Background and aims: An excess of bone frailty and fractures is described in women with type 2 diabetes mellitus (T2DM), exacerbating morbidity and hospitalization. Dipeptidyl peptidase 4 inhibitors (DPP4-I) have demonstrated potential bone-protective effects in preclinical studies, but clinical evidence in this context is lacking. This double-blinded, randomized, placebo-controlled trial aimed to assess the safety and efficacy of 52-week sitagliptin therapy in improving bone outcomes in women with T2DM. Materials and methods: 132 women with T2DM were enrolled and randomized to sitagliptin or placebo. Primary outcomes included changes in bone mineral density (BMD) and markers of bone turnover. Secondary objectives explored the associations between circulating DPP4 activity, serum vitamin D, and biomarkers of inflammation and bone metabolism. Results: Within the study cohort, 54 subjects in the sitagliptin group (81.8%) and 51 in the placebo group (77.3%) completed the study. After 12 months, sitagliptin preserved BMD in total femur, compared to a significant decrease in the placebo group (T-score estimated mean difference at the total femur level in favor of sitagliptin 0.11; 95%CI 0.03; 0.19; p=0.0063). Between groups comparisons show statistically significant differences in favor of the sitagliptin group at 24 weeks regarding the levels of several cytokines. No significant modifications were observed in other clinical and bone parameters, and glucose control. Conclusion: In this RCT, sitagliptin demonstrated efficacy in maintaining femur BMD in women with T2DM. This finding suggests a potential additional benefit beyond glycemic control, warranting further research with extended follow-up to comprehensively elucidate the mechanisms and potential clinical implications of sitagliptin on bone health.