INVESTIGATION OF THE ACUTE AND CHRONIC ANTIINFLAMMATORY PROPERTIES OF DIPHOSPHONATES USING A BROAD-SPECTRUM OF IMMUNE AND NONIMMUNE INFLAMMATORY REACTIONS

Diphosphonates are known to affect skeletal and soft tissue mineralization; however, several studies have shown that these compounds effectively suppress adjuvant-induced polyarthritis in the rat, reducing the edematous inflammatory component as well as skeletal changes. Therefore, we investigated the specific anti-inflammatory potential of two diphosphonates, ethane-1-hydroxy-1,1 diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP), using several different models of acute, non-immune- and immune-driven inflammation in the pleural cavity of rats and guinea pigs which afforded both a qualitative and quantitative assessment of leukocyte infiltration and exudate fluid (edema) formation. EHDP and Cl2MDP, administered at doses which suppressed the chronic inflammatory lesions induced in adjuvant arthritis, failed to inhibit acute inflammation regardless of the stimulus used (carrageenan; calcium pyrophosphate dihydrate crystals; hydroxyapatite crystals; immune complexes (Arthus reaction); delayed-type hypersensitivity to purified protein derivative). At the highest dose tested (15 mg/kg subcutaneously [sc]) both EHDP and Cl2MDP exacerbated hydroxyapatite- and delayed-type hypersensitivity-induced leukocyte infiltration; hydroxyapatite crystals precoated with EHDP or Cl2MDP caused enhanced leukocyte infiltration compared with hydroxyapatite alone. Cl2MDP caused a small but significant inhibition of the chronic inflammatory response to sc cotton pellet implantation. We conclude that EHDP and Cl2MDP may be effective in chronic rather than acute inflammation. Our observations suggest that further studies are warranted on the potential of diphosphonates as novel therapeutics for chronic inflammatory disease.