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A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer

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Abstract

Background

Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs).

Methods

In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1β, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up.

Results

Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1β and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1β: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98).

Conclusions

Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

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Data availability

The data analyzed in this study are available from the corresponding authors upon reasonable requests.

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Acknowledgements

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. None of the authors has conflict of interest to report related to the work presented in this manuscript.

Funding

The Pathways Study was supported by the National Cancer Institute at the National Institutes of Health (R01 CA166701, PIs: Kwan ML, Yao S; R01 CA105274, PI: Kushi LH; U01 CA195565, PIs: Kushi LH, Ambrosone CB). Dr. Ambrosone is a recipient of funding from the Breast Cancer Research Foundation. Roswell Park DBBR and Flow Cytometry Shared Resource are CCSG Shared Resource supported by P30 CA16056 (PI: Johnson C). Availability of treatment data for cancer research was supported in part by the Cancer Research Network (U24 CA171524, PI: Kushi).

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Authors and Affiliations

  1. Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA

    Emily Liang & Michael Beshara

  2. Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA

    Haiyang Sheng, Xin-Wei Huang, Jennifer Delmerico, Li Tang, Chi-Chen Hong, Christine B. Ambrosone & Song Yao

  3. Department of Biostatistics, University at Buffalo, Buffalo, NY, USA

    Haiyang Sheng & Xin-Wei Huang

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

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

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Correspondence to Song Yao.

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Liang, E., Beshara, M., Sheng, H. et al. A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07423-6

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