Abstract

Background: Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

Methods: A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.

Results: 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR=0.22; 95%CI:0.21-0.23; p<0.001), COVID-19 diagnosis (OR=0.23; 95%CI:0.22-0.24; p<0.001), and COVID-19-related hospitalization (OR=0.26; 95%CI:0.24-0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR=0.23; 95%CI:0.22-0.23; p<0.001) or pneumonia (OR=0.32; 95%CI:0.31-0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

Conclusions: Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.

Funding: This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to U.H.v.A.) and a CRI Irvington postdoctoral fellowship, CRI2453 (to P.H.).

Data availability

Excel spreadsheets of source data are provided as supplemental information for figures 1C, 2B, 3A-D, and 4B-E.The administrative claims data used in this study cannot be made publicly available as it as it is a business product of Komodo Health, who contracts with insurers to develop the combined de-identified dataset under agreements that no patient-level data is permitted outside of the Komodo Health analytics environment. All analyses for this current study were performed in the Komodo Health analytics environment.An interested researcher may contact the corresponding author listed in this article by electronic mail at the address listed, who can then further connect them to a researcher at the company who is familiar with the study. The data was analyzed using Microsoft Excel software.

Article and author information

Author details

  1. Jeffrey Thompson

    Cerner Enviza, Malvern, United States
    Competing interests
    Jeffrey Thompson, is a full time employee of Cerner Health and received support for attending ISPOR 2022 from Cerner Enviza (previously Kantar Health). The author has no other competing interests to declare..
  2. Yidi Wang

    Department of Immunology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  3. Tobias Dreischulte

    Institute of General Practice and Family Medicine, Ludwig-Maximilians-University, Munich, Germany
    Competing interests
    Tobias Dreischulte, received payments/honoraria from Techniker Krankenkasse (public insurance fund) for editing a report on COVID-19 treatments, and research grants from BMBF (German federal ministry for research) and from the Inoovationsfond (German federal research fund for health services research). The author has no other competing interests to declare..
  4. Olga Barreiro

    Department of Immunology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Rodrigo J Gonzalez

    Department of Immunology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Pavel Hanč

    Department of Immunology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  7. Colette Matysiak

    Department of Immunology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  8. Harold R Neely

    Department of Immunology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  9. Marietta Rottenkolber

    Institute of General Practice and Family Medicine, Ludwig-Maximilians-University, Munich, Germany
    Competing interests
    No competing interests declared.
  10. Thomas Haskell

    Cerner Enviza, Malvern, United States
    Competing interests
    Thomas Haskell, is a full time employee of Cerner Health and received support for attending ISPOR 2022 from Cerner Enviza (previously Kantar Health). The author has no other competing interests to declare..
  11. Stefan Endres

    Center of Integrated Protein Science Munich, Ludwig-Maximilians-University, Munich, Germany
    Competing interests
    Stefan Endres, received grants from BMBF (German Federal Ministry for Research) and Bio-M (Munich Cluster Organisation). The author received royalties/licenses from TCR2, Cambridge, MA, USA and Carina Biotech Ltd, Mawson Lakes, Australia. The author received honoraria for chairing the Scientific committee at Else Kröner Fresenius Foundation (non-profit), acting as scientific advisor for the Paul-Martini-Foundation (non-profit) and textbook editor and author for Elsevier. The author received payment for expert testimony from CMS Hasche Sigle, Law firm and Gilde Healthcare, Utrecht, Netherlands (private equity investor). The author holds stock options at TCR2, Cambridge, MA, USA. Patents have been issued for Bispecific antibody molecules with antigentransfected T cells and their use in medicine, and PD1-CD28 fusions proteins and their use in medicine. Patents are pending for CXCR6 transduced T cells for targeted tumor therapy, Improving adoptive cellular therapy, CCR8 transduced T cells for targeted tumor therapy and CSF1R-targeted immunotherapies. The author has no other competing interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4703-537X
  12. Ulrich H von Andrian

    Department of Immunology, Harvard Medical School, Boston, United States
    For correspondence
    uva@hms.harvard.edu
    Competing interests
    Ulrich H von Andrian, received the following grants unrelated to this project; HMS-AbbVie Alliance, Program Area 1; Project 1: 'Host-virus interaction dynamics in nasal mucosa and associated lymphoid tissues', Gates Foundation, OPP1155348 'Mucosal Vaccine Consortium' and Moderna-HMS ARTiMIS Alliance. Ulrich H von Andrian was granted the following patents unrelated to this project; US Patents #9539210, 8932595, 8277812, 8906381, 8343497 licensed to Selecta Biosciences, and US Patent #11111472 licensed to SQZ. Ulrich H von Andrian is a paid consultant of AbbVie, Avenge Bio, Beam Therapeutics, Bluesphere Bio, FL72, DNAlite, Gate Biosciences, Gentibio, Intergalactic, intrECate Biotherapeutics, Interon, Institute for Protein Innovation, Mallinckrodt Pharmaceuticals, Moderna, Monopteros Biotherapeutics, Morphic Therapeutics, Rubius, Selecta and SQZ. The author holds stock/stock options at Avenge Bio, Beam, Bluesphere, FL72, IntrECate, Interon, Moderna, Monopteros, Morphic, Rubius, Selecta and SQZ. The author received payment/honoraria for a Keynote Lecture at 'Applied Pharmaceutical Nanotechnology 2019', Cambridge, MA (organized by Pfizer), Nov. 2019 and Mallinckrodt Mini-Symposium, Oct. 2019. The author received support as a speaker at the following conferences: Ethics in Medicine Seminar, San Servolo Italy, May 2022; Keystone Symposium 'B and T cell Memory'; Keystone Symposium 'Stromal Cells in Immunity and Disease', Feb. 2020; and HIV Prevention Workshop, South Africa, Nov. 2019. The author is an inventor on the following pending patents: Ziegler et al. 'METHODS AND COMPOSITION FOR MODULATING IMMUNE RESPONSE AND IMMUNE HOMEOSTASIS', Docket # BROD-4830US; Thiriot et al. 'Modulating phenotype and function of high endothelial venules' Provisional docket # 00742-304001, von Andrian and Thiriot. 'Microvessel endothelial cells and uses thereof' Provisional docket #HRVY 026-001. The author holds a leadership/fiduciary role on the Monopteros Biotherapeutics Board of Directors, intrECate Biotherapeutics Board of Directors and Councilor of the American Association of Immunologists. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4231-2283

Funding

National Institute of Allergy and Infectious Diseases (AI155865)

  • Ulrich H von Andrian

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR068383)

  • Ulrich H von Andrian

MassCPR (Evergrande COVID‐19 Response Fund Award)

  • Ulrich H von Andrian

Cancer Research Institute (CRI2453)

  • Pavel Hanč

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study protocol was reviewed by Pearl IRB (Indianapolis, IN) and was determined to be Exempt according to FDA 21 CFR 56.104 and 45CFR46.104(b)(4): (4) Secondary Research Uses of Data or Specimens on 02/08/2021.Protocol #21-ACUT-101

Reviewing Editor

  1. Marc J Bonten, University Medical Center Utrecht, Netherlands

Version history

  1. Received: April 17, 2022
  2. Accepted: June 28, 2023
  3. Accepted Manuscript published: August 3, 2023 (version 1)

Copyright

© 2023, Thompson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jeffrey Thompson
  2. Yidi Wang
  3. Tobias Dreischulte
  4. Olga Barreiro
  5. Rodrigo J Gonzalez
  6. Pavel Hanč
  7. Colette Matysiak
  8. Harold R Neely
  9. Marietta Rottenkolber
  10. Thomas Haskell
  11. Stefan Endres
  12. Ulrich H von Andrian
(2023)
Association between Bisphosphonate use and COVID-19 related outcomes
eLife 12:e79548.
https://doi.org/10.7554/eLife.79548

Further reading

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    The short-term participation in mammography screening was reduced at the start of the pandemic, whilst only a minor reduction in the overall participation was observed with longer follow-up time, indicating that women postponed screening. Some groups of women, nonetheless, had a lower participation, indicating that the social inequity in screening participation was exacerbated during the pandemic.

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    The study was funded by the Danish Cancer Society Scientific Committee (grant number R321-A17417) and the Danish regions.

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