Immunosenescence and Bone Homeostasis: From Mechanisms of Homeostasis Disruption to Therapeutic Opportunities in Age-Related Skeletal Disorders

The progressive decline in immune function during aging, termed immunosenescence, is increasingly recognized as a critical driver of skeletal fragility and impaired bone regeneration. This age-associated phenomenon—driven by thymic involution, inflammaging, and the accumulation of senescent immune cells—disrupts bone homeostasis primarily through the establishment of a pro-inflammatory milieu, wherein senescence-associated secretory phenotype (SASP) factors directly reprogram the function and fate of mesenchymal stem cells, osteoblasts, osteoclasts, and chondrocytes. Clinically, this immune-driven disruption of the bone microenvironment manifests across a spectrum of age-related skeletal disorders—including osteoporosis and osteoarthritis as prototypes of systemic and local bone loss, respectively, as well as delayed fracture healing, intervertebral disc degeneration, and periodontitis as paradigms of impaired regenerative and defensive responses. Despite advances in osteoimmunology revealing bidirectional immune-bone interactions, the mechanistic links between senescent immune cells and bone pathophysiology remain incompletely defined, presenting a significant barrier to therapeutic innovation. Herein, we synthesize current evidence to elucidate how immunosenescence, through the dysfunction of both innate and adaptive immunity, progressively dismantles bone homeostasis. We critically evaluate current challenges in dissecting the relative contributions of immunological memory accumulation versus fundamental aging processes to skeletal decline. We identify key knowledge gaps and propose strategic research directions, including longitudinal human immunophenotyping studies and innovative organoid-immune aging models. Such approaches hold the potential to transform the therapeutic landscape of age-related skeletal diseases by enabling precision interventions that target specific immunosenescence pathways to rejuvenate the aging skeleton.