STRUCTURAL REQUIREMENTS FOR BISPHOSPHONATE ACTIONS IN-VITRO

We investigated the structural requirements for the binding of bisphos phonates to bone mineral and the relation between their affinity for b one and their effects on bone resorption in vitro. For this we used fe tal mouse long bones in culture and bisphosphonates with variable R(1) , and R(2) structures. In addition, we studied the effect of structura l differences in the incorporation of calcium into bone. We found that bisphosphonates containing a hydroxyl group in the R(1) position have the highest affinity for bone mineral. This was related to their capa city to inhibit the incorporation of calcium into long bones but not t o their antiresorptive potency. The latter was primarily determined by R(2). Furthermore, the effect of bisphosphonates on calcification, bu t not on resorption of bone explants, was mainly determined by the mod e of addition. The continuous presence of bisphosphonate during cultur e inhibited calcification even at very low concentrations, but short i ncubation of the bones with relatively high concentrations had no effe ct. This is probably a result of differences in the availability of th e compound to the process of calcification. Because, in vivo, the more potent bisphosphonates inhibit resorption without adversely affecting mineralization of the skeleton and they disappear rapidly from the ci rculation after administration, we suggest that cultures of bone expla nts incubated with bisphosphonates for short times rather than culture s in which the drugs are continuously present provide more accurate in formation about the in vivo effect of these compounds on both resorpti on and calcification.