Bisphosphonates and cardiac electrophysiology: should the red flag be raised higher?

Bisphosphonates are widely employed to decrease bone loss in disorders characterized by increased osteoclastmediated bone resorption, such as senile osteoporosis.1 Although generally well-tolerated, side effects such as an acute inflammatory phase reaction, osteonecrosis of the jaw, gastrointestinal disorders, or hypocalcemia have been described.1 Also, contradictory reports of an association between atrial fibrillation (AF) and the use of bisphosphonates has led to confusing statements and sent mixed messages to practitioners and patients.2 Details on these conflicting observations are summarized in previously published review articles.1-3 Interestingly, several hypotheses linking bisphosphonates to the onset of AF have been formulated: an acute increase in proinflammatory cytokines, disturbances in calcium homeostasis, or extracellular matrix remodeling.2 To date, however, none of these premises have been tested, the mechanisms by which bisphosphonates may impact cardiac electrophysiology are unknown, and as of late 2008, the Food and Drug Administration failed to identify a clear association and concluded that no change in prescribing practices was warranted.1,2 In this issue of the Journal of Cardiovascular Electrophysiology, Bonilla et al. present a multifaceted investigation describing plausible mechanisms for bisphosphonate-induced cardiac arrhythmias.4 Their results have substantial mechanistic depth and, albeit provocative, put at question the previous status quo on an association between bisphosphonates and cardiac arrhythmias. The authors started their work with a clinical observation compatible, although inconclusively, with a bisphosphonate-induced arrhythmia. A 55-year-old woman, having had a single dose of ibandronate—a commonly used bisphosphonate—experienced syncope and subsequently presented with QT/QTc interval prolongation, which normalized following ibandronate discontinuation. Based upon this suspicious observation, the authors conducted a comprehensive basic and translational investigation that included a