Comparative effects of metformin and lifestyle therapy on bone metabolism markers: A 6-month pilot, open-label randomized-clinical trial.

<h4>Background</h4>The metabolic effects of Metformin (Met) and lifestyle modification in early type 2 diabetes mellitus (T2DM) management are well established, but their influence on bone remodeling remains uncertain in under-investigated populations, particularly during early treatment when weight loss and metabolic shifts may transiently affect skeletal turnover. This study examined the short- and mid-term effects of metformin, lifestyle intervention, and their combination on bone turnover markers (BTMs) in treatment-naïve Saudi adults with T2DM.<h4>Methods</h4>In this 6-month pilot, open-label multicenter randomized controlled trial, 114 treatment-naïve Saudi adults with newly diagnosed T2DM (90 males, 24 females; mean age ± SD 53.6 ± 8.4 years; mean BMI 30.3 ± 3.9 kg/m²; mean HbA1c 7.0 ± 0.6) were assigned to Met (1000 mg/day), lifestyle modification, or combined therapy (n = 38/group). Serum markers of bone resorption (C-terminal telopeptide of type I collagen [CTX], primary outcome) and bone formation (procollagen type I N-terminal propeptide [P1NP], osteocalcin), along with sclerostin (SOST), were measured at baseline, 3 months, and 6 months. Anthropometric, glycemic, lipid, renal, and hepatic parameters were assessed as secondary outcomes.<h4>Results</h4>After adjustment for baseline P1NP levels, only the lifestyle group demonstrated a significant reduction in CTX after 6 months (p < 0.05), while osteocalcin, SOST and P1NP showed no significant changes across all interventions. All interventions were associated with improvements in anthropometric and glycemic measures; most pronounced in the combined intervention group.<h4>Conclusion</h4>In treatment-naïve adults with T2DM, lifestyle intervention alone was associated with a significant reduction in CTX after 6 months, while metformin-based interventions showed no significant effects on bone turnover markers. These exploratory findings may suggest short-term modulation of bone turnover but should be interpreted cautiously given the pilot design.