For the first time, this study demonstrated that sitagliptin, which is the first DPP IV inhibitor in anti-diabetic drugs approved by the US FDA, suppresses estrogen deficiency-induced osteoporosis in an OVX mouse model and exerts anti-osteoclastogenic effects by inhibiting the RANKL-induced activation of AKT, ERK, and c-Fos, thereby resulting in the inhibition of NFATc1 activity (Figure 7). This evidence concerns the gene TNFSF11 and osteoporosis.