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4 Bone (continued) + ward ' s science calcitonin is released from the thyroid, which rapidly inhibits the resorptive activity of osteoclasts. Most agents that promote bone resorption act on osteoblastic cells, which in turn convey signals to osteoclast precursors to differentiate into mature osteoclasts. These agents include the active form of vitamin D, parathyroid hormone, interleukins, and prostaglandins (for example, prostaglandin E2). Differentiation to fully functional osteoclasts also requires close contact between osteoclast precursors and osteoblastic cells. This dependency on contact for differentiation is the result of a molecule called osteoclast differentiation factor (ODF), which is located on the surface of osteoblasts, binds to receptors on the surface of osteoclast precursor cells, and induces their progression to osteoclasts. Bone formation, growth, and remodeling Osteogenesis is the development and formation of bone. The two types of bone—flat bones and long bones—are formed by different embryological means. Formation of flat bones occurs by intramembranous ossification, in which primitive mesen- chymal cells differentiate directly into osteoblasts and produce bony trabeculae within a periosteal membrane. The initial na- ture of this bone is relatively disorganized and is termed woven bone. Later, on the outside of flat bones, this woven bone is remodeled and replaced by the mature lamellae, consisting of layers of calcified matrix arranged in orderly fashion. Lamellae have much greater strength than woven bone. Conversely, long bones are formed by intracartilaginous development in which the future bone begins as cartilage. The cartilage template is gradually replaced by bone in an orderly sequence of events starting at the center of the grow- ing bone (the diaphysis). Cartilage remains at the ends of long bones during growth, forming a structure at each end termed the growth plate [or epiphyseal plate, (Fig. 5)]. Cartilage cells (chondrocytes) that arise in the growth plates proliferate and add to the length of the bone. Elongation of bone occurs dur- ing a complex series of events, with expansion away from the center of the bone and toward the center of the bone to create the metaphyses (that is, the regions adjacent to the growth plates). When the bone achieves its final length in maturity, expansion from the growth plate ceases and the cartilaginous growth plate calcifies into a structure called epiphyseal line. Cartilage persists at the ends of the long bones in a specific form called articular cartilage, which provides the smooth bear- ing surfaces for the joints. Bone is a dynamic tissue and is constantly being remodeled (Fig. 6) by the actions of osteoclasts and osteoblasts. The removal of bone by osteoclasts occurs both on the surface of trabecular bone and within cortical bone, at random sites, and at sites of microscopic damage. After bone removal, the osteo- clasts either move on to new resorption sites or die; this is followed by a reversal phase in which osteoblasts are attract- ed to the resorption site. It is thought that growth factors that are sequestered in an inac- tive form in the bone matrix are released and activated by the osteo- clast activity and that these in turn promote fresh osteoid produc- tion by the recruited osteoblasts. The new osteoid eventually calci- fies, and the bone is formed and replaced in layers (lamellae), which are the result of these repeated cycles. In growing bone, the activities of bone cells are skewed toward a net increase in bone. However, in healthy mature bone, there is an equilibrium between bone resorption and bone formation, due to com- munication between osteoblasts and osteoclasts. When the equilibrium between these two cell types breaks down, skeletal pathology results. Bone disease The most common bone disease is osteoporosis, in which there is a net loss of bone due to osteoclastic bone resorption that is not completely matched by new bone formation. The best-un- derstood cause of osteoporosis is that which occurs in women due to the loss of circulating estrogen after menopause. A pro- longed loss of bone in postmenopausal osteoporosis reduces bone strength, and it is the cause of a great deal of morbidity in the form of fractures, largely of the spine and femur. Another cause of osteoporotic bone loss is seen in disuse osteoporosis and in space flight. Just as bone can respond to increased load- ing with the production of additional bone, bone is also depen- dent on regular loading for its maintenance. Significant bone loss can occur during prolonged bed rest or, for example, in paraplegia and quadriplegia. Likewise, an unloading of the skel- eton (due to a lack of gravitational pull) in space flight results in severe bone loss in astronauts unless the effects of gravity are simulated by special exercises and devices. Fig. 5: In growing bones, the growth plate is the region between epiphysis and diaphysis that is cartilaginous and allows for cell proliferation to occur (light blue area with cells). (Copyright © McGraw Hill)