Inhibition of bone resorption by difluoromethylene diphosphonate in organ culture

A newly synthesized diphosphonate, difluoromethylene diphosphonate (F₂MDP), was studied for its effects on bone resorption, as measured by the release of previously incorporated ⁴⁵Ca. F₂MDP (10 μM to 1000 μM) effectively inhibited both unstimulated and parathyroid hormonestimulated resorption, and the amount of ⁴⁵Ca release decreased with time. Dichloromethylene diphosphonate (Cl₂MDP) and ethane- 1-hydroxyl-1,1-diphosphonate (EHDP) inhibited resorption to similar extents with two exceptions: At concentrations of 10 μM and 100 μM F₂MDP was more effective than EHDP and less effective than Cl₂MDP. No greater inhibition was observed when bones had been stimulated with PTH prior to the addition of F₂MDP In addition, bones treated with F₂MDP only during the first half of the incubation period exhibited reductions in tha amount of ⁴⁵Ca released during the second half similar to that observed when F2MDP was continuously in the medium, indicating a prolonged effect. Morphologic alterations of osteoclasts suggestive of cell degeneration were observed in F₂MDP-treated bones, which were similar to those observed in bones treated with Cl₂MDP and EHDP. Due to the presence of fluorine, F₂MDP may be useful as an experimental tool to investigate the mode of action of all diphosphonates, in addition to its possible use as a therapeutic agent for diseases of increased bone resorption.