Bone disuse leads to severe bone loss and deterioration of bone architecture. In our study we initially assessed the local distribution of mechanical properties of bone on a micro-nano scale and its correlation to strain distribution. Then the effects of disuse were investigated by investigating remodeling of mechanical properties of bone in the three orthogonal directions. Left tibia samples were obtained from 5-month old female Sprague Dawley rats, including baseline control (n=9) and hindlimb suspended (n=9) groups. Elastic modulus was measured by nanoindentation at the dedicated locations. Three additional tibias from control rats were loaded axially to measure bone strain, with 6-10N at 1Hz on a Bose machine for strain measurements. In the control group, the difference of the elastic modulus between periosteum and endosteum was much higher at the anterior and posterior regions (2.6GPa), where higher strain differences were observed (45μɛ). Minimum elastic modulus difference between periosteum and endosteum was observed at the medial region (0.2GPa), where neutral axis of the strain distribution was oriented with lower strain difference (5μɛ). Strong correlation between elastic modulus difference and strain difference in anterior, posterior, and medial regions was observed (R2>0.95). In the disuse group, however, the elastic modulus differences in the anterior posterior regions reduced to 1.2GPa from 2.6GPa in the control group, and increased in the medial region to 2.7GPa from 0.2GPa. It is suggested that material property of bone may be strongly influenced by the overall strain magnitude in the healthy skeleton. Such pattern was compromised in disuse osteopenia, suggesting that the remodeling in distribution of micro-nano elastic moduli among different regions may serve as a predictor for early stage of osteopenia. In the second part of the study, to obtain data in all directions, the bone was cut in - a) transverse plane (axial), b) coronal plane (circumferential), and c) sagittal plane (radial). Mechanical properties, such as elastic modulus (E) and hardness, were calculated by nanoindentation on the periosteal and endosteal surfaces over the lateral region of the bone samples. Results showed -1) an anisotropic bone structure with axial and radial directions with the highest and the lowest E values, respectively, on both periosteum and medullary endosteum;​ and 2) a statistically significant difference between the control and the disuse group on the E values of the endosteum in the radial and circumferential directions. It is suggested that the functional disuse weakened the mechanical properties of the endosteum but not the periosteum. These findings have high clinical significance for the study of drug designing and mechanotransduction pathways. It is also accrued that the nano-mechanical properties in the axial orientation were not affected from the one month of functional disuse, pointing geometrical anisotropy in the remodeling processes.