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  • In summary current evidence suggests that bone targeted agen


    In summary, current evidence suggests that bone-targeted agents reduce morbidity from metastatic disease to bone, and potentially improve quality of life in patients with metastatic breast cancer. As there are costs and potential adverse effects associated with these agents, care should be taken in their use. In addition, further work is needed in the creation of meaningful measures of quality of life in these patients [22].
    The vicious cycle: not so simple anymore! Metastatic tumor growth in the bone is affected by a complex network of cellular interactions and effector molecules. The interactions between osteoclasts, osteoblasts, and tumor tachykinin receptor have been shown to drive tumor growth through a “vicious cycle”. In this framework, tumor cells secrete factors such as parathyroid hormone-related protein (PTHrP) that induce osteoblast and osteoclast activity, leading to bone resorption and destruction, release of growth factors such as transforming growth factor (TGF)-β, and subsequent tumor growth and perpetuation of the destructive cycle [23]. What has become clear over the years is that while the “vicious cycle” was a relatively simple concept to explain some interactions occurring in metastatic bone disease and rationale for the development of bisphosphonates and denosumab—the real picture is a lot more complex [7]. Increasingly, the importance of the tumor microenvironment itself in this destructive cycle has come under scrutiny. Cells that are not directly involved in bone remodeling, including lymphocytes, macrophages, and stromal cells may affect tumor growth through their interactions with tumor cells. As part of the bone marrow stromal environment, adipocytes, fibroblasts, and chrondrocytes have been implicated in the differentiation and proliferation of both hematopoietic and cancer cells, in part through secretion of pro-resorption cytokines by tumor cells following their engagement with stromal cells via VCAM-1 mediated interactions [24]. Myeloid-derived suppressor cells (MDSC) represent a diverse population of myeloid-lineage cells that includes macrophages, dendritic cells, and granulocytes. They are known to proliferate in the setting of cancer, can down-regulate the immune response [25], and have been linked to multiple aspects of cancer progression, including tumor growth, angiogenesis, and metastasis [26,27]. In a xenograft mouse model, these cells have been shown to differentiate into osteoclasts and accelerate tumor growth and bone destruction [28]. The extracellular matrix (ECM) of the bone is also implicated in the metastatic process. The ECM contains a constellation of proteins and other biomolecules that serve both as a scaffold for mineral deposition, and as signaling molecules that help direct bone formation and resorption [29]. These interactions may become dysfunctional in the setting of metastatic cancer. Bone sialoprotein (BSP) is a major non-collagenous protein in the ECM, and can induce cell adhesion and promote osteoclastogenesis [30]. High BSP levels are seen in multiple cancers, and have been associated with excessive bone resorption in animal models [31]. Indeed, preliminary experiments in a mouse model using siRNA-mediated knockdown of the BSP gene revealed reductions in both osteolysis and tumor incidence [32].
    Bone-specific therapy in metastatic disease–an oncodynamic perspective Bone metastasis involves the dysregulation of normally tightly controlled bone homeostasis. Tumor cells release paracrine factors that stimulate osteoclast and osteoblast recruitment and differentiation. Bone resorption due to osteoclast activity can liberate growth factors from the bone matrix that can drive further tumor growth [33]. Similarly, growth factors secreted by osteoblasts may also stimulate tumors. This process is associated with significant morbidity including bone loss, pathologic fractures, and cancer-induced bone pain [20].