OBJECTIVE: Bisphosphonates may have a chondroprotective effect in patients with knee OA (KOA), but the results of clinical trials with oral bisphosphonates have been contradictory. In this Phase 2 randomized, partially blind clinical trial, we tested the efficacy of IA clodronate vs HA in patients with primary KOA. METHODS: One hundred and fifty men or women aged 50-75 years suffering from KOA were randomized to one of five IA therapies: (i) clodronate 0.5 mg one IA injection/week for 4 weeks; (ii) clodronate 1 mg one IA injection/week for 4 weeks; (iii) clodronate 2 mg one IA injection/week for 4 weeks; (iv) clodronate 1 mg two IA injections/week for 2 weeks (clodronate 1 + 1 mg); and (v) HA 20 mg one IA injection/week for 4 weeks. RESULTS: Visual analogue scores (VASs) for different types of pain and the Lequesne index significantly improved in all treatment groups after the first injection and continued to improve even 2-4 weeks after the last injection without significant difference among the groups. A significant (P = 0.03) linear trend for a dose-response (0.5-2 mg clodronate) relationship was found for active movement VAS pain. Both joint extension and mobility scores improved significantly at all time points in all treatment groups without statistical differences among them. CONCLUSIONS: This study indicates that IA clodronate provides symptomatic and functional improvements at least as good as those obtained with HA. Trial Registration. Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali - Agenzia Italiana del Farmaco. Comitato Etico Azienda Ospedaliera Universitaria Senese number CLIO 22/02 http://oss-sper-clin.agenziafarmaco.it.