1. Chapter 62 Chapter 62 Mechanisms of Bone Destruction in Myeloma Copyright © 2013 Elsevier Inc. All rights reserved.

2. FIGURE 62.1 Balanced physiologic bone remodeling. Physiologic bone remodeling is marked by balanced interactions between osteoclasts (OCL) and osteoblasts (OBL) within the bone marrow microenvironment. Locally produced cytokines and systemic hormones regulate the formation and activation of OCL. Systemic hormones (not pictured) stimulate OCL formation by inducing the expression of receptor activator of nuclear factor-κ B ligand (RANKL) on marrow stromal cells and OBL. Stromal cells also produce OCL-stimulating factors including interleukin-6, macrophage colony-stimulating factor (M-CSF), and vascular endothelial growth factor (VEGF) that induce OCL formation. In addition, stromal cells produce dickkopf (DKK)-1, an OBL inhibitory factor. Coupling factors produced by OCL such as ephrins (not shown), also drive OBL differentiation while suppressing further OCL formation and activity. OBLs produce osteoprotegerin (OPG), a soluble RANKL inhibitor. Under physiologic conditions, OBL and OCL activity is balanced, in part due to the OPG/RANKL ratio. In myeloma bone disease osteoclastogenesis is favored and osteoblastogenesis is inhibited. Source: Raje, N. and Roodman, G. D. (2011). Advances in the biology and treatment of bone disease in multiple myeloma. Clin Cancer Res 17, 1278–1286. 2

3. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 62.2 The vicious cycle of myeloma bone disease. Myeloma cells produce factors that directly or indirectly activate osteoclasts (OCL), such as macrophage inflammatory protein (MIP)-1α, interleukin (IL)-3, and hepatocyte growth factor (HGF). Myeloma cells also induce receptor activator of nuclear factor-κ B ligand (RANKL) and IL-6 production by marrow stromal cells to enhance OCL formation. OCLs in turn produce soluble factors such as annexin II (AXII) and IL-6 that stimulate tumor growth. The bone destructive process also releases growth factors (GF) that increase the growth of myeloma cells, further exacerbating the osteolytic process, resulting in a vicious cycle of bone destruction. Osteoblast (OBL) differentiation is suppressed by tumor-derived OBL-inhibitory factors such as dickkopf-related protein (DKK)-1, IL-3, IL-7, and the secreted frizzled-related proteins (sFRPs). In addition, the RANKL/OPG ratio is increased, promoting OCL development. DKK-1, MIP-1α, and RANKL levels are all increased in myeloma bone disease as compared with the physiologic state. Source: derived from Roodman, G. D. (2004). Mechanisms of bone metastasis. New Engl J Med 2004;350(16):1655–64. 3