High-dose clodronate therapy prevents joint destruction in chronic antigen-induced arthritis of the rat but inhibits bone formation at the axial skeleton

Objective: To investigate the effects of clodronate on clinical disease activity, inflammatory alterations and cartilage destruction, periarticular and axial bone volume and bone turnover in chronic antigen-induced arthritis (AIA; day 28). Methods: Rats with AIA were treated with clodronate (5 mg/kg/day continuously; 20 mg/kg/day intermittently or high-dose with 300 mg/kg 3 hours after arthritis induction +20 mg/kg/day continuously, respectively). Joint pathology was examined by histology. Bone volume and cellular turnover parameters of the right tibia head and the third lumbar vertebra were evaluated by histomorphometry. The findings were compared with those of healthy controls, sham-treated AIA and AIA treated continuously with 250 mu g/kg of dexamethasone. Results: All three therapy regimens with clodronate resulted in a significant reduction of joint swelling, histopathological inflammatory changes and cartilage destruction in comparison with sham-treated AIA. The antiinflammatory effect of high-dose clodronate was comparable with dexamethasone. The intermittent administration of 20 mg/kg/day of clodronate completely prevented periarticular bone loss by reduction of bone resorption without affecting bone formation at the periarticular and axial bone. Both continuous treatment with 5 mg/kg/day of clodronate and high-dose clodronate therapy partially prevented periarticular bone loss and reduced parameters of bone formation at the axial bone to values below those of healthy controls. Conclusion: High-dose clodronate therapy exerts an excellent preventive effect on clinical disease activity and on joint destruction in AIA. However, continuous treatment with high doses of clodronate may result in a low turnover state of bone remodelling.