The Effect of Low-Dose Continuous Estrogen and Progesterone Therapy With Calcium and Vitamin D on Bone in Elderly Women: A Randomized, Controlled Trial

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Abstract
Although conventional hormone replacement therapy (HRT) definitely prevents postmenopausal osteoporosis, its side effects are dose related and have limited the number of women who can benefit from its bone-sparing effects. This study was designed to evaluate a combination of 0.3 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone daily in 128 generally healthy white women older than 65 years whose spinal bone mineral density (BMD) at baseline (measured by dual-energy x-ray absorptiometry) was 0.9 gm/cc or less. A randomized, double-blind, placebo-controlled design was used, and a 3.5-year treatment time was planned. Patients whose dietary calcium intake was less than 1 gm daily received a calcium supplement sufficient to bring dietary calcium to 1 gm per day. Patients also received 25-hydroxyvitamin D if needed to increase the serum level to at least 75 nmol/liter. Compliance with treatment exceeded 90 percent for participants who completed the study period. BMD in the spine increased significantly in patients receiving HRT compared with placebo recipients, especially in the first 6 months (Fig. 1). The peak gain was 4 percent over baseline after 3 years of treatment (Fig. 2). Total-body bone mineral content increased steadily for 18 months to a gain of 3.1 percent over baseline in the HRT group; placebo patients gained 1.5 percent during the same time period. The overall gain in BMD in the femoral neck was not significant, but the trend for radial BMD significantly favored HRT. Side effects considered to be related to the HRT were mild and short-lasting and were easily tolerated by the majority of patients. Most of these effects no longer were present after 6 months of treatment, and no patients had vaginal bleeding or spotting after 12 months. FIGURE Fig. 1: Percentage change in spine bone mineral density (BMD) (top left), femoral neck bone mineral density (bottom left), total-body bone mineral content (BMC) (top right), and forearm bone mineral density (bottom right) in the hormone replacement therapy group (squares) and placebo group (diamonds). The effect of hormone replacement therapy was significant at all sites (P < .01) except the femoral neck (P = .19). Bone mass remained the same or increased in the placebo group at the spine, total body, and femoral neck and decreased at the forearm. Error bars represent SEs. Fig. 2: Total alkaline phosphatase level (top left), 24-hour urinary hydroxyproline:creatinine ratio (bottom left), osteocalcin level (top right), and 24-hour urinary calcium:creatinine ratio (bottom right) in the hormone replacement therapy group (squares) and placebo group (diamonds). Values shown are the mean ± SE. The treatment effect of hormone replacement therapy was significant for all four bone markers. To convert alkaline phosphatase values to microkatal per liter, multiply by 0.01667. To convert osteocalcin values to nanomoles per liter, multiply by 0.0171. Continuous low-dose HRT, when combined with calcium and vitamin D supplements, is an effective and relatively inexpensive way of preventing osteoporosis in elderly postmenopausal women. It has a potent bone-sparing effect, and side effects are tolerated by most patients. Ann Intern Med 1999;130:897–904

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