• YAP/TAZ and ERα exhibit synergistic cooperation and pathway antagonism, with context-dependent dynamics shaping skeletal adaptation.
• Mechanical potentiation of ERα transcriptional activity requires YAP/TAZ co-activation in bone mesenchymal stem cells.
• Estrogen signaling modulates YAP mechanosensitivity through cytoskeletal remodeling, linking hormonal and mechanical pathways.
• The YAP/TAZ-ERα axis is a promising therapeutic target for osteoporotic bone loss, especially in alveolar bone preservation.