Cellular senescence and the SASP in skeletal ageing: convergent mechanisms of progressive bone loss in osteoporosis.

Abstract

Skeletal ageing involves changes in endocrine regulation, mechanical loading and cellular function that can impair bone remodelling. Cellular senescence and the senescence-associated secretory phenotype (SASP) have emerged as mechanisms that help close this gap. In the ageing bone microenvironment, senescent osteocytes, mesenchymal stem cells, osteoblasts, immune cells, and vascular endothelial cells secrete pro-inflammatory cytokines, chemokines, matrix metalloproteinases, and Wnt antagonists such as sclerostin. Rather than acting as a parallel pathway, these factors converge on the same RANKL/OPG, Wnt/β-catenin, and NF-κB axes through which classical triggers operate, adding a locally generated, persistent input that promotes resorption and suppresses formation. Clearance of senescent cells prevents age-related bone loss in mice, indicating that the SASP is a distinct and independently addressable contributor to skeletal ageing. Here we review the components, regulation, and cell type-specific profiles of the bone-related SASP, and its differential involvement across age-related, postmenopausal, and secondary osteoporosis. We also assess senolytic and senomorphic approaches in relation to established osteoporosis treatments, discussing source-specific mechanisms, biomarker validation and longer-term skeletal outcomes as priorities for evaluating these approaches.