Lung transplantation with its attendant life-long immunosuppression contributes to bone loss and its sequelae, fractures and kyphosis, in patients with lung disease, many of whom already suffer from severe osteoporosis. Patients with cystic fibrosis (CF) are one of the most severely affected groups. We conducted a controlled, randomized, nonblinded trial of pamidronate (30 mg intravenously every 3 mo) with vitamin D (800 IU/d) and calcium (1 g/d) (n = 16) compared with vitamin D and calcium alone (n = 18, the control subjects) for 2 yr in 34 patients after lung transplant to improve bone mineral density (BMD). The treatment groups were similar in age, sex, baseline T-scores, renal function, hospitalization rates, immunosuppressant levels, change in lung function, and body mass index (BMI) over the study period. The patients treated with pamidronate gained 8.8 +/- 2.5% and 8.2 +/- 3.8% in spine and femur BMD after 2 yr in comparison to control subjects, who gained, on average (+/- SD), 2.6 +/- 3.2 and 0.3 +/- 2.2%, respectively (p </= 0.015 for both). Seven and six fractures occurred in the control and pamidronate groups, respectively (p > 0.2). Measures of bone resorption were highest immediately after lung transplant and improved with both pamidronate and time. Measures of bone formation were very poor after lung transplant, but recovered in the first post-lung transplant year irrespective of therapy. We conclude that pamidronate was more effective than control in improving bone mineral density after lung transplantation in patients with CF and appears to be one of the most promising agents studied to date for posttransplant osteoporosis.