Clinical Trial to Assess Efficacy, Tolerability of Rising Doses of Clodronate in Painful Knee Osteoarthritis Patients

The phase II will be a multicenter, double‐blind, randomized, placebo‐controlled, parallel group four‐arm study, according to the treatment dose (dose finding). Briefly, 4 groups of 74 patients (in order to have 64 fully evaluated patients taking into consideration 10 patients dropped out), i.e. a total of 296 patients, with knee OA each will be randomly allocated to the following treatments: 1. IA clodronate 2 mg/2 ml once a week for 4 weeks (total clodronate dose = 8 mg). 2. IA clodronate 5 mg/2 ml once a week for 4 weeks (total clodronate dose = 20 mg). 3. IA clodronate 10 mg/2 ml once a week for 4 weeks (total clodronate dose = 40 mg). 4. Placebo 2 ml once a week for 4 weeks (total clodronate dose = 0 mg). At the end of phase II, the minimum effective clodronate dose will be selected as DTD for the Phase III. The phase III will be a multicenter, double‐blind, randomized, placebo‐controlled, two parallel groups (DTD vs. placebo) study. Briefly, patients with knee OA will be randomly assigned to two experimental groups: 1. the DTD defined during the Phase II. 2. Matching placebo. The sample size of Phase III will be definitively calculated according to the extent of pain Visual Analogue Scale (VAS) reduction observed in the Phase II.