Bisphosphonates and metastatic bone disease.

Malignant bone disease is a frequent complication of several common solid tumours including breast, lung, prostate and renal cancer. A greater understanding of tropic bone tumour cells, especially the understanding of those properties which lead to their successful growth within the bone microenvironment is the first step to devise innovative approaches. Bone metastases are generally characterized as osteolytic, leading to bone destruction, or osteosclerotic (osteoblastic), leading to new bone formation. The classification of bone metastases as either osteolytic or osteoblastic is the schematic representation of a complex phenomenon wherein both biological scenarios coexist. Breast, lung and renal cancer metastases are usually osteolytic, on the other hand prostate cancer metastases are usually osteoblastic. The type of metastasis is a reflection of the primary mechanism of interference between tumour cells and the bone remodelling system. Hence, the development of osteolytic and osteoblastic lesions results from a functional interaction between tumour cells and osteoclasts or osteoblasts, respectively. Bone is a dynamic organ composed of cells of various embryonic origins; with regards to bone disease two cell types, osteoclasts and osteoblasts regulate bone modelling that occurs during development and bone remodelling that occurs in the adult. Osteoclasts are derived from precursors in the mononuclear-phagocyte lineage and are responsible for bone resorption [1]. Osteoblasts are derived from the stromal cell lineage and are responsible for laying down new bone matrix. A significant factor regulating bone remodelling is the direct interaction between osteoblasts and osteoclasts. The expression of RANK ligand (RANKL) on the surface of osteoblasts engages the receptor, RANK, on osteoclast precursors, leading to their maturation. Hence, osteoclasts release proteases that resorb bone matrix. In addition, a plethora of systemic and locally acting factors deriving from endocrine, immune, and other systems can impact osteoclast and osteoblast function, including the urokinase-type plasminogen activator (uPA), platelet derived growth factor (PDGF), endotheline-1 (ET-1), tumour necrosis factor (TNF-a), Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL10), paratyroid hormone-related protein (PTHrP), the insulinlike growth factor (IGF) and transphorming growth factor beta (TGF-beta). Such factors can enhance the activity of osteoclasts either indirectly through stimulating the expression of RANKL on osteoblasts, or through direct effects on osteoclast and osteoblast function. On the contrary osteolysis is suppressed by osteoprotegerin (OPG) which inhibits RANKL binding to the RANK receptor. In according to the above described mechanism breast cancer cells without RANKL expression fail to sustain osteoclastic activity [2]. From a clinical point of view, the epiphenomenon of this biological scenario is represented by bone disease and ultimately, for patients, in a significant skeletal morbidity, which can decrease the quality of life and, potentially, survival. Median survival after the development of bone metastases ranges from 6–48 months, depending on tumour type. The potential complications of bone metastases include pain, hypercalcemia, pathological fractures and spinal cord compression. Based on this background it is easy to understand why the preservation of skeletal health is emerging as an important aspect of patient care in the oncology setting. The management of skeletal complications is based on a multidisciplinary approach which includes radiotherapy, radiopharmaceuticals, orthopaedic surgery, chemotherapy, hormone therapy and bisphosphonates. The aim of a multidisciplinary approach in the management of bone metastases includes pain relief combined with restoration of skeletal function and improvement patients’ quality of life.