[Possible mechanism of the specific action of bisphosphonates on osteoclasts]

The mechanism of action of bisphosphonates on bone resorption was examined in mouse culture systems. Tiludronate did not inhibit the formation of osteoclasts induced by 1,25-dihydroxyvitamin D3 in cocultures of osteoblasts and bone marrow cells. Osteoclasts obtained from cocultures treated with tiludronate formed many resorption pits on dentine slices. However, pit formation by osteoclasts was dose-dependently inhibited by tiludronate. Treatment of osteoclasts with risedronate disrupted actin rings, and inhibited pit formation by osteoclasts. Bafilomycin A1, a vacuolar H(+)-ATPase inhibitor, inhibited the pit-forming activity of osteoclasts but did not disrupt actin rings. Risedronate failed to disrupt actin rings in the presence of bafilomycin A1. These results suggest that acidification by vacuolar H(+)-ATPase is involved in specific incorporation of bisphosphonates into osteoclasts.