Effect of bisphosphonates on surface hydrophobicity and phosphatidylcholine concentration of rodent gastric mucosa

Bisphosphonates are a family of chemically related zwitterionic molecules t hat are used clinically to retard bone resorption in individuals with osteo porosis and associated skeletal diseases. Inflammation and ulceration of th e upper gastrointestinal tract by a mechanism that relates to a topical irr itant action is associated with the consumption of some bisphosphonates. In the present study, we investigated the effects of three bisphosphonate mol ecules, pamidronate, alendronate, and risedronate on the surface hydrophobi city and phosphatidylcholine (PC) concentration of the antral mucosa. We al so examined how these surface changes related to mucosal injury in an estab lished rat model, in which the test compounds were administered in combinat ion with indomethacin. We initially determined that a combination of pamidr onate (300 mg/kg) and indomethacin (40 mg/kg) induced a significant reducti on in mucosal surface hydrophobicity and macroscopic lesion formation by 15 min and mucosal PC concentration by 30 min, with the magnitude of these ch anges increasing over the 4-hr study period. An equivalent dose of alendron ate or risedronate in combination with indomethacin produced modest or no m acroscopic injury, respectively, to the antral mucosa over the 4-hr study, although the bisphosphonates clearly induced surface injury and some glandu lar necrosis when examined at the light microscopic level. These bisphospho nates also induced modest decreases in antral surface hydrophobicity and mu cosal PC concentration that appeared to be related to their injurious poten tial. In conclusion, the variable toxicity of bisphosphonates to the antral mucosa appears to be associated with their ability to compromise the surfa ce hydrophobic phospholipid barrier of the tissue, with pamidronate > > > a lendronate > risedronate. This bisphosphonate effect on the surface barrier may trigger the development of mucosal injury and possible ulceration.