Forty patients with spinal cord injury (SCI) and heterotopic ossification (HO) were treated with etidronate and followed after therapy to determine the effects of long-term medication on heterotopic bone formation. Eighteen patients had tetraplegia and 22 had paraplegia. Early diagnosis of HO (positive bone scintigraphy and negative radiographic findings of HO) was established by 3-phase bone scintigraphy using 99m technetium-labeled methylene diphosphonate. All patients underwent treatment with etidronate, first with intravenous administration of 300 mg/day for 3 days followed by an oral administration of 20 mg/kg/day for 6 months. Eleven patients (27.5%) developed radiographic evidence of HO from 1.5 to 6 years after therapy. A low degree of HO was found in these patients; 8 had grade I and 3 had grade II ectopic ossification (Brooker’s scale). The analysis of data showed that 2 different types of ectopic bone may form in the later stages after SCI. In 5% of patients, HO was found in the same anatomical site initially and finally, suggesting a “rebound” in mineralization of bone matrix not prevented by the administration of etidronate. The other type of HO was found in the majority of patients (95%) where the localization of HO showed different involvement of joints than initially, indicating de novo appearance of HO following SCI. The data suggest that etidronate given for a prolonged period in higher doses has, in addition to an inhibitory effect on crystal formation, a cellular effect on bone-forming cells.