To assess the effects of long-term treatment of bone loss with alendronate in a group of paraplegic men, 55 patients were evaluated in a prospective randomized controlled open label study that was 2 years in duration comparing alendronate and calcium with calcium alone. Bone loss was stopped at all cortical and trabecular infralesional sites (distal tibial epiphysis, tibial diaphysis, total hip) with alendronate 10 mg daily. Introduction: Bone loss after spinal cord injury (SCI) leads to increased fracture risk in the lower limbs of paraplegics. The aim of this study was to document long-term treatment of bone loss with alendronate in a group of paraplegic men with complete motor lesion after SCI. Materials and Methods: Sixty-five men with complete motor post-traumatic medullary lesion between T 1 and L 3 with total motor and sensory loss (Frankel classification, stage A) or with total motor and partial sensory loss (Frankel classification, stage B) after SCI were included in this prospective randomized controlled open label study that was 2 years in duration. The patients were randomized to either the treatment group with alendronate 10 mg daily and elemental calcium 500 mg daily or to the control group with elemental calcium 500 mg daily alone. The primary endpoint was defined as the effect over 24 months of alendronate and calcium compared with calcium alone on the BMD values at the distal tibial epiphysis (as a surrogate for trabecular bone in the paralyzed zone). The secondary endpoints were changes in BMD at supra-and infralesional sites of measurement. Biochemical markers of bone turnover were assessed. Results: Fifty-five subjects, 0.1-29.5 years post-SCI, completed the study over 24 months. BMD at the distal tibial epiphysis significantly decreased from baseline in the calcium group (Ϫ10.8 Ϯ 2.7% at 24 months, p Ͻ 0.001), whereas it remained stable in the alendronate plus calcium group (Ϫ2.0 Ϯ 2.9% at 24 months, p ϭ not significant versus baseline), leading to a significant intergroup difference over time (p ϭ 0.017). At the tibial diaphysis, similar significant results were observed. At the ultradistal radius and the radial shaft, BMD did not change significantly from baseline in either treatment group. At the total hip, BMD decreased significantly in the calcium group (Ϫ4.1 Ϯ 1.6%, p ϭ 0.038) but remained stable in the alendronate plus calcium group (ϩ0.43 Ϯ 1.2%), with a significant intergroup difference (p ϭ 0.037). At the lumbar spine, BMD increased significantly (p Ͻ 0.0001) from baseline in both groups. Biochemical markers of bone resorption were significantly decreased with alendronate versus baseline and control. Alendronate and calcium were generally safe and well tolerated. Conclusions: In paraplegic men, SCI bone loss was stopped at all measured cortical and trabecular infralesional sites over 24 months with alendronate 10 mg daily.