Bisphosphonates induce osteoclast apoptosis, thereby decreasing bone resorption and reducing the rate of bone remodeling. Earlier work from our group and others has demonstrated that, additionally, bisphosphonates prevent osteoblast and osteocyte apoptosis in vivo and in vitro, raising the possibility that perhaps part of their anti-fracture efficacy may result from preserving the integrity of the osteocyte network and prolonging the working time of bone forming cells. Whereas induction of osteoclast apoptosis results from inhibition of the mevalonate pathway or from conversion to toxic ATP analogs, prevention of osteoblastic cell apoptosis is mediated by connexin43 hemichannel opening and activation of the extracellular signal-regulated kinases (ERKs). We examined here the ability of several bisphosphonates, including novel analogs, to exert these two effects. All 16 bisphosphonates studied inhibited etoposide-induced apoptosis of MLO-Y4 osteocytic cells and osteoblastic cells derived from calvaria, with EC50 between 10⁻¹² and 10⁻¹⁰ M. On the other hand, only 10 analogs induced apoptosis of RAW-264.7-cell-derived osteoclasts. Each of the 6 bisphosphonates that lack pro-apoptotic activity in osteoclasts but retain anti-apoptotic activity in osteoblasts and osteocytes has a structural-related analog that is active in both cell types. These findings indicate that the structural prerequisites for the anti-apoptotic effect of bisphosphonates on cells of the osteoblastic lineage are less stringent than the ones required to induce osteoclast apoptosis and confirm that bisphosphonates act on the two cell types by distinct mechanisms. Preservation of osteoblast and osteocyte viability without inducing osteoclast apoptosis by these bisphosphonates analogs opens new possibilities for the treatment of bone fragility in conditions in which a decrease in bone remodeling is not desirable.