Immunometabolic reprogramming in osteoporosis–osteoarthritis comorbidity: from inflammaging to osteochondral unit degeneration

Osteoporosis (OP) and osteoarthritis (OA) are common and highly co-occurring degenerative bone diseases in the elderly population, and their comorbidity mechanisms cannot be fully explained by traditional factors such as mechanical load, changes in bone mass, or hormonal imbalance. OP is primarily characterized by systemic decrease in bone mass and reduced bone strength, while OA is mainly manifested by cartilage degeneration within specific joints, synovial inflammation, and abnormal subchondral bone remodeling. Although both are influenced by aging, inflammation, and metabolic abnormalities, there are significant differences in their affected areas and pathological processes. In recent years, increasing evidence suggests that immunosenescence, chronic low-grade inflammation, and structural-functional imbalance of the osteochondral unit may constitute an important pathological basis for the progression of both diseases. Immunometabolic reprogramming is gradually being recognized as a potential mechanistic framework linking bone loss and joint degeneration, involving multiple processes such as enhanced glycolysis, impaired oxidative phosphorylation, lipid metabolism disorders, dysregulation of the NAD + /Sirtuins axis, and mitochondrial dysfunction, which can affect the functional status of key cell types including osteoclasts, osteoblasts, chondrocytes, and synovial macrophages. However, current evidence on the involvement of immunometabolic reprogramming in the progression of OP-OA comorbidity primarily comes from single-disease studies of OP or OA, while direct evidence from OP-OA comorbidity cohorts, integrated osteochondral unit models, and longitudinal clinical studies remains limited. Therefore, existing research is insufficient to establish that immunometabolic reprogramming constitutes a definitive causal pathway for the development of OP-OA comorbidity; rather, it should be regarded as a candidate integrative mechanism and a hypothesis to be validated for explaining the shared pathological basis of the two conditions. Centered on the thematic axis of “immunosenescence–immunometabolic reprogramming–osteochondral unit degeneration,” this article systematically reviews the key mechanisms, potential therapeutic insights, and current translational challenges in the comorbidity of osteoporosis and osteoarthritis, aiming to summarize the existing evidence base, clarify mechanistic boundaries, and provide new theoretical references for mechanistic analysis, risk stratification, and targeted intervention in OP-OA comorbidity.