Context: Persons with type 2 diabetes have increased fracture risk that existing fracture risk assessment tools underestimate.

Objective: Identify fracture predictors in persons with type 2 diabetes and overweight or obesity, considering traditional and diabetes-related risk factors.

Methods: This is a secondary analysis of a multicenter US study, the Look AHEAD: Action for Health in Diabetes randomized clinical trial, with randomization from 2001 to 2004 and fracture follow-up until 2015. Participants were men and women 45 to 75 years old with type 2 diabetes and body mass index ≥ 25 kg/m2. Potential fracture predictors ascertained at randomization included traditional and diabetes-related risk factors (diabetes duration, diabetic neuropathy, antidiabetic medication use, hemoglobin A1c, and renal function). Total hip bone mineral density (BMD) was measured in a subcohort. Primary outcome was all incident clinical fractures, ascertained by self-report and centrally adjudicated with medical records review.

Results: Over a median 12.2-year follow-up, 649 of the 4703 participants experienced at least one clinical fracture. Thiazolidinedione use (hazard ratio [HR] 1.22; 95% CI, 1.02-1.46) and insulin use (HR 1.34, 95% CI, 1.08-1.66) were significant diabetes-related predictors of all clinical fractures. When measured in a subcohort (n = 1285), total hip BMD was the strongest modifiable predictor of all clinical fractures (per 1 SD = 0.1 g/cm2 increase, HR 0.47; 95% CI, 0.39-0.58).

Conclusion: Thiazolidinedione and insulin use predict clinical fracture in middle-aged and older persons with type 2 diabetes and overweight or obesity. Evaluating BMD is advisable if these medications are prescribed. Fracture risk prediction tools may consider including thiazolidinedione and insulin use to refine prediction in this population.