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Results From a 3-Year Randomized Clinical Trial

Bruce Ettinger, MD; Dennis M. Black, PhD; Bruce H. Mitlak, MD; Ronald K. Knickerbocker, PhD; Thomas Nickelsen, MD; Harry K. Genant, MD; Claus Christiansen, MD; Pierre D. Delmas, MD, PhD; Jose R. Zanchetta, MD; Jacob Stakkestad, MD; Claus C. Glüer, PhD; Kathryn Krueger, MD; Fredric J. Cohen, MD; Stephen Eckert, PhD; Kristine E. Ensrud, MD, MPH; Louis V. Avioli, MD; Paul Lips, MD, PhD; Steven R. Cummings, MD; for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators

JAMA. 1999;282:637-645.

Context  Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known.

Objective  To determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures.

Design  The Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial.

Setting and Participants  A total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events.

Interventions  Participants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol.

Main Outcome Measures  Incident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry.

Results  At 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [CI], 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1% (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P<0.001 for all comparisons). Women receiving raloxifene had increased risk of venous thromboembolus vs placebo (RR, 3.1; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer.

Conclusions  In postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture.

Author Affiliations: Division of Research, Kaiser Permanente, Oakland, Calif (Dr Ettinger) and Departments of Epidemiology and Biostatistics (Drs Black and Cummings), Radiology (Dr Genant), and Medicine (Dr Cummings), University of California, San Francisco; Eli Lilly and Co, Indianapolis, Ind (Drs Mitlak, Knickerbocker, Nickelsen, Krueger, Cohen, and Eckert); Center for Clinical and Basic Research, Ballerup, Denmark (Dr Christiansen); INSERM, Lyon, France (Dr Delmas); Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina (Dr Zanchetta); Center for Clinical Osteoporosis Research CECOR AS, Haugesund, Norway (Dr Stakkestad); Department of Diagnostic Radiology, Cristian-Albrechts–Universität Kiel, Germany (Dr Glüer); Veterans Affairs Medical Center, Minneapolis, Minn (Dr Ensrud); Washington University, St Louis, Mo (Dr Avioli); and Vrije Universiteit, Amsterdam, the Netherlands (Dr Lips).

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