To investigate the dose-dependent effects of risedronate on cancellous bone remodeling, adult female beagle dogs were treated with either placebo, 0.1, 0.5, or 2.5 mg/kg/day of risedronate orally in an intermittent cyclic regimen (7 days on 21 days off), repeated three times. Iliac cancellous bone samples were subjected to histomorphometric analysis and three-dimensional (3-D) kinetic reconstruction of the remodeling site was performed. In the 0.1 mg/kg dose group, resorption and activation indices were no different from the placebo group. However, wall thickness was increased resulting in a positive bone balance at the level of the remodeling unit. In the 0.5 and 2.5 mg/kg dose groups, a dose-dependent reduction in activation frequency and tissue level bone formation was observed. Resorption rates were also significantly decreased, 60% and 80% for the 0.5- and 2.5-mg/kg groups, respectively. An approximate 25% reduction in final erosion depth was noted in both these groups. Analyses of the growth curves of the bone packet confirmed that the kinetics of the growth of a completed packet were different in the 0.5- and 2.5-mg/kg dose groups compared with placebo. These changes were associated with a significant increase in the final wall thickness in both groups indicating no net impairment of osteoblast function. These increases in wall thickness in combination with the reductions in final erosion depth in the 0.5 and 2.5 mg/kg groups resulted in a significant dose-dependent positive bone balance. This pharmacological profile suggests that risedronate may be of therapeutic utility in the treatment of metabolic bone diseases where reductions in activation frequency and resorptive cell activity at the level of the remodeling unit are a therapeutic goal.