Bone remodeling and regulating biomarkers in women at the time of breast cancer diagnosis
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.
KeywordsBreast 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.
The study was approved by institutional review boards of Roswell Park Cancer Institute and Kaiser Permanente Northern California for human subject protection.
Informed consent was obtained from all individual participants included in the study.
- 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.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.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
- 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
- 16.Bonnick SL (2009) Bone densitometry in clinical practice: application and interpretation (Current Clinical Practice). Humana Press, New YorkGoogle 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):474–481CrossRefPubMedGoogle 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):3216–3224CrossRefPubMedGoogle 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):2255–2269CrossRefPubMedPubMedCentralGoogle Scholar