Aeimlapa R.Panmanee J.Teerapornpuntakit J.Wongdee K.Thongbunchoo J.Panupinthu N.Svasti S.Apaijai N.Sa-nguanmoo P.Chattipakorn S.Chattipakorn N.Charoenphandhu N.Mahidol University2026-02-072026-02-072026-02-01Comprehensive Physiology Vol.16 No.1 (2026)https://repository.li.mahidol.ac.th/handle/123456789/114833Increased fracture risk in prediabetes and diabetes mellitus partly arises from bone collagen damage and enhanced bone resorption. Certain antidiabetic agents—particularly thiazolidinediones—paradoxically aggravate bone loss and fractures, especially in postmenopausal women with osteoporosis. However, dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., vildagliptin and omarigliptin) might help prevent diabetic osteopathy, although variable outcomes have been observed due to unknown mechanisms. Herein, we used high-fat diet-fed rats to demonstrate that oral administration of vildagliptin for 4 weeks not only alleviated insulin resistance but also improved tibial bone microstructure, as determined by bone histomorphometry. Further in vitro investigations in primary osteoblasts showed that both vildagliptin and omarigliptin similarly increased osteoblast viability, rather than upregulating the expression of osteoblast-specific genes (e.g., Runx2 and alkaline phosphatase). We also used primary multinucleated osteoclasts to elucidate how the two DPP-4 inhibitors modulated osteoclast functions. Interestingly, only omarigliptin, but not vildagliptin, reduced the number of TRAP-positive cells and the mRNA expression of osteoclast-specific genes (e.g., RANK and cathepsin K). In silico molecular dynamics revealed that omarigliptin and vildagliptin interacted differently with the DPP-4 homodimer. Transient binding to one chain and tight binding to the other chain of the DPP-4 homodimer by omarigliptin may be associated with its higher potency in inhibiting bone resorption. In conclusion, DPP-4 inhibitors could improve bone microstructure, in part by increasing osteoblast viability and inhibiting osteoclast-mediated bone resorption. Thus, omarigliptin may offer greater benefits to diabetic patients with osteoporosis, as it also helps suppress osteoclastogenesis and bone resorption.Biochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1002/cph4.701032-s2.0-1050282347732040460341566690