Age-related osteoporosis manifests as a complex pathology that disrupts bone homeostasis and elevates fracture risk, yet the mechanisms facilitating age-related shifts in bone marrow macrophages/osteoclasts (BMMs/OCs) lineage are not fully understood. To decipher these mechanisms, we conducted an investigation into the determinants controlling BMMs/OCs differentiation. We performed single-cell multi-omics profiling on bone marrow samples from mice of different ages (1, 6, and 20 months) to gain a holistic understanding of cellular changes across time. Our analysis revealed that aging significantly instigates OC differentiation. Importantly, we identified as a vital gene for osteoclastogenesis and bone resorption during the aging process. Counterbalancing the effects of , we found , , and to play crucial roles. By thoroughly examining the cellular dynamics underpinning bone aging, our study unveils novel insights into the mechanisms of age-related osteoporosis and presents potential therapeutic targets for future exploration.