title: Clinically favorable effects of raloxifene on bone mineral density and serum lipids: population assessment via bivariate analysis.
abstract: Introduction: Raloxifene is a nonsteroidal benzothiophene derivative that is classified as a selective estrogen receptor modulator (SERM). It has clinical promise because of its actions as an estrogen-agonist on bone and serum lipids and an estrogen-antagonist on the breast and uterus.Objectives: To determine the percentage of women who respond to raloxifene therapy with regard to bone mineral density (BMD) and serum low density lipoprotein cholesterol (LDL-C) concentration in a large population of healthy postmenopausal women.Methods: Pooled 24-month interim data from two multicenter, placebo-controlled, double-blind phase III studies were used in this analysis. The study population included 1145 healthy women, 45-60 years of age and 2-8 years postmenopausal, randomized to receive either placebo, raloxifene (RLX) 30 mg/day, RLX 60 mg/day, or RLX 150 mg/day. Changes in BMD, measured by dual x-ray absorptiometry, and serum LDL-C concentration, measured by enzymatic assay, were analyzed simultaneously by plotting the median percentage change (baseline to endpoint) in BMD of the lumbar spine and total hip on the y-axis against the corresponding median percentage change in serum LDL-C on the x-axis for each subject in the placebo group and each of the raloxifene groups. The data localized to one of four quadrants on the plot, the upper-left quadrant representing clinically favorable shifts (increased BMD and decreased LDL-C) and the lower-right quadrant representing clinically unfavorable shifts (decreased BMD and increased LDL-C). The bivariate mean, 50th and 95th percentile ellipses, and the percentage of patients improving in one, both, or neither of the measured parameters are displayed.Results: At the end of 24 months, the bivariate mean and the 50th and 95th percentile ellipses of the placebo group for lumbar spine BMD and LDL-C were shifted to the clinically unfavorable quadrant of the plot, reflecting a decrease in BMD and an increase in LDL-C. In contrast, the bivariate mean for all raloxifene groups had shifted to the clinically favorable quadrant of the plot, reflecting an increase in BMD and a decrease in LDL-C. There was a statistically significant difference (Hotelling-Lawley test, P <.001) in the bivariate mean for all doses of raloxifene compared to placebo. Only 19.1% of subjects in the placebo group exhibited improvement in both lumbar spine BMD and LDL-C, whereas 43.5%, 47.4%, and 49.8% of subjects in the RLX 30, RLX 60, and RLX 150 group, respectively, exhibited improvement in both of these variables. Furthermore, 35.9% of subjects in the placebo group exhibited no improvement in either lumbar spine BMD or LDL-C, whereas only 13.7%, 10.1%, and 11.6% of subjects in the RLX 30, RLX 60, and RLX 150 groups, respectively, exhibited no improvement in either of these variables. Similar results were obtained comparing total hip BMD and LDL-C.Conclusions: Compared with placebo, raloxifene has beneficial effects on BMD and LDL-C in a large sample of healthy postmenopausal women. Thus, insofar as these intermediate endpoints predict disease outcomes, long-term therapy with raloxifene may be beneficial in the prevention of osteoporosis and cardiovascular diseases.
authors.initials: A
authors.lastname: Shah
authors.initials: P
authors.lastname: Iversen
authors.initials: B
authors.lastname: Mitlak