Bone Turnover Markers and Prostate Cancer: Not Just a Measure of Bone Disease?

Abstract

Recent decades have seen improvements in survival for men with localized prostate cancer (PCa). However, in comparison, gains in overall survival have been more modest in men with metastatic castrate-resistant PCa (CRPC). The introduction of new therapies to treat castrate-resistant disease is exciting; however, our understanding of how best to use these agents is limited [1]. This argues for a need to improve our knowledge of how PCas metastasize to and grow in bone so thatwe can optimize the use of existing therapies and develop new approaches for effective treatment of disseminated disease. The skeleton remains one of themost the important sites for PCa spread: more than two-thirds of patients with advanced disease develop bone metastasis. Once present in the skeleton, PCa cells hijack the normal process of bone remodeling and promote the development of bone lesions. In PCa these lesions are typically osteosclerotic and result from increased activity of osteoblasts and uncontrolled formation of new bone. Despite the osteosclerotic nature of this bone disease, osteoclastic bone resorption is also increased inmenwith PCa andmay be higher than that seen for other tumors that grow in bone that are traditionally considered to be osteolytic, such as multiple myeloma and breast cancer bone metastasis. In this issue of European Urology, Fizazi et al [2] report on the prognostic value of bone-related parameters in men with CRPC. They showed that bone-related parameters, including biochemical markers of bone turnover such as urinary N-telopeptide (a marker of osteoclastic bone resorption) and bone-specific alkaline phosphatase (a marker of bone formation) are strong prognostic factors for overall survival. This is consistent with other studies of biochemical markers in men with castrate-resistant disease [3,4]. The strength of the relationship between bone resorption and formation markers and survival highlights the close relationships between PCa cells and bone cells. While these markers may simply reflect the skeletal complications of metastatic CRPC, it is possible that they also reflect tumor burden and/or the processes involved in tumor cell activation in bone. Emerging data certainly suggest that the relationship between bone cells and metastastic PCa cells is more complex than the tumor cells simply hijacking bone cells to cause bone disease. The notion that there is interdependence betweenmetastatic cells and bone cells stems largely from mouse models of breast cancer metastasis, in which breast cancer cells produce growth factors that stimulate expression of the critical osteoclastogenic factor RANKL (receptor activator of nuclear factor kB ligand) in bone to promote bone resorption. In turn, osteoclasts release growth factors, which further promote cancer cell growth. A similar interdependence may occur in PCa bone metastasis. However, this concept does not necessarily reflect the temporal development of bone metastasis, and bone cells may play different roles at different times during the evolution of PCa bone metastasis. In support of this, Shiozawa et al [5] demonstrated that disseminated PCa cells compete for the hemopoetic stem cell (HSC) niche, which contains osteoblasts, to establish themselves in the skeleton. Furthermore, it has recently been shown that dormant or slow-cycling PCa cells localize to bone surfaces and presumably to the osteoblast niche, E U RO P E AN URO LOGY 6 8 ( 2 0 1 5 ) 5 1 – 5 2