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The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma

Leukemia volume 21, pages 1875–1884 (2007)Cite this article

Abstract

Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.

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References

  1. Coleman RE . Bisphosphonates: clinical experience. Oncologist 2004; 9 (Suppl 4): 14–27.

    CAS  Google Scholar 

  2. Heider U, Hofbauer LC, Zavrski I, Kaiser M, Jakob C, Sezer O . Novel aspects of osteoclast activation and osteoblast inhibition in myeloma bone disease. Biochem Biophys Res Commun 2005; 338: 687–693.

    CAS  Google Scholar 

  3. Terpos E, Dimopoulos MA . Myeloma bone disease: pathophysiology and management. Ann Oncol 2005; 16: 1223–1231.

    CAS  Google Scholar 

  4. Giuliani N, Rizzoli V, Roodman GD . Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood 2006; 108: 3992–3996.

    CAS  Google Scholar 

  5. Terpos E . Biochemical markers of bone metabolism in multiple myeloma. Cancer Treat Rev 2006; 32 (Suppl 1): 15–19.

    CAS  Google Scholar 

  6. Barlogie B . Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas experience. Semin Hematol 2003; 40 (4 Suppl 4): 33–38.

    CAS  Google Scholar 

  7. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006; 108: 3458–3464.

    CAS  Google Scholar 

  8. Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 2007; 21: 151–157.

    CAS  Google Scholar 

  9. Sati HI, Greaves M, Apperley JF, Russell RG, Croucher PI . Expression of interleukin-1beta and tumour necrosis factor-alpha in plasma cells from patients with multiple myeloma. Br J Haematol 1999; 104: 350–357.

    CAS  Google Scholar 

  10. Oyajobi BO, Franchin G, Williams PJ, Pulkrabek D, Gupta A, Munoz S et al. Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. Blood 2003; 102: 311–319.

    CAS  Google Scholar 

  11. Mitsiades CS, Mitsiades NS, Munshi NC, Richardson PG, Anderson KC . The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 2006; 42: 1564–1573.

    CAS  Google Scholar 

  12. Tanaka Y, Abe M, Hiasa M, Oda A, Amou H, Nakano A et al. Myeloma cell–osteoclast interaction enhances angiogenesis together with bone resorption: a role for vascular endothelial cell growth factor and osteopontin. Clin Cancer Res 2007; 13: 816–823.

    Article  CAS  Google Scholar 

  13. Zannettino AC, Farrugia AN, Kortesidis A, Manavis J, To LB, Martin SK et al. Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res 2005; 65: 1700–1709.

    CAS  Google Scholar 

  14. Lee JW, Chung HY, Ehrlich LA, Jelinek DF, Callander NS, Roodman GD et al. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood 2004; 103: 2308–2315.

    CAS  Google Scholar 

  15. Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A . Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 1996; 88: 3998–4004.

    CAS  Google Scholar 

  16. Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Liau DF, Colman N et al. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA 2001; 98: 11581–11586.

    CAS  Google Scholar 

  17. Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barille S . Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood 2001; 98: 3527–3533.

    CAS  Google Scholar 

  18. Croucher PI, Shipman CM, Lippitt J, Perry M, Asosingh K, Hijzen A et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 2001; 98: 3534–3540.

    CAS  Google Scholar 

  19. Heider U, Langelotz C, Jakob C, Zavrski I, Fleissner C, Eucker J et al. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 2003; 9: 1436–1440.

    CAS  Google Scholar 

  20. Sezer O, Heider U, Zavrski I, Kühne CA, Hofbauer LC . RANK ligand and osteoprotegerin in myeloma bone disease. Blood 2003; 101: 2094–2098.

    CAS  Google Scholar 

  21. Standal T, Seidel C, Hjertner O, Plesner T, Sanderson RD, Waage A et al. Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 2002; 100: 3002–3007.

    CAS  Google Scholar 

  22. Silvestris F, Cafforio P, Calvani N, Dammacco F . Impaired osteoblastogenesis in myeloma bone disease: role of upregulated apoptosis by cytokines and malignant plasma cells. Br J Haematol 2004; 126: 475–486.

    Google Scholar 

  23. Giuliani N, Colla S, Morandi F, Lazzaretti M, Sala R, Bonomini S et al. Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood 2005; 106: 2472–2483.

    CAS  Google Scholar 

  24. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 2483–2494.

    CAS  Google Scholar 

  25. Oshima T, Abe M, Asano J, Hara T, Kitazoe K, Sekimoto E et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 2005; 106: 3160–3165.

    CAS  Google Scholar 

  26. Ehrlich LA, Chung HY, Ghobrial I, Choi SJ, Morandi F, Colla S et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood 2005; 106: 1407–1414.

    CAS  Google Scholar 

  27. Franchimont N, Rydziel S, Canalis E . Transforming growth factor-beta increases interleukin-6 transcripts in osteoblasts. Bone 2000; 26: 249–253.

    CAS  Google Scholar 

  28. Hayashi T, Hideshima T, Nguyen AN, Munoz O, Podar K, Hamasaki M et al. Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment. Clin Cancer Res 2004; 10: 7540–7546.

    CAS  Google Scholar 

  29. Takeuchi K, Abe M, Oda A, Amou H, Hiasa M, Asano J et al. SB431542, a TGF-beta receptor kinase inhibitor, restores bone formation which ameliorates myeloma-induced microenvironment. Blood 2006; 108: 992a, abstract 3479.

    Google Scholar 

  30. Silvestris F, Cafforio P, Tucci M, Grinello D, Dammacco F . Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease. Br J Haematol 2003; 122: 39–52.

    CAS  Google Scholar 

  31. Barille S, Bataille R, Amiot M . The role of interleukin-6 and interleukin-6/interleukin-6 receptor-alpha complex in the pathogenesis of multiple myeloma. Eur Cytokine Netw 2000; 11: 546–551.

    CAS  Google Scholar 

  32. Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T et al. Osteoclasts enhance myeloma cell growth and survival via cell–cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 2004; 104: 2484–2491.

    CAS  Google Scholar 

  33. Yaccoby S, Wezeman MJ, Zangari M, Walker R, Cottler-Fox M, Gaddy D et al. Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model. Haematologica 2006; 91: 192–199.

    CAS  Google Scholar 

  34. Yeh HS, Berenson JR . Treatment for myeloma bone disease. Clin Cancer Res 2006; 12 (Part 2): 6279s–6284s.

    CAS  Google Scholar 

  35. Shipman CM, Rogers MJ, Apperley JF, Russell RG, Croucher PI . Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997; 98: 665–672.

    CAS  Google Scholar 

  36. Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J et al. Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 2003; 18: 482–492.

    CAS  Google Scholar 

  37. Ashcroft AJ, Davies FE, Morgan GJ . Aetiology of bone disease and the role of bisphosphonates in multiple myeloma. Lancet Oncol 2003; 4: 284–292.

    CAS  Google Scholar 

  38. Dhodapkar MV, Singh J, Mehta J, Fassas A, Desikan KR, Perlman M et al. Anti-myeloma activity of pamidronate in vivo. Br J Haematol 1998; 103: 530–532.

    CAS  Google Scholar 

  39. Shipman CM, Vanderkerken K, Rogers MJ, Lippitt JM, Asosingh K, Hughes DE et al. The potent bisphosphonate ibandronate does not induce myeloma cell apoptosis in a murine model of established multiple myeloma. Br J Haematol 2000; 111: 283–286.

    CAS  Google Scholar 

  40. Belch AR, Bergsagel DE, Wilson K, O'Reilly S, Wilson J, Sutton D et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol 1991; 9: 1397–1402.

    CAS  Google Scholar 

  41. Daragon A, Humez C, Michot C, Le Loet X, Grosbois B, Pouyol F et al. Treatment of multiple myeloma with etidronate: results of a multicentre double-blind study. Eur J Med 1993; 2: 449–452.

    CAS  Google Scholar 

  42. Lahtinen R, Laakso M, Palva I, Virkkunen P, Elomaa I . Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet 1992; 340: 1049–1052.

    CAS  Google Scholar 

  43. Laakso M, Lahtinen R, Virkkunen P, Elomaa I . Subgroup and cost–benefit analysis of the Finnish multicentre trial of clodronate in multiple myeloma. Br J Haematol 1994; 87: 725–729.

    CAS  Google Scholar 

  44. McCloskey EV, MacLennan IC, Drayson MT, Chapman C, Dunn J, Kanis JA . A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 1998; 100: 317–325.

    CAS  Google Scholar 

  45. McCloskey EV, Dunn JA, Kanis JA, MacLennan IC, Drayson MT . Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol 2001; 113: 1035–1043.

    CAS  Google Scholar 

  46. Brincker H, Westin J, Abildgaard N, Gimsing P, Turesson I, Hedenus M et al. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo-controlled trial. Danish-Swedish co-operative study group. Br J Haematol 1998; 101: 280–286.

    CAS  Google Scholar 

  47. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996; 334: 488–493.

    CAS  Google Scholar 

  48. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 1998; 16: 593–602.

    CAS  Google Scholar 

  49. Menssen HD, Sakalova A, Fontana A, Herrmann Z, Boewer C, Facon T et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 2002; 20: 2353–2359.

    CAS  Google Scholar 

  50. Berenson JR, Rosen LS, Howell A, Porter L, Coleman RE, Morley W et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001; 91: 1191–1200.

    CAS  Google Scholar 

  51. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001; 7: 377–387.

    CAS  Google Scholar 

  52. Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003; 98: 1735–1744.

    CAS  Google Scholar 

  53. Benderson D, Karakunnel J, Kathuria S, Badros A . Scleritis complicating zoledronic acid infusion. Clin Lymphoma Myeloma 2006; 7: 145–147.

    Google Scholar 

  54. Munier A, Gras V, Andrejak M, Bernard N, Jean-Pastor MJ, Gautier S et al. Zoledronic acid and renal toxicity: data from French adverse effect reporting database. Ann Pharmacother 2005; 39: 1194–1197.

    CAS  Google Scholar 

  55. Berenson JR, Hillner BE, Kyle RA, Anderson K, Lipton A, Yee GC et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 2002; 20: 3719–3736.

    Google Scholar 

  56. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23: 8580–8587.

    Google Scholar 

  57. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006; 24: 945–952.

    CAS  Google Scholar 

  58. Dimopoulos MA, Kastritis E, Anagnostopoulos A, Melakopoulos I, Gika D, Moulopoulos LA et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica 2006; 91: 968–971.

    CAS  Google Scholar 

  59. Zervas K, Verrou E, Teleioudis Z, Vahtsevanos K, Banti A, Mihou D et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol 2006; 134: 620–623.

    CAS  Google Scholar 

  60. Kademani D, Koka S, Lacy MQ, Rajkumar SV . Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 2006; 81: 1100–1103.

    Google Scholar 

  61. Lacy MQ, Dispenzieri A, Gertz MA, Greipp PR, Gollbach KL, Hayman SR et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006; 81: 1047–1053.

    CAS  Google Scholar 

  62. Durie BGM . Use of bisphosphonates in multiple myeloma: IMWG response to Mayo Clinic consensus statement. Mayo Clin Proc 2007; 82: 516–522.

    Google Scholar 

  63. Corso A, Varettoni M, Zappasodi P, Klersy C, Mangiacavalli S, Pica G et al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia 2007 (in press); doi:10.1038/sj.leu.2404682.

    CAS  Google Scholar 

  64. Schey SA, Fields P, Bartlett JB, Clarke IA, Ashan G, Knight RD et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004; 22: 3269–3276.

    CAS  Google Scholar 

  65. Kumar S, Rajkumar SV . Thalidomide and lenalidomide in the treatment of multiple myeloma. Eur J Cancer 2006; 42: 1612–1622.

    CAS  Google Scholar 

  66. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354: 1021–1030.

    CAS  Google Scholar 

  67. Anderson G, Gries M, Kurihara N, Honjo T, Anderson J, Donnenberg V et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood 2006; 107: 3098–3105.

    CAS  Google Scholar 

  68. Breitkreutz I, Vallet S, Raab MS, Tai Y-T, Raje N, Hideshima T et al. Lenalidomide and bortezomib inhibit osteoclast differentiation and activation in multiple myeloma: clinical implications. Blood 2006; 108: 993a–994a, abstract 3485.

    Google Scholar 

  69. Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res 2005; 65: 11712–11720.

    CAS  Google Scholar 

  70. Verhelle D, Corral LG, Wong K, Mueller JH, Moutouh-de Parseval L, Jensen-Pergakes K et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007; 67: 746–755.

    CAS  Google Scholar 

  71. Terpos E, Mihou D, Szydlo R, Tsimirika K, Karkantaris C, Politou M et al. The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. Leukemia 2005; 19: 1969–1976.

    CAS  Google Scholar 

  72. Tosi P, Zamagni E, Cellini C, Parente R, Cangini D, Tacchetti P et al. First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma. Eur J Haematol 2006; 76: 399–404.

    CAS  Google Scholar 

  73. LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 2002; 62: 4996–5000.

    CAS  Google Scholar 

  74. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498.

    CAS  Google Scholar 

  75. Harousseau JL, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006; 91: 1498–1505.

    CAS  Google Scholar 

  76. Oyajobi BO, Garrett IR, Gupta A, Banerjee M, Esparza X, Flores A et al. Role of dickkopf 1 (Dkk) in myeloma bone disease and modulation by the proteasome inhibitor velcade. J Bone Miner Res 2004; 19: S4, abstract 1011.

    Google Scholar 

  77. Pennisi A, Ling W, Perkins P, Saha R, Li X, Barlogie B et al. PTH and bortezomib suppress growth of primary human myeloma through increased bone formation in vivo. Blood 2006; 108: 154a, abstract 509.

  78. von Metzler I, Krebbel H, Hecht M, Fleissner C, Mieth M, Kaiser M et al. Bortezomib inhibits human osteoclastogenesis. Leukemia 2007; doi:10.1038/sj.leu.2404806.

    CAS  Google Scholar 

  79. Zavrski I, Hecht M, Krebbel H, Fleissner C, Mieth M, Kaiser M et al. Bortezomib inhibits human osteoclastogenesis. Blood 2006; 108: 406a, abstract 1395.

  80. Zhao M, Qiao M, Oyajobi BO, Mundy GR, Chen D . E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 2003; 278: 27939–27944.

    CAS  Google Scholar 

  81. Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest 2003; 111: 1771–1782.

    CAS  Google Scholar 

  82. Mukherjee S, Raje N, Patel C, Vallet S, Aronson J, Chhetri S et al. Bortezomib induces proliferation of mesenchymal progenitor cells and promotes differentiation towards osteoblastic lineage. Blood 2006; 108: 30a, abstract 88.

  83. Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood 2007 (in press); doi:10.1182/Blood-2006-11-059188.

    CAS  Google Scholar 

  84. Zangari M, Esseltine D, Lee CK, Barlogie B, Elice F, Burns MJ et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol 2005; 131: 71–73.

    CAS  Google Scholar 

  85. Zangari M, Yaccoby S, Cavallo F, Esseltine D, Tricot G . Response to bortezomib and activation of osteoblasts in multiple myeloma. Clin Lymphoma Myeloma 2006; 7: 109–114.

    CAS  Google Scholar 

  86. Shimazaki C, Uchida R, Nakano S, Namura K, Fuchida SI, Okano A et al. High serum bone-specific alkaline phosphatase level after bortezomib-combined therapy in refractory multiple myeloma: possible role of bortezomib on osteoblast differentiation. Leukemia 2005; 19: 1102–1103.

    CAS  Google Scholar 

  87. Heider U, Kaiser M, Muller C, Jakob C, Zavrski I, Schulz CO et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur J Haematol 2006; 77: 233–238.

    CAS  Google Scholar 

  88. Terpos E, Heath DJ, Rahemtulla A, Zervas K, Chantry A, Anagnostopoulos A et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. Br J Haematol 2006; 135: 688–692.

    CAS  Google Scholar 

  89. Terpos E, Anagnostopoulos A, Heath D, Kastritis E, Christoulas D, Anagnostopoulos N et al. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMDT) is an effective regimen for relapsed/refractory myeloma and reduces serum levels of Dickkopf-1, RANKL, MIP-1α and angiogenic cytokines. Blood 2006; 108: 1010a–1011a, abstract 3541.

    Google Scholar 

  90. Peles S, Fisher NM, Gao F, Tomasson MH, Dipersio JF, Vij R . A prospective study of the effects of once weekly bortezomib on markers of bone metabolism in patients with multiple myeloma (MM). J Clin Oncol 2006; 24: 433s, abstract 7548.

  91. Terpos E, de la Fuente J, Szydlo R, Hatjiharissi E, Viniou N, Meletis J et al. Tartrate-resistant acid phosphatase isoform 5b: a novel serum marker for monitoring bone disease in multiple myeloma. Int J Cancer 2003; 106: 455–457.

    CAS  Google Scholar 

  92. Terpos E, Politou M, Szydlo R, Nadal E, Avery S, Olavarria E et al. Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. Leukemia 2004; 18: 1420–1426.

    CAS  Google Scholar 

  93. Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005; 23: 4925–4935.

    CAS  Google Scholar 

  94. Feng R, Anderson G, Xiao G, Elliott G, Leoni LM, Mapara MY et al. SDX-308, a structural analog of etodolac, inhibits NF-κB activity resulting in significant inhibition of osteoclast formation/activity and multiple myeloma cell growth. Blood 2006; 108, 986a, abstract 3456.

  95. Breitkreutz I, Vallet S, Raab MS, Li X, Raje N, Hideshima T et al. AZD6244 (ARRY-142886), a potent and selective MEK1/2 inhibitor blocks the ERK1/2 signaling pathway, inhibits osteoclast differentiation and activation in multiple myeloma: clinical implications. Blood 2006; 108: 989a, abstract 3467.

  96. Feng R, Hager JH, Hassig CA, Scranton SA, Payne JE, Mapara MY et al. A novel, mercaptoketone-based HDAC inhibitor, KD5170 exerts marked inhibition of osteoclast formation and anti-myeloma activity in vitro. Blood 2006; 108: 991a–992a, abstract 3477.

    Google Scholar 

  97. Rahman MM, Kukita A, Kukita T, Shobuike T, Nakamura T, Kohashi O . Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages. Blood 2003; 101: 3451–3459.

    CAS  Google Scholar 

  98. Nakamura T, Kukita T, Shobuike T, Nagata K, Wu Z, Ogawa K et al. Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-beta production. J Immunol 2005; 175: 5809–5816.

    CAS  Google Scholar 

  99. Feng R, Oton AB, Patrene K, Anderson G, Mapara MY, Belani C et al. Combination of the proteasome inhibitor bortezomib and a histone deacetylase inhibitor PXD101 results in synergistic inhibition of osteoclastogenesis and significantly stronger inhibition of multiple myeloma growth in vitro and in vivo. Blood 2006; 108: 153a–154a, abstract 507.

    Google Scholar 

  100. Zavrski I, Krebbel H, Wildemann B, Heider U, Kaiser M, Possinger K et al. Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function. Biochem Biophys Res Commun 2005; 333: 200–205.

    CAS  Google Scholar 

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Acknowledgements

Orhan Sezer was supported by the Deutsche Forschungsgemeinschaft (DFG, Klinische Forschergruppe KFO 105).

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Authors and Affiliations

  1. Department of Hematology and Medical Research, 251 General Air Force Hospital, Athens, Greece

    E Terpos

  2. Department of Hematology, Imperial College London, Hammersmith Hospital, London, UK

    E Terpos

  3. Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece

    M-A Dimopoulos

  4. Department of Hematology and Oncology, Charité-Universitaetsmedizin Berlin, Berlin, Germany

    O Sezer

Authors
  1. E Terpos
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  2. M-A Dimopoulos
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  3. O Sezer
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Correspondence to E Terpos.

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Terpos, E., Dimopoulos, MA. & Sezer, O. The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma. Leukemia 21, 1875–1884 (2007). https://doi.org/10.1038/sj.leu.2404843

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  • DOI: https://doi.org/10.1038/sj.leu.2404843

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