The appendicular skeleton has 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.
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 This ratio is in the femoral head and 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 mm long and 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. 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. 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 mm in thickness 3. Trabecular osteons are semilunar in shape, normally approximately 35 mm thick, and composed of concentric lamellae.
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 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 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.
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 Figure 2 and Haversian canals in cortical bone. The resorption phase is completed by mononuclear cells after the multinucleated osteoclasts undergo apoptosis 15 , Two forms of RANKL are produced by osteoblasts and osteoblast precursors to stimulate osteoclast recruitment and activation.
The membrane-bound form directly interacts with membrane-bound RANK molecules on adjacent osteoclast precursors. The soluble form is released from osteoblasts or osteoblast precursors to diffuse through the intercellular space and interact with membrane-bound RANK molecules on nearby osteoclast precursors.
Multinucleated osteoclasts resorb bone to form resorption pits known as Howship's lacunae. 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. The reversal phase has also been proposed to be mediated by the strain gradient in the lacunae 20 , 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 Bone formation takes approximately 4 to 6 mo to complete. Osteoblasts synthesize new collagenous organic matrix Figure 3 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 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 The osteocyte network within bone serves as a functional syncytium.
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 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 In patients with multiple myeloma, lining cells may be induced to express tartrate-resistant acid phosphatase and other classical osteoclast markers.
Osteoblasts synthesize proteinaceous matrix, composed mostly of type I collagen, to fill in resorption pits. The proteinaceous matrix is gradually mineralized to form new bone. 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 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 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 Figure 2.
Activated multinucleated osteoclasts are derived from mononuclear precursor cells of the monocyte-macrophage lineage 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. 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 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.
Bone resorption depends on osteoclast secretion of hydrogen ions and cathepsin K enzyme. Osteoclasts bind to bone matrix via integrin receptors in the osteoclast membrane linking to bone matrix peptides.
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.
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 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. Osteoprogenitor cells give rise to and maintain the osteoblasts that synthesize new bone matrix on bone-forming surfaces Figure 3 , 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 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 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 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 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.
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