Estrogen therapy recently has been shown to increase the risk of breast cancer, heart disease, stroke, and deep venous thrombosis, but it also decreases the risk of hip fracture. While conventional dosages of estrogen therapy reduced bone loss and bone turnover, lower dosages of estrogen appear to have an equally beneficial effect without adverse events when taken with adequate dosages of calcium and vitamin D. Prestwood and colleagues designed a study to determine the long-term effects of 0.25 mg a day of 17-beta-estradiol treatment on bone, as well as to establish the safety profile of this dosage.

Participants were healthy community-dwelling women with no recent estrogen or calcitonin use and no past bisphosphonate use. The women were randomized to receive 17-beta-estradiol or placebo. All women who had not had a hysterectomy also received 100 mg a day of micronized progesterone for two weeks every six months. All participants also received 1,300 mg a day of elemental calcium and 1,000 IU a day of vitamin D. The primary outcome was bone mineral density (BMD) of the hip, measured at baseline and annually for three years. Spine, wrist, and total-body BMD also were evaluated. Bone turnover was evaluated by measuring various markers and sex hormones. Endometrial thickness was evaluated at baseline, and all women were asked to undergo endometrial biopsies at three years, as well as annual mammography. Adverse effects were otherwise assessed by questionnaire.

Of the 167 women included in the study, 31 (37 percent) discontinued participation in the placebo group and 24 (29 percent) discontinued participation in the 17-beta-estradiol group. Low-dose estrogen significantly increased bone density at all BMD sites compared with placebo. Women who received progesterone had the same changes as those who did not. The estradiol group had significantly lower markers of bone turnover than the placebo group. Endometrial thickness increased slightly in both groups over the three years, with a significant difference found only at two years. There was no statistically significant difference in endometrial biopsy categories between the two groups. There were no significant differences in adverse symptoms or the total number of abnormal mammogram results in the two groups.

This study is the first to demonstrate that ultra-low-dose estrogen can increase BMD over the long term. A daily dose of 0.25 mg of 17-beta-estradiol increased BMD at the hip, spine, and wrist, and decreased markers of bone turnover in a three-year period. The side-effect profile was similar to that of placebo. Higher estradiol levels may not provide additional benefit to bone while increasing risk of adverse events. The authors call for longer studies to establish the efficacy of low dosages of estrogen in preventing fractures.