Evaluation of Quantitative Computed Tomography Cortical Hip Quadrant in a Clinical Trial With Rosiglitazone: A Potential New Study Endpoint.

Quantitative computed tomography (QCT) measurements have been used extensively to ascertain information about bone quality and density due to the 3-dimensional information provided and the ability to segment out trabecular and cortical bones. QCT imaging helps to improve our understanding of the role that each bone compartment plays in the pathogenesis and prognosis of fracture. This study was conducted to explore longitudinal changes in femoral neck (FN) cortical bone structure using both volumetric bone mineral density (vBMD) and cortical shell thickness assessments via QCT in a double-blind, randomized, multicenter clinical trial in postmenopausal women with type 2 diabetes mellitus. This study also examined whether treatment-associated changes in the cortical bone vBMD and thickness in femoral neck quadrants could be evaluated. Subjects were randomized to rosiglitazone (RSG) or metformin (MET) for 52 wk followed by 24 wk of open-label MET. A subset of 87 subjects underwent QCT scans of the hip at baseline, after 52 wk of double-blind treatment, and after 24 wk of treatment with MET using standard full-body computed tomography scanners. All scans were evaluated and analyzed centrally. Cortical vBMD at the FN was precisely segmented from trabecular bone and used to assess a possible therapeutic effect on this bone compartment. QCT analysis showed reductions in adjusted mean percentage change in vBMD and in absolute cortical thickness occurred with RSG treatment from baseline to week 52, whereas changes with MET were generally minimal. The reductions observed during RSG treatment for 1 yr appeared to partially reverse during the open-label MET phase from weeks 52 to 76. The femoral neck quadrant may provide utility as a potential endpoint in clinical trials for the understanding of the therapeutic effect of new entities on cortical bone vs trabecular bone; however, further clinical validation is needed. TRIAL REGISTRATION: The protocol (GSK study number AVD111179) was registered on ClinicalTrials.gov as NCT00679939.

Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus.

CONTEXT: Postmenopausal status and type 2 diabetes mellitus (T2DM) are independent risk factors for fractures. An increased fracture risk has been observed with rosiglitazone (RSG), a thiazolidinedione, in patients with T2DM. DESIGN AND SETTING: This was a randomized, double-blind study in postmenopausal women with T2DM. A 52-week double-blind phase (RSG or metformin [MET]) was followed by a 24-week open-label phase, during which time all patients received MET. MAIN OUTCOME MEASURES: The primary endpoint was to assess the mean percentage change in bone mineral density (BMD) at the femoral neck (FN) by dual-energy x-ray absorptiometry from baseline to week 52 in the RSG treatment group. Key secondary objectives included assessment of changes in BMD at the total hip, trochanter, and lumbar spine and to evaluate RSG effects on bone turnover markers. RESULTS: From baseline to week 52, RSG was associated with a reduction in FN BMD by dual-energy x-ray absorptiometry (-1.47%). During the open-label phase (weeks 52-76), no further loss in FN BMD was observed. A decrease in BMD occurred at the total hip during RSG or MET treatment at 52 weeks (-1.62 and -0.72%, respectively). Total hip BMD loss by RSG was attenuated after switching to MET and was similar between treatment groups at the end of the open-label phase. From baseline to week 52, bone turnover markers significantly increased with RSG compared with MET, but decreased significantly during the open-label phase. CONCLUSIONS: RSG for 52 weeks in postmenopausal women with T2DM was associated with small reductions in FN, total hip, and lumbar spine BMD and increased bone turnover markers. These effects are attenuated after cessation of RSG treatment.