Bone cell apoptosis is seen at sites of active turnover. We hypothesize that at these sites, factors released from resorbing bone induce apoptosis of vicinal cells. Related to this observation, earlier studies indicate that an elevation in the level of inorganic phosphate ions combined with a modest increase in the calcium (Ca2+) concentration, or a rise in the local concentration of RGD-containing peptides promote osteoblast apoptosis. The aim of the current investigation is to elucidate the mechanism by which these extracellular matrix components induce bone cell apoptosis. The data presented in this study clearly demonstrate that osteoblasts are sensitive to peptide fragments and solubilized mineral ions. It is reasonable to expect that these apoptogens would be generated by osteoclasts during resorption of the extracellular bone matrix. We suggest that these components conspire to regulate bone cell function. In terms of the mechanism by which these agents activate apoptosis, it is clear that while they share common pathways, there are some differences in the mechanism of apoptosis. These differences appear to be upstream of caspase activation. The observation that two such pathways exist lends strength to the notion that apoptosis is carefully regulated in bone and that signals from both matrix components act together to trigger the remodeling process.