Abstract
BACKGROUND: Women with type 2 diabetes have an increased risk of bone fragility and fractures. Experimental models suggest that dipeptidyl peptidase-4 inhibitors (DPP4-Is) may have protective effects on bone, but clinical data remain limited, and randomized trials targeting bone Outcomes are lacking. This study aimed to evaluate the efficacy and safety of 52 weeks of oral sitagliptin treatment in improving bone Outcomes in women with type 2 diabetes. METHODS: This multicenter, phase III, superiority, double-blind, randomized, placebo-controlled trial enrolled 132 women with type 2 diabetes in monotherapy with metformin and stable glycemic control. Participants were recruited from diabetes Outpatient clinics at Sapienza University of Rome, Italy, and were randomly assigned to receive sitagliptin or placebo for 52 weeks. The main outcome was a change in bone mineral density (BMD) and bone turnover biomarkers. Both intention-to-treat (ITT) and per-protocol (PP) analyses were conducted. RESULTS: Treatment with sitagliptin preserved the total proximal femur BMD T score over 52 weeks (estimated mean difference: - 0.02; 95% confidence interval: - 0.07; 0.03; p = 0.46), whereas the placebo group showed a significant reduction (estimated mean difference: - 0.13; 95% confidence interval: - 0.19; - 0.07; p < 0.0001). The between-group difference was significant in favor of sitagliptin (estimated mean difference: 0.11; 95% confidence interval: 0.03; 0.19; p = 0.0063). No significant differences were detected in other skeletal sites or bone turnover markers. PP analysis confirmed the results obtained in the ITT analysis. Compared with the placebo, sitagliptin significantly reduced the levels of inflammatory mediators involved in bone metabolism. No within- or between-group differences in glucose control at 52 weeks were reported. No serious adverse events were reported; five mild to moderate adverse events occurred and were equally distributed between the two groups. CONCLUSIONS: Sitagliptin treatment was associated with preservation of total hip T score in women with type 2 diabetes, without consistent effects on other bone sites or turnover markers. These findings suggest a potential additional benefit of sitagliptin beyond blood glucose control and warrant confirmation in longer-term studies, also including populations at higher fracture risk. TRIAL REGISTRATION: EudraCT number: 2018-000859-40 (registered 15 March 2018); ClinicalTrials.gov identifier: NCT06770894 (retrospectively registered).