title: Safety assessment of raloxifene over eight years in a clinical trial setting.
abstract: OBJECTIVE
  Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting.
  
  
  METHODS
  Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4-year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4-year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test.
  
  
  RESULTS
  Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93-3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (p = 0.028, p < 0.001, and p = 0.008, respectively).
  
  
  CONCLUSIONS
  These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.
authors.affiliation: The Angeles Clinic and Research Institute, Santa Monica, CA 90404, USA. smartino@cimg.theangelesclinic.org
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: Damon
authors.initials: D
authors.lastname: Disch
authors.forename: Sherie A
authors.initials: SA
authors.lastname: Dowsett
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Keech
authors.forename: John L
authors.initials: JL
authors.lastname: Mershon
mesh_terms: D000368:Aged; D015519:Bone Density / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D010919:Placebos; D020849:Raloxifene Hydrochloride / Q000009:adverse effects* / Q000627:therapeutic use; D012449:Safety; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects* / Q000627:therapeutic use; D020246:Venous Thrombosis / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D010919:Placebos; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride