Osteoimmune senescence in aging bone: from inflammaging dogma to cell-type-specific therapeutic windows

Aging-related bone diseases are often interpreted through hormonal decline, defective remodeling, and chronic low-grade inflammation, yet these accounts do not fully capture the cellular, spatial, and temporal heterogeneity of skeletal aging. Bone is an immune-active organ sustained by coordinated signaling among skeletal, hematopoietic, immune, adipose, vascular, and neural compartments. Cellular senescence perturbs this network through stable cell-cycle arrest, metabolic remodeling, and a heterogeneous senescence-associated secretory phenotype (SASP). Whereas recent osteoimmunology syntheses broadly catalog age-related immune-bone interactions, our specific advance is to treat p16- and p21-associated states as functionally non-equivalent and to translate cell identity, anatomical compartment, persistence, and disease stage into explicit therapeutic decision points. We compare senescence programs in bone marrow stromal cells, osteoblast-lineage cells, osteocytes, osteoclast precursors, and immune populations, and then place them within an aging marrow ecosystem shaped by hematopoietic drift, marrow adiposity, vascular decline, and neural degeneration. These mechanisms are mapped across osteoporosis, osteoarthritis, rheumatoid arthritis, periodontitis, and delayed fracture healing. Emerging interventions include senolytics, senomorphics, immune-mediated clearance, bone-targeted delivery, and biomarker-guided patient selection. By operationalizing cell- and stage-resolved therapeutic windows, this framework aims to move senescence-targeted treatment beyond broad senolysis and toward testable precision strategies for aging bone.