Structure-activity relationships of various bisphosphonates

A variety of bisphosphonates with aliphatic side chains of increasing length, as well as 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (AHPrBP, formerly APD), dichloromethylene-bisphosphonate (Cl2MBP, formerly Cl2MDP), and dibromomethylene bisphosphonate (Br2MBP, formerly Br2MDP), were compared in vitro and in vivo to find (a) a possible relationship between structure and activity in order to give some indication about their mechanism(s) of action on bone and (b) the most efficient and safe compound having an effect on bone resorption. Some relationship was found between inhibition of calcium phosphate precipitation in vitro and of mineralization in vivo. No correlation existed, however, between any parameter measured and bone resorption. The number of calvaria cells in culture was decreased by compounds with a chain length greater than 5-C, by AHPrBP, Cl2MBP, and Br2MBP. Lactate production by these cells in vitro was increased by the long chain bisphosphonates and AHPrBP, and was decreased by Cl2MBP. No good correlation existed between the inhibition of bone resorption measured in vitro on calvaria and that seen in vivo on rat tibiae metaphyses. The latter was inhibited the most efficiently by the bisphosphonates longer than 5-C and by AHPrBP; these were 10 times more effective than Cl2MBP. Taking into account all factors, 1-hydroxypentylidene-1,1-bisphosphonate and AHPrBP seem to be the most active compounds to inhibit bone resorption.