Introduction The number of patients with type diabetes is
The number of patients with type 2 diabetes is increasing globally, and has become a serious public health problem. Type 2 diabetic patients exhibit a higher risk of bone fracture . In addition, clinical studies have indicated that increased fracture risk is associated with long-term use of anti-hyperglycemic drugs . For example, patients treated with thiazolidinedione or human recombinant insulin exhibit higher fracture incidence [, , , ], whereas those treated with metformin show lower fracture risk . Osteoclasts differentiated from bone marrow Sarpogrelate hydrochloride mg are responsible for normal bone remodeling and pathologic bone resorption . In the pathophysiology of inflammatory diseases of bone, such as rheumatoid arthritis, osteoclast recruitment plays an important role in bone erosion . Receptor activator of NF-κB ligand (RANKL) and macrophage colony stimulating factor (M-CSF) are commonly accepted as two indispensable factors during the process of osteoclastogenesis . Moreover, it has been reported that tumor necrosis factor (TNF)-α can induce osteoclastogenesis both in vitro [, , ] and in vivo [14,15].
Lipopolysaccharide (LPS) is a strong inducer of inflammation, which results in inflammatory bone loss [, , , , ]. LPS can stimulate RANKL secretion  and M-CSF expression  from osteoblasts or bone marrow stromal cells. In addition, LPS has been found to induce the production of proinflammatory cytokines, such as TNF-α, from macrophages or other neighboring cells at sites of inflammation [23,24]. These pro-inflammatory cytokines are reportedly involved in LPS-induced osteoclastogenesis and bone destruction, both in vivo and in vitro [, , , , ].
Dipeptidyl peptidase-4 (DPP-4; also known as the T cell surface marker CD26) was initially investigated for its involvement in the activation of T cells [30,31]. Later, DPP-4 was identified as an enzyme responsible for degrading many chemokines and incretin hormones, which are involved in the regulation of the immune system . Therefore, DDP-4 has been considered as a possible participant in the inflammatory process [33,34].
DPP-4 inhibitor, a new anti-hyperglycemic therapy, maintains the blood glucose level by initially inhibiting the enzymatic activity of DPP-4, and subsequently inhibiting the degradation of incretin hormones that can stimulate insulin secretion from pancreatic β cells . Through this mechanism, DPP-4 inhibitor is effective in the treatment of type 2 diabetes without the production of major side effects. The role of DPP-4 inhibitors in the regulation of insulin and glucagon secretion is well-known, but there is currently little evidence that the use of a DPP-4 inhibitor can directly improve chronic inflammation [35,36]. However, the effect of DPP-4 inhibition in inflammation remains largely unknown.
Recently, the effect of DPP-4 inhibition on bone metabolism has been extensively studied. Clinical studies indicated that diabetic patients treated with DPP-4 inhibitors exhibit reduced fracture risk, compared with patients who were treated with other antidiabetic drugs. Furthermore, the DPP-4 inhibitor sitagliptin demonstrated positive effects on bone metabolism through improvements in bone quality, bone density, and bone markers [, , , ]. We suspect that these positive skeletal effects of DPP-4 inhibitors may arise from modulation of energy metabolism pathways associated with DPP-4 and incretin peptides.
Material and methods
Discussion Diabetic patients suffer from a higher risk of osteoporosis, possibly because of the decreased bone turnover associated with poor glycemic control . Moreover, many studies have indicated that long-term use of some antidiabetic drugs has a negative effect on bone metabolism [2,43]. However, recent clinical studies have indicated that diabetic patients treated with DPP-4 inhibitor demonstrate a reduced fracture rate, compared with diabetic patients treated with other therapies [, , , ]. Therefore, long-term use of DPP-4 inhibitors has received attention for its supplementary effect in the treatment of osteoporosis. Other skeletal effects of DPP-4 inhibitors, including effects on inflammatory bone resorption, are also promising. To the best of our knowledge, there have been few reports regarding the short-term effect of DPP-4 inhibitor administration on osteoclast formation in inflammatory conditions.