Background: Diabetes mellitus is characterised by increased fracture risk irrespective of bone mineral density (BMD). Some authors argued that this could result from altered bone quality, with subtler changes in bone microarchitecture that are not captured by BMD. In addition to diabetes itself, a further independent increase in fracture risk is described in patients treated with thiazolidinediones (TZD). In recent years, trabecular bone score (TBS) has emerged as a reliable non-invasive measure of bone quality and has already been widely validated as a predictor of fractures independently of BMD. Aim of this study was to evaluate the effect of diabetes and TZD use on bone quality, as assessed non-invasively by TBS. Methods: We conducted a secondary analysis of the population-based 2005-2008 cycles of the National Health and Nutrition Examination Survey (NHANES), in which TBS measurement was performed. The main outcome measures were TBS values and BMD T-scores at the lumbar spine, total hip and femoral neck. All analyses were adjusted for relevant confounders (age, sex, menopause, ethnicity, income, smoking, body mass index, chronic kidney disease, recent hospitalization, dietary calcium intake, 25OH-VitaminD levels, hormone-blocking therapy, chronic glucocorticoid use). Results: A total of 8326 patients (age 46.4±16.3 years, 50.7% females) were extracted; 1258 were affected by diabetes mellitus, and among them, 200 were currently treated with TZD. Patients with diabetes had a lower TBS compared to nondiabetic patients (β=-0.036, 95%CI: [-0.046, -0.027], p<0.001), while no difference was observed in terms of BMD T-scores at the lumbar spine (β=+0.09, 95%CI: [-0.03, +0.21], p=0.131), total hip (β=-0.01, 95%CI: [-0.13, +0.10], p=0.809) or femoral neck (β=+0.04, 95%CI: [-0.06, +0.14], p=0.403). Within the subgroup of diabetic patients, no association was observed between TZD use and TBS (β=-0.012, 95%CI: [-0.034, +0.011], p=0.303); similarly, no differences were observed also in terms of BMD (p>0.20 at all sites). Conclusions: Diabetes is associated with lower bone quality, as assessed non-invasively by TBS, with no significant effect on BMD. TZD use did not show a significant impact on either TBS or BMD.