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Bone metabolic markers as gauges of metastasis to bone: a review

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Abstract

Currently, imaging techniques are the leading methods used to diagnose of metastasis to bone. However, these techniques are expensive, expose patients to toxic and radioactive compounds, and monitor response to treatment poorly; these drawbacks have prompted the search for alternative screening methods. Therefore, bone metabolic markers have been evaluated as possible methods to diagnose and monitor the development and progression of metastatic bone disease. Although bone metabolic markers are often grouped as either resorption or formation markers, studies have revealed that each marker has its own biologic meaning and clinical relevance. Recent milestones in the use of bone metabolic markers as screening methods for metastatic bone disease and as evaluation methods for treatment response are shown in the following lists.

  1. 1.

    Bone metabolic marker measurements provide insight into mechanisms of metastasis to bone.

  2. 2.

    Although promising data have been reported, bone metabolic markers are not yet considered to be reliable screening methods for metastasis to bone.

  3. 3.

    Bone metabolic markers are reliable indicators of response to both conventional and bisphosphonate therapies.

  4. 4.

    Preliminary results indicate bone metabolic markers might be an independent prognostic factor in patients whose tumors metastasize to bone.

  5. 5.

    New or refined assays for bone metabolic markers are expected to improve the sensitivity and specificity of bone metabolic marker use in diagnosing and monitoring metastasis to bone.

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References

  1. Abrams HL, Spiro R, Goldstein N. Metastases in carcinomas: analysis of 1000 autopsied cases.Cancer 1950; 3: 74–85.

    Article  PubMed  CAS  Google Scholar 

  2. Koizumi M.Bone Scintigraphy in Oncology. Endo K (ed), Tokyo; Mediculture, 2000.

    Google Scholar 

  3. Krasnow AZ, Hellman RS, Timins M, Collier BD, Anderson T, Isitman AT. Diagnostic bone scanning in oncology.Semin Nucl Med 1997; 27: 107–141.

    Article  PubMed  CAS  Google Scholar 

  4. Yamamoto I. Skeletal nuclear medicine.KaKU IGAKU (Jpn J Nucl Med) 1995; 32: 523–529.

    CAS  Google Scholar 

  5. Vogel CL, Schoenfelder J, Shemano I, Hayes DF, Gams RA. Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer.J Clin Oncol 1995; 13: 1123–1128.

    PubMed  CAS  Google Scholar 

  6. Pollen JF, Witztum KF, Ashburn WL. The flare phenomenon on radionuclide bone scan in metastatic prostate cancer.Am J Roent 1984; 142: 773–776.

    CAS  Google Scholar 

  7. Koizumi M, Yoshimoto M, Kasumi F, Ogata E. What breast cancer patients benefit from staging bone scintigraphy?Jpn J Clin Oncol 2001; 31: 263–269.

    Article  PubMed  CAS  Google Scholar 

  8. American Society of Clinical Oncology. Recommended breast cancer surveillance guidelines.J Clin Oncol 1997; 15: 2149–2156.

    Google Scholar 

  9. Yamaguchi T, Tamai K, Yamamoto M, Honma K, Ueda Y, Saotome K. Intertrabecullar pattern of tumor metastatic to bone.Cancer 1996; 78: 1388–1394.

    Article  PubMed  CAS  Google Scholar 

  10. Vinholes J, Coleman R, Eastell R. Effects of bone metastases on bone metabolism: implications for diagnosis, imaging and assessment of response to cancer treatment.Cancer Treatment Reviews 1996; 22: 289–331.

    Article  PubMed  CAS  Google Scholar 

  11. Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover.Endocrine Reviews 1996; 17: 333–368.

    Article  PubMed  CAS  Google Scholar 

  12. Takahashi S, Yoshida N, Koizumi M, et al. Biochemical markers of bone metabolism predicts prognosis in patients with bone metastasis of breast cancer. [abstract]Breast Cancer Res Treat 2000; 64 (suppl): p97.

    Google Scholar 

  13. Halleen JM, Alatalo SL, Suominen H, Cheng S, Janckila AJ, Vaananen K. Tartrate-resistant acid phosphatase 5b: A novel serum marker of bone resorption.J Bone Miner Res 2000; 15: 1337–1345.

    Article  PubMed  CAS  Google Scholar 

  14. Hiraga T, Tanaka S, Ikegame M, Koizumi M, Iguchi H, Nakajima T, et al. Morphology of bone metastasis.Eur J Cancer 1998; 34: 230–239.

    Article  PubMed  CAS  Google Scholar 

  15. Delaisse JM, Eeckhout Y, Vaes G.In vivo andin vitro evidence for the involvement of cystein proteases in bone resorption.Biochem Biophys Res Commun 1984; 125: 441–447.

    Article  PubMed  CAS  Google Scholar 

  16. Tezuka K, Tezuka Y, Maejima A, Sato T, Nemoto K, Kamioka H, et al. Molecular cloning of a possible cysteine protease predominantly expressed in osteoclasts.J Biol Chem 1994; 269: 1106–1109.

    PubMed  CAS  Google Scholar 

  17. Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda T, et al. Determination of bone markers in Pycnodysostosis: Matrix degradation.J Bone Miner Res 1999; 14: 1902–1908.

    Article  PubMed  CAS  Google Scholar 

  18. Atley LM, Mort JS, Lalumiere M, Eyre DR. Proteolysis of human collagen by cathepsin K: Characterization of the cleavage sites generating the cross-linked N-telopeptide neoepitope.Bone 2000; 26: 241–247.

    Article  PubMed  CAS  Google Scholar 

  19. Sassi ML, Eriksen H, Risteli L, Niemi S, Mansell J, Gowen M, et al. Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: Loss of antigenecity by treatment with cathepsin K.Bone 2000; 26: 367–373.

    Article  PubMed  CAS  Google Scholar 

  20. Karsda MA, Garnero P, Ferreras M, Risteli J, Ovist P, Foged N, et al. Type I collagen fragments ICTP and CTx reveal distinct enzymatic pathways of bone collagen degradation.J Bone Miner Res 2001; 16 (suppl): p195.

    Google Scholar 

  21. Diel IJ, Solomayer EF, Siebel MJ, Pfeilschifter J, Maisenbacher H, Gollan C, et al. Serum sialoprotein in patients with primary breast cancer is prognostic marker for subsequent bone metastasis.Clin Cancer Res 1999; 5: 3914–3919.

    PubMed  CAS  Google Scholar 

  22. Stein GS, Lian JB, Owen TA. Relationship of cell growth to the regulation of tissue-specific gene expression during osteoblast differentiation.FASEB J 1990; 4: 3111–3123.

    PubMed  CAS  Google Scholar 

  23. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, et al. Increased bone formation in osteocalcin-deficient mice.Nature 1996; 382: 448–452.

    Article  PubMed  CAS  Google Scholar 

  24. Koizumi M, Yamada Y, Takiguchi T, Nomura E, Furukawa M, Kitahara T, et al. Bone metabolic markers in bone metastasis.J Cancer Res Clin Oncol 1995; 121: 542–548.

    Article  PubMed  CAS  Google Scholar 

  25. Demers LM, Costa L, Chinchilli VM, Gaydos L, Curley E, Lipton A. Biochemical markers of bone turnover in patients with metastatic bone disease.Clin Chem 1995; 41: 1489–1494.

    PubMed  CAS  Google Scholar 

  26. Yamamoto I, Morita R, Konishi J, Shigeno C, Ikekubo K, Hino M, et al. Clinical studies using measurement of N-telopeptides of type-I collagen (NTx) in patients with bone metastasis.KAKU IGAKU (Jpn J Nucl Med) 1995; 32: 501–510.

    CAS  Google Scholar 

  27. Koizumi M, Takahashi S, Ogata E. Bone metabolic marker in bone metastasis of breast cancer.Int J Clin Oncol 1999; 4: 241–246.

    Article  Google Scholar 

  28. Garnero P, Shin WJ, Gineyts E, Karpf DB, Dermas PD. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment.J Clin Endocrinol Metab 1994; 79: 1693–1700.

    Article  PubMed  CAS  Google Scholar 

  29. Koizumi M, Maeda H, Yoshimura K, Yamauchi T, Kawai T, Ogata E. Dissociation of bone metabolic markers in bone metastasis of prostate cancer.Br J Cancer 1997; 75: 1601–1604.

    PubMed  CAS  Google Scholar 

  30. Yoshida K, Sumi S, Arai K, Koga F, Umeda H, Hosoya Y, et al. Serum concentration of type I collagen metabolites as quantitative marker of bone metastases in patients with prostate carcinoma.Cancer 1997; 80: 1760–1767.

    Article  PubMed  CAS  Google Scholar 

  31. Maeda H, Koizumi M, Yoshimura K, Yamauchi T, Kawai T, Ogata E. Correlation of bone metabolic markers and bone scan in prostate cancer.J Urol 1997; 157: 539–543.

    Article  PubMed  CAS  Google Scholar 

  32. Sano M, Kushida K, Takahashi M, Ohishi T, Kawana K, Okada M, et al. Urinary pyridinoline and deoxypyridinoline in prostate carcinoma patients with bone metastasis.Br J Cancer 1994; 70: 701–703.

    PubMed  CAS  Google Scholar 

  33. Kylmala T, Tammela TLJ, Risteri L, Risteri J, Kontturi M, Elomaa I. Type I collagen degradation product (ICTP) gives information about the nature of bone metastases and has prognostic value in prostate cancer.Br J Cancer 1995; 71: 1061–1064.

    PubMed  CAS  Google Scholar 

  34. Koizumi M, Yonese J, Fukui I, Ogata E. Serum PINP level is a sensitive marker of prostate cancer metastasis to bone.BJU International 2001; 87: 348–351.

    Article  PubMed  CAS  Google Scholar 

  35. Koizumi M, Yonese J, Fukui I, Ogata E. Metabolic gaps in bone formation might be a novel marker to monitor the osseous metastasis of prostate cancer.J Urol 2002; 167: 1863–1866.

    Article  PubMed  Google Scholar 

  36. Elomaa I, Virkkunen P, Risteri L, Risteri J. Serum concentration of cross-linked carboxyterminal telopeptide of type-I collagen (ICTP) is useful prognostic indicator in multiple myeloma.Br J Cancer 1992; 66: 337–341.

    PubMed  CAS  Google Scholar 

  37. Aruga A, Koizumi M, Hotta R, Takahashi S, Ogata E. Usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastasis from lung cancer.Br J Cancer 1997; 76: 760–764.

    PubMed  CAS  Google Scholar 

  38. Hayward JL, Carbone PP, Heuson JC, Kumaoka S, Segaloff A, Rubens RD. Assessment of response to therapy in advanced breast cancer.Cancer 1997; 39: 1289–1294.

    Article  Google Scholar 

  39. Coleman RE. Monitoring of bone metastases.Eur J Cancer 1998; 34: 252–259.

    Article  PubMed  CAS  Google Scholar 

  40. Blomqvist C, Risteli L, Risteli J, Virkkunen P, Sarna S, Elomaa I. Markers of type I collagen degradation and synthesis in the monitoring of treatment response in bone metastases from breast cancer.Br J Cancer 1996; 73: 1074–1079.

    PubMed  CAS  Google Scholar 

  41. Koizumi M, Matsumoto S, Takahashi S, Yamashita T, Ogata E. Bone metabolic markers are useful in the diagnosis of bone scan flare phenomenon in bone metastases from breast cancers.Clin Nucl Med 1999; 24: 15–20.

    Article  PubMed  CAS  Google Scholar 

  42. Ikeda I, Miura T, Kondo I. Pyridinium cross-links as markers of bone metastases in patients with prostate cancer.Br J Urol 1996; 77: 102–106.

    PubMed  CAS  Google Scholar 

  43. Body JJ, Coleman RE, Piccart M. Use of bisphosphonates in cancer patients.Cancer Treatment Review 1996; 22: 265–287.

    Article  CAS  Google Scholar 

  44. Berenson JR, Lichtenstein A, Porter L, Dimopuolos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma.New Engl J Med 1996; 334: 488–493.

    Article  PubMed  CAS  Google Scholar 

  45. Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastasis.New Engl J Med 1996; 335: 1785–1791.

    Article  PubMed  CAS  Google Scholar 

  46. Lipton A. Bisphosphonates and breast cancer.Cancer 1997; 80: 1668–1673.

    Article  PubMed  CAS  Google Scholar 

  47. Kylmala T, Tammela L, Risteli L, Risteli J, Taube T, Elomaa I. Evaluation of effect of oral clodronate on skeletal metastases with type I collagen matabolites. A controlled trial of the Finish prostate cancer group.Eur J Cancer 1993; 29: 821–825.

    Article  Google Scholar 

  48. Coleman RE, Houston S, James I, Rodger A, Rubens RD, Leonard RCF, et al. Preliminary results of the use of urinary excretion of pyridium crosslinks for monitoring metastatic bone disease.Br J Cancer 1992; 65: 766–768.

    PubMed  CAS  Google Scholar 

  49. Garnero P, Gineyts E, Arbault P, Christiansen C, Dermas PD. Different effects of bisphosphonate and estrogen therapy on free and peptide-bound bone cross-links excretion.J Bone and Mineral Res 1995; 10: 641–649.

    Article  CAS  Google Scholar 

  50. Vinholes J, Guo CY, Purohit OP, Eastell R, Coleman RE. Metabolic effects of pamidronate in patients with metastatic bone disease.Br J Cancer 1996; 73: 1089–1095.

    PubMed  CAS  Google Scholar 

  51. Francini G, Gonnelli S, Petrioli R, Conti F, Paffetti P, Gennari C. Treatment of bone metastases with dichloromethylene bisphosphonate.J Clin Oncol 1992; 10: 591–598.

    PubMed  CAS  Google Scholar 

  52. Koizumi M, Sekine H, Aoki M, Hayashi S, Yamashita T, Oyamada H, et al. Efficacy of YM-175, a new bisphosphonate, in the treatment of metastatic bone tumor from breast cancer and its effect on scintigraphy.Int J Clin Oncol 1996; 1: 18–22.

    Article  Google Scholar 

  53. Koizumi M, Kobayashi M, Furukawa M, Yamashita T, Ogata E. The bisphosphonate incadronate for bone metastases of breast cancer.Int J Clin Oncol 2000; 5: 241–246.

    Article  Google Scholar 

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Correspondence to Mitsuru Koizumi.

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Koizumi, M., Ogata, E. Bone metabolic markers as gauges of metastasis to bone: a review. Ann Nucl Med 16, 161–168 (2002). https://doi.org/10.1007/BF02996296

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