Somnath Sarkar

Relationships Between Bone Mineral Density and Incident Vertebral Fracture Risk with Raloxifene Therapy

Although low absolute values of bone mineral density (BMD) predict increased fracture risk in osteoporosis, it is not certain how well increases in BMD with antiresorptive therapy predict observed reductions in fracture risk. This work examines the relationships between changes in BMD after 1 year or 3 years of raloxifene or placebo therapy and the risk for new vertebral fractures at 3 years. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis were randomized to placebo or raloxifene 60 mg/day or 120 mg/day. Relationships between baseline BMD and changes in BMD from baseline with the risk of new vertebral fractures were analyzed in this cohort using logistic regression models with the raloxifene doses pooled. As has been observed in other populations, women with the lowest baseline lumbar spine or femoral neck BMD in the MORE cohort had the greatest risk for vertebral fractures. Furthermore, for any percentage change, either increase or decrease in femoral neck or lumbar spine BMD at 1 year or 3 years, raloxifene‐treated patients had a statistically significantly lower vertebral fracture risk compared with placebo‐treated patients. The decrease in fracture risk with raloxifene was similar across the range of percentage change in femoral neck BMD observed at 3 years; patients receiving raloxifene had a 36% lower risk of vertebral fracture compared with those receiving placebo. At any percentage change in femoral neck and lumbar spine BMD observed at 1 year, raloxifene treatment decreased the risks of new vertebral fractures at 3 years by 38% and 41%, respectively. The logistic regression model showed that the percentage changes in BMD with raloxifene treatment accounted for 4% of the observed vertebral fracture risk reduction, and the other 96% of the risk reduction remains unexplained. The present data show that the measured BMD changes observed with raloxifene therapy are poor predictors of vertebral fracture risk reduction with raloxifene therapy.

Cognitive function in postmenopausal women treated with raloxifene.

Background In postmenopausal women, estrogen may have a beneficial effect on cognition or reduce the risk of decline in cognitive function. Whether raloxifene, a selective estrogen-receptor modulator, might have similar actions is not known. Methods As part of the Multiple Outcomes of Raloxifene Evaluation trial, we studied 7478 postmenopausal women with osteoporosis (mean age, 66 years), who were enrolled at 178 sites in 25 countries. The women were randomly assigned to receive raloxifene (60 mg or 120 mg) or placebo daily for three years. We compared the mean scores of the groups on six tests of cognitive function, which were administered at base line and at six months and one, two, and three years. Women were classified as having a decline in cognitive function if the change in their scores at three years was in the worst 10 percent. Results The mean cognitive scores in the three groups of women were similar at base line. The scores improved slightly in all three groups during the three-year study peri...

Relationship Between Changes in Biochemical Markers of Bone Turnover and BMD to Predict Vertebral Fracture Risk

The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One‐year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD.

Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis : a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial

Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.

Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation.

OBJECTIVE: To examine the effect of raloxifene on major adverse events that occur with postmenopausal estrogen therapy or tamoxifen. METHODS: The Multiple Outcomes of Raloxifene Evaluation, a multicenter, randomized, double-blind trial, enrolled 7,705 postmenopausal women with osteoporosis. Women were randomly assigned to raloxifene 60 mg/d or 120 mg/d or placebo. Outcomes included venous thromboembolism, cataracts, gallbladder disease, and endometrial hyperplasia or cancer. RESULTS: During a mean follow-up of 3.3 years, raloxifene was associated with an increased risk for venous thromboembolism (relative risk [RR] 2.1; 95% confidence interval [CI] 1.2–3.8). The excess event rate was 1.8 per 1,000 woman-years (95% CI −0.5–4.1), and the number needed to treat to cause 1 event was 170 (95% CI 100–582) over 3.3 years. Risk in the raloxifene group was higher than in the placebo group for the first 2 years, but decreased to about the same rate as in the placebo group thereafter. Raloxifene did not increase risk for cataracts (RR 0.9; 95% CI 0.8–1.1), gallbladder disease (RR 1.0; 95% CI 0.7–1.3), endometrial hyperplasia (RR 1.3; 95% CI 0.4–5.1), or endometrial cancer (RR 0.9; 95% CI 0.3–2.7). CONCLUSION: Raloxifene was associated with an increased risk for venous thromboembolism, but there was no increased risk for cataracts, gallbladder disease, endometrial hyperplasia, or endometrial cancer. LEVEL OF EVIDENCE: I

Monte Carlo Approximation of Bootstrap Variances

Abstract It is widely believed that the number of resamples required for bootstrap variance estimation is relatively small An argument based on the unconditional coefficient of variation of the Monte Carlo approximation, suggests that as few as 25 resamples will give reasonable results. In this article we argue that the number of resamples should, in fact, be determined by the conditional coefficient of variation, involving only resampling variability. Our conditional analysis is founded on a belief that Monte Carlo error should not be allowed to determine the conclusions of a statistical analysis and indicates that approximately 800 resamples are required for this purpose. The argument can be generalized to the multivariate setting and a simple formula is given for determining a lower bound on the number of resamples required to approximate an m-dimensional bootstrap variance-covariance matrix.

Antiresorptive treatment of postmenopausal osteoporosis: review of randomized clinical studies and rationale for the Evista alendronate comparison (EVA) trial.

SUMMARY Standard pharmacological antiresorptive therapy for the prevention and/or treatment of postmenopausal osteoporosis now consists of four categories of drugs: estrogens, a selective estrogen receptor modulator (SERM), bisphosponates, and calcitonin. All of these drugs have been studied in randomized controlled trials, but meaningful comparisons of the efficacy of drugs have been difficult due to differences in baseline risks for fracture and differences in study design, including calcium and vitamin D supplementation, definition of fracture, and discontinuation rates. The current paper reviews results from pivotal studies of antiresorptive therapies with fracture as a primary endpoint, as well as head-to-head trials comparing these therapies using surrogate markers of fracture risk, and introduces the first head-to-head trial with fracture as a primary endpoint. The Evista* Alendronate Comparison (EVA) trial, a multi-center, double-blind, double-dummy, randomized trial with two active treatment arms is currently underway to compare directly the osteoporotic fracture risk reduction efficacy of raloxifene and alendronate in postmenopausal women with osteoporosis as defined by bone mineral density. The results from this trial will permit more informed judgment by practitioners and provider groups concerning the relative clinical utility of these two drugs. * Evista is a registered trade name of Eli Lilly and Company, Indianapolis, IN, USA

Effect of raloxifene on serum triglycerides in postmenopausal women: Influence of predisposing factors for hypertriglyceridemia

BACKGROUND Estrogen increases serum triglyceride (TG) levels and induces hypertriglyceridemia in susceptible women. The effect of raloxifene (RLX), a selective estrogen-receptor modulator, on serum TG has not been studied in detail. OBJECTIVE The purpose of this study was to examine the effect of RLX on serum TG levels in postmenopausal women with and without osteoporosis, including those with predisposing factors for hypertriglyceridemia. METHODS Fasting serum TG levels were assessed over 36 months in 2738 osteoporotic postmenopausal women (mean age, 67 years) assigned to placebo or RLX (60 or 120 mg/d) in an osteoporosis treatment trial and over 24 months in 1318 postmenopausal women without osteoporosis (mean age, 54 years) assigned to placebo or RLX (60 or 150 mg/d) in 3 osteoporosis prevention trials. RESULTS In the osteoporosis treatment trial, the median serum TG concentration decreased in all groups, but significantly more in the placebo group (placebo, -3.4%; RLX 60 mg/d, -1.4%; RLX 120 mg/d, -1.3%; P = 0.002). In the osteoporosis prevention trials, the percentage change in median serum TG concentration was not significantly different among treatments (P = 0.22). Among women with varying degrees of hypertriglyceridemia at baseline (>2.82, >3.39, and >4.51 mmol/L), the median serum TG level at the end of the study decreased from baseline in all groups, with no significant differences among treatments (P > or = 0.13). The effect of RLX on serum TG level was not influenced by age, smoking status, use of alcohol, or presence of diabetes (P > or = 0.10 for all interactions). Among women in the highest tertile of body mass index (>26.4 kg/m2), RLX increased serum TG levels significantly compared with placebo (placebo, -3%; RLX 60 mg/d, 6%: RLX 120 mg/d, 4%; P < 0.05); the absolute increase from baseline with RLX in this subgroup was 0.05 mmol/L (4.4 mg/dL). CONCLUSIONS RLX did not increase serum TG in postmenopausal women overall or among women with elevated TG levels or evidence of diabetes at baseline. TG levels increased slightly but statistically significantly in women in the upper tertile of body mass index who were treated with RLX.

Effect of raloxifene on the incidence of elevated low density lipoprotein (LDL) and achievement of LDL target goals in postmenopausal women

SUMMARY Objective: To determine the extent to which raloxifene can maintain low density lipoprotein cholesterol (LDL-C) levels below 160 mg/dL or reduce elevated LDL-C levels to below lipidlowering goals in postmenopausal women. Patients and methods: The Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial randomized 7705 postmenopausal women to placebo or raloxifene (60 mg or 120 mg) daily for a core treatment phase of 3 years. Changes in LDL-C and other serum lipids in a subset of women was a predefined secondary objective. This post-hoc analysis included the 2413 women who did not take lipid-lowering medications at any time during the trial and for whom LDL-C measurements were available. The threshold for high LDL-C (≥ 160 mg/dL) and LDL-C lipid-lowering goals were defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines. Results: The percent of women with LDL-C < 160 mg/dL was comparable between treatment groups at baseline (placebo, 57.5%; raloxifene 60 mg, 56.4%; raloxifene 120 mg, 56.8%). At 3 years, the percent of these women whose LDL-C had increased to above 160 mg/dL was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 65% (95% CI, 44%–78%) and 64% (95% CI, 43%–77%), respectively. Among women with elevated (defined for these analyses as ≥ 160 mg/dL) LDL-C at baseline, the proportion having elevated LDL-C at 3 years was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 32% (95% CI, 24%–40%) and 40% (95% CI, 32%–48%), respectively. Fifty percent and 13% of these women achieved LDL-C goals of <160 mg/dL and <130 mg/dL, respectively (P <0.001 vs. placebo for both) in the raloxifene 60 mg group, with similar results for the raloxifene 120 mg group. Conclusions: In postmenopausal women with osteoporosis not taking concurrent lipid-lowering therapy, raloxifene significantly reduced the incidence of LDL-C ≥ 160 mg/dL and significantly increased the proportion achieving LDL-C goals for lipid-lowering compared with placebo. Whether these and other effects of raloxifene on cardiovascular risk markers will improve cardiovascular outcomes requires further study.

Relationships Between Bone Mineral Density and Incident Vertebral Fracture Risk With Raloxifene Therapy

Low bone mineral density (BMD) in osteoporotic patients predicts an increased risk of bone fracture, but it is not clear whether increasing BMD in those given antiresorptive drugs predicts a reduced risk. The investigators explored this relationship after 1 or 3 years of treatment with raloxifene or placebo in 7705 postmenopausal women with osteoporosis who participated in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial. Raloxifene was given in a daily dose of 60 or 120 mg. Logistic regression models were used to relate baseline BMD and changes in BMD to the risk of new vertebral fractures (Figs. 1 and 2). All women received supplemental calcium and vitamin D. BMD was estimated by dual-energy x-ray absorptiometry in the femoral neck and lumbar spine at yearly intervals. The risk of a new vertebral fracture was greatest in women having the lowest baseline BMD values at either measurement site. Raloxifene reduced the risk of incident vertebral fractures by 41% compared with the placebo group, regardless of baseline BMD at the femoral neck, but women with relatively low baseline lumbar spine BMD had the most marked reduction in fracture risk from raloxifene. After 3 years, raloxifene therapy was associated with increases of only 2% to 3% in BMD. Raloxifene-treated women had a significantly lower risk of spinal fracture than placebo patients regardless of the change in femoral neck BMD, and they also had a lower fracture risk at any percentage change in lumbar spine BMD. At the 75th percentile of the population, with a 6.1% increase in lumbar spinal BMD, the risk of incident vertebral fracture was reduced 52% by raloxifene therapy. With lesser increases in lumbar spine BMD at the 25th and 50th centiles, raloxifene lowered the risk of incident spinal fracture by 39% and 46%, respectively. These findings indicate that the percentage change in BMD in postmenopausal women treated with raloxifene account for only 4% of the observed reduction in risk of vertebral fracture. Not unexpectedly, changes in BMD during treatment are a poor predictor of risk reduction.