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Ther Adv Drug Saf. 2019 Apr 5;10:2042098619838138. doi: 10.1177/2042098619838138. eCollection 2019.

Bisphosphonates and cardiovascular risk in elderly patients with previous cardiovascular disease: a population-based nested case-control study in Italy.

Author information

Department of Epidemiology, Lazio Regional Health Service, Rome, Italy.
Department of Epidemiology, Lazio Regional Health Service, ASL Roma 1, Via Cristoforo Colombo 112, Rome, 00147, Italy.
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.
Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy.
Department of Geriatrics, Catholic University of Rome, Rome, Italy.
Epidemiology Unit, Regional Agency for Healthcare Services of Tuscany, Florence, Italy.
Laboratory of Healthcare Research & Pharmacoepidemiology, Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.
Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy.
Department of Neurosciences, Psychology, Drug Research and Children's Health, University of Florence, Florence, Italy.



In a globally aging population, chronic conditions with a high impact on healthcare costs and quality of life, such as osteoporosis and associated fractures, are a matter of concern. For osteoporosis, several drug treatments are available, but evidence on adverse cardiovascular and cerebrovascular (CCV) events, and in particular the risk of atrial fibrillation (AF), related to anti-osteoporotic drug use is inconclusive. The objective of this study was to evaluate the association between the use of bisphosphonates (BPs), strontium ranelate (SR), and other anti-osteoporosis drugs and the risk of AF and CCV events in a large cohort of patients affected by CCV diseases.


Based on a cohort of patients aged 65 years and over, discharged from the hospitals of five large Italian areas after a CCV event between 2008 and 2011, two nested case-control studies were conducted. Cases were patients with a subsequent hospital admission for AF or CCV; four controls for each case were randomly selected and matched by age group, sex and follow-up time. A total of three exposure measures were tested: ever use, adherence and recency of use. In the conditional logistic regression models, patients not treated with any anti-osteoporotic medication were considered as the reference category.


The initial cohort accounted for 657,246 patients. Neither BPs nor SR use was associated with an increased risk of AF regardless of the adherence and recency of use. Overall BP and SR use was associated with a slightly increased risk of CCV; however, results reversed when considering higher adherence: odds ratio (OR) 0.81, 95% confidence interval (CI) 0.71-0.92 for BPs and OR 0.71, 95% CI 0.52-0.97 for SR.


BPs do not increase cardiovascular risk and can be prescribed to elderly patients for osteoporosis treatment. However, patients with pre-existing cerebrovascular/cardiovascular conditions should be carefully monitored.


adverse events; atrial fibrillation; bisphosphonates; cardiovascular risk; nested case-control study; pharmacoepidemiology

Conflict of interest statement

Conflict of interest statement: The author(s) declared following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Giovanni Corrao received research support from the European Community, the Italian Agency of Drugs (AIFA), and the Italian Ministry for University and Research (MIUR). He took part in a variety of projects that were funded by pharmaceutical companies (i.e. Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as a member of the Advisory Board from Roche. None of these are related to this study. Francesco Lapi has provided consultancies for epidemiological studies and data analyses for Bayer, Alfasigma, Angelini and Bruno Farmaceutici. None of these are related to this study. Ursula Kirchmayer, Chiara Sorge, Janet Sultana, Graziano Onder, Nera Agabiti, Silvia Cascini, Giuseppe Roberto, Cristiana Vitale, Ersilia Lucenteforte, Alessandro Mugelli, Marina Davoli and all the collaborators of the Italian Group for Appropriate Drug Prescription in the Elderly (I-GrADE) have no conflicts of interest directly relevant to the content of this study.

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