Metformin and bone metabolism: unraveling their direct and indirect effects

Metformin is the most widely used antihyperglycemic agent for the treatment of a wide range of diseases. Activation of AMP-activated protein kinase (AMPK) is the best-known mechanism by which metformin exerts most of its beneficial effects. In recent years, research and applications of metformin in bone metabolism have made significant progress. The molecular mechanisms of its action are being elucidated with an increasingly complex understanding, raising the question of whether metformin acts directly or indirectly on bone. This review examines the indirect role of metformin in improving the bone marrow microenvironment by regulating autophagy, oxidative stress, inflammation, and skeletal aging. Furthermore, we focus on the direct mechanisms of metformin on osteoblasts, osteocytes, bone marrow adipocytes, and osteoclasts. In summary, metformin has been shown to affect bone in multiple ways and to exert osteoprotective effects. In light of the positive benefits of metformin in preventing osteoporosis, future treatment plans for patients with osteoporosis, particularly those with diabetes who are at high risk for fractures, may consider prioritizing the use of metformin as antidiabetic drug for bone protection. While metformin has been shown to improve bone health, particular attention should be paid to renal function, vitamin B12 status, and individual patient factors.