Cardiac transplantation is associated with severe bone loss caused by glucocorticoids, immunosuppressive treatment, and other factors. Treatment protocols for the prevention of bone loss is being studied. Forty patients who underwent cardiac transplantation were randomly given calcitonin (n = 13; 100 UI/d, nasal route), etidronate (n = 14; cyclical treatment 400 mg p.o./d/2 weeks/3 months), or calcidiol (n = 13; 32,000 IU/weekly) therapy for at least 18 months. Serum parameters (Ca, P, alkaline phosphatase, osteocalcin, intact PTH), urinary calcium, and vertebral mineral density (VMD; L2-L4, DXA Hologic QDR 1000) were measured immediately before treatment and after 6, 12, and 18 months of therapy after cardiac transplantation. Patients with cardiac transplantation had a VMD significantly lower than age and sex-matched Spanish controls. Prevalence of osteoporosis (Z-score below -2 SD) was 30%. Osteocalcin levels increased at 6, 12, and 18 months of treatment in the three groups. After 18 months of treatment, VMD increased significantly in the calcidiol 4.9%, vs. -1.19% and -0.19% in the calcitonin and etidronate groups, respectively. A lower incidence of fracture was found in patients treated with calcidiol during the study. In summary, we have found in this open randomized study that calcidiol was the most effective drug in the prevention and treatment of bone loss in patients after cardiac transplantation.