Background <p>Current treatments available for osteoporosis involve high risk and severe adverse effects hence, can’t be used in prolonged treatment.</p> Purpose <p>Development of effervescent granules containing a synergistic blend of psoralen and eggshell derived calcium butyrate (ECB) as a novel oral formulation for osteoporosis treatment.</p> Methods <p>Wet granulation method was used for preparation of effervescent granules, Psoralen dissolved in ethanol by vortex mixing was used as granulating agent. The eggshell powder was treated with butyric acid to get soluble calcium butyrate (ECB). Both psoralen and ECB were mixed with the effervescent base containing citric acid, sodium bicarbonate and mannitol. The formulation was optimized by using central composite design in design expert software version 7.1.6. Anti-osteoporotic activity of optimized formulation was studied by glucocorticoid induced osteoporosis model in female wistar rats.</p> Results <p>The optimized formulation demonstrated rapid dissolution, with over 90% of psoralen and calcium released within 30&#xa0;min, indicating enhanced bioavailability. Results revealed that the effervescent granules significantly improved alkaline phosphatase activity and calcium levels in osteoporotic animals; histopathological analysis confirmed improved bone architecture. These findings underscore the potential of this dual-action formulation for enhancing bone health and warrant further investigation into its clinical applications in osteoporosis management.</p> Conclusion <p>Psoralen and ECB effervescent granules (PECB-EG) are an effective treatment option for long term treatment of osteoporosis.</p> Graphical Abstract <p></p>