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Bone is a special form of connective tissue with a collagen framework impregnated with Ca2+ and PO43– salts, particularly hydroxyapatites, which have the general formula Ca10(PO4)6(OH)2. Bone is also involved in overall Ca2+ and PO43– homeostasis. It protects vital organs, and the rigidity it provides permits locomotion and the support of loads against gravity. Old bone is constantly being resorbed and new bone formed, permitting remodeling that allows it to respond to the stresses and strains that are put upon it. It is a living tissue that is well vascularized and has a total blood flow of 200–400 mL/min in adult humans.
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There are two types of bone: compact or cortical bone, which makes up the outer layer of most bones (Figure 21–8) and accounts for 80% of the bone in the body; and trabecular or spongy bone inside the cortical bone, which makes up the remaining 20% of bone in the body. In compact bone, the surface-to-volume ratio is low, and bone cells lie in lacunae. They receive nutrients by way of canaliculi that ramify throughout the compact bone (Figure 21–8). Trabecular bone is made up of spicules or plates, with a high surface to volume ratio and many cells sitting on the surface of the plates. Nutrients diffuse from bone extracellular fluid (ECF) into the trabeculae, but in compact bone, nutrients are provided via haversian canals (Figure 21–8), which contain blood vessels. Around each haversian canal, collagen is arranged in concentric layers, forming cylinders called osteons or haversian systems.
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The protein in bone matrix is over 90% type I collagen, which is also the major structural protein in tendons and skin. This collagen, which weight for weight is as strong as steel, is made up of a triple helix of three polypeptides bound tightly together. Two of these are identical α1 polypeptides encoded by one gene, and one is an α2 polypeptide encoded by a different gene. Collagens make up a family of structurally related proteins that maintain the integrity of many different organs. Over 40 collagen genes that contribute to at least 28 distinct trimeric collagens have so far been identified.
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During fetal development, most bones are modeled in cartilage and then transformed into bone by ossification (enchondral bone formation). The exceptions are the clavicles, the mandibles, and certain bones of the skull in which mesenchymal cells form bone directly (intramembranous bone formation).
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During growth, specialized areas at the ends of each long bone (epiphyses) are separated from the shaft of the bone by a plate of actively proliferating cartilage, the epiphysial plate (Figure 21–9). The bone increases in length as this plate lays down new bone on the end of the shaft. The width of the epiphysial plate is proportional to the rate of growth. The width is affected by a number of hormones, but most markedly by the pituitary growth hormone and IGF-I (see Chapter 18).
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Linear bone growth can occur as long as the epiphyses are separated from the shaft of the bone, but such growth ceases after the epiphyses unite with the shaft (epiphysial closure). The cartilage cells stop proliferating, become hypertrophic, and secrete vascular endothelial growth factor (VEGF), leading to vascularization and ossification. The epiphyses of the various bones close in an orderly temporal sequence, the last epiphyses closing after puberty. The normal age at which each of the epiphyses closes is known, and the “bone age” of a young individual can be determined by radiographing the skeleton and noting which epiphyses are open and which are closed.
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The periosteum is a dense fibrous, vascular, and innervated membrane that covers the surface of bones. This layer consists of an outer layer of collagenous tissue and an inner layer of fine elastic fibers that can include cells that have the potential to contribute to bone growth. The periosteum covers all surfaces of the bone except for those capped with cartilage (eg, at the joints) and serves as a site of attachment of ligaments and tendons. As one ages, the periosteum becomes thinner and loses some of its vasculature. This renders bones more susceptible to injury and disease.
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BONE FORMATION & RESORPTION
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The cells responsible for bone formation are osteoblasts and the cells responsible for bone resorption are osteoclasts.
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Osteoblasts are modified fibroblasts. Their early development from the mesenchyme is the same as that of fibroblasts, with extensive growth factor regulation. Later, ossification-specific transcription factors, such as runt-related transcription factor 2 (Runx2; also known as core binding factor subunit alpha-1), contribute to their differentiation. The importance of this transcription factor in bone development is underscored in knockout mice deficient for the RUNX2 gene. These mice develop to term with their skeletons made exclusively of cartilage; no ossification occurs. Normal osteoblasts are able to lay down type 1 collagen and form new bone.
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Osteoclasts, on the other hand, are members of the monocyte family. Stromal cells in the bone marrow, osteoblasts, and T lymphocytes all express receptor activator for nuclear factor kappa beta ligand (RANKL) on their surface. When these cells come in contact with appropriate monocytes expressing RANK (ie, the RANKL receptor) two distinct signaling pathways are initiated: (1) there is a RANKL/RANK interaction between the cell pairs, (2) mononuclear phagocyte colony stimulating factor (M-CSF) is secreted by the nonmonocytic cells and it binds to its corresponding receptor on the monocytes (colony stimulating factor 1 receptor, CSF1R). The combination of these two signaling events leads to differentiation of the monocytes into osteoclasts. The precursor cells also secrete osteoprotegerin (OPG), which limits differentiation of the monocytes by competing with RANK for binding of RANKL.
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Osteoclasts erode and absorb previously formed bone. They become attached to bone via integrins in a membrane extension called the sealing zone. This creates an isolated area between the bone and a portion of the osteoclast. Proton pumps (ie, H+-dependent ATPases) then move from endosomes into the cell membrane apposed to the isolated area, and they acidify the area to approximately pH 4.0. Similar proton pumps are found in the endosomes and lysosomes of all eukaryotic cells, but in only a few other instances do they move into the cell membrane. Note in this regard that the sealed-off space formed by the osteoclast resembles a large lysosome. The acidic pH dissolves hydroxyapatite, and acid proteases secreted by the cell break down collagen, forming a shallow depression in the bone (Figure 21–10). The products of digestion are then endocytosed and move across the osteoclast by transcytosis (see Chapter 2), with release into the interstitial fluid. The collagen breakdown products have pyridinoline structures, and pyridinolines can be measured in the urine as an index of the rate of bone resorption.
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Throughout life, bone is being constantly resorbed and new bone is being formed. The calcium in bone turns over at a rate of 100% per year in infants and 18% per year in adults. Bone remodeling is mainly a local process carried out in small areas by populations of cells called bone-remodeling units. First, osteoclasts resorb bone, and then osteoblasts lay down new bone in the same general area. This cycle takes about 100 days. Modeling drifts also occur in which the shapes of bones change as bone is resorbed in one location and added in another. Osteoclasts tunnel into cortical bone followed by osteoblasts, whereas trabecular bone remodeling occurs on the surface of the trabeculae. About 5% of the bone mass is being remodeled by about 2 million bone-remodeling units in the human skeleton at any one time. The renewal rate for bone is about 4% per year for compact bone and 20% per year for trabecular bone. The remodeling is related in part to the stresses and strains imposed on the skeleton by gravity.
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At the cellular level, there is some regulation of osteoclast formation by osteoblasts via the RANKL–RANK and the M-CSF–CSF1R mechanism; however, specific feedback mechanisms of osteoclasts on osteoblasts are not well defined. In a broader sense, the bone-remodeling process is primarily under endocrine control. Not surprisingly, hormonal control of bone metabolism can be quite complex, and this can be illustrated by examining effects of the weight-associated hormone leptin on bone metabolism. When administered intracerebroventricularly, leptin decreases bone formation. This is thought to occur via release of various substances from the hypothalamus that can reduce osteoblast function. However, circulating leptin can increase bone mass through osteoblast and pre-osteoblast cell signaling pathways. More generally, PTH accelerates bone resorption, and estrogens slow bone resorption by inhibiting the production of bone-eroding cytokines.
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The diseases produced by selective abnormalities of the cells and processes discussed above illustrate the interplay of factors that maintain normal bone function.
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In osteopetrosis, a rare and often severe disease, the osteoclasts are defective and are unable to resorb bone in their usual manner so the osteoblasts operate unopposed. The result is a steady increase in bone density, neurologic defects due to narrowing and distortion of foramina through which nerves normally pass, and hematologic abnormalities due to crowding out of the marrow cavities. Mice lacking the protein encoded by the immediate-early gene c-fos develop osteopetrosis; osteopetrosis also occurs in mice lacking the PU.1 transcription factor. This suggests that all these factors are involved in normal osteoclast development and function.
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On the other hand, osteoporosis is caused by a relative excess of osteoclastic function. Loss of bone matrix in this condition (Figure 21–11) is marked, and the incidence of fractures is increased. Fractures are particularly common in the distal forearm (Colles fracture), vertebral body, and hip. All of these areas have a high content of trabecular bone, and because trabecular bone is more active metabolically, it is lost more rapidly. Fractures of the vertebrae with compression cause kyphosis, with the production of a typical “widow’s hump” that is common in elderly women with osteoporosis. Fractures of the hip in elderly individuals are associated with a mortality rate of 12–20%, and half of those who survive require prolonged expensive care.
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Osteoporosis has multiple causes, but by far the most common form is involutional osteoporosis. Humans normally gain bone during growth early in life. After a plateau, they begin to lose bone as they grow older (Figure 21–12). When this loss is accelerated or exaggerated, it leads to osteoporosis (Clinical Box 21–4). Increased intake of calcium, particularly from natural sources such as milk, and moderate exercise may help prevent or slow the progress of osteoporosis, although their effects are not great. Bisphosphonates such as etidronate, which inhibit osteoclastic activity, increase the mineral content of bone and decrease the rate of new vertebral fractures when administered in a cyclical manner. Fluoride stimulates osteoblasts, making bone more dense, but it has proven to be of little value in the treatment of the disease.
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CLINICAL BOX 21–4 Osteoporosis
Adult women have less bone mass than adult men, and after menopause they initially lose it more rapidly than men of comparable age. Consequently, they are more prone to development of serious osteoporosis. The cause of bone loss after menopause is primarily estrogen deficiency, and estrogen treatment arrests the progress of the disease. Estrogens inhibit secretion of cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF-α), cytokines that otherwise foster the development of osteoclasts. Estrogen also stimulates production of transforming growth factor (TGF-β), and this cytokine increases apoptosis of osteoclasts.
Bone loss can also occur in both men and women as a result of inactivity. In patients who are immobilized for any reason, and during space flight, bone resorption exceeds bone formation and disuse osteoporosis develops. The plasma calcium level is not markedly elevated, but plasma concentrations of parathyroid hormone and 1,25-dihydroxycholecalciferol fall and large amounts of calcium are lost in the urine.
THERAPEUTIC HIGHLIGHTS Hormone therapy has traditionally been used to offset osteoporosis. Estrogen replacement therapy begun shortly after menopause can help maintain bone density. However, it appears that even small doses of estrogens may increase the incidence of uterine and breast cancer, and in carefully controlled studies, estrogens do not protect against cardiovascular disease. Therefore, treatment of a postmenopausal woman with estrogens is no longer used as a primary option. Raloxifene is a selective estrogen receptor modulator that can mimic the beneficial effects of estrogen on bone density in postmenopausal women without some of the risks associated with estrogen. However, this too carries risk of side effects (eg, blood clots). Other hormone treatments include the use of calcitonin and the parathyroid hormone analogue teriparatide. An alternative to hormone treatments is the bisphosphonates. These drugs can inhibit bone breakdown, preserve bone mass, and even increase bone density in the spine and hip to reduce the risk of fractures. Unfortunately, these drugs also can cause mild to serious side effects and require monitoring for patient suitability. In addition to hormones and medications listed above, physical therapy to increase appropriate mechanical load and improve balance and muscle strength can significantly improve quality of life.