# Effects of Epigallocatechin-3-O-Gallate on Bone Health
## 4 Conclusions and Future Research Directions  
Research on the effects of EGCG, the primary polyphenol found in green tea, on bone growth and development provides substantial evidence of its potential application in the treatment of skeletal system disorders. The findings summarised in this study suggest that it plays an important role in regulating bone metabolism, offering new perspectives for the treatment of bone diseases such as osteoporosis, and significantly contributing to bone tissue regeneration. The effects on bone health are summarised in Figure 5.  
EGCG demonstrates the ability to stimulate bone mineralisation by enhancing ALP activity and regulating the expression of osteogenic genes such as _R  
Figure 4: Toxic properties of EGCG; ER—endoplasmic reticulum. Figure 5: The effects of EGCG on bone health. In vitro studies on cell lines have shown that this compound promotes osteoblast differentiation and the formation of mineralised bone nodules. Furthermore, it supports bone regeneration by increasing bone callus formation and modifying collagen membranes. However, its effects are dose-dependent, and high concentrations (above 25 \(\upmu\)M) may inhibit the proliferation of mesenchymal cells involved in osteogenesis, whereas intermediate concentrations (1-10 \(\upmu\)M) promote these processes [26; 28; 30; 48]. EGCG also exerts a protective effect on bone tissue by inhibiting bone resorption. This mechanism involves the induction of osteoclast apoptosis through its influence on the Fenton reaction and caspase-3 activation. Additionally, by regulating the RANK/RANKL/OPG pathway, it reduces osteoclastogenesis. EGCG increases OPG expression while lowering the RANKL/OPG ratio, resulting in decreased osteoclast differentiation and activity, thus helping to prevent the loss of bone mass. Moreover, EGCG improves bone microarchitecture, enhancing parameters such as BMD and trabecular thickness [19; 44]. It is interesting that EGCG inhibits the production of IL-6 and the activation of MAPK pathways (e.g., p44/p42 and JNK), thereby reducing inflammation and bone resorption [54]. At the same time, it stimulates the synthesis of VEGF, supporting angiogenesis and osteogenesis. Similar to most flavonoids, it exhibits antioxidant properties, neutralising reactive oxygen species. As a result, it protects bone cells from oxidative stress and chronic inflammation, key risk factors for osteoporosis and other skeletal disorders, helping to maintain healthy bone structure and enhance regenerative processes [108; 109; 110; 112]. Additionally, it may influence calcium metabolism by modulating the expression of specific calcium transporters and receptors responsible for maintaining calcium homeostasis. Optimising calcium transport and storage in bone cells promotes more effective mineralisation and improves bone tissue quality (Figure 6) [30; 40; 49]. However, it is worth noting that the stability of this compound is limited because it undergoes rapid degradation on the way to epimerization and auto-oxidation, influenced by factors such as pH, temperature, and oxygen exposure [154]. This poses a challenge to its therapeutic application. Despite the fact that we already know a lot about this topic, there is still a need for more well-designed and controlled clinical trials to validate the results from preclinical studies. It is especially important for individuals at risk of osteoporosis to determine the effectiveness and safety of EGCG supplementation. What is more, research about the molecular mechanisms underlying its effects on bone cells is necessary. This is very important to provide insights into its potential therapeutic applications through the comprehension of specific pathways. Establishing a proper dose to determine the optimal influence and adverse effects for bone health is also a future research direction. Last but not least, research for the long-term effects of EGCG supplementation is necessary to assess its impact on bone mineral density, fracture risk, and overall bone quality.