Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pathogenesis of myeloma bone disease

Leukemia volume 23, pages 435–441 (2009)Cite this article

Abstract

Bone disease in multiple myeloma (MM) is characterized by lytic bone lesions, which can cause severe bone pain, pathologic fractures and hypercalcemia. However, the lytic bone disease in MM differs from that in other cancer patients who have lytic bone metastases. Although increased osteoclastic bone destruction is involved in MM and other tumors involving bone, in contrast to other tumors, once the MM tumor burden exceeds 50% in a local area, osteoblast activity is either suppressed or absent.1 The basis for this severe imbalance between increased osteoclastic bone resorption and decreased bone formation has been a topic of intensive investigation over the last several years and will be reviewed in this article.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

References

  1. Taube T, Beneton MN, McCloskey EV, Rogers S, Greaves M, Kanis JA . Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption. Eur J Haematol 1992; 49: 192–198.

    Article  CAS  PubMed  Google Scholar 

  2. Roodman GD . Pathogenesis of myeloma bone disease. Blood Cells Mol Dis 2004; 32: 290–292.

    Article  CAS  PubMed  Google Scholar 

  3. Melton III LJ, Kyle RA, Achenbach SJ, Oberg AL, Rajkumar SV . Fracture risk with multiple myeloma: a population-based study. J Bone Miner Res 2005; 20: 487–493.

    Article  PubMed  Google Scholar 

  4. Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R . Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 2007; 110: 1860–1867.

    Article  PubMed  Google Scholar 

  5. Diamond T, Levy S, Day P, Barbagallo S, Manoharan A, Kwan YK . Biochemical, histomorphometric and densitometric changes in patients with multiple myeloma: effects of glucocorticoid therapy and disease activity. Br J Haematol 1997; 97: 641–648.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Edwards CM, Zhuang J, Mundy GR . The pathogenesis of the bone disease of multiple myeloma. Bone 2008; 42: 1007–1013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI . Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 2004; 103: 3503–3510.

    Article  CAS  PubMed  Google Scholar 

  9. Nimmanapalli R, Gerbino E, Dalton WS, Gandhi V, Alsina M . HSP70 inhibition reverses cell adhesion mediated and acquired drug resistance in multiple myeloma. Br J Haematol 2008; 142: 551–561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J . Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol 2002; 116: 278–290.

    Article  PubMed  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  PubMed  Google Scholar 

  13. Cackowski FC, Roodman GD . Perspective on the osteoclast: an angiogenic cell? Ann N Y Acad Sci 2007; 1117: 12–25.

    Article  CAS  PubMed  Google Scholar 

  14. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 1999; 96: 3540–3545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 1998; 253: 395–400.

    Article  CAS  PubMed  Google Scholar 

  16. Boyle WJ, Simonet WS, Lacey DL . Osteoclast differentiation and activation. Nature 2003; 423: 337–342.

    Article  CAS  PubMed  Google Scholar 

  17. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998; 95: 3597–3602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hofbauer LC, Heufelder AE . Osteoprotegerin and its cognate ligand: a new paradigm of osteoclastogenesis. Eur J Endocrinol 1998; 139: 152–154.

    Article  CAS  PubMed  Google Scholar 

  19. Roodman GD . Treatment strategies for bone disease. Bone Marrow Transplant 2007; 40: 1139–1146.

    Article  CAS  PubMed  Google Scholar 

  20. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13: 2412–2424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tsukii K, Shima N, Mochizuki S, Yamaguchi K, Kinosaki M, Yano K et al. Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha,25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Commun 1998; 246: 337–341.

    Article  CAS  PubMed  Google Scholar 

  22. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397: 315–323.

    Article  CAS  PubMed  Google Scholar 

  23. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165–176.

    Article  CAS  PubMed  Google Scholar 

  24. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260–1268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 2000; 97: 1566–1571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309–319.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J et al. Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003; 102: 1064–1069.

    Article  CAS  PubMed  Google Scholar 

  29. Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD . Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 2001; 97: 3349–3353.

    Article  CAS  PubMed  Google Scholar 

  30. Magrangeas F, Nasser V, Avet-Loiseau H, Loriod B, Decaux O, Granjeaud S et al. Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood 2003; 101: 4998–5006.

    Article  CAS  PubMed  Google Scholar 

  31. Hashimoto T, Abe M, Oshima T, Shibata H, Ozaki S, Inoue D et al. Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma. Br J Haematol 2004; 125: 38–41.

    Article  CAS  PubMed  Google Scholar 

  32. Alsina M, Boyce B, Devlin RD, Anderson JL, Craig F, Mundy GR et al. Development of an in vivo model of human multiple myeloma bone disease. Blood 1996; 87: 1495–1501.

    CAS  PubMed  Google Scholar 

  33. Choi SJ, Oba Y, Gazitt Y, Alsina M, Cruz J, Anderson J et al. Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. J Clin Invest 2001; 108: 1833–1841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Masih-Khan E, Trudel S, Heise C, Li Z, Paterson J, Nadeem V et al. MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. Blood 2006; 108: 3465–3471.

    Article  CAS  PubMed  Google Scholar 

  35. Terpos E, Politou M, Szydlo R, Goldman JM, Apperley JF, Rahemtulla A . Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma. Br J Haematol 2003; 123: 106–109.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. Solary E, Guiguet M, Zeller V, Casasnovas RO, Caillot D, Chavanet P et al. Radioimmunoassay for the measurement of serum IL-6 and its correlation with tumour cell mass parameters in multiple myeloma. Am J Hematol 1992; 39: 163–171.

    Article  CAS  PubMed  Google Scholar 

  39. Roodman GD, Kurihara N, Ohsaki Y, Kukita A, Hosking D, Demulder A et al. Interleukin 6. A potential autocrine/paracrine factor in Paget's disease of bone. J Clin Invest 1992; 89: 46–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sati HI, Apperley JF, Greaves M, Lawry J, Gooding R, Russell RG et al. Interleukin-6 is expressed by plasma cells from patients with multiple myeloma and monoclonal gammopathy of undetermined significance. Br J Haematol 1998; 101: 287–295.

    Article  CAS  PubMed  Google Scholar 

  41. Karadag A, Oyajobi BO, Apperley JF, Russell RG, Croucher PI . Human myeloma cells promote the production of interleukin 6 by primary human osteoblasts. Br J Haematol 2000; 108: 383–390.

    Article  CAS  PubMed  Google Scholar 

  42. Nguyen AN, Stebbins EG, Henson M, O’Young G, Choi SJ, Quon D et al. Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation. Exp Cell Res 2006; 312: 1909–1923.

    Article  CAS  PubMed  Google Scholar 

  43. Vanderkerken K, Medicherla S, Coulton L, Van Camp B, Protter A, Higgins L et al. Inhibition of p38α MAPK reduces tumor burden, prevents the development of myeloma bone disease, and increases survival in the 5T2 and5T33 murine models of myeloma. Blood 2006; 108: 981a.

    Google Scholar 

  44. 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.

    Article  PubMed  Google Scholar 

  45. Hjorth-Hansen H, Seifert MF, Borset M, Aarset H, Ostlie A, Sundan A et al. Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. J Bone Miner Res 1999; 14: 256–263.

    Article  CAS  PubMed  Google Scholar 

  46. Kobayashi T, Kronenberg H . Minireview: transcriptional regulation in development of bone. Endocrinology 2005; 146: 1012–1017.

    Article  CAS  PubMed  Google Scholar 

  47. Franceschi RT, Xiao G . Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J Cell Biochem 2003; 88: 446–454.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. Thirunavukkarasu K, Halladay DL, Miles RR, Yang X, Galvin RJ, Chandrasekhar S et al. The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function. J Biol Chem 2000; 275: 25163–25172.

    Article  CAS  PubMed  Google Scholar 

  50. Lee SK, Kalinowski JF, Jacquin C, Adams DJ, Gronowicz G, Lorenzo JA . Interleukin-7 influences osteoclast function in vivo but is not a critical factor in ovariectomy-induced bone loss. J Bone Miner Res 2006; 21: 695–702.

    Article  PubMed  Google Scholar 

  51. Toraldo G, Roggia C, Qian WP, Pacifici R, Weitzmann MN . IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor kappa B ligand and tumor necrosis factor alpha from T cells. Proc Natl Acad Sci USA 2003; 100: 125–130.

    Article  CAS  PubMed  Google Scholar 

  52. Westendorf JJ, Kahler RA, Schroeder TM . Wnt signaling in osteoblasts and bone diseases. Gene 2004; 341: 19–39.

    Article  CAS  PubMed  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. Politou MC, Heath DJ, Rahemtulla A, Szydlo R, Anagnostopoulos A, Dimopoulos MA et al. Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 2006; 119: 1728–1731.

    Article  CAS  PubMed  Google Scholar 

  55. Kaiser M, Mieth M, Liebisch P, Oberlander R, Rademacher J, Jakob C et al. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol 2008; 80: 490–494.

    Article  CAS  PubMed  Google Scholar 

  56. Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy Jr JD . Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007; 109: 2106–2111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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.

    Article  CAS  PubMed  Google Scholar 

  58. Glass II DA, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005; 8: 751–764.

    Article  CAS  PubMed  Google Scholar 

  59. Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG . Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 2006; 119 (Pt 7): 1283–1296.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

  61. Berenson JR . Bone disease in myeloma. Curr Treat Options Oncol 2001; 2: 271–283.

    Article  CAS  PubMed  Google Scholar 

  62. Body JJ, Facon T, Coleman RE, Lipton A, Geurs F, Fan M et al. 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.

    Article  CAS  PubMed  Google Scholar 

  63. Vij R, Horvath N, Spencer A, Taylor K, Saroj V, Smith J et al. An open label phase 2 trial of Denosumab in the treatment of relapsed or plateau-phase myeloma. Blood 2007; 118: 1054A.

    Google Scholar 

  64. Kropff M, Bisping G, Wenning D, Berdel WE, Kienast J . Proteasome inhibition in multiple myeloma. Eur J Cancer 2006; 42: 1623–1639.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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.

    Article  CAS  PubMed  Google Scholar 

  67. 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.

    Article  CAS  PubMed  Google Scholar 

  68. Barille-Nion S, Bataille R . New insights in myeloma-induced osteolysis. Leuk Lymphoma 2003; 44: 1463–1467.

    Article  CAS  PubMed  Google Scholar 

  69. 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; 110: 334–338.

    Article  CAS  PubMed  Google Scholar 

  70. Oyajobi BO, Garrett IR, Gupta A, Flores A, Esparza J, Munoz S et al. Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease. Br J Haematol 2007; 139: 434–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  73. 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.

    Article  CAS  PubMed  Google Scholar 

  74. Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 2008; 22: 1925–1932.

    Article  CAS  PubMed  Google Scholar 

  75. Ozaki S, Tanaka O, Fujii S, Shigekiyo Y, Miki H, Choraku M et al. Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma. Int J Hematol 2007; 86: 180–185.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Preparation of this article was made possible by research funds from the Multiple Myeloma Research Foundation and from the Department of Veteran's Affairs (VA Merit Review Award). The materials are the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System, Research and Development.

Author information

Authors and Affiliations

  1. Department of Medicine/Hematology-Oncology, Veterans Affairs Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh, PA, USA

    G D Roodman

Authors
  1. G D Roodman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G D Roodman.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Roodman, G. Pathogenesis of myeloma bone disease. Leukemia 23, 435–441 (2009). https://doi.org/10.1038/leu.2008.336

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.336

Keywords

This article is cited by

Search

Advanced search

Quick links