Effects of metformin on bone mineral density and bone turnover markers: a systematic review and meta-analysis

OBJECTIVES: Metformin is associated with osteoblastogenesis and osteoclastogenesis. This study aims to investigate the impacts of metformin therapy on bone mineral density (BMD) and bone turnover markers. DESIGN: Systematic review and meta-analysis of randomised controlled trials. METHODS: Searches were carried out in PubMed, EMBASE, Web of science, Cochrane library, ClinicalTrials.gov from database inception to 26 September 2022. Two review authors assessed trial eligibility in accordance with established inclusion criteria. The risk of bias was assessed using the Cochrane Risk of Bias tool (RoB V.2.0). Data analysis was conducted with Stata Statistical Software V.16.0 and Review Manager Software V.5.3. RESULTS: A total of 15 studies with 3394 participants were identified for the present meta-analysis. Our pooled results indicated that metformin had no statistically significant effects on BMD at lumbar spine (SMD=−0.05, 95% CI=–0.19 to 0.09, p=0.47, participants=810; studies=7), at femoral (MD=−0.01 g/cm(2), 95% CI=−0.04 to 0.01 g/cm(2), p=0.25, participants=601; studies=3) and at hip (MD=0.01 g/cm(2), 95% CI=–0.02 to 0.03 g/cm(2), p=0.56, participants=634; studies=4). Metformin did not lead to significant change in osteocalcin, osteoprotegerin and bone alkaline phosphatase. Metformin induced decreases in N-terminal propeptide of type I procollagen (MD=−6.09 µg/L, 95% CI=–9.38 to −2.81 µg/L, p=0.0003, participants=2316; studies=7) and C-terminal telopeptide of type I collagen (MD=−55.80 ng/L, 95% CI=–97.33 to −14.26 ng/L, p=0.008, participants=2325; studies=7). CONCLUSION: This meta-analysis indicated that metformin had no significant effect on BMD. Metformin decreased some bone turnover markers as N-terminal propeptide of type I procollagen and C-terminal telopeptide of type I collagen. But the outcomes should be interpreted with caution due to several limitations.