Bisphosphonates have long been used with success in the treatment of Paget's disease of bone (PDB). The aim of this study was to evaluate the early (up to 3 months) and late (at 12 months) scintigraphic, biochemical, and clinical response to a single intravenous infusion of zoledronic acid (ZOL) in patients with PDB serially assessed for 1 year. Nine patients with 30 bone lesions caused by PDB were prospectively evaluated. Total serum alkaline phosphatase (SAP) was serially measured. Scintigraphy was performed before and at 3 and 12 months after ZOL administration, and bone lesions were assessed quantitatively. After treatment, pain was alleviated in five of six patients starting from the first month. At 3 months, a significant decrease of SAP levels compared to baseline values was found (322 +/- 211 IU/l before vs. 101 +/- 36 IU/l 3 months after; P < 0.05), with normal values attained in all except one patient. The scintigraphic index of involvement (SII), a marker for the per-patient activity of the disease, was reduced from 14.4 +/- 7.6 to 7.2 +/- 1.8 (P = 0.01). The scintigraphic ratio (SR), a marker for the per-lesion activity of the disease, was reduced from 12.8 +/- 7.7 to 7.0 +/- 2.9 (P < 0.001). The values of markers of disease activity remained unchanged up to 12 months. A single intravenous administration of ZOL leads to a favorable clinical, biochemical, and scintigraphic response in patients with PDB starting as early as 3 months after treatment and lasting no less than 12 months (i.e., considerably longer than the other existing therapies).