Phenolic-derived compounds in osteoporosis-Mechanisms, clinical evidence, and drug delivery: A review.

Osteoporosis is a degenerative skeletal disorder characterized by reduced bone mass and the deterioration of bone microarchitecture, resulting in an increased risk of fractures. Its development is driven by an imbalance in bone remodeling, where osteoclastic bone resorption surpasses osteoblastic bone formation. Factors such as oxidative stress, chronic inflammation, ferroptosis, and hormonal changes, particularly estrogen deficiency in postmenopausal women, contribute to this imbalance. Metabolites derived from phenolic compounds have emerged as promising natural agents for osteoporosis prevention due to their antioxidant, anti-inflammatory, and hormone-modulating properties. Key phenolic groups, including flavonoids (quercetin), isoflavones (genistein and daidzein), and stilbenes (resveratrol), have demonstrated significant osteoprotective effects by regulating receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG) signaling, activating Wnt and β-catenin pathways, and suppressing inflammatory cytokines. Clinical findings indicate that these compounds may enhance bone mineral density and modulate bone turnover markers in populations at risk for osteoporosis. However, their clinical application is limited by low bioavailability and rapid metabolism. Advances in drug delivery systems, including nanoencapsulation, liposomal formulations, and prodrug design, have improved stability, absorption, and targeted delivery to bone, thereby enhancing therapeutic potential while minimizing systemic effects. This review discusses the molecular mechanisms underlying osteoporosis, emphasizing oxidative and hormonal dysregulation, and highlights the therapeutic relevance of phenolic compounds. Additionally, it summarizes recent clinical observations and formulation strategies aimed at enhancing therapeutic efficacy. Overall, phenolic compounds represent promising plant-based strategies for the prevention and management of osteoporosis.