Finally MM patients have accelerated bone loss when compared

Finally, MM patients have accelerated bone loss when compared to age-matched controls. Bone mineral density is decreased in patients with MM as well as in patients with monoclonal gammopathy of undetermined significance (MGUS) [19,20], a clinically benign condition defined by a low level of monoclonal protein production and the absence of skeletal lesions [19].
Mechanisms of myeloma bone disease MMBD is characterized by purely osteolytic bone destruction due to increased OCL activity and suppressed or absent OBL activity, and myeloma bone lesions have a characteristic “punched-out” appearance on x-rays. The bone marrow microenvironment in myeloma includes both extracellular and cellular elements, including osteoblasts, osteoclasts, endothelial cells, immune Stattic and MM cells that contribute to tumor growth and the bone destructive process. Multiple interactions within the bone marrow microenvironment in myeloma are responsible for the abnormal bone remodeling of MMBD (Fig. 1, panels A and B). Myeloma cells drive bone destruction that in turn increases tumor growth; highlighting the critical role that bone disease plays in myeloma. In addition, myeloma cells both directly stimulate OCL formation and induce cells in the marrow microenvironment to produce factors that drive OCL formation and suppress OBL formation. Immune cells contribute to the bone destructive process through production of cytokines and adhesion molecules that increase myeloma cell growth and enhance myeloma cell chemoresistance, increase osteoclastogenesis, suppress osteoblastogenesis, and drive T cell polarization from a predominantly Th1 phenotype to Th17 [21–24]. Factors produced by marrow stromal cells and OCL promote tumor growth through direct action on myeloma cells [25] and indirectly by increasing angiogenesis (Fig. 1, panel C). [26–28]. Finally, the bone resorption process itself releases immobilized growth factors such as TGFβ from the bone matrix that also drive tumor growth [29].
Pathogenesis of the increased osteoclast activity in myeloma Histologic studies of bone biopsies from patients with MM demonstrate that increased OCL activity occurs adjacent to MM cells, suggesting that bone destruction in MM is a local event. This has led to the hypothesis that local cytokines produced or induced by MM cells are responsible for the increased OCL formation and subsequent bone resorptive activity in MM. These osteoclastogenic activating factors, (OAFs), directly increase OCL formation and activity and decrease production of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of NF-kB ligand (RANKL), a critical differentiation factor for OCLs produced by marrow stromal cells and OBL [30]. OAFs were initially identified in conditioned media from myeloma cell lines and found to stimulate bone resorption in bone organ culture systems [31]. Additional factors identified as OAFs important in MMBD include RANKL, MIP-1α, TNF-α, Interleukin 3 (IL-3), and IL-6. Interestingly, several of these OAFs also suppress OBL formation and/or support myeloma cells directly, indicating that they play multiple roles in MMBD. Myeloma cells also stimulate cells in the marrow microenvironment, particularly marrow stromal cells and T cells, resulting in increased production of OAFs and decreased production of OCL inhibitory factors. Adhesive interactions between myeloma cells and bone marrow stromal cells via binding of surface VLA-4 (α4β1 integrin) to VCAM-1 on stromal cells results in production of osteoclastogenic cytokines such as RANKL, M-CSF, IL-11, and IL-6 by marrow stromal cells and osteoclastogenic cytokines including macrophage inflammatory protein-1α (MIP-1α) and IL-3 by MM cells [32–35,36]. Additionally, OCLs themselves secrete factors that support myeloma cells [37], including IL-6 [38], annexin II [39], osteopontin [40], fibroblast activation protein [41], BAFF, and APRIL [42].