Inhibition of calculi fragment growth by metal-bisphosphonate complexes demonstrated with a new assay measuring the surface activity of urolithiasis inhibitors.

To evaluate compounds for the long-term inhibition of urinary calculi growth, we applied a newly developed in vitro assay to various metal-ligand complexes. The new experimental model--the preadsorbed calculi growth assay--was based upon the initiation of crystal growth in a metastable solution of calcium and oxalate with uniform granules derived from human renal calculi. Potential inhibitors were first absorbed onto the surface of the calculi granules, following which the loss of calcium from the seeded metastable solution was monitored as the indicator of calcium oxalate deposition. This assay allowed participation in the reaction by any matrix components present in the human calculi granules and limited the effect of the inhibitors to the calculi surface. Some complexes of metal ions with bisphosphonates had strong inhibitory effects, as opposed to citrate complexes which had minimal effect in this assay. Tin was the most potent metal ion, and pamidronate was the most potent bisphosphonate; together they slowed the growth of calculi granules to 9% of control. The inhibition by Tin-bisphosphonate complexes persisted despite a week of continual rinsing with a solution of sodium chloride and calcium. If the metal-bisphosphonate complexes are active in vivo as well, they might be considered for prophylaxis of calcium oxalate calculi or the prevention of regrowth of residual fragments following lithotripsy.