The relationships between mechanical loads and bone microstructure are of interest to those who seek to predict bone mechanical properties from microstructure or to predict how organization of bone microstructure is driven by mechanical loads. While strains and displacements in the material are inherently responsible for mechanically caused changes in the appearance of the microstructure, it is the morphometric measures of microstructural organization that are often available for assessment of bone quality. Therefore, an understanding of how strain history is reflected in morphometric measures of bone microstructure has practical implications in that it may provide clinically measurable indices of mechanical history in bone and improve interpretation of bone mechanical properties from microstructural information. The objective of the current study was to examine changes in morphometric measures of cancellous bone microstructure in response to varying levels of continuum level strains. The experimental approach included stereologic analysis of microcomputed tomography (μCT) images of human cancellous bone samples obtained at sequentially increasing levels of strain in a custom-made loading apparatus mounted in a μCT scanner. We found that the degree of anisotropy (DA) decreased from baseline to failure and from failure to postfailure. DA partially recovered from postfailure levels upon unloading; however, the final DA was less than at failure and less than at baseline. We also found that average trabecular thickness (Tb.Th.Av) increased with displacements at postfailure and did not recover when unloaded. Average trabecular number decreased when the specimens were unloaded. In addition, the heterogeneity of Tb.Th as measured by intra-specimen standard deviation (Tb.Th.SD) increased and that of trabecular number (Tb.N.SD) decreased with displacements at postfailure. Furthermore, the intraspecimen coefficient of variation of trabecular number decreased at postfailure displacements but did not recover upon unloading. Finally, the coefficient of variation of trabecular separation at unload was less than that at baseline. These measures can be developed into image-based indices to estimate strain history, damage, and residual mechanical properties where direct analysis of stresses and strains, such as through finite element modeling, may not be feasible. It remains to be determined how wide a time interval can be used to estimate strain history before remodeling becomes an overriding effect on the trabecular architecture.