The science behind metastatic bone pain

Metastatic bone pain is a significant cause of morbidity in patients with advanced cancer and greatly reduces quality of life. Standard palliative treatments such as opioids may not provide effective relief of metastatic bone pain, particularly acute breakthrough pain, without unacceptable side effects at the high doses required. A mouse model of metastatic bone pain has been developed in which tumor cells are injected directly into the marrow space of mice femora. As the tumor cells proliferate, mice display reproducible behaviors associated with pain, such as flinching or guarding the affected limb, that increase as bone destruction progresses. The model also enables measurement of other endpoints, including tumor growth and migration, and monitoring of relevant cell types such as osteoclasts, macrophages, and neurons. Mouse studies have provided important information on the mechanisms behind metastatic bone pain and the specific effects of potential therapies. These studies have demonstrated that metastatic bone disease is caused by multiple factors and that osteoclasts are particularly important in pain generation through destruction of bone and nerve fibers and acidotic stimulation of pH-sensitive receptors. Clinical studies with bisphosphonates demonstrate that these agents provide relief of metastatic bone pain, and preliminary experiments using the mouse model suggest that this may occur via multiple mechanisms. Further studies are under way.