Objective: To investigate the influence of both clinical and pharmacokinetic factors as determinants of response to tiludronate in Paget's bone disease (PBD).
Patients and methods: Twenty six PBD patients with serum alkaline phosphatase (SAP) levels at least twice the normal upper limit were enrolled. The sample included 17 (65%) men and 9 (35%) women whose mean age (SD) was 60.3 (9.8) (range: 38-76). Each patient received 400 mg/day of tiludronate, per os, for 90 (6) days. The SAP variations were considered as the main parameter of response. Plasma concentrations of tiludronate were assayed using the HPLC method with UV detection; the maximum and minimum (Cmin) concentration, as well as the area under a concentration-time curve were calculated. Multivariate regression analysis was performed to assess the influence on tiludronate effect.
Results: Mean (SD) percent reduction of SAP from the initial values ranged from 30.5 (13.9) at the end of the first month of drug intake to a nadir of 76.1 (8.8) achieved 6 months after the treatment was stopped. Serum SAP activity fell to normal range in 7 (27%) patients at the end of the therapy period, in 17 (65%) three months later, and in 18 (69%) one year thereafter. One year after the treatment ended only one patient had evidence of relapse. Final multivariate regression model showed that the percent reduction of SAP increases by 11.9 percent points per Cmin tiludronate unit and by 0.006 points per basal SAP unit, and decreases by 0.52 per year of age. Out of 13 patients with bone pain, 9 (69%) experienced relief within the second and third months of treatment. No clinical or laboratory severe side effects were seen and only five patients (19%) had mild adverse events.
Conclusions: These results confirm that tiludronate leads to a marked suppression of PDB clinical and biochemical activity. Cmin of tiludronate in plasma is the best predictor of biochemical response.