Osteoporosis, the result of abnormal loss of bone, leads to increased risk of bone fracture.1 It is a major health problem in postmenopausal woman and the elderly, who lose 3% of their bone mass per year. About 40% of women experience an osteoporotic fracture during life. Osteoporosis Is the result of an imbalance in the normal process of bone remodeling, the continuous formation of new bone and removal of existing bone. The deposition of new bone is effected by the osteoblast cell line, and the dissolution of bone is caused by osteoclast cells. The populations and activities of these cells, which are attached to the surface of bone, are coupled and tightly regulated by multiple factors.
One such factor is simply the mechanical stress on bone. It has been long known that prolonged immobilization due to illness or injury results in substantial loss of bone, as much as 15% over a three month period. Astronauts in the zero gravity environment of space lose bone mass at a rate of 2% per month (more than 20% per year). This "disuse" form of osteoporosis is a serious concern in planning for extended human exploration of space and an additional reason to understand bone homeostasis more deeply. Disuse osteoporosis is the result of both reduced osteoblast-mediated bone formation and enhanced osteoclast-mediated bone loss.
Osteoclasts secrete an enzyme, cathepsin K, which breaks down the collagen matrix of bone. They also generate acid which dissolves the mineral component, a form of calcium phosphate. Although there has been much research to find molecules that selectively inhibit cathepsin K, so far no useful therapeutic agent of this type has been discovered. Another approach to limiting osteoclast-induced bone resorption depends on downregulating the population of this cell line, which has a lifetime in vivo of only two weeks (vs. 4 months for osteoblasts). This development of new osteoclasts is strongly stimulated by a protein called receptor activator of nuclear factor-KB ligand (RANKL), a member of the TNF-a class. Other mediators that enhance osteoclast formation, activation or lifespan are (1) parathyroid hormone, (2) prostaglandin E2, (3) calcitriol, and (4) lnterleukin-11. A monoclonal antibody against RANKL, denosumab (Amgen), which is currently in Phase 3 clinical trials, has been shown to promote the formation of strong and dense bone. Inflammatory cytokines upregulate the levels of RANKL and, as a consequence, increase osteoclast action and bone loss. This is an important cause of the joint destruction that accompanies arthritis. On the other hand, the levels of RANKL are lowered with increasing concentrations of estrogen, which can explain the beneficial effect of estrogen on bone.
Osteoblast proliferation or development is stimulated by parathyroid hormone and by calcitriol. The balance between osteoblast and osteoclast populations is further maintained by the capacity of osteoblasts to secrete RANKL and stimulate the development of osteoclasts (and also by the reverse of this effect). Corticosteroids induce osteoporosis in part by inhibiting osteoblast function as well as by downregulating calcium levels.
There are rare human disorders of genetic origin that involve either abnormally high or low bone mass or strength One family, which had been found to possess strikingly high bone mass, turned out to have a single amino acid mutation in a protein on the Wnt signaling pathway that reduced its function and increased osteoblast proliferation. Genetic studies offer great promise in the fundamental understanding of osteoporosis.
The annual medical cost of osteoporosis in the US is roughly $15 billion for the 10 million affected Inividuals. The problem is even more serious in Asia. Worldwide, at least 200 million people are affected. The need for eariy diagnosis and improved treatment of osteoporosis will only increase as world demographics shift toward older ages. Increased muscle weakening with aging exacerbates the effects of osteoporosis. Both conditions are accelerated by physical inactivity (or the zero gravity of space).
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