of ERT in 50-year-old women were associated with an additional 0.67 quality-adjusted years of life. This benefit increased by 0.17 quality-years for each 10 percent decrease in fracture rates.

Despite data that consistently show a beneficial effect of estrogen on bone mass and fracture risk, only about 5 percent of post-menopausal women are on long-term ERT.17 The reluctance of physicians to prescribe and of women to comply with such therapy may be related to uncertainty regarding benefits and risks. Endometrial cancer is a concern18 unless progesterone is used concomitantly, but progesterone may negate the cardioprotective effects of unopposed estrogen.3 There is also the possibility of an increased incidence of breast cancer. Although such an increase appears to be small and has not been found in all studies, recent suggestions of a heightened risk of breast cancer following combined estrogen and progestin administration1 indicate a need for additional research to resolve this important question. On the other hand, almost all studies have found a decreased risk for cardiovascular disease in unopposed estrogen users,2,47 although no controlled clinical trials have been completed. Although the potential cardiovascular benefits of estrogen are likely to be greater than the benefits of fracture reduction, prevention of heart disease is not an approved indication for ERT. In short, many unanswered questions remain.

The other approved therapy for osteoporosis, calcitonin, has not been used extensively for preventing bone loss because of its expense and the need for parenteral administration of present formulations.35 Calcitonin, and investigational drugs like the bisphosphonates, also act by reducing bone loss. Sodium fluoride, an investigational drug known to increase bone mass in the spine and believed to reduce vertebral fracture rates, has little effect on bone mass in the limbs. Because hip fracture risk is not reduced and may actually be increased somewhat, fluoride has no role in osteoporosis prophylaxis.29 As is obvious from these observations, improved therapeutic approaches are needed, especially approaches that preserve bone without introducing unpleasant side effects or worrisome complications.

Age-related Bone Loss

This slow form of bone loss continues throughout life and is the major source of bone loss in both sexes. The determinants of age-related bone loss are not precisely known but may include impaired regulation of osteoblasts (the cells that make bone), deficiencies of calcium or vitamin D, and decreased muscle mass associated with inactivity. Bone cell function and regulation is the subject of



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