<![CDATA[General Background: Osteoporosis, a common condition exacerbated by glucocorticoid use, leads to significant bone loss and increased fracture risk. Specific Background: Conventional treatments primarily target calcium regulation, but emerging evidence suggests that natural compounds like isoflavonoids may offer therapeutic benefits. Knowledge Gap: Despite their potential, the efficacy of isoflavonoids and their nanoformulations in managing glucocorticoid-induced osteoporosis remains underexplored. Aims: This study aimed to evaluate the therapeutic effects of vitamin D, Ginkgo biloba isoflavonoid extract, and nanoisoflavonoids on glucocorticoid-induced osteoporosis in adult male rats. Results: Sixty rats were divided into five groups: a control, an osteoporosis model, and three treatment groups receiving vitamin D (10,000 IU/day), isoflavonoid extract (500 mg/kg/day), or nanoisoflavonoids (500 mg/kg/day) for one month. Molecular and physiological assessments revealed that nanoisoflavonoids were the most effective in restoring serum vitamin D levels, reducing parathyroid hormone concentrations, and downregulating parathyroid hormone gene expression, followed by isoflavonoid extract and vitamin D. Novelty: This study provides the first comprehensive evaluation of nanoisoflavonoids' superior efficacy in mitigating glucocorticoid-induced osteoporosis, highlighting their enhanced bioavailability and therapeutic potential. Implications: These findings suggest that nanoisoflavonoids could serve as a promising plant-derived nanotherapeutic for osteoporosis management, warranting further investigation through long-term studies and clinical trials to validate their safety and efficacy in human populations.Highlights: Glucocorticoid-induced osteoporosis lacks effective natural compound treatments. Nanoisoflavonoids restore vitamin D, reduce parathyroid hormone effectively. Nanoisoflavonoids offer a promising therapeutic strategy for osteoporosis management. Keywords: Osteoporosis, glucocorticoids, Ginkgo biloba, isoflavonoids, nanoisoflavonoids, vitamin D, parathyroid hormone, bone metabolism]]>
