Targeting cellular senescence mitigates chemotherapy-induced bone loss in young and aged mice

Chemotherapy-induced bone loss represents a major clinical challenge, particularly in aging populations, yet the contribution of cellular senescence to this process and its therapeutic potential remain incompletely understood. Here, we investigated the role of chemotherapy-induced cellular senescence in mediating skeletal deterioration following chemotherapy and evaluated the therapeutic potential of senolytic treatment. Young (3-month-old) and aged (20-month-old) male and female mice were treated with doxorubicin (DX), a chemotherapeutic agent, dasatinib/quercetin (DQ), senolytic agents, or their combination (DX/DQ). Chemotherapy-induced hallmark features of accelerated skeletal aging, including trabecular bone loss, increased marrow adiposity, and upregulation of senescence-associated and inflammatory gene expression. These effects were sex- and age-dependent and were more pronounced in females. Senolytic treatment with DQ partially restored osteogenic gene expression, including Alpl, Runx2, and Dmp1, and reduced marrow adiposity, particularly in aged females, indicating preservation of bone marrow niche function. Proteomic analysis of cortical bone revealed that DX-induced cellular senescence was associated with extracellular matrix remodeling and a metabolic shift toward glycolysis, characterized by increased inflammatory collagen isoforms and glycolytic enzymes. DQ treatment partially reversed these molecular signatures, including restoration of several extracellular matrix proteins associated with bone architecture and mineralization. Despite these molecular improvements, recovery of trabecular bone architecture remained modest, suggesting that senolytic-mediated molecular remodeling precedes detectable skeletal recovery. Collectively, these findings support a model in which chemotherapy-induced bone loss is driven by both early osteoblast suppression and senescence-driven microenvironmental dysfunction, identifying cellular senescence as a potential therapeutic target for preserving skeletal health following chemotherapy.