A new study published on the preprint server medRxiv* examines the effect of bisphosphonates (BPs) on the outcome of coronavirus disease 2019 (COVID-19) in American patients during the first wave of the pandemic. These findings are promising and indicate the need for further research to validate the protective effects of these agents that are achieved through their immunomodulatory activities.
Study: Association between Bisphosphonate Use And COVID-19 Related Outcomes: A Retrospective Cohort Study. Image Credit: Towfigu ashamed barbhuiya / Shutterstock.com
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Introduction
BPs are commonly used to prevent and treat female osteoporosis as a result of their inhibitory action on osteoclast-associated bone resorption. These agents are also used in the treatment of Paget disease, hypercalcemia of malignancy, and breast cancer.
BPs can be further categorized as amino-BPs or non-amino BPs. Amino BPs, for example, affect the immune activation of both innate and adaptive immune cells including neutrophils, monocytes, and macrophages, as well as γδT cells. This leads to altered antigen presentation by dendritic cells.
Earlier in vivo studies have shown that BPs elicit powerful adjuvant activity on humoral and cellular responses to viral antigens. In severely ill patients admitted to the intensive care unit (ICU), BPs have been associated with reduced death rates. In other ICU patients, BPs are associated with a lower incidence of pneumonia and death related to pneumonia.
BPs are available worldwide, inexpensive in their generic versions, easily used, and considered safe under standard prescribing conditions in both children and adults.
About the study
In the current study, the potential for repurposing BPs for prophylaxis and the treatment of COVID-19 was examined.
Repurposing refers to exploring the utility of a drug already approved for the treatment of another distinct condition. Since drug repurposing allows researchers to utilize drugs that have already passed safety and pharmacokinetic testing, this approach could allow for the approval of potentially useful agents at a faster rate as compared to that which is required for the development process of new drugs.
Drugs with antiviral activity have been of particular scientific interest since the onset of the COVID-19 pandemic. Similarly, researchers have also been interested in immunomodulatory agents, as these may reduce the severity of symptoms and prevent or reduce disease progression.
In the current study, the authors utilized observational evidence from health insurance claims data to identify a possible role for BPs against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the pathogen that causes COVID-19.
The aim of the current study was to determine how the use of BPs including alendronate, alendronic acid, etidronate, ibandronate, ibandronic acid, pamidronate, risedronate, and zoledronic acid was related to hospitalizations due to COVID-19. Furthermore, the researchers were interested in exploring the relationship between BP use and COVID-19 diagnosis.
The current study period was from March 1, 2020, to June 30, 2020. At this point, vaccines nor other effective treatments for COVID-19 were available.
BPs can accumulate in bone and are released gradually for years afterward. Thus, the use of BPs during the 14 months prior to the study period was defined as exposure to the drug because of its long half-life.
Study findings
BP users were significantly older than non-users, with over 80% of users over the age of 60 years as compared to less than 30% of non-users within this age range. Over 90% of BP users were female, whereas less than 60% of non-users were female.
BP users also had a higher number of underlying illnesses as compared to non-users. Almost 45% of BP users, as compared to less than 15% of non-users, were covered by Medicare. Furthermore, about 66% of BP users and less than 45% of non-users had a history of visiting a primary care physician in 2019.
After adjusting for these differences, the rate of testing among BP users was reduced by 78% as compared to non-users, while the incidence of COVID-19 was 77% lower in BP users. Hospitalizations were also reduced by 74% in BP users. These associations remained consistent across states, as well as within New York alone.
The likelihood of hospitalization was similar among users of zoledronic acid with a history of last use in January/February 2019, as well as those who had just started using this drug in February 2020. Otherwise, all BP users showed significant reductions in all three outcomes, irrespective of the period of use, whether they were using the BP agent during the study period, or the type of BP used.
Visits for acute bronchitis and pneumonia were less frequent among BP users in the second half of 2019, thus indicating the beneficial role of these medications in preventing respiratory tract infections.
Implications
“This dramatic difference in outcomes consistently observed when comparing BP users to BP non-users” supports the hypothesis that BPs may be useful as immunomodulatory agents in treating COVID-19. The study findings also corroborate earlier studies that reported a protective association between BP use and pneumonia-related morbidity and mortality.
However, other studies failed to show a protective role for BPs in COVID-19 diagnosis and hospitalization, perhaps because of the large differences in study size. Sensitivity analyses using other anti-bone resorptive medications as controls showed no marked protective effect compared to BPs. Notably, studies that included only women above the age of 50 with osteoporosis showed the same pattern as the current study.
Similarly, studies that examined the use of BPs on other outcomes unrelated to COVID-19 failed to show such associations. Conversely, healthy adherents, as well as those who used other protective COVID-19 preventatives, did not exhibit the same trends. The use of BPs also did not change trends among those who used or did not use other prophylactics.
Further research will be required to ensure that confounding factors such as race, ethnicity, and socioeconomic factors are accounted for, as these factors affect the rate of diagnosis and severity of COVID-19. However, another recent study involving females taking BPs found that the race-adjusted incidence of COVID-19 was 1.7% as compared to 2.1% for non-users. In contrast, the present study showed rates of COVID-19 diagnosis to be 2.5% and 0.5%, respectively, thus requiring further explanations for this difference.
We propose that immune-modulatory effects of BPs may enhance the anti-viral response of BP users to SARS-CoV-2 and mitigate the development of symptoms. Milder or absent symptoms may have caused infected BP users to be less likely to seek testing.”
Amino-BPs affect the mevalonate pathway in the cells, which could account for part of their protective effect against COVID-19, as inhibition of this process limits the maturation of endosomes in antigen-presenting cells. This could increase antigen presentation, as well as both humoral and T-cell immune responses, thus producing an effect similar to that of an adjuvant.
The arrest of this pathway also causes a chemical called isopentyl diphosphate (IPP) to accumulate within neutrophils and subsequently stimulate a subset of T-cells called Vγ9Vδ2 T-cells. These T-cells are innate lymphocytes that migrate to infected sites and improve viral clearance, thus reducing disease progression.
This activity of BPs is supported by the apparent lack of protection on this scale that is observed with statins. Despite the fact that both of these agents inhibit the same pathway, they do so at a different step, which does not account for the accumulation of IPP.
Impairment of neutrophil-released reactive oxygen species (ROS) may also protect against the dysregulated neutrophil activation implicated in severe and critical COVID-19. Furthermore, BPs may modulate both innate and adaptive immune responses.
Our results suggest that prophylactic BP therapy may be sufficient to achieve a potentially rapid and sustained immune modulation resulting in profound mitigation of the incidence and/or severity of infections by SARS-CoV-2. Additional studies will be needed to rigorously assess whether the observed reduction in COVID-19-related outcomes is directly caused by BPs and remains true in patient populations not commonly prescribed BPs.”
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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