Evaluation of the efficacy and safety of oral tiludronate in paget's disease of bone

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Abstract
Objective. To assess the optimal dosage of oral tiludronate in Paget's disease of bone. Methods. We studied 149 patients with Paget's disease, in a double‐blind, randomized, placebo‐controlled trial. Patients were randomly assigned to 1 of 5 therapeutic groups: a daily dose of 100 mg, 200 mg, 400 mg, or 800 mg of oral tiludronate, or a placebo. Treatment was for 3 months, followed by 3 months of placebo‐controlled followup. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured monthly, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self‐evaluated from a visual analog scale and a global pain index. Results. Statistical analysis revealed that beginning at a dosage of 200 mg/day, there was a direct dose‐dependent effect on the reduction of SAP and OH/Cr levels. Reduction of SAP levels was clinically significant at a dosage of 400 mg (44.9 ± 4.2% reduction at 90 days and 49.2 ± 4.5% at 180 days, mean ± SEM) and at 800 mg (53.4 ± 5% at 90 days and 59.3 ± 4.6% at 180 days). There was a significant reduction in pain in all groups, including the group taking placebo. In only those taking 800 mg/day of tiludronate was there a significant frequency of complete resolution of pain (versus placebo). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance of all 5 regimens was good. Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800‐mg daily dose investigated. Conclusion. Because of its significantly better antiresorptive effects and greater analgesic properties (compared with lower dosages), combined with the excellent clinical and biochemical tolerance, the 800‐mg daily dose of tiludronate appears to be optimal for the treatment of Paget's disease of bone.