Sie sind auf Seite 1von 30

Physiology of Bone Formation,

Remodeling, and Metabolism 2


Usha Kini and B.N. Nandeesh

Contents 2.1 Introduction


2.1 Introduction ................................................ 29
Bone is a highly specialized supporting frame-
2.2 Physiology of Bone Formation .................. 30
2.2.1 Bone Formation ............................................ 30
work of the body, characterized by its rigidity,
2.2.2 Osteoblasts ................................................... 31 hardness, and power of regeneration and repair. It
2.2.3 Bone Matrix ................................................. 31 protects the vital organs, provides an environ-
2.2.4 Bone Minerals .............................................. 32 ment for marrow (both blood forming and fat
2.2.5 Osteocytes .................................................... 32
2.2.6 Intramembranous (Mesenchymal)
storage), acts as a mineral reservoir for calcium
Ossification ................................................ 32 homeostasis and a reservoir of growth factors and
2.2.7 Intracartilaginous (Endochondral) cytokines, and also takes part in acidbase bal-
Ossification ................................................ 33 ance (Taichman 2005). Bone constantly under-
2.2.8 Biological Factors Involved in Normal
Bone Formation and Its Regulation ........... 37
goes modeling (reshaping) during life to help it
2.2.9 Bone Modeling ............................................. 37 adapt to changing biomechanical forces, as well
2.2.10 Determinants of Bone Strength .................... 37 as remodeling to remove old, microdamaged
2.3 Physiology of Bone Metabolism ................ 38 bone and replace it with new, mechanically stron-
2.3.1 Cellular and Intracellular Calcium ger bone to help preserve bone strength.
and Phosphorus Metabolism ...................... 38 The bones have two components the cortical
2.3.2 Regulation of Skeletal Metabolism .............. 38
bone which is dense, solid, and surrounds the
2.4 Bone Remodeling ........................................ 42 marrow space and the trabecular bone which is
2.4.1 Mediators of Remodeling ............................. 43 composed of a honeycomb-like network of trabe-
2.4.2 Remodeling Phases ...................................... 44
2.4.3 Regulatory Factors in Bone Remodeling ..... 46 cular plates and rods interspersed in the bone
2.4.4 Markers of Bone Metabolism....................... 51 marrow compartment. Cortical bone has an outer
2.4.5 Pathophysiology of Bone Remodeling......... 53 periosteal surface and inner endosteal surface.
References ............................................................... 55 The periosteum is a fibrous connective tissue
sheath that surrounds the outer cortical surface of
bone, except at joints where bone is lined by
articular cartilage. It contains blood vessels,
nerve fibers, osteoblasts, and osteoclasts. It pro-
tects, nourishes, and aides in bone formation. It
U. Kini, M.D., DCP, DNB, FICP () plays an important role in appositional growth
B.N. Nandeesh, M.D., DNB and fracture repair. The endosteum is a membra-
Department of Pathology,
nous structure covering the inner surface of corti-
St. Johns Medical College and Hospital,
Koramangala, Bangalore, Karnataka 560034, India cal and cancellous bone and the blood vessel
e-mail: drushakini@gmail.com; nandeeshbn@gmail.com canals (Volkmanns canals) present in bone.

I. Fogelman et al. (eds.), Radionuclide and Hybrid Bone Imaging, 29


DOI 10.1007/978-3-642-02400-9_2, Springer-Verlag Berlin Heidelberg 2012
30 U. Kini and B.N. Nandeesh

Fig. 2.1 Woven bone/


immature bone (W) rimmed
by osteoblasts (B) with
peripheral lamellar bone (L)
showing a Haversian
canal (H)

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

humerus, radius). This is the most important Mesenchymal stem cell


process occurring during fracture healing
when treated by cast immobilization. Hemopoietic
If the process of formation of bone tissue stem cell
occurs at an extraskeletal location, it is termed as Osteoblast
heterotopic ossification. precursor
Osteoclast precursors
Three basic steps involved in osteogenesis
are: Osteoblasts
Osteoclast
(a) Synthesis of extracellular organic matrix
(osteoid)
(b) Matrix mineralization leading to the forma- Bone
tion of bone
(c) Remodeling of bone by the process of resorp-
tion and reformation Fig. 2.2 Diagram to show evolution of osteoblasts and
osteoclasts in the formation of bone

2.2.2 Osteoblasts tors, physical activity, and other stimuli act


mainly through osteoblasts to bring about their
Osteoblasts originate from mesenchymal stem effects on bone (Harada and Rodan 2003).
cells (osteoprogenitor cells) (Fig. 2.2) of the bone
marrow stroma and are responsible for bone 2.2.2.1 Wnt Pathway on
matrix synthesis and its subsequent mineraliza- Osteoblastogenesis
tion. Commitment of mesenchymal stem cells to Wnts are secreted glycoproteins that regulate a
the osteoblast lineage requires the canonical Wnt/ variety of cellular activities, such as cell fate, deter-
j3-catenin pathway and associated proteins mination, proliferation, migration, survival, polar-
(Logan and Nusse 2004). ity and gene expression (Cadigan and Liu 2006;
Osteoblasts are mononucleated, and their shape Caetano-Lopes et al. 2007). This pathway is essen-
varies from flat to plump, reflecting their level of tial for the differentiation of mature osteoblasts
cellular activity, and, in later stages of maturity, and consequently for bone formation. Reduced
lines up along bone-forming surfaces (Fig. 2.1). Wnt signaling has been associated with osteoporo-
Osteoblasts are responsible for regulation of sis (Krishnan et al. 2006). The Wnt system is also
osteoclasts and deposition of bone matrix (Mackie important in chondrogenesis and hematopoiesis
2003). As they differentiate, they acquire the and may be stimulatory or inhibitory at different
ability to secrete bone matrix. Ultimately, some stages of osteoblast differentiation.
osteoblasts become trapped in their own bone
matrix, giving rise to osteocytes which, gradu-
ally, stop secreting osteoid. Osteocytes are the 2.2.3 Bone Matrix
most abundant cells in bone; these cells commu-
nicate with each other and with the surrounding The structure of bone is constituted by:
medium through extensions of their plasma mem- (a) Inorganic (69 %) component, consisting of
brane. Therefore, osteocytes are thought to act as hydroxyapatite (99 %)
mechanosensors, instructing osteoclasts where (b) Organic (22 %), constituted by collagen (90 %)
and when to resorb bone and osteoblasts where and noncollagen structural proteins which
and when to form it (Boulpaep and Boron 2005; include proteoglycans, sialoproteins, gla-
Manolagas 2000). The osteoblasts, rich in alka- containing proteins, and 2HS-glycoprotein
line phosphatase, an organic phosphate-splitting The functional component of the bone includes
enzyme, possess receptors for parathyroid hor- growth factors and cytokines. The hardness and
mone and estrogen. Also, hormones, growth fac- rigidity of bone is due to the presence of mineral
32 U. Kini and B.N. Nandeesh

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

Crystalline hydroxyapatite [Ca10(PO4)6(OH)2] is Intramembranous ossification is one of the two


the chief mineral component of bone, constituting essential processes during fetal development of
approximately about a quarter of the volume and the mammalian skeletal system resulting in the
half of the mass of normal adult bone. These min- formation of bone tissue. Intramembranous
eral crystals (according to electron microscopy) ossification mainly occurs during formation of
are deposited along, and in close relation to, the the flat bones of the skull but also the mandible,
bone collagen fibrils. The calcium and phosphorus maxilla, and clavicles; it is also an essential pro-
(inorganic phosphate) components of these crys- cess during the natural healing of bone fractures
tals are derived from the blood plasma and which and the rudimentary formation of bones of the
in turn is from nutritional sources. Amorphous cal- head. The bone is formed from connective tissue
cium phosphate matures through several interme- such as mesenchyme tissue rather than from car-
diate stages to form hydroxyapatite. The end result tilage. The steps in intramembranous ossification
is a highly organized amalgam of protein, primar- (Fig. 2.3) are:
ily collagen, and mineral, primarily hydroxyapa- 1. Formation of ossification center
tite, that has sufficient structural integrity to serve 2. Calcification
the mechanical functions of the skeleton. Vitamin 3. Formation of trabeculae
D metabolites and parathyroid hormone (PTH) are 4. Development of periosteum
2 Physiology of Bone Formation, Remodeling, and Metabolism 33

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

2.2.7.3 Primary Center of Ossication Formation of Periosteum. Once vascularized,


The first site of ossification occurs in the primary the perichondrium becomes the periosteum.
center of ossification, which is in the middle of The periosteum contains a layer of undifferen-
diaphysis (shaft) and is followed by the following tiated cells (osteoprogenitor cells) which later
events: become osteoblasts.
36 U. Kini and B.N. Nandeesh

Fig. 2.6 Endochondral A


ossification as seen at B
microscopy: A showing
resting hyaline cartilage,
B chondrocytes undergoing
hyperplasia with rapid
proliferation laid down as
distinctive-looking stacks,
C calcification of
the matrix occurs,
D chondrocytes are either
dying or dead, leaving
cavities that will later
become invaded by C
bone-forming cells

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

2.3 Physiology of Bone 2.3.1 Cellular and Intracellular


Metabolism Calcium and Phosphorus
Metabolism
Bone carries out some of the important metabolic
functions; the important ones being: Both calcium and phosphorous, as well as mag-
(a) Mineral Reservoir. Bones act as homeostatic nesium, are transported to blood from bone, renal,
reservoir of minerals important for the body, and gastrointestinal cells, and vice versa. Mineral
most important ones being calcium and phos- homeostasis requires the transport of calcium,
phorus (Deftos 1998, 2001; Deftos and Gagel magnesium, and phosphate across their target
2000). These bone minerals can be mobilized cells in bone, intestine, and kidney. Ninety-nine
to maintain systemic mineral homeostasis. percent of body calcium, 85 % of phosphorus,
This metabolic function of bone prevails over and 65 % percent of total body magnesium are
its structural function in that calcium and contained within the bones.
other minerals are removed from and replaced The regulation of bone and bone mineral
in bone to serve systemic homeostatic needs metabolism results from the interactions among
irrespective of loss of skeletal structural three important hormones parathyroid hormone
integrity. (PTH), calcitonin, and vitamin D at three target
(b) Growth Factor and Cytokine Depository. organs, bone, kidney, and GI tract, to regulate the
Mineralized bone matrix is also a depository bone minerals (calcium and phosphorus).
for certain cytokines and growth factors that
can be released upon its resorption and can
exert their effects locally and systemically; 2.3.2 Regulation of Skeletal
notable among these are insulin-like growth Metabolism (Fig. 2.7)
factors (IGF), transforming growth factor-b
(TGF-b) and bone morphogenetic proteins Skeletal metabolism is regulated by bone cells
(BMP) (see Sect. 2.4.3.1). and their progenitors. Among the population of
(c) Fat Repository. The yellow bone marrow acts bone cells are osteoblasts, osteocytes, and osteo-
as a storage reserve of fatty acids. clasts. Monocytes, macrophages, and mast cells
(d) Acidbase Equilibrium. Bone buffers the may also mediate certain aspects of skeletal
blood against excessive pH changes by metabolism.
absorbing or releasing alkaline salts. Osteoblasts express receptors to many bone-
(e) Detoxification. Bone tissues are capable of active agents such as PTH, parathyroid hor-
storing heavy metals and other extraneous mone-related protein (PTHrP), vitamin D
elements, thus removing them from the circu- metabolites, gonadal and adrenal steroids, and
lation and helping in reducing their effects on certain cytokines and growth factors. The major
other tissues. product of osteoblasts is type 1 collagen, which,
(f) Endocrine Function. Bone controls metabo- along with other proteins, forms the organic
lism of phosphate by releasing fibroblast osteoid matrix that is mineralized to hydroxy-
growth factor (FGF-23), which acts on kid- apatite. These osteoblasts become encased in
neys to reduce phosphate reabsorption. A hor- bone during its formation and mineralization
mone called osteocalcin is also released by and reside in the resulting lacuna as osteocytes.
bone, which contributes to the regulation of While their synthetic activity decreases, the cells
blood glucose and fat deposition. Osteocalcin develop processes that communicate as canali-
enhances both the insulin secretion and sensi- culi with other osteocytes, osteoblasts, and vas-
tivity, in addition to boosting up the number culature. These osteocytes, thus, present acres of
of insulin-producing b cells and reducing cellular syncytium that permit translocation of
stores of fat. bone mineral during times of metabolic activity
2 Physiology of Bone Formation, Remodeling, and Metabolism 39

25-(OH)D3

Ca
1,25-(OH)2D3

PTH PTH

Ca2+ Ca2+
Calcium
PTH
1,25-(OH)2D3

PO4 Phosphate PO4

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

2.3.2.1 Parathyroid Hormone primary and secondary hyperparathyroidism,


Parathyroid hormone (PTH) is an 84-amino acid increase osteoclastic bone resorption. Low levels,
peptide secreted by two pairs of parathyroid especially if delivered episodically, seem to
glands located posterior to thyroid gland. The increase osteoblastic bone formation. The skele-
mature PTH is packaged into dense secretory tal effects of PTH are mediated through the osteo-
granules for regulated secretion. The major regu- blast, since they are the major expressor of the
latory signal for PTH secretion is serum calcium. PTH receptor. However, osteoblasts communi-
Serum calcium inversely affects PTH secretion, cate with osteoclasts to mediate PTH effects.
with the steep portion of the sigmoidal response This communication seems mediated through the
curve corresponding to the normal range of both. RANK-OPG pathway (see Sect. 2.4.1.3).
The parathyroid gland senses the concentra- PTH increases the reabsorption of calcium in
tion of extracellular ionized calcium through a the kidney, predominantly in the distal convo-
cell-surface calcium-sensing receptor (CSR) for luted tubule, and inhibits the reabsorption of
which calcium is an agonist. The same sensor phosphate in the renal proximal tubule, causing
also regulates the responses to calcium of thyroid hypercalcemia and hypophosphatemia.
C cells, which secrete calcitonin in direct rela- PTH mediates these effects through the PTH
tionship to extracellular calcium; the distal receptor which is an 80,000-MW membrane gly-
nephron of the kidney, where calcium excretion coprotein of the G protein receptor superfamily,
is regulated; the placenta, where fetal-maternal while the parathyroid hormone-related protein
calcium fluxes occur; and the brain and GI tract, (PTHrP) is the major humoral mediator of the
where its function is unknown; and the bone cells. hypercalcemia of malignancy and is secreted by
Serum phosphate has an inverse effect on calcium many types of malignant tumors, notably by
concentration, and ambient phosphate directly breast and lung cancer. Both PTH and PTHrP
increases 1,25-D production. Thus, serum phos- generate cyclic adenosine monophosphate
phate may directly and indirectly regulate PTH (cAMP) as a cellular second messenger by acti-
expression. vating protein kinase A (PKA), and the phospho-
lipase C effector system increasing cellular IP3
Metabolism and Clearance and calcium and activating protein kinase C
of Parathyroid Hormone (PKC).
Parathyroid hormone, with a circulating half-life
of less than 5 min, is metabolized in the liver, kid- 2.3.2.2 Calcitonin
ney, and blood. The carboxyl-terminal fragments Calcitonin (CT) is a 32-amino acid peptide whose
are cleared by glomerular filtration, so they accu- main effect is to inhibit osteoclast-mediated bone
mulate in renal failure. As a result of the biosyn- resorption. CT is secreted by parafollicular C
thesis, secretion, and metabolism of PTH, the cells of the thyroid and other neuroendocrine
circulation contains several forms of the mole- cells. In contrast to PTH, hypercalcemia increases
cule. Overall, 1020 % of circulating PTH immu- secretion of hypocalcemia-inducing CT, while
noreactivity comprises the intact hormone, with hypocalcemia inhibits secretion. It inhibits
the remainder being a heterogeneous collection resorption of bone, increases calcium and phos-
of peptide fragments corresponding to the middle phorus excretion, and decreases the blood levels
and carboxy regions of the molecule. of calcium and phosphorus (Deftos 1998).

Biologic Effects of Parathyroid 2.3.2.3 Vitamin D


Hormone (Fig. 2.7) Vitamin D is a secosterol hormone that is pres-
Parathyroid hormone regulates serum calcium ent in humans in an endogenous (vitamin D3)
and phosphorus concentrations through its recep- and exogenous (vitamin D2) form. The endoge-
tor-mediated, combined actions on bone, intes- nous form of vitamin D, cholecalciferol (vita-
tine, and kidney. High levels of PTH, as seen in min D3), is synthesized in the skin from the
2 Physiology of Bone Formation, Remodeling, and Metabolism 41

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

cholesterol metabolite 7-dehydrocholesterol Effects of 1,25-Dihydroxyvitamin D


under the influence of ultraviolet radiation on Mineral Metabolism
(Deftos 1998) (Fig. 2.8). The exogenous form of (a) Intestinal Calcium Absorption. Vitamin D
vitamin D2 (ergocalciferol) is produced by ultra- increases intestinal calcium absorption, pri-
violet irradiation of the plant sterol ergosterol marily in the jejunum and ileum, by increas-
and is available through the diet. Both forms of ing calcium uptake through the brush border
vitamin D require further metabolism to be membrane of the enterocyte. In a vitamin
activated. d-deficient state, only 1015 % of dietary
42 U. Kini and B.N. Nandeesh

calcium is absorbed by the gastrointestinal added (a sub-process called ossification or bone


tract, but with adequate vitamin D, adults formation). Remodeling involves continuous
absorb approximately 30 % of dietary cal- removal of discrete packets of old bone, replace-
cium (Deftos 1998). During pregnancy, lacta- ment of these packets with newly synthesized
tion, and growth, increased circulating proteinaceous matrix, and subsequent mineral-
concentrations of 1,25-D promote the ization of the matrix to form new bone (Fernndez-
efficiency of intestinal calcium absorption by Tresguerres-Hernndez-Gil et al. 2006; Fraher
as much as 5080 %. Vitamin D also regu- 1993). These processes also control the reshaping
lates skeletal metabolism through the RANK or replacement of bone during growth and fol-
pathway. 1,25-D also increases the efficiency lowing injuries like fractures but also microdam-
of dietary phosphorus absorption by about age (prevents accumulation of bone microdamage
1520 %. through replacement of old bone with the new
(b) Bone. Vitamin D promotes the mineralization one) (Turner 1998) which occurs during normal
of osteoid and causes bone resorption by activity. Remodeling responds also to functional
mature osteoclasts, but this effect is indirect, demands of the mechanical loading. As a result,
requiring cell recruitment and interaction with bone is added where needed and removed where
osteoblasts and the fusion of monocytic pre- it is not required. This process is essential in the
cursors to osteoclasts. Vitamin D also regu- maintenance of bone strength and mineral homeo-
lates the expression of several bone proteins, stasis. The skeleton is a metabolically active
notably osteocalcin. It promotes the transcrip- organ that undergoes continuous remodeling
tion of osteocalcin and has bidirectional throughout life. This remodeling is necessary
effects on type I collagen and alkaline phos- both to maintain the structural integrity of the
phatase gene transcription. skeleton and to subserve its metabolic functions
(c) Kidney. The kidney decreases calcium and as a storehouse of calcium and phosphorus.
phosphorus excretion. Normal bone remodeling cycle requires that
(d) Blood. Blood increases calcium and phospho- the process of bone resorption and bone forma-
rus levels. tion take place in a coordinated fashion, which in
turn depends on the orderly development and
2.3.2.4 Other Hormones activation of osteoclasts and osteoblasts, respec-
In addition to the primary calcemic hormones, tively. This property of bone, which constantly
other hormones play an important role in calcium resorbs the old bone and forms new bone, makes
and skeletal metabolism. Gonadal steroids main- the bone a very dynamic tissue that permits the
tain skeletal mass. Glucocorticoids are deleteri- maintenance of bone tissue, the repair of dam-
ous to all skeletal functions. Insulin, growth aged tissue, and the homeostasis of the phospho-
hormone, androgens, and thyroid hormones pro- calcic metabolism. The bone remodeling cycle
mote skeletal growth and maturation. Excess pro- involves a series of highly regulated steps that
duction of the latter can cause hypercalcemia depend on the interactions of two cell lineages,
(Deftos 1998; Kawaguchi et al. 1994). While in the mesenchymal osteoblastic lineage and the
adults bone metabolism is basically limited to hematopoietic osteoclastic lineage (Fraher 1993).
bone maintenance, the most obvious feature of The balance between bone resorption and bone
bone metabolism in children and adolescents is deposition is determined by the activities of these
increase in bone size in all three dimensions. two principle cell types, namely, osteoclasts and
osteoblasts. Osteoblasts and osteoclasts, coupled
together via paracrine cell signaling, are referred
2.4 Bone Remodeling to as bone remodeling units.
In the young skeleton, the amount of resorbed
Bone remodeling is a lifelong process wherein bone is proportional to the newly formed. For this
old bone is removed from the skeleton (a sub- reason, it is referred to as a balanced process,
process called bone resorption), and new bone is linked in both space and time under normal
2 Physiology of Bone Formation, Remodeling, and Metabolism 43

conditions. The average lifespan of each remod- 2.4.1 Mediators of Remodeling


eled unit in humans is 28 months, the greater part
of this time being taken up by bone formation. 2.4.1.1 Osteoclasts
Bone remodeling occurs throughout life, but Osteoclasts are the only cells that are known to be
only up to the third decade is the balance posi- capable of resorbing bone. They are typically
tive. It is precisely in the third decade when the multinucleated. Osteoclasts are derived from
bone mass is at its maximum, and this is main- mononuclear precursor cells of the monocyte-
tained with small variations until the age of 50. macrophage lineage (hematopoietic stem cells
From then on, resorption predominates and the that give rise to monocytes and macrophages)
bone mass begins to decrease. Bone remodeling (Boyle et al. 2003). Mononuclear monocyte-
increases in perimenopausal and early postmeno- macrophage precursor cells have been identified
pausal women and then slows with further aging in various tissues, but bone marrow monocyte-
but continues at a faster rate than in premeno- macrophage precursor cells are thought to give
pausal women. rise to most osteoclasts.
Although cortical bone makes up 75 % of the
total volume, the metabolic rate is ten times 2.4.1.2 Osteoblasts
higher in trabecular bone, since the surface area- Osteoblasts can be stimulated to increase bone
to-volume ratio is much greater (trabecular bone mass through increased secretion of osteoid and
surface representing 60 % of the total). Therefore, by inhibiting the ability of osteoclasts to break
approximately 510 % of total bone is renewed down osseous tissue. Bone building through
per year. increased formation of osteoid is stimulated by
Osteoclasts are endowed with highly active ion the secretion of growth hormone by the pituitary,
channels in the cell membrane that pump protons the thyroid hormone and the sex hormones (estro-
into the extracellular space, thus lowering the pH gens and androgens). The functional aspects of
in their own microenvironment. This drop in pH osteoblasts have been discussed in detail in the
dissolves the bone mineral (Blair et al. 1989). earlier section (Sect. 2.2.1) on bone formation.
The bone remodeling cycle involves a com-
plex series of sequential steps (coupling of bone 2.4.1.3 RANK
formation and bone resorption). Bone balance is The cell surface receptor called RANK (for recep-
the difference between the old bone resorbed and tor activator of NFkB) prods osteoclast precursor
new bone formed. Periosteal bone balance is cells to develop into fully differentiated osteoclasts
mildly positive, whereas endosteal and trabecular when RANK is activated by its cognate partner
bone balances are mildly negative, leading to cor- RANK ligand (RANKL). RANKL belongs to the
tical and trabecular thinning with aging. These TNF superfamily and is critical for osteoclast for-
relative changes occur with endosteal resorption mation. It is one of the key signaling molecules
outstripping periosteal formation. that facilitate cross talk between the osteoblasts
The main recognized functions of bone remod- and osteoclasts and help coordinate bone remodel-
eling include preservation of bone mechanical ing. RANKL and macrophage CSF (M-CSF) are
strength by replacing older, microdamaged bone two cytokines that are critical for osteoclast for-
with newer, healthier bone and calcium and phos- mation. Both RANKL and M-CSF are produced
phate homeostasis. The relatively low adult corti- mainly by marrow stromal cells and osteoblasts in
cal bone turnover rate of 23 %/year is adequate membrane-bound and soluble forms, and osteo-
to maintain biomechanical strength of bone. The clastogenesis requires the presence of stromal
rate of trabecular bone turnover is higher, more cells and osteoblasts in bone marrow (Teitelbaum
than required for maintenance of mechanical and Ross 2003; Cohen 2006). Osteoprotegerin is
strength, indicating that trabecular bone turnover another protein released by osteoblasts that acts as
is more important for mineral metabolism. a decoy to prevent RANK and RANKL from com-
Increased demand for calcium or phosphorus ing in contact (Asagiri and Takayanagi 2007;
may require increased bone remodeling units. Boyle et al. 2003; Gori et al. 2000; Lacey et al.
44 U. Kini and B.N. Nandeesh

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

Fig. 2.10 Figure to show


Bone Osteoclasts
normal bone remodeling (a) lining cells
vs. defective resorption (b) Osteoblasts
seen in disease states

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

Table 2.1 Local factors in bone remodeling


Stimulate bone formation Stimulate bone resorption Inhibit bone resorption
Growth factors BMP-2, BMP-4, BMP-6, BMP-7, TNF, EGF, PDGF, FGF,
IGF-I, IGF-II TGF-b, FGF, and M-CSF, and GM-CSF
PDGF
Cytokines IL-4,IL-13, IFN, and OPG IL-1, IL-6, IL-8, IL-11, IFN-y IL-4
PGE2, PGE1, PGG2, PGI2,
and PGH2

(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

Matrix Proteins bone resorption (Kawaguchi et al. 1995).


The matrix proteins have recently been discov- This could also be important in inflammatory
ered to act as growth factor modulators (Young bone loss. The first step on PGE2 synthesis
2003). Matrix proteins are found in concentra- is carried out by an enzyme called cyclooxy-
tions a 1,000 times higher than growth factors and genase 2 (COX2), and inhibitors of this
could therefore play a more important role in the enzyme can prevent bone formation in
regulation of the different cell functions (Horowitz response to mechanical stress in animals.
2003). Matrix proteins also participate in regula- PGE2 may be required for exercise-induced
tion of the differentiation of the cells contained bone formation.
within the matrix. For example, collagen I is one (e) Leukotrienes. Leukotrienes are another set of
of the earliest markers which regulates the osteo- lipid molecules that appear to regulate bone
progenitor cells, and alkaline phosphatase is a sur- remodeling.
face protein that could participate in the regulation Thus, the growth factors that regulate bone
of the proliferation, migration, and differentiation remodeling are:
of the osteoblastic cells. Osteonectin, fibronectin, Insulin-like growth factors (IGF) I and II
and osteocalcin promote cell attachment, facili- Transforming growth factor-b (TGF-b) super-
tate cell migration, and activate cells. family, including the bone morphogenetic
proteins (BMPs)
Cytokines Fibroblast growth factors (FGFs)
These are polypeptides synthesized in the lym- Platelet-derived growth factors (PDGFs)
phocytic and monocytic cells and play an impor- Cytokines
tant role in multiple cellular functions, such as the
immunological response, inflammation, and
hematopoiesis, having both an autocrine and para- 2.4.4 Markers of Bone Metabolism
crine effect. The following are important in bone:
(a) Interleukin 1 (IL-1) directly stimulates osteo- Biochemical markers of bone metabolism pro-
clastic resorption, increasing the proliferation vide dynamic information about the turnover of
and differentiation of the preosteoblasts, as osseous tissue (Schneider et al. 1998). They can
well as the osteoclastic activity, and inhibiting be broadly classified as reflecting either bone for-
the apoptosis of the osteoclasts (Compston mation or bone resorption.
2001). In reality, they are three different
related molecules: IL-1 a, IL-1 b, and the 2.4.4.1 Markers of Bone Formation
IL-1 receptor antagonist, the last being the Alkaline Phosphatase
inhibitor of the first two. They act both directly Alkaline phosphatase in serum has been used
and indirectly on resorption through the syn- for more than 50 years to monitor bone metabo-
thesis of prostaglandins. lism and is still the most frequently used marker.
(b) Interleukin 6 (IL-6) stimulates bone resorp- Alkaline phosphatase is an ectoenzyme anchored
tion and appears to be implicated in the patho- to the cell surfaces of osteoblasts and other cells
genesis of Pagets disease (Roodman 1999). It (Delmas 1995). However, alkaline phosphatase
is believed to play an important role in the ini- is not specific to bone, and ideally selective
tial stages of osteoclastogenesis and is pro- measurement of the bone isoenzyme should be
duced in response to PTH, IL-1, and used as a marker of bone formation. The clear-
1,25(OH)2D3. ance from the circulation is relatively slow, with
(c) Interleukin 11 (IL-11). Recently discovered, a half-life in the order of 13 days for the bone
it is produced in bone marrow and induces isoenzyme. Its values in plasma and serum are
osteoclastogenesis. raised in conditions such as Pagets disease,
(d) Prostaglandins (PG). Prostaglandins, par- osteomalacia, and after fractures or ectopic
ticularly prostaglandin E2 (PGE2), stimulate bone formation.
52 U. Kini and B.N. Nandeesh

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

are currently receiving considerable attention 2.4.5 Pathophysiology of Bone


as the most promising markers of bone resorp- Remodeling (Fig. 2.11)
tion. Both are non-reducible crosslinks which
stabilize the collagen chains within the extra- Abnormalities of bone remodeling can produce a
cellular matrix and are formed by the conden- variety of skeletal disorders (Raisz 1999).
sation of three lysine and/or hydroxylysine Inflammatory bone loss in periodontal disease and
residues in adjacent alpha chains. arthritis is probably the combined result of stimu-
(b) Hydroxylysine glycosides and pyridinoline lation of resorption and inhibition of formation by
crosslinks (Delmas 1995) are derived from cytokines and prostaglandins. Interleukin 1 (IL-
type I collagen. Hydroxylysine, like hydroxy- 1), IL-6, and tumor necrosis factor, as well as
proline derived from proline, is produced by a growth factors, have been implicated in patho-
post-translational hydroxylation. The subse- logic responses in the skeleton, particularly in
quent glycosylation of hydroxylysine differs osteoporosis associated with estrogen deficiency,
in collagens in different tissues. The mono- hyperparathyroidism, and Pagets disease
glycosylated galactosyl hydroxylysine is (Lorenzo 1992; Mills and Frausto 1997; Raisz
enriched in bone compared with the diglyco- 1999; Papanicolaou et al. 1998). A few of the
sylated form, glucosyl galactosyl hydroxy- pathological entities wherein there is deranged
lysine, which is the major form in skin. This skeletal metabolism/remodeling are addressed
may be a useful marker of bone resorption, below, and their abnormalities are shown in
for example, in osteoporosis. Table 2.2.
(c) Acid Phosphatase. Acid phosphatase is a lys-
osomal enzyme which exists in several forms 2.4.5.1 Osteoporosis
in different tissues. The type 5 isoenzyme is Osteoporosis is a very common metabolic disor-
the one found in osteoclasts, which appear to der of the skeleton, where in the bone mineral
be released during bone resorption. Assays of density (BMD) is reduced, the bone microarchi-
total tartrate-resistant acid phosphatase tecture is disrupted (perforation of trabecular
(TRAP) in the circulation are moderately plates), and the amount and variety of noncollag-
raised in disorders associated with increased enous proteins in bone is altered, leading to
bone resorption, but the assays are difficult to increased risk of fracture. Osteoporosis may be:
perform because of the instability of the Primary (postmenopausal/senile)
enzyme and the relatively small changes Secondary cause (nutrition, endocrine, drug,
observed in pathological states. malignancy, chronic disease, idiopathic)
(d) Other Assays. In some circumstances, fasting (Raisz 1997)
urine calcium can give an indirect measure of The loss of bone mass and strength can be
bone resorption rates and may be useful in contributed by:
Pagets disease and in patients with metastatic (a) Failure to reach an optimal peak bone mass as
bone disease for following responses to treat- a young adult
ment. Other measurements include assays of (b) Excessive resorption of bone after peak mass
tartrate-resistant acid phosphatase and free has been achieved
gamma-carboxyglutamic acid. Many cytok- (c) An impaired bone formation response during
ines and growth factors influence bone metab- remodeling
olism (e.g., interleukins 1 & 6, tumor necrosis There is a defect in osteoblast function or
factors [TNFs], insulin-like growth factors I because of loss of template from excessive resorp-
& II and their binding proteins). These assays tion with perforation of trabecular plates and
have been of help with the diagnosis and man- removal of endosteal cortical bone. The defect in
agement of patients with florid disorders of osteoblast function could be the consequence of
bone metabolism, such as Pagets disease or cellular senescence but also may be the result of a
vitamin d-deficient osteomalacia. decrease in the synthesis or activity of systemic
54 U. Kini and B.N. Nandeesh

Fig. 2.11 Microphotograph


showing osteoclasts (star)
causing endosteal surface
resorption of bone

Table 2.2 Abnormalities of remodeling in disease 2.4.5.2 Hyperparathyroidism


conditions and Hyperthyroidism
Bone In these disorders, bone turnover may be mark-
Bone resorption formation edly increased with or without decreased bone
Osteoporosis mass. Both parathyroid hormones and thyroid
Glucocorticoid hormones can stimulate bone formation as well
osteoporosis as resorption, and if the cells of the osteoblastic
Hyperparathyroidism
lineage are sufficiently responsive, then bone loss
Hyperthyroidism
will not occur. Increased IL-6 has been reported
Paget disease
in hyperparathyroidism.
Inflammation
Immobilization
2.4.5.3 Pagets Disease
Pagets disease is the best example of a disease in
and local growth factors. A combination of bio- which biochemical markers of bone metabolism
chemical assays, including total alkaline phos- have been extensively used in clinical practice. A
phatase and osteocalcin in plasma and remarkable disorder of bone remodeling is Paget
hydroxyproline and calcium in fasting urine, have disease (Siris 1998). In this disorder, the osteo-
strong predictive power in relation to rates of bone clasts become abnormally activated, possibly by
loss subsequently measured by bone densitometry viral infection, and produce a bizarre and irregu-
techniques. lar pattern of resorption, to which there is usually
The two major needs for the use of markers in an intense osteoblastic response with irregular
osteoporosis are: new bone formation often in the form of woven
1. To identify the patients at greatest risk, for bone. Thus, in Pagets disease there may be
example, those with rapid rates of bone loss increased bone density, but because of the irregu-
compared with bone formation lar architecture, bone strength is decreased and
2. To monitor the effects of specific treatment pathologic fractures may occur.
(e.g., with estrogens, calcitonins and bisphos- Bone markers in Pagets disease are used to:
phonates, or with bone-forming agents) in 1. Assess and to monitor disease activity in indi-
individual patients vidual patients
2 Physiology of Bone Formation, Remodeling, and Metabolism 55

2. Evaluate doseresponse relationships to exist- Bonewald LF (1999) Establishment and characterization


ing and new drugs in therapeutic trials of an osteocyte-like cell line, MLO-Y4. J Bone Miner
Metab 17:6165
3. Evaluate the value of novel biochemical mark- Bonewald LF, Dallas SL (1994) Role of active and latent
ers of bone metabolism, compared with estab- transforming growth factor-b in bone formation. J Cell
lished markers (Mills and Frausto 1997) Biochem 55:350357
Bonewald LF, Mundy GR (1990) Role of transforming
growth factor beta in bone remodeling. Clin Orthop
2.4.5.4 Osteomalacia/Rickets Relat Res 2S:3540
The growth plates affecting children is seen in Boulpaep EL, Boron WF (2005) Medical physiology: a
rickets, while in osteomalacia affecting adults, cellular and molecular approach. Saunders,
there is incomplete mineralization of osteoid. Philadelphia, pp 10891091
Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast dif-
There is decrease in Ca/PO4 ratio, increase in ferentiation and activation. Nature 423:337342
alkaline phosphatase, and decrease in calcium Brighton CT, Hunt RM (1986) Histochemical localization
excretion [Ca PO4 < 2.4]. of calcium in the fracture callus with potassium
pyroantimonate: possible role of chondrocyte mito-
chondrial calcium in callus calcification. J Bone Joint
2.4.5.5 Osteopetrosis Surg 68-A:703715
Decreased bone turnover can also lead to skeletal Brighton CT, Hunt RM (1991) Early histological and
abnormalities. There are several syndromes of ultrastructural changes in medullary fracture callus.
osteopetrosis or osteosclerosis in which bone J Bone Joint Surg 73-A:832847
Brighton CT, Sugioka Y, Hunt RM (1973) Cytoplasmic
resorption is defective because of impaired for- structures of epiphyseal plate chondrocytes; quantita-
mation of osteoclasts or loss of osteoclast func- tive evaluation using electron micrographs of rat cos-
tion. In these disorders, bone modeling as well as tochondral junctions with specific reference to the fate
remodeling is impaired, and the architecture of of hypertrophic cells. J Bone Joint Surg 55:771784
Brodsky B, Persikov AV (2005) Molecular structure of the
the skeleton can be quite abnormal (Charles and collagen triple helix. Adv Protein Chem 70:301339
Key 1998; Schneider et al. 1998). Bruzzaniti A, Baron R (2007) Molecular regulation of
osteoclast activity. Rev Endocr Metab Disord 7:
2.4.5.6 Other Orthopedic Disorders 123139
Burr DB (2002) Targeted and nontargeted remodeling.
Pathologic changes in the skeleton that occur in Bone 30:24
association with orthopedic disorders have also Cadigan KM, Liu YI (2006) Wnt signaling: complexity at
been found to involve local factors. For example, the surface. J Cell Sci 119:395402
the heterotopic ossification that occurs after hip Caetano-Lopes J, Canhao H, Fonseca JE (2007)
Osteoblasts and bone formation. Acta Reumatol Port
surgery may be mediated by prostaglandin 32:103110
because it can be diminished by giving inhibitors Canalis E, McCarthy TL, Centrella M (1989) The role of
of prostaglandin synthesis, such as indomethacin. growth factors in skeletal remodeling. Endocrinol
The loosening of prostheses has been shown to Metab Clin North Am 18:903918
Canalis E, Economides AN, Gazzerro E (2003) Bone
involve local cytokine and prostaglandin produc- morphogenetic proteins, their antagonists, and the
tion by inflammatory cells (Knelles et al. 1997; skeleton. Endocr Rev 24:218235
Mohanty 1996). Charles JM, Key LL (1998) Developmental spectrum of
children with congenital osteopetrosis. J Pediatr
132:371374
Clarke B (2008) Normal bone anatomy and physiology.
Clin J Am Soc Nephrol 3:S131S139
References Cohen MM Jr (2006) The new bone biology: pathologic,
molecular, clinical correlates. Am J Med Genet A
Asagiri M, Takayanagi H (2007) The molecular understand- 140:26462706
ing of osteoclast differentiation. Bone 40:251264 Cohick WS, Clemmons DR (1993) The insulin-like
Baylink DJ, Finkelman RD, Mohan S (1993) Growth factors growth factors. Annu Rev Physiol 55:131153
to stimulate bone formation. J Bone Miner Res Compston JE (2001) Sex steroids and bone. Physiol Rev
8:565572 81:419447
Blair HC, Teitebaum SL, Ghiselli R et al (1989) Conover CA (2008) Insulin-like growth factor-binding
Osteoclastic bone resorption by a polarized vacuolar proteins and bone metabolism. Am J Physiol
proton pump. Science 245:855857 Endocrinol Metab 294:1014
56 U. Kini and B.N. Nandeesh

Deftos LJ (1998) Calcium and phosphate homeostasis, bone matrix formation and cell replication.
chapter 2. In: Clinical essentials of calcium and skel- Endocrinology 122:254260
etal metabolism, 1st edn. Professional Communication Hofbauer LC, Khosla S, Dunstan CR et al (1999) Estrogen
Inc., pp 1208. http://www.endotext.org/parathyroid/ stimulates gene expression and protein production of
parathyroid2/ch01s05.html. Accessed 20 Apr 2011 osteoprotegerin in human osteoblastic cells.
Deftos LJ (2001) Immunoassays for PTH and PTHrP, Endocrinology 140:43674370
chapter 9. In: Bilezikian JP, Marcus R, Levine A (eds) Horowitz M (2003) Matrix proteins versus cytokines in
The parathyroids, 2nd edn. Academic Press, San Diego, the regulation of osteoblast function and bone forma-
pp 143166 tion. Calcif Tissue Int 72:57
Deftos LJ, Gagel R (2000) Calcitonin and medullary thy- Horwood NJ, Elliott J, Martin TJ et al (1998) Osteotropic
roid carcinoma, chapter 265. In: Wyngarden JB, agents regulate the expression of osteoclast differenti-
Bennett JC (eds) Cecil textbook of medicine, 21st edn. ation factor and osteoprotegerin in osteoblastic stromal
WB Saunders Company, Philadelphia, pp 14061409 cells. Endocrinology 139:47434746
Delmas PD (1995) Biochemical markers for the assess- Kawaguchi H, Pilbeam CC, Raisz LG (1994) Anabolic
ment of bone turnover. In: Riggs BL, Melton J (eds) effects of 3,3,5- triiodothyronine and triiodothyroa-
Osteoporosis: etiology, diagnosis, and management, cetic acid in cultured neonatal mouse parietal bones.
2nd edn. Lippincott-Raven, Philadelphia Endocrinology 135:971976
Dempster DW, Cosman F, Parisien M et al (1993) Anabolic Kawaguchi H, Pilbean CC, Harrison JR et al (1995) The
actions of parathyroid hormone on bone. Endocr Rev role of prostaglandins in the regulation of bone metab-
14:690709 olism. Clin Orthop 313:3646
Eriksen EF (1986) Normal and pathological remodeling Knelles D, Barthel T, Kraus U et al (1997) Randomized
of human trabecular bone: three dimensional recon- trial comparing early postoperative irradiation vs. the
struction of the remodeling sequence in normals and in use of nonsteroidal anti-inflammatory drugs for pre-
metabolic bone disease. Endocr Rev 7:379408 vention of heterotopic ossification following prosthetic
Eriksen EF, Axelrod DW, Melsen F (1994) Bone histo- total hip replacement. Int J Radiat Oncol Biol Phys
morphometry. Raven Press, New York, pp 112 39:961966
Fernndez-Tresguerres-Hernndez-Gil I, Alobera-Gracia Kobayashi S, Takahashi HE, Ito A et al (2003) Trabecular
MA, del Canto-Pingarrn M et al (2006) Physiological minimodeling in human iliac bone. Bone 32:163169
bases of bone regeneration II. The remodeling process. Krishnan V, Bryant HU, Macdougald OA et al (2006)
Med Oral Patol Oral Cir Bucal 11:E151E157 Regulation of bone mass by Wnt signaling. J Clin
Fraher L (1993) Biochemical markers of bone turnover. Invest 116:12021209
Clin Biochem 26:431432 Lacey DL, Timms E, Tan HL et al (1998) Osteoprotegerin
Gallagher SK (1997) Biochemical markers of bone metab- ligand is a cytokine that regulates osteoclast differen-
olism as they relate to osteoporosis. MLO: Med Lab Obs tiation and activation. Cell 93:165176
29(8):50. FindArticles.com. Lind M, Deleuran B, Thestrup-Pedersen K et al (1995)
Gori F, Hofbauer LC, Dunstan CR et al (2000) The expres- Chemotaxis of human osteoblasts. Effects of osteotro-
sion of osteoprotegerin and RANK ligand and the sup- pic growth factors. APMIS 103:140146
port of osteoclast formation by stromal-osteoblast Lindsay R, Cosman F, Zhou H et al (2006) A novel tetra-
lineage cells is developmentally regulated. cycline labeling schedule for longitudinal evaluation
Endocrinology 141:47684776 of the short-term effects of anabolic therapy with a
Grant SFA, Ralston SH (1997) Genes and osteoporosis. single iliac crest biopsy: early actions of teriparatide.
Endocrinology 8:232239 J Bone Miner Res 21:366373
Hakeda Y, Kawaguchi H, Hurley M et al (1996) Intact Locklin RM, Oreffo RO, Triffitt JT et al (1999) Effects of
insulin-like growth factor binding protein-5 (IGFBP- TGFbeta and bFGF on the differentiation of human bone
5) associates with bone matrix and the soluble frag- marrow stromal fibroblasts. Cell Biol Int 23:185194
ments of IGFBP-5 accumulated in culture medium Logan CY, Nusse R (2004) The Wnt signaling pathway in
of neonatal mouse calvariae by parathyroid hormone development and disease. Annu Rev Cell Dev Biol
and prostaglandin E2-treatment. J Cell Physiol 166: 20:781810
370379 Lorenzo JA (1992) The role of cytokines in the regulation of
Harada S, Rodan GA (2003) Control of osteoblast function local bone resorption. Crit Rev Immunol 11:195213
and regulation of bone mass. Nature 423: 349355 Lukert BP, Kream BE (1996) Clinical and basic aspects of
Harvey S, Hull KL (1998) Growth hormone: a paracrine glucocorticoid action in bone. In: Bilezikian JP, Raisz
growth factor? Endocrine 7:267279 LG, Rodan GA (eds) Principles of bone biology.
Hill PA, Reynolds JJ, Meikle MC (1995) Osteoblasts Academic, San Diego, pp 533548
mediate insulin-like growth factor-I and -II stimulation Mackie EJ (2003) Osteoblasts: novel roles in orchestra-
of osteoclast formation and function. Endocrinology tion of skeletal architecture. Int J Biochem Cell Biol
136:124131 35:13011305
Hock JM, Centrella M, Canalis E et al (2004) Insulin-like Manolagas SC (2000) Birth and death of bone cells: basic
growth factor I (IGF-I) has independent effects on regulatory mechanisms and implications for the
2 Physiology of Bone Formation, Remodeling, and Metabolism 57

pathogenesis and treatment of osteoporosis. Endocr Schneider GB, Key LL, Popoff SN (1998) Osteopetrosis.
Rev 21:115137 Therapeutic strategies. Endocrinologist 8:409417
Marie PJ (2003) Fibroblast growth factor signaling con- Siris ES (1998) Pagets disease of bone. J Bone Miner Res
trolling osteoblast differentiation. Gene 316:2332 13:10611065
Mills BG, Frausto A (1997) Cytokines expressed in multi- Suda T, Takahashi N, Udagawa N et al (1999) Modulation
nucleated cells: Pagets disease and giant cell tumors of osteoclast differentiation and function by the new
versus normal bone. Calcif Tissue Int 61:1621 members of the tumor necrosis factor receptor and
Mohan S, Baylink DJ (1991) Bone growth factors. Clin ligand families. Endocr Rev 20:345357
Orthop 263:3048 Taichman RS (2005) Blood and bone: two tissues whose
Mohanty M (1996) Cellular basis for failure of joint pros- fates are intertwined to create the hematopoietic stem
thesis. Biomed Mater Eng 6:165172 cell niche. Blood 105:26312639
Nash TJ, Howlett CR, Martin C et al (1994) Effects of Teitelbaum SL, Ross FP (2003) Genetic regulation of
platelet-derived growth factor on tibial osteotomies in osteoclast development and function. Nat Rev Genet
rabbits. Bone 15:203208 4:638649
Netter FH (1987) Musculoskeletal system: anatomy, phys- Teitelbaum SL, Abu-Amer Y, Ross FP (1995) Molecular
iology, and metabolic disorders. Ciba-Geigy mechanisms of bone resorption. J Cell Biochem 59:110
Corporation, Summit, pp 129130. ISBN 0914168886 Theill LE, Boyle WJ, Penninger JM (2002) RANK-L and
Papanicolaou DA, Wilder RL, Manolagas SC et al (1998) RANK: T cells, bone loss, and mammalian evolution.
The pathophysiologic roles of interleukin-6 in human Annu Rev Immunol 20:795823
disease. Ann Intern Med 128:127137 Trueta J (1963) The role of blood vessels in osteogenesis.
Parfitt AM (2002) Targeted and nontargeted bone remod- J Bone Joint Surg Br 45:402
eling: relationship to basic multicellular unit origina- Turner CH (1998) Three rules for bone adaptation to
tion and progression. Bone 30:57 mechanical stimuli. Bone 23:339409
Plotkin LI, Manolagas SC, Bellido T (2002) Transduction Ubara Y, Fushimi T, Tagami T et al (2003) Histomorphometric
of cell survival signals by connexin-43 hemichannels. features of bone in patients with primary and secondary
J Biol Chem 277:86488657 hyperparathyroidism. Kidney Int 63:18091816
Plotkin LI, Aguirre JI, Kousteni S et al (2005) Ubara Y, Tagami T, Nakanishi S et al (2005) Significance
Bisphosphonates and estrogens inhibit osteocyte apop- of minimodeling in dialysis patients with adynamic
tosis via distinct molecular mechanisms downstream bone disease. Kidney Int 68:833839
of extracellular signal-regulated kinase activation. Vaananen HK, Zhao H, Mulari M et al (2000) The cell
J Biol Chem 280:73177325 biology of osteoclast function. J Cell Sci 113:377381
Pocock NA, Eisman JA, Hopper JL et al (1987) Genetic Wheeless CR. http://www.wheelessonline.com/ortho/
determinants of bone mass in adults: a twin study. bone_remodeling. Accessed 20 Apr 2011
J Clin Invest 80:706710 Whyte MP (1994) Hypophosphatasia and the role of alka-
Raisz LG (1993) Bone cell biology: new approaches and line phosphatase in skeletal mineralization. Endocr
unanswered questions. J Bone Miner Res 8:457465 Rev 15:439461
Raisz LG (1997) The osteoporosis revolution. Ann Intern Xing L, Boyce BF (2005) Regulation of apoptosis in
Med 126:458462 osteoclasts and osteoblastic cells. Biochem Biophys
Raisz LG (1999) Physiology and pathophysiology of bone Res Commun 328:709720
remodeling. Clin Chem 45:13531358 Yamaguchi A, Komori T, Suda T et al (2000) Regulation
Reddy SV (2004) Regulatory mechanisms operative in of osteoblast differentiation mediated by bone mor-
osteoclasts. Crit Rev Eukaryot Gene Expr 14:255270 phogenetic proteins, hedgehogs, and Cbfa1. Endocr
Roodman GD (1999) Cell biology of the osteoclast. Exp Rev 21:393411
Hematol 27:12291241 Yasuda H, Shima N, Nakagawa N et al (1998) Osteoclast
Roodman GD, Kurihara N, Ohsaki Y et al (1992) differentiation factor is a ligand for osteoprotegerin/
Interleukin-6: a potential autocrine/paracrine agent in osteoclastogenesis-inhibitory factor and is identical to
Pagets disease of bone. J Clin Invest 89:4652 TRANCE/RANKL. Proc Natl Acad Sci USA
Rosen CJ, Donahue LR (1998) Insulin-like growth factors 95:35973602
and bone the osteoporosis connection revisited. Proc Young MF (2003) Bone matrix proteins: more than mark-
Soc Exp Biol Med 219:17 ers. Calcif Tissue Int 72:24
Sakou T (1998) Bone morphogenetic proteins: from basic
studies to clinical approaches. Bone 22:591603
http://www.springer.com/978-3-642-02399-6

Das könnte Ihnen auch gefallen