Bisphosphonate-Associated Cardiac Adverse Reactions: Reports from the Italian Database of Spontaneous Reporting of Adverse Drug Reactions

Background: Oral and intravenous bisphosphonates (alendronate, clodronate, risedronate, pamidronate, ibandronate, and zoledronic acid) are front-line agents in the management of osteoporosis, malignant skeletal disease, and Paget’s disease. In the USA, in 2006, there were more than 30 million prescriptions for oral bisphosphonates alone and in Italy, in 2011, bisphosphonates have been the third class of drugs most prescribed by physicians. Different kinds of adverse drug reactions (ADRs), such as upper GI adverse events, renal toxicity, influenza-like illness, musculoskeletal pain, osteonecrosis of the jaw, and ocular events have been associated to bisphosphonates. The association with cardiac side effects are limited in the literature and particularly focalized on the atrial fibrillation.[1,2] The Italian Summary Products Characteristics of clodronate, zolendronate, ibandronate, pamidronate lists some cardiac ADRs, only the SPC of zoledronic acid reports atrial fibrillation. Aim: To describe and discuss the spontaneous reports of cardiac disorders associated to bisphosphonates from the Italian ADR database. Methods: The Italian database on spontaneous reporting (IDvigilance) holds reports of suspected ADRs submitted since 1988. Every 6 months the database is analysed to filter out potential signals. Signal detection is done by qualitative case-by-case analysis and by using as quantitative methodology the Proportional Reporting Rate. Results: Up to December 31st 2011, IDvigilance held 161 474 reports: 84% of them coming from physicians, 6% from pharmacists, 2% from nurses, and only 1% from consumers. In 1799 reports, one or more adverse reactions associated with bisphosphonate therapy were referred. Among these, 36 (2%) reported cardiac disorders as the preferred term. The percentage of female was 86%, the percentage of serious reports was 22% and the median age was 67 years. The drug more frequently reported was clodronate alone or in association with lidocaine (12 out of 36) followed by alendronate (8 out of 36) and zoledronic acid (7 out of 36). The most frequently reported bisphosphonates- related cardiac ADRs included hypertension (10 cases), tachycardia (7) and atrial fibrillation (4), most of them related to clodronate + lidocaine. Conclusions: Some reports, in the Italian database, indicate possible cardiac ADRs in association with bisphosphonates. Physicians and patients who use bisphosphonates should remain vigilant for cardiac side effects and in particular for atrial fibrillation. References 1. John Camm A. Review of the cardiovascular safety of zoledronic acid and other bisphosphonates for the treatment of osteoporosis. Clin Ther 2010; 32 (3): 426-36 2. Loke YK, Jeevantham V, Singh S. Bisphosphonates and atrial fibrillation: systematic review and meta-analysis.