JCT  Vol.5 No.4 , April 2014
Biology and Treatment of Skeletal Manifestations in Multiple Myeloma
Abstract:  MM is frequently associated with the development of osteolytic bone lesions, osteoporosis and pathological fractures. Bone destruction in MM is caused by osteoclasts recruited in areas adjacent to myeloma plasma cells; their contact triggers both cell types to secrete soluble factors sustaining one each other’s activation and proliferation. Osteoclasts differentiate and maturate upon binding of the receptor activator of NF-kappaB ligand (RANKL), secreted by bone marrow microenvironmental cells, to its receptor (RANK) on osteoclast progenitors, while osteoprotegerin (OPG), a natural decoy receptor, can block the aforementioned ligation. At the same time osteoblasts are inactivated by the Wnt/β-catenin signaling pathway inhibitor, Dickkopf-1 protein (DKK-1), secreted by malignant plasma cells. Furthermore, DKK-1 deregulates the OPG/RANKL equilibrium, promoting osteoclastogenesis. Myeloma bone disease (MBD) can be treated with myeloma-directed chemotherapy and agents inhibiting bone resorption such as aminobisphosphonates, although new promising biology driven monoclonal antibodies targeting osteoclastogenesis mechanisms are emerging. Palliative MBD treatment includes analgesics, orthotics, radiation therapy, vertebroplasty and kyphoplasty. In case of spinal cord compression, radiation therapy or surgical decompression, should be instantly performed, along with steroid administration. Surgery may also be an option especially in case of weight-bearing bone fractures. MBD is a morbid complication and should be carefully managed because it deteriorates patients’ quality of life and worsens disease outcome. 
Cite this paper: Stavropoulos, N. , Papadoyiannis, A. , Maltezas, D. , Stavrou, P. , Babis, G. , Papagelopoulos, P. , Pangalis, G. and Kyrtsonis, M. (2014) Biology and Treatment of Skeletal Manifestations in Multiple Myeloma. Journal of Cancer Therapy, 5, 387-402. doi: 10.4236/jct.2014.54045.

[1]   Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A., Lacy, M.Q., Dispenzieri, A., Fonseca, R., Rajkumar, S.V., Offord, J.R., Larson, D.R., Plevak, M.E., Therneau, T.M. and Greipp, P.R. (2003) Review of 1027 Patients with Newly Diagnosed Multiple Myeloma. Mayo Clinic Proceedings, 78, 21-33.

[2]   Rajkumar, S.V. (2012) Multiple Myeloma: 2012 Update on Diagnosis, Risk-Stratification, and Management. American Journal of Hematology, 87, 452.

[3]   Gay, F., Larocca, A., Wijermans, P., Cavallo, F., Rossi, D., Schaafsma, R., Genuardi, M., Romano, A., Liberati, A.M., Siniscalchi, A., Petrucci, M.T., Nozzoli, C., Patriarca, F., Offidani, M., Ria, R., Omedè, P., Bruno, B., Passera, R., Musto, P., Boccadoro, M., Sonneveld, P. and Palumbo, A. (2010) Complete Response Correlates with Long-Term Pro-gression-Free and Overall Survival in Elderly Myeloma Treated with Novel Agents: Analysis of 1175 Patients. Blood, 117, 3025-3031.

[4]   Roodman, G.D. (2008) Skeletal Imaging and Management of Bone Disease. Hematology American Society of Hematology Education Program, 2008, 313-319.

[5]   Kyle, R.A. (1975) Multiple Myeloma: Review of 869 Cases. Mayo Clinic Proceedings, 50, 29-40.

[6]   Lentzsch, S., Ehrlich, L.A. and Roodman, G.D. (2007) Pathophysiology of Multiple Myeloma Bone Disease. Hematlogy/Oncology Clinics of North America, 21, 1035-1049.

[7]   Saad, F., Lipton, A., Cook, R., Chen, Y.-M., Smith, M. and Coleman, R. (2007) Pathologic Fractures Correlate with Reduced Survival in Patients with Malignant Bone Disease. Cancer, 110, 1860-1867.

[8]   Chakraborti, C. and Miller, K.L. (2010) Multiple Myeloma Presenting as Spinal Cord Compression: A Case Report. Journal of Medical Case Reports, 4, 251.

[9]   Durie, B.G. and Salmon, S. (1975) A Clinical Staging System for Multiple Myeloma. Correlation of Measured Myeloma Cell Mass with Presenting. Clinical Features, Response to Treatment, and Survival. Cancer, 36, 842-854.<842::AID-CNCR2820360303>3.0.CO;2-U

[10]   Li, S.D., Wang, Y.F., Qi, J.Y. and Qiu, L.G. (2010) Clinical Features of Bone Complications and Prognostic Value of Bone Lesions Detected by X-Ray Skeletal Survey in Previously Untreated Patients with Multiple Myeloma. Indian Journal of Hematology and Blood Transfusion, 26, 83-88.

[11]   Kyrtsonis, M.-C., Maltezas, D., Koulieris, E., Bitsani, K., Pessach, I., Efthymiou, A., Bartzis, V., Tzenou, T. and Panayiotidis, P. (2012) The Contribution of Prognostic Factors to the Better Management of Multiple Myeloma Patients. In: Multiple Myeloma—An Overview, InTech-Open Access Publisher, 145-174.

[12]   Pearse, R.N., Sordillo, E.M., Yaccoby, S., Wong, B.R., Liau, D.F., Colman, N., Michaeli, J., Epstein, J. and Choi, Y. (2001) Multiple Myeloma Disrupts the TRANCE/Osteoprotegerin Cytokine Axis to Trigger Bone Destruction and Promote Tumor Progression. Proceedings of the National Academy of Sciences of the United States of America, 98, 11581-11586.

[13]   Barillé-Nion, S. and Bataille, R. (2003) New Insights in Myeloma-Induced Osteolysis. Leuk Lymphoma, 44, 1463-1467.

[14]   Roux, S., Meignin, V., Quillard, J., Meduri, G., Guiochon-Mantel, A., Fermand, J.P., Milgrom, E. and Mariette, X. (2002) RANK (Receptor Activator of Nuclear Factor-KappaB) and RANKL Expression in Multiple Myeloma. British Journal of Haematology, 117, 86-92.

[15]   Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., Tsuda, E., Morinaga, T., Higashio, K., Udagawa, N., Takahashi, N. and Suda, T. (1998) Osteoclast Differentiation Factor Is a Ligand for Osteoprotegerin/Osteoclastogenesis-Inhibitory Factor and Is Identical to TRANCE/RANKL. Proceedings of the National Academy of Sciences of the United States of America, 95, 3597-3602.

[16]   Giuliani, N., Bataille, R., Mancini, C., Lazzaretti, M. and Barillé, S. (2001) Myeloma Cells Induce Imbalance in the Osteoprotegerin/Osteoprotegerin Ligand System in the Human Bone Marrow Environment. Blood, 98, 3527-3533.

[17]   Blair, J.M., Zhou, H., Seibel, M.J. and Dunstan, C.R. (2006) Mechanisms of Disease: Role of OPG, RANKL and RANK in the Pathophysiology of Skeletal Metastasis. Nature Clinical Practice Oncology, 3, 41-49.

[18]   Kelly, T., Suva, L.J., Nicks, K.M., MacLeod, V. and Sanderson, R.D. (2010) Tumor-Derived Syndecan-1 Mediates Distal Cross-Talk with Bone That Enhances Osteoclastogenesis. Journal of Bone and Mineral Research, 25, 1295-1304.

[19]   Seidel, C., Hjertner, Ø., Abildgaard, N., Heickendorff, L., Hjorth, M., Westin, J., Nielsen, J.L., Hjorth-Hansen, H., Waage, A., Sundan, A. and BØrset, M., Nordic Myeloma Study Group (2001) Serum Osteoprotegerin Levels Are Reduced in Patients with Multiple Myeloma with Lytic Bone Disease. Blood, 98, 2269-2271.

[20]   Terpos, E., Szydlo, R., Apperley, J.F., Hatjiharissi, E., Politou, M., Meletis, J., Viniou, N., Yataganas, X., Goldman, J.M. and Rahemtulla, A. (2003) Soluble Receptor Activator of Nuclear Factor κB Ligand-Osteoprotegerin Ratio Predicts Survival in Multiple Myeloma: Proposal for a Novel Prognostic Index. Blood, 102, 1064-1069.

[21]   Goranova-Marinova, V., Goranov, S., Pavlov, P. and Tzvetkova, T. (2007) Serum Levels of OPG, RANKL and RANKL/OPG Ratio in Newly-Diagnosed Patients with Multiple Myeloma. Clinical Correlations. Haematologica, 92, 1000-1001.

[22]   Martini, G., Gozzetti, A., Gennari, L., Avanzati, A., Nuti, R. and Lauria, F. (2006) The Effect of Zoledronic Acid on Serum Osteoprotegerin in Early Stage Multiple Myeloma. Haematologica, 91, 1720-1721.

[23]   Terpos, E., Mihou, D., Szydlo, R., Tsimirika, K., Karkantaris, C., Politou, M., Voskaridou, E., Rahemtulla, A., Dimopoulos, M.A. and Zervas, K. (2005) 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, 19, 1969-1976.

[24]   Kraj, M., Owczarska, K., Sokolowska, U., Centkowski, P., Poglod, R. and Kruk, B. (2005) Correlation of Osteoprotegerin and sRANKL Concentrations in Serum and Bone Marrow of Multiple Myeloma Patients. Archivum Immunologiae et Therapia Experimentalis, 53, 454-464.

[25]   Depil, S., Mathiot, C., Leleu, X., Moreau, A.S., Faucompré, J.L., Hennache, B., Bauters, F., Bataille, R. and Facon, T. (2005) Evaluation and Prognostic Value of Serum Osteoprotegerin in Multiple Myeloma. British Journal of Haematology, 129, 706-707.

[26]   Corso, A., Dovio, A., Rusconi, C., Sartori, M.L., Klersy, C., Varettoni, M., Mangiacavalli, S., Zappasodi, P., Ventura, M., Angeli, A. and Lazzarino, M. (2004) Osteoprotegerin Serum Levels in Multiple Myeloma and MGUS Patients Compared with Age-and Sex-Matched Healthy Controls. Leukemia, 18, 1555-1557.

[27]   Kyrtsonis, M.C., Vassilakopoulos, T.P., Siakantaris, M.P., Kokoris, S.I., Gribabis, D.A., Dimopoulou, M.N., Angelopoulou, M.K. and Pangalis, G.A. (2004) Serum Syndecan-1, Basic Fibroblast Growth Factor and Osteoprotegerin in Myeloma Patients at Diagnosis and during the Course of the Disease. European Journal of Haematology, 72, 252-258.

[28]   Terpos, E., Politou, M., Szydlo, R., Nadal, E., Avery, S., Olavarria, E., Kanfer, E., Goldman, J.M., Apperley, J.F. and Rahemtulla, A. (2004) Autologous Stem Cell Transplantation Normalizes Abnormal Bone Remodeling and sRANKL/ Osteoprotegerin Ratio in Patients with Multiple Myeloma. Leukemia, 18, 1420-1426.

[29]   Seidel, C., Hjertner, Ø., Abildgaard, N., Heickendorff, L., Hjorth, M., Westin, J., Nielsen, J.L., Hjorth-Hansen, H., Waage, A., Sundan, A. and BØrset, M., Nordic Myeloma Study Group (2001) Serum Osteoprotegerin Levels Are Reduced in Patients with Multiple Myeloma with Lytic Bone Disease. Blood, 98, 2269-2271.

[30]   Bekker, P.J., Holloway, D., Nakanishi, A., Arrighi, M., Leese, P.T. and Dunstan, C.R. (2001) The Effect of a Single Dose of Osteoprotegerin in Postmenopausal Women. Journal of Bone and Mineral Research, 16, 348-360.

[31]   Body, J.J., Greipp, P., Coleman, R.E., Facon, T., Geurs, F., Fermand, J.P., Harousseau, J.L., Lipton, A., Mariette, X., Williams, C.D., Nakanishi, A., Holloway, D., Martin, S.W., Dunstan, C.R. and Bekker, P.J. (2003) A Phase I Study of AMGN-0007, a Recombinant Osteoprotegerin Construct, in Patients with Multiple Myeloma or Breast Carcinoma Related Bone Metastases. Cancer, 97, 887-892.

[32]   Charopoulos, I., Orme, S. and Giannoudis, P.V. (2011) The Role and Efficacy of Denosumab in the Treatment of Osteoporosis: An Update. Expert Opinion on Drug Safety, 10, 205-217.

[33]   Qiang, Y.W., Chen, Y., Stephens, O., Brown, N., Chen, B., Epstein, J., Barlogie, B. and Shaughnessy Jr., J.D. (2008) Myeloma-Derived Dickkopf-1 Disrupts Wnt-Regulated Osteoprotegerin and RANKL Production by Osteoblasts: A Potential Mechanism Underlying Osteolytic Bone Lesions in Multiple Myeloma. Blood, 112, 196-207.

[34]   Edwards, C.M., Edwards, J.R., Lwin, S.T., Esparza, J., Oyajobi, B.O., McCluskey, B., Munoz, S., Grubbs, B. and Mundy, G.R. (2008) Increasing Wnt Signaling in the Bone Marrow Microenvironment Inhibits the Development of Myeloma Bone Disease and Reduces Tumor Burden in Bone in Vivo. Blood, 111, 2833-2842.

[35]   Tian, E., Zhan, F., Walker, R., Rasmussen, E., Ma, Y., Barlogie, B., Shaughnessy Jr., J.D. (2003) The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma. The New England Journal of Medicine, 349, 2483-2494.

[36]   Li, J., Sarosi, I., Cattley, R.C., Pretorius, J., Asuncion, F., Grisanti, M., Morony, S., Adamu, S., Geng, Z., Qiu, W., Kostenuik, P., Lacey, D.L., Simonet, W.S., Bolon, B., Qian, X., Shalhoub, V., Ominsky, M.S., Ke, H.Z., Li, X. and Richards, W.G. (2006) Dkk1-Mediated Inhibition of Wnt Signaling in Bone Results in Osteopenia. Bone, 39, 754-766.

[37]   Morvan, F., Boulukos, K., Clément-Lacroix, P., Roman Roman, S., Suc-Royer, I., Vayssière, B., Ammann, P., Martin, P., Pinho, S., Pognonec, P., Mollat, P., Niehrs, C., Baron, R. and Rawadi, G. (2006) Deletion of a Single Allele of the Dkk1 Gene Leads to an Increase in Bone Formation and Bone Mass. Journal of Bone and Mineral Research, 21, 934-945.

[38]   Politou, M.C., Heath, D.J., Rahemtulla, A., Szydlo, R., Anagnostopoulos, A., Dimopoulos, M.A., Croucher, P.I. and Terpos, E. (2006) Serum Concentrations of Dickkopf-1 Protein Are Increased in Patients with Multiple Myeloma and Reduced after Autologous Stem Cell Transplantation. International Journal of Cancer, 119, 1728-1731.

[39]   Kaiser, M., Mieth, M., Liebisch, P., Oberländer, R., Rademacher, J., Jakob, C., Kleeberg, L., Fleissner, C., Braendle, E., Peters, M., Stover, D., Sezer, O. and Heider, U. (2008) Serum Concentrations of DKK-1 Correlate with the Extent of Bone Disease in Patients with Multiple Myeloma. European Journal of Haematology, 80, 490-494.

[40]   Stavropoulos, N., Maltezas, D., Koulieris, E., Tzenou, T., Bartzis, V., Georgiou, G., Dimou, M., Papanikolaou, X., Repousis, P., Panagiotidis, P. and Kyrtsonis, M.-C. (2011) Dickkopf-1 Protein (Dkk1) Concentration in Serum at Diagnosis Is Strongly Correlated to Fractures in Patients with Multiple Myeloma (MM). Proceedings of Conference 13th International Myeloma Workshop on Haematologica, 130.

[41]   Edwards, C.M. and Mundy, G.R. (2010) Proteasome Inhibitors and the Wnt Signaling Pathway in Myeloma Bone Disease. In: Roodman, G.D., Ed., Myeloma Bone Disease, Chap. 12, Humana Press, Springer, New York Dordrecht Heidelberg London, 211-229.

[42]   Lentzsch, S., Gries, M., Janz, M., Bargou, R., DÖrken, B. and Mapara, M.Y. (2003) Macrophage Inflammatory Protein 1-Alpha (MIP-1α) Triggers Migration and Signaling Cascades Mediating Survival and Proliferation in Multiple Myeloma (MM) Cells. Blood, 101, 3568-3573.

[43]   Menu, E., De Leenheer, E., De Raeve, H., Coulton, L., Imanishi, T., Miyashita, K., Van Valckenborgh, E., Van Riet, I., Van Camp, B., Horuk, R., Croucher, P. and Vanderkerken, K. (2006) Role of CCR1 and CCR5 in Homing and Growth of Multiple Myeloma and in the Development of Osteolytic Lesions: A Study in the 5TMM Model. Clinical and Experimental Metastasis, 23, 291-300.

[44]   Abe, M., Hiura, K., Wilde, J., Moriyama, K., Hashimoto, T., Ozaki, S., Wakatsuki, S., Kosaka, M., Kido, S., Inoue, D. and Matsumoto, T. (2002) Role for Macrophage Inflammatory Protein (MIP)-1Alpha and MIP-1Beta in the Development of Osteolytic Lesions in Multiple Myeloma. Blood, 100, 2195-2202.

[45]   Hata, H. (2005) Bone Lesions and Macrophage Inflammatory Protein-1 Alpha (MIP-1α) in Human Multiple Myeloma. Leukemia & Lymphoma, 46, 967-972.

[46]   Oba, Y., Lee, J.W., Ehrlich, L.A., Chung, H.Y., Jelinek, D.F., Callander, N.S., Horuk, R., Choi, S.J. and Roodman, G.D. (2005) MIP-1Alpha Utilizes Both CCR1 and CCR5 to Induce Osteoclast Formation and Increase Adhesion of Myeloma Cells to Marrow Stromal Cells. Experimental Hematology, 33, 272-278.

[47]   Han, J.H., Choi, S.J., Kurihara, N., Koide, M., Oba, Y. and Roodman, G.D. (2001) Macrophage Inflammatory Protein-1Alpha Is an Osteoclastogenic Factor in Myeloma That Is Independent of Receptor Activator of Nuclear Factor Kappab Ligand. Blood, 97, 3349-3353.

[48]   Terpos, E., Politou, M., Szydlo, R., Goldman, J.M., Apperley, J.F. and Rahemtulla, A. (2003) Serum Levels of Macrophage Inflammatory Protein-1 Alpha (MIP-1 Alpha) Correlate with the Extent of Bone Disease and Survival in Patients with Multiple Myeloma. British Journal of Haematology, 123, 106-109.

[49]   Terpos, E., Politou, M., Viniou, N. and Rahemtulla, A. (2005) Significance of Macrophage Inflammatory Protein-1 Alpha (MIP-1α) in Multiple Myeloma. Leukemia & Lymphoma, 46, 1699-1707.

[50]   Papadogiannis, A., Kyrtsonis, M.-C., Vassilakopoulos, T.P., Tzenou, T., Antoniadis, A.G., Kalpadakis, C., Sachanas, S., Dimopoulou, M.N., Siakantaris, M.P., Kokoris, S.I., Dimitriadou, E.M., Angelopoulou, M.K., Plata, E., Tsaftaridis, P. and Pangalis, G. (2005) Serum Levels of OPG and MIP-1αin Untreated Multiple Myeloma Patients. Correlations with Staging, Survival and Bone Disease. Blood, 106, Abstract 5074.

[51]   Vanderkerken, K., Asosingh, K., Braet, F., Van Riet, I. and Van Camp, B. (1999) Insulin-Like Growth Factor-1 Acts as a Chemoattractant Factor for 5T2 Multiple Myeloma Cells. Blood, 93, 235-241.

[52]   Ge, N.L. and Rudikoff, S. (2000) Insulin-Like Growth Factor I Is a Dual Effector of Multiple Myeloma Cell Growth. Blood, 96, 2856-2861.

[53]   Mitsiades, C.S., Mitsiades, N.S., McMullan, C.J., Poulaki, V., Shringarpure, R., Akiyama, M., Hideshima, T., Chauhan, D., Joseph, M., Libermann, T.A., García-Echeverría, C., Pearson, M.A., Hofmann, F., Anderson, K.C. and Kung, A.L. (2004) Inhibition of the Insulin-Like Growth Factor Receptor-1 Tyrosine Kinase Activity as a Therapeutic Strategy for Multiple Myeloma, Other Hematologic Malignancies, and Solid Tumors. Cancer Cell, 5, 221-230.

[54]   Georgii-Hemming, P., Wiklund, H.J., Ljunggren, O. and Nilsson, K. (1996) Insulin-Like Growth Factor I Is a Growth and Survival Factor in Human Multiple Myeloma Cell Lines. Blood, 88, 2250-2258.

[55]   Abboud, S.L., Bethel, C.R. and Aron, D.C. (1991) Secretion of Insulin-Like Growth Factor I and Insulinlike Growth Factor-Binding Proteins by Murine Bone Marrow Stromal Cells. Journal of Clinical Investigation, 88, 470-475.

[56]   Middleton, J., Arnott, N., Walsh, S. and Beresford, J. (1995) Osteoblasts and Osteoclasts in Adult Human Osteophyte Tissue Express the mRNAs for Insulin-Like Growth Factor I and II and the Type I IGF Receptor. Bone, 16, 287-293.

[57]   Freund, G.G., Kulas, D.T., Way, B.A. and Mooney, R.A. (1994) Functional Insulin and Insulin-Like Growth Factor-1 Receptors Are Preferentially Expressed in Multiple Myeloma Cell Lines as Compared to B-Lymphoblastoid Cell Lines. Cancer Research, 54, 3179-3185.

[58]   Jelinek, D.F., Witzig, T.E. and Arendt, B.K. (1997) A Role for Insulin-Like Growth Factor in the Regulation of IL-6-Responsive Human Myeloma Cell Line Growth. Journal of Immunology, 159, 487-496.

[59]   Abroun, S., Ishikawa, H., Tsuyama, N., Liu, S., Li, F.J., Otsuyama, K., Zheng, X., Obata, M. and Kawano, M.M. (2004) Receptor Synergy of Interleukin-6 (IL-6) and Insulin-Like Growth Factor-I That Highly Express IL-6 Receptor α Myeloma Cells. Blood, 103, 2291-2298.

[60]   Ferlin, M., Noraz, N., Hertogh, C., Brochier, J., Taylor, N. and Klein, B. (2000) Insulin-Like Growth Factor Induces the Survival and Proliferation of Myeloma Cells through an Interleukin-6-Independent Transduction Pathway. British Journal of Haematology, 111, 626-634.

[61]   Tu, Y., Gardner, A. and Lichtenstein, A. (2000) The Phosphatidylinositol 3-Kinase/AKT kinase Pathway in Multiple Myeloma Plasma Cells: Roles in Cytokine-Dependent Survival and Proliferative Responses. Cancer Research, 60, 6763-6770.

[62]   Qiang, Y.W., Kopantzev, E. and Rudikoff, S. (2002) Insulin-Like Growth Factor-I Signaling in Multiple Myeloma: Downstream Elements, Functional Correlates, and Pathway Cross-Talk. Blood, 11, 4138-4146.

[63]   Pollak, M. (2008) Insulin and Insulin-Like Growth Factor Signalling in Neoplasia. Nature Reviews Cancer, 8, 915-928.

[64]   Melton 3rd, L.J., Rajkumar, S.V., Khosla, S., Achenbach, S.J., Oberg, A.L. and Kyle, R.A. (2004) Fracture Risk in Monoclonal Gammopathy of Undetermined Significance. Journal of Bone and Mineral Research, 19, 25-30.

[65]   Kumar, S.K., Rajkumar, S.V., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., Zeldenrust, S.R., Dingli, D., Russell, S.J., Lust, J.A., Greipp, P.R., Kyle, R.A. and Gertz, M.A. (2008) Improved Survival in Multiple Myeloma and the Impact of Novel Therapies. Blood, 111, 2516-2520.

[66]   Lonial, S. (2010) Presentation and Risk Stratification—Improving Prognosis for Patients with Multiple Myeloma. Cancer Treatment Reviews, 36, 12-17.

[67]   Terpos, E., Heath, D.J., Rahemtulla, A., Zervas, K., Chantry, A., Anagnostopoulos, A., Pouli, A., Katodritou, E., Verrou, E., Vervessou, E.C., Dimopoulos, M.A. and Croucher, P.I. (2006) 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. British Journal of Haematology, 135, 688-692.

[68]   Terpos, E., Christoulas, D., Kastritis, E., Katodritou, E., Papatheodorou, A., Pouli, A., Kyrtsonis, M.C., Michalis, E., Papanikolaou, X., Gkotzamanidou, M., Koulieris, E., Gavriatopoulou, M., Zervas, K. and Dimopoulos, M.A., on behalf of the Greek Myeloma Study Group (2014) The Combination of Lenalidomide and Dexamethasone Reduces Bone Resorption in Responding Patients with Relapsed/Refractory Multiple Myeloma but Has No Effect on Bone Formation: Final Results on 205 Patients of the Greek Myeloma Study Group. American Journal of Hematology, 89, 34-40.

[69]   Greenberger, J.S. (2010) Radiation Therapy in Multiple Myeloma. In: Roodman, G.D., Ed., Myeloma Bone Disease, Chap. 4, Humana Press, Springer, New York Dordrecht Heidelberg London, 91-100.

[70]   DeVita, V., Hellman, S. and Rosenberg, S. (2005) Cancer, Principles and Practice of Oncology. In: DePinho, R. and Weimberg, R., Eds., Cancer, Principles and Practice of Oncology, Lippincott Williams and Wilkins, Philadelphia.

[71]   George, R., Jeba, J., Ramkumar, G., Chacko, A.G., Leng, M. and Tharyan, P. (2008) Interventions for the Treatment of Metastatic Extradural Spinal Cord Compression in Adults. The Cochrane Database of Systematic Reviews, No. 4, CD006716.

[72]   Hussein, M. (2010) Surgical Management of Bone Disease. In: Roodman, G.D., Ed., Myeloma Bone Disease, Chap. 5, Humana Press, Springer, New York Dordrecht Heidelberg London, 101-116.

[73]   Fourney, D.R., Schomer, D.F., Nader, R., Chlan-Fourney, J., Suki, D., Ahrar, K., Rhines, L.D. and Gokaslan, Z.L. (2003) Percutaneous Vertebroplasty and Kyphoplasty for Painful Vertebral Body Fractures in Cancer Patients. Journal of Neurosurgery, 98, 21-30.

[74]   Papadopoulos, E.C., Edobor-Osula, F., Gardner, M.J., Shindle, M.K. and Lane, J.M. (2008) Unipedicular Balloon Kyphoplasty for the Treatment of Osteoporotic Vertebral Compression Fractures: Early Results. Journal of Spinal Disorders & Techniques, 21, 589-596.

[75]   Malempati, H., Qamirani, E. and Yee, A.J.M. (2012) Metastatic/Myeloma Disease-Operative Management. In: Evidence Based Orthopaedics, Wiley-Blackwell, BMJ Books, 721-727.

[76]   Hussein, M.A., Vrionis, F.D., Allison, R., Berenson, J., Berven, S., Erdem, E., Giralt, S., Jagannath, S., Kyle, R.A., LeGrand, S., Pflugmacher, R., Raje, N., Rajkumar, S.V., Randall, R.L., Roodman, D., Siegel, D., Vescio, R., Zonder, J. and Durie, B.G., International Myeloma Working Group (2008) The Role of Vertebral Augmentation in Multiple Myeloma: International Myeloma Working Group Consensus Statement. Leukemia, 22, 1479-1484.

[77]   Harrington, K.D. (1986) Impending Pathologic Fractures from Metastatic Malignancy: Evaluation and Management. Instructional Course Lectures, 35, 357-381.

[78]   Mirels, H. (1989) Metastatic Disease in Long Bones: A Proposed Scoring System for Diagnosing Impending Pathologic Fractures. Clinical Orthopaedics and Related Research, 249, 256-264.

[79]   Papagelopoulos, P.J., Galanis, E.C., Greipp, P.R. and Sim, F.H. (1997) Prosthetic Hip Replacement for Pathologic or Impending Pathologic Fractures in Myeloma. Clinical Orthopaedics and Related Research, 341, 192-205.

[80]   Allan, D.G., Bell, R.S., Davis, A. and Langer, F. (1995) Complex Acetabular Reconstruction for Metastatic Tumor. The Journal of Arthroplasty, 10, 301-306. (05)80178-0

[81]   Benevenia, J., Cyran, F.P., Biermann, J.S., Patterson, F.R. and Leeson, M.C. (2004) Treatment of Advanced Metastatic Lesions of the Acetabulum Using the Saddle Prosthesis. Clinical Orthopaedics and Related Research, 426, 23-31. 01.blo.0000141387.03035.3e

[82]   Stark, A. and Nauer, H.C. (1996) Reconstruction in Metastatic Destruction of the Acetabulum: Support Rings and Arthroplasty in 12 Patients. Acta Orthopaedica, 67, 435-438.

[83]   Coleman, R.E. (2004) Bisphosphonates: Clinical Experience. The Oncologist, 9, 14-27.

[84]   Baulch-Brown, C., Molloy, T.J., Yeh, S.L., Ma, D. and Spencer, A. (2007) Inhibitors of the Mevalonate Pathway as Potential Therapeutic Agents in Multiple Myeloma. Leukemia Research, 31, 341-352.

[85]   Shipman, C.M., Rogers, M.J., Apperley, J.F., Russell, R.G. and Croucher, P.I. (1997) Bisphosphonates Induce Apoptosis in Human Myeloma Cell Lines: A Novel Anti-Tumour Activity. British Journal of Haematology, 98, 665-672.

[86]   Tassone, P., Forciniti, S., Galea, E., Morrone, G., Turco, M.C., Martinelli, V., Tagliaferri, P. and Venuta, S. (2000) Growth Inhibition and Synergistic Induction of Apoptosis by Zoledronate and Dexamethasone in Human Myeloma Cell Lines. Leukemia, 14, 841-844.

[87]   Ural, A.U., Yilmaz, M.I., Avcu, F., Pekel, A., Zerman, M., Nevruz, O., Sengul, A. and Yalcin, A. (2003) The Bisphosphonate Zoledronic Acid Induces Cytotoxicity in Human Myeloma Cell Lines with Enhancing Effects of Dexamethasone and Thalidomide. International Journal of Hematology, 78, 443-449.

[88]   Corso, A., Ferretti, E., Lunghi, M., Zappasodi, P., Mangiacavalli, S., De Amici, M., Rusconi, C., Varettoni, M. and Lazzarino, M. (2005) Zoledronic Acid Down-Regulates Adhesion Molecules of Bone Marrow Stromal Cells in Multiple Myeloma: A Possible Mechanism for Its Antitumor Effect. Cancer, 104, 118-125.

[89]   Zwolak, P., Manivel, J.C., Jasinski, P., Kirstein, M.N., Dudek, A.Z., Fisher, J. and Cheng, E.Y. (2010) Cytotoxic Effect of Zoledronic Acid-Loaded Bone Cement on Giant Cell Tumor, Multiple Myeloma, and Renal Cell Carcinoma Cell Lines. The Journal of Bone & Joint Surgery, 92, 162-168.

[90]   Uchida, R., Ashihara, E., Sato, K., Kimura, S., Kuroda, J., Takeuchi, M., Kawata, E., Taniguchi, K., Okamoto, M., Shimura, K., Kiyono, Y., Shimazaki, C., Taniwaki, M. and Maekawa, T. (2007) Gamma Delta T Cells Kill Myeloma Cells by Sensing Mevalonate Metabolites and ICAM-1 Molecules on Cell Surface. Biochemical and Biophysical Research Communications, 354, 613-618.

[91]   Kunzmann, V., Bauer, E., Feurle, J., Weissinger, F., Tony, H.P. and Wilhelm, M. (2000) Stimulation of γδCells by Aminobisphosphonates and Induction of Antiplasma Cell Activity in Multiple Myeloma. Blood, 96, 384-392.

[92]   Moschetta, M., Di Pietro, G., Ria, R., Gnoni, A., Mangialardi, G., Guarini, A., Ditonno, P., Musto, P., D’Auria, F., Ricciardi, M.R., Dammacco, F., Ribatti, D. and Vacca, A. (2010) Bortezomib and Zoledronic acid on Angiogenic and Vasculogenic Activities of Bone Marrow Macrophages in Patients with Multiple Myeloma. European Journal of Cancer, 46, 420-429.

[93]   Schmidmaier, R., Simsek, M., Baumann, P., Emmerich, B. and Meinhardt, G. (2006) Synergistic Antimyeloma Effects of Zoledronate and Simvastatin. Anti-Cancer Drugs, 17, 621-619.

[94]   Koizumi, M., Nakaseko, C., Ohwada, C., Takeuchi, M., Ozawa, S., Shimizu, N., Cho, R., Nishimura, M. and Saito, Y. (2007) Zoledronate Has an Antitumor Effect and Induces Actin Rearrangement in Dexamethasone-Resistant Myeloma Cells. European Journal of Haematology, 79, 382-391.

[95]   Lacy, M.Q., Dispenzieri, A., Gertz, M.A., Greipp, P.R., Gollbach, K.L., Hayman, S.R., Kumar, S., Lust, J.A., Rajkumar, S.V., Russell, S.J., Witzig, T.E., Zeldenrust, S.R., Dingli, D., Bergsagel, P.L., Fonseca, R., Reeder, C.B., Stewart, A.K., Roy, V., Dalton, R.J., Carr, A.B., Kademani, D., Keller, E.E., Viozzi, C.F. and Kyle, R.A. (2006) Mayo Clinic Consensus Statement for the Use of Bisphosphonates in Multiple Myeloma. Mayo Clinic Proceedings, 81, 1047-1053.

[96]   Terpos, E., Morgan, G., Dimopoulos, M.A., Drake, M.T., Lentzsch, S., Raje, N., Sezer, O., García-Sanz, R., Shimizu, K., Turesson, I., Reiman, T., Jurczyszyn, A., Merlini, G., Spencer, A., Leleu, X., Cavo, M., Munshi, N., Rajkumar, S.V., Durie, B.G. and Roodman, G.D. (2013) International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma-Related Bone Disease. Journal of Clinical Oncology, 31, 2347-2357.

[97]   Terpos, E., Dimopoulos, M.A. and Berenson, J. (2011) Established Role of Bisphosphonate Therapy for Prevention of Skeletal Complications from Myeloma Bone Disease. Critical Reviews in Oncology/Hematology, 77, 13-23.

[98]   Nicolatou-Galitis, O., Papadopoulou, E., Sarri, T., Boziari, P., Karayianni, A., Kyrtsonis, M.C., Repousis, P., Barbounis, V. and Migliorati, C.A. (2011) Osteonecrosis of the Jaw in Oncology Patients Treated with Bisphosphonates: Prospective Experience of a Dental Oncology Referral Center. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 112, 195-202.

[99]   Pozzi, S., Fulciniti, M., Yan, H., Vallet, S., Eda, H., Patel, K., Santo, L., Cirstea, D., Hideshima, T., Schirtzinge, L., Kuhstoss, S., Anderson, K.C., Munshi, N., Scadden, D., Kronenberg, H.M. and Raje, N. (2013) In Vivo and in Vitro Effects of a Novel Anti-Dkk1 Neutralizing Antibody in Multiple Myeloma. Bone, 53, 487-496.

[100]   Fulciniti, M., Tassone, P., Hideshima, T., Vallet, S., Nanjappa, P., Ettenberg, S.A., Shen, Z., Patel, N., Tai, Y.T., Chauhan, D., Mitsiades, C., Prabhala, R., Raje, N., Anderson, K.C., Stover, D.R. and Munshi, N.C. (2009) Anti-DKK1 mAb (BHQ880) as a Potential Therapeutic Agent for Multiple Myeloma. Blood, 114, 371-379.

[101]   Padhi, D., Jang, G., Stouch, B., Fang, L. and Posvar, E. (2011) Single-Dose, Placebo-Controlled, Randomized Study of AMG 785, a Sclerostin Monoclonal Antibody. Journal of Bone and Mineral Research, 26, 19-26.

[102]   Young, R.F., Post, E.M. and King, G.A. (1980) Treatment of Spinal Epidural Metastases. Randomized Prospective Comparison of Laminectomy and Radiotherapy. Journal of Neurosurgery, 53, 741-748.

[103]   Klimo Jr., P., Thompson, C.J., Kestle, J.R. and Schmidt, M.H. (2005) A Meta-Analysis of Surgery versus Conventional Radiotherapy for the Treatment of Metastatic Spinal Epidural Disease. Neuro-Oncology, 7, 64-76.

[104]   Patchell, R.A., Tibbs, P.A., Regine, W.F., Payne, R., Saris, S., Kryscio, R.J., Mohiuddin, M. and Young, B. (2005) Direct Decompressive Surgical Resection in the Treatment of Spinal Cord Compression Caused by Metastatic Cancer: A Randomised Trial. Lancet, 366, 643-648.