Risedronate does not reduce mechanical loading-related increases in cortical and trabecular bone mass in mice

Toshihiro Sugiyama,Lee B. Meakin,Frank H. Ebetino,Brendan F. Jackson,R. Graham G. Russell,Joanna S. Price,Gabriel L. Galea,Lance E. Lanyon

doi:10.1016/j.bone.2011.03.775

Abstract

To establish whether the combination of anti-resorptive therapy with mechanical loading has a negative, additive or synergistic effect on bone structure, we assessed the separate and combined effects of risedronate and non-invasive dynamic loading on trabecular and cortical bone. Seventeen-week-old female C57BL/6 mice were given daily subcutaneous injections of vehicle (n = 20) or risedronate at a dose of 0.15, 1.5, 15 or 150 μg/kg/day (n = 10 in each) for 17 days. From the fourth day of treatment, the right tibiae were subjected to a single period of axial loading (40 cycles/day) for three alternate days per week for two weeks. The left tibiae were used as internal controls. Trabecular and cortical sites in the tibiae were analyzed by high-resolution micro-computed tomography and imaging of fluorochrome labels. In the non-loaded tibiae, treatment with the higher doses of risedronate at 15 or 150 μg/kg/day resulted in higher trabecular bone volume and trabecular number than in vehicle-treated controls, whereas such treatment was associated with no differences in cortical bone volume at any dose. In the loaded tibiae, loading induced increases in trabecular and cortical bone volume compared with contra-lateral controls primarily through increased trabecular thickness and periosteal expansion, respectively, independently of risedronate treatment. In conclusion, the response to mechanical loading in both trabecular and cortical bone in mice is therefore not impaired by short-term treatment with risedronate, even over a 1000-fold dose range. In considering the optimization of treatments for osteoporosis, it is reassuring that anti-resorptive therapy and mechanical loading can exert independent beneficial effects.This article is part of a Special Issue entitled Bisphosphonates.

Highlights

Bisphosphonates play a central role in the management of osteoporosis [1,2,3]
There were no significant differences between the body weights or bone lengths of mice treated with vehicle or risedronate at any dose
There were no significant differences in bone volume between vehicle-treated and risedronate-treated animals at any dose

Summary

Introduction

Bisphosphonates play a central role in the management of osteoporosis [1,2,3] Their major mechanism of action is to suppress osteoclast function and survival [4,5]. Due to the normal coupling of bone resorption to formation, one of their effects is to lower bone turnover [6]. Some of these drugs have recently been demonstrated to protect osteocytes from apoptosis in vivo [7,8]. In contrast to the anti-resorptive effects of bisphosphonates, mechanical loading is the predominant functional osteogenic factor responsible for maintaining structurally appropriate levels of bone mass in adults [9,10]. In experiments involving treadmill exercise in ovariectomized rats, the combination of etidronate, alendronate or risedronate treatment with exercise had additive or synergistic effects on bones [21,22,23], whereas zoledronic acid and exercise did not show either effect [24]

Methods

Results

Conclusion