Background: Osteoporosis poses a global health challenge, particularly with an ageing population. Quercetin, isorhamnetin, avicularin, isoquercetin, quercitrin, and taxifolin are natural flavonoids with similar structure that induce ontogenesis. Methods: In the present study, proteins in oestrogen signalling and bone morphogenesis were analysed, and hub genes were identified with Cytoscape, followed by pathway analysis. Then, molecular targets of flavonoids and osteoporosis-related targets were identified, and overlaps were detected. Molecular docking and dynamics simulations assessed flavonoid interactions with ERs. Results: The study identified 14 gene products linked to osteoporosis, including ESR1 and ESR2. Enrichment analyses confirmed ESR involvement in various biological processes. SwissTargetPrediction highlighted quercetin and isorhamnetin as favourable targets for ESR1 and ESR2. Molecular docking and dynamics revealed favourable and stable binding of flavonoids to ERα and ERβ. Conclusion: These interactions suggest therapeutic potential of natural flavonoids for osteoporosis treatment by targeting ERs, laying a foundation for future research in preclinical and clinical settings.

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