Numerous clinical cohorts are exposed to reduced skeletal loading and associated bone loss, including surgical patients, stroke and spinal cord injury victims, and women on bed rest during pregnancy. In this context, understanding disuse-related bone loss is critical to developing interventions to prevent fractures and the associated morbidity, mortality, and cost to the health care system. The aim of this pilot study was to use high-resolution peripheral QCT (HR-pQCT) to examine changes in trabecular and cortical microstructure and biomechanics during a period of non weight bearing (WB) and during recovery following return to normal WB. Surgical patients requiring a 6-week non WB period (n=12, 34.8±7.7 yrs) were scanned at the affected and contralateral tibia prior to surgery, after the 6-week non WB period, and 6 and 13 weeks after returning to full WB. At the affected ultradistal tibia, integral vBMD (including both trabecular and cortical compartments) decreased with respect to baseline (-1.2%), trabecular number increased (+5.6%), while trabecular thickness (-5.4%), separation (-4.6%), and heterogeneity (-7.2%) decreased (all p<0.05). Six weeks after return to full WB, trabecular structure measures reverted to baseline levels. In contrast, integral vBMD continued to decrease after 6 (-2.0%, p<0.05) and 13 weeks (-2.5%, p=0.07) of full WB. At the affected distal site, the disuse period resulted in increased porosity (+16.1%, p<0.005), which remained elevated after 6 weeks (+16.8%, p<0.01) and after 13 weeks (+16.2%, p<0.05). A novel topological analysis applied to the distal tibia cortex demonstrated increased number of canals with surface topology ("slabs" +21.7%, p<0.01) and curve topology ("tubes" +15.0%, p<0.05) as well as increased number of canal junctions (+21.4%, p<0.05) following the disuse period. Porosity increased uniformly through increases in both pore size and number. Finite element analysis at the ultradistal tibia showed decreased stiffness and failure load (-2.8% and -2.4%, p<0.01) following non WB. These biomechanical predictions remained depressed following 6 and 13 weeks of full WB. Finite element analysis at the distal site followed similar trends. Our results suggest that detectable microstructural and biomechanical degradation occurs--particularly within the cortical compartment--as a result of non WB and persists following return to normal loading. A better understanding of these microstructural changes and their short- and long-term influence on biomechanics may have clinical relevance in the context of disuse-related fracture prevention.