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Japanese Journal of Clinical Oncology Pages 26-30

Sequential Changes of Urinary Pyridinoline and Deoxypyridinoline as Markers of Metastatic Bone Tumor in Patients with Prostate Cancer: a Preliminary Study
Introduction
Subjects and Methods
Results
   Correlation between U-Pyr and U-Dpyr
   Changes in Markers in Five Patients Without Bone Metastasis.
   Changes in Markers in Six Patients With Bone Metastasis.
   Changes in Markers in the Early Phase of Treatment in Six Patients with Bone Metastasis
Discussion
References

Sequential Changes of Urinary Pyridinoline and Deoxypyridinoline as Markers of Metastatic Bone Tumor in Patients with Prostate Cancer: a Preliminary Study

Sequential Changes of Urinary Pyridinoline and Deoxypyridinoline as Markers of Metastatic Bone Tumor in Patients with Prostate Cancer: a Preliminary Study Shoji Samma4, Yoriaki Kagebayashi2, Motonobu Yasukawa1, Yoshinao Fukui2, Seiichiro Ozono2, Yoshihiko Hirao2, Haruhiko Sato3 and Eigoro Okajima2

1Department of Urology, Nara Kokuho Chuo Hospital, 2Department of Urology, Nara Medical University, 3SRL, Inc., Tokyo, 4Department of Urology, Nara Prefectural Nara Hospital, Nara, Japan

Urinary concentration of pyridinoline and deoxypyridinoline, novel markers of bone resorption, was measured serially in patients with prostate cancer as markers of metastatic bone tumor. In 11 patients, five without bone metastasis and six with bone metastasis, pyridinoline and deoxypyridinoline were serially monitored for between 6 and 24 months. All patients received some hormonal therapy with or without radical prostatectomy. Pyridinoline and deoxypyridinoline were measured by ion-paired high-performance liquid chromatography and were adjusted according to urinary creatinine concentration. The sequential changes of pyridinoline and deoxypyridinoline were compared with those of prostatic specific antigen and alkaline phosphatase as well as with the findings of bone scintigrams. During the observation periods, no metastatic bone lesion developed and no significant changes in pyridinoline and deoxypyridinoline occurred in the five patients without bone metastasis. In the six patients with bone metastasis, the levels of prostatic-specific antigen showed relatively rapid decreases after starting therapy. In contrast, the levels of pyridinoline, deoxypyridinoline and alkaline phosphatase showed transient increases followed by gradual decreases in most cases. Correlations were observed between the changes of pyridinoline and deoxypyridinoline and the findings of bone scintigrams. The data suggest that serial monitoring of pyridinoline and deoxypyridinoline could be clinically useful as markers of metastatic bone tumors and may allow less frequent bone scintigrams during patient followup.

Key words: urinary pyridinoline - urinary deoxypyridinoline - bone metastasis - prostate cancer - serial measurement

Introduction

It is relatively easy to diagnose metastatic bone lesions in patients with prostate cancer by using diagnostic imaging such as bone scintigrams, MRI (magnetic resonance imaging) and CT (computed tomography). However, it is often difficult to evaluate the effects of therapies on bone lesions. Prostatic specific antigen (PSA) is not a good marker for monitoring metastatic bone lesions.

Recently, novel markers of bone resorption, urinary pyridinoline (U-Pyr) and deoxypyridinoline (U-Dpyr), have been the focus of attention. Pyr and Dpyr are highly specific crosslinks of bone collagen, which are released into the blood during bone degradation and rapidly exereted in the urine without being metabolized (1,2). They are not influenced by diet (3) (Figs 1 and 2). Urinary concentrations of these crosslinks could therefore be excellent markers for bone diseases such as osteoporosis (4), hyperparathyroidism (5) and metastatic bone tumors (6,7). In addition, serum levels of Pyr and Dpyr are useful for monitoring renal osteodystrophy in dialysis patients (8,9). In prostatic cancer patients, it has been reported that these crosslinks are useful in the diagosis of bone metastasis (10,11). However, it is unclear whether the sequential changes of U-Pyr or U-Dpyr represent the clinical course of bone metastasis in prostate cancer.

In this study, U-Pyr and U-Dpyr were measured in 11 patients with prostate cancer with or without bone metastasis. The clinical usefulness of serial measurement of U-Pyr and U-Dpyr as markers of bone metastasis was evaluated by analyzing the changes of U-Pyr and U-Dpyr together with those of serum PSA, alkaline phosphatase (ALP) and the findings of bone scintigrams. In addition, the changes in markers in the early phase of treatment were analyzed in patients with bone metastasis.


Figure 1. Structures of pyridinoline and deoxypyridinoline. Upper: Pyridinoline (molecular weight: 429); lower, Deoxypyridinoline (molecular weight: 413).


Figure 2. Metabolic pathway of pyridinoline and deoxypyridinoline.

Subjects and Methods

From May 1993 to April 1995, U-Pyr and U-Dpyr were measured serially in 11 patients (62-79 years of age) with prostate cancer who were treated at the Department of Urology, Nara Kokuho Chuo Hospital. Bone metastasis was negative in five patients and positive in six at the time of diagnosis. Out of five patients without bone metastasis, four underwent radical prostatectomy, and U-Pyr and U-Dpyr measurement was started after initiation of therapy but confirmation of no metastasis in three. In all six patients with bone metastasis, measurement was started at the time of diagnosis. U-Pyr and U-Dpyr together with serum levels of PSA and ALP were measured at intervals of 1-2 weeks after initiation of treatment and 2-3 months during outpatient follow-up. In all patients, treatment was initiated during hospitalization and all received some hormonal or chemohormonal therapy. One patient, who had extensive bone metastases, received hormonal therapy and radiotherapy. The observation periods ranged from 6 to 24 months.

U-Pyr and U-Dpyr were measured with ion-paired reversed-phase high-performance liquid chromatography (HPLC), which detected U-Pyr and U-Dpyr simultaneously in a series of measurements. The method used in this study was developed by us (8,9) to measure serum concentrations of Pyr and Dpyr in a modification of the original HPLC method reported by Black and associates (12). U-Pyr and U-Dpyr values were adjusted according to urinary creatinine (Cr) concentration and represented as µmol/mol Cr. The standard values of U-Pyr and U-Dpyr in adult males in this system are 10-25 µmol/mol Cr and less than 6 µmol/mol Cr, respectively. Urine samples were collected from the second voiding of the day in inpatients and before 11 am from outpatients. Ten ml of urine was kept frozen at -20°C until measurement. U-Pyr, U-Dpyr and PSA (Markit M) were measured at SRL Inc. The grade of bone metastasis was scored according to the Extension of Disease (EOD) system advocated by Soloway and associates (13).

Patients were given adequate explanation of the objectives and methods of this study, and an oral agreement to submit the urine samples for measurement of the crosslinks was obtained from all the patients.

Results

Correlation between U-Pyr and U-Dpyr

A total of 83 urine samples from 11 patients were submitted for measurement. Since a close correlation between U-Pyr and U-Dpyr in each sample was observed (r = 0.962, P < 0.002; t-test), the following analyses were made by focusing mainly on U-Pyr.

Changes in Markers in Five Patients Without Bone Metastasis.

The changes in U-Pyr, U-Dpyr and PSA in five patients without bone metastasis (Cases l-5) are shown in Table 1. There were no remarkable changes in the markers during the observation periods. In all patients, PSA normalized after hormonal therapy with or without radical prostatectomy, and no hot areas were observed in the follow-up bone scintigrams.

Table 1 Changes in markers in patients without bone metastasis
Case


 Age


 Treatment


 Follow-
up (mo)

 Pyr (µmol/mol Cr) Dpyr (µmol/mol Cr) PSA (ng/ml)

 Findings of
bone scintigram
        pre

 post

 pre

 post

 pre

 post

 (mo after treatment)
1

 68

 Radical Px
+ hormone		 20

 41*

 31

 9*

 6

 5.0

 <0.8

 No hot area (20)
2

 78

 Hormone

 19

 49

 43

 8

 7

 5.8

 1.0

 No hot area (12)
3

 68

 Radical Px
+ hormone		 16

 21

 28

 3

 3

 54

 <0.8

 No hot area (16)
4

 66

 Radical Px
+ hormone		 15

 61*

 45

 6*

 6

 38

 <0.8

 No hot area (10)
5

 70

 Radical Px
+ hormone		 6

 21

 42

 3

 5

 38

 <0.8

 No hot area (6)
Pyr, pyridinoline; Dpyr, deoxypyrimidine; PSA, prostatic specific antigen; Px, prostatectomy; * measurement was started after initiation of treatment

Table 2. Changes in markers in patients with bone metastasis
Case


 Age


 Treatment


 EOD


 Follow-
up (mo)

 Pyr
(µmol/mol Cr)		 PSA
(ng/ml)

 ALP
(IU/l)

 Findings of
bone scintigram
          pre

 post*

 pre

 post*

 pre

 post*

 (mo after treatment)
6

 79

 Hormone

 1

 18

 45

 25

 17

 <0.8

 174

 124

 Complete response (12)
7

 62

 Hormone

 4

 24

 153

 21

 260

 <0.8

 4510

 192

 No change (3)
uptake <=> <=> (18)
8

 79

 Hormone
+ chemo		 4

 14

 105

 104

 330

 28

 704

 1068

 Uptake [drarr] (9)
9 67

 Hormone

 2

 12

 20

 16

 51

 <0.8

 178

 127

 Uptake <=> (6)
10



 65



 Hormone



 3



 12



 37



 25



 48



 <0.8



 241



 106



 Progressive disease (3)
uptake <=> (10)
11

 79

 Hormone
+ rad.		 3

 11

 393

 126

 36

 <0.8

 4561

 227

 No change (4)
Pyr, pyridinoline; PSA, prostatic specific antigen; ALP, alkaline phosphatase; EOD, grade of extent of disease before treatment; * values at the time of final evaluation; chemo, chemotherapy; rad, radiotherapy; uptake of radioisotope: <=> <=> , markedly decreased; <=> , moderately decreased; [drarr], slightly decreased.

Changes in Markers in Six Patients With Bone Metastasis.

Table 2 shows the changes in U-Pyr, ALP and PSA and the findings of bone scintigrams during follow-up in six patients with bone metastasis (Cases 6-11). Two patients showed a `super' bone scan (uptake of radioisotope in every bone) (EOD 4) in bone scintigrams. Another two had EOD 3, while EOD 1 and EOD 2 were observed in one each. PSA was elevated in all patients, while a normal U-Pyr level was observed in only one. All patients but one showed relatively rapid normalization of PSA. In two patients, U-Pyr and ALP remained high during treatment. The levels of U-Dpyr moved in parallel with those of U-Pyr.

Obvious improvement in the findings of bone scintigrams was observed in four patients in 6-18 months. In these four patients, all the markers normalized. In two patients whose bone scintigrams showed mild improvement or no change, U-Pyr and ALP remained high in spite of normalized or markedly decreased PSA levels. Sequential changes in the markers and the findings of bone scintigrams in two patients (Cases 7 and 10) who had had high EOD scores are shown in Figs 3 and 4. In Case 7, PSA rapidly normalized in one month, while U-Pyr and ALP required 6 months for normalization. Serial bone scintigrams revealed gradual improvement. The markers were kept within normal limits and uptake of radioisotope in both kidneys became obvious at 18 months. In Case 10, all the markers showed transient elevations followed by gradual falls. At 3 months, a new bone lesion was detected. For normalization, PSA and ALP required 4 months and U-Pyr 8 months. At 10 months, all the markers were within normal limits and the findings of a bone scintigram was markedly improved.


Figure 3. Sequential changes in U-Pyr, PSA and ALP in Case 7, 62-yr-old, T4N2M1, EOD 4. PSA normalized rapidly after initiation of treatment with LH-RH analogue and diethylstilbestrol. In contrast, U-Pyr and ALP showed transient elevations followed by sharp falls. ALP began to fall slightly earlier than U-Pyr. Bone scintigrams at the start of and after 3 months of treatment showed `super' bone scans. Follow-up scans showed gradual improvement, and uptake of radioisotope in both kidneys was seen at 18 months. DES, diethylstilbestrol; abscissa, time in months after start of treatment; [circle]--[circle], Pyr (µmol/mol Cr); ------, PSA (ng/ml);[squf]......[squf], ALP (IU/l)


Figure 4. Sequential changes in U-Pyr, PSA and ALP in Case 10, 65-yr-old, T3N2M1, EOD 3. All three markers showed transient elevations after initiation of treatment with LH-RH analogue alone, interpreted as `flare-up'. PSA began to fall first, then ALP, followed by U-Pyr. Although a new bone lesion was detected at 3 months, uptake of radioisotope markedly decreased at 10 months. Note that ALP began to fall slightly earlier than U-Pyr, as in Case 7 (Fig.2). DES, diethylstilbestrol; abscissa, time in months after start of treatment; [circle]--[circle], Pyr (µmol/mol Cr); ------, PSA (ng/ml);[squf]......[squf], ALP (IU/l)

Changes in Markers in the Early Phase of Treatment in Six Patients with Bone Metastasis

The level of PSA began to decrease after the initiation of treatment in all the patients but one, Case 10, in whom a transient elevation of PSA was observed, while the levels of U-Pyr showed a transient elevation followed by a gradual fall in all the patients but one, Case 6. The level of ALP also showed a transient elevation in four patients, Cases 7-10. The peak of U-Pyr elevation was observed after 3-8 weeks and that of ALP elevation after 3-12 weeks.

Discussion

Since bone destruction progresses locally in lesions of bone metastasis, measurement of bone metabolic markers could be useful in the diagnosis and evaluation of therapy of bone metastasis. Osteocalcin (14), ALP (15) and hydroxyproline (16) have been investigated for these functions. In therapy of malignant tumors such as cancers of the prostate and breast, in which bone is a frequent metastatic site, clinically useful markers of bone metastasis have been sought. While bone scintigraphy is a good tool for diagnosis and patient followup, its problems include cost effectiveness and limited availability. Markers could reduce the need for frequent bone scintigraphy.

Recently, very specific crosslinks of bone collagen, Pyr and Dpyr, have been found (17). Pyr and Dpyr have now been recognized as highly specific markers of bone resorption (2-5,8,9). In addition, they are thought to be markers of bone metastasis (6,7). Although prostate cancer generally shows osteoblastic changes in metastatic bone lesions, not only ALP but also U-Pyr and U-Dpyr have been shown to be clinically useful in the diagnosis of bone metastasis of this cancer (10,11). Even in lesions showing osteoblastic change, abnormal bone formation and bone destruction are coupled. Markers of bone resorption are thus considered useful in most metastatic bone lesions. However, there are few reports on the clinical usefulness of serial Pyr and Dpyr measurement (10,18). We measured these crosslinks and other markers serially in 11 patients with prostate cancer, and investigated the correlation of these markers with clinical courses. In particular, we focused on their changes in the early phase of treatment.

In this study, no remarkable changes in U-Pyr or PSA were observed in the followup of five patients without bone metastasis. No new bone lesion was confirmed by bone scintigrams. Furthermore, in six patients with bone metastasis, PSA normalized relatively rapidly after starting treatment. In contrast, in most cases with bone metastasis U-Pyr and ALP showed transient elevations in the early phase of treatment, followed by gradual decreases. Furthermore, there was a correlation between the bone scan findings and the crosslink changes. These results suggested that serial measurement of these crosslinks could be useful not only in the diagnosis but also in the follow-up of prostate cancer, and might reduce the frequency of bone scintigrams during follow-up.

Levels of both U-Pyr and ALP increased after treatment initiation, suggesting that bone resorption and normal bone formation take place in bone lesions accompanied by tumor cell necrosis. However, similar elevations of ALP and U-Pyr were observed in Case 10, in whom a `flare-up phenomenon' developed after treatment with leutenizing hormone-releasing hormone (LH-RH) analogue alone (Fig. 3). Thus both the improvement and progression of bone lesions result in an increase in these parameters. Arai and associates (14) suggested direct effects of estrogen on the osteoblast activity in a study of osteocalcin in prostate cancer patients. The mechanisms of these phenomena require further investigation.

When these crosslinks are used as clinical markers of bone metastasis, the following must be considered: the level of U-Pyris influenced by factors such as age, performance status and renal function. Since prostate cancer patients are usually older, the presence of metabolic bone disease such as osteoporosis must be ruled out at diagnosis, as must the progression of bone resorption with bed rest accounting for elevated levels of U-Pyr (19). In the present study, U-Pyr levels were elevated in two patients (Cases 3 and 5) after radical prostatectomy. U-Pyr moved from 21 to 34 µmol/mol Cr after radical prostatectomy in Case 3 and from 21 to 54 µmol/mol Cr in Case 5. This may explain the elevated U-Pyr values in Cases 1 and 4, in whom the measurement was started after radical prostatectomy. In addition, we recently demonstrated a close correlation between creatinine clearance and pyridinoline clearance in patients with chronic renal failure prior to dialysis. The accumulation of these compounds in the blood develops with the progression of renal failure in addition to the progression of bone resorption due to renal osteodystrophy (20). Urinary exeretion of U-Pyr is thus influenced by renal function. However, these problems may possibly be overcome by observing sequential changes in U-Pyr.

Another question is whether both ALP and U-Pyr should be measured in prostate cancer patients. In this study, the movement of U-Pyr was similar to that of ALP in all cases with bone metastasis. It is unclear whether U-Pyr could be more sensitive than ALP, so the relationship between ALP isoenzyme and U-Pyr needs further investigation. Finally, the possibility remains that small bone lesions cannot be detected by this method.

In conclusion, U-Pyr and U-Dpyr are potential markers of bone metastasis, although they have some limitations. U-Pyr and U-Dpyr become more clinically useful when measured serially and may decrease the need for bone scintigrams for patient followup. Further studies of larger numbers of patients over time are necessary to elucidate the remaining questions.

References

1. Fujimoto D, Suzuki M, Uchiyama A, Miyamoto S, Inoue T. Analysis of pyridinoline, cross-linking compound of collagen fibers, in human urine. J Biochem 1983;94:1133-6. MEDLINE Abstract

2. Eyre DR, Koob TJ, Van Ness KP. Quantitation of hydroxypyridinium cross-links in collagen by high-performance liquid chromatography. Anal Biochem 1984;137:380-8. MEDLINE Abstract

3. Segrest JP. Urinary metabolites of collagen. Method Enzymol 1982;82: 398-410. MEDLINE Abstract

4. Delmas PD. Clinical use of biochemical markers of bone remodeling in osteoporosis. Bone 1992;13:S17-S21. MEDLINE Abstract

5. Uebelhart D, Gineyts E, Chapuy M-C, Delmas PD. Urinary exeretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner 1990;8:87-96. MEDLINE Abstract

6. Paterson CR, Robins SP, Horobin JM, Preece PE, Cuschieri A. Pyridinium crosslinks as markers of bone resorption in patients with breast cancer. Brit J Cancer 1991;64:884-6. MEDLINE Abstract

7. Lipton A, Demers L, Daniloff Y, Curley E, Hamilton C, Harvey H et al. Increased urinary excretion of pyridinium cross-links in cancer patients. Clin Chem 1993;39:614-8. MEDLINE Abstract

8. Samma S, Kagebayashi Y, Yoneda T, Fukui Y, Yoshida K, Hirao Y et al. Plasma pyridinium crosslinks as markers of renal osteodystrophy in patients on maintenance hemodialysis. Nippon Tosekiryoho Gakkai Zasshi 1994;27: 1235-40 (in Japanese).

9. Kagebayashi Y, Samma S, Yoneda T, Arai K, Yoshida K, Maruyama Y et al. Measurement and clinical significance of serum concentrations of pyridinium cross-links in patients with renal osteodystrophy. Nippon Jinzo Gakkai Zasshi 1995;37:397-403. (in Japanese) MEDLINE Abstract

&form=6&uid=7637210&Dopt=r">MEDLINE Abstract

10. Miyamoto KK, McSherry SA, Robins SP, Besterman JM, Mohler JL. Collagen cross-link metabolites in urine as markers of bone metastasis in prostatic carcinoma. J Urol 1994;151:909-13. MEDLINE Abstract

11. Sano M, Kushida K, Takahashi T,Ohishi K, Kawana K, Okada M, Inoue T. Urinary pyridinoline and deoxypyridinoline in prostate carcinoma patients with bone matastasis. Brit J Cancer 1994;70:701-3. MEDLINE Abstract

12. Black D, Duncan A, Robins SP. Quantitative analysis of the pyridinium crosslinks of collagen in urine using ion-paired reversed-phase high-performance liquid chromatography. Anal Biochem 1988;169:197-203. MEDLINE Abstract

13. Soloway MS, Hardeman SW, Hickey D, Raymond J, Todd B, Soloway S et al. Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 1988;81:195-202.

14. Arai Y, Takeuchi H, Oishi K, Yoshida O. Osteocalcin: Is it a useful marker of bone metastasis and response in advanced prostate cancer? Prostate 1992; 20:169-77. MEDLINE Abstract

15. Stepan JJ, Mikulecky M, Bek V, Broulik P, Pacovsky V. Bone alkaline phosphatase isoenzyme and urinary hydroxyproline in healthy subjects, patients with osteolytic metastases, and patients with primary hyperparathyroidism. Neoplasma 1989;36:495-501. MEDLINE Abstract

16. Gielen F, Dequeker J, Drochmans A, Wildiers J, Merlevede M. Relevance of hydroxyproline exeretion to bone metastasis in breast cancer. Brit J Cancer 1976;34:279-85. MEDLINE Abstract

17. Fujimoto D, Moriguchi T, Ishida T, Hayashi H. The structure of pyridinoline, a collagen crosslink. Biochem Biophys Res Commun 1978;84:52-7. MEDLINE Abstract

18. Coleman RE, Houston S, James I, Rodger A, Rubens RD, Leonard RCF et al. Preliminary results of the use of urinary exeretion of pyridinium crosslinks for monitoring metastatic bone disease. Brit J Cancer 1992;65:766-8. MEDLINE Abstract

19. Lueken SA, Arnaud SB, Taylor AK, Baylink DJ. Changes in markers of bone formation and resorption in a bed rest model of weightlessness. J Bone Miner Res 1993;8:1433-8. MEDLINE Abstract

20. Kagebayashi Y, Samma S, Yoshida K, Ozono S, Motomiya Y, Hirao Y et al. Serum and urinary pyridinium cross-links in patients with predialysis chronic renal failure. Nippon Jinzo Gakkai Zasshi 1996;38:248-53 (in Japanese). MEDLINE Abstract

Received June 13, 1996; accepted September 12, 1996
For reprints and all correspondence: Shoji Samma, Department of Urology, Nara Prefectural Nara Hospital, 30-1,Hiramatsu 1-chome, Nara-shi, Nara 631, Japan
Abbreviations: PSA, Prostatic specific antigen; U-Pyr, urinary pyridinoline; U-Dpyr, urinary deoxypyridinoline; ALP, alkaline phosphatase; HPLC, high-performance liquid chromatography, Cr, creatinine; EOD, Extension of Disease; LH-RH, leutenizing hormone- releasing hormone; PO, per os.

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