Boomsma, JHB

Elferink, RO

Groenier, K

Mensink, HJA

Wymenga, LFA

English

Objective To assess the predictive role of the bone markers alkaline phosphatase (ALP) and urinary deoxypyridinoline (DPD), as indicators of bone turnover, at baseline in patients with prostate cancer.Patients, subjects and methods Urinary DPD, serum ALP and prostate-specific antigen (PSA) were evaluated in 23 patients with benign prostatic hyperplasia (BPH), 115 with prostatic carcinoma, of whom 21 had bone metastasis, and in 16 age-matched control subjects.Results Patients with newly diagnosed prostate cancer and bone metastasis had a higher urinary excretion of DPD, and a higher serum PSA and ALP than had patients with BPH and those with prostate cancer but no metastasis. Receiver operating curve analysis for PSA, ALP and DPD showed a significant discriminating ability for positive and negative bone scans (P=0.0684). However, from logistic regression of the combinations, only serum ALP was a significant independent predictor of bone metastasis in patients with prostate cancer.Conclusion Serum ALP or urinary DPD are the best predictors of bone metastasis in patients with prostate cancer; further studies with more patients are required.</p

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   University of GroningenPretreatment levels of urinary deoxypyridinoline as a potential marker in patients with prostatecancer with or without bone metastasisWymenga, LFA; Groenier, K; Boomsma, JHB; Elferink, RO; Mensink, HJAPublished in:BJU InternationalIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2001Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Wymenga, LFA., Groenier, K., Boomsma, JHB., Elferink, RO., & Mensink, HJA. (2001). Pretreatment levelsof urinary deoxypyridinoline as a potential marker in patients with prostate cancer with or without bonemetastasis. BJU International, 88(3), 231-235.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Pretreatment levels of urinary deoxypyridinoline asa potential marker in patients with prostate cancerwith or without bone metastasisL.F.A. WYMENGA, K. GROENIER*, J . SCHUURMAN², J .H.B. BOOMSMA³, R. OUDE ELFERINK" andH.J .A. MENSINK§Departments of Urology, ²Nuclear Medicine, ³Radiology and "Clinical Chemistry, Martini Hospital, and the Departments of*General Practice and §Urology, University Hospital, Groningen, The NetherlandsObjective To assess the predictive role of the bonemarkers alkaline phosphatase (ALP) and urinarydeoxypyridinoline (DPD), as indicators of bone turn-over, at baseline in patients with prostate cancer.Patients, subjects and methods Urinary DPD, serum ALPand prostate-speci®c antigen (PSA) were evaluated in23 patients with benign prostatic hyperplasia (BPH),115 with prostatic carcinoma, of whom 21 had bonemetastasis, and in 16 age-matched control subjects.Results Patients with newly diagnosed prostate cancerand bone metastasis had a higher urinary excretion ofDPD, and a higher serum PSA and ALP than hadpatients with BPH and those with prostate cancer butno metastasis. Receiver operating curve analysis forPSA, ALP and DPD showed a signi®cant discriminat-ing ability for positive and negative bone scans(P=0.0684). However, from logistic regression ofthe combinations, only serum ALP was a signi®cantindependent predictor of bone metastasis in patientswith prostate cancer.Conclusion Serum ALP or urinary DPD are the bestpredictors of bone metastasis in patients with prostatecancer; further studies with more patients arerequired.Keywords prostate cancer, bone metastasis, serumprostate-speci®c antigen, alkaline phosphatase, urin-ary deoxypyridinolineIntroductionIn many Western countries prostate cancer is the secondmost common cause of cancer death in men, and theincidence is increasing [1,2]. At initial presentation 40%of patients with prostate cancer have bone metastases [3];these are predominantly osteoblastic. Bone is a dynamicstructure and constantly in a state of turnover, ametabolic process termed remodelling. This includesdegradation (bone resorption) mediated by the action ofosteoclasts, and building (bone formation), mediatedby the action of osteoblasts. Remodelling is requiredfor the maintenance and overall health of bone, and istightly coupled. In normal bone there is a constantbalance between bone formation and bone resorption.In abnormal situations of bone metabolism this processbecomes uncoupled and, when resorption exceedsformation, results in a net loss of bone.The introduction of new biochemical markers of bonemetabolism has revealed various aspects of benign andmalignant bone diseases. Of the organic matrix in bone,< 90% contains type 1 collagen, a triple helical protein[4]. Type 1 collagen of bone is cross-linked by speci®cmolecules that provide rigidity and strength. Crosslinksof mature type 1 collagen in bone are the pyridiniumcrosslinks, pyridinoline and deoxypyridinoline (DPD) [5].DPD is formed by the enzymatic action of lysyl oxidase onthe amino-acid lysine, is released into the circulationduring the bone resorption process and represents, to agreater or lesser extent, the activity of metastases. DPD isexcreted unmetabolized in urine; its uptake is unaffectedby diet [6], allowing a suitable assessment of resorption.Urinary DPD concentration has been used to estimatethe degree of bone resorption. In the present studywe investigated the utility of PSA, alkaline phosphatase(ALP) and urinary DPD as markers of bone metastasisin patients with prostate cancer.Patients, subjects and methodsThe study group comprised 138 men, referred to theurological outpatient clinic and who provided informedconsent. Exclusion criteria were; bone, endocrine orchronic disorders, the use of medication known toAccepted for publication 18 April 2001BJU International (2001), 88, 231±235# 2001 BJU International 231in¯uence bone metabolism (e.g. corticosteroids, GnRHanalogues, anticonvulsants, thyroid medications orheparins). Patients in the study group had BPH orprostate cancer, the latter being clinically con®ned to theprostate (T1±2) or locally advanced (T3±4) or with bonemetastases.Patients with prostate cancer underwent bone scinti-graphy to diagnose or exclude bone metastasis; 3±4 hafter an intravenous injection with 700 MBq 99mTc-methylene diphosphonate, anterior and posteriorwhole-body images were obtained. Detailed imageswere acquired when considered necessary. Accordingto the bone-scan results, the patients were divided intothose with or with no bone metastases.The control group of men, in which only DPD andcreatinine were measured in the urine, comprised 16presumably healthy young men aged 20±50 years. Asthese men were not part of a screening programme, noDRE or other laboratory results were known.The level of serum PSA and ALP was determined in allpatients. Blood samples were collected using a standardvenipuncture technique and serum separated aftercentrifuging blood at 4uC and 1500 g for 10 min;samples were then stored at x20uC until analysis.Urine samples for the determination of DPD crosslinkswere obtained from the ®rst or second morning void,collected on the day of the bone scan. In the controlgroup the urine samples were collected within 2 weeks oftheir outpatient department visit. The urine specimenswere immediately frozen at x20uC. The concentration ofDPD was expressed relative to the concentration ofurinary creatinine (mmol/mol creatinine) to control fordifferences in body mass and urine dilution.Serum ALP was analysed according to the manufac-turer's instructions on a Synchron LX 20 autoanalyserand reagents (Beckman Coulter Instruments Inc.,Fullerton, CA, USA); the reference value for normalsubjects is 40±130 U/L.PSA in serum was determined using a chemilumines-cent assay on an Immulite 2000 automatic immunoas-say system, according to the manufacturer's instructions(DPC, Breda, The Netherlands); the threshold value usedwas 4 mg/L.The urinary concentration of free deoxypyridinolinewas determined using a chemiluminescent enzymeimmunoassay according to the manufacturer's instruc-tion (Immulite Pyrilinks-D, a solid-phase, chemilumines-cent enzyme immunoassay for use with the Immulite IAutomated Analyser, and designed for the quantitativemeasurement of DPD in urine; DPC). The normalreference range for urinary DPD (normalized to creati-nine level) was 2.3±5.4 nmol/mmol creatinine. Urinarycreatinine concentrations were determined using theJaffe rate method (Synchron LX 20).All analyte levels are presented as the median (range),with the signi®cance of differences between the controland the different groups of patients assessed using theMann±Whitney U-test, and P<0.05 considered toindicate statistical signi®cance. The relative effectivenessof the diagnostic tests was assessed by plotting the true-positive (sensitivity) vs false-positive (1-speci®city) ratioson a ROC curve. This analysis is particularly useful forcomparing two diagnostic tests when the threshold for apositive or negative test has not been clearly de®ned.Areas under the ROC curve were compared. To evaluatethe independent contribution of PSA, ALP and DPD inpredicting bone metastasis, correlation coef®cients werecalculated, and followed by logistic regression analysis.For this analysis all values were transformed onto alogarithmic scale and linear regression analysis used,with P<0.05 considered signi®cant.ResultsTwenty-three patients had clinically diagnosed BPH,later con®rmed pathologically from TURP material; 115patients had prostate cancer, histologically con®rmedafter biopsy and/or surgery (TURP, open prostatectomyor radical prostatectomy). The characteristics of thepatients are shown in Table 1. The patients with BPH hadnormal values of PSA and, as expected, those withprostate cancer had an elevated PSA level. The medianPSA level differed signi®cantly between patients with andwith no bone metastasis, although there was someoverlap in the PSA values between the groups.Table 1 also gives the values of ALP and DPD for thethree patient groups and the controls. The urinaryexcretion of DPD relative to creatinine and serum ALPwas signi®cantly greater in the 21 patients with bonemetastasis than in those with BPH or with no bonemetastasis (P<0.001). The urinary excretion of DPD wassimilar in the last two groups. Similarly patients withprostate cancer and bone metastasis had a signi®cantlyhigher level of PSA (P<0.001) and ALP (P<0.001) thanthose with no metastasis (Table 1).The relative effectiveness of PSA, ALP and DPD/creatinine in urine for discriminating between T3±4prostate cancer with and without bone metastasis isshown in the ROC curves (Fig. 1). The sensitivityappeared to be comparable, at 0.643 for PSA, 0.792for DPD/creatinine and 0.815 for ALP. The relationshipsamong PSA, ALP and DPD in patients with prostatecancer are shown in Fig. 2. Although all correlationcoef®cients were signi®cantly positive (P<0.005), thecorrelation between PSA and ALP was low (r=0.268,Fig. 2a), and between PSA and DPD only moderate(r=0.317, Fig. 2b). The strongest relationship wasbetween ALP and DPD (r=0.635, Fig. 2c). Logistic232 L.F.A. WYMENGA et al .# 2001 BJU International 88, 231±235regression showed that in combination, only ALP hada signi®cant independent contribution to predictingthe presence of bone metastasis, the odds ratios (95%CI) being 1.04 (0.685±1.593) for PSA, 5.88 (1.156±29.873) for ALP and 1.92 (0.460±8.019) for DPD/creatinine. Table 2 gives the sensitivity, speci®city,positive predictive value, false-positive and false-negativevalues for ALP, DPD and PSA at various thresholds forthe individual patients.DiscussionBone metastases are a major cause of morbidity inpatients with prostate cancer, causing subsequentsigni®cant clinical problems, including pain and patho-logical fractures. Therefore detecting bone metastasisis crucial for the staging, treatment and follow-up ofprostate cancer. Bone scintigraphy, used in the initialstaging and during the follow-up of prostate cancer, hasbeen the most sensitive but not the most speci®c methodto detect bone metastasis. `Hot spots' on a bone scan arenot always metastases, but can be associated with benign1–Specificity0.25 0.50 0.75 1.000.00Sensitivity0.250.500.751.000.00Fig. 1. ROC curves for PSA (red, solid), ALP (light red, dashed) andDPD (green, dotted) in patients with T3±4 prostatic carcinoma withand with no bone metastasis. Areas under the ROC curves suggestedthat sensitivity for all markers was comparable and not signi®cantlydifferent from each other.Table 1 Characteristics of the patient groups and the levels of the markersVariable BPHProstate cancerControlsT1±2 T3±4 Bone metastasisNo. of patients 23 46 48 21 16Median (range)Age, years 68 (48±87) 73 (52±80) 69 (36±89) 74 (48±91) ±PSA, mg/L 3.05 (0.2±11.5)* 17 (0.5±328)² 39.2 (0.1±1053) 81 (0.74±3063) ±ALP, U/L 75 (43±185) 73 (34±313) 68 (44±204) 152 (29±1190)³ ±DPD/creatinine, 6.2 (3.94±13.3) 6.0 (1.9±300) 6.3 (4.8±50.0) 14.09 (4.6±300)³ 4.42 (2.96±6.58)mmol/mmolP<0.001, *BPH vs prostate cancer with no metastasis; ²prostate cancer with no metastasis vs prostate cancer with metastasis (Mann±WhitneyU-test). ³Control group vs BPH vs prostate cancer with no metastasis vs prostate cancer with metastasis (Kruskal±Wallis test).Table 2 Sensitivity, speci®city, positive predictive value (PPV), false-positives and false-negatives for ALP, DPD/creatinine and PSA atvarious thresholdsMarker/threshold Sensitivity, % Speci®city, % PPV, % False-positive, n False-negative, nALP (N=69)60 91 31 37 33 280 81 71 55 14 4100 71 88 71 6 6DPD/creatinine (N=66)6 90 37 38 29 27 85 57 46 20 310 65 83 62 7 8PSA (N=69)10 86 13 30 42 320 81 21 31 38 440 76 50 40 24 560 62 69 46 15 8URINARY DEOXYPYRIDINOLINE AS A MARKER OF BONE METASTASIS IN PROSTATE CANCER 233# 2001 BJU International 88, 231±235diseases, e.g. degenerative changes or trauma. Further-more, bone scans are expensive and time-consuming.More sensitive and speci®c serum markers to discriminatebetween patients with and with no bone metastasisfrom prostate cancer would be valuable for the clinician,particularly in the early diagnosis and additional treat-ment of advanced prostate cancer.PSA is the most useful marker for determining theextent of prostate cancer; in patients with a PSA level off10 mg/L an initial bone scan is, according to publishedstudies, usually unnecessary [7,8]. PSA is not speci®c forbone metastases and is affected by other metastaticburdens. Moreover, in poorly differentiated carcinoma,there is not always a correlation between tumour volumeand the serum PSA value [9]. PSA expression is regulatedby androgen and after hormonal manipulation 34% ofpatients have a normal PSA, despite progression of bonemetastasis [10].In the present study, patients with bone metastasishad signi®cantly greater levels of DPD in urine thanhad patients with no bone metastasis or with BPH(P<0.001). However, the combination of ALP andDPD appeared to be the most powerful predictor ofbone metastasis (Table 2). This result refocuses atten-tion on serum ALP as an important marker of metastaticdisease. Urinary DPD may provide a useful marker tosupplement ALP and PSA in evaluating bone scan resultsand the response to hormonal therapy [11,12].In conclusion, the detection of possible bone metastasisis essential in the treatment of patients with prostatecancer. Serum ALP and PSA combined with the assay ofurinary DPD may provide valuable additional indicatorsof metastases to the bone in untreated patients, and inmonitoring the ef®cacy of therapy [11,12]. Additionalstudies with more patients and information during thefollow-up are needed.References1 Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics.CA Cancer J Clin 1996; 46: 5±272 Dijkman GA, Debruyne FMJ. Epidemiology of prostatecancer. Eur Urol 1996; 30: 281±953 Veterans Administration Co-Operative Urological ResearchGroup. Treatment and survival of patients with cancer ofthe prostate. Surg Gynec Obst 1967; 124: 10114 Seyedin SM, Rosen DM. Matrix proteins of the skeleton. CurrOpin Cell Biol 1990; 2: 914±95 Delmas PD. Biochemical markers for the assessment of boneturnover. In Riggs BL, Melton LJ eds, Osteoporosis: Etiology,Diagnosis, and Management. Philadelphia: Lippincott-Raven,1995: 319±336 Delmas PD, Gineyts E, Bertholin A, Garnero P, Marchand F.Immunoassay of pyridinoline crosslink excretion in normal—2Natural logarithm of PSA0 2 4 6 8 10—4Natural logarithm of ALP456783ar = 0.268—2Natural logarithm of PSA0 2 4 6 8 10—4Natural logarithm of DPD/Creat123460br = 0.3174Natural logarithm of ALP5 6 7 83Natural logarithm of DPD/Creat123460cr = 0.63555Fig. 2. Relationships between a, PSA and ALP (r=0.268), b, PSAand DPD/creatinine (r=0.317), and c, ALP and DPD/creatinine(r=0.635). All values are expressed on a logarithmic scale. Allcorrelation coef®cients are signi®cantly different from 0 atP<0.005.234 L.F.A. WYMENGA et al .# 2001 BJU International 88, 231±235adults and in Paget's disease. J Bone Miner Res 1993;8: 643±87 Chybowski FM, Keller JJ, Bergstralh EJ, Oesterling JE.Predicting radionuclide bone scan ®ndings in patientswith newly diagnosed, untreated prostate cancer: prostatespeci®c antigen is superior to all other clinical parameters.J Urol 1991; 145: 313±88 O'Dowd GJ, Veltri RW, Orozco R, Miller MC, Oesterling JE.Update on the appropriate staging evaluation for newlydiagnosed prostate cancer. J Urol 1997; 158: 687±989 Wolff JM, Zimny M, Borchers H, Wildberger J, Buell U, JakseG. Is prostate-speci®c antigen a reliable marker of bonemetastasis in patients with newly diagnosed cancer ofthe prostate? Eur Urol 1998; 33: 376±8110 Leo ME, Bilhartz DL, Bergstrahl EJ et al. Prostate speci®cantigen in hormonally treated stage D2 prostate cancer: is italways an accurate indicator of disease status? J Urol 1991;145: 802±611 Ikeda I, Miura T, Kondo I. Pyridinium cross-links as urinarymarkers of bone metastases in patients with prostate cancer.Br J Urol 1996; 77: 102±612 Berruti A, Dogliotti L, Bitossi R et al. Incidence of skeletalcomplications in patients with bone metastatic prostatecancer and hormone refractory disease: predictive roleof bone resorption and formation markers evaluated atbaseline. J Urol 2000; 164: 1248±53AuthorsL.F.A. Wymenga, MD, Urologist.K. Groenier, MD, Epidemiologist.J. Schuurman, MD, Nuclear Specialist.J.H.B. Boomsma, MD, PhD, Radiologist.R. Oude Elferink, MD, Clinical Chemist.H.J.A. Mensink, MD, PhD, Professor of Urology.Correspondence: L.F.A. Wymenga, Department of Urology, loc.vs. Ketwich, Martini Hospital, PO Box 30.033, NL-9700 RMGroningen, The Netherlands.Abbreviations: DPD, deoxypyridinoline; ALP, alkalinephosphatase.URINARY DEOXYPYRIDINOLINE AS A MARKER OF BONE METASTASIS IN PROSTATE CANCER 235# 2001 BJU International 88, 231±235

Pretreatment levels of urinary deoxypyridinoline as a potential marker in patients with prostate cancer with or without bone metastasis

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Pretreatment levels of urinary deoxypyridinoline as a potential marker in patients with prostate cancer with or without bone metastasis

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