After acute spinal cord injury (SCI), rapid depletion of the sublesional skeleton occurs, particularly at the distal femur and proximal tibia. Subsequently, fragility fractures of the knee may occur. We determined the efficacy of zoledronic acid to prevent sublesional bone mineral density (BMD) loss at 6 and 12 months after acute SCI. Thirteen subjects with acute motor-complete SCI were prospectively studied: 6 patients received zoledronic acid (5 mg) and 7 subjects did not receive the drug (controls). Zoledronic acid was administered intravenously within 16 weeks of acute injury. Areal BMD was performed by dual energy X-ray absorptiometry at baseline, 6, and 12 months after administration of drug. The treatment group demonstrated sparing of BMD at the total hip at month 6 (p < 0.0006) and at month 12 (p < 0.01). In contrast to the findings at the hip, the treatment group had a greater loss of BMD compared to the control group at the distal femur and proximal tibia at month 6 (-7.9% ± 3.4 vs.-2.7% ± 5.0, respectively, p = 0.054; and -10.5% ± 6.4 vs. -4.8% ± 6.8, respectively, p = NS) and at month 12 (-18.5% ± 3.9 vs. -8.4% ± 7.2, respectively, p = 0.01; and -20.4% ± 8.8 vs.-7.9% ± 12.3, respectively, p = 0.06). A single dose of zoledronic acid administered soon after acute SCI reduced the %BMD loss at the hip, but appeared to have no effect to prevent %BMD loss at the knee, the site where fracture risk is greatest in persons with SCI.