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 US 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 achieved through their immunomodulatory activities.
Study: Association between bisphosphonate use and COVID-19-related outcomes: a retrospective cohort study† Image Credit: Towfigu embarrassed barbhuiya / Shutterstock.com
BPs are commonly used to prevent and treat osteoporosis in women due to their inhibitory action on osteoclast-associated bone resorption. These agents are also used in the treatment of Paget’s disease, hypercalcemia of malignancy and breast cancer.
BPs can be further categorized as amino BPs or non-amino BPs. For example, amino-BPs affect immune activation of both innate and adaptive immune cells, including neutrophils, monocytes, and macrophages, as well asT cells† This leads to altered antigen presentation by dendritic cells.
earlier in vivo studies have shown that BPs elicit potent adjuvant activity on humoral and cellular responses to viral antigens† In critically ill patients admitted to the intensive care unit (ICU), BPs have been associated with lower 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, easy to use and considered safe under standard prescribing conditions in both children and adults.
About the study
The current study explored the potential for repurposing BPs for prophylaxis and treatment of COVID-19.
Repurposing refers to investigating the usefulness of a drug that is already approved for the treatment of another separate condition. Since drug reuse allows researchers to use drugs that have already passed safety and pharmacokinetic testing, this approach could allow the approval of potentially useful agents at a faster rate than what 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 are also interested in immunomodulatory agents, as they can reduce the severity of symptoms and prevent or reduce disease progression.
In the current study, the authors used observational evidence from health insurance data to identify a potential role for borderlines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 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, were associated with hospitalizations due to COVID-19. In addition, the researchers were interested in examining the relationship between BP use and COVID-19 diagnosis.
The current study period ran from March 1, 2020 to June 30, 2020. At that time, vaccines or other effective treatments for COVID-19 were available.
BPs can build up in bone and are gradually released over years after that. For example, use of BPs during the 14 months prior to the study period was defined as exposure to the drug due to its long half-life.
BP users were significantly older than non-users: more than 80% of users were over 60 years old, compared to less than 30% of non-users in this age range. More than 90% of BP users were female, while less than 60% of non-users were female.
BP users also had a higher rate of underlying diseases than non-users. Nearly 45% of BP users, compared to less than 15% of non-users, were covered by Medicare. In addition, approximately 66% of BP users and less than 45% of non-users had a history of a GP visit in 2019.
After adjusting for these differences, the testing rate among BP users was reduced by 78% compared to non-users, while the incidence of COVID-19 was 77% lower among BP users. Hospital admissions were also reduced by 74% in BP users. These associations remained consistent across all states, as well as within New York alone.
The likelihood of hospitalization was similar among zoledronic acid users with a history of last use in January/February 2019, as well as those who just started taking this drug in February 2020. Furthermore, all BP users showed significant reductions in all three outcomes regardless of the period of use, whether they used the BP drug during the study period, or the type of BP used.
Visits for acute bronchitis and pneumonia decreased in frequency among BP users in the second half of 2019, indicating the beneficial role of these drugs in preventing respiratory infections.
†This dramatic difference in outcomes was consistently observed when comparing BP users with BP non-users” supports the hypothesis that BPs may be useful as immunomodulatory agents in the treatment of COVID-19. The study results also confirm previous studies reporting a protective association between BP use and pneumonia-related morbidity and mortality.
However, other studies showed no protective role for BPD in the diagnosis and hospitalization of COVID-19, perhaps because of the large differences in study size. Susceptibility analyzes with other anti-bone resorption medications as controls showed no apparent protective effect compared to BPs. In particular, studies that included only women over the age of 50 with osteoporosis showed the same pattern as the current study.
Similarly, studies using BPD on other outcomes unrelated to COVID-19 failed to show such associations. Conversely, healthy adherents, as well as those using other protective COVID-19 prevention tools, did not show the same trends. The use of BPs also did not change trends among those who did or did not use other prophylactics.
Further research will be needed to ensure confounding factors such as race, ethnicity and socioeconomic factors are taken into account, as these factors influence the speed of diagnosis and severity of COVID-19. However, another recent study in which women used BPs found that the race-adjusted incidence of COVID-19 was 1.7%, compared to 2.1% for non-users. In contrast, the present study showed that the rate of COVID-19 diagnosis was 2.5% and 0.5%, respectively, thus requiring further explanations for this difference.
We propose that immunomodulatory effects of BPs may enhance the antiviral response of BP users to SARS-CoV-2 and reduce the development of symptoms. Milder or absent symptoms may have made infected BP users less likely to seek a test†
Amino-BPs affect the mevalonate pathway in the cells, which could explain 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, producing an effect similar to that of an adjuvant.
The shutdown of this pathway also causes a chemical called isopentyl diphosphate (IPP) to accumulate in neutrophils and then 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, thereby reducing disease progression.
This activity of BPs is supported by the apparent lack of protection at this scale seen with statins. Despite the fact that both agents inhibit the same pathway, they do so in a different step, which does not explain the accumulation of IPP.
Impairment of neutrophil-released reactive oxygen species (ROS) may also protect against the dysregulated neutrophil activation involved in severe and critical COVID-19. In addition, BPs can modulate both innate and adaptive immune responses.
Our results suggest that prophylactic BP therapy may be sufficient to achieve potentially rapid and sustained immune modulation, resulting in a profound reduction in the incidence and/or severity of SARS-CoV-2 infections.† Additional studies are needed to rigorously assess whether the observed reduction in COVID-19-related outcomes is directly caused by BPs and remains true in patient populations that are infrequently prescribed BPs†
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, should guide clinical practice/health-related behavior, or be treated as established information.
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