Myeloma bone disease: Pathophysiology and management

Abstract

Multiple myeloma bone disease is marked by severe dysfunction of both bone formation and resorption and serves as a model for understanding the regulation of osteoblasts (OBL) and osteoclasts (OCL) in cancer. Myeloma bone lesions are purely osteolytic and are associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Interactions within the bone marrow microenvironment in myeloma are responsible for the abnormal bone remodeling in myeloma bone disease. Myeloma cells drive bone destruction that increases tumor growth, directly stimulates the OCL formation, and induces cells in the marrow microenvironment to produce factors that drive OCL formation and suppress OBL formation. Factors produced by marrow stromal cells and OCL promote tumor growth through direct action on myeloma cells and by increasing angiogenesis. Current therapies targeting MMBD focus on preventing osteoclastic bone destruction; however regulators of OBL inhibition in MMBD have also been identified, and targeted agents with a potential anabolic effect in MMBD are under investigation. This review will discuss the mechanisms responsible for MMBD and therapeutic approaches currently in use and in development for the management of MMBD.

Keywords: Angiogenesis; Bone marrow microenvironment; Myeloma; Myeloma bone disease; Osteoblast; Osteoclast.

Fig. 1

Cellular interactions in the bone marrow microenvironment in myeloma bone disease. The bone marrow microenvironment in myeloma includes osteoblasts (OBL), osteoclasts (OCL), stromal cells, endothelial cells, and osteocytes. Multiple interactions within the bone marrow microenvironment in myeloma are responsible for the abnormal bone remodeling of multiple myeloma bone disease (MMBD). (A) OCL Activation in MMBD. Myeloma cells directly stimulate OCL formation and induce cells in the marrow microenvironment to produce factors that drive OCL formation. Osteoclast activating factors (OAFs) produced by myeloma cells include RANKL, MIP-1α, IL-3, and TNF-α. Myeloma cells also induce marrow stromal cell production of growth factors that enhance OCL formation including RANKL, MCSF, and (not pictured) IL-6 and TNF-α and decrease production of OCL inhibitory factors, such as OPG. OCLs secrete soluble factors such as osteopontin, MIP-1α, IL-6, AXII, BAFF, and APRIL that stimulate tumor growth. In addition, factors produced by marrow stromal cells and OCL promote tumor growth through direct action on myeloma cells. Osteocytes also regulate osteoclastognesis and bone resorption through expression of RANKL. Finally, the bone destructive process releases bone matrix-derived growth factors such as TGFβ, IGFs, FGF, PDGFs, and BMPs that increase the growth of myeloma cells, further exacerbating the osteolytic process. (B) OBL Suppression in MMBD. MM cell derived OBL-inhibitory factors include DKK1, sclerostin, HGF, IL-7, and TNF-α. MM cells also induce other cells in the marrow microenvironment to increase production of OBL suppressors such as sclerostin (from osteocytes), and TNF-α and GFI1 (from marrow stromal cells). Myeloma cells also induce marrow stromal cells to produce factors that support the myeloma cells, including IL-6, VCAM1, VEGF, and IGF-1. (C) Angiogenesis is enhanced in MMBD. Angiogenesis is enhanced in MM. OCL and endothelial cells are closely apposed in the bone marrow microenvironment, and increased OCL activity appears to contribute to both the increased angiogenesis in MM as well as to tumor growth. Endothelial cell proliferation is enhanced by angiogenic factors such as VEGF produced by myeloma cells and stromal cells. Osteoclasts also secrete angiogenic factors, such as osteopontin and MMP9.