title: Risk of fracture with thiazolidinediones: an individual patient data meta-analysis.
abstract: BACKGROUND
  The use of thiazolidinediones (TZDs) has been associated with increased fracture risks. Our aim was to estimate the risk of fracture with TZDs in three different healthcare registries, using exactly the same study design, and to perform an individual patient data meta-analysis of these three studies.
  
  
  METHODS
  Population-based cohort studies were performed utilizing the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System (RLS), and the Danish National Health Registers. In all three databases, the exposed cohort consisted of all patients (aged 18+) with at least one prescription of antidiabetic (AD) medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. The total period of follow-up for each patient was divided into periods of current exposure and past exposure, with patients moving between current and past use.
  
  
  RESULTS
  In all three registries, the risk of fracture was increased for women who were exposed to TZDs: HR 1.48 (1.37-1.60) in GPRD, HR 1.35 (1.15-1.58) in PHARMO, and HR 1.22 (1.03-1.44) in Denmark. Combining the data in an individual patient data meta-analysis resulted, for women, in a 1.4-fold increased risk of any fracture for current TZD users versus other AD drug users [adj. HR 1.44 (1.35-1.53)]. For men, there was no increased fracture risk [adj. HR 1.05 (0.96-1.14)]. Risks were increased for fractures of the radius/ulna, humerus, tibia/fibula, ankle, and foot, but not for hip/femur or vertebral fractures. Current TZD users with more than 25 TZD prescriptions ever before had a 1.6-fold increased risk of fracture compared with other AD drug users [HR 1.59 (1.46-1.74)].
  
  
  CONCLUSIONS
  In this study, we consistently found a 1.2- to 1.5-fold increased risk of fractures for women using TZDs, but not for men, across three different healthcare registries. TZD users had an increased risk for fractures of the extremities, and risks further increased for prolonged users of TZDs.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University Utrecht, Netherlands.
authors.forename: Marloes T
authors.initials: MT
authors.lastname: Bazelier
authors.forename: Frank
authors.initials: F
authors.lastname: de Vries
authors.forename: Peter
authors.initials: P
authors.lastname: Vestergaard
authors.forename: Ron M C
authors.initials: RM
authors.lastname: Herings
authors.forename: Arlene M
authors.initials: AM
authors.lastname: Gallagher
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
authors.forename: Tjeerd-Pieter
authors.initials: TP
authors.lastname: van Staa
keywords: epidemiology; fracture; individual patient data; meta-analysis; thiazolidinediones
references.citation: Dan Med Bull. 1999 Jun;46(3):263-8
references.pmid: 10421985
references.citation: J Bone Miner Res. 1997 Feb;12(2):283-9
references.pmid: 9041062
references.citation: J Clin Endocrinol Metab. 2010 Feb;95(2):592-600
references.pmid: 20061432
references.citation: J Endocrinol Invest. 2007 Oct;30(9):RC26-30
references.pmid: 17993761
references.citation: Arch Intern Med. 2009 Aug 10;169(15):1395-402
references.pmid: 19667303
references.citation: N Engl J Med. 2010 May 6;362(18):1675-85
references.pmid: 20427778
references.citation: J Clin Endocrinol Metab. 2008 May;93(5):1696-701
references.pmid: 18285411
references.citation: Diabetes Obes Metab. 2010 Aug;12(8):716-21
references.pmid: 20590749
references.citation: Pharmacoepidemiol Drug Saf. 2012 May;21(5):507-14
references.pmid: 22392882
references.citation: Calcif Tissue Int. 2012 Jun;90(6):450-7
references.pmid: 22488176
references.citation: Am J Epidemiol. 2007 Sep 1;166(5):495-505
references.pmid: 17575306
references.citation: PPAR Res. 2011;2011:867180
references.pmid: 22135675
references.citation: J Bone Miner Res. 2002 Jul;17(7):1237-44
references.pmid: 12096837
references.citation: CMAJ. 2009 Jan 6;180(1):32-9
references.pmid: 19073651
references.citation: J Am Coll Cardiol. 2007 May 1;49(17):1772-80
references.pmid: 17466227
references.citation: Diabetes Obes Metab. 2010 Dec;12(12):1023-35
references.pmid: 20977573
references.citation: Osteoporos Int. 2008 Feb;19(2):129-37
references.pmid: 17901911
references.citation: J Clin Epidemiol. 2012 Apr;65(4):384-93
references.pmid: 22197519
references.citation: Acta Endocrinol (Copenh). 1979 Mar;90(3):463-72
references.pmid: 425786
references.citation: N Engl J Med. 2004 Sep 9;351(11):1106-18
references.pmid: 15356308
references.citation: Diabet Med. 2011 Jul;28(7):759-71
references.pmid: 21672000
references.citation: Ugeskr Laeger. 1995 Jun 26;157(26):3741-5
references.pmid: 7631448
references.citation: J Clin Endocrinol Metab. 2007 Apr;92(4):1305-10
references.pmid: 17264176
references.citation: Lancet. 2009 Jun 20;373(9681):2125-35
references.pmid: 19501900
references.citation: Cancer Res. 2000 Mar 15;60(6):1604-8
references.pmid: 10749129
references.citation: Arch Intern Med. 2008 Apr 28;168(8):820-5
references.pmid: 18443256
references.citation: Folia Biol (Praha). 2011;57(4):133-8
references.pmid: 21978754
references.citation: J Clin Epidemiol. 1996 Jan;49(1):115-9
references.pmid: 8598504
references.citation: Osteoporos Int. 2007 Apr;18(4):427-44
references.pmid: 17068657
references.citation: PLoS Med. 2009 Sep;6(9):e1000154
references.pmid: 19787025
references.citation: Calcif Tissue Int. 1991 Sep;49(3):155-60
references.pmid: 1933578
references.citation: Stat Med. 1998 Dec 30;17(24):2815-34
references.pmid: 9921604
references.citation: Br J Clin Pharmacol. 2010 Jan;69(1):4-14
references.pmid: 20078607
references.citation: Transl Res. 2013 Mar;161(3):145-55
references.pmid: 23022285
references.citation: Biochem Biophys Res Commun. 1997 Jun 27;235(3):646-51
references.pmid: 9207213