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