Introduction. Canonical Wnt inhibitor Sclerostin (SOST) may be a key mechanotransduction regulator. Methods. Unloading/loading 10 week old Sost−/− and WT mice. Unloading: Quads and calf muscles injected each with 0.5U botulinum toxin (BTX, Allergan) caused tibial unloading. Loading: 1200 cycles of tibial axial loading, 1200μe on mid-shaft, 4Hz, 5 days/week. Treated and control tibiae μCT scanned (Skyscan 1174) at 2 weeks. Results. Unloading the WT tibiae significantly decreased cortical bone volume (−5%) and thickness (−7%) compared to WT control (p<0.01). Larger bone volume loss (−25%) was seen in the trabecular compartment (p<0.01), along with 10% and 22% decreases in trabecular thickness and number (p<0.01). These parameters were not altered between unloaded and control Sost−/− tibiae. Tibial loading increased cortical bone volume in WT (18%) and Sost−/− (25%) mice (p<0.01). Cortical thickness was also increased in WT (19%) and Sost−/− (17%) mice (p<0.01). The trabeculae of the WT loaded tibiae showed significant thickening (15%, p<0.01) not seen in the Sost−/− tibiae. Metaphyseal cortical bone volume increased in both loaded WT (13%) and Sost−/− (31%) tibiae compared to their controls (p<0.01), suggestive of metaphyseal corticalisation. Conclusion. SOST knockout inhibited unloading-induced bone loss, but not loading-induced bone gain. SOST may have an important role in bones response to unloading, but may not be essential for the response to loading