The Osteoimmune Axis in Aging: Role of Immunosenescence, Inflammaging and Senescent Cells in the Pathogenesis of Osteoporosis

Background: Age-related osteoporosis is increasingly recognized as a disorder of disrupted immune–skeletal communication rather than solely impaired bone turnover. Immunosenescence, cellular senescence, and inflammaging interact within the bone microenvironment and may contribute to progressive bone loss and remodeling imbalance.
Methods: This narrative review integrates current evidence on the interplay among immunosenescence, cellular senescence, inflammaging, and age-related osteoporosis. Emphasis is placed on inflammatory cytokines, the RANKL/RANK/OPG axis, senescence-associated secretory phenotype (SASP), immune–skeletal interactions, and key signaling pathways, including NF-κB, JAK/STAT, MAPK, NLRP3 inflammasome, oxidative stress, TGF-β, and Wnt/β-catenin. Emerging therapeutic strategies targeting these mechanisms are also discussed.
Results: Evidence indicates that age-associated alterations in immune-cell function can reshape the bone marrow microenvironment and enhance osteoclastogenesis through inflammatory cytokines and dysregulation of the RANKL/RANK/OPG axis. TNF-α, IL-1β, IL-6, and IL-17 may further promote osteoclast activity while impairing osteoblast and mesenchymal stromal-cell function. Accumulation of senescent skeletal, stromal, and immune cells may amplify inflammation through SASP-mediated signaling. These processes converge on interconnected molecular pathways, while epigenetic and miRNA-mediated mechanisms provide additional regulation. Potential interventions include RANKL/OPG modulation, anti-inflammatory therapies, senolytics, senomorphics, immunosenescence-targeted approaches, and nutritional or natural compounds.
Conclusion: Age-related osteoporosis may represent a complex osteoimmune disorder driven by progressive disruption of immune–skeletal communication. Integrating immune, inflammatory, senescence, and skeletal biomarkers may facilitate osteoimmune phenotyping and support personalized therapeutic strategies.