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Denosumab—A Powerful RANKL Inhibitor to Stop Lytic Metastases and Other Bone Loss Actions by Osteoclasts

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Pathology & Oncology Research

Abstract

Denosumab is a perfect example on the targeted anticancer therapy. The inhibition of RANKL activity suppressed the osteoclasts’ resorptive function and so prevented skeletal related events. This effect is useful not only against bone metastases, but also in the treatment of other diseases caused by bone loss. In different solid tumors with bone metastasis the quality of life also improved, although the overall survival usually showed no change. On the market the main competitors for denosumab are still the bisphosphonates (questions of costs and reimbursement are not discussed) and some potential new agents e.g. Src kinases (as dasatinib, saracatinib, bosutinib), cathepsin K inhibitors, (e.g. odanacatib), and new selective estrogen receptor modulators (e.g. bazedoxifene, lasofoxifene). Nevertheless, today denosumab is one of the most powerful agents in bone-saving area.

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References

  1. Baron R, Ferrari S, Russel RGG (2011) Denosumab and bisphosphonates: Different mechanisms of action and effects. Bone 48:677–692

    Article  PubMed  CAS  Google Scholar 

  2. Brown JE, Coleman RE (2011) Denosumab in patients with cancer—a surgical strike against the osteoclast. Nature Rev Clin Oncol 9:110–118

    Article  Google Scholar 

  3. Martin T, Gooi JH, Sims NA (2009) Molecular mechanisms in coupling of bone formation to resorption. Crit Rev Eukaryot Gene Expr 19:73–88

    Article  PubMed  CAS  Google Scholar 

  4. Bruzzaniti A, Baron R (2006) Molecular regulation of osteoclast activity. Rev J Endocr Metab Disord 7:123–139

    Article  CAS  Google Scholar 

  5. Theoleyre S, Wittrant Y, Tat SK et al (2004) The molecular triad OPR/RANK/RANKL involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 15:457–475

    Article  PubMed  CAS  Google Scholar 

  6. Weight HL, McCarthy HS, Middleton J, Marshall MJ (2009) RANK, RANKL, and osteoprotegerin in bone biology and disease. Curr Rev Musculoskelet Med 2:56–64

    Article  Google Scholar 

  7. Pederson L, Ruan M, Wetendorf JJ et al (2008) Regulation of bone formationby osteoclasts involvesWnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 105:20764–20769

    Article  PubMed  CAS  Google Scholar 

  8. Sims N (2010) EPHs and ephrins: many pathways to regulate osteoblasts and osteoclasts. IBMS BoneKEy 7:304–313

    Article  Google Scholar 

  9. Dougall WC, Chaisson M (2006) The RANK/RANKL/OPG triad in cancer induced bone diseases. Cancer Metast Rev 25:541–549

    Article  CAS  Google Scholar 

  10. Akiyama T, Choong PF, Dass CR (2010) RANK-Fc inhibits malignancy via inhibiting ERK activation and evoking caspase3-mediated anoikis in human osteosarcoma cells. Clin Exp Metast 27:207–215

    Article  CAS  Google Scholar 

  11. Akiyama T et al (2010) Systemic RANK-Fc protein therapy is efficacious against primary osteosarcoma growth in murine model via activity against osteoclasts. J Pharm Pharmacol 62:470–476

    PubMed  CAS  Google Scholar 

  12. Russell RG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759

    Article  PubMed  CAS  Google Scholar 

  13. Kostenuik P, Nguyen HG, McCabe J et al (2009) Denosumab, a fully human monoclonal antibody to RNAKL inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 24:182–195

    Article  PubMed  CAS  Google Scholar 

  14. Weinstein RS, Roberson PK, Manolagas SC (2009) Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 360:53–62

    Article  PubMed  CAS  Google Scholar 

  15. Bekker PJ, Holloway DI, Rasmussen AS et al (2004) A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19:1059–1066

    Article  PubMed  CAS  Google Scholar 

  16. Lin JH (1996) Bisphosphonates: a review of their pharmacokinetic properties. Bone 18:85–95

    Article  Google Scholar 

  17. Cremers S, Sparidqans R et al (2002) A pharmacokinetic and pharmacodynamic model for intravenous bisphosphonate (pamidronate) in osteoporosis. Eur J Clin Pharmacol 57:883–8890

    Article  PubMed  CAS  Google Scholar 

  18. Body JJ et al (2003) A phase I study of ANGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 97(Suppl 3):887–892

    Article  PubMed  Google Scholar 

  19. Body JJ et al (2006) Study of the biological receptor activator of nuclear factor kB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 12:1221–1228

    Article  PubMed  CAS  Google Scholar 

  20. Lipton A et al (2007) Randomized, active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 25:4431–4437

    Article  PubMed  CAS  Google Scholar 

  21. Ellis GK et al (2008) Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for non-metastatic breast cancer. J Clin Oncol 26:4875–4882

    Article  PubMed  CAS  Google Scholar 

  22. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS (2005) Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154–164

    Article  PubMed  CAS  Google Scholar 

  23. Smith MR et al (2006) Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer. J Urol 136–139

  24. Smith MR et al (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745–755

    Article  PubMed  CAS  Google Scholar 

  25. Smith MR et al Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase III, randomized, placebo-controlled trial. Lancet. doi:10.1016/S0140-6736(11)61226-9

  26. Brodowitz T, O’Byrne K, Manegold C Bone matters in lung cancer. Ann Oncol. doi:10.1093/annoncol/mds009

  27. Fizazi K et al (2009) Randomized phase II trial of denosunab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571

    Article  PubMed  CAS  Google Scholar 

  28. Fizazi K, Carducci M, Smith M et al (2011) Denosumab versus zoledronic acid for the treatment of bone metastases in men with castration-resistant prostate cancer. A randomised, double-blind study. The Lancet 377:813–822

    Article  CAS  Google Scholar 

  29. Stopeck AT, Lipton A, Body J-J et al (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  PubMed  CAS  Google Scholar 

  30. Henry DH et al (2011) A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastasis in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132

    Article  PubMed  CAS  Google Scholar 

  31. Huang L, Xu J, Wood DJ, Zheng MH (2000) Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-kB in giant cell tumour of bone: possible involvement in tumour-cell induced osteoclast-like cell formation. Am J Pathol 156:761–767

    Article  PubMed  CAS  Google Scholar 

  32. Thomas D, Henshaw R, Skubicz K et al (2010) Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol 11:275–280

    Article  PubMed  CAS  Google Scholar 

  33. Saylor PJ (2011) Denosumab –a new option for solid tumors metastatic to bone. Nature Rev Clin Oncol 8:322–324

    CAS  Google Scholar 

  34. Hofbauer LC, Rachner DT, Harnann C (2011) From bone to breast and back—the bone cytokine RANKL and breast cancer. Breast Cancer Rev 13:107–108

    Article  CAS  Google Scholar 

  35. Smith MR, Sand F, Colemann R et al (2012) Denosumab and bone-metastasis-free survival in men with castration-rersistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. The Lancet 379:3946

    Google Scholar 

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Correspondence to László Kopper.

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Kopper, L. Denosumab—A Powerful RANKL Inhibitor to Stop Lytic Metastases and Other Bone Loss Actions by Osteoclasts. Pathol. Oncol. Res. 18, 743–747 (2012). https://doi.org/10.1007/s12253-012-9538-4

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  • DOI: https://doi.org/10.1007/s12253-012-9538-4

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