title: A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record.
abstract: OBJECTIVE
  Recently, the European Medicines Agency reported that strontium ranelate increases myocardial infarction risk in postmenopausal women, 8.5 years after it was registered for use in osteoporosis. Unreported serious adverse events in clinical trials for other pharmaceuticals have been described in recent years. We assessed reporting of adverse events and fracture efficacy of strontium.
  
  
  METHODS
  We compared data on adverse effects (myocardial infarction, venous thromboembolism and pulmonary embolism) and fracture efficacy of strontium in publicly available regulatory documents with data in publications retrieved from searching PubMed.
  
  
  RESULTS
  We identified 5 regulatory documents and 9 primary publications of 7 randomised, placebo-controlled trials of strontium that reported relevant data. We identified several areas of concern in these reports: the increased risk of myocardial infarction with strontium was not identified in a pivotal phase 3 clinical trial despite specific regulatory review of cardiovascular events; data on myocardial infarction were not included in any primary publication; increased risks of venous thromboembolism and pulmonary embolism with strontium were not reported in either of the phase 3 clinical trials; data on venous thromboembolism were reported in only 5 of 9 primary publications, data on pulmonary embolism in only 2 of 9 primary publications, and either was discussed in <50% of subsequent review articles. There were differences in participant numbers, fracture cases and venous thromboembolism cases between regulatory documents and primary publications. Based on all available data from primary publications and regulatory documents, the number of fractures prevented by strontium use is similar to the number of extra cases of venous thromboembolism, pulmonary embolism and myocardial infarction caused by strontium use.
  
  
  CONCLUSIONS
  The risks of strontium use are similar to the benefits. Full disclosure of the clinical trial data and regulatory documents would allow clinicians and their patients to decide whether use of the drug is worthwhile.
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bolland
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grey
mesh_terms: D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004335:Drug and Narcotic Control; D006801:Humans; D009203:Myocardial Infarction / Q000139:chemically induced*; D010024:Osteoporosis / Q000150:complications / Q000188:drug therapy*; D058866:Osteoporotic Fractures / Q000209:etiology / Q000517:prevention & control*; D010506:Periodicals as Topic; D011655:Pulmonary Embolism / Q000139:chemically induced*; D058028:Research Report; D018570:Risk Assessment; D013876:Thiophenes / Q000009:adverse effects* / Q000627:therapeutic use; D054556:Venous Thromboembolism / Q000139:chemically induced*
chemical_list: D050071:Bone Density Conservation Agents; D013876:Thiophenes; C081587:strontium ranelate
keywords: GERIATRIC MEDICINE; STATISTICS & RESEARCH METHODS