OBJECTIVES: Tight control of diabetes mellitus (DM) with insulin has the potential to increase hypoglycemic episodes which may result in fall and fracture risk.  Moreover, patients with chronic obstructive pulmonary disease (COPD) are at high risk of fractures which may put patients with combination COPD and diabetes are particular risk. Our goal was to compare the risk of fractures associated with insulin use compared to TZDs in patients with COPD and DM. METHODS: We conducted a nested case-control study using the IMS LifeLink® Health Plan Claims database, including patients at least 45 years old with a diagnosis of COPD and DM that were new users of either a TZD or insulin.  Cases were individuals that experienced a fracture between January 2006 and December 2011. Controls were matched with cases at a 4:1 ratio on the following characteristics: gender, age, geographic region, and date of first dispensing of a TZD or insulin prescription. We conducted conditional logistic regression analyses to estimate the odds ratios (ORs) of having a fracture associated with the use of insulin compared to TZD while controlling for other covariates. RESULTS: There were 2,842 cases matched to 8,238 controls. The mean (standard deviation) age of the study subjects was 46.5 years (0.9) and 57.6% were women.  Among cases, 32.8% used insulin and 67.2% used TZDs, and for controls 30.3% used insulin and 69.7% used TZDs. The crude OR for insulin users compared with TZD was 1.14 (95% confidence interval [CI], 1.04-1.25). After adjustment for other antidiabetic drugs, comedication, and comorbidities, the OR was 1.28 (95% CI, 1.09-1.49). CONCLUSIONS: We found an association between use of insulin and fractures compared to TZDs in patients with COPD and DM. While further research is needed, clinicians and policy makers should assure that screening guidelines consider this relative risk in patients with COPD and DM.