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Oral bisphosphonate use and the risk of female breast, ovarian, and cervical cancer: a nationwide population-based cohort study

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Abstract

Summary

Bisphosphonate use was not associated with the risk of female breast, ovarian, or cervical cancer. The results according to bisphosphonate type or concurrent drug uses were not associated with the cancer risk. The protective effect of bisphosphonate use on female breast cancer was significant in the low comorbidity group.

Purpose

Despite the antitumor mechanisms, the effect of bisphosphonates on the risk of cancer is still unclear. We investigated the association between oral bisphosphonate use and the development of female breast, ovarian, and cervical cancer.

Methods

We accomplished a population-based cohort study using the National Health Insurance Services (NHIS) database. A total of 204,525 participants were included in a cohort, and we identified the incident cases of each cancer from 2007 to 2013. We assessed cumulative bisphosphonate exposure from 2003 to 2006 using the defined daily dose (DDD) system. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were presented to assess the association between bisphosphonate use and cancer incidence using multivariate Cox proportional hazard regression models. Subgroup analyses were performed to assess cancer development according to risk factors and concurrent drug use.

Results

There was a total of 1547, 266, and 370 incident cases of female breast, cervical, and ovarian cancer, respectively, during the study period of 1,367,294 person-years. Bisphosphonate exposure was not significantly associated with risk of female breast (adjusted HR (aHR), 0.78; 95% CI, 0.60–1.02), ovarian (aHR, 1.30; 95% CI, 0.82–2.07), nor cervical cancer (aHR, 0.70; 95% CI, 0.44–1.12). Further subgroup analyses also revealed no statistically significant effects of bisphosphonate use with various risk factors and concurrent drug use.

Conclusions

Our study showed no significant associations between bisphosphonate exposure and female breast, cervical, and ovarian cancer. In the future, large prospective studies or a meta-analysis would be needed to verify the associations.

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References

  1. Lewiecki EM (2010) Bisphosphonates for the treatment of osteoporosis: insights for clinicians. Ther Adv Chronic Dis 1(3):115–128

    Article  CAS  Google Scholar 

  2. Clézardin P, Ebetino FH, Fournier PG (2005) Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. Cancer Res 65(12):4971–4974

    Article  Google Scholar 

  3. Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M et al (2000) Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60(11):2949–2954

    CAS  PubMed  Google Scholar 

  4. Roelofs AJ, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12(20):6222s–6230s

    Article  CAS  Google Scholar 

  5. Newcomb P, Trentham-Dietz A, Hampton J (2010) Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer 102(5):799–802

    Article  CAS  Google Scholar 

  6. Cardwell CR, Abnet CC, Veal P, Hughes CM, Cantwell MM, Murray LJ (2012) Exposure to oral bisphosphonates and risk of cancer. Int J Cancer 131(5):E717–E725

    Article  CAS  Google Scholar 

  7. Chlebowski RT, Chen Z, Cauley JA, Anderson G, Rodabough RJ, McTiernan A, Lane DS, Manson JAE, Snetselaar L, Yasmeen S, O’Sullivan MJ, Safford M, Hendrix SL, Wallace RB (2010) Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol 28(22):3582–3590

    Article  CAS  Google Scholar 

  8. Vestergaard P, Fischer L, Mele M, Mosekilde L, Christiansen P (2011) Use of bisphosphonates and risk of breast cancer. Calcif Tissue Int 88(4):255–262

    Article  CAS  Google Scholar 

  9. Ou YJ, Chiu HF, Wong YH, Yang CC, Yang YH (2017) Bisphosphonate use and the risk of breast cancer: a meta-analysis of observational studies. Pharmacoepidemiol Drug Saf 26(10):1286–1295

    Article  CAS  Google Scholar 

  10. Monsees GM, Malone KE, Tang M-TC, Newcomb PA, Li CI (2011) Bisphosphonate use after estrogen receptor–positive breast cancer and risk of contralateral breast cancer. J Natl Cancer Inst 103(23):1752–1760

    Article  CAS  Google Scholar 

  11. Vinogradova Y, Coupland C, Hippisley-Cox J (2013) Exposure to bisphosphonates and risk of common non-gastrointestinal cancers: series of nested case–control studies using two primary-care databases. Br J Cancer 109(3):795–806

    Article  CAS  Google Scholar 

  12. Rennert G, Pinchev M, Rennert HS (2010) Use of bisphosphonates and risk of postmenopausal breast cancer. J Clin Oncol 28(22):3577–3581

    Article  CAS  Google Scholar 

  13. Newcomb PA, Passarelli MN, Phipps AI, Anderson GL, Wactawski-Wende J, Ho GY et al (2015) Oral bisphosphonate use and risk of postmenopausal endometrial cancer. J Clin Oncol 33(10):1186–1190

    Article  Google Scholar 

  14. Alford SH, Rattan R, Buekers TE, Munkarah AR (2015) Protective effect of bisphosphonates on endometrial cancer incidence in data from the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Cancer. 121(3):441–447

    Article  CAS  Google Scholar 

  15. Rennert G, Rennert HS, Pinchev M, Lavie O (2014) The effect of bisphosphonates on the risk of endometrial and ovarian malignancies. Gynecol Oncol 133(2):309–313

    Article  CAS  Google Scholar 

  16. Hue TF, Cummings SR, Cauley JA, Bauer DC, Ensrud KE, Barrett-Connor E, Black DM (2014) Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid. JAMA Intern Med 174(10):1550–1557

    Article  Google Scholar 

  17. 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 Res 27(9):1951–1958

    Article  CAS  Google Scholar 

  18. Lee W-Y, Sun L-M, Lin M-C, Liang J-A, Chang S-N, Sung F-C, Muo CH, Kao CH (2012) A higher dosage of oral alendronate will increase the subsequent cancer risk of osteoporosis patients in Taiwan: a population-based cohort study. PLoS One 7(12):e53032

    Article  CAS  Google Scholar 

  19. Torre LA, Siegel RL, Ward EM, Jemal A (2016) Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiology and Prevention Biomarkers 25(1):16–27

    Article  Google Scholar 

  20. Shin J-Y, Park M-J, Lee SH, Choi S-H, Kim M-H, Choi N-K et al (2015) Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study. BMJ 351:h3517

    Article  Google Scholar 

  21. World Health Organization (2006) The anatomical therapeutic chemical classification system with defined daily doses (ATC/DDD). WHO, Oslo

    Google Scholar 

  22. Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi J-C, Saunders LD, Beck CA, Feasby TE, Ghali WA (2005) Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 43:1130–1139

    Article  Google Scholar 

  23. Who EC (2004) Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet (London, England) 363(9403):157

    Article  Google Scholar 

  24. Park B, Sung J, Park K, Seo S, Kim S (2003) Report of the evaluation for validity of discharged diagnoses in Korean Health Insurance database. Seoul National University, Seoul, pp 19–52

    Google Scholar 

  25. Clézardin P (2011) Bisphosphonates’ antitumor activity: an unravelled side of a multifaceted drug class. Bone. 48(1):71–79

    Article  Google Scholar 

  26. Yancik R, Wesley MN, Ries LA, Havlik RJ, Edwards BK, Yates JW (2001) Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285(7):885–892

    Article  CAS  Google Scholar 

  27. Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9–expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114(5):623–633

    Article  CAS  Google Scholar 

  28. Drake MT, Clarke BL, Khosla S (2008: Elsevier) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83:1032–1045

    Article  CAS  Google Scholar 

  29. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD et al (2001) Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296(2):235–242

    CAS  PubMed  Google Scholar 

  30. Kim M-h, Chang J, Kim WJ, Banerjee S, Park SM (2018) Cumulative dose threshold for the chemopreventive effect of aspirin against gastric cancer. Am J Gastroenterol 113(6):845

    CAS  PubMed  Google Scholar 

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Contributions

SM Park had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: YS Bae, J Chang, and SM Park.

Acquisition of data: YS Bae and J Chang.

Analysis and interpretation of data: YS Bae, J Chang, and SM Park.

Drafting of the manuscript: YS Bae and SM Park.

Critical revision of the manuscript: YS Bae, J Chang, and SM Park.

Statistical analysis: YS Bae and J Chang.

Administrative, technical, or material support: YS Bae.

Corresponding author

Correspondence to Sang Min Park.

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Bae, Y., Chang, J. & Park, S. Oral bisphosphonate use and the risk of female breast, ovarian, and cervical cancer: a nationwide population-based cohort study. Arch Osteoporos 14, 41 (2019). https://doi.org/10.1007/s11657-019-0588-z

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