Table 1

Characteristics of the studies testing the association between bisphosphonate prescribing and esophageal and gastric cancer or UGI cancer

Author, country, year of publicationGender (mean age, years)Study population (exposed/cases)Study population (controls)nclusion/exclusion criteriaFollow-up (mean years)Outcome studied— cancer type/drug (number of exposed cases if quoted)Risk ratio (p Value), 95% CIAdjusted variablesComments
Vestergaard, Denmark, 201117M+F (70.5)Cohort of 103 562 bisphosphonate users, subset of 53 935 (alendronate users) from Danish National Registries including the National Pharmacological Database310 683 age-matched and sex-matched controls from the general population,161 207 alendronate-matched controlsPatients prescribed any bisphosphonate between 1/1/96 and 31/12/06/ Prior GI malignancy>5Esophageal/alendronate (14) Gastric/alendronate (10)2.1, 1.01 to 4.35
1.16, 0.54 to 2.53
Age, gender, alcohol, inhaled bronchodilator or steroid therapy (smoking proxy), antacids, NSAID, employment, marital status, income, prior gastric surgeryFunded By AP Moller Foundation, Servier and Dandy
Abrahamsen et al, Denmark, 201216F (79)Cohort of 30 606 females from Danish National Registries between 1995 and 2005, prescribed alendronate122 424 patients, matched 4:1 on gender and year of birthWomen aged 50±/Prior hospital diagnosis of any cancer3.5UGI/alendronate (44) Esophageal/alendronate (19)
Gastric/alendronate (22)
0.63, 0.45 to 0.87
0.71, 0.43 to 1.19
0.61, 0.39 to 0.67
age, gender, PPI use, upper endoscopy, co-medications, Charlton comorbidity indexResearchers have grants from Merck (makers of alendronate) and multiple other drug companies
Cardwell et al, UK, 201019M+F (70)Cohort of 41 826 patients on bisphosphonates from the UK General Practice Research Database41 826 age, sex and GP practice-matched controlsPatients treated with oral bisphosphonates between January 1996 and December 2006/patients with less than 6 months follow-up4.5 bisphosphonates/4.4 controlsUGI/bisphosphonate (116)
Esophageal/bisphosphonate (79)
UGI/alendronate (55)
Esophageal/alendronate (33)
0·96, 0.74 to 1.25
1.07, 0.77 to 1.49
0.79, 0.55 to 1.15
0.77, 0.48 to 1.23
Age, gender, smoking, alcohol, BMI,GP practiceFunded by CPRD/MRC licence
Green et al, UK, 201020M+F (72)2954 cases of esophageal cancer, 2018 cases of gastric cancer, 10 641 cases of colorectal cancer from the UK General Practice Research Database14 770 controls matched 5:1 per caseMen and women aged 40+diagnosed between 1995 and 2005 with at least 12 months follow-up before diagnosis/patients treated with bisphosphonates licensed for Paget's disease or bone metastases7.5Esophageal/bisphosphonate (90) Esophageal (<10 prescriptions) Esophageal (>10 prescriptions)
Gastric (49)
Colorectal (276)
1·3, 1.02 to 1.66
0.93, 0.66 to 1.31
1.93, 1.37 to 2.70
0.87, 0.64 to 1.19
0.87, 0.77 to 1.00
Smoking, gender, age, alcohol, BMIFunded by CPRD/MRC licence
Wright et al, UK, 20129M+F (64.7)5226 cases of esophageal cancer, 3410 cases of gastric cancer from the UK General Practice Research Database 20 904 and 13 640 controls matched 4:1 by age and sexAll men and women registered with practices with up to standard data in the CPRD from 1995 to 20076.1UGI/bisphosphonate (342)
Esophageal/bisphosphonate (225)
Gastric/bisphosphonate (93) F Esophageal/alendronate (95) F
1·3, 1.21 to 1.39
1.43, 1.18 to 1.72
1.06, 0.83 to 1.35
1.42, 1.1 to 1.83
Smoking
smoking
Gender difference identified. Funded by CPRD/MRC licence
Vinogradova et al, UK, 20132M+F (>50)5132 cases of esophageal cancer from CPRD 3157 cases of gastric cancer23 110 controls 14 686 controlsPatients aged above 50 with at least 2 years of data before index date/patients with prescriptions of bisphosphonates licensed for malignancies, patients with Paget's diseaseStratified<6, 7–36, 37–72, ≥73 monthsEsophageal/bisphosphonate (262)
Esophageal/alendronate(167)
Gastric/bisphosphonate (139)
Gastric/alendronate (100)
1.18 (0.09), 0.97 to 1.43
1.03 (0.8), 0.83 to 1.13
0.79 (0.06), 0.62 to 1.01
0.93 (0.6), 0.71 to 1.22
BMI, smoking, alcohol, ethnicity, osteoporosis history, previous fracture, steroid use, H2 antagonists, PPIs, antacids, NSAIDs, vitamin D prescribed more than 1 year beforeNested case–control using two large national databases funded by University of Nottingham
Vinogradova et al, UK, 20132M+F (>50)5364 cases of esophageal cancer from Q-Research database3155 cases of gastric cancer25 101 controls, matched 5:1 by age, sex, practice and calendar year 14 715 controlsAs aboveStratified <6, 7–36, 37–72, ≥73 monthsEsophageal/bisphosphonate(252)
Esophageal/alendronate(163)
Gastric/bisphosphonate (141)
Gastric/alendronate(102)
0.97 (0.7), 0.79 to 1.18
0.91 (0.4), 0.73 to 1.14
1.12 (0.4), 0.87 to 1.44
1.47 (0.008), 1.11 to 1.95
As aboveAs above
Nguyen et al, USA, 20101897% M (69) 116 cases of incident EAC out of 11 823 patients with BE from the US Department of Veterans Affairs Database 696 controls matched 6:1 on age (± 5 years) and BE index date (± 14 days)Patients aged 18–90 with ICD code for BE and endoscopy 1 year before BE index date to 9 months after/Pts with ICD code for EAC between 10/96 and 6 months after BE index date691 days (SD 386)Esophageal/alendronate0·92, 0.21 to 4.15Completed bisphosphonate prescriptions were very uncommon (1·7% in cases vs 1·9% in controls) Funding—NIH and Texas Gulf Coast Digestive Diseases Center
Chen et al, Taiwan, 201121M+F282 cases of esophageal cancer from a cohort of osteoporosis treatment initiators between 2001 and 2008 from National Health Insurance Research Database2811 controls without cancer matched by age, sex and cohort entry yearCases hospitalised for esophageal cancer since entry into cohort1Esophageal/alendronate (88)0.61 (0.36), 0.21 to 1.75

Age, sex, comorbidities, PPI use, cohort entryGovernment-funded research (National Science Council)
Chiang et al, Taiwan, 201222 F (73.5) Cohort of 6906 women selected from NHRI cohort (1 000 000 randomly selected patients of National Health Insurance Claims Database from 1995 onward)20 697 women with osteoporosis, age and comorbidity matched, with no record of taking bisphosphonates between 1996 and 2009Women with osteoporosis over 55taking alendronate from 1 January 1998 to 31 December 2009/exposure to oral steroids, malignancy, vitamin D deficiency, hyperparathyroidism, coeliac disease, hyperthyroidism, Paget's disease4.8All cancers/alendronate (821)
Esophageal/alendronate (13)
Gastric/alendronate (37)
1.05, 0.97 to 1.93
1.5, 0.78 to 2.88
1.04, 0.72 to 1.50
Age, gender, hypertension, diabetes, COPD, dyslipidaemia, CKD, CAD, colorectal polyp, benign breast disease, obesity, statin useNHRI cohort is representative of general Taiwanese population. Not controlled for smoking or alcohol. Study supported by grants from National Science council and Taipei Veterans General Hospital
Lee et al, Taiwan, 201223M+FCohort of 5624 patients with osteoporosis from National Health Insurance Research Database (100 000 patients randomly selected between 1996 and 2000)16 294 patients with osteoporosis, not on antiosteoporosis medication over the same time period, matched 3:1 by age and genderPatients taking alendronate between 1998 and 2009/patients taking bisphosphonates other than alendronate, patients with a cancer history predating the first alendronate prescription2.92 to 3.04Esophageal/alendronate, <1 g/year (2)
Esophageal/alendronate, >1 g/year
(1)
Gastric/alendronate,<1 g/year (8)
Gastric/alendronate, >1 g/year (4)
1.08, 0.23 to 5.08
1.15, 0.14 to 9.23
0.77, 0.36 to 1.63
0.75, 0.27 to 2.09
Age, sex, hypertensionFunded by Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH101-TD-B-111–004), and (DOH101-TD-C-111–005.
  • BE, Barrett's esophagus; BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research Data Link Database; EAC, esophageal adenocarcinoma; GP, general practitioner; ICD, International Classification of Diseases; MRC, Medical Research Council; NIH, National Institutes of Health; NHRI, National Health Research Institutes; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor; UGI, upper gastrointestinal.