N-bisphosphonates cause gastric epithelial injury independent of effects on the microcirculation.
BACKGROUND
Nitrogen-containing bisphosphonates have been shown to be effective for the treatment of osteoporosis and Paget's disease of bone. Unfortunately, these drugs also have the capacity to irritate the upper gastrointestinal mucosa. In this study we investigated the ability of alendronate and pamidronate to directly damage the gastric epithelium and attempted to determine whether these drugs caused injury through gastric microcirculatory alterations.


METHODS
An ex vivo gastric chamber model was used. Effects of topically applied alendronate and pamidronate on transmucosal potential difference and epithelial integrity (histology) were determined. Also, the effects of agents capable of preventing microvascular injury in the stomach (PGE2 and two nitric oxide donors) were examined for their ability to prevent gastric injury induced by the two N-bisphosphonates.


RESULTS
Alendronate and pamidronate caused a concentration-dependent decrease in transmucosal potential difference, widespread epithelial injury and infiltration of neutrophils into the mucosa. PGE2 and the two nitric oxide donors did not prevent the changes in potential difference or the epithelial injury, but did reduce neutrophil infiltration. Significant release of PGE2 into the lumen was observed following application of the two bisphosphonates, but neither drug altered mucosal blood flow.


CONCLUSIONS
These results suggest that these N-bis- phosphonates directly damage the gastric epithelium independent of actions on the microvasculature.
Wallace
J L
JL
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. wallacej@ucalgary.ca
Dicay
M
M
McKnight
W
W
Bastaki
S
S
Blank
M A
MA
D000287:Administration, Topical; D019386:Alendronate / Q000633:toxicity*; D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology; D004164:Diphosphonates / Q000633:toxicity*; D004347:Drug Interactions; D004848:Epithelium / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D000077268:Pamidronate; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
D004164:Diphosphonates; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D015232:Dinoprostone; D000077268:Pamidronate; D019386:Alendronate