Risedronate and alendronate suppress osteocyte apoptosis following cyclic fatigue loading

Purpose: The purpose of this study was to determine whether bisphosphonate treatment can prevent or delay osteocyte apoptosis in a cyclic fatigue animal model and if there are differences between two different bisphosphonates in their effects on osteocyte apoptosis. Introduction: Fatigue loading induces microdamage in long bones in rats and causes osteocyte apoptosis. In vitro data suggest that the bisphosphonates can prevent osteocyte apoptosis. Materials and methods: Six month old female Sprague-Dawley rats (n=72) were given a daily subcutaneous (sc) injection of saline vehicle, risedronate (RIS: 0.05 mu g/kg per day) or alendronate (ALN: 0.1 mu g/kg per day). On the 8th day of drug treatment, an axial compressive load was applied to the right ulna using a load-controlled electromagnetic device (17N, 6000 cycles, 2 Hz, 10% loss of stiffness similar to 1 h). Three, seven or ten days after loading, the animals were sacrificed. Immunohistochemistry for caspase-3 was performed to assess the extent of osteocyte apoptosis in loaded and non-loaded ulnas. Results: Microdamage (Mdx) created by cyclic loading of the ulna induced a significant increase (p-0.03) in the number of apoptotic osteocytes compared to non-damaged regions of the same ulna, and compared to the contralateral non-loaded ulna. Risedronate and alendronate had an early effect (3 days after loading) on reducing load-induced osteocyte apoptosis. Risedronate significantly reduced the density of apoptotic osteocytes compared to vehicle-treated controls by similar to 50% in the Mdx area, whereas alendronate reduced it by similar to 40%. There were no differences among groups by seven days following loading. Conclusions: (1) Low doses of risedronate or alendronate suppressed osteocyte apoptosis induced by fatigue loading of the ulna in rats. (2) There was no difference between the effects of risedronate or alendronate on osteocyte apoptosis at these doses. (c) 2006 Elsevier Inc. All rights reserved.