Osteoporosis International

, Volume 24, Issue 1, pp 279–286 | Cite as

Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies

Original Article

Abstract

Summary

The use of bisphosphonates and the risk of esophageal cancer have recently received increasing concern and related studies have yielded controversial results. The present meta-analysis of observational studies shows that no clear association between bisphosphonate treatment and risk of esophageal cancer was observed.

Introduction

Epidemiological evidence suggests that bisphosphonate treatment can increase the risk of esophageal cancer. However, data on this issue are unstable and controversial. We conducted a meta-analysis to provide a quantitative assessment of the association between use of bisphosphonates and risk of esophageal cancer.

Methods

We searched the Medline and Embase databases up to May 2012 to identify studies related to bisphosphonates and esophageal cancer. Summary effect estimates with 95 % confidence intervals (CI) were derived using a fixed or random effects model, depending on the heterogeneity of the included studies.

Results

Seven epidemiologic studies that consisted of four cohort studies and three case–control studies were included in this meta-analysis. In our primary analysis, bisphosphonate treatment was not associated with risk of esophageal cancer in both cohort studies [pooled relative risk (RR) 1.23, 95 % CI 0.79–1.92] and case–control studies [pooled odds ratio (OR) 1.24, 95 % CI 0.98–1.57]. Evidence for the presence of significant heterogeneity was found in cohort studies (p = 0.009, I 2 = 74 %) but not in case–control studies (p = 0.338, I 2 = 7.8 %). In our secondary analysis, no significant increased risk of esophageal cancer was found in alendronate users (pooled RR 1.08, 95 % CI 0.67–1.75 in cohort studies; pooled OR 1.16, 95 % CI 0.82–1.63 in case–control studies).

Conclusions

Based on current evidences, bisphosphonate treatment was not significantly associated with excess risk of esophageal cancer.

Keywords

Bisphosphonates Case–control study Cohort study Esophageal cancer Meta-analysis 

Notes

Acknowledgments

We thank Jiayi Dong for his consultation on data analysis.

Conflicts of interest

None.

References

  1. 1.
    Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR (2009) Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 301:513–521PubMedCrossRefGoogle Scholar
  2. 2.
    Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA (1999) Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 353:878–882PubMedCrossRefGoogle Scholar
  3. 3.
    Mulder JE, Kolatkar NS, LeBoff MS (2006) Drug insight: existing and emerging therapies for osteoporosis. Nat Clin Pract Endocrinol Metab 2:670–680PubMedCrossRefGoogle Scholar
  4. 4.
    Macedo JM, Macedo CR, Elkis H, De Oliveira IR (1998) Meta-analysis about efficacy of anti-resorptive drugs in post-menopausal osteoporosis. J Clin Pharm Ther 23:345–352PubMedCrossRefGoogle Scholar
  5. 5.
    Black DM, Schwartz AV, Ensrud KE et al (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938PubMedCrossRefGoogle Scholar
  6. 6.
    Arrain Y, Masud T (2011) A current update on osteonecrosis of the jaw and bisphosphonates. Dent Updat 38:672–676, 678Google Scholar
  7. 7.
    Ruggiero SL (2011) Bisphosphonate-related osteonecrosis of the jaw: an overview. Ann N Y Acad Sci 1218:38–46PubMedCrossRefGoogle Scholar
  8. 8.
    Rhee CW, Lee J, Oh S, Choi NK, Park BJ (2012) Use of bisphosphonate and risk of atrial fibrillation in older women with osteoporosis. Osteoporos Int 23:247–254PubMedCrossRefGoogle Scholar
  9. 9.
    Howard PA, Barnes BJ, Vacek JL, Chen W, Lai SM (2010) Impact of bisphosphonates on the risk of atrial fibrillation. Am J Cardiovasc Drugs 10:359–367PubMedCrossRefGoogle Scholar
  10. 10.
    Black DM, Kelly MP, Genant HK et al (2010) Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362:1761–1771PubMedCrossRefGoogle Scholar
  11. 11.
    Shane E, Burr D, Ebeling PR et al (2010) Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 25:2267–2294PubMedCrossRefGoogle Scholar
  12. 12.
    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:c4444PubMedCrossRefGoogle Scholar
  13. 13.
    Vestergaard P (2011) Occurrence of gastrointestinal cancer in users of bisphosphonates and other antiresorptive drugs against osteoporosis. Calcif Tissue Int 89:434–441PubMedCrossRefGoogle Scholar
  14. 14.
    Wysowski DK (2009) Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360:89–90PubMedCrossRefGoogle Scholar
  15. 15.
    de Groen PC, Lubbe DF, Hirsch LJ, Daifotis A, Stephenson W, Freedholm D, Pryor-Tillotson S, Seleznick MJ, Pinkas H, Wang KK (1996) Esophagitis associated with the use of alendronate. N Engl J Med 335:1016–1021PubMedCrossRefGoogle Scholar
  16. 16.
    Tosteson AN, Grove MR, Hammond CS, Moncur MM, Ray GT, Hebert GM, Pressman AR, Ettinger B (2003) Early discontinuation of treatment for osteoporosis. Am J Med 115:209–216PubMedCrossRefGoogle Scholar
  17. 17.
    MacLean C, Newberry S, Maglione M et al (2008) Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 148:197–213PubMedGoogle Scholar
  18. 18.
    Cardwell CR, Abnet CC, Cantwell MM, Murray LJ (2010) Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 304:657–663PubMedCrossRefGoogle Scholar
  19. 19.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097PubMedCrossRefGoogle Scholar
  20. 20.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRefGoogle Scholar
  21. 21.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560PubMedCrossRefGoogle Scholar
  22. 22.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  23. 23.
    Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19:251–253PubMedCrossRefGoogle Scholar
  24. 24.
    Fleurence RL, Iglesias CP, Johnson JM (2007) The cost effectiveness of bisphosphonates for the prevention and treatment of osteoporosis: a structured review of the literature. PharmacoEconomics 25:913–933PubMedCrossRefGoogle Scholar
  25. 25.
    Schousboe JT, Ensrud KE, Nyman JA, Melton LJ 3rd, Kane RL (2005) Universal bone densitometry screening combined with alendronate therapy for those diagnosed with osteoporosis is highly cost-effective for elderly women. J Am Geriatr Soc 53:1697–1704PubMedCrossRefGoogle Scholar
  26. 26.
    Liu H, Michaud K, Nayak S, Karpf DB, Owens DK, Garber AM (2006) The cost-effectiveness of therapy with teriparatide and alendronate in women with severe osteoporosis. Arch Intern Med 166:1209–1217PubMedCrossRefGoogle Scholar
  27. 27.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCrossRefGoogle Scholar
  28. 28.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101PubMedCrossRefGoogle Scholar
  29. 29.
    Abrahamsen B, Pazianas M, Eiken P, Russell RG, Eastell R (2012) Esophageal and gastric cancer incidence and mortality in alendronate users. J Bone Miner Res 27:679–686PubMedCrossRefGoogle Scholar
  30. 30.
    Chen YM, Chen DY, Chen LK, Tsai YW, Chang LC, Huang WF, Liu CL, Chen YT, Hsiao FY (2011) Alendronate and risk of esophageal cancer: a nationwide population-based study in Taiwan. J Am Geriatr Soc 59:2379–2381PubMedCrossRefGoogle Scholar
  31. 31.
    Chiang CH, Huang CC, Chan WL, Huang PH, Chen TJ, Chung CM, Lin SJ, Chen JW, Leu HB (2012) Oral alendronate use and risk of cancer in postmenopausal women with osteoporosis: a nationwide study. J Bone Miner ResGoogle Scholar
  32. 32.
    Nguyen DM, Schwartz J, Richardson P, El-Serag HB (2010) Oral bisphosphonate prescriptions and the risk of esophageal adenocarcinoma in patients with Barrett’s esophagus. Dig Dis Sci 55:3404–3407PubMedCrossRefGoogle Scholar
  33. 33.
    Black DM, Cummings SR, Karpf DB et al (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541PubMedCrossRefGoogle Scholar
  34. 34.
    Russell RG (2011) Bisphosphonates: the first 40 years. Bone 49:2–19PubMedCrossRefGoogle Scholar
  35. 35.
    Van Poznak CH (2002) The use of bisphosphonates in patients with breast cancer. Cancer Control 9:480–489PubMedGoogle Scholar
  36. 36.
    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 13:782–789PubMedCrossRefGoogle Scholar
  37. 37.
    Senaratne SG, Colston KW (2002) Direct effects of bisphosphonates on breast cancer cells. Breast Cancer Res 4:18–23PubMedCrossRefGoogle Scholar
  38. 38.
    Michailidou M, Holen I (2012) Combinations of bisphosphonates and classical anticancer drugs: a preclinical perspective. Recent Results Cancer Res 192:145–169PubMedCrossRefGoogle Scholar
  39. 39.
    Chlebowski RT, Chen Z, Cauley JA et al (2010) Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol 28:3582–3590PubMedCrossRefGoogle Scholar
  40. 40.
    Robles NR, Fernandez Carbonero E, Romero B, Sanchez Casado E, Cubero JJ (2009) Long-term antiproteinuric effect of dual renin-angiotensin system blockade. Cardiovasc Ther 27:101–107PubMedCrossRefGoogle Scholar
  41. 41.
    Haber SL, McNatty D (2012) An evaluation of the use of oral bisphosphonates and risk of esophageal cancer. Ann Pharmacother 46:419–423PubMedCrossRefGoogle Scholar
  42. 42.
    Cramer JA, Gold DT, Silverman SL, Lewiecki EM (2007) A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int 18:1023–1031PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2012

Authors and Affiliations

  • K. Sun
    • 1
    • 2
  • J. M. Liu
    • 1
    • 2
  • H. X. Sun
    • 1
    • 2
  • N. Lu
    • 1
    • 2
  • G. Ning
    • 1
    • 2
  1. 1.Department of Endocrinology and MetabolismRui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghaiChina
  2. 2.Key Laboratory for Endocrine and Metabolic Diseases of Ministry of HealthRui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, E-Institute of Shanghai UniversitiesShanghaiChina

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