Study of oral tissues to understand the mechanisms of osteoporosis and oral bone loss includes histologic, biochemical, and molecular assessments of the tissue itself, as well as in vivo analysis of the biology of resident cells. Tissue sampling is limited by the nature of the defect and the use of appropriate controls (contralateral site vs same site, different subjects vs repeated measures of the same sites). Experimental parameters may include histomorphometrics, histochemistry, immunohistochemistry, and in situ hybridization. Molecular and biochemical technology also can be used to study the tissue in vivo. The presence of mineral is a confounding variable. To understand the underlying mechanisms of oral bone loss, cell culture is a powerful tool. The location in the oral cavity, the type of tissue (periosteum/cortical bone/trabecular bone), and the presence of pathology (periodontal disease) affect the biology of the cultured cells. Enzymatic release of cells from their extracellular matrix yields heterogeneous cell populations. Migratory cells from explant cultures are more homogeneous but less differentiated. Fibroblastic and bacterial contamination may be problems. Although cell culture data must be considered in the context of the intact tissue, the potential exists for developing bone cell function tests with diagnostic use in the treatment of bone disease.