Ibandronate and Ventricular Arrhythmia Risk

Abstract

Background Ibandronate is given monthly or quarterly to postmenopausal women to treat or reduce osteoporosis. We report a case of cardiac arrest in an otherwise healthy 55-year-old female, 2 weeks after her first dose of ibandronate, with associated hypokalemia and QTc prolongation (575 ms). The QT/QTc remained prolonged after correction of hypokalemia but returned toward normal after drug discontinuation. We examined potential proarrhythmic mechanisms of ibandronate. Methods A 3-mg injection was given to 4 dogs; ECG was monitored for 6 weeks by telemetry. Adult canine ventricular myocytes were used to study action potentials (0.5, 1, and 2 Hz), K + currents, and Ca 2+ handling during perfusion with ibandronate (0.001–1000 μg/L), and washout. Results Three of 4 dogs exhibited increased short-term variability in repolarization starting 4+ weeks post dose. In myocytes, ibandronate caused reverse use–dependent prolongation of the action potential (APD 50 and APD 90 ) as well as increased beat-to-beat variability in APD 90 ( P to conductance ∼30% ( P Kr or I Ks was observed. Buffering Ca 2+ with BAPTA prevented ibandronate-induced APD 90 instability and afterdepolarizations. In separate experiments, ibandronate increased sarcoplasmic reticulum Ca 2+ load ( P 2+ sparks and waves were increased ( P Conclusions Ibandronate alters myocyte Ca 2+ regulation (reversible inhibition of ryanodine receptor that is lost upon washout) and ventricular myocyte electrophysiology to induce cellular arrhythmias; in vivo data are consistent with late onset of torsadogenic repolarization instability. We conclude that current paradigms to detect proarrhythmia risk may not be sufficiently sensitive.