# An in-depth investigation of NAs-induced osteoporosis adverse events: a real-world, network toxicology and molecular docking analysis

## TL;DR

This study investigates how nucleoside analogs used for hepatitis B treatment may cause osteoporosis, using real-world data and molecular techniques to identify risks and mechanisms.

## Contribution

The study provides new insights into the adverse skeletal effects of adefovir and tenofovir through pharmacovigilance, network toxicology, and molecular docking.

## Key findings

- Adefovir and tenofovir show significant associations with various osteoporosis-related adverse events.
- Both drugs may contribute to osteoporosis via shared biological pathways like G protein-coupled receptor signaling.
- Molecular docking suggests the drugs bind to genes like ADORA1 and JAK1, potentially causing bone-related side effects.

## Abstract

Nucleoside and nucleotide analogs are one of the mainstays of treatment for chronic hepatitis B, but their effects on bone density are highly controversial.

In this study, four pharmacovigilance analysis methods and Bonferroni-corrected p-values were used to analyze the FDA Adverse Event Reporting System database to investigate the relationship between adefovir and tenofovir and osteoporosine-related adverse events. In addition, the biological pathways and target proteins were studied by network toxicology and molecular docking techniques.

Adefovir showed signs of adverse skeletal events at the two PT levels of OSTEOPOROSIS and BONE DENSITY DECREASED, while tenofovir showed signs of adverse skeletal events at the five PT levels of BONE DENSITY DECREASED, BONE LOSS, OSTEOPENIA, OSTEOPOROSIS and OSTEOPOROTIC FRACTURE. Furthermore, at the overall SMQ level, positive signals of adverse skeletal events were also valid. Subgroup analysis showed that adefovir was more likely to cause osteoporosis in the elderly and women, while tenofovir exhibited the opposite trend. Furthermore, GO and KEGG analyses indicated that both drugs may jointly promote osteoporosis through pathways such as cell migration, G protein-coupled receptor and Toll-like receptor signaling pathways. Molecular docking technology further reveals that the two drugs can produce pathological effects by binding to osteoporosis-related genes such as ADORA1 and JAK1.

This study comprehensively reported the risk and mechanisms of osteoporosis caused by the clinical use of NAs drugs, and provided more detailed recommendations for clinical improvement and prevention of adverse events.