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Clinical use of markers of bone turnover in metastatic bone disease

Nature Clinical Practice Oncology volume 2, pages 504–517 (2005)Cite this article

Abstract

Bone metastases profoundly perturb normal bone remodeling. Biochemical markers of bone turnover have been shown to reflect these tumor-induced changes in bone remodeling and might therefore be useful in the diagnosis and follow-up of patients with malignant bone disease. Most markers of bone turnover, particularly those of bone resorption, are elevated in patients with established bone metastases. While this might indicate a role for bone markers as diagnostic tools in cancer patients, the available evidence does not provide any final conclusions as to the accuracy and validity of the markers presently used in the early diagnosis of bone metastases. Markers of bone resorption respond promptly and profoundly to bisphosphonate and antineoplastic therapy, and this response is associated with a favorable clinical outcome. Most markers, however, have been more useful in groups of patients monitored in clinical studies than in studies of individuals. While this makes them a good tool for drug development, it remains unknown whether the use of bone markers in a routine clinical setting has any defined beneficial effects on overall outcome in cancer patients. In particular, no study has addressed the question of whether patients with bone metastases should be treated according to their rate of bone turnover and what the treatment goals are in this respect. While it is unlikely that bone-turnover markers have sufficient diagnostic or prognostic value when used in isolation, the combination of these markers with other diagnostic techniques might be the way forward to improve the clinical assessment of patients with cancers of the bone.

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Figure 1: Interactions between cancer and bone cells.
Figure 2: Biochemical markers of bone remodeling.
Figure 3: Urinary excretion of deoxypyridinoline in healthy subjects and patients with and without bone metastases.
Figure 4: Urinary excretion of pyridinium crosslinks in healthy adults and patients with multiple myeloma, monoclonal gammopathy of undetermined significance and osteoporosis.
Figure 5: Discriminative power of biochemical markers of bone turnover in patients with multiple myeloma, monoclonal gammopathy of unknown significance and osteoporosis.
Figure 6: High urinary levels of NTX-I (the amino-terminal crosslinked telopeptide of collagen type I) at baseline predict skeletal-related events.
Figure 7: High serum levels of NTX-I (the amino-terminal crosslinked telopeptide of collagen type I) are associated with shorter survival times in breast cancer patients with bone metastases.
Figure 8: Bone-metastasis-free survival in patients with primary breast cancer, with patients grouped according to preoperative serum bone sialoprotein levels.
Figure 9: Probability of survival according to serum bone sialoprotein concentrations in patients with multiple myeloma.
Figure 10: Short-term and long-term changes in markers of bone turnover after treatment with intravenous pamidronate.

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References

  1. Rubens RD (2000) Clinical aspects of bone metastases. In Tumor Bone Diseases and Osteoporosis in Cancer Patients, 85–96 (Ed Body J-J) New York: Marcel Dekker

    Google Scholar 

  2. Lipton A et al. (2000) Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomised placebo-controlled trials. Cancer 88: 1082–1090

    Article  CAS  PubMed  Google Scholar 

  3. Ross JR et al. (2003) Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 327: 469–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bubley G et al. (1999) Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate Specific Antigen Working Group. J Clin Oncol 18: 3461–3477

    Article  Google Scholar 

  5. Yoneda T and Hiraga T (2005) Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun 328: 679–687

    Article  CAS  PubMed  Google Scholar 

  6. Chung LW et al. (2005) Molecular insights into prostate cancer progression: the missing link of tumor microenvironment. J Urol 173: 10–20

    Article  PubMed  Google Scholar 

  7. Seibel MJ (2003) Biochemical markers of bone remodeling. Endocrinol Metab Clin North Am 32: 83–113

    Article  CAS  PubMed  Google Scholar 

  8. Fukumitsu N et al. (2002) Correlation of urine type I collagen-cross-linked N telopeptide levels with bone scintigraphic results in prostate cancer patients. Metabolism 51: 814–818

    Article  CAS  PubMed  Google Scholar 

  9. Meijer WG et al. (2003) Bone metastases in carcinoid tumors: clinical features, imaging characteristics, and markers of bone metabolism. J Nucl Med 44: 184–191

    PubMed  Google Scholar 

  10. Ebert W et al. (2004) Comparison of bone scintigraphy with bone markers in the diagnosis of bone metastasis in lung carcinoma patients. Anticancer Res 24: 3193–3201

    CAS  PubMed  Google Scholar 

  11. Springer IN et al. (2003) Follow-up of collagen crosslink excretion in patients with oral squamous cell carcinoma and analysis of tissue samples. Br J Cancer 89: 1722–1728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Francini G et al. (1990) Comparison between CEA, TPA, CA 15-3 and hydroxyproline, alkaline phosphatase, whole body retention of 99mTc MDP in the follow-up of bone metastases in breast cancer. Int J Biol Markers 5: 65–72

    Article  CAS  PubMed  Google Scholar 

  13. Berruti A et al. (1999) Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases. Clin Chem 45: 1240–1247

    CAS  PubMed  Google Scholar 

  14. Kanakis I et al. (2004) Determination and biological relevance of serum cross-linked type I collagen N-telopeptide and bone-specific alkaline phosphatase in breast metastatic cancer. Pharm Biomed Anal 34: 827–832

    Article  CAS  Google Scholar 

  15. Oremek GM et al. (2003) Diagnostic value of bone and tumour markers in patients with malignant diseases. Anticancer Res 23: 987–990

    CAS  PubMed  Google Scholar 

  16. Lorente JA et al. (1999) Serum bone alkaline phosphatase levels enhance the clinical utility of prostate specific antigen in the staging of newly diagnosed prostate cancer patients. Eur J Nucl Med 26: 625–632

    Article  CAS  PubMed  Google Scholar 

  17. Wymenga LF et al. (2001) Pretreatment levels of urinary deoxypyridinoline as a potential marker in patients with prostate cancer with or without bone metastasis. Br J Urol 88: 231–235

    Article  CAS  Google Scholar 

  18. Bombardieri E et al. (1997) Can bone metabolism markers be adopted as an alternative to scintigraphic imaging in monitoring bone metastases from breast cancer? Eur J Nucl Med 24: 1349–1355

    Article  CAS  PubMed  Google Scholar 

  19. Wada S et al. (1993) Changes of bone metabolic markers in patients with bone metastases: clinical significance in assessing bone response to chemotherapy. Int Med 32: 611–618

    Article  CAS  Google Scholar 

  20. Bataille R et al. (1990) Abnormal serum bone Gla protein levels in multiple myeloma. Crucial role of bone formation and prognostic implications. Cancer 66: 167–172

    Article  CAS  PubMed  Google Scholar 

  21. Mejjad O et al. (1996) Osteocalcin is not a marker of progress in multiple myeloma. Eur J Haematol 56: 30–34

    Article  CAS  PubMed  Google Scholar 

  22. Carlson K et al. (1999) Evaluation of bone disease in multiple myeloma: a comparison between the resorption markers urinary deoxypyridinoline/creatinine (DPD) and serum ICTP, and an evaluation of the DPD/osteocalcin and ICTP/osteocalcin ratios. Eur J Haematol 62: 300–306

    Article  CAS  PubMed  Google Scholar 

  23. Berenson JR et al. (2001) A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clin Cancer Res 7: 478–485

    CAS  PubMed  Google Scholar 

  24. Tian E et al. (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349: 2483–2494

    Article  CAS  PubMed  Google Scholar 

  25. Jukkola A et al. (1997) Aggressive breast cancer leads to discrepant serum levels of the type I procollagen propeptides PINP and PICP. Cancer Res 57: 5517–5520

    CAS  PubMed  Google Scholar 

  26. Ylisirnio S et al. (1999) Serum type I collagen degradation markers, ICTP and CrossLaps, are factors for poor survival in lung cancer. Anticancer Res 19: 5577–5581

    CAS  PubMed  Google Scholar 

  27. Koizumi M et al. (2003) Comparison of serum bone resorption markers in the diagnosis of skeletal metastasis. Anticancer Res 23: 4095–4099

    CAS  PubMed  Google Scholar 

  28. Paterson CR et al. (1991) Pyridinium crosslinks as markers of bone resorption in patients with breast cancer. Br J Cancer 64: 884–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pecherstorfer M et al. (1995) The diagnostic value of urinary pyridinium cross-links of collagen, serum total alkaline phosphatase, and urinary calcium excretion in neoplastic bone disease. J Clin Endocrinol Metab 80: 97–103

    CAS  PubMed  Google Scholar 

  30. Alatas F et al. (2002) Usefulness of bone markers for detection of bone metastases in lung cancer patients. Clin Biochem 35: 293–296

    Article  CAS  PubMed  Google Scholar 

  31. Behrens P et al. Pyridinoline cross-links as markers for primary and secondary bone tumors. Scand J Clin Lab Invest 63: 37–44

  32. Motellon JL et al. (2000) Relationship of plasma bone cytokines with hypercalcemia in cancer patients. Clin Chim Acta 302: 59–68

    Article  CAS  PubMed  Google Scholar 

  33. Pecherstorfer M et al. (1997) Bone resorption in multiple myeloma and in monoclonal gammopathy of undetermined significance: quantification by urinary pyridinium cross-links of collagen. Blood 90: 3743–3750

    CAS  PubMed  Google Scholar 

  34. Ulrich U et al. (2001) Cross-linked type I collagen C- and N-telopeptides in women with bone metastases from breast cancer. Arch Gynecol Obstet 264: 186–190

    Article  CAS  PubMed  Google Scholar 

  35. Wada N et al. (2001) Evaluation of bone metabolic markers in breast cancer with bone metastasis. Breast Cancer 8: 131–137

    Article  CAS  PubMed  Google Scholar 

  36. Costa L et al. (2002) Prospective evaluation of the peptide-bound collagen type I crosslinks N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20: 850–856

    Article  CAS  PubMed  Google Scholar 

  37. Kiuchi K et al. (2002) Cross-linked collagen C- and N-telopeptides for an early diagnosis of bone metastasis from breast cancer. Oncol Rep 9: 595–598

    CAS  PubMed  Google Scholar 

  38. Cloos PA et al. (2004) An immunoassay for measuring fragments of newly synthesized collagen type I produced during metastatic invasion of bone. Clin Lab 50: 279–289

    CAS  PubMed  Google Scholar 

  39. Koizumi M et al. (2002) Metabolic gaps in bone formation may be a novel marker to monitor the osseous metastasis of prostate cancer. J Urol 167: 1863–1866

    Article  PubMed  Google Scholar 

  40. Noguchi M and Noda S (2001) Pyridinoline cross-linked carboxy terminal telopeptide of type I collagen as a useful marker for monitoring metastatic bone activity in men with prostate cancer. J Urol 166: 1106–1110

    Article  CAS  PubMed  Google Scholar 

  41. de la Piedra C et al. (2003) Bone remodeling markers in the detection of bone metastases in prostate cancer. Clin Chim Acta 331: 45–53

    Article  CAS  PubMed  Google Scholar 

  42. Nabeya Y et al. (2002) Serum cross-linked carboxy terminal telopeptide of type I collagen (ICTP) as a prognostic tumor marker in patients with esophageal squamous cell carcinoma. Cancer 94: 940–949

    Article  CAS  PubMed  Google Scholar 

  43. Capeller B et al. (2003) Evaluation of tartrate-resistant acid phosphatase (TRAP) 5b as serum marker of bone metastases in human breast cancer. Anticancer Res 23: 1011–1015

    CAS  PubMed  Google Scholar 

  44. Chao TY et al. (2004) Tartrate-resistant acid phosphatase 5b as a serum marker of bone metastasis in breast cancer patients. J Biomed Sci 11: 511–516

    Article  CAS  PubMed  Google Scholar 

  45. Halleen JM et al. (2001) Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption. Clin Chem 47: 597–600

    CAS  PubMed  Google Scholar 

  46. Jain A et al. (2002) Three SIBLINGs enhance Factor H's cofactor activity enabling MCP-like cellular evasion of complement-mediated attack. J Biol Chem 277: 13700–13708

    Article  CAS  PubMed  Google Scholar 

  47. Seibel MJ et al. (1996) Serum immunoreactive bone sialoprotein as a new marker of bone turnover in metabolic and malignant bone disease. J Clin Endocrinol Metab 81: 3289–3294

    CAS  PubMed  Google Scholar 

  48. Bellahcene A et al. (1996) Expression of bone sialoprotein in primary human breast cancer is associated with poor survival. Int J Cancer 69: 350–353

    Article  CAS  PubMed  Google Scholar 

  49. Fedarko et al. (2001) Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 7: 4060–4066

    CAS  PubMed  Google Scholar 

  50. Woitge HW et al. (2001) Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma. Br J Cancer 84: 344–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Woitge HW et al. (1999) Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res 14: 792–801

    Article  CAS  PubMed  Google Scholar 

  52. Brown JE et al. (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97: 59–69

    Article  CAS  PubMed  Google Scholar 

  53. Vinholes J et al. (1999) Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European Organization for Research and Treatment of Cancer. Br J Cancer 80: 221–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Coleman RE et al. (2005) Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23: 4925–4935

    Article  CAS  PubMed  Google Scholar 

  55. Jukkola A et al. (2001) Postoperative PINP in serum reflects metastatic potential and poor survival in node-positive breast cancer. Anticancer Res 21: 2873–2876

    CAS  PubMed  Google Scholar 

  56. Ali SM et al. (2004) Baseline serum NTx levels are prognostic in metastatic breast cancer patients with bone-only metastasis. Ann Oncol 15: 455–459

    Article  CAS  PubMed  Google Scholar 

  57. Berruti A et al. (2002) Metabolic effects of single-dose pamidronate administration in prostate cancer patients with bone metastases. Int J Biol Markers 17: 244–252

    Article  CAS  PubMed  Google Scholar 

  58. Kylmälä T et al. (1995) Type I collagen degradation product (ICTP) gives information about the nature of bone metastases and has prognostic value in prostate cancer. Br J Cancer 71: 1061–1064

    Article  PubMed  PubMed Central  Google Scholar 

  59. Petrioli R et al. (2004) Analysis of biochemical bone markers as prognostic factors for survival in patients with hormone-resistant prostate cancer and bone metastases. Urology 63: 321–326

    Article  PubMed  Google Scholar 

  60. Seibel MJ et al. (2002) Markers of bone turnover do not predict bone metastases in breast cancer. Clin Lab 48: 583–588

    CAS  PubMed  Google Scholar 

  61. Seibel MJ et al. (2002) Long-term variability of markers of bone turnover in patients with breast cancer. Clin Lab 48: 576–582

    Google Scholar 

  62. De Pinieux G et al. (2001) Bone sialoprotein, bone morphogenetic protein 6 and thymidine phosphorylase expression in localized human prostatic adenocarcinoma as predictors of clinical outcome: a clinicopathological and immunohistochemical study of 43 cases. J Urol 166: 1924–1930

    Article  CAS  PubMed  Google Scholar 

  63. Diel I et al. (1999) Serum bone sialoprotein in patients with primary breast cancer as a prognostic marker for subsequent bone metastasis. Clin Cancer Res 5: 3914–3919

    CAS  PubMed  Google Scholar 

  64. Fonseca R et al. (2000) Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients. Br J Haematol 109: 24–29

    Article  CAS  PubMed  Google Scholar 

  65. Abildgaard N et al. (1998) Long-term oral pamidronate treatment inhibits osteoclastic bone resorption and bone turnover without affecting osteoblastic function in multiple myeloma. Eur J Haematol 61: 128–134

    Article  CAS  PubMed  Google Scholar 

  66. Jagdev SP et al. (2001) Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 12: 1433–1438

    Article  CAS  PubMed  Google Scholar 

  67. Terpos E et al. (2000) Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma. Eur J Haematol 65: 331–336

    Article  CAS  PubMed  Google Scholar 

  68. Body JJ et al. (1997) Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy. Br J Cancer 75: 408–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lipton A et al. (1998) Markers of bone resorption in patients treated with pamidronate. Eur J Cancer 34: 2021–2026

    Article  CAS  PubMed  Google Scholar 

  70. Martinetti A et al. (2002) Serum levels of tartrate resistant acid phosphatase-5b in breast cancer patients treated with pamidronate. Int J Biol Markers 17: 253–258

    Article  CAS  PubMed  Google Scholar 

  71. Carlson K et al. (1992) Serum osteocalcin concentrations in patients with multiple myeloma: correlation with disease stage and survival. J Intern Med 231: 133–137

    Article  CAS  PubMed  Google Scholar 

  72. Magnusson P et al. (1998) Differences of bone alkaline phosphatase isoforms in metastatic bone disease and discrepant effects of clodronate on different skeletal sites indicated by the location of pain. Clin Chem 44: 1621–1628

    CAS  PubMed  Google Scholar 

  73. Koizumi M et al. (2001) The serum level of the amino-terminal propeptide of type I procollagen is a sensitive marker for prostate cancer metastasis to bone. BJU Int 87: 348–3451

    Article  CAS  PubMed  Google Scholar 

  74. Blomqvist C et al. (1987) The response evaluation of bone metastases in mammary carcinoma. The value of radiology, scintigraphy, and biochemical markers of bone metabolism. Cancer 60: 2907–2912

    Article  CAS  PubMed  Google Scholar 

  75. Vinholes JJ et al. (1997) Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease. Ann Oncol 8: 1243–1250

    Article  CAS  PubMed  Google Scholar 

  76. Luftner D et al. (2003) Normalisation of biochemical markers of bone formation correlates with clinical benefit from therapy in metastatic breast cancer. Anticancer Res 23: 1017–1026

    CAS  PubMed  Google Scholar 

  77. Chen T et al. (2002) Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 42: 1228–1236

    Article  CAS  PubMed  Google Scholar 

  78. Brown JE et al. (2003) Bone resorption predicts for skeletal complications in metastatic bone disease. Br J Cancer 89: 2031–2037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Marttunen MB et al. (1999) Effects of tamoxifen and toremifene on urinary excretion of pyridinoline and deoxypyridinoline and bone density in postmenopausal patients with breast cancer. Calcif Tissue Int 65: 365–368

    Article  CAS  PubMed  Google Scholar 

  80. Kenny AM et al. (1995) The short term effects of tamoxifen on bone turnover in older women. J Clin Endocrinol Metab 80: 3287–3291

    CAS  PubMed  Google Scholar 

  81. Li F et al. (1993) Biochemical markers of bone turnover in women with surgically treated carcinoma of the breast. Eur J Clin Invest 23: 566–571

    Article  CAS  PubMed  Google Scholar 

  82. Noguchi M et al. (2003) Serum levels of bone turnover markers parallel the results of bone scintigraphy in monitoring bone activity of prostate cancer. Urology 61: 993–998

    Article  PubMed  Google Scholar 

  83. Diamond T et al. (1997) Biochemical, histomorphometric and densitometric changes in patients with multiple myeloma: effects of glucocorticoid therapy and disease activity. Br J Haematol 97: 641–648

    Article  CAS  PubMed  Google Scholar 

  84. Piovesan A et al. (1997) Comparison of assay of total and bone-specific alkaline phosphatase in the assessment of osteoblast activity in patients with metastatic bone disease. Calcif Tissue Int 61: 362–369

    Article  CAS  PubMed  Google Scholar 

  85. Clark RE et al. (2000) Biochemical markers of bone turnover following high-dose chemotherapy and autografting in multiple myeloma. Blood 96: 2697–2702

    CAS  PubMed  Google Scholar 

  86. Nguyen T et al. Variability of bone marker measurements. In Dynamics of Bone and Cartilage Metabolism, (Eds Seibel MJ et al.) San Diego: Elsevier/Academic, in press

  87. Meier C et al. Monitoring of anti-resorptive treatment. In Dynamics of Bone and Cartilage Metabolism, (Eds Seibel MJ et al.) San Diego: Elsevier/Academic, in press

  88. Delmas PD et al. (2000) The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int 11 (Suppl 6): S2–S17

    Article  PubMed  Google Scholar 

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Acknowledgements

For his support and witful company, I would like to dedicate this work to my father, Dr M Roger Seibel, PhD, on the occasion of his 80th birthday.

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  1. Professor of Endocrinology and holds a Chair at the University of Sydney,

    Markus J Seibel

  2. the Director of the Bone Research Program at the ANZAC Research Institute, Sydney

    Markus J Seibel

  3. the Head of the Department of Endocrinology and Metabolism at Concord Hospital, Sydney, Australia

    Markus J Seibel

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Seibel, M. Clinical use of markers of bone turnover in metastatic bone disease. Nat Rev Clin Oncol 2, 504–517 (2005). https://doi.org/10.1038/ncponc0320

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