Osteoporosis is characterized by low bone mass and a deterioration of bone architecture and likely is influenced by genetic factors. The ovariectomized (OVX) mouse is well suited for osteoporosis research, as shown to date by cross-sectional studies. Here, we investigate longitudinal changes by in vivo micro-computed tomography (micro-CT) to examine the skeletal response to OVX and patterns of change in three inbred strains of mice. We address whether higher baseline bone mass among the strains of mice provides protection against bone loss and if there is a common base level of bone quantity despite genetic background after the effects of OVX have stabilized. Groups of mice (n = 7 or 8/group) from three inbred strains (C3H/HeJ, C57BL/6J, BALB/cByJ) were subjected to OVX or sham OVX surgery at 12 weeks of age. Weekly in vivo micro-CT scans were performed for 5 weeks at the proximal tibia (skipping week 4). Femurs were harvested after week 5 for analysis of the distal metaphysis and midshaft. The baseline bone architecture differed among the three inbred strains of mice, as did the longitudinal patterns of change due to OVX. At the end point, all three strains retained different bone architecture at the proximal tibia, distal femur, and femur midshaft. Rate of bone loss was correlated to amount of baseline bone volume (R = 0.82, P < 0.001). Morphological analysis indicated that trabecular bone loss due to OVX was manifested through reduced connectivity instead of overall thinning and that the quantity and rate of bone loss due to estrogen deficiency were in part genetically regulated.