Breast Cancer

, Volume 24, Issue 2, pp 245–253 | Cite as

Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases

  • Arisa Nishimukai
  • Tomoko Higuchi
  • Hiromi Ozawa
  • Ayako Yanai
  • Yoshimasa Miyagawa
  • Keiko Murase
  • Michiko Imamura
  • Yuichi Takatsuka
  • Yasuo MiyoshiEmail author
Original Article



Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared.


For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrate-resistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment.


Serum TRACP-5b (p < 0.0001), NTX (p = 0.0007) and BAP (p = 0.0032) decreased significantly after treatment. The baseline median value of TRACP-5b (457.5 mU/dL, range 173–1630 mU/dL) decreased to 137 mU/dL (91–795 mU/dL) 1 month after treatment. Reduction in serum NTX and BAP was greatest after 3 and 6 months, respectively. TRACP-5b, NTX and BAP were above normal levels at baseline in 62.5, 25 and 35.3 % of patients, respectively, and nearly 80 % of these patients attained normal levels during the treatment.


Although bone-modifying agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases.


Breast cancer Bone metastasis Bone-modifying agent Bone turnover marker 



This study was supported by a Grant from the Hyogo College of Medicine.

Compliances with ethical standards

Conflict of interest

YM. received honoraria and research funds from AstraZeneca K.K., Novartis Pharma K.K., Daiichi Sankyo Co., Ltd. and Nittobo Medical Co., Ltd. The other authors declare that they have no conflict of interest.


  1. 1.
    Manders K, van de Poll-Franse LV, Creemers GJ, Vreugdenhil G, van der Sangen MJ, Nieuwenhuijzen GA, et al. Clinical management of women with metastatic breast cancer: a descriptive study according to age group. BMC Cancer. 2006;6:179.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.CrossRefPubMedGoogle Scholar
  3. 3.
    Coleman RE. Adjuvant bisphosphonates in breast cancer: are we witnessing the emergence of a new therapeutic strategy? Eur J Cancer. 2009;45(11):1909–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Lipton A, Cook RJ, Major P, Smith MR, Coleman RE. Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity. Oncologist. 2007;12(9):1035–43.CrossRefPubMedGoogle Scholar
  5. 5.
    Wong MH, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev. 2012;2:CD003474. doi: 10.1002/14651858.CD003474.pub3.Google Scholar
  6. 6.
    Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. 2004. J Bone Miner Res. 2005;20(12):2275–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80(8 suppl):1546–56.CrossRefPubMedGoogle Scholar
  9. 9.
    Massidda B, Ionta MT, Foddi MR, Mascia L, Bruder F, Aloi MB, et al. Usefulness of pyridinium crosslinks and CA 15-3 as markers in metastatic bone breast carcinoma. Anticancer Res. 1996;16(4B):2221–3.PubMedGoogle Scholar
  10. 10.
    Tähtelä R, Thölix E. Serum concentrations of type I collagen carboxyterminal telopeptide (ICTP) and type I procollagen carboxy-and aminoterminal propeptides (PICP, PINP) as markers of metastaticbone disease in breast cancer. Anticancer Res. 1996;16(4B):2289–93.PubMedGoogle Scholar
  11. 11.
    Demers LM, Costa L, Lipton A. Biochemical markers and skeletal metastases. Cancer. 2000;88(12 Suppl):2919–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Ali SM, Demers LM, Leitzel K, Harvey HA, Clemens D, Mallinak N, et al. Baseline serum NTx levels are prognostic in metastatic breast cancer patients with bone-only metastasis. Ann Oncol. 2004;15(3):455–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97(1):59–69.CrossRefPubMedGoogle Scholar
  14. 14.
    Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M, et al. Predictive value of bone resorption and formation markers in cancer patients with bonemetastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. 2005;23(22):4925–35.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhao X, Xu X, Zhang Q, Jia Z, Sun S, Zhang J, et al. Prognostic and predictive value of clinical and biochemical factors in breast cancer patients with bone metastases receiving “metronomic” zoledronic acid. BMC Cancer. 2011;22(11):403. doi: 10.1186/1471-2407-11-403.CrossRefGoogle Scholar
  16. 16.
    Barnadas A, Manso L, de la Piedra C, Meseguer C, Crespo C, Gómez P, et al. Bone turnover markers as predictive indicators of outcome in patients with breast cancer and bone metastases treated with bisphosphonates: results from a 2-year multicentre observational study (ZOMAR study). Bone. 2014;68:32–40.CrossRefPubMedGoogle Scholar
  17. 17.
    Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer. 2008;113(1):193–201.CrossRefPubMedGoogle Scholar
  18. 18.
    Halleen JM, Alatalo SL, Suominen H, Cheng S, Janckila AJ, Väänänen HK. Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res. 2000;15(7):1337–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Janckila AJ, Takahashi K, Sun SZ, Yam LT. Tartrate-resistant acid phosphatase isoform 5b as serum marker for osteoclastic activity. Clin Chem. 2001;47(1):74–80.PubMedGoogle Scholar
  20. 20.
    Chao TY, Ho CL, Lee SH, Chen MM, Janckila A, Yam LT. Tartrate-resistant acid phosphatase 5b as a serum marker of bone metastasis in breast cancer patients. J Biomed Sci. 2004;11(4):511–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Halleen JM, Alatalo SL, Janckila AJ, Woitge HW, Seibel MJ, Väänänen HK. Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption. Clin Chem. 2001;47(3):597–600.PubMedGoogle Scholar
  22. 22.
    Ohashi T, Igarashi Y, Mochizuki Y, Miura T, Inaba N, Katayama K, et al. Development of a novel fragments absorbed immunocapture enzyme assay system for tartrate-resistant acid phosphatase 5b. Clin Chim Acta. 2007;376(1–2):205–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Kiyohara T, Kuroe K, Chichibu K, Fukunaga H. Radioimmunoassay of 1CTP (cross-linked carboxyterminal telopeptide of type I collagen) in serum. (Japansese) Horumon to Rinshou. 1994;42:1189–93.Google Scholar
  24. 24.
    Woitge HW, Pecherstorfer M, Li Y, Keck AV, Horn E, Ziegler R, et al. Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res. 1999;14(5):792–801.CrossRefPubMedGoogle Scholar
  25. 25.
    Overgaard K, Alexandersen P, Riis BJ, Christiansen C. Evaluation of a new commercial IRMA for bone-specific alkaline phosphatase during treatment with hormone replacement therapy and calcitonin. Clin Chem. 1996;42(6 Pt 1):973–4.PubMedGoogle Scholar
  26. 26.
    Kress BC, Mizrahi IA, Armour KW, Marcus R, Emkey RD, Santora AC 2nd. Use of bone alkaline phosphatase to monitor alendronate therapy in individual postmenopausal osteoporotic women. Clin Chem. 1999;45(7):1009–17.PubMedGoogle Scholar
  27. 27.
    Wada N, Ishii S, Ikeda T, Enomoto K, Kitajima M. Serum tartrate resistant acid phosphatase as a potential marker of bone metastasis from breast cancer. Anticancer Res. 1999;19(5C):4515–21.PubMedGoogle Scholar
  28. 28.
    Chao TY, Yu JC, Ku CH, Chen MM, Lee SH, Janckila AJ, et al. Tartrate-resistant acid phosphatase 5b is a useful serum marker for extensive bone metastasis in breast cancer patients. Clin Cancer Res. 2005;11(2 Pt 1):544–50.PubMedGoogle Scholar
  29. 29.
    Wu YY, Janckila AJ, Ku CH, Yu CP, Yu JC, Lee SH, et al. Serum tartrate-resistant acid phosphatase 5b activity as a prognostic marker of survival in breast cancer with bone metastasis. BMC Cancer. 2010;10:158. doi: 10.1186/1471-2407-10-158.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Chung YC, Ku CH, Chao TY, Yu JC, Chen MM, Lee SH. Tartrate-resistant acid phosphatase 5b activity is a useful bone marker for monitoring bone metastases in breast cancer patients after treatment. Cancer Epidemiol Biomark Prev. 2006;15(3):424–8.CrossRefGoogle Scholar
  31. 31.
    Mountzios G, Terpos E, Syrigos K, Papadimitriou C, Papadopoulos G, Bamias A, et al. Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid. Transl Res. 2010;155(5):247–55.CrossRefPubMedGoogle Scholar
  32. 32.
    Bandeira F, Costa AG, Soares Filho MA, Pimentel L, Lima L, Bilezikian JP. Bone markers and osteoporosis therapy. Arq Bras Endocrinol Metabol. 2014;58(5):504–13.CrossRefPubMedGoogle Scholar
  33. 33.
    Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung MR, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):530–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Inage K, Orita S, Yamauchi K, Sakuma Y, Kubota G, Oikawa Y, et al. The time course changes in bone metabolic markers after administering the anti-receptor activator of nuclear factor-kappa B ligand antibody and drug compliance among patients with osteoporosis. Asian Spine J. 2015;9(3):338–43.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2016

Authors and Affiliations

  • Arisa Nishimukai
    • 1
  • Tomoko Higuchi
    • 1
  • Hiromi Ozawa
    • 1
  • Ayako Yanai
    • 1
  • Yoshimasa Miyagawa
    • 1
  • Keiko Murase
    • 1
  • Michiko Imamura
    • 1
  • Yuichi Takatsuka
    • 1
  • Yasuo Miyoshi
    • 1
    Email author
  1. 1.Department of Surgery, Division of Breast and Endocrine SurgeryHyogo College of MedicineNishinomiyaJapan

Personalised recommendations