Background: Mechanical stimulation prevents osteocyte apoptosis and activates Wnt signaling. Results: ERK-mediated anti-apoptosis is abolished by antagonists of Wnt signaling, and conversely, -catenin accumulation is blocked by inhibiting the caveolin-1/ERK pathway. Conclusion: Caveolin-1/ERK and Wnt/-catenin signaling pathways cooperate in transducing mechanical cues into osteocyte survival. Significance: This novel bidirectional crosstalk might be targeted to increase bone strength by preserving osteocyte viability.