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Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study

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Abstract

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998–1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4+CD28− T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60–0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01–1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37–0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

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Funding

The research reported in this article was supported by R01HL120854 and R01HL135625 from the National Heart, Lung, and Blood Institute (NHLBI) and contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. Rick Saha, MD’s participation in this work was made possible by funding from the Rheumatology Research Foundation Medical & Graduate Student Research Preceptorship. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the National Institutes of Health, the Rheumatology Research Foundation or the United States government.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, Augusta University, Augusta, GA, USA

    Rachel E. Elam & Laura D. Carbone

  2. Charlie Norwood Veterans Affairs Medical Center, Veterans Affairs Health Care System, Augusta, GA, USA

    Rachel E. Elam & Laura D. Carbone

  3. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Petra Bůžková

  4. Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA

    Joseph A. C. Delaney & Bruce M. Psaty

  5. College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada

    Joseph A. C. Delaney

  6. Geriatric Research Education and Clinical Center, Veterans Affairs Health Care System, Minneapolis, MN, USA

    Howard A. Fink

  7. Division of Endocrinology, Kaiser Permanente of Georgia, Emory University School of Medicine, Atlanta, GA, USA

    Joshua I. Barzilay

  8. Department of Internal Medicine, New York University Langone, New York, NY, USA

    Rick Saha

  9. Department of Medicine, University of California Davis, Davis, CA, USA

    John A. Robbins

  10. Department of Medicine, Beth Israel Deaconess Medical Center, Brookline, MA, USA

    Kenneth J. Mukamal

  11. Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Rodrigo J. Valderrábano

  12. Department of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA

    Bruce M. Psaty

  13. Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA

    Russell P. Tracy, Nels C. Olson, Sally A. Huber & Margaret F. Doyle

  14. Department of Biochemistry, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA

    Russell P. Tracy

  15. Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA

    Alan L. Landay

  16. Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Jane A. Cauley

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  1. Rachel E. Elam
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Corresponding author

Correspondence to Rachel E. Elam.

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Conflict of interest

Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Rachel E. Elam, Petra Bůžková, Joseph A.C. Delaney, Howard A. Fink, Joshua I. Barzilay, Laura D. Carbone, Rick Saha, John A. Robbins, Kenneth J. Mukamal, Rodrigo J Valderrábano, Russell P. Tracy, Nels C. Olson, Sally A. Huber, Margaret F. Doyle, Alan L. Landay, and Jane A. Cauley declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

The Cardiovascular Health Study (CHS) was approved by the Institutional Review Board (IRB) at each study site. All participants gave written informed consent. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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Elam, R.E., Bůžková, P., Delaney, J.A.C. et al. Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study. Calcif Tissue Int 113, 581–590 (2023). https://doi.org/10.1007/s00223-023-01126-8

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