Denosumab: The era of targeted therapies in bone metastatic diseases

Current Cancer Drug Targets

Volumn 9, Issue 7, 2009, Pages 834-842

  Santini, D ^a   Fratto, M E ^a   Vincenzi, B ^a   Napoli, N ^a   Galluzzo, S ^a   Tantardini, M ^b   Abbruzzese, A ^a   Caraglia, M ^a   Tonini, G ^a  

^a UNIVERSITY CAMPUS BIO MEDICO   (Italy)

^b Second University of Naples ^*

Author keywords

Bone metastases; Denosumab; Osteoprotegerin; Rank; Rankl

Indexed keywords

AROMATASE INHIBITOR; BISPHOSPHONIC ACID DERIVATIVE; DENOSUMAB; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; PAMIDRONIC ACID; PLACEBO; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; ZOLEDRONIC ACID;

ADJUVANT THERAPY; BONE DENSITY; BONE METASTASIS; BONE PAIN; BONE REMODELING; BREAST CANCER; CELLULITIS; CHEMICAL STRUCTURE; CLINICAL TRIAL; DIARRHEA; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TARGETING; FLU LIKE SYNDROME; HUMAN; HYPERCALCEMIA; JAW OSTEONECROSIS; MULTIPLE MYELOMA; NAUSEA; NONHUMAN; OSTEOLYSIS; OSTEOPOROSIS; REVIEW; SIDE EFFECT; VOMITING;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; BONE DENSITY CONSERVATION AGENTS; BONE NEOPLASMS; BONE REMODELING; CHEMOTHERAPY, ADJUVANT; CLINICAL TRIALS AS TOPIC; DRUG DELIVERY SYSTEMS; HUMANS; MODELS, BIOLOGICAL; RANK LIGAND; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-KAPPA B;

EID: 72849114497     PISSN: 15680096     EISSN: None     Source Type: Journal    
DOI: 10.2174/156800909789760375     Document Type: Review

References (59)

1. Carlin, B. I.; Andriole, G. L. The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer 2000, 8, 2989-2994.
2. Von Moos, R. Bisphosphonate treatment recommendations for oncologists. Oncologist 2005, 10(Suppl 1), 19-24.
3. Manolagas, S. C. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 2000, 21, 115-137.
4. Matsuo, K.; Irie, N. Osteoclast-osteoblast communication. Arch. Biochem. Biophys. 2008, 473(2), 201-209.
5. Suda, T.; Takahashi, N.; Udagawa, N.; Jimi, E.; Gillepsie, M. T.; Martin, T. J. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev. 1999, 20, 345-357. (Pubitemid 30649812)
6. Ikeda, T.; Kasai, M.; Utsuyama, M.; Hirokawa, K. Determination of three isoforms of the receptor activator of nuclear factor-[kappa]B ligand and their differential expression in bone and thymus. Endocrinology 2001, 142, 1419-1426. (Pubitemid 32299669)
7. Wada, T.; Nakashima, T.; Hiroshi, N.; Penninger, J. M. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol. Med. 2006, 12, 17-25.
8. Kollet, O.; Dar, A.; Shivtiel, S.; Kalinkovich, A.; Lapid, K.; Sztainberg, Y.; Tesio, M.; Samstein, R. M.; Goichberg, P.; Spiegel, A.; Elson, A.; Lapidot, T. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 2006, 12, 657-664. (Pubitemid 43865234)
9. Josien, R.; Wong, B. R.; Li, H. -L.; Steinman, R. M.; Choi, Y. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J. Immunol. 1999, 162, 2562-2568.
10. Dougall, W. C.; Glaccum, M.; Charrier, K.; Rohrbach, K.; Brasel, K.; De Smedt, T.; Daro, E.; Smith, J.; Tometsko, M. E.; Maliszewski, C. R.; Armstrong, A.; Shen, V.; Bain, S.; Cosman, D.; Anderson, D.; Morrissey, P. J.; Peschon, J. J.; Schuh, J. RANK is essential for osteoclast and lymph node development. Genes. Dev. 1999, 13(18), 2412-2424. (Pubitemid 29453612)
11. Darnay, B. G.; Ni, J.; Moore, P. A.; Aggarwal, B. B. Activation of NF-kB by RANK requires tumor necrosis factor receptorassociated factor (TRAF) 6 and NF-kB-inducing kinase. Identification of a novel TRAF6 interaction motif. J. Biol. Chem. 1999, 274, 7724-7731. (Pubitemid 129518159)
12. Nakagawa, N.; Kinosaki, M.; Yamaguchi, K.; Shima, N.; Yasuda, H.; Yano, K.; Morinaga, T.; Higashio, K. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem. Biophys. Res. Commun. 1998, 253, 395-400. (Pubitemid 29026714)
13. Wong, B. R.; Besser, D.; Kim, N.; Arron, J. R.; Vologodskaia, M.; Hanafusa, H.; Vologodskaia, M.; Hanafusa, H.; Choi, Y. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol. Cell. 1999, 4, 1041-1049.
14. Lacey, D. L.; Timms, E.; Tan, H. -L.; Kelley, M. J.; Dunstan, C. R.; Burgess, T.; Elliott, R.; Colombero, A.; Elliott, G.; Scully, S.; Hsu, H.; Sullivan, J.; Hawkins, N.; Davy, E.; Capparelli, C.; Eli, A.; Qian, Y. X.; Kaufman, S.; Sarosi, I.; Shalhoub, V.; Senaldi, G.; Guo, J.; Delaney, J.; Boyle, W. J. Osteoprotegerin (OPG) ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998, 93, 165-176.
15. Hofbauer, L. C.; Neubauer, A.; Heufelder, A. E. Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer 2001, 92(3), 460-470. (Pubitemid 32735180)
16. Hofbauer, L. C.; Heufelder, A. E. The role of osteoprotegerin and osteoprotegerin ligand in the pathogenesis and treatment of metabolic bone diseases. J. Clin. Endocrinol. Metab. 2000, 85, 2355-2363.
17. Rogers, A.; Eastell, R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J. Clin. Endocrinol. Metab. 2005, 90(11), 6323-6331. (Pubitemid 41606564)
18. Hofbauer, L. C.; Khosla, S.; Dunstan, C. R.; Lacey, D. L.; Spelsberg, T. C.; Riggs, B. L. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999, 140, 4367-4370. (Pubitemid 30647136)
19. Saika, M.; Inoue, D.; Kido, S.; Matsumoto, T. 17b-Estradiol stimulates expression of osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) by a mouse stromal cell line, ST-2. J. Bone Miner. Res. 1999, 14(Suppl 1), F095.
20. Hofbauer, L. C.; Gori, F.; Riggs, B. L.; Lacey, D. L.; Dunstan, C. R.; Spelsberg, T. C.; Khosla, S. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999, 140, 4382-4389. (Pubitemid 30666099)
21. Sasaki, N.; Kusano, E.; Ando, Y.; Yano, K.; Tsuda, E.; Asano, Y. Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis.Nephrol. Dial. Transplant. 2001, 16, 479-482. (Pubitemid 32229277)
22. Humphrey, E. L.; Williams, J. H.; Davie, M. W.; Marshall, M. J. Effects of dissociated glucocorticoids on OPG and RANKL in osteoblastic cells. Bone 2006, 38(5), 652-661.
23. Lee, S. K.; Lorenzo, J. A. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 1999, 140, 3552-3561.
24. Roodman, G. D.; Dougall, W. C. RANK ligand as a therapeutic target for bone metastases and multiple myeloma. Cancer Treat. Rev. 2008, 34, 92-101. (Pubitemid 351181016)
25. Hauschka, P. V.; Chen, T. L.; Mavrakos, A. E. Polypeptide growth factors in bone matrix. Ciba. Found. Symp. 1988, 136, 207-225.
26. Uehara, H.; Kim, S. J.; Karashima, T. Shepherd, D. L.; Fan, D.; Tsan, R.; Killion, J. J.; Logothetis, C.; Mathew, P.; Fidler, I. J. Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J. Natl. Cancer Inst. 2003, 95, 458-470.
27. Guise, T. A. Molecular mechanisms of osteolytic bone metastases. Cancer 2000, 88, 2892-2898.
28. Brandstrom, H.; Jonsson, K. B.; Ohlsson, C.; Vidal, O.; Ljunghall, S.; Ljunggren, O. Regulation of osteoprotegerin mRNA levels by prostaglandin E2 in human bone marrow stroma cells. Biochem. Biophys. Res. Commun. 1998, 247, 338-341. (Pubitemid 28420824)
29. Hofbauer, L. C.; Lacey, D. L.; Dunstan, C. R.; Spelsberg, T. C.; Riggs, B. L.; Khosla, S. Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 1999, 25, 255-259.
30. Roudier, M. P.; Bain, S. D.; Dougall, W. C. Effects of the RANKL inhibitor, osteoprotegerin, on the pain and histopathology of bone cancer in rats. Clin. Exp. Metastasis 2006, 23(3-4), 167-175.
31. Mori, K.; Le Goff, B.; Charrier, C.; Battaglia, S.; Heymann, D.; Redini, F. DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process. Bone 2007, 40, 981-990. (Pubitemid 46386537)
32. Jones, D. H. ; Nakashima, T. ; Sanchez, O. H.; Kozieradzki, I.; Komarova, S. V.; Sarosi, I.; Morony, S.; Rubin, E.; Sarao, R.; Hojilla, C. V.; Komnenovic, V.; Kong, Y. Y.; Schreiber, M.; Dixon, S. J.; Sims, S. M.; Khokha, R.; Wada, T.; Penninger, J. M. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006, 440, 692-696.
33. Chen, G.; Sircar, K.; Aprikian, A.; Potti, A.; Goltzman, D.; Rabbani, S. A. Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer 2006, 107, 289-298.
34. Armstrong, A. P.; Miller, R. E.; Jones, J. C.; Zhang, J.; Keller, E. T.; Dougall, W. C. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate 2008, 68(1), 92-104.
35. Oyajobi, B. O.; Williams, P. J.; Traianedes, K.; Yoneda, T.; Anderson, D. M.; Mundy, G. R. Efficacy of a genetically engineered soluble receptor activator of NF-kB (RANK) fusion protein on bone resorption in vitro and in vivo. J. Bone Miner. Res. 1999, 14(Suppl 1), 1124.
36. Capparelli, C.; Kostenuik, P. J.; Morony, S.; Starnes, C.; Weimann, B.; Van, G.; Scully, S.; Qi, M.; Lacey, D. L.; Dunstan, C. R. Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy. Cancer Res. 2000, 60, 783-787.
37. Morony, S.; Warmington, K.; Adamu, S.; Asuncion, F.; Geng, Z.; Grisanti, M.; Tan, H. L.; Capparelli, C.; Starnes, C.; Weimann, B.; Dunstan, C. R.; Kostenuik, P. J. The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy. Endocrinology 2005, 146(8), 3235-3243.
38. Morony, S.; Capparelli, C.; Sarosi, I.; Lacey, D. L.; Dunstan, C. R.; Kostenuik, P. J. Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res. 2001, 61, 4432-4436.
39. Honore, P.; Luger, N. M.; Sabino, M. A. C.; Schwei, M. J.; Rogers, S. D.; Mach, D. B.; O'keefe, P. F.; Ramnaraine, M. L.; Clohisy, D. R.; Mantyh, P. W. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat. Med. 2000, 5, 521-528.
40. Lamoureux, F. ; Richard, P. ; Wittrant, Y.; Battaglia, S. ; Pilet, P. ; Trichet, V. ; Blanchard, F. ; Gouin, F.; Pitard, B.; Heymann, D.; Redini, F. Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption. Cancer Res. 2007, 67(15), 7308-7318. (Pubitemid 47206560)
41. Chanda, D.; Isayeva, T.; Kumar, S.; Siegal, G. P.; Szafran, A. A.; Zinn, K. R.; Reddy, V. V.; Ponnazhagan, S. Systemic osteoprotegerin gene therapy restores tumor-induced bone loss in a therapeutic model of breast cancer bone metastasis. Mol. Ther. 2008, 16(5), 871-878. (Pubitemid 351587096)
42. Virk, M. S.; Petrigliano, F. A.; Liu, N. Q.; Chatziioannou, A. F.; Stout, D.; Kang, C. O.; Dougall, W. C.; Lieberman, J. R. Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone. Bone 2009, 44(1), 160-167
43. Green, L. Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies. J. Immunol. Methods 1999, 231, 11-23. (Pubitemid 30394721)
44. Scallon, B. J.; Moore, M. A.; Trinh, H.; Knight, D. M.; Ghrayeb, J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995, 7, 251-259.
45. Kostenuik, P. J. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr. Opin. Pharmacol. 2005, 5, 618-625.
46. Bekker, P. J.; Holloway, D. L.; Rasmussen, A. S.; Murphy, R.; Martin, S. W.; Leese, P. T.; Holmes, G. B.; Dunstan, C. R.; De-Paoli, A. M. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J. Bone Miner. Res. 2004, 19, 1059-1066.
47. Body, J. J.; Facon, T.; Coleman, R. E.; Lipton, A.; Geurs, F.; Fan, M.; Holloway, D.; Peterson, M. C.; Bekker, P. J. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin. Cancer Res. 2006, 12, 1221-1228.
48. Lipton, A.; Steger, G. G.; Figueroa, J.; Alvarado, C.; Solal-Celigny, P.; Body, J. J.; de Boer, R.; Berardi, R.; Gascon, P.; Tonkin, K. S.; Coleman, R.; Paterson, A. H.; Peterson, M. C.; Fan, M.; Kinsey, A.; Jun, S. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J. Clin. Oncol. 2007, 25, 4431-4437. (Pubitemid 350013849)
49. Fizazi, K.; Lipton, A.; Mariette, X.; Body, J. J.; Rahim, Y.; Gralow, J. R.; Gao, G.; Wu, L.; Sohn, W.; Jun, S. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J. Clin. Oncol. 2009, 27(10), 1534-1536.
50. Lipton, A.; Steger, G. G.; Figueroa, J.; Alvarado, C.; Solal-Celigny, P.; Body, J. J.; de Boer, R.; Berardi, R.; Gascon, P.; Tonkin, K. S.; Coleman, R. E.; Paterson, A. H.; Gao, G. M.; Kinsey, A. C.; Peterson, M. C.; Jun, S. Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin. Cancer Res. 2008, 14(20), 6690-6696.
51. Lumachi, F.; Brunello, A.; Roma, A.; Basso, U. Cancer-induced Hypercalcemia. Anticancer Res. 2009, 29(5), 1551-1555.
52. Saad, F.; Adachi, J. D.; Brown, J. P.; Canning, L. A.; Gelmon, K. A.; Josse, R.G.; Pritchard, K. I. Cancer treatment-induced bone loss in breast and prostate cancer. J. Clin. Oncol. 2008, 26(33), 5465-5476.
53. Brufsky, A. M. Zoledronic acid for cancer therapy - induced and postmenopausal bone loss. Expert Opin. Pharmacother. 2008, 9(6), 1013-1028.
54. Smith, M. R.; Egerdie, B.; Hernández Toriz, N.; Feldman, R.; Tammela, T. L.; Saad, F.; Heracek, J.; Szwedowski, M.; Ke, C.; Kupic, A.; Leder, B. Z.; Goessl, C.; Denosumab HALT Prostate Cancer Study Group. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N. Engl. J. Med. 2009, 361(8), 745-755.
55. Cummings, S. R.; San Martin, J.; McClung, M. R.; Siris, E. S.; Eastell, R.; Reid, I. R.; Delmas, P.; Zoog, H. B.; Austin, M.; Wang, A.; Kutilek, S.; Adami, S.; Zanchetta, J.; Libanati, C.; Siddhanti, S.; Christiansen, C.; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 2009, 361(8), 756-765.
56. Whyte, M. P. The long and the short of bone therapy. N. Engl. J. Med. 2006, 354, 860-863.
57. Flick, L. M.; Weaver, J. M.; Ulrich-Vinther, M.; Abuzzahab, F.; Zhang, X.; Dougall, W. C.; Anderson, D.; O'Keefe, R. J.; Schwarz, E. M. Effects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing. J. Orthop. Res. 2003, 21, 676-684.
58. Bachmann, M. F.; Wong, B. R.; Josien, R.; Steinman, R. M.; Oxenius, A.; Choi, Y. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J. Exp. Med. 1999, 189, 1025-1031.
59. Stolina, M.; Guo, J.; Faggioni, R.; Brown, H.; Senaldi, G. Regulatory effects of osteoprotegerin on cellular and humoral immune responses. Clin. Immunol. 2003, 109, 347-354. (Pubitemid 38091454)