Immune ageing in skeletal fragility: clonal haematopoiesis and failure of inflammatory resolution during fracture repair.

Older adults with comparable bone mineral density or fracture-risk estimates may nevertheless differ markedly in fracture occurrence, repair kinetics and functional recovery. This heterogeneity suggests that skeletal fragility reflects, at least in part, ageing of the bone-immune-haematopoietic system rather than bone mass alone. Here, we synthesise evidence linking the aged osteoimmune niche to inflammatory bone loss and impaired fracture repair. We focus on four interrelated processes: CHIP-associated amplification of myeloid inflammation, shaped by driver mutation and clone size; age-related skewing of T- and B-cell compartments; persistent cellular senescence and senescence-associated secretory signalling; and failure of macrophage- and regulatory T-cell-mediated inflammatory resolution. Among CHIP drivers, direct skeletal evidence is strongest for DNMT3A-mutant clones in inflammatory bone loss. Bone-specific evidence for TET2 remains limited, whereas evidence for ASXL1 is largely absent. In fracture repair, the most direct preclinical evidence concerns cellular senescence and age-altered macrophage function, while the ability of CHIP to predict delayed union has not been validated. We define immune resilience as the capacity to mount a proportionate acute response, clear damaged cells and debris, actively resolve inflammation, and transition to reparative and remodelling states. Current evidence is insufficient to support routine immune-guided fracture care. The immediate priority is to determine, in prospective fracture cohorts, whether phase-resolved local and circulating measures explain variation in repair beyond bone mineral density, frailty, fracture characteristics, biological sex and treatment exposure.