Skip to main content

Advertisement

SpringerLink
Log in

Bone remodeling and regulating biomarkers in women at the time of breast cancer diagnosis

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

The majority of breast cancer patients receive endocrine therapy, including aromatase inhibitors known to cause increased bone resorption. Bone-related biomarkers at the time of breast cancer diagnosis may predict future risk of osteoporosis and fracture after endocrine therapy.

Methods

In a large population of 2,401 female breast cancer patients who later underwent endocrine therapy, we measured two bone remodeling biomarkers, TRAP5b and BAP, and two bone regulating biomarkers, RANKL and OPG, in serum samples collected at the time of breast cancer diagnosis. We analyzed these biomarkers and their ratios with patients’ demographic, lifestyle, clinical tumor characteristics, as well as bone health history.

Results

The presence of bone metastases, prior bisphosphonate (BP) treatment, and blood collection after chemotherapy had a significant impact on biomarker levels. After excluding these cases and controlling for blood collection time, several factors, including age, race/ethnicity, body mass index, physical activity, alcohol consumption, smoking, and hormonal replacement therapy, were significantly associated with bone biomarkers, while vitamin D or calcium supplements and tumor characteristics were not. When prior BP users were included in, recent history of osteoporosis and fracture was also associated.

Conclusions

Our findings support further investigation of these biomarkers with bone health outcomes after endocrine therapy initiation in women with breast cancer.

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

Access this article

Log in via an institution

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

References

  1. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS (2008) The cell biology of bone metabolism. J Clin Pathol 61(5):577–587

    Article  CAS  PubMed  Google Scholar 

  2. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ 3rd, Khaltaev N (2008) A reference standard for the description of osteoporosis. Bone 42(3):467–475

    Article  CAS  PubMed  Google Scholar 

  3. Rabenda V, Bruyere O, Reginster JY (2011) Relationship between bone mineral density changes and risk of fractures among patients receiving calcium with or without vitamin D supplementation: a meta-regression. Osteoporos Int 22(3):893–901

    Article  CAS  PubMed  Google Scholar 

  4. Wheater G, Elshahaly M, Tuck SP, Datta HK, van Laar JM (2013) The clinical utility of bone marker measurements in osteoporosis. J Transl Med 11:201

    Article  PubMed  PubMed Central  Google Scholar 

  5. Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE (2006) Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 21(8):1215–1223

    Article  CAS  PubMed  Google Scholar 

  6. Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE et al (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 24(22):3629–3635

    Article  CAS  PubMed  Google Scholar 

  7. Lonning PE, Geisler J, Krag LE, Erikstein B, Bremnes Y, Hagen AI, Schlichting E, Lien EA, Ofjord ES, Paolini J et al (2005) Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23(22):5126–5137

    Article  PubMed  Google Scholar 

  8. McCaig FM, Renshaw L, Williams L, Young O, Murray J, Macaskill EJ, McHugh M, Hannon R, Dixon JM (2010) A study of the effects of the aromatase inhibitors anastrozole and letrozole on bone metabolism in postmenopausal women with estrogen receptor-positive breast cancer. Breast Cancer Res Treat 119(3):643–651

    Article  CAS  PubMed  Google Scholar 

  9. Zhang Y, Kiel DP, Kreger BE, Cupples LA, Ellison RC, Dorgan JF, Schatzkin A, Levy D, Felson DT (1997) Bone mass and the risk of breast cancer among postmenopausal women. N Engl J Med 336(9):611–617

    Article  CAS  PubMed  Google Scholar 

  10. Chen Z, Arendell L, Aickin M, Cauley J, Lewis CE, Chlebowski R (2008) Hip bone density predicts breast cancer risk independently of Gail score: results from the Women’s Health Initiative. Cancer 113(5):907–915

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cauley JA, Lucas FL, Kuller LH, Vogt MT, Browner WS, Cummings SR (1996) Bone mineral density and risk of breast cancer in older women: the study of osteoporotic fractures. Study of Osteoporotic Fractures Research Group. JAMA 276(17):1404–1408

    Article  CAS  PubMed  Google Scholar 

  12. Kwan ML, Ambrosone CB, Lee MM, Barlow J, Krathwohl SE, Ergas IJ, Ashley CH, Bittner JR, Darbinian J, Stronach K et al (2008) The Pathways Study: a prospective study of breast cancer survivorship within Kaiser Permanente Northern California. Cancer Causes Control 19(10):1065–1076

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ambrosone CB, Nesline MK, Davis W (2006) Establishing a cancer center data bank and biorepository for multidisciplinary research. Cancer Epidemiol Biomark Prev 15(9):1575–1577

    Article  Google Scholar 

  14. Kwan ML, Lo JC, Tang L, Laurent CA, Roh JM, Chandra M, Hahn TE, Hong CC, Sucheston-Campbell L, Hershman DL et al (2014) Bone health history in breast cancer patients on aromatase inhibitors. PLoS ONE 9(10):e111477

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lo JC, Pressman AR, Chandra M, Ettinger B (2011) Fracture risk tool validation in an integrated healthcare delivery system. Am J Manag Care 17(3):188–194

    PubMed  Google Scholar 

  16. Bonnick SL (2009) Bone densitometry in clinical practice: application and interpretation (Current Clinical Practice). Humana Press, New York

    Google Scholar 

  17. Schousboe JT, Shepherd JA, Bilezikian JP, Baim S (2013) Executive summary of the 2013 international society for clinical densitometry position development conference on bone densitometry. J Clin Densitom 16(4):455–466

    Article  PubMed  Google Scholar 

  18. Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, Vessella R, Corey E, Padalecki S, Suva L et al (2006) Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 12(20 Pt 2):6213s–6216s

    Article  CAS  PubMed  Google Scholar 

  19. Dougall WC, Holen I, Gonzalez Suarez E (2014) Targeting RANKL in metastasis. Bonekey Rep 3:519

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jung K, Lein M (2014) Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis. Biochim Biophys Acta 1846(2):425–438

    CAS  PubMed  Google Scholar 

  21. Shimozuma K, Sonoo H, Fukunaga M, Ichihara K, Aoyama T, Tanaka K (1999) Biochemical markers of bone turnover in breast cancer patients with bone metastases: a preliminary report. Jpn J Clin Oncol 29(1):16–22

    Article  CAS  PubMed  Google Scholar 

  22. Leeming DJ, Koizumi M, Byrjalsen I, Li B, Qvist P, Tanko LB (2006) The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients. Cancer Epidemiol Biomark Prev 15(1):32–38

    Article  CAS  Google Scholar 

  23. Leeming DJ, Delling G, Koizumi M, Henriksen K, Karsdal MA, Li B, Qvist P, Tanko LB, Byrjalsen I (2006) Alpha CTX as a biomarker of skeletal invasion of breast cancer: immunolocalization and the load dependency of urinary excretion. Cancer Epidemiol Biomark Prev 15(7):1392–1395

    Article  CAS  Google Scholar 

  24. LaCroix AZ, Jackson RD, Aragaki A, Kooperberg C, Cauley JA, Chen Z, Leboff MS, Duggan D, Wactawski-Wende J (2013) OPG and sRANKL serum levels and incident hip fracture in postmenopausal Caucasian women in the Women’s Health Initiative Observational Study. Bone 56(2):474–481

    Article  CAS  PubMed  Google Scholar 

  25. Warming L, Hassager C, Christiansen C (2002) Changes in bone mineral density with age in men and women: a longitudinal study. Osteoporos Int 13(2):105–112

    Article  CAS  PubMed  Google Scholar 

  26. Imai Y, Youn MY, Kondoh S, Nakamura T, Kouzmenko A, Matsumoto T, Takada I, Takaoka K, Kato S (2009) Estrogens maintain bone mass by regulating expression of genes controlling function and life span in mature osteoclasts. Ann N Y Acad Sci 1173(Suppl 1):E31–E39

    Article  CAS  PubMed  Google Scholar 

  27. Rapuri PB, Gallagher JC, Balhorn KE, Ryschon KL (2000) Alcohol intake and bone metabolism in elderly women. Am J Clin Nutr 72(5):1206–1213

    CAS  PubMed  Google Scholar 

  28. Marrone JA, Maddalozzo GF, Branscum AJ, Hardin K, Cialdella-Kam L, Philbrick KA, Breggia AC, Rosen CJ, Turner RT, Iwaniec UT (2012) Moderate alcohol intake lowers biochemical markers of bone turnover in postmenopausal women. Menopause 19(9):974–979

    PubMed  Google Scholar 

  29. Sampson HW (1998) Effect of alcohol consumption on adult and aged bone: a histomorphometric study of the rat animal model. Alcohol Clin Exp Res 22(9):2029–2034

    CAS  PubMed  Google Scholar 

  30. Hagberg JM, Zmuda JM, McCole SD, Rodgers KS, Ferrell RE, Wilund KR, Moore GE (2001) Moderate physical activity is associated with higher bone mineral density in postmenopausal women. J Am Geriatr Soc 49(11):1411–1417

    Article  CAS  PubMed  Google Scholar 

  31. Trautvetter U, Neef N, Leiterer M, Kiehntopf M, Kratzsch J, Jahreis G (2014) Effect of calcium phosphate and vitamin D(3) supplementation on bone remodelling and metabolism of calcium, phosphorus, magnesium and iron. Nutr J 13:6

    Article  PubMed  PubMed Central  Google Scholar 

  32. Seamans KM, Hill TR, Wallace JM, Horigan G, Lucey AJ, Barnes MS, Taylor N, Bonham MP, Muldowney S, Duffy EM et al (2010) Cholecalciferol supplementation throughout winter does not affect markers of bone turnover in healthy young and elderly adults. J Nutr 140(3):454–460

    Article  CAS  PubMed  Google Scholar 

  33. Aloia J, Bojadzievski T, Yusupov E, Shahzad G, Pollack S, Mikhail M, Yeh J (2010) The relative influence of calcium intake and vitamin D status on serum parathyroid hormone and bone turnover biomarkers in a double-blind, placebo-controlled parallel group, longitudinal factorial design. J Clin Endocrinol Metab 95(7):3216–3224

    Article  CAS  PubMed  Google Scholar 

  34. Bikle DD (2014) Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 21(3):319–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ et al (2014) Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol 32(21):2255–2269

    Article  PubMed  PubMed Central  Google Scholar 

  36. Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE (2002) Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20(3):751–757

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Pathways Study was supported by the National Cancer Institute at the National Institutes of Health (R01 CA105274, PI: Kushi LH; R01 CA166701, PIs: Kwan ML, Yao S). Electronic clinical data abstraction and integration was supported in part by Cancer Research Network (CRN) (U19 CA079689, U24 CA171524, PI: Kushi LH). RPCI DBBR is CCSG Shared Resource supported by P30 CA16056 (PI: Ambrosone CB). The authors thank office and field staff for data collection, processing, and preparation and DBBR staff for biospecimen processing. We thank all Pathways Study participants for their numerous contributions to this study. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies.

Funding

This study was funded by National Institute of Health (R01 CA105274; U24 CA171524; P30 CA16056; R01 CA166701).

Author information

Authors and Affiliations

  1. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Song Yao, Yali Zhang, Li Tang, Chi-Chen Hong & Christine B. Ambrosone

  2. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    Yali Zhang & Theresa Hahn

  3. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

    Janise M. Roh, Cecile A. Laurent, Joan C. Lo, Lawrence H. Kushi & Marilyn L. Kwan

Authors
  1. Song Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yali Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Janise M. Roh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cecile A. Laurent
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chi-Chen Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Theresa Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joan C. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christine B. Ambrosone
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lawrence H. Kushi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marilyn L. Kwan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Song Yao.

Ethics declarations

Conflict of interest

J.L. and/or an immediate family member has received past or current research funding from Amgen, Sanofi, AstraZeneca, GlaxoSmithKline, Novartis, CSL Behring, and Milestone Pharmaceuticals, all unrelated to the current study. The other authors declare that they have no conflict of interest.

Ethnical approval

The study was approved by institutional review boards of Roswell Park Cancer Institute and Kaiser Permanente Northern California for human subject protection.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yao, S., Zhang, Y., Tang, L. et al. Bone remodeling and regulating biomarkers in women at the time of breast cancer diagnosis. Breast Cancer Res Treat 161, 501–513 (2017). https://doi.org/10.1007/s10549-016-4068-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-016-4068-5

Keywords

Search

Navigation