Seven randomized controlled trials, including 1656 patients with diabetes mellitus, were included in this systematic review and meta-analysis comparing metformin versus thiazolidinediones (TZDs). Pooled outcomes of interest included bone mineral density (BMD), C-terminal telopeptide of type I collagen (CTX), procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (BAP), and urine n-telopeptide of type I collagen (u-NTX). The pooled results showed that metformin was associated with a 2.77% higher BMD than TZDs until 52 weeks but a 0.83% lower BMD from 52 to 76 weeks. CTX and PINP levels decreased by 18.46% and 9.94%, respectively, in the metformin group compared with the TZD group. The findings suggest that metformin may have a transient protective effect on bone density compared to TZDs, but this effect diminishes over time.