title: Cardiovascular, ocular and bone adverse reactions associated with thiazolidinediones: a disproportionality analysis of the US FDA adverse event reporting system database.
abstract: BACKGROUND
  : The risk of myocardial infarction, macular oedema and bone fractures associated with thiazolidinediones (TZDs) has been extensively investigated.
  
  
  OBJECTIVE
  : The aim of the study was to verify if the analysis of a large spontaneous reporting database could generate early signals on these adverse drug reactions (ADRs) associated with TZDs.
  
  
  METHODS
  : A case/non-case study, restricted to antidiabetic drugs, was performed on spontaneous reports of ADRs (2005-2008) in the US FDA Adverse Event Reporting System (AERS). The method was applied to TZDs, both as a drug class and as single agents. The reporting odds ratio (ROR) with 95% CI was calculated as a measure of disproportionality in the whole dataset and in a quarter-by-quarter analysis.
  
  
  RESULTS
  : TZD use was registered in 49 589 out of 301 950 drug-reaction pairs (16%), with significant disproportionality for myocardial infarction (ROR 4.71; 95% CI 4.40, 5.05), macular oedema (3.88; 2.79, 5.39) and bone fractures (1.73; 1.53, 1.96). Separate analysis of the two TZDs showed that only rosiglitazone was associated with myocardial infarction (7.86; 7.34, 8.34) and macular oedema (5.55; 3.94, 7.79), whereas pioglitazone was associated with multiple site fractures (2.00; 1.70, 2.35), in particular upper and lower limb and pelvic fractures. The quarter-by-quarter analysis identified disproportionality for myocardial infarction (3.13; 2.38, 4.10) and bone fractures since January-March 2005 (2.70; 1.04, 2.78).
  
  
  CONCLUSIONS
  : The frequency of reporting of myocardial infarction, macular oedema and fractures was significantly higher for TZDs in comparison with other antidiabetic drugs, with large intraclass differences. Both myocardial infarction and bone fracture signals appeared before major publications on these safety issues.
authors.affiliation: Department of Pharmacology, University of Bologna, Bologna, Italy. domenico.motola@unibo.it
authors.forename: Domenico
authors.initials: D
authors.lastname: Motola
authors.forename: Carlo
authors.initials: C
authors.lastname: Piccinni
authors.forename: Chiara
authors.initials: C
authors.lastname: Biagi
authors.forename: Emanuel
authors.initials: E
authors.lastname: Raschi
authors.forename: Anna
authors.initials: A
authors.lastname: Marra
authors.forename: Giulio
authors.initials: G
authors.lastname: Marchesini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Poluzzi
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D001842:Bone and Bones / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D002986:Clinical Trials as Topic; D016208:Databases, Factual / Q000706:statistics & numerical data; D005123:Eye / Q000187:drug effects; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008269:Macular Edema / Q000139:chemically induced*; D008297:Male; D015201:Meta-Analysis as Topic; D009203:Myocardial Infarction / Q000139:chemically induced*; D016017:Odds Ratio; D000077205:Pioglitazone; D012306:Risk; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone