A single infusion of zoledronic acid (ZOL) after acute spinal cord injury (SCI) attenuates bone loss at the hip (proximal femur) and knee (distal femur and proximal tibia) for at least 6 months. The objective of this study was to examine the effects of timing and frequency of ZOL over 2 years. In this double-blind, placebo-controlled trial, we randomized 60 individuals with acute SCI (<120 days of injury) to receive either ZOL 5-mg infusion (n = 30) or placebo (n = 30). After 12 months, groups were again randomized to receive ZOL or placebo, resulting in four treatment groups for year 2:​ (i) ZOL both years;​ (ii) ZOL year 1, placebo year 2;​ (iii) placebo year 1, ZOL year 2;​ and (iv) placebo both years. Our primary outcome was bone loss at 12 months;​ compared to placebo, a single infusion of ZOL attenuated bone loss at the proximal femur, where median changes relative to baseline were −1.7% to −2.2% for ZOL versus −11.3% to −12.8% for placebo (p < 0.001). Similarly, the distal femur and proximal tibia showed changes of −4.7% to −9.6% for ZOL versus −8.9% to −23.0% for placebo (p ≤ 0.042). After 24 months, differences were significant at the proximal femur only (−3.2% to −6.0% for ZOL vs. −16.8% to −21.8% for placebo;​ p ≤ 0.018). Although not statistically significant, median bone density losses suggested some benefit from two annual infusions compared to a single baseline infusion, as well as from a single infusion 12 months after baseline compared to 2 years of placebo;​ therefore, further investigation in the 12-month to 24-month treatment window is warranted. 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 following SCI.