Raloxifene, in a dosage of 60 mg daily, is effective in the prevention of osteoporosis. This selective estrogen receptor modulator (SERM) has been shown in animals to stimulate the endometrium minimally, if at all, but data on the endometrial effects in humans are limited. Davies and associates analyzed data from six clinical trials of raloxifene to evaluate the endometrial effects as assessed by vaginal bleeding and endometrial thickness.

Data were available on 1,157 women who participated in six clinical trials of raloxifene. Placebo-controlled data were obtained from three double-blind randomized trials. Data were also analyzed from a 24-month open-label, randomized controlled trial of cyclic hormone replacement therapy (HRT) and a six-month double-blind randomized estrogen-controlled trial.

Common to all six trials was a raloxifene dosage of 60 mg per day. The estrogen used in the cyclic HRT-controlled trial and the unopposed estrogen-controlled trial was conjugated estrogen, in a dosage of 0.625 mg per day. The progestin used in the HRT regimen was medroxyprogesterone acetate, in a dosage of 5 mg per day, or norgestrel, in a dosage of 0.15 mg per day, which was taken on the 17th through 28th days of the cycle. Because the endometrial data were similar in both progestin groups, the data were pooled for this study.

In the three placebo-controlled trials, no statistically significant difference was observed in the percentage of women who reported vaginal bleeding in the raloxifene and placebo groups at any time during the studies. At six, 12 and 30 months, the incidence of vaginal bleeding was 2.5, 3.6 and 4.4 percent, respectively, in the placebo group, compared with an incidence of 2.3, 2.8 and 2.8 percent, respectively, in the raloxifene group.

In the HRT-controlled and estrogen-controlled trials, the incidence of vaginal bleeding was significantly greater in the hormone therapy groups. After 24 months of HRT, vaginal bleeding was reported by 88.8 percent of the 205 patients in the HRT group, compared with 9.6 percent of the 208 patients in the raloxifene group. In the estrogen-controlled trial, which included 33 patients, 50 percent of the 14 patients in the estrogen group reported bleeding, compared with none of the 19 patients in the raloxifene group.

In the three placebo-controlled trials, the mean change from baseline in endometrial thickness was not significantly different between the raloxifene and placebo groups. In the hormone-controlled trials, significant increases in endometrial thickness occurred in women who received cyclic HRT or unopposed estrogen compared with that noted in patients who received raloxifene.

To evaluate whether raloxifene produced subtle (less than 5 mm) changes in endometrial thickness, the proportion of women with endometrial thickness increases of 1, 2, 3, 4 and 5 mm was compared in the raloxifene and placebo groups. No significant differences between raloxifene and placebo were noted for any increase in thickness at 12 or 24 months.

Among patients in whom endometrial biopsy was performed, no cases of endometrial hyperplasia or cancer were identified in the placebo or raloxifene groups. In the HRT-controlled trial, one case of endometrial hyperplasia without atypia was diagnosed in the HRT group. In the estrogen-controlled trial, two cases of hyperplasia without atypia were diagnosed in the estrogen group after six months of therapy.

The authors conclude that raloxifene in a dosage of 60 mg per day is not associated with an increased incidence of vaginal bleeding or increased endometrial thickness. The results provide further evidence for the lack of endometrial effects with raloxifene through at least 30 months of use. Raloxifene differs significantly from tamoxifen with regard to endometrial activity.

editor's note: A common reason for discontinuation of HRT in postmenopausal women is unscheduled and unwanted vaginal bleeding. Many women receiving cyclic HRT have withdrawal bleeding. One of the major benefits of raloxifene for prevention of osteoporosis may be not only a lack of endometrial proliferation but also the absence of unscheduled vaginal bleeding.—b.a.