Update on Estrogens and the Skeleton

Context: The very clinical trial, the Women's Health Initiative, which definitely established the antifracture efficacy of estrogen therapy, led to the demise of estrogen treatment as a viable, long-term option for prevention of bone loss in postmenopausal women due to the well-publicized adverse effects of estrogen plus progestin therapy on a number of nonskeletal endpoints. Given the diminishing clinical use of estrogen, it is logical to question whether estrogen regulation of bone remains a relevant issue at a clinical or basic research level. Evidence Acquisition: Findings of this update are based on a PubMed search and the author's knowledge of the field. Evidence Synthesis: Basic and clinical studies on the mechanisms of estrogen effects on bone will continue to provide potential novel drug targets for the prevention and treatment of osteoporosis. At a clinical level, it is clear that even the low levels of estrogen present in postmenopausal women have a significant impact on bone turnover, leading to a more aggressive approach to prevent bone loss in patients with breast cancer on aromatase inhibitors. Conversely, increasing these low estrogen levels with small doses of estrogen may have beneficial skeletal effects in postmenopausal women without adverse effects on reproductive tissues. Finally, the search continues for new selective estrogen receptor modulators with beneficial effects on bone and other tissues. Conclusions: Even in the post-WHI era, basic and clinical investigation on estrogen and bone will continue to yield important insights that not only expand our knowledge at a basic level but also impact the health of our aging population. (J Clin Endocrinol Metab 95: 3569-3577, 2010)