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Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort

BMJ 2010; 341 doi: (Published 02 September 2010) Cite this as: BMJ 2010;341:c4444
  1. Jane Green, clinical epidemiologist1,
  2. Gabriela Czanner, statistician1,
  3. Gillian Reeves, statistical epidemiologist1,
  4. Joanna Watson, epidemiologist1,
  5. Lesley Wise, manager, Pharmacoepidemiology Research and Intelligence Unit2,
  6. Valerie Beral, professor of cancer epidemiology1
  1. 1Cancer Epidemiology Unit, University of Oxford, Oxford OX3 7LF
  2. 2Medicines and Healthcare products Regulatory Agency, Pharmacoepidemiology Research Unit, London SW8 5NQ
  1. Correspondence to: J Green{at}
  • Accepted 23 June 2010


Objective To examine the hypothesis that risk of oesophageal, but not of gastric or colorectal, cancer is increased in users of oral bisphosphonates.

Design Nested case-control analysis within a primary care cohort of about 6 million people in the UK, with prospectively recorded information on prescribing of bisphosphonates.

Setting UK General Practice Research Database cohort.

Participants Men and women aged 40 years or over—2954 with oesophageal cancer, 2018 with gastric cancer, and 10 641 with colorectal cancer, diagnosed in 1995-2005; five controls per case matched for age, sex, general practice, and observation time.

Main outcome measures Relative risks for incident invasive cancers of the oesophagus, stomach, and colorectum, adjusted for smoking, alcohol, and body mass index.

Results The incidence of oesophageal cancer was increased in people with one or more previous prescriptions for oral bisphosphonates compared with those with no such prescriptions (relative risk 1.30, 95% confidence interval 1.02 to1.66; P=0.02). Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (1.93, 1.37 to 2.70) than for one to nine prescriptions (0.93, 0.66 to 1.31) (P for heterogeneity=0.002), and for use for over 3 years (on average, about 5 years: relative risk v no prescription, 2.24, 1.47 to 3.43). Risk of oesophageal cancer did not differ significantly by bisphosphonate type, and risk in those with 10 or more bisphosphonate prescriptions did not vary by age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, or corticosteroids. Cancers of the stomach and colorectum were not associated with prescription of bisphosphonate: relative risks for one or more versus no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00). The specificity of the association for oesophageal cancer argues against methodological problems in the selection of cases and controls or in the analysis.

Conclusions The risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over about a five year period. In Europe and North America, the incidence of oesophageal cancer at age 60-79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years’ use of oral bisphosphonates.


  • We are grateful to patients and general practitioners participating in the General Practice Research Database and to General Practice Research Database staff for help and advice.

  • Contributors: All authors participated in the design of the study, the interpretation of the analysis, and the writing of the report. All authors have seen and approved the final version of the report. GC did the analyses. VB and JG are the guarantors.

  • Funding: The General Practice Research Database dataset for this study was obtained under the collaborative research licence funded by the Medical Research Council, and the study was approved by the Independent Scientific Advisory Committee of the General Practice Research Database (protocol number 06_090). Cancer Research UK provided further funding for the study. The funders had no role in study design, in the analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

  • Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare that they have no financial or non-financial interests that may be relevant to the submitted work.

  • Ethical approval: Not needed.

  • Data sharing: No additional data available.

  • Answer CME questions related to this article.

  • Accepted 23 June 2010

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