Effects of lower doses of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) on bone.

Abstract

Objective: To evaluate the effects of variable doses of CEE, either alone or with one of two daily doses of MPA, on bone mineral density (BMD) and markers of bone remodeling. Design: 749 healthy postmenopausal women who participated in the Osteoporosis and Metabolic substudy of the double-blind, placebo-controlled Women’s Health, Osteoporosis, Progestin, Estrogen (Women’s HOPE) study were randomized to receive CEE 0.625 mg/day, CEE 0.625/MPA 2.5 mg/day, CEE 0.45 mg/day, CEE 0.45/MPA 2.5 mg/day, CEE 0.45/MPA 1.5 mg/day, CEE 0.3 mg/day, CEE 0.3/MPA 1.5 mg/day, or placebo. All women received calcium carbonate (600 mg elemental calcium daily). Women were between 1 and 4 years post-menopause at enrollment. Materials/Methods: BMD (lumbar spine, femoral neck, trochanter, and total body; Lunar DPX-L, Lunar Corp., Madison, WI) and bone remodeling markers (serum osteocalcin [OC] and urine N-telopeptide [NTX]) were measured at baseline and every 6 months for 2 years. Replicate BMD measurements were obtained at baseline and study completion. A single technician following a standard protocol performed all BMD scans. To examine the effects of each dose, data were analyzed using a modified efficacy-evaluable population that excluded patients who were >80% compliant with study medication, used non-study medications that affected calcium or skeletal homeostasis, or did not have at least 1 baseline scan and 2 on-treatment scans. Scans performed >60 days after stopping study medication were not included in analyses. Statistical significance was set a priori at P<.05. Results: By study completion, placebo-treated patients had lost BMD at spine, femoral neck, and total body while trochanter BMD remained stable (loss ∼2%–3% over 2 years). All doses of CEE and CEE/MPA produced significant increases in BMD at all sites relative to placebo, with differences ranging from 4%–6.4% (spine) to 2%–2.6% (total body), with hip differences intermediate. All doses increased BMD from baseline at all sites, except CEE 0.3 mg, which just failed to reach statistical significance. There was a dose-response relationship across all doses in the spine, confirmed by a responder analysis that indicated that 87% of individuals increased BMD in the spine at 0.625 CEE, but only 63% at 0.3 mg. Total body BMD also showed a dose-response relationship. As expected, CEE and CEE/MPA reduced both OC and NTX by 26%–38% and 36%–55%, respectively, with little evidence of a dose-response. Conclusions: Lower doses of CEE, alone or in combination with either 2.5 or 1.5 mg/day of MPA, preserve BMD and reduce markers of bone remodeling in postmenopausal women. The findings also confirm that calcium alone, supplemented at 600 mg/day, does not prevent bone loss in the early, postmenopausal years. Supported By: Wyeth-Ayerst Research.