Osteoporosis (OP) features reduced bone mass and impaired microarchitecture, increasing fragility fractures. Current antiresorptive/anabolic therapies are effective but limited by variable response, adverse events, and underappreciation of skeletal immune regulation. The immune-bone coupling paradigm highlights the bone immune microenvironment as an upstream determinant of osteoclastogenesis and osteogenesis, yet a unified mechanism linking these cues to remodeling imbalance is lacking. Lysosomes serve not only as degradative/recycling organelles but also as hubs integrating nutrient sensing, acidification, ion signaling, and transcriptional switching, positioning them as a key set point connecting immunometabolic dysregulation to bone loss. This review proposes a lysosome-centric osteoimmune network, summarizing core lysosomal modules (nutrient metabolism, acidification, biogenesis) and their cell type-specific roles. In the osteoclast lineage, lysosomal competence governs differentiation and resorptive execution; in osteoblasts and osteocytes, it sustains proteostasis, secretion, and stress adaptation, shaping osteogenic capacity and niche signaling. In macrophages, T cells, and B cells, lysosomes modulate metabolic adaptation and polarization, rebalancing pro- vs anti-osteoclastogenic cues. Translationally, we synthesize lysosome-targeted strategies spanning effector blockade at the resorptive arm, immunometabolic resetting, and bone-targeted delivery to improve specificity and therapeutic window, including natural products as modulators. Future priorities include quantitative lysosomal state readouts, cell type- and stage-specific causal validation, and bone-directed translation to enable testable, actionable interventions.
Zhou et al. (2026) studied this question.