The combination of linagliptin and metformin rescues bone loss in type 2 diabetic osteoporosis

To develop an approach to reduce the type 2 diabetic osteoporosis, this study investigated the protective effects of the combination of linagliptin and metformin against osteoporosis. Micro-CT and dynamic biomechanical measurements were used to determine the bone microstructure in the type 2 diabetes mellitus (T2DM) rats. MC3T3-E1 cells were cultured in high glucose environments. In addition, we used qRT-PCR and Western blotting to assess osteogenic markers and p38 and extracellular signal-regulated kinase (ERK) protein expression. The combination of linagliptin and metformin treatment significantly restored bone micro-architecture and femoral mechanical properties in the T2DM rats. In contrast, bone markers including osteocalcin, NH2-terminal propeptide of type I procollagen, COOH-terminal telopeptide of type I collagen and tartrate-resistant acid phosphatase were significantly reduced by the combination of linagliptin and metformin treatment. We used high glucose treated MC3T3-E1 cells to mimic the condition of T2DM. Linagliptin combined with metformin treatment significantly inhibited the phosphorylation of p38 and ERK induced by high glucose treatment. In conclusion, the linagliptin combined with metformin treatment improved the rats' bone mineral density, bone structure, and osteogenic markers. Both p38 and ERK phosphorylation were reduced in high glucose MC3T3-E1 cells. Our findings highlight the potential of linagliptin combined with metformin for the treatment of T2DM-related osteoporosis.