The aim of this study was to compare the action of two regimens of intravenous (iv) pamidronate in the primary prevention of glucocorticoid-induced osteoporosis (GC-OP). The primary purpose of the study was to determine whether any differences in bone mineral density (BMD) appeared after 1 year. A secondary endpoint aimed at assessing the remodeling parameters in order to better understand the mechanisms of action of the various regimens. Thirty-two patients, who required first-time, long-term glucocorticoid therapy at a daily dose of at least 10 mg of prednisolone, were studied. Simultaneously with the initiation of their glucocorticoid treatment, patients also were randomly allocated to receive a single iv infusion of 90 mg of pamidronate at the start (group A); a first infusion of 90 mg of pamidronate followed, subsequently, by an iv infusion of 30 mg pamidronate every 3 months (group B); and a daily 800-mg elemental calcium supplement given as calcium carbonate (group C), which also was taken by patients in groups A and B. Patients were matched for starting glucocorticoid doses, sex, menopausal status, and hormonal replacement therapy. Lumbar spine and hip (total and subregions) BMDs were measured at the outset and repeated at 6-month intervals by dual-energy X-ray absorptiometry (DXA; Hologic QDR-2000). Bone turnover was assessed by measurement of total and bone-specific serum alkaline phosphatase activity (B-ALP), serum osteocalcin (OC), and serum C-telopeptide cross-links of type I collagen (CTX). After 1 year, the mean BMD changes for groups A, B, and C were, respectively, 1.7, 2.3, and -4.6% at the lumbar spine; 1.2, 1.2, and -3.1% at the femoral neck; 1.0, 2.6, and -2.2% for the total hip region. No difference was observed between pamidronate regimens but a highly significant difference was observed between both pamidronate regimens and the control group at the lumbar spine (p < 0.001), at the femoral neck (p < 0.01), and for the total hip (p < 0.05). A significant decrease of serum C-telopeptide was observed, after 3 months, in groups A and B (p = 0.029), but a sustained decrease of bone resorption over time was observed only in group B. As far as BMD evolution over 1 year was concerned, iv pamidronate, given either as a single infusion or once every 3 months, effectively achieved primary prevention of GC-OP.