Senescent immune cells, inflammaging, and bone loss: therapeutic potential and translational challenges of senolytics in osteoporosis

Abstract

Osteoporosis is a common age-related skeletal disorder characterized by low bone mass, deterioration of bone microarchitecture, and increased susceptibility to fragility fractures. Although antiresorptive and anabolic therapies have substantially improved fracture prevention, current treatments do not fully address the aging-related biological processes that disrupt skeletal homeostasis. Increasing evidence from osteoimmunology, immunosenescence, and cellular senescence research suggests that inflammaging contributes to age-related bone loss by reshaping the bone marrow immune microenvironment. Immune cells with senescence-associated features may promote bone remodeling imbalance through excessive production of senescence-associated secretory phenotype factors, including interleukin-1β, interleukin-6, tumor necrosis factor-α, chemokines, matrix-degrading enzymes, and receptor activator of nuclear factor-κB ligand. These mediators enhance osteoclast differentiation and survival, impair osteoblast function, suppress osteogenic differentiation of bone marrow mesenchymal stromal cells, and propagate paracrine senescence within the bone marrow niche. Senolytics are pharmacological agents that selectively induce apoptosis in senescent cells by targeting senescent-cell anti-apoptotic pathways. Preclinical studies, including those using dasatinib plus quercetin, fisetin, and bone-targeted delivery platforms, have demonstrated the capacity to reduce global senescent-cell burden, attenuate SASP-related inflammation, and improve certain skeletal parameters in models of aging, postmenopausal osteoporosis, and radiotherapy-associated bone loss. However, it remains unclear whether these benefits arise from the elimination of immune cells with senescence-associated features, stromal cells, osteocytes, or a combination thereof. Critically, direct evidence that currently available senolytics selectively eliminate senescence-associated immune-cell subsets within the osteoporotic bone marrow is lacking. Early clinical evidence supports feasibility and hypothesis generation but does not yet establish senolytics as routine osteoporosis therapy. This narrative review synthesizes the mechanistic links among immunosenescence, inflammaging, immune cells with senescence-associated features, and bone remodeling imbalance; critically evaluates current preclinical and clinical evidence for senolytics in osteoporosis; and proposes a structured research roadmap—centered on fate-mapping, lineage-specific depletion, and single-cell multi-omics—to convert the prevailing hypothesis into experimentally testable and clinically actionable evidence, while delineating the translational challenges that must be overcome to achieve precision senolytic therapy.