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Zoledronic acid and skeletal-related events in patients with bone metastatic cancer or multiple myeloma

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Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

Investigations of ZA effectiveness using large, real-world databases are rare. We examined whether zoledronic acid (ZA) decreased the risk of skeletal-related events (SREs) among patients with bone metastases (BMs) from breast cancer (BC) or prostate cancer (PC), or multiple myeloma (MM) in routine clinical practice.

Materials and methods

We conducted a propensity score-matched cohort study using the Korean National Health Insurance database. Our cohort included patients diagnosed with BM after BC or PC, or MM between 2004 and 2015. SRE was defined as having a record of pathologic fracture, spinal cord compression, radiation, or surgery to bone. The incidence of multiple SREs was calculated according to SRE history. We calculated the incidence rate ratio (IRR) to examine the relative difference in the risk of SREs of ZA users compared to those of ZA non-user.

Results

Among 111,679 patients, diagnosed with BM and one of the three cancer types, 5608 were included in the analysis after propensity score matching. A decreased risk of SREs was observed for the ZA use in patients with history of SRE in BC [IRR = 0.74, 95% confidence interval (CI) = 0.66–0.83], PC (IRR = 0.86, 95% CI = 0.73–1.02), and MM (IRR = 0.74, 95% CI = 0.59–0.93). For patients without SRE history, ZA use was not associated with decreased risks of SREs, but rather increased the risks (BC: IRR = 1.96, 95% CI 1.87–2.05; PC: IRR = 1.66, 95% CI 1.54–1.80; MM: IRR = 1.92, 95% CI 1.57–2.34).

Conclusions

Our study suggests that the ZA use was associated with a decreased risk of SRE for patients with SRE history. However, no preventive effects of ZA were observed for patients without history.

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References

  1. Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176

    Article  CAS  Google Scholar 

  2. Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350:1655–1664

    Article  CAS  Google Scholar 

  3. Oster G, Lamerato L, Glass AG, Richert-Boe KE, Lopez A, Chung K, Richhariya A, Dodge T, Wolff GG, Balakumaran A, Edelsberg J (2013) Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Support Care Cancer 21:3279–3286 (Official Journal of the Multinational Association of Supportive Care in Cancer)

    Article  Google Scholar 

  4. Costa L, Badia X, Chow E, Lipton A, Wardley A (2008) Impact of skeletal complications on patients’ quality of life, mobility, and functional independence. Support Care Cancer 16:879–889 (Official Journal of the Multinational Association of Supportive Care in Cancer)

    Article  Google Scholar 

  5. Delea T, Langer C, McKiernan J, Liss M, Edelsberg J, Brandman J, Sung J, Raut M, Oster G (2004) The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer. Oncology 67:390–396

    Article  Google Scholar 

  6. Rogers MJ, Watts DJ, Russell RG (1997) Overview of bisphosphonates. Cancer 80:1652–1660

    Article  CAS  Google Scholar 

  7. Yoneda T, Michigami T, Yi B, Williams PJ, Niewolna M, Hiraga T (1999) Use of bisphosphonates for the treatment of bone metastasis in experimental animal models. Cancer Treat Rev 25:293–299

    Article  CAS  Google Scholar 

  8. Coleman RE (2000) Management of bone metastases. Oncologist 5:463–470

    Article  CAS  Google Scholar 

  9. Kohno N, Aogi K, Minami H, Nakamura S, Asaga T, Iino Y, Watanabe T, Goessl C, Ohashi Y, Takashima S (2005) Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 23:3314–3321 (Official Journal of the American Society of Clinical Oncology)

    Article  CAS  Google Scholar 

  10. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hussein M, Coleman RE, Reitsma DJ, Seaman JJ, Chen BL, Ambros Y (2001) Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J (Sudbury, Mass) 7:377–387

    CAS  Google Scholar 

  11. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468

    Article  CAS  Google Scholar 

  12. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Zheng M (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879–882

    Article  CAS  Google Scholar 

  13. Rosen LS, Gordon D, Tchekmedyian S, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M, de Souza P, Zheng M, Urbanowitz G, Reitsma D, Seaman JJ (2003) Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150–3157 (Official journal of the American Society of Clinical Oncology)

    Article  CAS  Google Scholar 

  14. Hatoum HT, Lin SJ, Smith MR, Barghout V, Lipton A (2008) Zoledronic acid and skeletal complications in patients with solid tumors and bone metastases: analysis of a national medical claims database. Cancer 113:1438–1445

    Article  CAS  Google Scholar 

  15. Hatoum HT, Lin SJ, Smith MR, Guo A, Lipton A (2011) Treatment persistence with monthly zoledronic acid is associated with lower risk and frequency of skeletal complications in patients with breast cancer and bone metastasis. Clin Breast Cancer 11:177–183

    Article  CAS  Google Scholar 

  16. Siegel RL, Miller RD, Jemal A (2016) Cancer statistics. CA 66:7–30 (A Cancer Journal For Clinicians

    PubMed  Google Scholar 

  17. Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, Lee KH (2015) Cancer Statistics in Korea: incidence, Mortality, Survival, and Prevalence in 2012. Cancer Res Treat 47:127–141 (Official Journal of Korean Cancer Association)

    Article  CAS  Google Scholar 

  18. Lee J, Lee JS, Park SH, Shin SA, Kim K (2017) Cohort Profile: the National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol 46:e15

    PubMed  Google Scholar 

  19. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132 (Official Journal of the American Society of Clinical Oncology)

    Article  CAS  Google Scholar 

  20. Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA (2010) First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet (Lond, Engl) 376:1989–1999

    Article  CAS  Google Scholar 

  21. Suissa S (2008) Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 167:492–499

    Article  Google Scholar 

  22. Jensen AO, Jacobsen JB, Norgaard M, Yong M, Fryzek JP, Sorensen HT (2011) Incidence of bone metastases and skeletal-related events in breast cancer patients: a population-based cohort study in Denmark. BMC Cancer 11:29

    Article  Google Scholar 

  23. Rothman KJ, Lash TL (2008) Modern epidemiology. Lippincott Williams and Wilkins, Philadelphia

    Google Scholar 

  24. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139 (Official journal of the American Society of Clinical Oncology)

    Article  CAS  Google Scholar 

  25. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet (Lond, Engl) 377:813–822

    Article  CAS  Google Scholar 

  26. Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, 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 

  27. Kim HA, Shin JY, Kim MH, Park BJ (2014) Prevalence and predictors of polypharmacy among Korean elderly. PLoS One 9:e98043

    Article  Google Scholar 

  28. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R (2014) Clinician’s guide to prevention and treatment of osteoporosis. Osteoporosis 25:2359–2381 (International: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA)

    Article  CAS  Google Scholar 

  29. Parsons LS (2001) Reducing bias in a propensity score matched-pair sample using greedy matching techniques. In: Proceedings of the twenty-sixth Annual SAS users group international conference 2001: SAS Institute Inc.

  30. Yang K, Dalton JE (2012) A unified approach to measuring the effect size between two groups using SAS. SAS Global Forum, Washington

    Google Scholar 

  31. Govindan R, DeVita VT (2009) DeVita, Hellman, and Rosenberg’s cancer: principles and practice of oncology review. Lippincott Williams and Wilkins, Philadelphia

    Google Scholar 

  32. National Comprehensive Cancer Network (NCCN) (2018) NCCN Guidelines for Breast Cancer. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 10 Apr 2018

  33. National Comprehensive Cancer Network (NCCN) (2018) NCCN Guidelines for Prostate Cancer. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed 10 Apr 2018

  34. Baek YH, Jeon HL, Oh IS, Yang H, Park J, Shin JY (2019) Incidence of skeletal-related events in patients with breast or prostate cancer-induced bone metastasis or multiple myeloma: a 12-year longitudinal nationwide healthcare database study. Cancer Epidemiol 61:104–110

    Article  Google Scholar 

  35. Shintani AK, Girard TD, Arbogast PG, Moons KGM, Ely EW (2009) Immortal time bias in critical care research: application of time-varying Cox regression for observational cohort studies. Crit Care Med 37:2939–2945

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Amgen Inc. We would like to thank Editage (www.editage.co.kr) for English language editing.

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Authors and Affiliations

Authors

Contributions

HLJ: data analysis, interpretation of data, writing (original draft), and writing (review and editing). ISO: conceptualization, data analysis, and writing (original draft). YHB: conceptualization, and data analysis. HY: interpretation of data and project administration. JHP: interpretation of data and project administration. SH: interpretation of data. JYS: conceptualization, funding acquisition, and writing (review and editing).

Corresponding author

Correspondence to Ju-Young Shin.

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Conflict of interest

Dr. Shin received grant support to her institution from Amgen. Hyowon Yang and Jeehye Park are employees of Amgen Limited Korea.

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Jeon, HL., Oh, IS., Baek, YH. et al. Zoledronic acid and skeletal-related events in patients with bone metastatic cancer or multiple myeloma. J Bone Miner Metab 38, 254–263 (2020). https://doi.org/10.1007/s00774-019-01052-6

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