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

Metformin is a well-established agent for improving insulin sensitivity and lowering hepatic glucose output, and the most common first-line pharmacological approach in type 2 diabetes mellitus (T2DM) and prediabetes management []. A recent umbrella review also documented that structured lifestyle interventions, which often include caloric restriction, increased physical activity, and behavioral counseling, are similarly effective in improving glycemic indices and reducing cardiometabolic risk, although notable anthropometric benefits appeared to be lacking in combination with metformin []. While their metabolic benefits are well-documented, less is known about their effects on bone turnover and bone-related biomarkers, particularly in the context of weight loss. A synthesis of evidence done on animal models with T2DM nevertheless demonstrated that metformin can improve bone density []. In human trials, evidence from a meta-analysis of 19 randomized controlled trials ( = 4,914) participants indicated that although anti-T2DM therapies as a group were associated with higher bone mineral density (BMD) at the lumbar spine and femoral neck compared with placebo, metformin showed a relative advantage over other anti-T2DM agents, with direct comparisons showing that overall treatment effects favored metformin []. Notably, the absence of clinically meaningful changes in bone turnover markers (BTMs) associated with metformin, together with the high heterogeneity across the included studies [], further reinforces the variability and overall inconclusiveness of metformin’s effects on BTMs []. Bone remodeling is influenced by endocrine, metabolic, and mechanical factors []. Weight reduction, for instance, alters mechanical loading and can modify circulating bone markers [], including osteocalcin, C-terminal telopeptide of type I collagen (CTX), Procollagen type I N-terminal propeptide (P1NP), and sclerostin (SOST) []. Osteocalcin and P1NP are markers of bone formation, whereas CTX reflects bone resorption. SOST is a Wnt-signalling antagonist that regulates osteoblastic activity and may also respond to metabolic shifts []. Understanding how lifestyle and pharmacological interventions influence bone metabolism is clinically relevant, especially in genetically predisposed populations at risk for both metabolic and skeletal disorders. Despite the lack of convincing evidence in humans, it has been proposed that metformin influences bone turnover primarily through its canonical AMP-activated protein kinase (AMPK) activation, which reduces oxidative stress, inflammation, and cellular senescence within the bone marrow niche. By suppressing reactive-oxygen species (ROS) production and pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B (NF-κB)-dependent cytokines, metformin limits osteoclastogenesis and bone resorption-related markers []. Simultaneously, existing literature suggested that AMPK-mediated inhibition of mammalian targets of rapamycin (mTOR) enhances autophagy and osteogenic signalling in mesenchymal stem cells, promoting bone formation and a favourable bone turnover profile [].