Functional skeletal adaptation is thought to be a local phenomenon controlled by osteoctyes. However, the nervous system also may have regulatory effects on adaptation. The aim of this study was to determine the effects of loading of a single bone on adaptation of other appendicular long bones and whether these responses were neuronally regulated. Young male Sprague-Dawley rats were used. The right ulna was loaded to induce a modeling response. In other rats, a second regimen was used to induce bone fatigue with a mixed modeling/remodeling response; a proportion of rats from each group received brachial plexus anesthesia to induce temporary neuronal blocking during bone loading. Sham groups were included. Left and right long bones (ulna, humerus, tibia, and femur) from each rat were examined histologically 10 days after loading. In fatigue- and sham-loaded animals, blood plasma concentrations of TNF-Ξ±, RANKL, OPG, and TRAP5b were determined. We found that loading the right ulna induced an increase in bone formation in distant long bones that were not loaded and that this effect was neuronally regulated. Distant effects were most evident in the rats that received loading without bone fatigue. In the fatigue-loaded animals, neuronal blocking induced a significant decrease in plasma TRAP5b at 10 days. Histologically, bone resorption was increased in both loaded and contralateral ulnas in fatigue-loaded rats and was not significantly blocked by brachial plexus anesthesia. In young, growing male rats we conclude that ulna loading induced increased bone formation in multiple bones. Systemic adaptation effects were, at least in part, neuronally regulated. Β© 2010 American Society for Bone and Mineral Research.