For many centuries, the osteoblast is considered to be responsible for bone formation. It is also believed that an imbalance of osteoblasts (weak) and osteoclasts (strong) is the main cause for bone diseases such as osteomalacia and osteoporosis and periodontal diseases, globally the most prevalent dental disease. Most studies are aimed at these two surface cells, although neither of them penetrates into the deep bone matrix. Osteocytes, terminally differentiated osteoblasts, are buried deep in the bone and account for up to 95% of all bone cells. Due to the high mineral density around osteocytes, most people consider them “quiescent” cells. Only recent research revealed more profound and important roles of osteocytes, such as mechano-sensors. In this study, we developed the innovative “FITC-Imaris technique”, which combines FITC (Fluorescein isothiocyanate), confocal microscopy and Imaris software. With this method, we could visualize the 3-D morphology of embedded osteocytesand statistically quantitate the osteocyte structure cell surface total cell volume, and dendrite numbers. We examined Dmp1 (dentin matrix protein 1) mutant mice, an established osteomalacia animal model, and showed both significant morphological and statistical differences in the osteocyte structure between the Dmp1-null mice and their age-matched control littermates, suggesting a high correlation between osteocytes and osteomalacia. Then, we studied periostin knockout mice, a periodontal disease mouse model, and found that osteocyte’ morphological and pathological changes are closely linked to alveolar bone loss. Monoclonal anti-SOST antibody) restores not only bone loss, but also osteocyte morphology, suggesting osteocytes may be responsible for bone loss in periostin mutant mice. Lastly, we examined OVX rats as an osteoporosis model and showed that Ocys failed to maintain their shape, dendrite number and size in response to estrogen deficiency. Abnormalities in blood vessel morphology and bone matrices also developed, resulting in osteoporotic changes in both compact and trabecular bone. Similarly, administering SOST antibody normalized osteocyte morphology and recovered bone loss from osteoporosis. Altogether, we demonstrated that Ocy maturation was directly linked to a slow mineralization process. Minerals were constantly “pumped” via Ocy-dendrites to the surrounding matrix and to the bone surface. These study results expanded our understanding of how osteocytes regulate bone development and mineralization. These findings have clinical relevance, as SOST antibody improved bone phenotypes in all osteomalacia, periodontal disease and osteoporosis animal models, holding great potential for treating human bone disease. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/155190