title: Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial.
abstract: Pioglitazone reduces cardiovascular risk in nondiabetic patients after an ischemic stroke or transient ischemic attack (TIA) but is associated with increased risk for bone fracture.
  
  
  
  To characterize fractures associated with pioglitazone by location, mechanism, severity, timing, and sex.
  
  
  
  Patients were 3876 nondiabetic participants in the Insulin Resistance Intervention after Stroke trial randomized to pioglitazone or placebo and followed for a median of 4.8 years. Fractures were identified through quarterly interviews.
  
  
  
  At 5 years, the increment in fracture risk between pioglitazone and placebo groups was 4.9% [13.6% vs 8.8%; hazard ratio (HR), 1.53; 95% confidence interval (CI), 1.24 to 1.89). In each group, ∼80% of fractures were low energy (i.e., resulted from fall) and 45% were serious (i.e., required surgery or hospitalization). For serious fractures most likely to be related to pioglitazone (low energy, nonpathological), the risk increment was 1.6% (4.7% vs 3.1%; HR, 1.47; 95% CI, 1.03 to 2.09). Increased risk for any fracture was observed in men (9.4% vs 5.2%; HR, 1.83; 95% CI, 1.36 to 2.48) and women (14.9% vs 11.6%; HR, 1.32; 95% CI, 0.98 to 1.78; interaction P = 0.13).
  
  
  
  Fractures affected 8.8% of placebo-treated patients within 5 years after an ischemic stroke or TIA. Pioglitazone increased the absolute fracture risk by 1.6% to 4.9% and the relative risk by 47% to 60%, depending on fracture classification. Our analysis suggests that treatments to improve bone health and prevent falls may help optimize the risk/benefit ratio for pioglitazone.
authors.affiliation: Yale School of Medicine, New Haven, Connecticut 06510.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Viscoli
authors.affiliation: Yale School of Medicine, New Haven, Connecticut 06510.
authors.forename: Silvio E
authors.initials: SE
authors.lastname: Inzucchi
authors.affiliation: Yale School of Medicine, New Haven, Connecticut 06510.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
authors.affiliation: Yale School of Medicine, New Haven, Connecticut 06510.
authors.forename: Karl L
authors.initials: KL
authors.lastname: Insogna
authors.affiliation: National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892.
authors.forename: Robin
authors.initials: R
authors.lastname: Conwit
authors.affiliation: Alpert Medical School of Brown University, Providence, Rhode Island 02903.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Furie
authors.affiliation: Maine Medical Center, Portland, Maine 04102; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Gorman
authors.affiliation: Division of Neurology, Cook County Health and Hospitals System, Chicago, Illinois 60612.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kelly
authors.affiliation: Yale School of Medicine, New Haven, Connecticut 06510.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Lovejoy
authors.affiliation: Yale School of Medicine, New Haven, Connecticut 06510.
authors.forename: Walter N
authors.initials: WN
authors.lastname: Kernan
mesh_terms: D000058:Accidental Falls; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D016016:Proportional Hazards Models; D012307:Risk Factors; D012737:Sex Factors; D020521:Stroke / Q000188:drug therapy*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone