title: Use of thiazolidinediones and risk of osteoporotic fracture: disease or drugs?
abstract: OBJECTIVE
  Clinical and observational studies suggest that use of thiazolidinediones (TZDs) is associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) is a risk factor for osteoporotic fracture. Our aim was to estimate fracture risks in TZD users and users of other antidiabetic drugs, classified according to proxies of disease severity.
  
  
  METHODS
  We conducted a population-based cohort study utilizing the Dutch PHARMO database (1998-2008). PHARMO links pharmacy-dispensing data to the National Hospital Registry. Oral antidiabetic users (n = 123,452) were matched 1:4 by year of birth and sex to non-users. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture in TZD users. We created a proxy indicator for disease severity. The first stage was defined as current use of either a biguanide or a sulfonylureum, the second stage as current use of a biguanide and a sulfonylureum at the same time, the third stage was assigned to patients using TZDs and the fourth stage to patients using insulin.
  
  
  RESULTS
  The risk of osteoporotic fracture was increased 1.5-fold (HR 1.49, 95%CI 1.28-1.73) in patients who currently used TZDs (stage 3), and for patients using insulin (stage 4), the risk was increased 1.2-fold (HR 1.24, 1.14-1.36), as compared with controls. In the first and second stages, risks were lower: HR 1.11 (1.06-1.17) for stage 1 and HR 1.03 (0.96-1.11) for stage 2.
  
  
  CONCLUSIONS
  When observational studies assess risk of fracture in patients with TZDs, the severity of T2DM should be taken into account.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. m.t.bazelier@uu.nl
authors.forename: Marloes T
authors.initials: MT
authors.lastname: Bazelier
authors.forename: Arlene M
authors.initials: AM
authors.lastname: Gallagher
authors.forename: Tjeerd-Pieter
authors.initials: TP
authors.lastname: van Staa
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
authors.forename: Peter
authors.initials: P
authors.lastname: Vestergaard
authors.forename: Frank
authors.initials: F
authors.lastname: de Vries
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D058866:Osteoporotic Fractures / Q000453:epidemiology* / Q000209:etiology; D016016:Proportional Hazards Models; D012042:Registries; D012307:Risk Factors; D012720:Severity of Illness Index; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones