Skip to main content
Log in

Bone metabolic markers in bisphosphonate therapy for skeletal metastases in patients with breast cancer

  • Review Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

The use of bisphosphonates for skeletal metastasis of breast cancer is now well established. Although clinical judgement for treating skeletal metastasis is based on symptoms and imaging studies, accurate or quantitative means are few. Various bone metabolic markers have been developed and these were evaluated in patients with metastasis to bone. Bone metabolic markers, especially resorption markers, have been shown to be a good tool for the monitoring the response to therapy for skeletal metastasis. This is also true for bisphosphonate treatment for skeletal metastasis. Bone metabolic markers are produced by different mechanisms. There are some different classes of resorption markers; tartrate-resistant acid phosphatase (TRAP) is secreted by osteoclast, N- and C-terminal cross-linking telopeptide of type I collagen (NTx and CTx) are the degradation the products of type I collagen, mainly produced by cathepsin K, and pyridinoline cross-linked carboxyl-terminal telopeptides of type I collagen (ICTP) is also a degradation product of type I collagen, by matrix metalloproteases. Even though bone resorption markers are a good tool to monitor response to bisphosphonate therapy, there remains the question of which class of bone resorption markers is best suited to the task.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Al-p:

Alkaline phosphatase

BAI-p:

Bone specific alkaline phosphatase

BGP:

Bone gla protein also called osteocalcin

BSP:

Bone sialoprotein

Cat K:

Cathepsin K

CTx:

C-terminal cross-linking telopeptide of type I collagen

DPD:

Deoxy-pyridinoline

fDPD:

Free deoxy-pyridinoline

ICTP:

Pyridinoline cross-linked carboxyl-terminal telopeptides of type I collagen

MMP:

Matrix metalloprotease

MRI:

Magnetic resonance imaging

NTx:

N-terminal cross-linking telopeptide of type I collagen

OC:

Osteocalcin

PICP:

Carboxy-terminal propeptide of type I procollagen

PINP:

amino-terminal propeptide of type I procollagen

PYP:

Pyridinolone

TRAP:

Tartrate resistant acid pnosphatase

TRAP 5b:

Tartrate resistant acid phosphatase 5b

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone JF, Seaman J, Knight RD, Hefferman M, Reitsma DJ: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastasis.New Engl J Med 335: 1785–1791, 1996.

    Article  PubMed  CAS  Google Scholar 

  3. Lipton A: Bisphosphonates and breast cancer.Cancer 80: 1668–1673, 1997.

    Article  PubMed  CAS  Google Scholar 

  4. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, Kaufmann M, Bastert G: Reduction in new metastases in breast cancer with adjuvant clodronate treatment.New Engl J Med 339: 357–363, 1998.

    Article  PubMed  CAS  Google Scholar 

  5. Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C,et al: Long term prevention of skeletal complication of metastatic breast cancer with pamidronate.J Clin Oncol 16: 2038–2044, 1998.

    PubMed  CAS  Google Scholar 

  6. Berenson JB, Rosen LS, Howell A, Porter L, Coleman RE, Morley W, Dreicer R, Kuross SA, Lipton A, Seaman JJ: Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. A double-blind, randomized dose-response study.Cancer 91: 1191–1200, 2001.

    Article  PubMed  CAS  Google Scholar 

  7. Hillner BE, Ingle JN, Berenson JR, Janjan NA, Albain KS, Lipton A,et al: American Society of Clinical Oncology Guideline on the role of bisphosphonates in breast cancer.J Clin Oncol 18: 1378–1391, 2000.

    PubMed  CAS  Google Scholar 

  8. Koizumi M: Bone scintigraphy in oncology. Endo K ed, Mediculture, Tokyo, 2000 (in Japanese).

    Google Scholar 

  9. Yamamoto I: Skeletal nuclear medicine.Kakuigaku 32: 523–529, 1995 (in Japanese with English abstract).

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Algra PR, Bloem JL, Tissing H, Falke THM, Arndt JW, Verboom LJ: Detection of vertebral metastases: comparison between MR imaging and bone scintigraphy.Radiographics 11: 219–232, 1991.

    PubMed  CAS  Google Scholar 

  12. 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 13: 1123–1128, 1995.

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. 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 15: 1337–1345, 2000.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  19. Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda T, Desnick RJ, Gelb B: Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation.J Bone Miner Res 14: 1902–1908, 1999.

    Article  PubMed  CAS  Google Scholar 

  20. 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 26: 241–247, 2000.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Karsda MA, Garnero P, Ferreras M, Risteli J, Ovist P, Foged N, Delaisse JM: Type I collagen fragments ICTP and CTx reveal distinct enzymatic pathways of bone collagen degradation.J Bone Miner Res 16(suppl): 195, 2001.

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  24. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonario J, Goldstein S, Gundberg C, Bradley A, Karsenty G: Increased bone formation in osteocalcin-deficient mice.Nature 382: 448–452, 1996.

    Article  PubMed  CAS  Google Scholar 

  25. Diel IJ, Solomayer EF, Siebel MJ, Pfeilschifter J, Maisenbacher H, Gollan C, Pecherstofer M, Conradi R, Kehr G, Boehm E, Armbruster FP, Bastert G: Serum sialoprotein in patients with primary breast cancer is prognostic marker for subsequent bone metastasis.Clin Cancer Res 5: 3914–3919, 1999.

    PubMed  CAS  Google Scholar 

  26. 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 Treat Rev 22: 289–331, 1996.

    Article  PubMed  CAS  Google Scholar 

  27. Koizumi M, Yamada Y, Takiguchi T, Nomura E, Furukawa M, Kitahara T, Yamashita T, Maeda H, Takahashi S, Aiba K, Ogata E: Bone metabolic markers in bone metastasis.J Cancer Res Clin Oncol 121: 542–548, 1995.

    Article  PubMed  CAS  Google Scholar 

  28. 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 41: 1489–1494, 1995.

    PubMed  CAS  Google Scholar 

  29. Yamamoto I, Morita R, Konishi J, Shigeno C, Ikekubo K, Hino M, Sone T, Fujimoto R: Clinical studies using measurement of N-telopeptides of type-I collagen (NTx) in patients with bone metastasis.Kakuigaku 32: 501–510, 1995.

    CAS  Google Scholar 

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

    Article  Google Scholar 

  31. 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 79: 1693–1700, 1994.

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  34. 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 73: 1074–1079, 1996.

    PubMed  CAS  Google Scholar 

  35. 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 24: 15–20, 1999.

    Article  PubMed  CAS  Google Scholar 

  36. Body JJ, Coleman RE, Piccart M: Use of bisphosphonates in cancer patients.Cancer Treat Rev 22: 265–287, 1996.

    Article  PubMed  CAS  Google Scholar 

  37. Kanis JA, Powels T, Paterson AH, McCloskey EV, Ashley S: Clodronate decreases the frequency of skeletal metastases in women with breast cancer.Bone 19: 663–667, 1996.

    Article  PubMed  CAS  Google Scholar 

  38. Saarto T, Blomquvist C, Virkkunen P, Elomaa I: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node positive breast cancer patients: 5-year results of randomized controlled trial.J Clin Oncol 19: 10–17, 2001.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  40. 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 10: 641–649, 1995

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. Koizumi M, Sekine H, Aoki M, Hayashi S, Yamashita T, Oyamada H, Ogata E: 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 1: 18–22, 1996.

    Article  Google Scholar 

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

    Article  Google Scholar 

  45. Berenson JR, Vescio R, Henick K, Nishikubo C, Rettig M, Swift RA, Conde F, von Teichert JM: A phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease.Cancer 91: 144–154, 2001.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mitsuru Koizumi.

Additional information

Reprint requests to Mitsuru Koizumi, Department of Nuclear Medicine, Cancer Institute Hospital, 1-37-1, Kami-ikebukuro, Toshimaku, Tokyo 170-8455, Japan.

About this article

Cite this article

Koizumi, M., Takahashi, S. & Ogata, E. Bone metabolic markers in bisphosphonate therapy for skeletal metastases in patients with breast cancer. Breast Cancer 10, 21–27 (2003). https://doi.org/10.1007/BF02967621

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02967621

Key words

Navigation