title: Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study.
abstract: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy.
  
  
  BACKGROUND
  A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data.
  
  
  METHODS
  This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates.
  
  
  RESULTS
  A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses.
  
  
  CONCLUSIONS
  The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.
authors.affiliation: Department of Medical Informatics, Erasmus MC University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands. p.coloma@erasmusmc.nl.
authors.forename: P M
authors.initials: PM
authors.lastname: Coloma
authors.affiliation: Department of Medical Informatics, Erasmus MC University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Ridder
authors.affiliation: PHARMO Institute NV, 3528 AE, Utrecht, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Bezemer
authors.affiliation: PHARMO Institute NV, 3528 AE, Utrecht, The Netherlands.
authors.forename: R M C
authors.initials: RM
authors.lastname: Herings
authors.affiliation: Agenzia Regionale di Sanità della Toscana, 50141, Florence, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gini
authors.affiliation: Società Italiana di Medicina Generale, 50141, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pecchioli
authors.affiliation: Università di Milano-Bicocca, 20126, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Scotti
authors.affiliation: Department of Medical Informatics, Erasmus MC University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Rijnbeek
authors.affiliation: Department of Medical Informatics, Erasmus MC University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Mosseveld
authors.affiliation: Department of Medical Informatics, Erasmus MC University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van der Lei
authors.affiliation: Department of Medical Informatics, Erasmus MC University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.|Department of Clinical and Experimental Medicine, University of Messina, 98122, Messina, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Trifirò
authors.affiliation: Department of Medical Informatics, Erasmus MC University Medical Center Rotterdam, 3000 CA, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Sturkenboom
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016022:Case-Control Studies; D016208:Databases, Factual; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D006349:Heart Valve Diseases / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010024:Osteoporosis / Q000188:drug therapy / Q000453:epidemiology; D018570:Risk Assessment / Q000379:methods; D012680:Sensitivity and Specificity; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates
keywords: Bisphosphonates; Cardiac valve disorders; Cardiac valve regurgitation; Drug-induced valvular heart disease; Drug-induced valvulopathy