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Purpose: Immobilization of weight bearing skeletons or microgravity results in disuse osteoporosis in both human and animals. Our previous study demonstrated that electrical stimulation at the dorsal root ganglion (DRG) with an implantable micro-electrical stimulation system (IMESS) could trigger secretion of bone anabolic calcitonin gene-related peptide (CGRP) and prevent bone loss in a short-term hindlimb unloading rat model. This study was designed to further investigate whether electrical stimulation to the DRG could prevent bone loss due to prolonged unloading., Methods: Eighteen adult rats were randomly assigned into three groups: cage control (CC), hindlimb unloading (HU), and hindlimb unloading with electrical stimulation (HUES). Electrical stimulation was applied via IMESS to the right DRGs at vertebral levels L4-L6 in HUES group for 6 weeks., Results: Following unloading for 6 weeks, proximal tibia metaphysis was shown 64.0% decrease in bone mineral content (BMC) and 47.0% decrease in bone mineral density (BMD) in HU group while significant reduced bone lose with 2.7% increase in total BMC and only 9.2% decrease in total BMD in HUES group. Diaphyseal BMD decreased significantly in both HU and HUES group as compared with CC group. There was enhancement of CGRP expression in the DRGs in HUES group., Conclusion: This experimental study proved the proposed concept using electrical stimulation at the DRG for prevention of disuse-induced bone loss in a rat hindlimb suspension model., (© 2016 International Neuromodulation Society.)