Ellagic acid and bone health: a systematic review of preclinical studies on its protective role against osteoporosis.

Abstract

BACKGROUND AND OBJECTIVE: Osteoporosis is a prevalent metabolic bone disorder characterized by reduced bone mineral density and disrupted bone microarchitecture, leading to increased fracture risk. Growing interest has focused on natural bioactive compounds as potential complementary therapeutic agents. This systematic review aimed to comprehensively evaluate preclinical evidence regarding the protective effects of ellagic acid (EA), a naturally occurring polyphenolic compound, and to elucidate the molecular mechanisms underlying its role in alleviation of osteoporosis. METHODS: A systematic literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar databases up to November 2025, following PRISMA guidelines. Eligible studies included English-language in vivo and in vitro investigations assessing the effects of EA on osteoporosis. Data were extracted on experimental models, EA dosage and administration, evaluated signaling pathways, and bone-related outcomes. RESULTS: 13 preclinical studies met the inclusion criteria. Evidence consistently demonstrated that EA enhances osteoblast differentiation, viability, and bone-forming capacity by upregulating key osteogenic markers and activating signaling pathways such as SMAD2/3, BMP2, and SIRT1/Nrf2/HO‑1, while inhibiting negative regulators including CDK12. Concurrently, EA markedly suppressed osteoclast differentiation and bone resorption by disrupting RANKL-RANK interactions and inhibiting downstream NF‑κB, MAPK, and ERK signaling pathways. In multiple animal models, including ovariectomy- and microgravity-induced osteoporosis, EA administration improved bone mineral density, trabecular microarchitecture, and mechanical strength. These effects were accompanied by attenuation of oxidative stress and inflammatory responses within the bone microenvironment. CONCLUSION: Collectively, preclinical evidence indicates that EA exerts multifaceted osteoprotective effects by restoring the balance between bone formation and resorption and modulating oxidative and inflammatory pathways. Although these findings support EA as a promising natural candidate for osteoporosis prevention and treatment, large-scale and long-term clinical studies are required to confirm its efficacy, optimize dosing strategies, and address bioavailability challenges.

Key Findings

• Ellagic acid (EA) enhances osteoblast differentiation, viability, and bone-forming capacity by upregulating osteogenic markers and activating signaling pathways including SIRT1/Nrf2/HO-1.
• EA suppresses osteoclast differentiation and bone resorption by disrupting RANKL-RANK interactions and inhibiting NF-κB, MAPK, and ERK signaling pathways.
• EA administration in animal models improves bone mineral density, trabecular microarchitecture, and mechanical strength, accompanied by reduced oxidative stress and inflammation in bone tissue.

Clinical Significance

Citation

Gholizadeh Masoomeh, Sarajar Behnam Omidi, Asadi Jahanbakhshet al.. Ellagic acid and bone health: a systematic review of preclinical studies on its protective role against osteoporosis. Molecular biology reports. 2026-Sep-05.