title: Oral bisphosphonates and upper gastrointestinal toxicity: a study of cancer and early signals of esophageal injury.
abstract: CONCLUSIONS
  We evaluated the association between bisphosphonate use and (1) upper gastrointestinal cancer, (2) upper endoscopy, (3) incident Barrett's esophagus, and (4) prescription antacid initiation among Medicare beneficiaries. We found no bisphosphonate-cancer association and negative bisphosphonate-Barrett's association.
  
  
  BACKGROUND
  Bisphosphonates can irritate the esophagus; a cancer association has been suggested. Widespread bisphosphonates use compels continued investigation of upper gastrointestinal toxicity.
  
  
  METHODS
  Using a 40% Medicare random sample denominator, inpatient, outpatient (2003-2011), and prescription (2006-2011) claims, we studied patients age 68 and older with osteoporosis and/or oral bisphosphonate use. Inverse propensity weighting estimated marginal structural models for the effect of bisphosphonate intensity (pills per month) and cumulative bisphosphonate pills received on upper gastrointestinal cancer risk. Secondary analyses of sub-cohorts without past bisphosphonates or upper endoscopy assessed bisphosphonate initiation and risk of (1) upper endoscopy, (2) incident Barrett's esophagus, and (3) prescription antacid initiation.
  
  
  RESULTS
  The cohort included 1.64 million beneficiaries: 87.9% women, mean age, 76.8 (standard deviation (SD) 9.3); mean follow-up, 39.6 months; 38.1% received oral bisphosphonates. Cumulative bisphosphonate receipt, among users, ranged from 4 to 252 pills (5th to 95th percentile). We identified 2,308 upper gastrointestinal cancers (0.43/1000 person years). We found no association between cumulative bisphosphonate pills and cancer, odds ratio (OR) for each additional pill 1.00 (95% confidence interval (CI) 1.00, 1.00). In sub-cohorts, compared to none, lowest cumulative bisphosphonate use (one to nine pills) was associated with higher risk of endoscopy (OR 1.11, 95% CI 1.08-1.14) and antacid initiation (OR 1.13, 95% CI 1.10-1.16); higher intensity conferred no increased risk. Higher intensity and higher cumulative bisphosphonate category were associated with lower Barrett's risk.
  
  
  CONCLUSIONS
  We found no bisphosphonate-cancer association and negative bisphosphonate-Barrett's association. Bisphosphonate initiation appears to identify patients susceptible to early irritating effects; clinicians might offer alternatives and delay endoscopy or antacids.
authors.affiliation: The Dartmouth Institute for Health Policy & Clinical Practice, Geisel School of Medicine at Dartmouth, 35 Centerra Parkway, Room 3088, Lebanon, NH, 03766, USA, nancy.e.morden@dartmouth.edu.
authors.forename: N E
authors.initials: NE
authors.lastname: Morden
authors.forename: J C
authors.initials: JC
authors.lastname: Munson
authors.forename: J
authors.initials: J
authors.lastname: Smith
authors.forename: T A
authors.initials: TA
authors.lastname: Mackenzie
authors.forename: S K
authors.initials: SK
authors.lastname: Liu
authors.forename: A N A
authors.initials: AN
authors.lastname: Tosteson
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000139:chemically induced* / Q000453:epidemiology; D015331:Cohort Studies; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D004363:Drug Utilization / Q000706:statistics & numerical data; D004938:Esophageal Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D004945:Esophagoscopy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy / Q000453:epidemiology; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000453:epidemiology; D014481:United States / Q000453:epidemiology
chemical_list: D004164:Diphosphonates