Survival Markers Related to Bone Metastases in Prostate Cancer

Prognostic value of a bone resorption marker, tartrate-resistant acid phosphatase isoform 5b (TRACP 5b), and two matrix metalloproteinases (MMP-2 and MMP-9) was compared with the standard clinical analyses of total alkaline phosphatase (tALP) and prostate-specific antigen (PSA), in prostate cancer (PC) patients with (BM+) or without (BM-) bone metastases. Diagnostic accuracy evaluation showed the highest area under the curve for tALP (AUC=0.98), followed by PSA (AUC=0.87), TRACP 5b (AUC=0.82), MMP-9 (AUC=0.62) and MMP-2 (AUC=0.53). Significantly shorter survival was observed for patients with tALP (p<0.001), TRACP 5b (p=0.002) and PSA (p<0.001) levels, above the determined cut-off values compared with lower marker levels. In multivariate Cox regression analysis, only tALP and PSA, in addition to Gleason score were independent prognostic factors for survival. Of the three novel markers tested, only TRACP 5b proved to be predictive of survival in PC with bone metastases. MMP-2 and -9 are thus not recommended for further studies in this context. Bone metastases occur in the majority of patients with advanced prostate cancer (PC) (1), and cause severe pain to the patients, as well as significant resource requirements and costs to the care providers. The median survival after the diagnosis of bone metastases in PC ranges from 12 to 53 months (2). As effective treatment for cancer-related skeletal changes is available (2), it is important to evaluate bone metastases markers, which could be useful for early intervention to prevent the development of serious skeletal alterations. The interaction between cancer and bone is mediated largely by the osteoclasts, irrespective of the underlying tumour type (3). Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) is synthesized and secreted by osteoclasts into the circulation in the course of bone resorption. Circulating TRACP 5b is produced by osteoclasts, and thus constitutes an excellent marker of bone resorption (4) and an interesting target of study for clinical applications in PC, where skeletal metastases are common. Compared to other markers of bone metabolism generally used, TRACP 5b has several advantages, amongst them, very low diurnal variation and high specificity to bone. Serum levels of TRACP 5b are not affected by fasting, renal or hepatic failure, or long storage, when kept under -70AEC (5,6). Matrix metalloproteinases (MMPs) are zinc-dependent neutral endopeptidases, characterized by their ability to degrade extracellular matrix (ECM) components. The MMP family consists of 23 members, which can be divided into eight structural classes or, on the basis of their substrate specificity and primary structure, into the more familiar subgroups of collagenases, gelatinases, stromelysins, MT- MMPs and novel MMPs (7). Gelatinases, i.e. gelatinase A (MMP-2) and gelatinase B (MMP-9) can degrade denaturated collagens. MMP-2 is expressed by various types of cells in culture and in vivo (7). MMP-9 is produced by epithelial cells, such as migrating keratinocytes, and it is also involved in angiogenesis. Increased expression levels of various MMPs have been associated with poorer prognosis in patients with several malignant tumours, including PC (8), but their possible prognostic role in PC calls for further characterization.The aim of this cross-sectional study was to evaluate whether serum TRACP 5b, MMP-2 or MMP-9 levels might be useful or not, as markers of bone metastases and survival prognosticators, when compared with the routinely used tALP and PSA levels in prostate cancer.