Breakdown products of type I collagen by osteolysis as cross-linked collagen peptides (the amino (N)- and carboxy (C)-terminal cross-linked telopeptide of type I collagen, NTX and CTX, respectively), and the terminal peptides that are cleaved from procollagen before its integration into new bone matrix (e.g. procollagen type I N-terminal and C-terminal peptides, or P1NP and P1CP), can provide meaningful insights into the ongoing effects of tumour growth on bone turnover (Fig. 2.2). Bone-specific alkaline phosphatase (bone ALP) concentrations in serum reflect the ongoing rate of osteogenesis [2]. The International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine recommend that a marker of bone formation (serum procollagen type I N propeptide) and a marker of bone resorption (serum C-terminal telopeptide of type I collagen) be used as reference analytes for bone turnover markers in clinical studies [2] (Fig. 2.3). Nowadays, a number of bone markers can be determined using enzyme immunological procedures (enzyme-linked immunosorbant assay) by means of a commercial kit that can be easily adapted to laboratory automated machines to achieve greater analytical reliability during determination compared with manual methods [3]. Although a great deal of the data in the literature are obtained on markers analysed from urine samples (i.e. NTX), analysis of makers of bone turnover on serum and plasma are recommended because of lower inter- and intraindividual variability [2]. Standardised assays are available for many bone turnover markers and normal or reference ranges for several markers have been established. As the normal range changes with age and sex, selection of appropriate reference values is critical for data interpretation [2, 4]. In systemic metabolic bone diseases, such as osteoporosis, primary hyperparathyroidism and osteomalacia, biochemical markers reflect ongoing rates of bone resorption and formation in the body as a whole. Therefore, bone marker assessments in “focal” diseases, such as Paget disease or BMT, do not provide information specific to individual lesion sites. Moreover, changes in bone marker levels are tissue specific (bone) and not disease specific and are associated with an imbalance in skeletal metabolism independently of the underlying cause [1, 5]. In cancer patients, bone turnover markers may be very high for many concomitant causes, such as age, vitamin D deficiency, adjuvant hormone therapy and BMT, but it is impossible to distinguish the contributions of the different components that elevate the marker levels in the serum and urine (Figs. 2.1 and 2.3). For example, NTX levels were similar in PC patients on androgen deprivation therapy with and without BMT. Furthermore differences between bone resorption markers and bone formation markers were not found in patients with BMT from different cancers [6, 7]. In an attempt to differentiate the source of the marker (BMT vs non-metastatic skeletal), the non-isomerised form of CTX and type I collagen breakdown products generated by matrix metalloprotease (ICTP), apparently more specific for BMT breakdown, have been evaluated (Fig. 2.2) [8].

The clinical utility of bone markers as diagnostic indicators of bone metastatic disease and as prognostic indicators has been extensively examined. Several studies have revealed an association between bone turnover marker and the presence or progression of skeletal metastases from prostate cancer (PC) [9, 11, 12]. In these studies the formation marker and resorption markers are elevated in the case of typical osteoblastic osseous metastasis expressing a disrupted balance between bone formation and resorption. P1NP, bone sialoprotein (BSP), and osteoprotegerin (OPG) showed more significant differences between PC patients with and without BMT. BSP is not a typical bone marker and works as a general tumour marker [13]. In addition to being elevated in PC patients with BMT, OPG correlates with the extent of osseous metastasis. Furthermore, in association with RANKL, it may predict recurrence after radical prostatectomy [14–16]. P1NP as bone ALP correlates with the extent of osseous changes (bone scan index). Bone ALP had the highest diagnosis accuracy (72 % sensitivity, 88 % specificity) and P1NP the greatest diagnostic specificity (92 %) [11]. Recently, the elevated alkaline velocity was found to be an independent predictor of OS and BMT-free survival in patients with CRPC [17]. On the other hand, recent data do not confirm the diagnostic performance of P1NP. Current consensus is that the diagnostic sensitivity and/or specificity of bone markers for the presence of BMT or the prognostic role of bone lesion progression are not sufficient to utilise the results to diagnose BMT [18]. The mean values of the areas under the ROC curve from several studies were 0.81, 0.80 and 0.77 for P1NP, bone ALP and ICTP suggesting that these markers might have diagnostic values in interaction with safely defined reference thresholds or during their course [5, 10, 19]. Data on the use of bone markers as predictors for SRE and survival are quite encouraging [18, 20]. Retrospective analyses of data from phase III trials of zoledronic acid in patients with CRPC and BMT showed that both baseline and on-study elevation in bone marker levels, specifically NTX, were associated with increased risks of SRE, disease progression and death [18, 21–23]. A high baseline level of urinary NTX (above 180 nmol/mmol creatinine) was associated with a more than 2.5-fold increase in the risk of death (RR 2.58, 95 % CI 1.92–3.47) compared with low baseline levels of NTX (<55 nmol/mmol creatinine) [18, 22]. Also, baseline bone ALP was associated with a 4 % increase in the risk of death and SRE per 200 IU/L increase. Elevated bone ALP levels at baseline were associated with a shorter time to the first on-study SRE and a shorter time to the first pathological fracture. The cumulative incidence of SRE over a 1-year period was nearly doubled (50.7 % vs 26.5 %) among patients with elevated versus normal baseline bone ALP [23]. Adequate suppression of NTX and bone ALP levels during treatment (zoledronic acid plus docetaxel vs docetaxel alone) was associated with longer survival time, and similar results have been confirmed by others [23, 24]. Recently, bone ALP velocity (>6.3 IU/L/year) was found to be an independent predictor of overall survival in CRPC. A fivefold increase in death was observed among CRPC patients with rapid bone ALP velocity (OR 5.11, 95 % CI 2.24–11.67) [17]. Other more recent bone markers have been found to be associated with prognosis in PC patients. P1NP and ICTP were associated with survival after 15 months of zoledronic acid therapy [25]. Baseline and 3 months after, zoledronic acid P1NP and CTX predict survival and (only P1NP) risk of SRE [26]. The association of CTX or NTX with P1NP confirmed the prognostic role of these bone markers [27].

The data summarised above suggest that bone turnover markers might be useful to optimise the use of bone-targeted therapy for metastatic bone disease. Promoting lifelong therapy contradictory with the paucity of data regarding the usefulness and the safety (osteonecrosis of jaw and atypical hip fractures) of treatment durations with bone-modifying agents beyond 2—3 years. The serial measurement of BTMs could be a strategy in tailoring the therapy regimen and could help the decision on the optimal duration of antiresorptive therapy, which could allow treatment frequency to be reduced and even theoretically removed for periods in the context of optimal bone metabolism control [28]. In summary, at present, the potential for the clinical use of markers of bone turnover for diagnosis, prognosis and monitoring therapy in cancer patients with BMT remains unfulfilled and the routine use of these markers cannot yet be recommended. As stated in consensus publications, there is a need for harmonisation, standardisation and common reference ranges [18, 29, 30] although a recent position paper solicited their introduction into a clinical setting [28].