osteoinductive (Sakou 1998). They stimulate an increase in vascular permeability. It is pro-
the differentiation of the stem cells toward duced in hypoxia and is currently considered
different cell lines (adipose tissue, cartilage, one of the key factors in the first phases of
and bone). They are highly abundant in bone fracture repair and bone regeneration, as well
tissue and during embryogenesis participate as in tumor growth.
in the formation of bone and cartilage (h) Granulocyte/macrophage-colony stimulating
(Yamaguchi et al. 2000). They strongly pro- factor (GM-CSF) is important in osteoclasto-
mote osteoblastic differentiation and are genesis and may play a role in the pathogen-
believed to inhibit osteoclastogenesis in addi- esis of osteopetrosis.
tion to stimulating osteogenesis (Canalis et al. (i) Macrophage-colony stimulating factor
2003). Another cell surface receptor called (M-CSF) is produced by osteoblasts and med-
the low-density lipoprotein (LDL)-related ullar stromal cells. It is an essential factor in the
protein 5 receptor (LRP5) is also important first phases of osteoclastogenesis and is required
for bone formation. for the formation of giant multinucleate cells
(d) Platelet-derived growth factor (PDGF), on but have no effect on osteoclastic activity.
the one hand, stimulates protein synthesis (j) Tumor Necrosis Factor (TNF). Tumor necro-
brought about the osteoblasts and, on the sis factor in vitro stimulates resorption and
other, favors bone resorption. Other effects has been related with bone loss in arthritis and
are the proliferation of fibroblasts and smooth periodontal disease.
2 Physiology of Bone Formation, Remodeling, and Metabolism 51
In clinical practice, the major problem for diag- or production of alkaline phosphatase to an
nostic purposes is to distinguish between the equivalent degree. Serum osteocalcin values
isoenzymes derived from liver and bone, can reflect the age-related increase in bone
although the intestinal enzyme may be raised turnover, and the values rise after the menopause
after meals and the placental isoenzyme during and fall after treatment with estrogens. Serum
pregnancy. The bone isoenzyme can be distin- osteocalcin correlates with skeletal growth at
guished based on sialic acid residues. In normal the time of puberty and is increased in a variety
individuals, about half of the total alkaline phos- of conditions characterized by increased bone
phatase is derived from bone and the rest from turnover, such as primary and secondary hyper-
liver. In conditions such as Pagets disease, the parathyroidism, hyperthyroidism, Pagets dis-
changes in alkaline phosphatase are often very ease, and acromegaly (Fraher 1993).
substantial.
Procollagen Peptides
Osteocalcin Collagen is the major structural protein of bone
Osteocalcin, also known as bone gla protein and comprises about 90 % of the organic mate-
(BGP), is a bone specific protein, which has rial. Collagen clearly contributes to the integrity
proven to be a sensitive and specific marker of and strength of bone matrix, and defects in its
osteoblast activity in a variety of metabolic production, for example, in osteogenesis imper-
bone diseases. Its synthesis is dependent upon the fecta, leads to bone of poor quality, susceptible to
presence of active metabolites of vitamin D, espe- fracture. Attempts to measure collagen synthesis
cially 1,25-dihydroxyvitamin D and requires vita- is, therefore, a more logical approach than mea-
min K for the conversion by carboxylation of suring other less abundant matrix constituents in
three glutamate residues to gamma-carboxygluta- the assessment of bone formation. During colla-
mate (gla) (Delmas 1995). The post-translational gen synthesis, pro-peptides are released both
modifications confer calcium-binding properties from the amino-terminal (N-terminal) and car-
on osteocalcin. This can be used to differentiate boxyterminal (C-terminal) ends of the procol-
fully carboxylated from partially carboxylated lagen molecule, after the three individual alpha
osteocalcin in the circulation, and it has been chains have formed the triple helix, which will
shown that a significant proportion of osteocalcin become part of the collagen fibril. Assays for
in osteoporotic elderly patients is incompletely both the N- and C-terminal pro-peptides exist.
carboxylated. The values are increased during growth and in
Measurements of serum osteocalcin by situations of increased bone formation, such as
immunoassays show increased values in condi- occur in Pagets disease, and in response to
tions associated with increased bone formation, growth hormone.
for example, hyperparathyroidism, hyperthy-
roidism, and bone metastases. In Pagets dis- 2.4.4.2 Markers of Bone Resorption
ease, however, the rises are less than expected, Biochemical markers used to monitor bone
perhaps reflecting differential incorporation resorption include urinary measurements of:
into bone matrix or altered synthesis by osteo- (a) Hydroxyproline-Containing Peptides. Studies
blasts (Gallagher 1997). Reduced levels of in relation to osteoporosis show that, when
osteocalcin may reflect lower rates of bone for- measurements are made carefully, urinary
mation, as seen, for example, in myeloma. hydroxyproline values rise after the meno-
Osteocalcin values may be substantially reduced pause and fall again when antiresorptive drugs
during treatment with glucocorticosteroids, such as estrogens, calcitonins, and bisphos-
although in this case, it should be remembered phonates are given. Pyridinoline crosslinks
that glucocorticoids specifically suppress osteo- pyridinoline (Pyr) and deoxypyridinoline
calcin synthesis by osteoblasts, while not nec- (DPyr) also called hydroxylysyl pyridinoline
essarily similarly depressing collagen synthesis (HL) and lysyl pyridinoline (LP), respectively,
2 Physiology of Bone Formation, Remodeling, and Metabolism 53
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