Biochemical approach to the detection and monitoring of metastatic bone disease: What do we know and what questions need answers?

Metastatic spread to bones frequently occurs in several types of cancer diseases, in particular breast, prostate, and lung cancer. Infiltration of bone by tumour cells is a source of several complications including severe bone pain, spinal cord compression, hypercalcemia, pathologic fractures, all reducing quality of life and worsening prognosis. Therefore, early recognition of bone metastases is among the highest priorities in the clinical management of cancer disease. Currently, detection and staging relies on radiological imaging techniques (scintigraphy, radiography, computer tomography, etc.). Due to their limited sensitivity and/or inconveniences, irradiation, and considerable costs related to serial use, they are not suited for close monitoring of cancer patients to capture skeletal spread in an early stage or to follow-up on therapeutical responses. Interaction of tumour cells with surrounding bone cells leads to enhanced bone resorption and/or bone formation. These cellular processes result in the release of numerous epitopes that, if detected by immunoassays, can reflect the changes of the rate of bone turnover and the occurrence of metastatic spread to bone. Numerous studies reported elevated levels of bone turnover markers in patients with bone metastases proportionally to the extent of skeletal involvement. Furthermore, preliminary data suggest that biomarkers can predict skeletal-related events (SREs), disease progression, and even cancer-related death. The present review intends to summarize the list of emerged biomarkers, major studies assessing their relative utility for detection of bone metastases in different types of cancer disease, and discuss their potentials for becoming part of screening protocols for improving our success rate in the early detection of metastatic bone disease.