The Use of Bisphosphonates in Patients With Breast Cancer

Catherine H. Van Poznak, MD

Disclosures

Cancer Control. 2002;9(6) 

In This Article

Pathophysiology of Bone Metastases

Normal bone is comprised of both organic and cellular elements. The bone matrix serves as a reservoir for minerals, cytokines, and growth factors. The cellular component contains both bone and hematopoietic cell lines.

Normal bone is constantly remodeling, and this healthy bone metabolic activity is characterized by two opposite actions: the formation of new bone by osteoblasts and the resorption of old bone by osteoclasts. The normal balance between resorption and deposition is disturbed by cancer. When the tumor has metastasized to bone, it can directly alter the bone and cause lesions that may be lytic (due to increased resorption), blastic (due to increased deposition) or a combination of both, causing a mixed lesion.

When the osteoclast resorbs bone, growth factors and cytokines are liberated to interact with the tumor cells. In turn, the tumor cell may express cell signals that then stimulate the osteoclast and a "vicious cycle" of cell signaling is established. In the development of osteolytic lesions, these signals include parathyroid hormone-related protein (PTHrP) and transforming growth factor beta (TGF-ß).[9] Tumor cells in the bone micro-environment may produce PTHrP, thereby stimulating osteoclastic bone resorption that in turn results in the release of active TGF-ß. TGF-ßcan then act on the tumor cells, stimulating their metastatic capacity and their ability to produce of PTHrP. Other cell signaling occurs through receptor activator of nuclear factor B (NF B (RANK), its ligand (RANKL), and its soluble decoy receptor osteoprotegerin as well as signaling through insulin-like growth factors (Figure 1). The net results are tumor growth and the development of osseous lesions.

Signaling between the breast cancer metastases and the bone microenvironment involves parathyroid hormone-related protein (PTHrP), transforming growth factor beta (TGF-ß), receptor activator of NF B (RANK), receptor activator of NF B Ligand (RANK-L), and insulin-like growth factor 1 (IGF-1). Other factors believed to be involved in tumor to bone signaling include (but are not limited to) platelet-derived growth factors, plasminogen activator, gonadal steroids, bone morphogenic proteins, tumor necrosis factors, vascular endothelial growth factor, epidermal growth factor, interleukins, prostaglandins, and fibroblast growth factor. Copyright 2002, Catherine Van Poznak.

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