Ronald Keith Knickerbocker

Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial.

Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascular systems. We conducted a 1‐year prospective, randomized, double‐blind trial in 143 postmenopausal osteoporotic women (mean ± SD age, 68.4 ± 5.0 years) with at least one prevalent vertebral fractures and low bone mineral density (BMD), comparing groups receiving raloxifene at 60 mg/day (RLX60) or 120 mg/day (RLX120) and a control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D. There were no differences among groups in the occurrence of uterine bleeding, thrombophlebitis, breast abnormalities, or increased endometrial thickness (assessed by ultrasonography). As compared with controls, the changes in values over 1 year for RLX60 and RLX120, respectively, were significant for serum bone alkaline phosphatase (−14.9%, −8.87%), serum osteocalcin (−20.7%, −17.0%), and urinary C‐telopeptide fragment of type I collagen/creatinine (−24.9%, −30.8%), markers of bone turnover; for serum total cholesterol (−7.0% for RLX60) and low density lipoprotein cholesterol (LDL) (−11.4% for RLX60) and for the LDL/HDL cholesterol ratio (−13.2%, −8.3%). BMD increased significantly in the total hip (1.66% for RLX60) and ultradistal radius (2.92%, 2.50%). There were nonsignificant trends toward increases over controls in BMD for lumbar spine, total body, and total hip (for RLX120). Using a >15% cutoff definition, raloxifene had no effect on incident fractures, but using a >30% cutoff, there was a dose‐related reduction (p = 0.047). We conclude that raloxifene therapy is well tolerated, reduces serum lipids, and does not stimulate the uterus or breasts. It has beneficial effects on bone, although, under the conditions of this study, these appear to be of a smaller magnitude than have been reported with estrogen therapy.

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