Rapid bone loss is a universal accompaniment of acute spinal cord injury (SCI) and leads to severe loss of bone mass and bone strength with a marked increased risk of fracture. This 24 month double-blind, randomized, placebo-controlled study evaluated in 60 participants the efficacy (bone mass and bone strength) and safety of zoledronic acid (ZOL) administered early after acute SCI to prevent bone loss, the duration of its effects and the value of using biomarkers to guide therapy. Data collection (bone imaging and biomarkers) occurred at baseline and after 3, 6 and 12 months during the first year; participants were re-randomized after 12 months with subsequent data collection at 18 and 24 months. Forty-nine out of the 60 participants who were randomized and treated at baseline completed both years of the study. Data demonstrated that a single infusion of ZOL after acute SCI attenuates bone loss at the hip (proximal femur) and knee (distal femur and proximal tibia) for at least 6months. Two annual infusions did not provide significant attenuation of bone loss beyond a single baseline infusion, and a single infusion 12 months after baseline did not provide significant attenuation of bone loss beyond two years of placebo. No unanticipated adverse events associated with drug treatment were observed. In summary, ZOL 5 mg infusion after acute SCI was well-tolerated and may provide an effective therapeutic approach to prevent bone loss in the first few years after SCI.