Analysis

Ten years too long: strontium ranelate, cardiac events, and the European Medicines Agency

BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i5109 (Published 30 September 2016) Cite this as: BMJ 2016;354:i5109
  1. Mark J Bolland, associate professor of medicine,
  2. Andrew Grey, associate professor of medicine
  1. Department of Medicine, University of Auckland, Private Bag 92 019, Auckland 1142, New Zealand
  1. Correspondence to: M Bolland m.bolland{at}auckland.ac.nz
  • Accepted 19 September 2016

Delays in acting on cardiovascular safety concerns of the osteoporosis drug strontium ranelate have placed patients at risk, argue Mark Bolland and Andrew Grey

Strontium ranelate was registered in Europe in 2004 for postmenopausal osteoporosis. Sales reached about €200m (£170m; $220m) a year by 2010,1 with 3.4 million patient years of use by February 2013.2 In April 2013 the European Medicines Agency (EMA) reported that strontium increased the risk of myocardial infarction.2 Surprisingly, this was driven by the results of TROPOS, a phase III trial completed in November 2003, almost 10 years earlier. No further large clinical trials of strontium had been conducted, and cardiac safety concerns were not mentioned in previous trial publications or publicly available regulatory documents (fig 1).3

Fig 1 Timeline of key trials and regulatory events for strontium ranelate. PRAC=Pharmacovigilance Risk Assessment Committee. CHMP=Committee for Medicinal Products for Human Use.

To understand how it could take 10 years for an important adverse effect to be reported, we requested the clinical safety reports (CSRs, box 1) of the two phase III trials, SOTI and TROPOS. Our request was declined by the EMA on the grounds of commercial sensitivity, but we successfully appealed. The CSRs, together with data derived from safety assessments carried out by the EMA in 2006-07, confirm that the agency identified cardiac safety concerns in 2007 but did not report them, raising concerns about the regulatory process.

Box 1: EMA definitions, documents, and committees

  • Adverse event—Any untoward medical occurrence in a patient or clinical trial participant given a medicinal product that does not necessarily have a causal relationship with treatment

  • Adverse reaction—A response to a medicinal product that is noxious and unintended. A causal relationship between the product and an adverse event is at least a reasonable possibility

  • Serious adverse reaction—An adverse reaction …

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