Bone Homeostasis

This Page describes normal bone anatomy and physiology.

Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called bone resorption) and new bone tissue is formed (a process called ossification or new bone formation).

These processes also control the reshaping or replacement of bone following injuries like fractures but also micro-damage, which occurs not only during physical exertion and sports, but also during normal activity. Remodeling responds proportionally to functional demands of the mechanical loading.

In the first year of life, almost 100% of the skeleton is replaced. In adults, remodeling proceeds at about 10% per year.[1]

An imbalance in the regulation of bone remodeling’s two sub-processes, bone resorption and bone formation, results in many metabolic bone diseases, such as osteoporosis.[2]

Section A

Physiology and Bone Homeostasis

Bone homeostasis involves multiple but coordinated cellular and molecular events.[3] Two main types of cells are responsible for bone metabolism: osteoblasts (which secrete new bone), and osteoclasts (which break bone down). The structure of bones as well as adequate supply of calcium requires close cooperation between these two cell types and other cell populations present at the bone remodeling sites (ex. immune cells).[4]

Bone metabolism relies on complex signaling pathways and control mechanisms to achieve proper rates of growth and differentiation. These controls include the action of several hormones, including parathyroid hormone (PTH), vitamin D, growth hormone, steroids, and calcitonin, as well as several bone marrow-derived membrane and soluble cytokines and growth factors (ex. M-CSF, RANKL, VEGF, IL-6 family…).

It is in this way that the body is able to maintain proper levels of calcium required for physiological processes. Thus bone remodeling is not just occasional “repair of bone damage” but rather an active, continual process that is always happening in a healthy body.

Subsequent to appropriate signaling, osteoclasts move to resorb the surface of the bone, followed by deposition of bone by osteoblasts. Together, the cells that are responsible for bone remodeling are known as the basic multicellular unit (BMU), and the temporal duration (i.e. lifespan) of the BMU is referred to as the bone remodeling period.[5]

1 Jump up
Wheeless Textbook

2 Jump up
Online Medical Dictionary

3 Jump up
Raggatt, L. J.; et al. (May 25, 2010). “Cellular and Molecular Mechanisms of Bone Remodeling”. The Journal of Biological Chemistry. 285 (33): 25103–25108. doi:10.1074/jbc.R109.041087. PMC 2919071pastedGraphic.png. PMID 20501658.

4 Jump up
Sims, N. A.; et al. (8 January 2014). “Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit”. BoneKEy Reports. 3. doi:10.1038/bonekey.2013.215. Retrieved 8 January 2014.

5 Jump up
Pietrzak, WS. Musculoskeletal tissue regeneration: biological materials and methods, Humana Press, 2008. ISBN 1-58829-909-0 page 48

The Skeleton

The adult human skeleton has a total of 213 bones, excluding the sesamoid bones (1). The appendicular skeleton has 126 bones, axial skeleton 74 bones, and auditory ossicles six bones. Each bone constantly undergoes modeling during life to help it adapt to changing biomechanical forces, as well as remodeling to remove old, microdamaged bone and replace it with new, mechanically stronger bone to help preserve bone strength.

The four general categories of bones are long bones, short bones, flat bones, and irregular bones. Long bones include the clavicles, humeri, radii, ulnae, metacarpals, femurs, tibiae, fibulae, metatarsals, and phalanges. Short bones include the carpal and tarsal bones, patellae, and sesamoid bones. Flat bones include the skull, mandible, scapulae, sternum, and ribs. Irregular bones include the vertebrae, sacrum, coccyx, and hyoid bone. Flat bones form by membranous bone formation, whereas long bones are formed by a combination of endochondral and membranous bone formation.

The skeleton serves a variety of functions. The bones of the skeleton provide structural support for the rest of the body, permit movement and locomotion by providing levers for the muscles, protect vital internal organs and structures, provide maintenance of mineral homeostasis and acid-base balance, serve as a reservoir of growth factors and cytokines, and provide the environment for hematopoiesis within the marrow spaces (2).

The long bones are composed of a hollow shaft, or diaphysis; flared, cone-shaped metaphyses below the growth plates; and rounded epiphyses above the growth plates. The diaphysis is composed primarily of dense cortical bone, whereas the metaphysis and epiphysis are composed of trabecular meshwork bone surrounded by a relatively thin shell of dense cortical bone.

The adult human skeleton is composed of 80% cortical bone and 20% trabecular bone overall (3). Different bones and skeletal sites within bones have different ratios of cortical to trabecular bone. The vertebra is composed of cortical to trabecular bone in a ratio of 25:75. This ratio is 50:50 in the femoral head and 95:5 in the radial diaphysis.

Cortical bone is dense and solid and surrounds the marrow space, whereas trabecular bone is composed of a honeycomb-like network of trabecular plates and rods interspersed in the bone marrow compartment. Both cortical and trabecular bone are composed of osteons.

Cortical osteons are called Haversian systems. Haversian systems are cylindrical in shape, are approximately 400 mm long and 200 mm wide at their base, and form a branching network within the cortical bone (3).

The walls of Haversian systems are formed of concentric lamellae. Cortical bone is typically less metabolically active than trabecular bone, but this depends on the species. There are an estimated 21 × 106 cortical osteons in healthy human adults, with a total Haversian remodeling area of approximately 3.5 m2. Cortical bone porosity is usually <5%, but this depends on the proportion of actively remodeling Haversian systems to inactive cortical osteons. Increased cortical remodeling causes an increase in cortical porosity and decrease in cortical bone mass. Healthy aging adults normally experience thinning of the cortex and increased cortical porosity.

Cortical bone has an outer periosteal surface and inner endosteal surface. Periosteal surface activity is important for appositional growth and fracture repair. Bone formation typically exceeds bone resorption on the periosteal surface, so bones normally increase in diameter with aging. The endosteal surface has a total area of approximately 0.5 m2, with higher remodeling activity than the periosteal surface, likely as a result of greater biomechanical strain or greater cytokine exposure from the adjacent bone marrow compartment. Bone resorption typically exceeds bone formation on the endosteal surface, so the marrow space normally expands with aging.

Trabecular osteons are called packets. Trabecular bone is composed of plates and rods averaging 50 to 400 mm in thickness (3). Trabecular osteons are semilunar in shape, normally approximately 35 mm thick, and composed of concentric lamellae. It is estimated that there are 14 × 106 trabecular osteons in healthy human adults, with a total trabecular area of approximately 7 m2.

Cortical bone and trabecular bone are normally formed in a lamellar pattern, in which collagen fibrils are laid down in alternating orientations (3). Lamellar bone is best seen during microscopic examination with polarized light, during which the lamellar pattern is evident as a result of birefringence. The mechanism by which osteoblasts lay down collagen fibrils in a lamellar pattern is not known, but lamellar bone has significant strength as a result of the alternating orientations of collagen fibrils, similar to plywood. The normal lamellar pattern is absent in woven bone, in which the collagen fibrils are laid down in a disorganized manner. Woven bone is weaker than lamellar bone. Woven bone is normally produced during formation of primary bone and may also be seen in high bone turnover states such as osteitis fibrosa cystica, as a result of hyperparathyroidism, and Paget’s disease or during high bone formation during early treatment with fluoride.

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, which contains blood vessels, nerve fibers, and osteoblasts and osteoclasts. The periosteum is tightly attached to the outer cortical surface of bone by thick collagenous fibers, called Sharpeys’ fibers, which extend into underlying bone tissue. The endosteum is a membranous structure covering the inner surface of cortical bone, trabecular bone, and the blood vessel canals (Volkman’s canals) present in bone. The endosteum is in contact with the bone marrow space, trabecular bone, and blood vessel canals and contains blood vessels, osteoblasts, and osteoclasts.

Bone Growth, Modeling, and Remodeling

Bone undergoes longitudinal and radial growth, modeling, and remodeling during life. Longitudinal and radial growth during growth and development occurs during childhood and adolescence. Longitudinal growth occurs at the growth plates, where cartilage proliferates in the epiphyseal and metaphyseal areas of long bones, before subsequently undergoing mineralization to form primary new bone.

Modeling is the process by which bones change their overall shape in response to physiologic influences or mechanical forces, leading to gradual adjustment of the skeleton to the forces that it encounters. Bones may widen or change axis by removal or addition of bone to the appropriate surfaces by independent action of osteoblasts and osteoclasts in response to biomechanical forces. Bones normally widen with aging in response to periosteal apposition of new bone and endosteal resorption of old bone. Wolff’s law describes the observation that long bones change shape to accommodate stresses placed on them. During bone modeling, bone formation and resorption are not tightly coupled. Bone modeling is less frequent than remodeling in adults (4). Modeling may be increased in hypoparathyroidism (5), renal osteodystrophy (6), or treatment with anabolic agents (7).

Bone remodeling is the process by which bone is renewed to maintain bone strength and mineral homeostasis. Remodeling involves continuous removal of discrete packets of old bone, replacement of these packets with newly synthesized proteinaceous matrix, and subsequent mineralization of the matrix to form new bone. The remodeling process resorbs old bone and forms new bone to prevent accumulation of bone microdamage. Remodeling begins before birth and continues until death. The bone remodeling unit is composed of a tightly coupled group of osteoclasts and osteoblasts that sequentially carry out resorption of old bone and formation of new bone. Bone remodeling increases in perimenopausal and early postmenopausal women and then slows with further aging, but continues at a faster rate than in premenopausal women. Bone remodeling is thought to increase mildly in aging men.

The remodeling cycle is composed of four sequential phases. Activation precedes resorption, which precedes reversal, which precedes formation. Remodeling sites may develop randomly but also are targeted to areas that require repair (8,9). Remodeling sites are thought to develop mostly in a random manner.

Activation involves recruitment and activation of mononuclear monocyte-macrophage osteoclast precursors from the circulation (10), lifting of the endosteum that contains the lining cells off the bone surface, and fusion of multiple mononuclear cells to form multinucleated preosteoclasts. Preosteoclasts bind to bone matrix via interactions between integrin receptors in their cell membranes and RGD (arginine, glycine, and asparagine)-containing peptides in matrix proteins, to form annular sealing zones around bone-resorbing compartments beneath multinucleated osteoclasts.

Osteoclast-mediated bone resorption takes only approximately 2 to 4 wk during each remodeling cycle. Osteoclast formation, activation, and resorption are regulated by the ratio of receptor activator of NF-κB ligand (RANKL) to osteoprotegerin, IL-1 and IL-6, colony-stimulating factor (CSF), parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin (11,12). Resorbing osteoclasts secrete hydrogen ions via H+-ATPase proton pumps and chloride channels in their cell membranes into the resorbing compartment to lower the pH within the bone-resorbing compartment to as low as 4.5, which helps mobilize bone mineral (13). Resorbing osteoclasts secrete tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase 9, and gelatinase from cytoplasmic lysosomes (14) to digest the organic matrix, resulting in formation of saucer-shaped Howship’s lacunae on the surface of trabecular bone and Haversian canals in cortical bone. The resorption phase is completed by mononuclear cells after the multinucleated osteoclasts undergo apoptosis (15,16).

During the reversal phase, bone resorption transitions to bone formation. At the completion of bone resorption, resorption cavities contain a variety of mononuclear cells, including monocytes, osteocytes released from bone matrix, and preosteoblasts recruited to begin new bone formation. The coupling signals linking the end of bone resorption to the beginning of bone formation are as yet unknown. Proposed coupling signal candidates include bone matrix—derived factors such as TGF-β, IGF-1, IGF-2, bone morphogenetic proteins, PDGF, or fibroblast growth factor (17–19).

TGF-β concentration in bone matrix correlates with histomorphometric indices of bone turnover and with serum osteocalcin and bone-specific alkaline phosphatase. TGF-β released from bone matrix decreases osteoclast resorption by inhibiting RANKL production by osteoblasts. The reversal phase has also been proposed to be mediated by the strain gradient in the lacunae (20,21). As osteoclasts resorb cortical bone in a cutting cone, strain is reduced in front and increased behind, and in Howship’s lacunae, strain is highest at the base and less in surrounding bone at the edges of the lacunae. The strain gradient may lead to sequential activation of osteoclasts and osteoblasts, with osteoclasts activated by reduced strain and osteoblasts by increased strain. The osteoclast itself has also been proposed to play a role during reversal (22).

Bone formation takes approximately 4 to 6 mo to complete. Osteoblasts synthesize new collagenous organic matrix and regulate mineralization of matrix by releasing small, membrane-bound matrix vesicles that concentrate calcium and phosphate and enzymatically destroy mineralization inhibitors such as pyrophosphate or proteoglycans (23). Osteoblasts surrounded by and buried within matrix become osteocytes with an extensive canalicular network connecting them to bone surface lining cells, osteoblasts, and other osteocytes, maintained by gap junctions between the cytoplasmic processes extending from the osteocytes (24). The osteocyte network within bone serves as a functional syncytium. At the completion of bone formation, approximately 50 to 70% of osteoblasts undergo apoptosis, with the balance becoming osteocytes or bone-lining cells. Bone-lining cells may regulate influx and efflux of mineral ions into and out of bone extracellular fluid, thereby serving as a blood-bone barrier, but retain the ability to redifferentiate into osteoblasts upon exposure to parathyroid hormone or mechanical forces (25). Bone-lining cells within the endosteum lift off the surface of bone before bone resorption to form discrete bone remodeling compartments with a specialized microenvironment (26). In patients with multiple myeloma, lining cells may be induced to express tartrate-resistant acid phosphatase and other classical osteoclast markers.

The end result of each bone remodeling cycle is production of a new osteon. The remodeling process is essentially the same in cortical and trabecular bone, with bone remodeling units in trabecular bone equivalent to cortical bone remodeling units divided in half longitudinally (27). Bone balance is the difference between the old bone resorbed and new bone formed. Periosteal bone balance is mildly positive, whereas endosteal and trabecular bone balances are mildly negative, leading to cortical and trabecular thinning with aging. These relative changes occur with endosteal resorption outstripping periosteal formation.

The main recognized functions of bone remodeling include preservation of bone mechanical strength by replacing older, microdamaged bone with newer, healthier bone and calcium and phosphate homeostasis. The relatively low adult cortical bone turnover rate of 2 to 3%/yr is adequate to maintain biomechanical strength of bone. The rate of trabecular bone turnover is higher, more than required for maintenance of mechanical strength, indicating that trabecular bone turnover is more important for mineral metabolism. Increased demand for calcium or phosphorus may require increased bone remodeling units, but, in many cases, this demand may be met by increased activity of existing osteoclasts. Increased demand for skeletal calcium and phosphorus is met partially by osteoclastic resorption and partly by nonosteoclastic calcium influx and efflux. Ongoing bone remodeling activity ensures a continuous supply of newly formed bone that has relatively low mineral content and is able to exchange ions more easily with the extracellular fluid. Bone remodeling units seem to be mostly randomly distributed throughout the skeleton but may be triggered by microcrack formation or osteocyte apoptosis. The bone remodeling space represents the sum of all of the active bone remodeling units in the skeleton at a given time.


Osteoclasts are the only cells that are known to be capable of resorbing bone. Activated multinucleated osteoclasts are derived from mononuclear precursor cells of the monocyte-macrophage lineage (11). Mononuclear monocyte-macrophage precursor cells have been identified in various tissues, but bone marrow monocyte-macrophage precursor cells are thought to give rise to most osteoclasts.

RANKL and macrophage CSF (M-CSF) are two cytokines that are critical for osteoclast formation. Both RANKL and M-CSF are produced mainly by marrow stromal cells and osteoblasts in membrane-bound and soluble forms, and osteoclastogenesis requires the presence of stromal cells and osteoblasts in bone marrow (28). RANKL belongs to the TNF superfamily and is critical for osteoclast formation. M-CSF is required for the proliferation, survival, and differentiation of osteoclast precursors, as well as osteoclast survival and cytoskeletal rearrangement required for bone resorption. OPG is a membrane-bound and secreted protein that binds RANKL with high affinity to inhibit its action at the RANK receptor (29).

Bone resorption depends on osteoclast secretion of hydrogen ions and cathepsin K enzyme. H+ ions acidify the resorption compartment beneath osteoclasts to dissolve the mineral component of bone matrix, whereas cathepsin K digests the proteinaceous matrix, which is mostly composed of type I collagen (11).

Osteoclasts bind to bone matrix via integrin receptors in the osteoclast membrane linking to bone matrix peptides. The β1 family of integrin receptors in osteoclasts binds to collagen, fibronectin, and laminin, but the main integrin receptor facilitating bone resorption is the αvβ3 integrin, which binds to osteopontin and bone sialoprotein (30).

Binding of osteoclasts to bone matrix causes them to become polarized, with the bone resorbing surface developing a ruffled border that forms when acidified vesicles that contain matrix metalloproteinases and cathepsin K are transported via microtubules to fuse with the membrane. The ruffled border secretes H+ ions via H+-ATPase and chloride channels and causes exocytosis of cathepsin K and other enzymes in the acidified vesicles (31).

Upon contact with bone matrix, the fibrillar actin cytoskeleton of the osteoclast organizes into an actin ring, which promotes formation of the sealing zone around the periphery of osteoclast attachment to the matrix. The sealing zone surrounds and isolates the acidified resorption compartment from the surrounding bone surface (32). Disruption of either the ruffled border or actin ring blocks bone resorption. Actively resorbing osteoclasts form podosomes, which attach to bone matrix, rather than focal adhesions as formed by most cells. Podosomes are composed of an actin core surrounded by αvβ3 integrins and associated cytoskeletal proteins.


Osteoprogenitor cells give rise to and maintain the osteoblasts that synthesize new bone matrix on bone-forming surface, the osteocytes within bone matrix that support bone structure, and the protective lining cells that cover the surface of quiescent bone. Within the osteoblast lineage, subpopulations of cells respond differently to various hormonal, mechanical, or cytokine signals. Osteoblasts from axial and appendicular bone have been shown to respond differently to these signals.

Self-renewing, pluripotent stem cells give rise to osteoprogenitor cells in various tissues under the right environmental conditions. Bone marrow contains a small population of mesenchymal stem cells that are capable of giving rise to bone, cartilage, fat, or fibrous connective tissue, distinct from the hematopoietic stem cell population that gives rise to blood cell lineages (33). Cells with properties that are characteristic of adult bone marrow mesenchymal stem cells have been isolated from adult peripheral blood and tooth pulp and fetal cord blood, liver, blood, and bone marrow. Multipotential myogenic cells that are capable of differentiating into bone, muscle, or adipocytes have also been identified. Mesenchymal cells that are committed to one phenotype may dedifferentiate during proliferation and develop another phenotype, depending on the local tissue environment. Blood vessel pericytes may develop an osteoblastic phenotype during dedifferentiation under the right circumstances (34).

Commitment of mesenchymal stem cells to the osteoblast lineage requires the canonical Wnt/β-catenin pathway and associated proteins (35). Identification of a high bone mass phenotype associated with activating mutations of LDL receptor–related protein 5 highlighted the importance of the canonical Wnt/β-catenin pathway in embryonic skeletal patterning, fetal skeletal development, and adult skeletal remodeling (36,37). The Wnt system is also important in chondrogenesis and hematopoiesis and may be stimulatory or inhibitory at different stages of osteoblast differentiation.

Flattened bone-lining cells are thought to be quiescent osteoblasts that form the endosteum on trabecular and endosteal surfaces and underlie the periosteum on the mineralized surface. Osteoblasts and lining cells are found in close proximity and joined by adherens junctions. Cadherins are calcium-dependent transmembrane proteins that are integral parts of adherens junctions and together with tight junctions and desmosomes join cells together by linking their cytoskeletons (38).

Osteoblast precursors change shape from spindle-shaped osteoprogenitors to large cuboidal differentiated osteoblasts on bone matrix surfaces after preosteoblasts stop proliferating. Preosteoblasts that are found near functioning osteoblasts in the bone remodeling unit are usually recognizable because of their expression of alkaline phosphatase. Active mature osteoblasts that synthesize bone matrix have large nuclei, enlarged Golgi structures, and extensive endoplasmic reticulum. These osteoblasts secrete type I collagen and other matrix proteins vectorially toward the bone formation surface.

Populations of osteoblasts are heterogeneous, with different osteoblasts expressing different gene repertoires that may explain the heterogeneity of trabecular microarchitecture at different skeletal sites, anatomic site-specific differences in disease states, and regional variation in the ability of osteoblasts to respond to agents used to treat bone disease.

Bone Extracellular Matrix

Bone protein is composed of 85 to 90% collagenous proteins (Table 1). Bone matrix is mostly composed of type I collagen (39), with trace amounts of types III and V and FACIT collagens at certain stages of bone formation that may help determine collagen fibril diameter. FACIT collagens are members of the family of Fibril-Associated Collagens with Interrupted Triple Helices, a group of nonfibrillar collagens that serve as molecular bridges that are important for the organization and stability of extracellular matrices. Members of this family include collagens IX, XII, XIV, XIX, XX, and XXI. Noncollagenous proteins compose 10 to 15% of total bone protein. Approximately 25% of noncollagenous protein is exogenously derived, including serum albumin and α2-HS-glycoprotein, which bind to hydroxyapatite because of their acidic properties. Serum-derived noncollagenous proteins may help regulate matrix mineralization, and α2-HS-glycoprotein, which is the human analogue of fetuin, may regulate bone cell proliferation. The remaining exogenously derived noncollagenous proteins are composed of growth factors and a large variety of other molecules in trace amounts that may affect bone cell activity.

Osteoblasts synthesize and secrete as much noncollagenous protein as collagen on a molar basis. The noncollagenous proteins are divided broadly into several categories, including proteoglycans, glycosylated proteins, glycosylated proteins with potential cell-attachment activities, and γ-carboxylated (gla) proteins. The roles of each of the bone proteins are not well defined at present, and many seem to serve multiple functions, including regulation of bone mineral deposition and turnover and regulation of bone cell activity. Serum osteocalcin synthesized by osteoblasts was previously thought to function as a promoter or initiator of calcium deposition at the nidus between the ends of collagen fibrils and therefore regarded as a marker of bone formation. The observation that the osteocalcin knockout mouse has a high bone mass phenotype suggests that osteocalcin normally inhibits bone formation. Because serum osteocalcin is derived from both matrix release by osteoclast activity and osteoblast synthesis, it is currently regarded as a marker of bone turnover rather than a specific marker of bone formation.

The main glycosylated protein present in bone is alkaline phosphatase. Alkaline phosphatase in bone is bound to osteoblast cell surfaces via a phosphoinositol linkage and also is found free within mineralized matrix. Alkaline phosphatase plays an as-yet-undefined role in mineralization of bone (40). The most prevalent noncollagenous protein in bone is osteonectin, accounting for approximately 2% of total protein in developing bone. Osteonectin is thought to affect osteoblast growth and/or proliferation and matrix mineralization.

Go to:

Bone Matrix Mineralization

Bone is composed of 50 to 70% mineral, 20 to 40% organic matrix, 5 to 10% water, and <3% lipids. The mineral content of bone is mostly hydroxyapatite [Ca10(PO4)6(OH)2], with small amounts of carbonate, magnesium, and acid phosphate, with missing hydroxyl groups that are normally present. Compared with geologic hydroxyapatite crystals, bone hydroxyapatite crystals are very small, measuring only approximately 200 Å in their largest dimension. These small, poorly crystalline, carbonate-substituted crystals are more soluble than geologic hydroxyapatite crystals, thereby allowing them to support mineral metabolism.

Matrix maturation is associated with expression of alkaline phosphatase and several noncollagenous proteins, including osteocalcin, osteopontin, and bone sialoprotein. It is thought that these calcium- and phosphate-binding proteins help regulate ordered deposition of mineral by regulating the amount and size of hydroxyapatite crystals formed.

Bone mineral provides mechanical rigidity and load-bearing strength to bone, whereas the organic matrix provides elasticity and flexibility. Bone mineral is initially deposited in “hole” zones between the ends of collagen fibrils (41). This process may be facilitated by extracellular matrix vesicles in bone, as it is in calcifying cartilage and mineralizing turkey tendon (23). Matrix extracellular vesicles are synthesized by chondrocytes and osteoblasts and serve as protected microenvironments in which calcium and phosphate concentrations can increase sufficiently to precipitate crystal formation. The extracellular fluid is not normally supersaturated with hydroxyapatite, so hydroxyapatite does not spontaneously precipitate. Matrix extracellular vesicles contain a nucleational core that is composed of proteins and a complex of acidic phospholipids, calcium, and inorganic phosphate that is sufficient to precipitate hydroxyapatite crystals. It is not yet certain how matrix extracellular vesicles contribute to mineralization at specific sites at the ends of collagen fibrils, because the vesicles apparently are not directly targeted to the ends of fibrils (23).

There is no evidence that noncrystalline calcium phosphate clusters (amorphous calcium phosphate) forms in bone before it is converted to hydroxyapatite (42). As bone matures, hydroxyapatite crystals enlarge and reduce their level of impurities. Crystal enlargement occurs both by crystal growth and by aggregation. Bone matrix macromolecules may facilitate initial crystal nucleation, sequester mineral ions to increase local concentrations of calcium and/or phosphorus, or facilitate heterogeneous nucleation. Macromolecules also bind to growing crystal surfaces to determine the size, shape, and number of crystals formed.

Confirmed mineralization promoters (nucleators) include dentin matrix protein 1 and bone sialoprotein. Type I collagen is not a bone mineralization promoter. Phosphoprotein kinases and alkaline phosphatase regulate the mineralization process. Bone alkaline phosphatase may increase local phosphorus concentrations, remove phosphate-containing inhibitors of hydroxyapatite crystal growth, or modify phosphoproteins to control their ability to act as nucleators.

Vitamin D plays an indirect role in stimulating mineralization of unmineralized bone matrix. After absorption or skin production of vitamin D, the liver synthesizes 25-hydroxyvitamin D and the kidneys subsequently produce biologically active 1,25-dihydroxyvitamin D [1,25-(OH)2D]. Serum 1,25-(OH)2D is responsible for maintaining serum calcium and phosphorus in adequate concentrations to allow passive mineralization of unmineralized bone matrix. Serum 1,25-(OH)2D does this primarily by stimulating intestinal absorption of calcium and phosphorus. Serum 1,25-(OH)2D also promotes differentiation of osteoblasts and stimulates osteoblast expression of bone-specific alkaline phosphatase, osteocalcin, osteonectin, OPG, and a variety of other cytokines. Serum 1,25-(OH)2D also influences proliferation and apoptosis of other skeletal cells, including hypertrophic chondrocytes.


Osteocytes represent terminally differentiated osteoblasts and function within syncytial networks to support bone structure and metabolism. Osteocytes lie within lacunae within mineralized bone (Figure 3) and have extensive filipodial processes that lie within the canaliculi in mineralized bone (43). Osteocytes do not normally express alkaline phosphatase but do express osteocalcin, galectin 3, and CD44, a cell adhesion receptor for hyaluronate, as well as several other bone matrix proteins. Osteocytes express several matrix proteins that support intercellular adhesion and regulate exchange of mineral in the bone fluid within lacunae and the canalicular network. Osteocytes are active during osteolysis and may function as phagocytic cells because they contain lysosomes.

Osteocytes maintain connection with each other and the bone surface via their multiple filipodial cellular processes. Connexins are integral cellular proteins that maintain gap junctions between cells to allow direct communication through intercellular channels. Osteocytes are linked metabolically and electrically through gap junctions composed primarily of connexin 43 (44). Gap junctions are required for osteocyte maturation, activity, and survival.

The primary function of the osteocyte-osteoblast/lining cell syncytium is mechanosensation (45). Osteocytes transduce stress signals from bending or stretching of bone into biologic activity. Flow of canalicular fluid in response to external forces induces a variety of responses within osteocytes. Rapid fluxes of bone calcium across filipodial gap junctions are believed to stimulate transmission of information between osteoblasts on the bone surface and osteocytes within the bone (46). Signaling mechanisms involved in mechanotransduction include prostaglandin E2, cyclo-oxygenase 2, various kinases, Runx2, and nitrous oxide.

Osteocytes may live for decades in human bone that is not turned over. The presence of empty lacunae in aging bone suggests that osteocytes may undergo apoptosis, probably caused by disruption of their intercellular gap junctions or cell–matrix interactions (47). Osteocyte apoptosis in response to estrogen deficiency or glucocorticoid treatment is harmful to bone structure. Estrogen and bisphosphonate therapy and physiologic loading of bone may help prevent osteoblast and osteocyte apoptosis (48).

Determinants of Bone Strength

Bone mass accounts for 50 to 70% of bone strength (49). Bone geometry and composition are important, however, because larger bones are stronger than smaller bones, even with equivalent bone mineral density. As bone diameter expands radially, the strength of bone increases by the radius of the involved bone raised to the fourth power. The amount and proportion of trabecular and cortical bone at a given skeletal site affect bone strength independently. Bone material properties are important for bone strength. Some patients with osteoporosis have abnormal bone matrix. Mutations in certain proteins may cause bone weakness (e.g., collagen defects cause decreased bone strength in osteogenesis imperfecta, impaired γ-carboxylation of Gla proteins). Bone strength can be affected by osteomalacia, fluoride therapy, or hypermineralization states. Bone microstructure affects bone strength also. Low bone turnover leads to accumulation of microfractures. High bone turnover, with bone resorption greater than bone formation, is the main cause of microarchitectural deterioration.

What Keeps Bones Healthy?

Both genes and the environment contribute to bone health. Some elements of bone health (e.g., the size and shape of the skeleton) are determined largely by genes, and errors in signaling by these genes can result in birth defects. External factors, such as diet and physical activity, are critically important to bone health throughout life and can be modified. As noted above, the mechanical loading of the skeleton is essential for maintenance of normal bone mass and architecture. In addition, the skeleton needs certain nutritional elements to build tissue. Not only does the skeleton require the same nutritional elements as the rest of the body, but it also has a special requirement for large amounts of calcium and phosphorus. While adequate levels of these minerals can be obtained from the mother during pregnancy and nursing, they must come from the diet thereafter.

The growth of the skeleton, its response to mechanical forces, and its role as a mineral storehouse are all dependent on the proper functioning of a number of systemic or circulating hormones produced outside the skeleton that work in concert with local regulatory factors. The systemic hormones that affect the supply of calcium and phosphorus and the formation and breakdown of bones are key. This complex system of regulatory hormones responds to changes in blood calcium and phosphorus, acting not only on bone but also on other tissues such as the intestine and the kidney. The system is illustrated for calcium regulation in Figure 2-4. Under normal conditions only part of the dietary calcium is absorbed and some calcium is secreted into the intestinal tract so that the net amount of calcium entering the body normally is only a small proportion of dietary calcium. In healthy young adults there is calcium balance, where the amount taken in is equal to the amount excreted. The bones are constantly remodeling, but breakdown and formation are equal. The kidney filters the blood, including a large amount of calcium, but most of this is taken back into the body by the kidney cells. When calcium and/or phosphorus are in short supply, the regulating hormones take them out of the bone to serve vital functions in other systems of the body. Too many withdrawals can weaken the bone. The regulatory hormones also play critical roles in determining how much bone is formed at different phases of skeletal growth and how well bone strength and mass is maintained throughout life. For example, sex hormones and the growth hormone system described below are increased during puberty, a time of rapidly increased skeletal growth. Finally, it is important to remember that the effects of hormones and mechanical forces on the skeleton are closely linked. For example, the ability of bone to respond to mechanical loading is impaired in animals lacking the receptor for estrogen (Lee et al. 2003).

Key Hormones

What follows is a brief description of the most important regulating hormones with respect to bone health.

Calcium-Regulating Hormones

Three calcium-regulating hormones play an important role in producing healthy bone: 1) parathyroid hormone or PTH, which maintains the level of calcium and stimulates both resorption and formation of bone; 2) calcitriol, the hormone derived from vitamin D, which stimulates the intestines to absorb enough calcium and phosphorus and also affects bone directly; and 3) calcitonin, which inhibits bone breakdown and may protect against excessively high levels of calcium in the blood.

Parathyroid hormone or PTH

PTH is produced by four small glands adjacent to the thyroid gland. These glands precisely control the level of calcium in the blood. They are sensitive to small changes in calcium concentration so that when calcium concentration decreases even slightly the secretion of PTH increases. PTH acts on the kidney to conserve calcium and to stimulate calcitriol production, which increases intestinal absorption of calcium. PTH also acts on the bone to increase movement of calcium from bone to blood. Excessive production of PTH, usually due to a small tumor of the parathyroid glands, is called hyperparathyroidism and can lead to bone loss. PTH stimulates bone formation as well as resorption. When small amounts are injected intermittently, bone formation predominates and the bones get stronger (Rubin, Cosman et al. 2002). This is the basis for a new treatment for osteoporosis (see Chapter 9).

In recent years a second hormone related to PTH was identified called parathyroid hormone-related protein (PTHrP). This hormone normally regulates cartilage and bone development in the fetus, but it can be over-produced by individuals who have certain types of cancer. PTHrP then acts like PTH, causing excessive bone breakdown and abnormally high blood calcium levels, called hypercalcemia of malignancy (Stewart 2002).


Calcitriol is the hormone produced from vitamin D (Norman, Okamura et al. 2002). Calcitriol, also called 1,25 dihydroxy vitamin D, is formed from vitamin D by enzymes in the liver and kidney. Calcitriol acts on many different tissues, but its most important action is to increase intestinal absorption of calcium and phosphorus, thus supplying minerals for the skeleton. Vitamin D should not technically be called a vitamin, since it is not an essential food element and can be made in the skin through the action of ultra violet light from the sun on cholesterol. Many people need vitamin D in their diet because they do not derive adequate levels from exposure to the sun. This need occurred as people began to live indoors, wear clothes, and move further north. In northern latitudes the sun’s rays are filtered in the winter and thus are not strong enough to make sufficient vitamin D in the skin. Vitamin D deficiency leads to a disease of defective mineralization, called rickets in children and osteomalacia in adults. These conditions can result in bone pain, bowing and deformities of the legs, and fractures. Treatment with vitamin D can restore calcium supplies and reduce bone loss.


Calcitonin is a third calcium-regulating hormone produced by cells of the thyroid gland, although by different cells than those that produce thyroid hormones (Sexton, Findlay et al. 1999). Calcitonin can block bone breakdown by inactivating osteoclasts, but this effect may be relatively transient in adult humans. Calcitonin may be more important for maintaining bone development and normal blood calcium levels in early life. Excesses or deficiencies of calcitonin in adults do not cause problems in maintaining blood calcium concentration or the strength of the bone. However, calcitonin can be used as a drug for treating bone disease.

Sex Hormones

Along with calcium-regulating hormones, sex hormones are also extremely important in regulating the growth of the skeleton and maintaining the mass and strength of bone. The female hormone estrogen and the male hormone testosterone both have effects on bone in men and women (Falahati-Nini, Riggs et al. 2000). The estrogen produced in children and early in puberty can increase bone growth. The high concentration that occurs at the end of puberty has a special effect—that is, to stop further growth in height by closing the cartilage plates at the ends of long bone that previously had allowed the bones to grow in length.

Estrogen acts on both osteoclasts and osteoblasts to inhibit bone breakdown at all stages in life. Estrogen may also stimulate bone formation. The marked decrease in estrogen at menopause is associated with rapid bone loss. Hormone therapy was widely used to prevent this, but this practice is now controversial because of the risks of increased breast cancer, strokes, blood clots, and cardiovascular disease with hormone therapy (see Chapter 9).

Testosterone is important for skeletal growth both because of its direct effects on bone and its ability to stimulate muscle growth, which puts greater stress on the bone and thus increases bone formation. Testosterone is also a source of estrogen in the body; it is converted into estrogen in fat cells. This estrogen is important for the bones of men as well as women. In fact, older men have higher levels of circulating estrogen than do postmenopausal women.

Other Important Hormones

Growth hormone from the pituitary gland is also an important regulator of skeletal growth. It acts by stimulating the production of another hormone called insulin-like growth factor-1 (IGF-1), which is produced in large amounts in the liver and released into circulation. IGF-1 is also produced locally in other tissues, particularly in bone, also under the control of growth hormone. The growth hormone may also directly affect the bone—that is, not through IGF-1 (Wang et al. 2004). Growth hormone is essential for growth and it accelerates skeletal growth at puberty. Decreased production of growth hormone and IGF-1 with age may be responsible for the inability of older individuals to form bone rapidly or to replace bone lost by resorption (Yakar and Rosen 2003). The growth hormone/IGF-1 system stimulates both the bone-resorbing and bone-forming cells, but the dominant effect is on bone formation, thus resulting in an increase in bone mass.

Thyroid hormones increase the energy production of all body cells, including bone cells. They increase the rates of both bone formation and resorption. Deficiency of thyroid hormone can impair growth in children, while excessive amounts of thyroid hormone can cause too much bone breakdown and weaken the skeleton (Vestergaard and Mosekilde 2002). The pituitary hormone that controls the thyroid gland, thyrotropin or TSH, may also have direct effects on bone (Abe et al. 2003).

Cortisol, the major hormone of the adrenal gland, is a critical regulator of metabolism and is important to the body’s ability to respond to stress and injury. It has complex effects on the skeleton (Canalis and Delany 2002). Small amounts are necessary for normal bone development, but large amounts block bone growth. Synthetic forms of cortisol, called glucocorticoids, are used to treat many diseases such as asthma and arthritis. They can cause bone loss due both to decreased bone formation and to increased bone breakdown, both of which lead to a high risk of fracture (Kanis et al. 2004).

There are other circulating hormones that affect the skeleton as well. Insulin is important for bone growth, and the response to other factors that stimulate bone growth is impaired in individuals with insulin deficiency (Lu et al. 2003, Suzuki et al. 2003). A recently discovered hormone from fat cells, leptin, has also been shown to have effects on bone (Elefteriou et al. 2004, Cornish et al. 2002).

Go to:

What Causes Diseases of Bone?

Maintaining a strong and healthy skeleton is a complicated process that requires having the right amount of bone with the right structure and composition in the right place. There are many things that can go wrong along the way.

Genetic abnormalities can produce weak, thin bones, or bones that are too dense. The disease osteogenesis imperfecta is caused by abnormalities in the collagen molecule that make the matrix weak and can lead to multiple fractures. In another congenital disorder, osteopetrosis, the bones are too dense because of failure of osteoclast formation or function. This failure of the remodeling process results in persistence of trabecular bone in the marrow space so that the marrow cavity may not be large enough to form red and white blood cells normally. These dense bones cannot remodel well in response to mechanical forces or micro damage and hence may be weaker and subject to fracture even though bone mass is increased. There are also other abnormalities of the genes that affect the size and shape of the skeleton and can cause deformities or abnormal growth.

Nutritional deficiencies, particularly of vitamin D, calcium, and phosphorus, can result in the formation of weak, poorly mineralized bone. In children, vitamin D deficiency produces rickets in which there is not only a marked weakness of bone and fractures but also bowing of the long bones and a characteristic deformity due to overgrowth of cartilage at the ends of the bones. In adults, vitamin D deficiency leads to a softening of the bone (a condition known as osteomalacia) that can also lead to fractures and deformities.

Many hormonal disorders can also affect the skeleton. Overactive parathyroid glands or hyperparathyroidism can cause excessive bone breakdown and increase the risk of fractures. In severe cases, large holes or cystic lesions appear in the bone, which makes them particularly fragile. A deficiency of the growth hormone/IGF-1 system can inhibit growth, leading to short stature. Loss of gonadal function or hypogonadism in children and young adults can cause severe osteoporosis due to loss of the effects of testosterone and estrogen. In addition, too much cortisol production by the adrenal gland can occur in Cushing’s syndrome.

Use of glucocorticoids as medication is a common cause of bone disease. Excess glucocorticoids will stop bone growth in children and cause marked thinning of the bone in adults, often leading to fracture.

Many bone disorders are local, affecting only a small region of the skeleton. Inflammation can lead to bone loss, probably through the production of local resorbing factors by the inflammatory white cells. This process can occur around the affected joints in patients with arthritis. Bacterial infections, such as severe gum inflammation or periodontal disease, can produce loss of the bones around the teeth, and osteomyelitis can produce a loss of bone at the site of infection. This type of bone loss is due to the direct damaging effect of bacterial products as well as the production of resorbing factors by white cells. Paget’s disease is a multifaceted condition in which the first change is the formation of large, highly active, and unregulated osteoclasts that produce abnormal bone resorption. The precise cause of Paget’s disease is not known, but it appears to be the consequence of both genetic factors and environmental factors, possibly a viral infection. The osteoblasts try to repair this damage by increasing bone formation. However, the normal bone architecture has been disrupted, leading to weak bones and the potential for fractures and deformities (even though the bones may appear dense on an x-ray). One reason for this is that the new bone formed is disorderly, “woven” bone, which does not have the proper alignment of mineral crystals and collagen matrix. In addition, the new bone may not be in the right place to provide strength.

Go to:

What Is Osteoporosis?

Osteoporosis is by far the most common bone disease. Osteoporosis is “a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture” (Osteoporosis 2000). The composition of the mineral and matrix, the fine structure of the trabecular bone, the porosity of the cortical bone, and the presence of micro-fractures and other forms of damage in bone are all important in determining bone strength. Changes in the fine structure or micro-architecture of trabecular bone are particularly important since the most common fractures in osteoporosis occur at the spine, wrist, and hip, sites where trabecular bone predominates. As shown in Figure 2-5, the structure of normal trabecular bone consists of well-connected plates or broad bands that provide great strength. In individuals with osteoporosis these bands are disrupted and often become thin, weakened rods. Some of these rods are no longer connected to another piece of bone, meaning that they no longer contribute to bone strength.

However, fractures due to bone fragility rather than severe injury are uncommon in young adults. It is typically not until later in life that bone loss begins due to bone breakdown, a process that accelerates around the time of menopause in women. At the same time, bone formation tends to decrease with age in both men and women, typically failing to keep up with the rate of bone resorption. An imbalance between bone resorption and bone formation results in loss of bone mass, leading to the development of structural abnormalities that make the skeleton more fragile. There are a number of different combinations of increased resorption and decreased formation that can result in a weakened skeletal structure . Each of these pathways can be involved in producing skeletal fragility at different times or sites within an individual patient. Since bone breakdown is the first step in this process, blocking bone resorption is one way to decrease bone loss and prevent fractures. It is currently the most widely used therapeutic approach in osteoporosis. Stimulation of bone formation can also reverse skeletal fragility; new therapies based on this approach have recently been developed (Chapter 9).

The Future: Where a Better Understanding of Bone Biology Can Take Us

This brief overview of the basics of bone health and disease provides a framework for the discussion of what is known about the causes, prevention, and treatment of skeletal disorders today. Many knowledge gaps remain, and it is still unclear precisely why so many people suffer fractures. Fortunately there have recently been a number of exciting new discoveries about skeletal regulation, and there are undoubtedly many more to come. These discoveries will further increase our understanding of bone health and disease.

For example, recent discoveries have shown how osteoblastic and osteoclastic cells communicate and provide signals to begin the process of resorption. The osteoblastic cells produce macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) (Khosla 2001), proteins that bind to receptors on the osteoclast precursors, stimulate their proliferation and differentiation, and increase osteoclast activity. Osteoblastic cells also produce a protein called osteoprotegerin that can bind RANKL and prevent it from interacting with osteoclastic cells. The hormones and local factors that stimulate bone resorption act on this system. The balance between RANKL and osteoprotegerin (OPG) production is probably critical in determining how fast bone breaks down. RANKL in bone is increased in individuals with estrogen deficiency (Eghbali-Fatourechi et al. 2003). While RANKL excess or osteoprotegerin deficiency would be expected to cause bone loss, measurements of the amounts of these proteins in circulating blood do not support this theory. OPG levels are higher and RANKL levels are lower in patients with fractures or low bone mass (Schett et al. 2004, Jorgensen et al. 2004). On the other hand, OPG or drugs that act like it by interfering with the binding of RANKL could be useful in the treatment of osteoporosis.

However it is important to recognize that the bones, joints, and muscles are the key parts of an integrated “musculoskeletal system.” Problems with any one component of this system can affect the other components. Thus, weakness of the muscles can lead to loss of bone and joint damage, while degeneration of the joints leads to changes in the underlying bone, such as the bony spurs or protuberances that occur in osteoarthritis.

Key Take-aways

•The bony skeleton is a remarkable organ that serves both a structural function, providing mobility, support, and protection for the body, and a reservoir function, as the storehouse for essential minerals.

•During childhood and adolescence bones are sculpted by a process called modeling, which allows for the formation of new bone at one site and the removal of old bone from another site within the same bone. This process allows individual bones to grow in size and to shift in space.

•Much of the cellular activity in a bone consists of removal and replacement at the same site, a process called remodeling. The remodeling process occurs throughout life and becomes dominant by the time that bone reaches its peak mass (typically by the early 20s). Remodeling continues throughout life so that most of the adult skeleton is replaced about every 10 years.

•Both genes and the environment contribute to bone health. Some elements of bone health are determined largely by genes, and errors in signaling by these genes can result in birth defects. External factors, such as diet and physical activity, are critically important to bone health throughout life, and these factors can be modified.

•The growth of the skeleton, its response to mechanical forces, and its role as a mineral storehouse are all dependent on the proper functioning of a number of systemic or circulating hormones that respond to changes in blood calcium and phosphorus. If calcium or phosphorus are in short supply, the regulating hormones take them out of the bone to serve vital functions in other systems of the body. Too many withdrawals can weaken the bone.

•Many things can interfere with the development of a strong and healthy skeleton. Genetic abnormalities can produce weak, thin bones, or bones that are too dense. Nutritional deficiencies can result in the formation of weak, poorly mineralized bone. Many hormonal disorders can also affect the skeleton. Lack of exercise, immobilization, and smoking can also have negative effects on bone mass and strength.

•Osteoporosis, the most common bone disease, typically does not manifest until late in life, when bone loss begins due to bone breakdown and decreased levels of bone formation. Loss of bone mass leads to the development of structural abnormalities that make the skeleton more fragile.


The skeleton serves multiple functions. Bone modeling and remodeling preserve skeletal function throughout life. The bone remodeling unit normally couples bone resorption and formation. Bone matrix regulates bone mineralization. Bone strength depends on bone mass, geometry and composition, material properties, and microstructure.


1. Musculoskeletal system. In: Gray’s Anatomy, 39th Ed., edited by Standring S, New York, Elsevier,2004. , pp83 –135

2. Taichman RS: Blood and bone: Two tissues whose fates are intertwined to create the hematopoietic stem cell niche. Blood 105 :2631 –2639,2005 [PubMed]

3. Eriksen EF, Axelrod DW, Melsen F. Bone Histomorphometry, New York, Raven Press,1994. , pp1 –12

4. Kobayashi S, Takahashi HE, Ito A, Saito N, Nawata M, Horiuchi H, Ohta H, Ito A, Iorio R, Yamamoto N, Takaoka K: Trabecular minimodeling in human iliac bone. Bone 32 :163 –169,2003 [PubMed]

5. Ubara Y, Tagami T, Nakanishi S, Sawa N, Hoshino J, Suwabe T, Kaitori H, Takemoto F, Hara S, Takaichi K: Significance of minimodeling in dialysis patients with adynamic bone disease. Kidney Int 68 :833 –839,2005 [PubMed]

6. Ubara Y, Fushimi T, Tagami T, Sawa N, Hoshino J, Yokota M, Kaitori H, Takemoto F, Hara S: Histomorphometric features of bone in patients with primary and secondary hyperparathyroidism. Kidney Int 63 :1809 –1816,2003 [PubMed]

7. Lindsay R, Cosman F, Zhou H, Bostrom M, Shen V, Cruz J, Nieves JW, Dempster DW: A novel tetracycline labeling schedule for longitudinal evaluation of the short-term effects of anabolic therapy with a single iliac crest biopsy: Early actions of teriparatide. J Bone Miner Res 21 :366 –373,2006 [PubMed]

8. Burr DB: Targeted and nontargeted remodeling. Bone 30 :2 –4,2002 [PubMed]

9. Parfitt AM: Targeted and nontargeted bone remodeling: Relationship to basic multicellular unit origination and progression. Bone 30 :5 –7,2002 [PubMed]

10. Roodman GD: Cell biology of the osteoclast. Exp Hematol 27 :1229 –1241,1999 [PubMed]

11. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 423 :337 –342,2003 [PubMed]

12. Blair HC, Athanasou NA: Recent advances in osteoclast biology and pathological bone resorption. Histol Histopathol 19 :189 –199,2004 [PubMed]

13. Silver IA, Murrills RJ, Etherington DJ: Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res 175 :266 –276,1988 [PubMed]

14. Delaisse JM, Andersen TL, Engsig MT, Henriksen K, Troen T, Blavier L: Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclast activities. Microsc Res Tech 61 :504 –513,2003 [PubMed]

15. Eriksen EF: Normal and pathological remodeling of human trabecular bone: Three-dimensional reconstruction of the remodeling sequence in normals and metabolic bone disease. Endocr Rev 7 :379 –408,1986 [PubMed]

16. Reddy SV: Regulatory mechanisms operative in osteoclasts. Crit Rev Eukaryot Gene Expr 14 :255 –270,2004 [PubMed]

17. Bonewald L, Mundy GR: Role of transforming growth factor beta in bone remodeling. Clin Orthop Rel Res 2S :35 –40,1990

18. Hock JM, Centrella M, Canalis E: Insulin-like growth factor I (IGF-I) has independent effects on bone matrix formation and cell replication. Endocrinology 122 :254 –260,2004 [PubMed]

19. Locklin RM, Oreffo RO, Triffitt JT: Effects of TGFbeta and bFGF on the differentiation of human bone marrow stromal fibroblasts. Cell Biol Int 23 :185 –194,1999 [PubMed]

20. Smit TH, Burger EH, Huyghe JM: Is BMU-coupling a strain-regulated phenomenon? A finite element analysis. J Bone Miner Res 15 :301 –307,2002 [PubMed]

21. Smit TH, Burger EH, Huyghe JM: A case for strain-induced fluid flow as a regulator of BMU-coupling and osteonal alignment. J Bone Miner Res 17 :2021 –2029,2002 [PubMed]

22. Martin TJ, Sims NA: Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11 :76 –81,2005 [PubMed]

23. Anderson HC: Matrix vesicles and calcification. Curr Rheumatol Rep 5 :222 –226,2003 [PubMed]

24. Burger EH, Klein-Nuland J, Smit TH: Strain-derived canalicular fluid flow regulates osteoclast activity in a remodeling osteon: A proposal. J Biomech 36 :1452 –1459,2003 [PubMed]

25. Dobnig H, Turner RT: Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 136 :3632 –3638,1995 [PubMed]

26. Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F: Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers. J Bone Miner Res 16 :1575 –1582,2001 [PubMed]

27. Parfitt AM: Osteonal and hemiosteonal remodeling: The spatial and temporal framework for signal traffic in adult bone. J Cell Biochem 55 :273 –276,1994 [PubMed]

28. Teitelbaum SL, Ross FP: Genetic regulation of osteoclast development and function. Nat Rev Genet 4 :638 –649,2003 [PubMed]

29. Cohen MM Jr: The new bone biology: Pathologic, molecular, clinical correlates. Am J Med Genet A 140 :2646 –2706,2006 [PubMed]

30. Ross FP, Teitelbaum SL: αvβ3 and macrophage colony-stimulating factor: Partners in osteoclast biology. Immunol Rev 208 :88 –105,2005 [PubMed]

31. Teitelbaum SL, Abu-Amer Y, Ross FP: Molecular mechanisms of bone resorption. J Cell Biochem 59 :1 –10,1995 [PubMed]

32. Vaananen HK, Zhao H, Mulari M, Halleen JM: The cell biology of osteoclast function. J Cell Sci 113 :377 –381,2000 [PubMed]

33. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science 284 :143 –147,1990 [PubMed]

34. Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE: Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 13 :828 –838,1998 [PubMed]

35. Logan CY, Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20 :781 –810,2004 [PubMed]

36. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP: High bone density due to a mutation in LDL receptor-related protein 5. N Engl J Med 346 :1513 –1521,2002 [PubMed]

37. Little RD, Recker RR, Johnson ML: High bone density due to a mutation in LDL receptor-related protein 5. N Engl J Med 347 :943 –944,2002 [PubMed]

38. Shin CS, Lecanda F, Sheikh S, Weitzmann L, Cheng SL, Civitelli R: Relative abundance of different cadherins defines differentiation of mesenchymal precursors into osteogenic, myogenic, or adipogenic pathways. J Cell Biochem 78 :566 –577,2000 [PubMed]

39. Brodsky B, Persikov AV: Molecular structure of the collagen triple helix. Adv Protein Chem 70 :301 –339,2005 [PubMed]

40. Whyte MP: Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15 :439 –461,1994 [PubMed]

41. Landis WJ: The strength of a calcified tissue depends in part on the molecular structure and organization of its constituent mineral crystals in their organic matrix. Bone 16 :533 –544,1995 [PubMed]

42. Weiner S, Sagi I, Addadi L: Structural biology: Choosing the crystallization path less traveled. Science 309 :1027 –1028 [PubMed]

43. Bonewald LF: Establishment and characterization of an osteocyte-like cell line, MLO-Y4. J Bone Miner Metab 17 :61 –65,1999 [PubMed]

44. Plotkin LI, Manolagas SC, Bellido T: Transduction of cell survival signals by connexin-43 hemichannels. J Biol Chem 277 :8648 –8657,2002 [PubMed]

45. Rubin CT, Lanyon LE: Osteoregulatory nature of mechanical stimuli: Function as a determinant for adaptive bone remodeling. J Orthop Res 5 :300 –310,1987 [PubMed]

46. Jorgensen NR, Teilmann SC, Henriksen Z, Civitelli R, Sorensen OH, Steinberg TH: Activation of L-type calcium channels is required for gap junction-mediated intercellular calcium signaling in osteoblastic cells. J Biol Chem 278 :4082 –4086,2003 [PubMed]

47. Xing L, Boyce BF: Regulation of apoptosis in osteoclasts and osteoblastic cells. Biochem Biophys Res Commun 328 :709 –720,2005 [PubMed]

48. Plotkin LI, Aguirre JI, Kousteni S, Manolagas SC, Bellido T: Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J Biol Chem 280 :7317 –7325,2005 [PubMed]

49. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PH, Eberl S: Genetic determinants of bone mass in adults: A twin study. J Clin Invest 80 :706 –710,1987 [PMC free article] [PubMed]post-content

Happiness Medicine & Holistic Medicine Posts



Follow me on Twitter

Translate »
error: Content is protected !!