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Comparative cardiovascular safety of strontium ranelate and bisphosphonates: a multi-database study in 5 EU countries by the EU-ADR Alliance

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Abstract

Summary

Strontium ranelate use, compared with oral bisphosphonates, is not associated with increased risk of AMI in patients with no contraindications for SR use. However, current strontium ranelate (compared with current bisphosphonate) appears associated with 25–30% excess risk of VTE and 35% excess risk of CVDeath.

Introduction

Evaluate the risk of cardiac and thromboembolic events among new users of SR and oral BPs without contraindications for SR.

Methods

We conducted three multi-national, multi-database (Aarhus-Denmark, HSD-Italy, IPCI-Netherlands, SIDIAP-Spain, THIN-UK) case-control studies nested within a cohort of new users of SR/BP. We matched cases of acute myocardial infarction (AMI), venous thromboembolism (VTE), and cardiovascular death (CVDeath), up to 10 controls on gender, year of birth, index date, and country. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) according to current SR vs current BP use and current vs past SR use, adjusting for potential confounders. Data were pooled using random effects meta-analysis.

Results

No excess risk of AMI (5477 cases/54,674 controls) was found with current SR vs current BP (OR 0.89 (95%CI 0.70, 1.12)) nor with current vs past SR use (0.71(0.56, 0.91)). For VTE (5614 cases/6036 controls), an excess risk was found with current SR compared with current BP use, 1.24 (0.96, 1.61), and current vs past SR use, 1.30 (1.04, 1.62). For CVDeath (3019 cases/29,871 controls), an increased risk was seen with current SR vs current BP use, 1.35 (1.02, 1.80), but not with current vs past SR use (0.68 (0.48, 0.96)).

Conclusion

In patients without contraindications for SR, we found no evidence of an increased risk of AMI but a 25–30% excess risk of VTE and a 35% excess risk of CVDeath with current SR vs current BP users. This is despite a reduction in risk in CVDeath with current vs past SR users. The latter disparity could still be partially explained by cessation of preventative therapies in end-of-life or residual confounding by indication.

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Date availability

The different data sources have provided the research team with data subject to different licences, which do not allow sharing.

The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned have been explained.

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Acknowledgements

We thank to our colleagues Eva Molero and Natasha Yefimenko (SYNAPSE Research Management Partners S.L.) who provided the project management of this study and helped with formatting of the related full study report.

Role of funding source

The study funder had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. All authors had full access to all of the data in the study and take responsibility for the integrity of such data and the accuracy of the data analysis.

Code availability (software application or custom code)

Not Applicable.

Funding

This work was funded by Servier through a research grant to the EU-ADR Alliance.

DPA is funded by a National Institute for Health Research Clinician Scientist award (CS-2013-13-012). This article presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This work was partially supported by the NIHR Biomedical Research Centre, Oxford.

At the time of study, Miriam Sturkenboom was co-coordinating the work from Erasmus University Medical Center.

Author information

Authors and Affiliations

  1. Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK

    M.S. Ali, K. Berencsi & D. Prieto-Alhambra

  2. Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St, Bloomsbury, London, WC1E 7HT, UK

    M.S. Ali

  3. Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark

    K. Berencsi & L. Pedersen

  4. Department of Pharmacoepidemiology and Real World Evidence, Servier, Suresnes, France

    K. Marinier & N. Deltour

  5. RTI Health Solutions, Barcelona, Spain

    S. Perez-Guthann

  6. Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands

    P. Rijnbeek & J. Van der Lei

  7. Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy

    F. Lapi & M. Simonetti

  8. GREMPAL Research Group, Idiap Jordi Gol Primary Care Research Institute and CIBERFes, Universitat Autonoma de Barcelona and Instituto de Salud Carlos III, Barcelona, Spain

    C. Reyes & D. Prieto-Alhambra

  9. Julius Global Health, University Medical Center, Utrecht, Netherlands

    M. Sturkenboom

Authors
  1. M.S. Ali
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  2. K. Berencsi
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  3. K. Marinier
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  6. L. Pedersen
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  8. F. Lapi
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  9. M. Simonetti
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  10. C. Reyes
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  11. J. Van der Lei
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  13. D. Prieto-Alhambra
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Contributions

DPA, MS, SPG, KM, ND, and MSA conceived and planned the study. MSA, KB, LP, PR, FL, MS, CR, JVdL, and MS extracted and/or prepared the data for the statistical analyses. MSA conducted the statistical analysis. MSA, DPA, and SPG completed the interpretation of the results with contributions from all authors. MSA drafted of the manuscript, which was reviewed, commented, and approved by all authors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Corresponding author

Correspondence to M.S. Ali.

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Conflicts of interest

The manuscript is accompanied by completed ‘Authorship & Disclosure Form’.

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare SPG as employee of RTI Health Solutions receives grants and consultation from pharmaceutical companies including Servier for other regulatory safety studies and for supporting the role in the scientific advisory board for this study; DPA’s department has received fees for speaker services and advisory board membership from Amgen, consultancy fees from UCB Biopharma, and research grants from UCB Biopharma and Amgen; KM and ND are employees of Servier.

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Ali, M., Berencsi, K., Marinier, K. et al. Comparative cardiovascular safety of strontium ranelate and bisphosphonates: a multi-database study in 5 EU countries by the EU-ADR Alliance. Osteoporos Int 31, 2425–2438 (2020). https://doi.org/10.1007/s00198-020-05580-0

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