High-dose risedronate treatment partially preserves cancellous bone mass and microarchitecture during long-term disuse

Abstract

Disuse induces rapid and severe bone loss in larger mammals as a result of greatly elevated osteoclastic resorption. In this study, we tested whether risedronate (RIS), a potent inhibitor of osteoclastic activity, would effectively prevent cancellous bone loss in female beagles (5–7 years old, N = 28) subjected to single forelimb immobilization (IM) for 12 months. Age-matched, non-IM dogs served as controls (Con). Half the animals from each group received RIS 1 mg/kg p.o. daily (Con + RIS, IM + RIS). Remaining dogs received sterile water (Con, IM). Histomorphometry showed that IM caused a dramatic reduction in cancellous bone mass (−71%) of distal 2nd metacarpals, characterized by marked decreases in trabecular width (−51%) and number (−41%), and 4-fold increases in the indices of bone resorption (eroded surface, osteoclast number, and surface). Bone formation indices (calcein-labeled surface, osteoid surface, and bone formation rate) were also significantly higher in IM than in controls. Activation frequency in IM increased about 4-fold beyond control level. RIS treatment reduced, but did not abolish cancellous bone loss due to immobilization. IM animals treated with RIS lost nearly 50% of cancellous bone mass, while trabecular width and number were reduced by 31% and 25%, respectively. In both RIS-treated control and IM animals, overall bone formation parameters (mineralized bone surface fraction and bone formation rate) remained roughly at intact control levels; however, mineral apposition rate relative to intact control was reduced 40% in RIS-treated control and 86% in RIS-treated IM animals. These results indicate that high-dose RIS treatment might suppress osteoblastic function, especially under long-term disuse. Interestingly, bone resorption parameters in RIS-treated IM animals reached levels even higher than in vehicle-treated IM animals; values for eroded surface, osteoclast number, and surface were 84%, 53%, and 83% above vehicle-treated IM values, respectively. Our data indicate that risedronate treatment is partially effective in preventing cancellous bone loss during long-term disuse. Moreover, our results suggest that bisphosphonates can impair the ability of mature osteoclasts to resorb bone, but cannot overcome the strong stimulus for osteoclast recruitment caused by long-term disuse.