Zoledronic acid and skeletal-related events in patients with bone metastatic cancer or multiple myeloma
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.
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).
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.
KeywordsZoledronic acid Skeletal-related events Bone metastasis Cancer Multiple myeloma
This work was supported by Amgen Inc. We would like to thank Editage (www.editage.co.kr) for English language editing.
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).
Compliance with ethical standards
Conflict of interest
Dr. Shin received grant support to her institution from Amgen. Hyowon Yang and Jeehye Park are employees of Amgen Limited Korea.
- 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) CrossRefGoogle 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) CrossRefGoogle 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) 7:377–387Google 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 96:879–882CrossRefGoogle 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) CrossRefGoogle 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) CrossRefGoogle 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) 376:1989–1999CrossRefGoogle Scholar
- 23.Rothman KJ, Lash TL (2008) Modern epidemiology. Lippincott Williams and Wilkins, PhiladelphiaGoogle 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) CrossRefGoogle 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) 377:813–822CrossRefGoogle 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) CrossRefGoogle 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.Google Scholar
- 30.Yang K, Dalton JE (2012) A unified approach to measuring the effect size between two groups using SAS. SAS Global Forum, WashingtonGoogle Scholar
- 31.Govindan R, DeVita VT (2009) DeVita, Hellman, and Rosenberg’s cancer: principles and practice of oncology review. Lippincott Williams and Wilkins, PhiladelphiaGoogle 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