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.).
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.
- Ulrich H von Andrian
- Ulrich H von Andrian
- Ulrich H von Andrian
- Pavel Hanč
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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
- Marc J Bonten, University Medical Center Utrecht, Netherlands
- Received: April 17, 2022
- Accepted: June 28, 2023
- Accepted Manuscript published: August 3, 2023 (version 1)
© 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.
In most of the world, the mammography screening programmes were paused at the start of the pandemic, whilst mammography screening continued in Denmark. We examined the mammography screening participation during the COVID-19 pandemic in Denmark.
The study population comprised all women aged 50–69 years old invited to participate in mammography screening from 2016 to 2021 in Denmark based on data from the Danish Quality Database for Mammography Screening in combination with population-based registries. Using a generalised linear model, we estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) of mammography screening participation within 90, 180, and 365 d since invitation during the pandemic in comparison with the previous years adjusting for age, year and month of invitation.
The study comprised 1,828,791 invitations among 847,766 women. Before the pandemic, 80.2% of invitations resulted in participation in mammography screening within 90 d, 82.7% within 180 d, and 83.1% within 365 d. At the start of the pandemic, the participation in screening within 90 d was reduced to 69.9% for those invited in pre-lockdown and to 76.5% for those invited in first lockdown. Extending the length of follow-up time to 365 d only a minor overall reduction was observed (PR = 0.94; 95% CI: 0.93–0.95 in pre-lockdown and PR = 0.97; 95% CI: 0.96–0.97 in first lockdown). A lower participation was, however, seen among immigrants and among women with a low income.
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.
The study was funded by the Danish Cancer Society Scientific Committee (grant number R321-A17417) and the Danish regions.
Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is partially maintained among repeated serial samples from the same host, it can transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.