Sciadopitysin Attenuates Ovariectomy-induced Bone Loss via Restoration of the OPG/RANKL Axis and Suppression of Inflammatory Signaling

Abstract

Postmenopausal osteoporosis (PMO) is primarily caused by estrogen deficiency, which disrupts physiological bone remodeling by enhancing osteoclast-mediated bone resorption while suppressing osteoblast-mediated bone formation. These changes promote a pro-inflammatory microenvironment, accelerate skeletal deterioration, and increase fracture risk. Consequently, the development of safer and more effective therapeutic strategies for PMO remains a major clinical priority. This study investigated the osteoprotective potential of sciadopitysin (SP), a naturally occurring biflavonoid with established antioxidant and anti-inflammatory properties, in an ovariectomy-induced rat model of PMO. Adult female Sprague-Dawley rats were randomly assigned to four groups: sham-operated controls, ovariectomized (OVX) controls, OVX rats treated with SP (25 mg/kg/day, orally), and OVX rats treated with alendronate (2.5 mg/kg/day, orally) for 16 weeks. Serum bone turnover markers, calcium and phosphorus levels, pro-inflammatory cytokines, and bone remodeling regulators, including osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL), Runx2, and osterix, were evaluated. Femoral biomechanical properties were assessed using a standardized three-point bending test. Ovariectomy significantly increased bone turnover markers, serum calcium and phosphorus levels, and pro-inflammatory cytokines, while reducing osteogenic markers and impairing femoral biomechanical strength. SP treatment significantly attenuated these alterations by normalizing bone turnover markers, restoring mineral homeostasis, suppressing inflammatory cytokines, improving the OPG/RANKL balance, and enhancing the expression of the osteogenic markers Runx2 and osterix. Furthermore, SP improved femoral biomechanical properties, indicating enhanced bone strength. These protective effects were similar to those observed in the alendronate-treated group. SP effectively mitigated estrogen deficiency-induced skeletal deterioration through coordinated anti-resorptive, anti-inflammatory, and osteogenic mechanisms. These findings suggest that SP may represent a promising natural therapeutic candidate for the management of PMO.