Within the study period, in QResearch we identified 20
106 cases of colorectal cancer, 5364 cases of oesophageal cancer, and 3155 cases of gastric cancer matched to 93
101, and 14
715 controls, respectively. From CPRD, there were 19
035 cases of colorectal cancer, 5132 cases of oesophageal cancer, and 3157 cases of gastric cancer matched to 89
053, and 14
686 controls, respectively.
Tables 1, 2 and 3
show the characteristics for all cases and controls for both databases. Most of the descriptive statistics were similar in QResearch and CPRD. Cases and controls from QResearch were slightly younger than CPRD cases and controls, and Townsend score as a measure of deprivation was available only for a third of cases and controls in CPRD (table 1). BMI, smoking status, and alcohol consumption had slightly fewer missing values in CPRD with higher proportions of non-smokers and moderate and high alcohol consumption than in QResearch (table 2).
Table 1 Baseline demographic characteristics in cases (all gastrointestinal cancers) and all matched controls by database (QResearch or CPRD). Values are percentages and numbers
Table 2 Baseline characteristics in cases (all gastrointestinal cancers) and all matched controls by database (QResearch or CPRD). Values are percentages and numbers unless stated otherwise
Table 3 Medical history at baseline in cases (all gastrointestinal cancers) and all matched controls by database (QResearch or CPRD). Values are percentages and numbers.
Most of the comorbidities had similar proportions in cases selected from both databases and their controls (table 3). Upper gastrointestinal morbidities were recorded slightly more often in CPRD (29% in cases and 27% in controls v 22% and 20% in QResearch) with higher proportions for gastro-oesophageal reflux (9% and 8% v 6% and 5%, respectively) and dyspepsia (13% and 12% v 7% and 7%, respectively). Use of common drug treatments was similar in the databases with slightly more frequent prescribing of NSAIDs and less frequent prescribing of corticosteroids in CPRD compared with QResearch. Prescribing of calcium supplements also had different patterns with more patients prescribed calcium in CPRD.
Patterns of bisphosphonate use
In QResearch 4.6% of cases and 4.5% of controls had one or more prescriptions for bisphosphonates, as did 4.8% and 4.6%, respectively, in CPRD. About two thirds of patients with a diagnosis of osteoporosis had been prescribed bisphosphonates (64% of cases and 65% of controls in QResearch and 61% and 60%, respectively, in CPRD) and 2% of cases and controls in both databases had prescriptions for bisphosphonates without records of osteoporosis. Bisphosphonate users were more likely to be women and to have a lower BMI. Upper gastrointestinal problems were slightly more common (QResearch: cases 25% in users v 22% in non-users, controls 25% v 20%; CPRD: cases 35% v 29%, controls 33% v 27%) and use of acid lowering drugs was much more common in bisphosphonate users (QResearch: cases 62% in users v 37% in non-users, controls 61% v 32; CPRD: cases 65% v 39%, controls 63% v35%). Among bisphosphonate users, the proportion of patients with rheumatoid arthritis was more than five times higher than in non-users, and there were similar patterns for use of anti-inflammatory drugs, non-steroidal drugs, and corticosteroids.
More than three quarters of the bisphosphonate users were prescribed only one type of drug (77% in cases and 77% in controls in QResearch and 80% and 79% in CPRD), one fifth had prescriptions for two different types (20% in cases and 20% in controls in QResearch and 17% and 19% in CPRD), and less than 3% (2% in cases and 3% controls in QResearch and 3% and 2% in CPRD) had prescriptions for three different types during the observation period. Alendronate was the most commonly prescribed type (69% in cases and 66% in control users in QResearch and 69% and 69% in CPRD) and mostly prescribed for weekly use (87% in cases, 88% in controls in QResearch and 89% and 88% in CPRD). The second most common type was etidronate (34% in cases and 36% in controls users in QResearch and 30% and 32% in CPRD) with daily use for 14 days in 90 day cycles. The third most common was risedronate (21% in cases and 22% controls users in QResearch and 22% and 21% in CPRD), prescribed mostly for weekly use (76% in cases and 80% in controls users in QResearch and 82% and 81% in CPRD). Ibandronate (2% in cases and in controls users in QResearch and CPRD) was prescribed for monthly use only and no one received it as injections. In only one case (in QResearch) was a patient prescribed zoledronic acid.
In both databases, the minimum duration of bisphosphonate prescription was one week, and over half of bisphosphonate users had prescriptions for at least 20 months (median 20 (interquartile range 7-43) and 21 (8-44) for cases and controls, respectively, for QResearch; 19 (6-4) and 20 (7-41) for CPRD). Two thirds of bisphosphonate users (64% cases and 65% controls in QResearch, and 63% cases and controls in CPRD) had no gap of longer than 60 days between the first and last prescriptions, with 17% of cases and 18% of controls in QResearch and 19% of cases and 20% of controls in CPRD having only one gap longer than 60 days.
Associations with cancer
Tables 4, 5, and 6 show the associations between regimen and duration of bisphosphonate prescriptions and different types of the drug and risk for oesophageal, gastric, and colorectal cancer. Table 7 contains the results from the first three sensitivity analyses for short and long term use for the three cancers.
Table 4 Bisphosphonate use in oesophageal cancer cases and controls, numbers and odds ratios (95% confidence intervals) compared with non-use by database
Table 5 Bisphosphonate use in gastric cancer cases and controls, numbers and odds ratios (95% confidence intervals) compared to non-use by database
Table 6 Bisphosphonate use in cases of colorectal cancer and controls, numbers and odds ratios (95% confidence intervals) compared with non-use by database
Table 7 Sensitivity analyses by definition of length of use of bisphosphonates (short term (≤1 year) and long term (>1 year)) and varying definitions of use
After adjustment for confounders, both studies showed no significant association between overall bisphosphonate use and risk of oesophageal cancer (adjusted odds ratio 0.97, 95% confidence interval 0.79 to 1.18, for QResearch; and 1.18, 0.97 to 1.43, for CPRD). Similarly, there were no differences for frequency of use or duration (P=1.0 for trend) in QResearch. In CPRD, although odds ratios were progressively higher for longer use of bisphosphonates, none of them nor the trend test reached significance (P=0.07 for trend). There were no significant associations for individual types of bisphosphonate. None of the sensitivity analyses showed any significant associations.
After adjustment for confounders, both studies showed no significant association between overall bisphosphonate use and risk of gastric cancer (adjusted odds ratio 1.12, 95% confidence interval 0.87 to 1.44, for QResearch, and 0.79, 0.62 to 1.01, for CPRD). Daily use of bisphosphonates was associated with a decreased risk (0.60, 0.41 to 0.87; P=0.008) in CPRD, but this was not confirmed by any of the sensitivity analyses. Of the different bisphosphonates, alendronate use was significantly associated with cancer risk only in QResearch (1.47, 1.11 to 1.95; P=0.008), but a direct test between the different types of bisphosphonates was not significant (P=0.053). Short term use (<1 year) of alendronate was associated with a significantly higher risk of cancer in QResearch (1.91, 1.34 to 2.72; P<0.001), but there was no significant increase for longer term use (1.08, 0.74 to 1.59; P=0.7). These findings were also significant in the first sensitivity analysis, which classified use as two or more prescriptions (2.23, 1.54 to 3.22; P<0.001 for shorter term), but results of the second sensitivity analysis, which classified use as all prescriptions including the last six months, failed to reach significance (1.49, 1.06 to 2.08; P=0.02 for shorter term). In CPRD, the odds ratio for alendronate use (0.93, 0.71 to 1.22) was also higher than for other bisphosphonates, but the difference between drugs was not significant (P=0.2). There were no significant relations with duration for any of the drugs. No other significant associations were observed in the sensitivity analyses.
Use of bisphosphonates was similar in cases of colorectal cancer and their matched controls (4.6% in both), and adjustment for the confounders did not show any association between bisphosphonate use and risk of cancer (adjusted odds ratio 1.03, 95% confidence interval 0.94 to 1.14, for QResearch; and 1.10, 1.00 to 1.22, for CPRD). Daily use had similar effects as weekly or monthly use. In CPRD data, short term use was associated with an increased risk, although this reached significance only for one to six months’ use (1.27, 1.09 to 1.48; P=0.002), but this finding was not confirmed by any of the sensitivity analyses. The relation between duration of bisphosphonate use and risk of colorectal cancer was not significant in either database (P=0.3 for trend for QResearch and P=0.5 for CPRD). For QResearch, the adjusted odds ratio for any use of alendronate was higher than for etidronate or risedronate, but it was not significantly increased and the difference between the drugs was not significant (P=0.09). For CPRD, the effect of drugs seemed to be similar (P=0.5). The results from the sensitivity analyses were in line with these.
Results obtained from pooling the results from both databases presented in tables 4, 5, and 6 did not show any significant findings.