Slow-Release Clodronate in Prevention of Inflammation and Bone Loss Associated with Adjuvant Arthritis

The effects of slow-release calcium clodronate on rat adjuvant arthritis were investigated using two different dosing schedules. In prophylactic treatment, calcium clodronate was given on the same day as the adjuvant injection, and in therapeutic treatment, calcium clodronate administration was delayed until the animals had active disease, to day 14 postadjuvant. Calcium clodronate was given as single i.m. injections into the thigh muscles. Arthritis index, histopathology of hindpaw, quantitative histomorphometry, bone mineral density and serum osteocalcin, alkaline phosphatase and calcium were studied. Calcium clodronate given therapeutically decreased the severity of paw swelling slightly more than prophylactic treatment, a result seen as lower scores of arthritis index. Histopathological evaluation of hindpaws showed that calcium clodronate protected against inflammation-induced bone loss and reactive bone formation in the hindpaw, but not against inflammatory changes involving articular cartilage. Quantitative histomorphometric analysis of the distal femur indicated that trabecular bone area was decreased by 86% in arthritic rats compared with normal untreated controls. Both the prophylactic and the therapeutic treatment with calcium clodronate prevented this osteopenia (P < .001). Bone mineral density measured by computed tomography was also significantly reduced in distal femoral metaphysis in adjuvant arthritic rats, but restoration to virtually normal values occurred with calcium clodronate (P < .001). In both dosing schedules, we observed a suppression of arthritis, which was associated with a decrease in paw swelling and an inhibition of the severe osteopenia in the distal femoral metaphysis. The long duration of action after a single injection of calcium clodronate indicates that the insoluble salt remains at the injection site and is released slowly into the bloodstream.