Serial Markers of Bone Turnover in Men with Metastatic Prostate Cancer Treated with Zoledronic Acid for Detection of Bone Metastases Progression

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1 european urology 52 (2007) available at journal homepage: Prostate Cancer Serial Markers of Bone Turnover in Men with Metastatic Prostate Cancer Treated with Zoledronic Acid for Detection of Bone Metastases Progression Michael Lein a, *, Manfred Wirth b, Kurt Miller c, Hans-Udo Eickenberg d, Lothar Weißbach e, Katja Schmidt f, Ulrike Haus f, Carsten Stephan a, Sven Meissner a, Stefan A. Loening a, Klaus Jung a a Department of Urology, Charité Hospital Berlin Mitte, University Medicine Berlin, Berilin, Germany b Department of Urology, Hospital of Technical University Carl Gustav Carus, Dresden, Germany c Department of Urology, Charite Hospital Benjamin Franklin, University Medicine Berlin, Germany d Private Practice, Bielefeld, Germany e EuromedClinic Fürth, Fürth, Germany f Novartis Pharma GmbH BU Oncology, Nürnberg, Germany Article info Article history: Accepted February 9, 2007 Published online ahead of print on February 20, 2007 Keywords: Bisphosphonate treatment Bone markers Bone metastases Prostate cancer Abstract Objectives: This study assessed the usefulness of serial measurements of bone turnover markers in men with metastatic prostate cancer treated with zoledronic acid to detect disease progression. Methods: Serum measurements of total alkaline phosphatase (talp), bone-specific alkaline phosphatase (balp), cross-linked N-terminal (NTx) and cross-linked C-terminal (CTx) telopeptides of type I collagen, amino-terminal procollagen propeptides of type I collagen (PINP), C-terminal telopeptides of type I collagen (ICTP), and prostate-specific antigen (PSA) were performed in 77 prostate cancer patients suffering from bone metastases and treated with zoledronic acid up to 15 mo. Fifty patients were with and 27 patients without objective evidence of metastatic bone progression during the administration of zoledronic acid. Results: The baseline bone marker concentrations were not significantly different between the groups. After administration of zoledronic acid all bone markers except of ICTP decreased compared with baseline. CTx showed the greatest decrease. In patients with metastatic bone progression PINP, talp, balp, and ICTP were significantly higher at weeks 24, 36, 48, and 60 after starting treatment with zoledronic acid compared with patients without progression. In addition to the information of prostate-specific antigen as a monitoring parameter, the bone formation marker showed a better distinction between patients with and without disease progression. Conclusions: Selected bone turnover markers provide valuable information regarding progression of bone metastasis in men with metastatic prostate cancer under bisphosphonate therapy. The clinical impact should be confirmed in prospective randomised studies. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, CCM, Charité University Hospital, Charitéplatz 1, Berlin, Germany. Tel ; Fax: address: michael.lein@charite.de (M. Lein) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 1382 european urology 52 (2007) Introduction Prostate cancer is the most frequent malignancy in men. Bone metastases play a crucial role in this cancer entity and are an important cause of morbidity and disability. Since the introduction of the determination of prostate-specific antigen (PSA), earlier diagnosis of prostate cancer resulting in a shift to local or regional prostate cancer has been observed [1]. Despite this favourable situation 65 75% of men with advanced disease suffer from bone metastases [2]. Therefore, a sensitive and specific identification of bone metastases is crucial for deciding whether a local or systemic therapy is indicated in each individual with prostate cancer. Hormonal treatment is the standard therapy for advanced prostate cancer, whereas in hormonerefractory patients chemotherapy is the treatment of choice. Bisphosphonates (eg, zoledronic acid) have been shown to reduce and possibly obviate skeletal complications caused by bone metastases [3 5]. Once bone metastasis have been diagnosed, follow-up and management of men with bone metastases lesions require quantification during specific therapy. To detect and monitor metastatic bone involvement, bone scintigraphy is widely applied standard method. X-ray, magnetic resonance imaging (MRI), and computed tomography (CT) are used to improve diagnostic accuracy in some cases. However, despite these improvements, the follow-up of bone metastases under therapy is insufficient because in patients in later stages the prognostic significance of PSA declines. Serum bone markers have been suggested to improve quantification of such lesions [6]. However, results and recommendations regarding the diagnostic impact of specific bone markers after treatment of patients with metastatic prostate cancer are limited [3]. Bone turnover markers have been recommended to predict patients at risk for progression of bone lesions and subsequent skeletal complications [3,5]. Identification of clinically useful biomarkers could add to earlier diagnosis of bone metastasis and influence the treatment regimes [3,5]. The aims of this study were to (1) measure different bone turnover markers before and during the application of zoledronic acid in men with bone metastases, (2) characterise the behaviour of such markers in patients with and without bone progression during zoledronic acid treatment, and (3) assess the usefulness of the markers as tools to monitor disease progression. For that purpose, we studied the bone formation markers total alkaline phosphatase (talp), bone-specific alkaline phosphatase (balp), and amino-terminal procollagen propeptides of type I collagen (PINP) as well as the bone resorption markers cross-linked N-terminal (NTx) and cross-linked C-terminal (CTx) telopeptides of type I collagen and C-terminal telopeptides of type I collagen (ICTP). 2. Materials and methods 2.1. Patients Between December 2002 and December 2005, 77 men with prostate cancer with bone metastases treated with zoledronic acid (Zometa 1, Novartis Pharma, Nürnberg, Germany) were evaluated for the present study. All those patients and corresponding data were taken from the study: Effect and tolerability of intravenous Zometa (zoledronic acid) 4 mg in bisphosphonate naïve prostate cancer patients with bone metastasis. A prospective, open label, single-arm clinical study. Protocol No. CZOL446E DE07. The purpose of this study was to determine if therapy with zoledronic acid would be an effective treatment to decrease the complications associated with metastatic bone disease in men with prostate cancer. The patient population consisted of 308 prostate cancer patients with metastatic bone disease in 36 German study centres. Objective evidence of metastatic bone lesions was detected by bone scan and confirmed by additional radiographic investigations (CT, MRI, X-ray). Zoledronic acid was administered as a 15-min infusion every 4 wk for a 15-mo treatment period. During the administration of study medication standard antineoplastic therapies including androgen suppression and marketed cytotoxic chemotherapy agents, radiation therapy to treat nonskeletal and skeletal tumour sites, and corticosteroids were additionally allowed. Of the 308 men enrolled in the Zometa study (CZOL446E DE07), 77 patients were selected because all essential information regarding the follow-up of metastatic bone lesions was available (further details see Results). All patients received a baseline bone scan before the treatment with zoledronic acid was started. The patients received zoledronic acid every 4 wk for up to a 15-mo treatment period or up to the evidence of bone progression. The local or systemic bone progression was documented and proved by bone scan, MRI, or X-ray. Clinical symptoms (eg, bone pain) were the reasons to search for bone progression during or at the end of treatment period by bone scan, MRI, or X-ray. Progression was defined as the occurrence of at least one new bone lesion or increase of >25% of the present lesions compared to baseline scans [7,8] Methods Blood sampling was performed before the start of the zoledronic acid treatment and at 12-wk intervals. Samples were collected in plastic tubes (Sarstedt, Nümbrecht, Germany) and centrifuged at 1600g for 15 min at 4 8C after allowing the blood to clot for 1 h at room temperature. Samples were

3 european urology 52 (2007) stored at 20 8C within 2 h after collection. As all samples were analysed at the Department of Urology, Charité, frozen samples were shipped on dry ice to Berlin and stored until analysed. After thawing, samples were processed within 4 h. We selected as bone turnover markers talp, balp, PINP, NTx, CTx, and ICTP. talp was measured with the standard enzyme assay on the Hitachi 717 analyser (Roche Diagnostics, Mannheim, Germany) and balp was determined by the Metra BAP EIA kit (Quidel, San Diego, CA). NTx was determined by the enzyme-linked immunosorbent assay (ELISA) Osteomark NTX Assay (Ostex Int, Seattle, WA). CTx (b-crosslaps), PINP (total PINP Assay), and PSA were measured on Elecsys 2010 analyser (Roche, Mannheim, Germany). ICTP was quantified by the Orion ELISA (Orion Diagnostica, Espoo, Finland) Statistical calculations Statistical analysis was performed with SPSS 13 for Window (SPSS Software, München, Germany). The tests used (t test according to Student, x 2 ) are given in the text. The program MedCalc version (MedCalc Software, Mariakerke, Belgium) was used for receiver-operating characteristic (ROC) analyses. Significance was defined as p < Results Seventy-seven patients were included in this study and were divided into men with proven metastatic bone progression and without metastatic bone progression during the course of the study. Fifty patients had disease progression, whereas the diagnosis no progression for 27 patients without clinical symptoms was confirmed by bone scanning at the final visit of this study at week 60. Baseline characteristics are given in Table 1. Patients in the progression group had higher baseline PSA values than patients without disease progression (Table 1). However, the percentage of patients with multiple bone lesions on bone scan (>6) was equal in both groups (76% vs. 74%; p = 0.926) before study entry. Seventy-one (25 without, 46 with progression; p = ) of these 77 patients were treated with hormone-therapy before study entry. Mean treatment duration of androgen deprivation before the beginning of the zoledronic acid treatment was comparable between the two groups (24.3 vs mo). Ten patients treated with hormone therapy were hormone naive before study entry. Thirty patients continued hormone therapy during the study with nonsignificant differences between patients with and without progression (38% vs. 41%; p = ). Fourteen (11 in the progress, 3 in the no-progress group; p = ) of 77 patients had prior chemotherapy before entering the study, whereas 25 patients (21 in the progress, 4 in the no-progress group; p = ) underwent chemotherapy during the study. It is noteworthy that the rise in bone markers in the progression group was mainly before treatment with chemotherapy started because the progression was the reason for starting chemotherapy. At study entry, 30 patients (39%) received analgesics for bone pain (patients without progression: 41%; patients with progression: 38%; p = 0.989). At the final visit, more patients in the progression group (n = 35; 70%) used analgesics than in the group without progression (n = 15; 44%; p = ). In Table 1 the baseline values of all measured bone turnover markers before administration of zoledronic acid are presented. Although there were no significant differences between the two groups studied, the trend to higher bone markers in patients with metastatic bone progression seems to be obvious. In further statistical analyses, the concentrations of each bone marker at baseline were set for each patient as 100%. The time courses of all six bone Table 1 Baseline characteristics of the study groups Variable Patients with progression (n = 50) Patients without progression (n = 27) p Age, yr 66.7 ( ) 70.6 ( ) PSA, mg/l 30.9 ( ) 8.5 ( ) talp, U/l 118 ( ) 92.1 ( ) balp, ng/l 46.2 ( ) 34.4 ( ) PINP, mg/l 108 ( ) 70.6 ( ) NTx, nmol/l 27.9 ( ) 22.6 ( ) CTx, ng/l 323 ( ) 227 ( ) ICTP, mg/l 5.64 ( ) 4.32 ( ) Values are given as mean and 95% confidence interval for age and geometric mean and 95% confidence interval for the analytes. Significances were tested by the t test according to Student. PSA = prostate-specific antigen; talp = total alkaline phosphatase; balp = bone-specific alkaline phosphatase; PINP = amino-terminal procollagen propeptides of type I collagen; NTx = cross-linked N-terminal telopeptides of type I collagen; CTx = cross-linked C-terminal telopeptides of type I collagen; ICTP = C-terminal telopeptides of type I collagen.

4 1384 european urology 52 (2007) of bone markers but also of PSA. Taking into account the decline of the markers after the zoledronic acid application and using that value as a baseline value (in our study the value at week 12 after the beginning of the treatment), the increased value compared with the baseline value was a significant indicator of progression. For example, comparing the data between week 12 and 24, patients with progression showed a significantly higher proportion with increased values compared with the baselines for all markers except for CTx than the patients without progression (x 2 test, p = ) who showed rather a further decline of marker values. ROC analyses resulted in areas under the curves of for PINP, for talp, for balp, for NTx, for PSA, for ICTP to for CTx. Thus, bone formation markers generally showed a better discrimination ability than bone resorption markers. Similar results were obtained at the subsequent time intervals. Therefore, after application of zoledronic acid increased bone marker concentrations above the baseline can be considered a serious sign of progression. Fig. 1 Changes in mean concentrations of all bone markers and prostate-specific antigen. Zoledronic acid was administered every 4 wk for a 15-mo treatment period. Blood serum for bone markers was collected prior to start of zoledronic acid treatment (week 0) and every 12 wk. The percent of changes related to pretreatment values as shown in Table 1 is presented. (A) Patients without bone progression (n = 27). (B) Patients with metastatic bone progression (n = 50). markers and PSA in both groups with and without bone progression are given as surveys (Fig. 1A and B). Five of the 6 bone markers (talp, balp, PINP, NTx, CTx) decreased after beginning treatment with zoledronic acid. This observation was noted in both groups studied and showed the treatment effect of zoledronic acid. Detailed data and significances of the bone markers are demonstrated in Fig. 2 for both groups. The most important result of the study was, in addition to the PSA changes, the significant difference of marker concentrations between patients with and without bone progression during the time course. At weeks 24, 36, 48, and 60 after the beginning of administration of zoledronic acid prostate cancer patients with evidence of metastatic bone progression showed significantly higher levels 4. Discussion The vast majority of patients with advanced prostate cancer have skeletal metastases. Skeletal complications due to metastatic disease include bone pain, spinal cord compression, and pathologic fractures. Overall, bisphosphonates reduce the frequency of skeletal events [9]. Zoledronic acid is one of the most potent bisphosphonates with proven efficacy in reduction of skeletal complications in patients with prostate cancer [3,5]. An essential problem remains the bone-specific control of therapy efficacy by bisphosphonates. Bone scintigraphy is considered to be the gold standard for monitoring metastatic bone lesions. However, because scintigraphy is expensive and also lacks specificity, measurements of bone turnover markers have become more common in recent trials and in clinical practice in patients with bone metastases as adjunctive tools to facilitate monitoring in the follow-up of patients and to reduce both the expenses of bone scans and the exposure of patients to radiation [10 12]. These potential markers provide specific insight into rates of bone resorption and formation. Bone metastases typically increase both bone resorption and formation rates, and these increases can be evaluated through measurements of biochemical markers of bone metabolism in serum and urine [13]. It has been described that various biochemical markers of bone

5 european urology 52 (2007) Fig. 2 Means and 1/5 of standard deviation of bone markers and prostate-specific antigen in patient groups with (-&-) and without (-*-) progression during the entire time course. Y-axes = related to pretreatment values (%). *Significant differences of at least p < 0.05 between both groups studied, t test according to Student. turnover showed significant differences between prostate cancer patients with and without metastases [14 16]. The levels of markers seem to correlate with the severity of bone pain and tumour burden in the skeleton. Moreover, decrease in marker correlate with response to systematic anticancer treatment [12,14]. The current study should give an answer to two essential questions, the behaviour of various bone turnover markers under treatment with zoledronic acid and the diagnostic usefulness of these markers to detect patients with disease progression. Our results clearly showed that the markers did not behave similarly with regard to these two aspects.

6 1386 european urology 52 (2007) Concerning the effect of treatment with zoledronic acid, our data confirmed the well-known response effect of bone turnover markers to bisphosphonate treatment. It is of interest that CTx as a resorption marker showed the highest decrease after zoledronic acid application, but also the other bone markers decreased except for ICTP that was widely unaffected by zoledronic acid treatment. The analysis of markers with respect to discrimination between patients with and without progression showed a more complex situation. The formation markers PINP, talp, and balp had the better discriminatory power between patients with and without bone progression during zoledronic acid treatment than the resorption markers. The usefulness of the three bone formation markers as diagnostic markers corresponds to the results when we compared various bone formation and resorption markers to use them in the diagnosis of bone metastases in prostate cancer patients [17]. Recently, serum balp and urine NTx were measured in a large multicentre study of hormonerefractory metastatic prostate cancer [18]. High serum balp but not NTx values were significantly associated with shorter overall survival. Another study of patients with metastatic prostate cancer and other cancer entities receiving bisphosphonates proved that patients with high urine NTx levels had an increased risk of progression of bone lesions and subsequently of skeletal complications [19]. Other studies also reported that NTx values correlated with the extent of bone metastases and bone scintigraphy [20,21]. These results of NTx and data of former studies are encouraging [10,14]. However, our present results and also data of the previous study [17] dealing with the comparison of 10 various bone markers proved a rather worse diagnostic validity of the resorption marker NTx in serum in comparison with bone formation markers. It should be taken into account that different bone metastases (lytic, blastic) were investigated in the other studies mentioned and the number of patients with the various tumour entities was limited. More studies, including simultaneous determination in urine and serum, are necessary to evaluate the diagnostic validity of NTx for metastatic bone diseases. We measured bone markers exclusively in serum to avoid interfering variability due to the instability of bone markers in urine [22,23]. In addition, in elderly patients blood sampling is always more reliable and more practicable than urine sampling [24]. Regarding CTx as another bone resorption marker, contradictory data have been reported [15,25]. In a recent work by Santini et al [26] a single infusion of zoledronic acid (n = 24) was able to induce a decrease of b-ctx plasma levels of cancer patients suffering from bone metastases. However, the diagnostic impact to detect patients with disease progression was limited as shown in our study. On the other hand, Piedra et al [25] found that CTx showed the best sensitivity and specificity with respect to the detection of bone metastases. Recently, Brasso et al [27] analysed CTx in addition to serum PINP and balp in 153 patients with metastatic prostate cancer. The markers were increased in patients compared to healthy controls. Interestingly, analysis showed an association with survival. Some limitations of this study should be mentioned. Among others, first, this study was a singlearm study with a limited number of patients so that a reliable multivariate analysis of data to make a clear decision on the best parameter or parameter combination could not be performed. Second, measurements of bone markers were performed only after every three zoledronic acid applications without consistent bone scanning at the same intervals. Despite these limitations we obtained valuable information regarding behaviour of bone markers in patients with prostate cancer and bone lesions during zoledronic acid treatment. The present study is, to our knowledge, the only report with the maximum number of bone turnover markers in bone metastatic prostate cancer patients treated with zoledronic acid. It is obvious that PSA monitoring remains an essential part in the follow-up of patients with bone metastases to control progression. However, the described results add weight to the argument that bone markers should be measured as an adjunctive tool to PSA as routine parameters in the treatment of prostate cancer patients with bone metastases before bone scanning is performed. Bone formation markers seem to be more indicative than resorption markers for diagnostic as well as prognostic information [18]. It is unlikely that a single bone marker has sufficient diagnostic value in prostate cancer patients with bone metastases. The combination of several bone markers with imaging techniques is likely to enhance the clinical assessment and could be helpful to individualise therapy such as chemotherapy and bisphosphonate therapy. However, as discussed in recent reviews, recommendations adhering to the principles of evidence-based medicine could not be given at present [3,4]. 5. Conclusion Serum bone markers are helpful tools to differentiate between patients with and without metastatic

7 european urology 52 (2007) bone progression receiving bisphosphonate treatment. Bone formation markers seem to be more indicative. Conflicts of interest This study was supported by Novartis Pharma GmbH, BU Oncology, Nürnberg, Germany. Authors have no commercial relationship to Novartis Pharma GmbH BU Oncology, Nürnberg, Germany. References [1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2006;56: [2] Coleman RE. Skeletal complications of malignancy. Cancer 1997;80: [3] Clarke NW. Management of the spectrum of hormone refractory prostate cancer. Eur Urol 2006;50: [4] Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96: [5] Saad F, Clarke N, Colombel M. Natural history and treatment of bone complications in prostate cancer. Eur Urol 2006;49: [6] Lipton A, Demers L, Curley E, et al. 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