Bone-Targeted Therapy in Advanced Breast Cancer

  • Ece Esin
  • Irfan CicinEmail author


The bone is one of the three most common metastatic sites of breast cancer. Bone metastatic disease has a favorable prognosis compared to visceral metastatic disease, but skeletal event (pain, pathologic fractures, hypercalcemia and spinal cord compression)-related morbidity and decreased quality of life have a large overall impact. Osteoclasts and the loss of equilibrium between osteoclasts and osteoblasts play major roles in bone metastasis. Bisphosphonates inhibit bone resorption by inducing apoptosis of osteoclasts. Denosumab is as a monoclonal antibody against receptor activator of nuclear factor (NF)-KB ligand, which is essential for osteoclast survival. To reduce the burden of bone metastasis, prevention is crucial in advanced cancer patients without skeletal involvement. However, given the available data regarding bisphosphonates in advanced breast cancer (ABC) without osseous involvement, international guidelines do not support the preventive use of bone-targeted agents. The toxicities of bisphosphonates and denosumab include hypocalcemia, renal toxicity, gastrointestinal disturbance and osteonecrosis of the jaw, which should be carefully reviewed when administering drugs and making decisions about dose, interval and duration.


Bone metastasis Targeted therapy Bisphosphonates Denosumab Osteonecrosis 


  1. 1.
    Colleoni M, O'Neill A, Goldhirsch A, Gelber RD, Bonetti M, Thürlimann B, et al. Identifying breast cancer patients at high risk for bone metastases. J Clin Oncol. 2000;18:3925–35.CrossRefGoogle Scholar
  2. 2.
    Body J. Biphosphonates in breast cancer and other solid tumors. In: Mundy RD, Rubens RD, editors. Cancer and the skeleton. London: Martin Dunitz; 2000.Google Scholar
  3. 3.
    Van Poznak C, Cross SS, Saggese M, Hudis C, Panageas KS, Norton L, et al. Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours. J Clin Pathol. 2006;59:56–63.CrossRefGoogle Scholar
  4. 4.
    Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.CrossRefGoogle Scholar
  5. 5.
    Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3:537–49.CrossRefGoogle Scholar
  6. 6.
    Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9:285–93.CrossRefGoogle Scholar
  7. 7.
    Wong M, Pavlakis N. Optimal management of bone metastases in breast cancer patients. Breast Cancer. 2011;3:35–60.PubMedGoogle Scholar
  8. 8.
    Roelofs AJ, Thompson K, Gordon S, Rogers MJ. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res. 2006;12:6222s–30s.CrossRefGoogle Scholar
  9. 9.
    Thompson K, Roelofs AJ, Jauhiainen M, Monkkonen H, Monkkonen J, Rogers MJ. Activation of gammadelta T cells by bisphosphonates. Adv Exp Med Biol. 2010;658:11–20.CrossRefGoogle Scholar
  10. 10.
    O’Carrigan B, Wong MH, Willson ML, Stockler MR, Pavlakis N, Goodwin A. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2017;10:CD003474.PubMedGoogle Scholar
  11. 11.
    Rosen LS, Gordon DH, Dugan W Jr, Major P, Eisenberg PD, Provencher L, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer. 2004;100:36–43.CrossRefGoogle Scholar
  12. 12.
    Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. 2014;15:114–22.CrossRefGoogle Scholar
  13. 13.
    Dhesy-Thind S, Fletcher GG, Blanchette PS, Clemons MJ, Dillmon MS, Frank ES, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35:2062–81.CrossRefGoogle Scholar
  14. 14.
    Amadori D, Aglietta M, Alessi B, Gianni L, Ibrahim T, Farina G, et al. Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol. 2013;14:663–70.CrossRefGoogle Scholar
  15. 15.
    Hortobagyi GN, Van Poznak C, Harker WG, Gradishar WJ, Chew H, Dakhil SR, et al. Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: the OPTIMIZE-2 randomized clinical trial. JAMA Oncol. 2017;3:906–12.CrossRefGoogle Scholar
  16. 16.
    Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial. JAMA. 2017;317:48–58.CrossRefGoogle Scholar
  17. 17.
    Bouganim N, Clemons MJ. Bone-targeted agents in the treatment of bone metastases: RANK outsider or new kid on the block? Future Oncol. 2011;7:381–3.CrossRefGoogle Scholar
  18. 18.
    Lipton A, Jacobs I. Denosumab: benefits of RANK ligand inhibition in cancer patients. Curr Opin Support Palliat Care. 2011;5:258–64.CrossRefGoogle Scholar
  19. 19.
    Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–22.CrossRefGoogle Scholar
  20. 20.
    Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. 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. 2011;29:1125–32.CrossRefGoogle Scholar
  21. 21.
    Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. 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. 2010;28:5132–9.CrossRefGoogle Scholar
  22. 22.
    Van Poznak C, Somerfield MR, Barlow WE, Biermann JS, Bosserman LD, Clemons MJ, et al. Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology-Cancer Care Ontario focused guideline update. J Clin Oncol. 2017;35:3978–86.CrossRefGoogle Scholar
  23. 23.
    Kanis JA, Powles T, Paterson AH, McCloskey EV, Ashley S. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone. 1996;19:663–7.CrossRefGoogle Scholar
  24. 24.
    van Holten-Verzantvoort AT, Hermans J, Beex LV, Blijham G, Cleton FJ, van Eck-Smit BC, et al. Does supportive pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patients? Eur J Cancer. 1996;32A:450–4.CrossRefGoogle Scholar
  25. 25.
    Sheedy KC, Camara MI, Camacho PM. Comparison of the efficacy, adverse effects, and cost of zoledronic acid and denosumab in the treatment of osteoporosis. Endocr Pract. 2015;21:275–9.CrossRefGoogle Scholar
  26. 26.
    Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int. 2003;64:281–9.CrossRefGoogle Scholar
  27. 27.
    Markowitz GS, Fine PL, D’Agati VD. Nephrotic syndrome after treatment with pamidronate. Am J Kidney Dis. 2002;39:1118–22.CrossRefGoogle Scholar
  28. 28.
    Anghel R, Bachmann A, Beksac M, Brodowicz T, Finek J, Komadina R, American Society of Clinical Oncology, National Comprehensive Cancer Network, et al. Expert opinion 2011 on the use of new anti-resorptive agents in the prevention of skeletal-related events in metastatic bone disease. Wien Klin Wochenschr. 2013;125:439–47.CrossRefGoogle Scholar
  29. 29.
    Prommer E. Palliative oncology: denosumab. Am J Hosp Palliat Care. 2015;32:568–72.CrossRefGoogle Scholar
  30. 30.
    Domschke C, Schuetz F. Side effects of bone-targeted therapies in advanced breast cancer. Breast Care. 2014;9:332–6.CrossRefGoogle Scholar
  31. 31.
    Campisi G, Fedele S, Fusco V, Pizzo G, Di Fede O, Bedogni A. Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncol. 2014;10:257–75.CrossRefGoogle Scholar
  32. 32.
    Wang X, Yang KH, Wanyan P, Tian JH. Comparison of the efficacy and safety of denosumab versus bisphosphonates in breast cancer and bone metastases treatment: a meta-analysis of randomized controlled trials. Oncol Lett. 2014;7:1997–2002.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Medical Oncology,Dr. A. Y. Ankara Oncology Education and Research HospitalAnkaraTurkey
  2. 2.Department of Medical Oncology, Faculty of Medicine, Balkan Oncology HospitalTrakya University of MedicineEdirneTurkey

Personalised recommendations