Inhibition of calcium oxalate urolithiasis in a rat model of lithogenesis using bisphosphonates

Bisphosphonates bind renal calculi and inhibit calcium oxalate crystal growth in vitro. We evaluated their ability to inhibit calcium oxalate urolithiasis in a lithogenic rat model. Male Sprague-Dawley rats (four groups, eight rats each) were fed 1.0% ethylene glycol in their drinking water for 6 weeks. All rats had implantation of a 50- to 60-mg zinc pellet in their urinary bladder at the beginning of the 6-week period. The control group received no treatment. The other three groups received six weekly intraperitoneal injections of one of three bisphosphonates: pamidronate (APD), clodronate (CLO), or methylene diphosphonate (MDP). At the end of 6 weeks, the zinc pellet was retrieved and weighed; the kidneys were sectioned and stained to evaluate inflammation, tubular dilation, and crystal deposition; and blood and urine samples were analyzed for calcium and creatinine. There were no detectable biochemical differences between the control and the treatment groups, Zinc pellets removed from control animals had a significantly greater increase in weight secondary to crystal deposition than those from the treatment groups (mean 28.4% for control v 18.9%, 15.3%, and 18.6%, respectively, for animals given APD, CLO, and MDP). The control animals also had significantly higher scores for inflammation, tubular dilation, and crystal deposition than animals treated with MDP and CLO. Older and newer-generation bisphosphonates have an inhibitory effect on calcium oxalate urolithiasis that is demonstrable at relatively infrequent dosing intervals in vivo. More frequent dosing or higher doses may allow greater inhibition of stone formation.