Association between bisphosphonates and highly pathogenic human coronavirus diseases: A protocol for systematic review and meta-analysis
Author Identifier (ORCID)
Abstract
Rationale for the review: Bisphosphonates (BPs) or diphosphonates, are class of drugs approved for treatment of bone metastases, osteoporosis and Paget's disease. They have two phosphonate groups and high affinity for metal ions especially calcium. BPs are primarily divided into two categories as per their mechanism of action to prevent bone loss: nitrogen-containing BPs (NBPs) and nitrogen-free BPs (non-amino-BPs). Existing literature suggests that BPs are associated with increased lifespan, reduced cardiovascular disease, and exert immunomodulatory effects (Ebetino et al. 2022). It is well documented that cells of the innate and adaptive immune systems contribute to the excessive inflammatory response (cytokine storm) observed in severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) (Zanza et al. 2022). A similar hyper inflammatory response has also been considered as one of the potential mechanisms contributing to COVID-19-associated coagulopathy (Conway et al. 2022). Using cross-sectional data from 2,102 participants in Spain, Blanch-Rubio et al. (2020) were the first to report a negative association between intravenous zoledronate (bisphosphonate) use and COVID-19 incidence (RR=0.62; 95% CI: 0.27-1.41). In another study from Italy, Degli Esposti et al. (2021) conducted a retrospective observational study involving 126,370 participants and concluded that the use of oral amino-bisphosphonates was not associated with reduced COVID-19-related hospitalization, intensive care unit (ICU) admission, or mortality. Although there are several observational studies on bisphosphonate use and coronavirus diseases, their outcomes are inconsistent. Few studies reported no effects, while other authors have reported a negative association in bisphosphonate use and coronavirus related severe outcomes.
Review objectives:
• To assess the association between bisphosphonate exposure and the likelihood of highly pathogenic human coronavirus infections
• To assess the association between bisphosphonate exposure and clinical progression of highly pathogenic human coronavirus infections, including diagnosis, severity, hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and mortality.
Keywords
bisphosphonates, COVID-19, MERS, osteoporosis, SARS
Document Type
Other
Date of Publication
2026
Publication Title
PROSPERO
Publisher
National Institute for Health and Care Research
School
School of Medical and Health Sciences
Content Type
Metadata only
Recommended Citation
Awasthi, A., Dubey, M., Muzaffar-Ur-Rehman, M., Sharma, I., Stewart, C., & Vasan, S. (2026). Association between bisphosphonates and highly pathogenic human coronavirus diseases: A protocol for systematic review and meta-analysis. PROSPERO. National Institute for Health and Care Research. [Protocol] https://www.crd.york.ac.uk/PROSPERO/view/CRD420261525067
Comments
Protocol