Observational studies and clinical trials have shown that estrogen use can attenuate bone loss and reduce fracture risk in postmenopausal women. The Women's Health Initiative (WHI) supports findings from previous studies of estrogen and osteoporosis.1 In this large, population-based primary prevention trial, the rate of total osteoporotic fractures among women with unknown baseline bone density who were randomized to treatment with estrogen and progestin was significantly reduced compared with women randomized to receive placebo (adjusted hazard ratio: 0.77; 95 percent confidence interval: 0.63 to 0.94). Hip and vertebral fracture rates also were reduced, although these decreases were not statistically significant.
The WHI also demonstrated higher rates of cardiovascular events and breast cancer among estrogen users in the trial. These breast cancer findings were consistent with findings from some previous studies. The cardiovascular findings were inconsistent with conclusions of several observational studies2 that showed benefit but more consistent with the findings of the Heart and Estrogen/progestin Replacement Study follow-up randomized controlled trial,3 which showed that hormone replacement did not reduce the risk of cardiovascular events in women with coronary heart disease.
The WHI report presents a dilemma for clinicians and patients by offering stronger evidence that estrogen use is associated with both benefit and harm in postmenopausal women in the general population. In light of this new evidence, we must ask, “Does estrogen have a role in osteoporosis prevention and treatment?”
Role in Prevention
A meta-analysis of 57 randomized controlled trials of hormone therapy show a consistent bone-sparing effect at the lumbar spine, femoral neck, and forearm, and a non-significant trend toward reduced incidence of vertebral and nonvertebral fractures.4 This evidence is not definitive. Prevention trials would need to be very large and extend over 20 to 30 years to clarify who might benefit from therapy, when preventive therapy should be initiated, and how long it should continue.
Observational data from the Study of Osteoporotic Fractures,5 a large, prospective cohort of U.S. women 65 years of age and older, suggest that women should begin taking estrogen at menopause and continue indefinitely to be protected against fractures. Once estrogen use is discontinued, the beneficial effect diminishes to the level of the never-user. Even among women who take estrogen continuously beginning at menopause, older women still commonly sustain fractures, although at lower rates than non–estrogen-users.6 Prevention trials of bisphosphonates and selective estrogen receptor modulators report improved bone density but not reduced fracture rates.7–9
How does this evidence apply to patient care? The role of estrogen in fracture prevention has been diminished because of potential harms. The U.S. Preventive Services Task Force (USPSTF) recently recommended against the routine use of estrogen and progestin for the prevention of chronic conditions in post-menopausal women (grade D recommendation) and concluded that the evidence was insufficient to recommend for or against the use of unopposed estrogen for chronic disease prevention (grade I recommendation).10 The Task Force encourages clinicians to counsel patients about other strategies for preventing osteoporosis and fractures.
To date, no studies have been conducted that compare the effects of different prevention strategies. Randomized, head-to-head comparisons of medical and nonmedical interventions would improve our current approach to osteoporosis prevention. A limited number of studies of nonmedical interventions, such as exercise, adequate intake of calcium and vitamin D,11 and the use of hip protectors in frail patients, suggest benefit.12 A recent analysis of data from the Nurses' Health Study indicated that walking for at least four hours per week was associated with a 41 percent lower risk of hip fracture.13 Levels of fracture risk in women who were not using estrogen approximated that of estrogen users as exercise levels increased.
Role in Treatment
The U.S. Food and Drug Administration has approved the use of estrogen for prevention, but not treatment, of postmenopausal osteoporosis. No large treatment trials have examined the effect of estrogen in reducing fractures in women with existing osteoporosis.
Trials of bisphosphonates enrolled predominantly older women and showed that women with the lowest bone density were the most likely to benefit.14 In these women, risks for vertebral and nonvertebral fractures were reduced by 40 to 50 percent compared with risks in placebo groups.7,8 Mean T scores in women in bisphosphonate treatment trials ranged from −2.2 to −3.3 (the diagnostic threshold for osteoporosis is a T score of −2.5). Because no fracture benefit was reported in women with mildly reduced bone density in these trials, identification of treatment candidates with bone density testing is important before initiating therapy.
According to the recently updated USPSTF guidelines, all women 65 years of age and older should receive routine bone density testing.15 Women with additional risk factors for bone loss such as new low-trauma fractures, certain metabolic disorders, or corticosteroid use are among those who could benefit from testing.16
The best current evidence supports selective use of bisphosphonates, not estrogen, to treat women with low bone density or previous low-trauma fractures. The long-term effects of bisphosphonate therapy are currently under investigation. As with any therapy, individual benefits and harms should be considered, and not all eligible women will be good treatment candidates. Trials of combined estrogen and bisphosphonate therapy suggest enhanced bone density outcomes compared with single-therapy treatment; however, studies with fracture outcomes have not been published.
Other approved medications may be appropriate in patients who do not tolerate or respond to bisphosphonates. Trials of raloxifene9 indicate benefit for vertebral fractures only. New medications, such as teriparatide (recombinant human parathyroid hormone; Forteo), and agents under investigation may expand our treatment options in the future.