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ORIGINAL RESEARCH |
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From the *Division of Research, Kaiser Permanente Medical Care Program, Oakland, California; Epidemiology Clinical Research Center, University of Minnesota, and Veteran's Administration Medical Center, Minneapolis, Minnesota; Department of Epidemiology, University of Iowa, Iowa City, Iowa; Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee; ¶Department of Epidemiology and Biostatistics, University of California, and Clinical Research Division, California Pacific Medical Center Research Institute, San Francisco, California; ||Ferring Pharmaceuticals, Inc, Suffern, New York; and **Department of Epidemiology and Biostatistics and Women's Health Clinical Research Center, Mount Zion Medical Center, University of California, San Francisco, California.
Address reprint requests to: Bruce Ettinger, MD, 156 Lombard Street, #13, San Francisco, CA 94111; e-mail: vmettinger{at}aol.com.
OBJECTIVE: Because small increments in levels of endogenous plasma estradiol are associated with higher postmenopausal bone mineral density, we investigated the safety and effectiveness in preventing bone loss of unopposed, very-low-dose transdermal estradiol for postmenopausal women.
METHODS: This was a randomized, placebo-controlled, double-blind trial with 2-year follow-up at 9 United States clinical centers. The study population comprised 417 postmenopausal women, aged 60–80 years, with intact uterus and bone mineral density z scores of –2.0 or higher, who were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). All participants received calcium and vitamin D supplementation. Lumbar spine and total hip bone mineral density change was measured by dual-energy X-ray absorptiometry; endometrial hyperplasia incidence was assessed by endometrial biopsy.
RESULTS: Median plasma estradiol level in the estradiol group increased from 4.8 pg/mL at baseline to 8.5 pg/mL at 1 year (P < .001 versus baseline) and to 8.6 pg/mL at 2 years (P < .001 versus baseline) and was unchanged in the placebo group. Lumbar spine bone mineral density increased 2.6% in the estradiol group and 0.6% in the placebo group (between-group difference 2.0%, P < .001). Mean total hip bone mineral density increased 0.4% in the estradiol group and decreased 0.8% in the placebo group (between-group difference 1.2%, P < .001). Osteocalcin levels and bone-specific alkaline phosphatase were lower in the estradiol group than the placebo group (P < .001 each). Endometrial hyperplasia developed in 1 woman in the estradiol group but in none of the placebo group (difference in 2-year rates 0.5%, 95% confidence interval 0–7.3%).
CONCLUSION: Postmenopausal treatment with low-dose, unopposed estradiol increased bone mineral density and decreased markers of bone turnover without causing endometrial hyperplasia.
LEVEL OF EVIDENCE: I
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