It is generally believed that mechanical signals must be large in order to be anabolic to bone tissue. Recent evidence indicates, however, that extremely low-magnitude (<10 microstrain) mechanical signals readily stimulate bone formation if induced at a high frequency. We examined the ability of extremely low-magnitude, high-frequency mechanical signals to restore anabolic bone cell activity inhibited by disuse. Adult female rats were randomly assigned to six groups: baseline control, age-matched control, mechanically stimulated for 10 min/day, disuse (hind limb suspension), disuse interrupted by 10 min/day of weight bearing, and disuse interrupted by 10 min/day of mechanical stimulation. After a 28 day protocol, bone formation rates (BFR) in the proximal tibia of mechanically stimulated rats increased compared with age-matched control (+97%). Disuse alone reduced BFR (-92%), a suppression only slightly curbed when disuse was interrupted by 10 min of weight bearing (-61%). In contrast, disuse interrupted by 10 min per day of low-level mechanical intervention normalized BFR to values seen in age-matched controls. This work indicates that this noninvasive, extremely low-level stimulus may provide an effective biomechanical intervention for the bone loss that plagues long-term space flight, bed rest, or immobilization caused by paralysis.