Data was received from GPRD for 46,036 oral bisphosphonate users and 46,036 matched controls. 314 cohort members had esophageal or gastric cancer codes recorded during follow-up. In 27 cases (8.6%) the codes were inconsistent and the diagnosis was not accepted, leaving a total of 287 incident esophageal or gastric cancer diagnoses (0.34% of the combined cohorts); 181 esophageal cancer (92 in the control cohort) and 106 gastric cancers (57 in the control cohort). Data on cancer histological subtypes was unavailable. The SIRs of esophageal and gastric cancer in the control cohort were 1.18 (95%CI 0.95, 1.45) and 0.70 (95%CI 0.53, 0.91) respectively, showing under-recording of gastric cancer. The combined esophageal and gastric cancer SIR was 0.94 (95%CI 0.79, 1.10). These SIRs suggest that tumours arising at the gastro-esophageal junction or in the gastric cardia may have been classified as esophageal cancers rather than gastric cancers. Our principal analysis was therefore for gastric and esophageal cancers combined.
41,826 bisphosphonate users had at least 6 months of follow-up and further analyses were restricted to these patients and their matched controls. 81% of both cohorts were female and the mean age (SD) was 70.0 (11.4) years (). Mean (SD) follow-up was 4.5 (2.6) years and 4.4 (2.6) years in the bisphosphonate and control cohorts, respectively, and both had a maximum follow-up period of 12.9 years. All of the bisphosphonate cohort and 9% of the control cohort received at least one prescription for oral bisphosphonates during the follow-up period. The mean (SD) number of bisphosphonate DDDs prescribed per day in the bisphosphonate and control cohorts during this period was 0.59 (0.49) and 0.03 (0.16), respectively. Data on BMI was available for 48.3% of the bisphosphonate and 41.9% of the control cohort members: mean BMI was higher in the control cohort than the bisphosphonate cohort, 27.1 Kg/m2 compared to 25.5 Kg/m2. There were only small differences in smoking and alcohol status between the cohorts. Ever use of HRT, NSAIDs, PPIs and H2RAs before the index date was higher in the bisphosphonate cohort than in the control cohort.
Participant characteristics in bisphosphonate cohort and matched control cohort (including only individuals with more than 6 months follow-up).
Any bisphosphonate use
shows the cumulative incidences of combined esophageal and gastric cancers and esophageal cancers in the cohorts. There was no difference in combined esophageal and gastric cancer risk between the cohorts before or after adjustments for potential confounders; HR (95% CI) 1.00 (0.77, 1.29) and 0.96 (0.74, 1.25) respectively, . Similarly, there was no difference in esophageal cancer risk between the two cohorts; adjusted HR (95% CI) 1.07 (0.77, 1.49), . and also show that after receiving specified amounts of bisphosphonate DDDs there was no evidence of an increase in esophageal and gastric cancer risk (or esophageal cancer risk). For instance, after receiving 365 bisphosphonate DDDs (equivalent to a 1 year supply) the risk of esophageal and gastric cancer (or esophageal cancer) were similar in the bisphosphonate and control cohorts: unadjusted HR (95% CI) 0.94 (0.64, 1.39) and 0.88 (0.55, 1.43), respectively . also shows no increase in esophageal and gastric cancer risk (or esophageal cancer risk) in the groups with higher use of bisphosphonates based on DDDs per day. There was no association between any bisphosphonate use and risk of these cancers when members of the control cohort who were prescribed bisphosphonates subsequent to the index date (and their matched bisphosphonate cohort member) were excluded from the analysis, adjusted HRs (95% CI), 0.92 (0.70, 1.21) and 1.01 (0.72, 1.42) for risk of esophageal and gastric cancer and esophageal cancer only, respectively. When, in order to maximise follow-up, we restricted the analysis to patients whose date of first receipt of bisphosphonates was before 1/1/2000 (and their matched controls), the adjusted HRs (95% CI) for esophageal and gastric cancer risk, and esophageal cancer risk, were 1.19 (0.69, 2.05) and 1.23 (0.66, 2.30), respectively, for any bisphosphonate use. This analysis included 7,082 members (17%) from each cohort and mean (SD) follow-up was 6.8 (3.7) years.
Time to esophageal and gastric cancer or esophageal cancer only in the bisphosphonate (—) and contol (--) cohort.
Esophageal and gastric cancer incidence in the bisphosphonate and control cohorts.
Esophageal (only) cancer incidence in the bisphosphonate and control cohorts.
also shows no association between the risk of esophageal and gastric cancer or esophageal cancer only and nitrogen containing bisphosphonates (adjusted HRs 0.91 and 0.96), aldendronate (adjusted HRs 0.79 and 0.77, respectively) or non-nitrogen containing bisphosphonates. Similarly, there was no evidence of an association with risk of these cancers after receiving over 1 year (or 2 years) of prescriptions for either nitrogen containing bisphosphonates or alendronate.
Cancer risk in cohort members with a history of gastro-esophageal reflux disease (GERD) or Barrett’s esophagus
5,016 (12%) and 3,657 (9%) members of the bisphosphonate cohort and control cohorts, respectively, had GERD codes recorded prior to their index date (). The association between GERD and incidence of esophageal and gastric cancer, or esophageal cancer only, did not differ between the bisphosphonate and control cohort (P for interaction term = 0.74 and 0.99, respectively). Specifically, GERD diagnosis was associated with a 49% increase in the incidence of esophageal and gastric cancer (HR =1.49, 95%CI 0.85, 2.61) in the bisphosphonate cohort and a 69% increase in the control cohort (HR=1.69, 95%CI 1.06, 2.71), with similar increases in risk seen for esophageal cancer only. 198 (0.47%) and 145 (0.35%) members of the bisphosphonate cohort and control cohorts, respectively, had Barrett’s esophagus codes recorded prior to their index date (). Only one of these (in the control cohort) developed esophageal or gastric cancer.