Disuse is associated with bone loss, which may not be recoverable. It is not known whether intensified remobilization is beneficial in restoring disuse-related bone loss nor if any such benefit would depend upon continuing mobilization for its maintenance. After an immobilization period of 3 weeks, the effects of free remobilization (11 weeks), and low-and high-intensity treadmill running (11 weeks) with and without subsequent deconditioning (18 weeks) on the bone mineral content (BMC) and density (BMD) of the hindlimb femora of Sprague-Dawley rats (n = 98) were studied using a dual-energy X-ray absorptiometric (DXA) scanner. Our hypothesis was that intensified remobilization is beneficial in restoring the BMC and BMD from disuse to normal while subsequent deconditioning is deleterious to these parameters. Immobilization for 3 weeks produced a significant BMC and BMD loss in the immobilized left femur (range -4.4 to -12.8%; p < 0.05-0.001). In the groups with free remobilization (free cage activity), the body weight-adjusted BMCs and BMDs always remained below those in the controls (range -2.3 to -12.1%; p values ranging from NS to < 0.01). Both low- and high-intensity running restored BMC and BMD in the immobilized limb, the effect being better in the latter group. In both of these groups, the values of the immobilized left limbs and those of the free right limbs exclusively exceeded the corresponding values of the age-matched control rats (left limb values 3.0-21.1% higher with p values ranging from NS to < 0.01; right limb values 7.9-21.4% higher with p < 0.05-0.01). However, after the deconditioning period of 18 weeks, the above described beneficial effects of low- and high-intensity running were lost, the left and right limb BMC and BMD values being lower than those in the age-matched controls (range -3.8 to -8.7%; p values ranging from NS to < 0.05). In conclusion, this study clearly indicates the need for greater than normal activity to restore the BMC and BMD after disuse to normal levels. However, the benefits of intensified remobilization are lost if the activity is terminated, and therefore, after immobilization and disuse, bone loading activities should be continued, perhaps indefinitely.