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Prolonged reduction in weightbearing causes bone loss. Disuse of bone is associated with recovery from common musculoskeletal injury and trauma, bed rest resulting from various medical conditions, and spaceflight. The hindlimb‐suspension rodent model is popular for simulating unloading and disuse. We hypothesized that controlled mechanical loading of the tibia would protect against bone loss occurring from concurrent disuse. Additionally, we hypothesized that areas of high mechanical peak strains (midshaft) would provide more protection than areas of lower strain (distal shaft). Adult C57BL6/J mice were suspended for 3 weeks, with one limb subjected to tibial compression four times per week. μCT imaging was completed at days 0, 11, and 21, in addition to serum analysis. Significant bone loss caused by hindlimb suspension was detected in trabecular bone by day 11 and worsened by day 21 (p < 0.05). Bone loss was also detected in cortical thickness and area fraction by day 21. However, four short bouts per week of compressive loading protected the loaded limb from much of this bone loss. At day 21, we observed a 50% loss in trabecular bone volume/total volume and a 6% loss in midshaft cortical thickness in unloaded limbs, but only 15% and 2% corresponding losses in contralateral loaded limbs (p = 0.001 and p = 0.02). Many bone geometry parameters of the loaded limbs of suspended animals did not significantly differ from non‐suspended control limbs. Conversely, this protective effect of loading was not detected in cortical bone at the lower‐strained distal shaft. Analysis of bone metabolism markers suggested that the benefits of loading occurred through increased formation instead of decreased resorption. This study uniquely isolates the role of externally applied mechanical loading of the mouse tibia, in the absence of muscle stimulation, in protecting bone from concurrent disuse‐related loss, and demonstrates that limited bouts of loading may be highly effective during prolonged disuse. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]