title: Ibandronate and ventricular arrhythmia risk.
abstract: BACKGROUND
  Bisphosphonates, including ibandronate, are used in the prevention and treatment of osteoporosis.
  
  
  RESULTS
  We report a case of suspected ibandronate-associated arrhythmia, following a single dose of ibandronate in a 55-year-old female. ECG at presentation revealed frequent ectopy and QT/QTc interval prolongation; at follow-up 9 months later the QT/QTc intervals were normalized. Proarrhythmic potential of ibandronate was assessed with a combination of in vivo and in vitro approaches in canines and canine ventricular myocytes. We observed late onset in vivo repolarization instability after ibandronate treatment. Myocytes superfused with ibandronate exhibited action potential duration (APD) prolongation and variability, increased early afterdepolarizations (EADs) and reduced Ito (P < 0.05), with no change in IKr . Ibandronate-induced APD changes and EADs were prevented by inhibition of intracellular calcium cycling. Ibandronate increased sarcoplasmic reticulum calcium load; during washout there was an increase in calcium spark frequency and spontaneous calcium waves. Computational modeling was used to examine the observed effects of ibandronate. While reductions in Ito alone had modest effects on APD, when combined with altered RyR inactivation kinetics, the model predicted effects on APD and SR Ca(2+) load consistent with observed experimental results.
  
  
  CONCLUSIONS
  Ibandronate may increase the susceptibility to ventricular ectopy and arrhythmias. Collectively these data suggest that reduced Ito combined with abnormal RyR calcium handling may result in a previously unrecognized form of drug-induced proarrhythmia.
authors.affiliation: College of Pharmacy.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Bonilla
authors.forename: Pedro
authors.initials: P
authors.lastname: Vargas-Pinto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishijima
authors.forename: Adriana
authors.initials: A
authors.lastname: Pedraza-Toscano
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.forename: Victor P
authors.initials: VP
authors.lastname: Long
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.forename: Patric
authors.initials: P
authors.lastname: Glynn
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Houmsse
authors.forename: Troy
authors.initials: T
authors.lastname: Rhodes
authors.forename: Raul
authors.initials: R
authors.lastname: Weiss
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hamlin
authors.forename: Sandor
authors.initials: S
authors.lastname: Györke
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004164:Diphosphonates / Q000009:adverse effects*; D004285:Dogs; D005260:Female; D006801:Humans; D000077557:Ibandronic Acid; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D014693:Ventricular Fibrillation / Q000139:chemically induced* / Q000175:diagnosis* / Q000503:physiopathology
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000077557:Ibandronic Acid
keywords: Torsade de Pointes; biophosphonates; calcium; ibandronate; ion channels; long-QT; pharmacology; potassium; proarrhythmia