OBJECTIVE: Hypoglycemic treatments could modulate the risk for fractures in many ways. Most studies have not explored the effect on the incidence of bone fractures of individual oral hypoglycemic agents, rather all oral treatments as a whole. The aim of this case-control study, nested within a retrospective cohort, is the assessment of the risk for bone fractures associated with exposure to insulin or different oral hypoglycemic agents. RESEARCH DESIGN AND METHODS: A case-control study nested within a cohort of 1,945 diabetic outpatients with a follow-up of 4.1 +/- 2.3 years was performed, comparing 83 case subjects of bone fractures and 249 control subjects matched for age, sex, duration of diabetes, BMI, A1C, comorbidity, smoking, and alcohol abuse. Exposure to hypoglycemic drugs during the 10 years preceding the event (or matching index date) was assessed. RESULTS: In a model including treatment with insulin secretagogues metformin and insulin for at least 36 months during the previous 10 years, no significant association was observed between bone fractures and medications. In an alternative model considering treatments at the time of fracture, insulin treatment was significantly associated with bone fractures in men (OR 3.20 [95% CI 1.32-7.74]) but not in women (1.41 [0.73-2.73]). CONCLUSIONS: Insulin-sensitizing treatment with metformin is not associated with a higher incidence of bone fractures, suggesting that the negative effect of thiazolidinediones is due to a specific action on bone metabolism rather a reduction of insulinemia. Conversely, current treatment with insulin increases the risk of fractures; at the same time, exposure to this agent in the longer term does not appear to affect bone frailty.