Aarti Shah

Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.

BACKGROUND Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues. METHODS We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women. The women were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months. RESULTS The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine, hip, and total body, whereas those receiving placebo had decreases in bone mineral density. For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change. Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study. The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo. CONCLUSIONS Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.

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.

Raloxifene HCl is not stimulatory in the endometrium as assessed by the blaustein criteria and an estrogenicity scoring system

Introduction: Raloxifene, a selective estrogen receptor modulator (SERM), acts as an estrogen agonist in the bone and on serum lipids and an estrogen antagonist in breast tissue. The effect of raloxifene on the endometrium of postmenopausal women is a key factor in determining its clinical application.Objectives: The objectives are to determine and compare the histologic outcomes of endometrial samples from healthy postmenopausal women receiving either a high dose of raloxifene or hormone replacement therapy (HRT).Design: The current study is a 24-month, multicenter, double-blind, randomized study of 136 healthy postmenopausal women randomized to receive either raloxifene 150 mg/day (RLX) or continuous combined HRT (Premarin(R) 0.625 mg/day and Provera(R) 2.5 mg/day).Materials and Methods: Endometrial samples obtained by Pipelle biopsy at baseline and endpoint were evaluated using Blausteins criteria (Kurman RJ, editor Blausteins pathology of the female genital tract. 1994), which is composed of descriptive diagnostic categories and a newly developed estrogenicity scoring system to quantify subtle morphologic changes in the postmenopausal endometrium (Boss et al. Am J Obstet Gynecol, in press). All subjects with adequate baseline and post-baseline endometrial samples were included in the analyses. The results from the 12-month interim analyses are reported and the Blausteins criteria and the estrogenicity scoring system are compared.Results: Overall, 95.2% of the baseline biopsies were normal. At endpoint 30.6% of the subjects in the HRT group with normal baseline biopsies developed proliferative endometrium and 2.8% developed a polyp, while none in the RLX group developed either. Histological evaluation of stromal and glandular features revealed substantially lower estrogenicity scores in the RLX group. As shown in the table, a high degree of agreement was observed between the estrogen effect grades and the Blausteins descriptive diagnostic categories at endpoint as shown by a Spearman correlation coefficient of 0.75 and a Kappa coefficient of 0.91.Conclusion: Results from the 12-month interim analyses reveal that, in contrast to HRT, raloxifene does not have stimulatory effects on the endometrium. Also, there is high degree of agreement between Blausteins criteria and the estrogenicity scoring system used to evaluate endometrial histology.

What is Mentoring

ABSTRACT What is mentoring? Is it just a buzz word or is this really valuable? How can mentoring help one to grow and advance personally and professionally? How and where does one even begin? Many of us have these questions. In this article, I will share my perspective and provide some reflections on these questions based on my own personal and professional journey.

Statistical and Operational Issues Arising in an Interim Analysis When the Study Will Continue

Guidelines for conducting interim analyses in clinical trials sponsored by the pharmaceutical industry have been recently published (1). Usually, the clinical trial will terminate or the design will change when the interim analysis shows outstanding efficacy results. There are situations, however, where the interim analysis shows outstanding efficacy results and yet the study continues, for example, when regulatory requirements in the United States and Europe differ concerning study duration. A case study is presented which describes the statistical and operational issues encountered while performing a two-year interim analysis of a three-year registration study when the study was to continue to the three-year timepoint with the same design regardless of the outcome of the interim analysis. The statistician plays a central role in developing and implementing the strategy to effectively resolve these issues.

Clinically favorable effects of raloxifene on bone mineral density and serum lipids: population assessment via bivariate analysis

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.