The potential effects of metformin, DPP4 inhibitors, and TZDs on bone metabolism. Metformin has a positive effect on osteoblast differentiation by activating the osteoblast-specific Runx2 transcription factor via the AMPK/USF-1/SHP regulatory cascade and an adverse effect on osteoclast differentiation by decreasing RANKL and increasing osteoprotegerin levels. PPARγ activation is associated with fewer osteoblasts, an increased number of adipocytes, greater support for osteoclastogenesis. DPP-4 inhibitors act to stabilize active forms of GIP and GLP-2. GIP increases osteoblast activity, and GLP-2 decreases osteoclast action. iDPP4 dipeptidyl peptidase-4 inhibitor, GIP glucose-dependent insulinotropic peptide, GLP-2 glucagon-like peptide-2, TZDs thiazolidinediones, PPARγ peroxisome proliferator-activated receptor-gamma, Runx2 runt-related transcription factor 2. Modified from Gilbert et al.