Breast Cancer Research and Treatment

, Volume 161, Issue 3, pp 501–513 | Cite as

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

  • Song Yao
  • Yali Zhang
  • Li Tang
  • Janise M. Roh
  • Cecile A. Laurent
  • Chi-Chen Hong
  • Theresa Hahn
  • Joan C. Lo
  • Christine B. Ambrosone
  • Lawrence H. Kushi
  • Marilyn L. Kwan



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.


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.


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.


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


Breast cancer Aromatase inhibitor Tamoxifen Bone Biomarker 



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.


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

Compliance with ethnical standards

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.

Supplementary material

10549_2016_4068_MOESM1_ESM.xlsx (14 kb)
Supplementary material 1 (XLSX 13 kb)


  1. 1.
    Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS (2008) The cell biology of bone metabolism. J Clin Pathol 61(5):577–587CrossRefPubMedGoogle Scholar
  2. 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):467–475CrossRefPubMedGoogle Scholar
  3. 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):893–901CrossRefPubMedGoogle Scholar
  4. 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 11:201CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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):1215–1223CrossRefPubMedGoogle Scholar
  6. 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):3629–3635CrossRefPubMedGoogle Scholar
  7. 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):5126–5137CrossRefPubMedGoogle Scholar
  8. 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):643–651CrossRefPubMedGoogle Scholar
  9. 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):611–617CrossRefPubMedGoogle Scholar
  10. 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):907–915CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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):1404–1408CrossRefPubMedGoogle Scholar
  12. 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):1065–1076CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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):1575–1577CrossRefGoogle Scholar
  14. 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):e111477CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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):188–194PubMedGoogle Scholar
  16. 16.
    Bonnick SL (2009) Bone densitometry in clinical practice: application and interpretation (Current Clinical Practice). Humana Press, New YorkGoogle Scholar
  17. 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):455–466CrossRefPubMedGoogle Scholar
  18. 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–6216sCrossRefPubMedGoogle Scholar
  19. 19.
    Dougall WC, Holen I, Gonzalez Suarez E (2014) Targeting RANKL in metastasis. Bonekey Rep 3:519CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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):425–438PubMedGoogle Scholar
  21. 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):16–22CrossRefPubMedGoogle Scholar
  22. 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):32–38CrossRefGoogle Scholar
  23. 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):1392–1395CrossRefGoogle Scholar
  24. 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):474–481CrossRefPubMedGoogle Scholar
  25. 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):105–112CrossRefPubMedGoogle Scholar
  26. 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–E39CrossRefPubMedGoogle Scholar
  27. 27.
    Rapuri PB, Gallagher JC, Balhorn KE, Ryschon KL (2000) Alcohol intake and bone metabolism in elderly women. Am J Clin Nutr 72(5):1206–1213PubMedGoogle Scholar
  28. 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):974–979PubMedGoogle Scholar
  29. 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):2029–2034PubMedGoogle Scholar
  30. 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):1411–1417CrossRefPubMedGoogle Scholar
  31. 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 13:6CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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):454–460CrossRefPubMedGoogle Scholar
  33. 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):3216–3224CrossRefPubMedGoogle Scholar
  34. 34.
    Bikle DD (2014) Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 21(3):319–329CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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):2255–2269CrossRefPubMedPubMedCentralGoogle Scholar
  36. 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):751–757CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Song Yao
    • 1
  • Yali Zhang
    • 1
    • 2
  • Li Tang
    • 1
  • Janise M. Roh
    • 3
  • Cecile A. Laurent
    • 3
  • Chi-Chen Hong
    • 1
  • Theresa Hahn
    • 2
  • Joan C. Lo
    • 3
  • Christine B. Ambrosone
    • 1
  • Lawrence H. Kushi
    • 3
  • Marilyn L. Kwan
    • 3
  1. 1.Department of Cancer Prevention and ControlRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of MedicineRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Division of ResearchKaiser Permanente Northern CaliforniaOaklandUSA

Personalised recommendations