Breast Cancer Research and Treatment

, Volume 127, Issue 2, pp 429–438 | Cite as

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01–04) for women with stage II/III breast cancer

  • R. Coleman
  • E. Woodward
  • J. Brown
  • D. Cameron
  • R. Bell
  • D. Dodwell
  • M. Keane
  • M. Gil
  • C. Davies
  • R. Burkinshaw
  • S. J. Houston
  • R. J. Grieve
  • P. J. Barrett-Lee
  • H. Thorpe
Clinical Trial


The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3–1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.


Breast cancer Zoledronic acid Adjuvant therapy Safety Osteonecrosis of the jaw 


  1. 1.
    Ferlay J, Bray F, Pisani P, Parkin DM (2004) GLOBOCAN2002: cancer incidence, mortality and prevalence worldwide. IARCpress, Lyon [06/01/2010]. Available from:
  2. 2.
    Benson JR, Jatoi I, Keisch M, Esteva FJ, Makris A, Jordan VC (2009) Early breast cancer. Lancet 373:1463–1479PubMedCrossRefGoogle Scholar
  3. 3.
    Ottewell PD, Monkkonen H, Jones M, Lefley DV, Coleman RE, Holen I (2008) Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst 100:1167–1178PubMedCrossRefGoogle Scholar
  4. 4.
    Neville-Webbe HL, Rostami-Hodjegan A, Evans CA, Coleman RE, Holen I (2005) Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer 113:364–371PubMedCrossRefGoogle Scholar
  5. 5.
    Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C et al (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691PubMedCrossRefGoogle Scholar
  6. 6.
    Perazella MA, Markowitz GS (2008) Bisphosphonate nephrotoxicity. Kidney Int 74:1385–1393PubMedCrossRefGoogle Scholar
  7. 7.
    Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G et al (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587PubMedCrossRefGoogle Scholar
  8. 8.
    Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D et al (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491PubMedCrossRefGoogle Scholar
  9. 9.
    Cancer therapy evaluation program common toxicity criteria, version 2.0. DCTD, NCI, NIH, DHHSGoogle Scholar
  10. 10.
    Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117PubMedCrossRefGoogle Scholar
  11. 11.
    Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws-2009 update. J Oral Maxillofac Surg 67(Supplement 1):2–12PubMedGoogle Scholar
  12. 12.
    Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C et al (2007) Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25:829–836PubMedCrossRefGoogle Scholar
  13. 13.
    Eidtmann H, de Boer R, Bundred N, Llombart A, Davidson N, Neven P, von Minckwitz G, Miller J, Schenk N, Coleman R (2010) Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST study. Ann Oncol 21:2188–2194PubMedCrossRefGoogle Scholar
  14. 14.
    Schenk N, Lombart A, Frassoladti A, Neven P, Jerusalem G, Deleu I et al (2007) The E-ZO-FAST trial: zoledronic acid (ZOL) effectively inhibits aromatase inhibitor associated bone loss (AIBL) in postmenopausal women (PMW) with early breast cancer (EBC) receiving adjuvant letrozole (Let). Eur J Cancer 5(suppl):186–187 9absGoogle Scholar
  15. 15.
    Coleman R, Burkinshaw R, Winter M, Neville-Webbe H, Lester J, Woodward E, Brown J (2011) Zoledronic acid. Expert Opin Drug Saf 10(1):133–145PubMedCrossRefGoogle Scholar
  16. 16.
    Stopeck A (2009) A comparison of denosumab versus zoledronic acid on the incidence of skeletal-related events in breast cancer patients with bone metastases. Cancer Research, 69(24): San Antonio breast cancer conference presentation Abs 22Google Scholar
  17. 17.
    Guarneri V, Miles D, Robert N, Diéras V, Glaspy J, Smith I et al (2010) Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 122:181–188Google Scholar
  18. 18.
    Fehm T, Beck V, Banys M, Lipp HP, Hairass M, Reinert S et al (2009) Bisphosphonate-induced osteonecrosis of the jaw (ONJ): incidence and risk factors in patients with breast cancer and gynaecological malignancies. Gynecol Oncol 112:605–609PubMedCrossRefGoogle Scholar
  19. 19.
    Walter C, Al-Nawas B, Bois Ad, Buch L, Harter P, Grötz KA (2009) Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients. Cancer 115:1631–1637PubMedCrossRefGoogle Scholar
  20. 20.
    Coleman RE (2008) Risks and benefits of bisphosphonates. Br J Cancer 98:1736–1740PubMedCrossRefGoogle Scholar
  21. 21.
    Munier A, Gras V, Andrejak M, Bernard N, Jean-Pastor M-J, Gautier S et al (2005) Zoledronic acid and renal toxicity: data from French adverse effect reporting database. Ann Pharmacother 39(7):1194–1197PubMedCrossRefGoogle Scholar
  22. 22.
    Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822PubMedCrossRefGoogle Scholar
  23. 23.
    Solomon DH, Rekedal L, Cadarette SM (2009) Osteoporosis treatments and adverse events. Curr Opin Rheumatol 21:363–368PubMedCrossRefGoogle Scholar
  24. 24.
    Bunch TJ, Anderson JL, May HT, Muhlestein JB, Horne BD, Crandall BG et al (2009) Relation of bisphosphonate therapies and risk of developing atrial fibrillation. Am J Cardiol 103:824–828PubMedCrossRefGoogle Scholar
  25. 25.
    Wilkinson GS, Baillargeon J, Kuo YF, Freeman JL, Goodwin JS (2010) Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer. J Clin Oncol 28(33):4898–4905PubMedCrossRefGoogle Scholar
  26. 26.
    Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A (1999) Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology 60:68–73PubMedCrossRefGoogle Scholar
  27. 27.
    Munns CF, Rauch F, Ward L, Glorieux FH (2004) Maternal and fetal outcome after long-term pamidronate treatment before conception: a report of two cases. J Bone Miner Res 19:1742–1745PubMedCrossRefGoogle Scholar
  28. 28.
    Illidge TM, Hussey M, Godden CW (1996) Malignant hypercalcaemia in pregnancy and antenatal administration of intravenous pamidronate. Clin Oncol 8:257–258CrossRefGoogle Scholar
  29. 29.
    Levy S, Fayez I, Taguchi N, Han J-Y, Aiello J, Matsui D et al (2009) Pregnancy outcome following in utero exposure to bisphosphonates. Bone 44:428–430PubMedCrossRefGoogle Scholar
  30. 30.
    Ornoy A, Wajnberg R, Diav-Citrin O (2006) The outcome of pregnancy following pre-pregnancy or early pregnancy alendronate treatment. Reprod Toxicol 22:578–579PubMedCrossRefGoogle Scholar
  31. 31.
    Brown JE, Ellis SP, Lester JE, Gutcher S, Khanna T, Purohit OP et al (2007) Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res 13:5406–5410PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • R. Coleman
    • 1
  • E. Woodward
    • 1
    • 2
  • J. Brown
    • 1
    • 2
  • D. Cameron
    • 2
    • 3
  • R. Bell
    • 4
  • D. Dodwell
    • 2
  • M. Keane
    • 5
  • M. Gil
    • 6
  • C. Davies
    • 7
  • R. Burkinshaw
    • 1
  • S. J. Houston
    • 8
  • R. J. Grieve
    • 9
  • P. J. Barrett-Lee
    • 10
  • H. Thorpe
    • 7
  1. 1.Academic Unit of Clinical Oncology, Weston Park HospitalUniversity of SheffieldSheffieldUK
  2. 2.St James Institute of OncologyUniversity of LeedsLeedsUK
  3. 3.Western General HospitalUniversity of EdinburghEdinburghUK
  4. 4.Andrew Love Cancer CentreGeelongAustralia
  5. 5.University Hospital GalwayGalwayIreland
  6. 6.Institut Català d’Oncologia—IDIBELL. L’Hospitalet de LlobregatBarcelonaSpain
  7. 7.Clinical Trials Research UnitUniversity of LeedsLeedsUK
  8. 8.St Lukes Cancer CentreRoyal Surrey County HospitalGuildfordUK
  9. 9.University Hospitals Coventry and Warwickshire NHS TrustCoventryUK
  10. 10.Velindre Cancer CenterCardiffUK

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