Potential Metabolic Pathways Involved in Osteoporosis and Evaluation of Fracture Risk in Individuals with Diabetes

Abstract

Diabetes has a significant global prevalence. Chronic hyperglycemia affects multiple organs and tissues, including bones. A large number of diabetic patients develop osteoporosis; however, the precise relationship between diabetes and osteoporosis remains incompletely elucidated. The activation of the AGE-RAGE signaling pathway hinders the differentiation of osteoblasts and weakens the process of bone formation due to the presence of advanced glycation end products. High glucose environment can induce ferroptosis of osteoblasts and then develop osteoporosis. Hyperglycemia also suppresses the secretion of sex hormones, and the reduction of testosterone is difficult to effectively maintain bone mineral density. As diabetes therapy, thiazolidinediones control blood glucose by activating PPAR-γ. Activated PPAR-γ can promote osteoclast differentiation and regulate osteoblast function, triggering osteoporosis. The effects of metformin and insulin on bone are currently controversial. Currently, there are no appropriate tools available for assessing the risk of fractures in diabetic patients, despite the fact that the occurrence of osteoporotic fractures is considerably greater in diabetic individuals compared to those without diabetes. Further improving the inclusion criteria of FRAX risk factors and clarifying the early occurrence of osteoporosis sites unique to diabetic patients may be an effective way to diagnose and treat diabetic osteoporosis and reduce the risk of fracture occurrence.

Figure 1

The AGEs were increased in diabetic patients. AGEs inhibit osteoblast differentiation after binding to RAGE. RAGE binding to ligand increases ROS formation, leading to osteoblast dysfunction. Intracellular accumulation of AGEs can induce apoptosis in osteoblasts. The high glucose environment aggravates ferroptosis, leading to osteoblast dysfunction. Male diabetic patients have decreased testosterone levels. Decreased testosterone levels increase bone turnover, leading to bone loss. The above process eventually leads to osteoporosis.