Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy

Figure 1 Metformin actions via osteoblasts are pro-osteogenic and anti-resorptive. Metformin is incorporated into osteoblasts, where it inhibits intracellular ROS production and induces AMPK phosphorylation/activation. This increases eNOS activity and NO production, promoting osteoblast proliferation. In addition, activated AMPK up regulates osteoblastic differentiation and mineralization via expression of Runx2 and SHP, while decreasing osteoclastic recruitment and bone-resorbing activity through a reduction in osteoblastic RANKL/OPG ratio. ROS: Reactive oxygen species; AMPK: AMP-activated protein kinase; OPG: Osteoprotegerin; RANKL: Reduced receptor activator of nuclear factor-κB ligand; SHP: Small heterodimer partner; RUNX2: Runt-related transcription factor 2; AMP: Adenosine monophosphate; ATP: Adenosine triphosphate; Met: Metformin.