Osteocytes play a crucial role in the maintenance and integrity of bone. They are the most abundant bone cell type in bone, and participate in signaling mechanisms that initiate targeted bone remodeling. Bone remodeling is defined as the sequential resorption and replacement of bone tissue at a defined site. Many recent studies have confirmed that osteocyte apoptosis has been linked to bone resorption resulting from estrogen depletion and other resorptive stimuli;​ however, precise spatial and temporal relationships between the two events have not been clearly established. Estrogen in bone health is of critical importance since osteoporosis, a low bone mass disease associated with an increased fracture risk, is the most prevalent degenerative disease worldwide amongst postmenopausal women. Although bone is clearly a target tissue with respect to estrogen, the mechanisms by which estrogen exerts its effects on bone remodeling remain unclear. We set out to characterize the spatial and temporal relationship between estrogen withdrawal, osteocyte apoptosis, pro-osteoclastogenic signaling and bone resorption. A well-characterized murine model was used to show activation of cortical and cancellous bone resorption in highly consistent patterns. Our studies revealed that osteocyte apoptosis is significantly elevated following estrogen loss, and that the apoptosis occurs regionally, rather than uniformly throughout the cortex. Moreover, we found that apoptotic osteocytes were overwhelmingly localized within the area where subsequent endocortical resorption is known to occur after ovariectomy in B6 mice. This led us to hypothesize that osteocyte apoptosis plays a comparable controlling role in the activation or targeting of osteoclastic resorption. We tested this by pharmacologically inhibiting osteocyte apoptosis post-ovariectomy and assessed subsequent bone resorption activity. Osteoclastic resorption was elevated only in ovariectomized animals that did not receive treatment, demonstrating that osteocyte apoptosis is a necessary and controlling step in the activation of bone remodeling. Assessment of microenviromental and biological differences in the regions containing elevated osteocyte apoptosis revealed reduced solute transport and increased oxidative damage account for the pattern of exhibited apoptosis post-ovariectomy. Together, these results have clinical significance because they provide increased understanding of factors that initiate remodeling, which is fundamental towards understanding women’s bone health and disease.