Bone metastases: Causes, consequences and therapeutic opportunities

Abstract

Although the skeleton is a common site of metastasis for many solid tumours, metastatic bone disease is particularly relevant in prostate and breast cancers. Thus, bone is the most frequent – and often the only – location of metastasis in patients with advanced prostate cancer. Moreover, up to 70% of patients with metastatic breast cancer develop bone metastases over the course of their disease. Metastatic bone involvement usually results in multiple skeletal complications leading to a significant deterioration in the quality of life for cancer patients. Pain, hypercalcemia and skeletal-related events (SREs) – such as the use of radiotherapy or surgery of bone, pathological fractures and spinal cord compression – are problems typically derived from bone metastases [1]. The pathogenesis of bone metastases is a complex process involving many interactions between tumour cells and osteoclasts and osteoblasts. Receptor activator of nuclear factor-κb (RANK) ligand (RANKL), which is expressed by osteoblasts and marrow stromal cells, is a potent inducer of osteoclast formation. In bone metastases, cytokines and growth factors secreted by tumour cells (interleukins 1 and 6, parathyroid-hormone-related peptide, tumour necrosis factor, prostaglandin E2, and macrophage-colony-stimulating factor, amongst others) increase the expression of RANKL on marrow stromal cells and osteoblasts [2]. Following this, RANKL binds to its receptor, RANK, on the surface of osteoclast precursors and stimulates the differentiation of these cells to mature osteoclasts. This excessive RANKL-induced osteoclast activity results in increased bone resorption and local bone destruction, leading to the release of growth factors from the bone matrix that subsequently promotes tumour progression. This relationship between tumour and bone cells constitutes the vicious cycle of bone metastases. For all these reasons, patients with metastatic bone involvement who show higher levels of bone turnover markers have a particularly high risk for SREs in addition to worse clinical outcomes [3]. Treatment of bone metastases requires a broad strategy with different therapeutic options, including both local and systemic therapies. External-beam radiotherapy remains the mainstay of treatment for symptomatic bone metastases. However, considering that osteoclast-mediated bone resorption plays a critical role in the development of metastatic bone disease, its inhibition represents an attractive target for treating bone metastases. Below, some of the major management approaches are very briefly summarised.