Research presents new evidence which strengthens the plausibility that treatment with the novel anti-osteoporotic medicine, romosozumab, may lead to excess cardiovascular complications.
Writing in Science Translational Medicine, the authors, from the University of Oxford's Big Data Institute and the Nuffield Department of Population Health, report that by combining data across clinical trials of romosozumab, there is some evidence that use of this drug leads to increased cardiovascular risk.
The team then analysed genetic data in more than one million people, and found that people whose DNA carried genetic markers that mimic the effect of romosozumab, a sclerostin blocker, had, on average, a 41% lower risk of sustaining a fracture but an 18% increased risk of heart attack, supporting the increased risk of heart attacks seen in the trials of romosozumab.
Dr Jonas Bovijn, first author of the study and from the Big Data Institute at the University of Oxford, said:
'Our findings support the warning labels issued by regulatory authorities such as the FDA and EMA, and suggest that the cardiovascular effects seen in some trials of this medicine are real.'
'This emphasizes the importance of conducting further rigorous clinical studies to evaluate the cardiovascular safety of this class of medicines.'
The investigators from the Big Data Institute and the Nuffield Department of Population Health worked, in collaboration with researchers from the University of Tartu, the Broad Institute, Massachusetts General Hospital and the MRC Integrative Epidemiology Unit at the University of Bristol, to analyse data from clinical trials and large-scale human genetic datasets to assess the evidence for this potential risk, including more than 50,000 people who had experienced a fracture and more than 100,000 people who had a stroke or heart attack.
Previous clinical trials of romosozumab have suggested that participants taking this medicine may be at higher risk of developing serious cardiovascular complications such as heart attacks or strokes. This finding was not consistently seen across all trials of romosozumab, which limited conclusions about the safety of this medicine. In 2019, the U.S. Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) approved romosozumab for the use in post-menopausal women with osteoporosis, with both agencies issuing warning labels related to the potential risk of cardiovascular complications.
Professor Michael Holmes, of the MRC Population Health Research Unit and Nuffield Department of Population Health at the University of Oxford, one of the study's lead authors, concludes:
'This new medicine is effective at lowering risk of fracture, which can be life-threatening particularly for the elderly.'
'Patients and their healthcare providers should jointly consider whether the benefits of fracture prevention outweigh the potential risk of heart disease.'
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The large-scale human genetic datasets included UK Biobank, Estonian Biobank, Partners HealthCare Biobank and China Kadoorie Biobank.
Osteoporosis is a skeletal condition characterised by low bone density (i.e. thinning of the bones). This condition is estimated to affect more than 200 million people world-wide and disproportionately affects post-menopausal women. A major complication of osteoporosis is fractures, which when they occur in the hip, are associated with high rates of mortality. A novel class of medicines called sclerostin inhibitors has recently been developed to lower the risk of fracture in patients with osteoporosis.
The Big Data Institute
The Big Data Institute is located in the Li Ka Shing Centre for Health Informatics and Discovery at the University of Oxford. It is an interdisciplinary research centre that focuses on the analysis of large, complex data sets for research into the causes, consequences, prevention and treatment of disease. Research is conducted in areas such as genomics, population health, infectious disease surveillance and the development of new analytic methods. The Big Data Institute is supported by funding from the Medical Research Council, the UK Research Partnership Investment Fund, the National Institute for Health Research Oxford Biomedical Research Centre, and philanthropic donations from the Li Ka Shing and Robertson Foundations. Further details are available at http://www.bdi.ox.ac.uk
Nuffield Department of Population Health
The Nuffield Department of Population Health (NDPH) is a world-leading research institute, based at the University of Oxford, which investigates the causes and prevention of disease. NDPH has over 600 staff working in a number of world-leading research groups, including the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), the Cancer Epidemiology Unit (CEU), the National Perinatal Epidemiology Unit (NPEU) and other groups working on public health, health economics, ethics and health record linkage. It is also a key partner in the Oxford University Big Data Institute.
About Oxford University
Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the third year running, and at the heart of this success is our ground-breaking research and innovation. Oxford is world-famous for research excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research sparks imaginative and inventive insights and solutions.
Science Translational Medicine