Osteoprotegerin (OPG) is an antiresorptive cytokine and a key regulator of osteoclastogenesis and activity. Since OPG is downregulated by glucocorticoids and cyclosporine A in vitro we examined whether immunosuppressive therapy would play a role in the development of transplantation osteoporosis. We enrolled 57 cardiac transplant recipients (median time since transplantation, 3.2 years (1.1-11.5 years)) in this cross-sectional study. Standardized spinal X-rays as well as hip bone density measurements were performed in all patients. Serum OPG was determined using a commercially available ELISA. Vertebral fractures were present in 56% of the patients. Bone densities of all femoral neck subregions were correlated to serum OPG concentrations (r values between 0.40 and 0.48, all P < 0.005). Multiple regression analysis revealed OPG levels to be independently correlated to femoral neck Z scores (r = 0.49, P = 0.002). After adjustment for age, BMI, neck Z score, renal function, and months since transplantation, serum OPG was the only significant predictor of prevalent vertebral fractures (P = 0.001). In a separate 6-month prospective study of 14 heart transplant recipients receiving calcium and vitamin D serum OPG levels fell by 41% (P = 0.0004) after 3 months and 47% (P = 0.0001) after 6 months following cardiac transplantation. Bone loss at the lumbar spine and femoral neck after 6 months was correlated to the decrease in serum OPG at 6 months (r = 0.82, P < 0.0001, and r = 0.60, P = 0.02, respectively) as well as 3 months after cardiac transplantation (r = 0.65, P = 0.01, and r = 0.69, P = 0.006, respectively). Serum OPG alone accounted for 67% of the variance of lumbar spine bone density changes over the first 6 months posttransplantation. We conclude that serum OPG levels decline consistently in all patients following initiation of immunosuppressive therapy and are independently correlated with changes in bone density. We hypothesize that OPG plays a major role in the development of transplantation osteoporosis.