Despite clinical strides in the treatment of osteoporosis in several diverse medical conditions, the ability to maintain bone has proven to be exceedingly difficult in individuals with severe immobilization. Fifty to 60% of bone mineral density (BMD) at the epiphyseal and metaphyseal regions of the long-bones of the lower extremities may be lost over the first couple of years after spinal cord injury (SCI). Once a large amount of bone has been lost, it would be challenging to restore BMD, trabecular architectural integrity, and mechanical strength to provide protection against long-bone fractures of the lower extremities. Persons with neurologically complete forms of SCI have marked loss of BMD of the lower extremities, predisposing to fracture, especially at the knee. Denosumab, a commercially available human monoclonal antibody of the IgG2 immunoglobulin isotype with a high affinity and specificity for binding RANKL to antagonize its action, may provide an immunopharmacological solution to the rapid progressive deterioration of sublesional bone after SCI. Twenty-six patients with motor-complete SCI [International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) grade A and B] were randomized to receive denosumab or placebo at baseline (BL), 6, and 12 months. Ten participants in the denosumab group and 8 participants in the placebo group completed the 18-month clinical trial [ClinicalTrials.gov (NCT01983475)]. Dual energy x-ray absorptiometry (DXA; Lunar Prodigy Advance, all software version 12.20.023; EnCORE, GE Medical Systems, Madison, WI) and peripheral quantitative computed tomography (pQCT; Stratec XCT 3000; STIM designs, Carmel, CA) imaging were performed. Within group paired analysis revealed a significant decrease for areal BMD (aBMD) from BL in the placebo group that started at month 3 for the distal femoral epiphysis (DFE), distal femoral metaphysis (DFM), and total hip (TH) and at month 6 for the femoral neck (FN), and at month 12 for the proximal tibial epiphysis (PTE); the loss in aBMD progressed to 18 months for all the skeletal regions of interest (ROI). At 18 months, the percent change at the ROI for the denosumab vs. placebo groups were: DFE (1.1% ± 7.5 vs. -30.0% ± 11.9, respectively, p<0.001 and p<0.001), DFM (1.2% ± 6.4 vs. -17.2% ± 14.2, p<0.01), TH (3.3% ± 8.7 vs. -25.6% ± 7.6, p < 0.001), and PTE (-1.7% ± 8.2 vs. -24.1% ± 12.3, p<0.001). At 18 months, pQCT at the 4% tibial region confirmed the DXA findings at proximal tibial; at the 38% tibial region, a trend toward loss of total volumetric BMD (vBMD) was observed (-0.7% ± 4.5 vs. -16.9% ± 20.0, p<0.09), but cortical vBMD was similar between the denosumab and placebo groups, suggesting trabecular loss at the tibial shaft. In summary, the findings suggest that denosumab, if treatment is initiated within 3 months of acute SCI, appears to be an efficacious approach to maintain BMD at the knee and hip regions.