Prolonged corticosteroid therapy is known to result in an increased risk of osteoporotic fracture, probably as a consequence of enhanced bone resorption and depressed bone formation. We examined the effects of prophylactic treatment with 1,25-dihydroxyvitamin D3 (calcitonin) and nasal salmon calcitonin on corticosteroid-induced bone loss in 103 patients being treated with long-term corticosteroids for the first time in a randomized, double-masked prospective study. Patients were randomly allocated to one of three groups receiving either calcium supplementation alone, calcium plus calcitriol, or calcium plus calcitriol and nasal salmon calcitonin. Treatment was given for 12 months. Bone mineral density (BMD) was measured every 4 months by dual-photon absorptiometry in the lumbar spine and femoral neck. Calcium supplementation alone did not prevent bone loss at either site. In the lumbar spine calcitriol, with or without nasal calcitonin, significantly reduced bone loss (p < 0.0001). Neither calcitriol alone nor calcitriol with calcitonin prevented bone loss at the femoral neck. These data suggest that treatment with calcium and calcitriol, or with calcium and intranasal calcitonin, greatly reduced or prevented corticosteroid-induced bone loss in the lumbar spine.