BACKGROUND: Observation studies have suggested that hormone replacement therapy (HRT) prevents osteoporotic fractures; however, few randomized trials have been reported. The influential Heart and Estrogen/progestin Replacement Study (HERS) was a randomized multicenter trial that reported HRT as not effective for secondary prevention of coronary artery disease (CAD) events. The investigators took advantage of data from the HERS trial to further study the relationship between HRT and fracture risk.
POPULATION STUDIED: The study enrolled 2763 postmenopausal women (all younger than 80 years) with an intact uterus and documented coronary artery disease (CAD). Two thirds of the women were 65 years or older. Women were excluded if they had had a coronary event within 6 months, serum triglycerides of 300 mg per dL or greater, hormone use within 3 months, history of deep vein thrombosis, pulmonary embolism, breast or endometrial cancer, uncontrolled hypertension, diabetes, or any other life-threatening disease.
STUDY DESIGN AND VALIDITY: This was a randomized double-blind, placebo-controlled trial. Participants were randomized to either placebo or combined conjugated equine estrogen 0.625 mg and medroxyprogestrone acetate 2.5 mg daily. The average follow-up was 4.1 years with 64% of the women still having HRT at the end of the study period. Allocation to treatment group was concealed, and the study was well designed. The 2 groups did not differ in their baseline characteristics. No attempt was made to assess or augment subjects’ intake of calcium or vitamin D.
OUTCOMES MEASURED: The primary outcome was clinical fractures determined by reviewing interval diagnoses of a fracture. In a subset of 408 women older than 65 years, bone mineral density (BMD) was measured at baseline and on the final visit. Standing height, measured with a height rod or a Harpenden Stadiometer, was assessed at baseline and annually, and served as a validated surrogate for vertebral fractures.
RESULTS: During 10,554 person-years of follow-up, 286 women experienced fractures: 138 in the treatment group, 148 in the placebo group (relative hazard = 0.94; 95% confidence interval [CI], 0.8-1.2), a nonstatistically significant difference. HRT did not prevent fractures at any specific location (wrist, hip, spine, or other). Similarly, the relative risk of experiencing a height loss of 2 cm or greater was 0.8 (0.6 to 1.1) for all women studied, regardless of treatment group. Of women with the lowest hip BMD ( 0.7 g/cmx2), HRT use had a relative risk of fracture of 0.4 (95% CI, 0.2-1.2). Total hip BMD did increase 3.3% in the HRT group, compared with a 2.7% loss in the placebo group.
This trial did not find a statistically significant reduction of fracture risk in women treated with HRT for an average of 4 years. Note that this study was designed primarily to test the effect of HRT on CAD, not osteoporosis. Cohort studies and other small, randomized controlled trials have suggested that at least 5 years of therapy are needed, and treatment must be instituted within 2 years of menopause to reduce fractures. It is also unclear whether appropriate supplementation with calcium and vitamin D would alter the results. This study was the largest in a recent meta-analysis1 that did find a statistically significant reduction in the risk of fractures for women on HRT (relative risk = 0.73; 95% CI, 0.56-0.94). This meta-analysis found the strongest benefit for HRT was in women younger than 60 years. Although this study does not definitively resolve the question, it appears that women older than 60 years are unlikely to benefit with a reduced fracture risk as a result of HRT therapy, at least in the first few years of therapy. At a minimum, these women should receive adequate calcium and at least 700 IU of vitamin D daily.2