Rosiglitazone-Associated Fractures in Type 2 Diabetes

An analysis from A Diabetes Outcome Progression Trial (ADOPT)

  1. Steven E. Kahn, MB, CHB1,
  2. Bernard Zinman, MD2,
  3. John M. Lachin, SCD3,
  4. Steven M. Haffner, MD4,
  5. William H. Herman, MD5,
  6. Rury R. Holman, MD6,
  7. Barbara G. Kravitz, MS7,
  8. Dahong Yu, PHD7,
  9. Mark A. Heise, PHD7,
  10. R. Paul Aftring, MD, PHD7,
  11. Giancarlo Viberti, MD8 and
  12. for the A Diabetes Outcome Progression Trial (ADOPT) Study Group*
  1. 1Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington
  2. 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada
  3. 3Biostatistics Center, George Washington University, Rockville, Maryland
  4. 4University of Texas Health Science Center at San Antonio, San Antonio, Texas
  5. 5Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, Michigan
  6. 6Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K.
  7. 7GlaxoSmithKline, King of Prussia, Pennsylvania
  8. 8King's College London School of Medicine, King's College London, London, U.K.
  1. Corresponding author: Steven E. Kahn, MB, ChB, VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA 98108. E-mail: skahn{at}


OBJECTIVE—The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT).

RESEARCH DESIGN AND METHODS—Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures.

RESULTS—In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified.

CONCLUSIONS—Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.


  • Published ahead of print at on 5 February 2008. DOI: 10.2337/dc07-2270. Clinical trial reg. no. NCT00279045,

  • *

    * A list of members of the ADOPT Study Group can be found in ref. 11. ADOPT was overseen by a steering committee comprising Steven Kahn and Giancarlo Viberti (cochairs), Steven Haffner, William Herman, Rury Holman, Paul Aftring, Nigel Jones, John Lachin, Colleen O'Neill, and Bernard Zinman.

  • S.E.K., B.Z., J.M.L., S.M.H., W.H.H., R.R.H., and G.V. have received honoraria, consulting fees, and/or grant support from GlaxoSmithKline. G.V. holds stock in GlaxoSmithKline. B.G.K., D.Y., M.A.H., and R.P.A. are employees of GlaxoSmithKline and hold equity interest in the company.

    Additional information for this article can be found in an online appendix at

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

    • Accepted January 22, 2008.
    • Received November 30, 2007.
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  1. Diabetes Care vol. 31 no. 5 845-851
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