Bolland Mark J, Grey Andrew
Department of Medicine, University of Auckland, Auckland, New Zealand.
BMJ Open. 2014 Oct 7;4(10):e005787. doi: 10.1136/bmjopen-2014-005787.
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.
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.
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.
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.
最近，欧洲药品管理局报告称，雷奈酸锶在用于治疗骨质疏松症注册8.5年后，增加了绝经后女性心肌梗死的风险。近年来，已报道了其他药物在临床试验中未报告的严重不良事件。我们评估了雷奈酸锶不良事件的报告情况及其骨折疗效。
我们将公开的监管文件中有关雷奈酸锶不良反应（心肌梗死、静脉血栓栓塞和肺栓塞）及骨折疗效的数据，与通过检索PubMed获得的出版物中的数据进行了比较。
我们识别出5份监管文件以及7项雷奈酸锶随机、安慰剂对照试验的9篇主要出版物，这些文献报告了相关数据。我们在这些报告中发现了几个值得关注的领域：尽管对心血管事件进行了专门的监管审查，但在一项关键的3期临床试验中未发现雷奈酸锶增加心肌梗死风险；任何主要出版物均未纳入心肌梗死的数据；两项3期临床试验均未报告雷奈酸锶增加静脉血栓栓塞和肺栓塞的风险；9篇主要出版物中只有5篇报告了静脉血栓栓塞的数据，只有2篇报告了肺栓塞的数据，且在随后的综述文章中，讨论这两种情况的均不到50%。监管文件与主要出版物之间在参与者数量、骨折病例和静脉血栓栓塞病例方面存在差异。根据主要出版物和监管文件中的所有可用数据，使用雷奈酸锶预防的骨折数量与使用雷奈酸锶导致的静脉血栓栓塞、肺栓塞和心肌梗死额外病例数量相似。
使用雷奈酸锶的风险与益处相似。全面披露临床试验数据和监管文件将使临床医生及其患者能够决定使用该药物是否值得。
