Significance The explanation of how bone senses and adapts to mechanical stimulation still relies on hypotheses. The fluid flow hypothesis claims that a load-induced fluid flow through the lacunocanalicular network can be sensed by osteocytes, which reside within the network structure. We show that considering the network architecture results in a better prediction of bone remodeling than mechanical strain alone. This was done by calculating the fluid flow through the lacunocanalicular network in bone volumes covering the complete cross-sections of mouse tibiae, which underwent controlled in vivo loading. The established relationship between mechanosensitivity and network architecture in individual animals implies possibilities for patient-specific therapies. A new connectomics approach to analyze lacunocanalicular network properties is necessary to understand skeletal mechanobiology.