INHIBITORY EFFECTS OF BISPHOSPHONATES ON GROWTH OF AMEBAS OF THE CELLULAR SLIME-MOLD DICTYOSTELIUM-DISCOIDEUM

Bisphosphonates are inhibitors of bone resorption and are used increas ingly as therapeutic agents for treating clinical disorders of skeleta l metabolism. Their mode of action is still not fully understood. The demonstration that methylenebisphosphonate, a simple methylene analog of pyrophosphate, inhibits the axenic growth of amoebae of the slime m old Dictyostelium discoideum and is incorporated into adenine nucleoti des suggested that this organism might be useful in elucidating the ce llular effects of bisphosphonates. We examined 24 bisphosphonates, inc luding all those of clinical interest as inhibitors of osteoclast-medi ated bone resorption in vivo, for their effects on D. discoideum, All the geminal bisphosphonates inhibited growth of Dictyostelium, althoug h the effectiveness of individual compounds varied widely. When the bi sphosphonates were ranked there was a remarkable similarity between th e order of potency as inhibitors of growth of Dictyostelium and the or der of potency as inhibitors of bone resorption. Thus, bisphosphonates with more complex side-chain structures, especially those containing a nitrogen group, were more potent than simple substituted bisphosphon ates, some inhibiting Dictyostelium growth even at concentrations belo w 10 mu M. It therefore appears that the mechanism by which bisphospho nates prevent Dictyostelium growth could be similar to the mechanism b y which these compounds affect the activity of osteoclasts. Because th e mechanisms of action of bisphosphonates on osteoclasts remains uncle ar, Dictyostelium may provide an additional model for studying the bio chemical mode of action of bisphosphonates, Furthermore, these studies suggest that Dictyostelium may also be a convenient organism for rapi d evaluation of potentially active bisphosphonates.