In patients with monoclonal gammopathy of undetermined significance (MGUS) the increase of bone turnover rate can increase the risk of fracture. Thus, a treatment normalizing this negative balance could be of benefit in these patients. We studied 100 patients affected by MGUS, grouped according to the presence (group A, 50 patients) or absence (group B) of vertebral fractures and/or osteoporosis. Group A was treated with alendronate (70 mg/weekly) plus calcium and cholecalciferol for 18 months, and group B was treated with calcium and cholecalciferol. After 18 months, the mean bone mineral density (BMD) of the lumbar spine and total femur had increased by 6.1% and 1.5%, respectively, in group A. In the nine patients of this group not taking alendronate, BMD values of the lumbar spine and total femur decreased by 1.6% (P < or = 0.001 ) and 1.3% (P < or = 0.01), respectively. In patients of group B, BMD increased by 1.2% at the lumbar spine and decreased by 1.2% at the total femur. Corresponding figures of those patients in the same group not taking calcium and vitamin D supplementation were -0.1% and -1.2%, respectively. At 18 months we observed significant decreases of serum bone markers: the difference between the groups was -23.2 (P < or = 0.01) for bone alkaline phosphatase, -23.6 for osteocalcin (P < or = 0.01), -35.1 for C-terminal telopeptides of collagen type I (P < or = 0.001), and -0.47 for bone sialoprotein (P = nonsignificant). Treatment with alendronate could lead to a significant reduction in fracture risk in MGUS patients with skeletal fragility.