Skip to main content

Advertisement

SpringerLink
Log in

Differences between zoledronic acid and denosumab for breast cancer treatment

  • Invited Review
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Zoledronic acid and denosumab are bone-modifying agents that are clinically important in multiple aspects of bone management for breast cancer patients. These aspects include the prevention of osteoporosis induced by cancer-treatment bone loss, treatment and prevention of bone metastasis, and improvement of survival directly or indirectly by maintaining bone health. Interestingly, zoledronic acid and denosumab have different anticancer activities, and they may be associated with the improvement of survival of breast cancer patients under different mechanisms. Zoledronic acid is the most potent bisphosphonate. It provides significant benefits for improving breast cancer mortality in patients with suppressed estrogen level such as in postmenopausal or ovarian suppression condition. Although denosumab’s anticancer activity has not been clearly proven compared with zoledronic acid’s anticancer activity, denosumab is promising in preventing BRCA1 mutant breast cancer because RANKL is a targetable pathway in BRCA1-associated tumorigenesis. Further studies and more effective clinical use of these agents are anticipated to contribute to the improvement of the clinical outcome of breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2015) Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386:1353–1361

    Article  Google Scholar 

  2. Pagani S, Fini M, Giavaresi G, Salamanna F, Borsari V (2015) The active role of osteoporosis in the interaction between osteoblasts and bone metastases. Bone 79:176–182

    Article  CAS  PubMed  Google Scholar 

  3. Salamanna F, Borsari V, Contartese D, Nicoli Aldini N, Fini M (2018) Link between estrogen deficiency osteoporosis and susceptibility to bone metastases: a way towards precision medicine in cancer patients. Breast 41:42–50

    Article  CAS  PubMed  Google Scholar 

  4. Ottewell PD, Wang N, Brown HK, Reeves KJ, Fowles CA, Croucher PI, Eaton CL, Holen I (2014) Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Cancer Res 20:2922–2932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yoneda T, Hashimoto N, Hiraga T (2004) Bisphosphonate actions on bone and visceral metastases. Cancer Treat Res 118:213–229

    Article  CAS  PubMed  Google Scholar 

  6. Michigami T, Hiraga T, Williams PJ, Niewolna M, Nishimura R, Mundy GR, Yoneda T (2002) The effect of the bisphosphonate ibandronate on breast cancer metastasis to visceral organs. Breast Cancer Res Treat 75:249–258

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B, Zoledronic Acid Prostate Cancer Study Group (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  PubMed  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

    Article  CAS  PubMed  Google Scholar 

  10. Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S et al (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691

    Article  CAS  PubMed  Google Scholar 

  11. Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M et al (2015) Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian breast and colorectal cancer study group trial 12. Ann Oncol 26:313–320

    Article  CAS  PubMed  Google Scholar 

  12. Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, Barrett-Lee P, Ritchie D, Liversedge V, Hinsley S, Marshall H (2014) Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol 15:997–1006

    Article  CAS  PubMed  Google Scholar 

  13. Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M (2010) Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 11:421–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, Gil M, Ritchie D, Passos-Coelho JL, Wheatley D, Burkinshaw R, Marshall SJ, Thorpe H (2010) The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer 102:1099–1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hasegawa Y, Tanino H, Horiguchi J, Miura D, Ishikawa T, Hayashi M, Takao S, Kim SJ, Yamagami K, Miyashita M, Konishi M, Shigeoka Y, Suzuki M, Taguchi T, Kubota T, Akazawa K, Kohno N (2015) Randomized controlled trial of zoledronic acid plus chemotherapy versus chemotherapy alone as neoadjuvant treatment of HER2-negative primary breast cancer (JONIE Study). PLoS ONE 10:e0143643

    Article  PubMed  PubMed Central  Google Scholar 

  16. Charehbili A, van de Ven S, Smit VTHB, Meershoek-Klein-Kranenbarg E, Hamdy NAT et al (2014) Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2 negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010–01). Ann Oncol 25:998–1004

    Article  CAS  PubMed  Google Scholar 

  17. Kroep JR, Charehbili A, Coleman RE, Aft RL, Hasegawa Y, Winter MC, Weilbaecher K, Akazawa K, Hinsley S, Putter H, Liefers GJ, Nortier JWR, Kohno N (2016) Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: a meta-analysis of randomised trials. Eur J Cancer 54:57–63

    Article  CAS  PubMed  Google Scholar 

  18. NCCN guidelines Version 3. 2022 Invasive breast cancer

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R et al (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433–443

    Article  CAS  PubMed  Google Scholar 

  21. Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Periañez AM, Tonkin K, Deleu I, Sohn J, Crown J, Delaloge S, Dai T, Zhou Y, Jandial D, Chan A (2020) Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 21:60–72

    Article  CAS  PubMed  Google Scholar 

  22. González-Suárez E, Sanz-Moreno A (2016) RANK as a therapeutic target in cancer. FEBS J 283:2018–2033

    Article  PubMed  Google Scholar 

  23. Reyes ME, Fujii T, Branstetter D, Krishnamurthy S, Masuda H, Wang X, Reuben JM, Woodward WA, Edwards BJ, Hortobagyi GN, Tripathy D, Dougall WC, Eckhardt BL, Ueno NT (2017) Poor prognosis of patients with triple-negative breast cancer can be stratified by RANK and RANKL dual expression. Breast Cancer Res Treat 164:57–67

    Article  CAS  PubMed  Google Scholar 

  24. Link T, Blohmer J, Just M, Untch M, Stötzer O, Fasching PA, Schneeweiss A, Wimberger P, Seiler S, Huober J, Schmitt WD, Jackisch C, Rhiem KE, Hanusch C, Denkert C, Sinn BV, Engels K, Nekljudova V, Loibl S (2020) GeparX: denosumab as add-on to different regimen of nab-paclitaxel-anthracycline based neoadjuvant chemotherapy in early breast cancer: subgroup analyses by RANK expression and HR status. Ann Oncol 31:S303–S339

    Article  Google Scholar 

  25. Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Rohrbach K, Huang LY, Soriano R, Smyth GK, Dougall WC, Visvader JE, Lindeman GJ (2016) RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 22:933–939

    Article  CAS  PubMed  Google Scholar 

  26. Kotsopoulos J, Singer C, Narod SA (2017) Can we prevent BRCA1-associated breast cancer by RANKL inhibition? Breast Cancer Res Treat 161:11–16

    Article  CAS  PubMed  Google Scholar 

  27. Bhulani N, Wood M, Tsai J, Bedrosian I, Hopkins JO, Brunet J, Michaelson-Cohen R, Schmutzler RK, Evans GD, Gnant M, Fesl C, Mystek A, Lindeman GJ, Singer CF, Garber JE (2022) A phase 3 study to determine the breast cancer risk reducing effect of denosumab in women carrying a germline BRCA1 mutation (BRCA-P study). J Clin Oncol. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS10616

    Article  Google Scholar 

  28. Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Nagata T, Urade M, Shibahara T, Toyosawa S (2017) Antiresorptive anti-agent osteonecrosis of the jaw: position paper 2017 ofthe Japanese allied committee on osteonecrosis of the jaw. J Bone Miner Metab 35:6–19

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Breast Oncology and Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan

    Takashi Ishikawa

Authors
  1. Takashi Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Ishikawa.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ishikawa, T. Differences between zoledronic acid and denosumab for breast cancer treatment. J Bone Miner Metab 41, 301–306 (2023). https://doi.org/10.1007/s00774-023-01408-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-023-01408-z

Keywords

Search

Navigation