Fredric J. Cohen

IN SEARCH OF OPTIMAL LONG-TERM FEMALE HORMONE REPLACEMENT : THE POTENTIAL OF SELECTIVE ESTROGEN RECEPTOR MODULATORS

Selective estrogen receptor modulators (SERMs) comprise a group of structurally diverse compounds which are distinguished from estrogens by their ability to interact with the estrogen receptor but to act as either an estrogen agonist or antagonist depending on the target tissue and hormonal milieu. The mechanisms by which SERMs elicit tissue-specific responses are being intensively investigated, and recently a novel pathway for estrogen receptor-mediated gene activation by the SERM raloxifene has been demonstrated. The tissue-specific activity of SERMs suggests that they may be clinically useful as, for example, potential substitutes for long-term female hormone replacement therapy. Large-scale clinical testing currently in progress for raloxifene, and soon to begin for other SERMs, will evaluate this important potential.

Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60.

Objective To assess the uterine effects of 3 years of therapy with raloxifene in healthy, postmenopausal women under age 60. Methods Integrated data from two identically designed, randomized, double-masked, placebo-controlled clinical trials were analyzed. Nine hundred sixty-nine healthy women with uteri (ages 45 through 60, 2 to 8 years postmenopausal) were assigned randomly to raloxifene 30, 60, or 150 mg per day, or an identical placebo for 3 years. Endometrial thickness was evaluated with transvaginal ultrasonography every 6 months for 2 years and again after 3 years. Further uterine evaluation, including endometrial sampling if necessary, was initiated for vaginal bleeding or findings of endometrial thickness greater than 5 mm. Results Endometrial thickness was unchanged by raloxifene and not significantly different from placebo at any time. One hundred seventy-two women had at least one episode of endometrial thickness greater than 5 mm or vaginal bleeding distributed equally among all groups. A total of 102 (10.5%) women underwent endometrial sampling at least once: 15 (1.5%) for vaginal bleeding, 78 (8.0%) for endometrial thickness greater than 5 mm, and nine (0.9%) for other reasons. There were no significant treatment differences in the proportion of women sampled, in the clinical findings, or in the histologic diagnoses. Conclusion Raloxifene given to healthy postmenopausal women at doses from 30 to 150 mg per day does not stimulate uterine growth and does not cause vaginal bleeding, spotting, or discharge through 3 years of therapy. Thus, any bleeding during therapy should be deemed unexpected and prompt a clinical evaluation.

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.

Reduction of Vertebral Fracture Risk in Postmenopausal Women With Osteoporosis Treated With Raloxifene: Results From a 3-year Randomized Clinical Trial

Raloxifene is a selective estrogen receptor modulator that has been shown to prevent bone loss in postmenopausal women. Whether it also reduces the risk of fracture remains uncertain, prompting the present trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The randomized, blinded, placebo-controlled trial enlisted 7705 women in 25 countries, ranging in age from 31 to 80 years, who had been postmenopausal for 2 years or longer and met World Health Organization criteria for osteoporosis. Participants were assigned to receive raloxifene in a daily dose of 60 or 120 mg or placebo pills, and, in addition, all of them were given supplemental calcium and cholecalciferol. Follow-up extended for at least 3 years. Baseline and follow-up radiographs were available for 89 percent of women entering the study. One or more new vertebral fractures developed in 7.4 percent of women within 3 years of entry into the study. Those given raloxifene had fewer new fractures, regardless of whether fractures were present at the outset. No overall dose-related difference was found, although women with baseline fractures had fewer new lesions when given the higher dose of raloxifene. The rate of nonvertebral fracture at 3 years was 9.3 percent in the placebo group and 8.5 percent for raloxifene-treated women. Bone mineral density increased by 2 to 3 percent at various sites in the raloxifene group compared with the placebo group. Nearly one fourth of women had serious adverse effects regardless of treatment assignment, but the only ones considered causally related to raloxifene were deep thrombophlebitis and pulmonary embolism. This developed in 1 percent of each dose group and in 0.3 percent of placebo patients. Breast cancer was less frequent in women given raloxifene. Withdrawals due to adverse events were slightly more frequent in the raloxifene group than in the placebo group (10.3 vs. 8.8 percent). Hot flashes were the most common nonserious adverse event. No clinically important renal, hepatic, or hematological abnormalities were noted. These findings indicate that raloxifene treatment over 3 years not only preserves bone mass but also lowers the risk of new vertebral fractures in postmenopausal women with osteoporosis, regardless of whether they have had fractures before starting treatment. J Am Med Assoc 1999;282:637–645