Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Exposure to oral bisphosphonates and risk of gastrointestinal cancer

Abstract

Summary

Few studies have explored the association of oral bisphosphonate exposure and gastrointestinal cancer within Asian populations. In this study, we investigated 45,397 Korean women from the nationwide population-based cohort from 2002 to 2013. Oral bisphosphonate exposure did not appear to be associated with elevated or reduced risk for gastrointestinal cancer.

Introduction

While several studies suggested increased risk in upper gastrointestinal (GI) cancer or reduced risk in colorectal cancer upon bisphosphonate exposure, the association is less explored within Asian populations. We investigated the effect of oral bisphosphonate exposure on the risk of GI cancers within a nationwide population-based cohort.

Methods

This study used two separate cohorts. The first cohort included 45,397 women aged 60 years or older from the National Health Insurance Service-Health Screening Cohort during 2002–2013. Participants were classified into bisphosphonate users and non-users based on drug exposure during 2002–2007, and followed-up from the index date of January 1, 2008. The second cohort included 25,665 newly diagnosed osteoporosis patients who started taking oral bisphosphonate during 2003–2008. After 4 years of drug exposure period, patients were separated into quartiles based on cumulative oral bisphosphonate exposure. Participants were followed-up until December 31, 2013 for GI cancer, stomach cancer, and colorectal cancer. Cox proportional hazard regression models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) for the cancer risks.

Results

Compared to bisphosphonate non-users, no significant risk difference was observed among bisphosphonate users on GI (HR 1.06; 95% CI 0.87–1.28), stomach (HR 1.11; 95% CI 0.85–1.47) and colorectal cancers (HR 1.04; 95% CI 0.79–1.37). Among bisphosphonate users, increasing doses of bisphosphonate exposure was not associated with elevated or reduced risk for GI cancer (p for trend 0.573).

Conclusion

Oral bisphosphonate use did not appear to be associated with elevated or reduced risk for GI cancers.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B (2014) The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 29:2520–2526

  2. 2.

    Whitaker M, Guo J, Kehoe T, Benson G (2012) Bisphosphonates for osteoporosis – where do we go from here? N Engl J Med 366:2048–2051

  3. 3.

    Watson J, Wise L, Green J (2007) Prescribing of hormone therapy for menopause, tibolone, and bisphosphonates in women in the UK between 1991 and 2005. Eur J Clin Pharmacol 63:843–849

  4. 4.

    Ryan JM, Kelsey P, Ryan BM, Mueller PR (1998) Alendronate-induced esophagitis: case report of a recently recognized form of severe esophagitis with esophageal stricture – radiographic features. Radiology 206:389–391

  5. 5.

    Lagergren J, Bergstrom R, Lindgren A, Nyren O (1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340:825–831

  6. 6.

    Lassen A, Hallas J, de Muckadell OB (2006) Esophagitis: incidence and risk of esophageal adenocarcinoma – a population-based cohort study. Am J Gastroenterol 101:1193–1199

  7. 7.

    Wysowski DK (2009) Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360:89–90

  8. 8.

    Vinogradova Y, Coupland C, Hippisley-Cox J (2013) Exposure to bisphosphonates and risk of gastrointestinal cancers: series of nested case-control studies with QResearch and CPRD data. BMJ 346:f114

  9. 9.

    Vogtmann E, Corley DA, Almers LM, Cardwell CR, Murray LJ, Abnet CC (2015) Oral bisphosphonate exposure and the risk of upper gastrointestinal cancers. PLoS One 10:e0140180

  10. 10.

    Wright E, Schofield PT, Molokhia M (2015) Bisphosphonates and evidence for association with esophageal and gastric cancer: a systematic review and meta-analysis. BMJ Open 5:e007133

  11. 11.

    Wright E, Schofield PT, Seed P, Molokhia M (2012) Bisphosphonates and risk of upper gastrointestinal cancer – a case control study using the general practice research database (GPRD). PLoS One 7:e47616

  12. 12.

    Oh YH, Yoon C, Park SM (2012) Bisphosphonate use and gastrointestinal tract cancer risk: meta-analysis of observational studies. World J Gastroenterol 18:5779–5788

  13. 13.

    Newcomb PA, Trentham-Dietz A, Hampton JM (2010) Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer 102:799–802

  14. 14.

    Rennert G, Pinchev M, Rennert HS (2010) Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol 28:3577–3581

  15. 15.

    Santini D, Virzi V, Fratto ME, Bertoldo F, Sabbatini R, Berardi R, Calipari N, Ottaviani D, Ibrahim T (2010) Can we consider zoledronic acid a new antitumor agent? Recent evidence in clinical setting. Curr Cancer Drug Targets 10:46–54

  16. 16.

    Sewing L, Steinberg F, Schmidt H, Goke R (2008) The bisphosphonate zoledronic acid inhibits the growth of HCT-116 colon carcinoma cells and induces tumor cell apoptosis. Apoptosis 13:782–789

  17. 17.

    Khalili H, Huang ES, Ogino S, Fuchs CS, Chan AT (2012) A prospective study of bisphosphonate use and risk of colorectal cancer. J Clin Oncol 30:3229–3233

  18. 18.

    Singh H, Nugent Z, Demers A, Mahmud S, Bernstein C (2012) Exposure to bisphosphonates and risk of colorectal cancer: a population-based nested case-control study. Cancer 118:1236–1243

  19. 19.

    Thosani N, Thosani SN, Kumar S, Nugent Z, Jimenez C, Singh H, Guha S (2013) Reduced risk of colorectal cancer with use of oral bisphosphonates: a systematic review and meta-analysis. J Clin Oncol 31:623–630

  20. 20.

    Cardwell CR, Abnet CC, Cantwell MM, Murray LJ (2010) Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 304:657–663

  21. 21.

    Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V (2010) Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 341:c4444

  22. 22.

    Rennert G, Pinchev M, Rennert HS, Gruber SB (2011) Use of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol 29:1146–1150

  23. 23.

    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386

  24. 24.

    Cheol Seong S, Kim YY, Khang YH et al (2017) Data resource profile: the National Health Information Database of the National Health Insurance Service in South Korea. Int J Epidemiol 46:799–800

  25. 25.

    Seong SC, Kim YY, Park SK et al (2017) Cohort profile: the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) in Korea. BMJ Open 7:e016640

  26. 26.

    Jee SH, Sull JW, Park J, Lee SY, Ohrr H, Guallar E, Samet JM (2006) Body-mass index and mortality in Korean men and women. N Engl J Med 355:779–787

  27. 27.

    Son JS, Choi S, Kim K, Kim SM, Choi D, Lee G, Jeong SM, Park SY, Kim YY, Yun JM, Park SM (2018) Association of Blood Pressure Classification in Korean young adults according to the 2017 American College of Cardiology/American Heart Association guidelines with subsequent cardiovascular disease events. JAMA 320:1783–1792

  28. 28.

    WHO Collaborating Centre for Drug Statistics Methodology (2020) Guidelines for ATC classification and DDD assignment. . https://wwwwhoccno/atc_ddd_index_and_guidelines/atc_ddd_index/. Accessed 24 Jan 2020

  29. 29.

    Bae YS, Chang J, Park SM (2019) Oral bisphosphonate use and the risk of female breast, ovarian, and cervical cancer: a nationwide population-based cohort study. Arch Osteoporos 14:41

  30. 30.

    Choi S, Chang J, Kim K, Park SM, Lee K (2018) Effect of smoking cessation and reduction on the risk of cancer in Korean men: a population based study. Cancer Res Treat 50:1114–1120

  31. 31.

    Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA (2004) New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol 57:1288–1294

  32. 32.

    Dixon WG, Solomon DH (2011) Bisphosphonates and esophageal cancer – a pathway through the confusion. Nat Rev Rheumatol 7:369–372

  33. 33.

    Seo HJ, Oh IH, Yoon SJ (2012) A comparison of the cancer incidence rates between the national cancer registry and insurance claims data in Korea. Asian Pac J Cancer Prev 13:6163–6168

Download references

Funding

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (grant number: 2017R1D1A1B03033721) and the Seoul National University Research Fund (grant number: 04-2018-0370). S.C. received a grant from the Brain Korea 21-Plus Education Program from the National Research Foundation of Korea.

Author information

D.C., S.C., J.C. and S.M.P. contributed to the conception and design, analysis and interpretation of data, critical revision for important intellectual content, and final approval of the article. D.C., S.C., and J.C. contributed to the drafting of the article. D.C. conducted collection and assembly of the data. All authors approved the final copy of the article. S.M.P. is the corresponding author and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Correspondence to S. M. Park.

Ethics declarations

Conflicts of interest

None.

Role of the sponsors

None of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 20 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Choi, D., Choi, S., Chang, J. et al. Exposure to oral bisphosphonates and risk of gastrointestinal cancer. Osteoporos Int (2020). https://doi.org/10.1007/s00198-020-05327-x

Download citation

Keywords

  • Bisphosphonate
  • Colorectal cancer
  • Gastrointestinal cancer
  • Stomach cancer