ALENDRONATE DISTRIBUTED ON BONE SURFACES INHIBITS OSTEOCLASTIC BONE-RESORPTION IN-VITRO AND IN EXPERIMENTAL HYPERCALCEMIA MODELS

Alendronate is an aminobisphosphonate that acts as a potent inhibitor of osteoclastic bone resorption, To understand the mechanism of action of alendronate in vivo, in this study we investigated the relationshi p between distribution of [C-14]alendronate in rat bone and its effect s on bone resorption in vitro or in rat hypercalcemic models, A single IV dose of 0.05 similar to 1.25 mg/kg inhibited the increase in plasm a calcium level induced by bovine PTH or 1 alpha(OH)D-3. The minimal e ffective dose of pamidronate (1.25 mg/kg) and etidronate (over 31.25 m g/kg) were at least 5 times and 25 times, respectively, higher than th e dose of alendronate in the rat hypercalcemic model prepared by 1 alp ha(OH)D-3. The relative potencies of compounds in the hypercalcemic ra t models reflected those of inhibitory effects on bone resorption in v itro, We conducted the ivory-slice assay under two conditions: (a) add ition of a given bisphosphonate after adherence of the osteoclasts; an d (b) preincubation of the ivory slices with a given bisphosphonate, T he inhibitory IC50 values of alendronate under condition (b) were simi lar to those under condition (a), To evaluate the interaction between osteoclasts and alendronate in bone, we investigated the localization of [C-14]-alendronate in the tibia of growing rats (4-day-old rats), A lendronate did not distribute uniformly in the tibia, At 1 day after i njection (0.05 mg SC), dense labeling was seen primarily under osteocl asts, We injected 0.05 mg/kg of [C-14]-alendronate (single IV) into ra ts [C-14]-alendronate was rapidly eliminated from plasma, and mainly d istributed to the bone in rats, These data suggest that alendronate wh ich distributed on bone surface mainly contributed to the antihypercal cemic action in vivo.