Background: Osteoporosis is characterized by a reduction of bone mass and destruction of bone structures, followed by high bone fragility and susceptibility. Primary osteoporosis is caused by estrogen deficiency and constitutes 95% of all cases. The pomegranate seed oil (PSO) contains 17-α-estradiol, one of the newly found phytosterols with synergistic health effects on estrogen-related physiological reactions. This study aims to evaluate the protective effects of PSO on the treatment of osteoporosis. Methods: Nine databases (PubMed, Scopus, Google Scholar, Cochrane Library, Magiran, SID, Medline, Embase, and Lilacs) were searched for published articles on the Immunomodulatory and antioxidant effects of pomegranate seed oil on treatments of osteoporosis in rats from January 2000 to January 2023. Twelve affiliated articles with complete abstracts were included in this study. All data were extracted from interconnected papers and analyzed with R version 4.2.1 artificial intelligence software. Results: Estrogen modifies the production of bone-resolving cytokines such as interleukin 1 and 6, bone-stimulating factors such as colony-stimulating factor, insulin-like growth factors 1 and 2, osteoprotegerin, and the number of vitamin D receptors in bone. Hesperidin\\\'s antioxidant activity and inhibition of osteoclastic superoxide availability may help to decrease bone resorption. Another theory is that the plant metabolite acts on bone cells via estrogen receptors. Estrogen receptors are found in bone marrow osteoblasts and stromal cells. The primary steroidal estrogen in pomegranate seed oil has been identified as 17-alpha-estradiol, a biosimilar to estrogen that is less dangerous than other forms of estrogen. Conclusion: According to the findings of this research, PSO reduced the pathological effects of osteoporosis in the bones of ovariectomized rats. It can be inferred that it is beneficial for postmenopausal women undergoing estrogen replacement therapy.

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