Abstract
Background and Objectives: Estrogen deficiency after menopause accelerates bone loss through oxidative stress and inflammatory cytokines. Sodium phenylbutyrate (SP), a histone deacetylase inhibitor, exhibits antioxidative and anti-inflammatory effects, but its impact on postmenopausal osteoporosis remains unclear. Materials and Methods: Thirty female Wistar rats were divided into control, ovariectomy (OVX), and OVX+SPB groups (n = 10 each). After 12 weeks, bone mineral density (BMD), histomorphometry, bone marrow biomarkers (MDA, TNF-α, IL-6, RANKL), and plasma Cathepsin K were evaluated. Results: OVX induced trabecular deterioration with reduced number, area, and thickness (all p < 0.001), increased separation (p < 0.001), and decreased femoral and lumbar BMD (p < 0.001). SPB significantly improved these indices (TN, p < 0.05; TA, p < 0.01; TH, p < 0.05; femoral BMD, p < 0.05; lumbar BMD, p < 0.001; TS, p = 0.001). OVX elevated MDA, TNF-α, IL-6, RANKL, and Cathepsin K (all p < 0.001), which were significantly reduced by SPB (MDA, p < 0.001; TNF-α, p < 0.01; IL-6, p < 0.01; RANKL, p < 0.001; Cathepsin K, p < 0.001). Conclusions: SPB mitigates OVX-induced oxidative stress, inflammatory cytokine release, and osteoclast-mediated resorption, resulting in partial but significant improvements across biochemical, structural, and histomorphometric parameters in estrogen-deficient rats. Given its established clinical safety profile, SPB emerges as a cost-effective candidate for repurposing in postmenopausal osteoporosis, warranting further translational and clinical studies.