Effects of Ultralow-Dose Transdermal Estradiol on Bone Mineral Density: A Randomized Clinical Trial

University of California, San Francisco, San Francisco, California, United States
Obstetrics and Gynecology (Impact Factor: 5.18). 10/2004; 104(3):443-51. DOI: 10.1097/01.AOG.0000137833.43248.79
Source: PubMed


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.
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.
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%).
Postmenopausal treatment with low-dose, unopposed estradiol increased bone mineral density and decreased markers of bone turnover without causing endometrial hyperplasia.

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    • "Results from a number of trials have shown that lower doses of HT are effective in improving BMD in the hip and lumbar spine (Table 2) [39–47]. In a substudy (n = 822) of the Women's Health, Osteoporosis, Progestin, Estrogen (HOPE) trial, standard and lower doses of orally administered CEE alone or in combination with MPA resulted in significant improvements from baseline (1.33–3.46%) in spine and hip BMD, as well as biochemical markers of bone turnover in healthy postmenopausal women within 4 years since the onset of menopause [40]. "
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    • "Transdermal estrogen therapies have long been shown to be effective in maintaining or increasing bone mineral density among menopausal women (Samsioe 2004). However, the study by Ettinger and colleagues (2004) showing beneficial bone mineral density effects of an “ultralow-dose” transdermal estradiol patch provides important information to women and clinicians considering osteoporotic preventive and therapeutic options. Ettinger and colleagues were able to show in this randomized, placebo-controlled trial that a transdermal patch delivering 0.014 mg/d, did not impact vasomotor symptomatology but did increase lumbar spine bone mineral density by 2.6% versus 0.6 in the placebo group (p < 0.001) and did increase total hip bone mineral density by 0.4% compared to a 0.8% reduction among women in the placebo group (p < 0.001). "
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