Distinguishing the proapoptotic and antiresorptive functions of risedronate in murine osteoclasts: Role of the Akt pathway and the ERK/Bim axis

Objective Nitrogen‐containing bisphosphonates are one of the most successful therapeutics for osteoporosis. The aim of this study was to elucidate the functional mechanism of one of the typical nitrogen‐containing bisphosphonates, risedronate. Methods Osteoclasts generated from murine bone marrow macrophages were treated with risedronate in vitro, and its effects on apoptosis and bone‐resorbing activity were examined. The mechanism of action of risedronate was examined by gene induction of constitutively active Akt‐1 and constitutively active MEK‐1, and by gene deletion of Bim. Bim−/− mice, in which osteoclasts were resistant to apoptosis, were treated with risedronate and analyzed radiographically, biochemically, and histologically. Results Risedronate induced osteoclast apoptosis through the mitochondria‐dependent pathway with an increased expression of Bim, and the proapoptotic effect of risedronate was suppressed by Bim deletion and constitutively active MEK‐1 introduction. In contrast, the risedronate‐induced suppression of bone resorption was completely reversed by inducing constitutively active Akt‐1, but not by Bim deletion or constitutively active MEK‐1 introduction. These results suggested that apoptosis and bone‐resorbing activity of osteoclasts were regulated through the ERK/Bim axis and the Akt pathway, respectively, both of which were suppressed by risedronate. Although osteoclast apoptosis in response to risedronate administration was suppressed in the Bim−/− mice, risedronate treatment increased bone mineral density in Bim−/− mice at a level equivalent to that in wild‐type mice. Conclusion Our findings indicate that the antiresorptive effect of risedronate in vivo is mainly mediated by the suppression of the bone‐resorbing activity of osteoclasts and not by the induction of osteoclast apoptosis.