Rosiglitazone-Associated Fractures in Type 2 Diabetes

Steven E. Kahn, MB, CHB; Bernard Zinman, MD; John M. Lachin, SCD; Steven M. Haffner, MD; William H. Herman, MD; Rury R. Holman, MD; Barbara G. Kravitz, MS; Dahong Yu, PHD; Mark A. Heise, PHD; R. Paul Aftring, MD, PHD; Giancarlo Viberti, MD


Diabetes Care. 2008;31(5):845-851. 

In This Article

Abstract and Introduction

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.

Type 2 diabetes is associated with an increased risk of fractures, with the risk increasing with longer duration of disease.[1,2] These fractures affect predominantly the hip, arm, and foot[1,2,3,4,5] and occur despite the fact that bone mineral density is either normal or even increased in patients with type 2 diabetes compared with those who are not hyperglycemic.[5,6,7] Although the reason for this increased risk is unclear, it has been postulated that in older patients some of the risk may be related to disability and falls.[8] In the context of specific diabetes therapy, a recent report from the Health, Aging and Body Composition Study—an observational study—noted that older women with type 2 diabetes who were taking thiazolidinediones experienced increased bone loss compared with control subjects, whereas no differences were seen in men.[9] However, a recent retrospective study suggested a greater loss of bone mineral density in men taking rosiglitazone.[10]

A Diabetes Outcome Progression Trial (ADOPT) was a randomized, controlled clinical trial comparing the effect of the thiazolidinedione rosiglitazone, the biguanide metformin, and the sulfonylurea glyburide on glucose control in drug-naive patients recently diagnosed (<3 years) with type 2 diabetes.[11] In the study it was shown that treatment with rosiglitazone produced more durable glycemic control than metformin or glyburide as measured by fasting glucose and A1C. This effect resulted from a greater preservation of β-cell function with rosiglitazone. After unblinding and completion of the prespecified statistical analysis plan, a review of adverse events of special interest uncovered an increase in the number of fractures in women taking rosiglitazone; a brief description of the finding was added as a postscript to the primary manuscript then in press.[11] In women we observed an increased occurrence of bone fractures in the upper and lower limbs, but an increase in hip or vertebral fractures was not noted. An increased fracture risk was subsequently reported in women receiving pioglitazone,[12] the other thiazolidinedione currently in clinical use. We now report in greater detail the ADOPT findings related to fractures.


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