This investigation elucidates the critical molecular determinants associated with the comorbidity of osteoporosis (OP) and periodontitis (PD) through proteomic profiling, while delineating the regulatory function of CD44 in experimental periodontitis in an OP murine model. Phase I involved collecting serum specimens from patients with OP+PD (n = 3) and healthy controls (n = 6) undergoing routine health evaluations at our institution for comparative proteomic analysis. Subsequent translational validation of differentially expressed genes (DEGs) and associated signaling cascades was conducted across clinical specimens and OP+PD murine models. To mechanistically characterize CD44's role in PD progression under osteoporotic conditions, an OP murine model was generated through bilateral ovariectomy, followed by experimental PD induction via ligature placement. Comprehensive assessments included histomorphometric alterations via hematoxylin-eosin staining, microarchitectural bone analysis at the maxillary first molar region using micro-CT, and immunoblotting evaluation of phosphoinositide-3-kinase (PI3K)/Akt pathway components. Parallel network pharmacological screening coupled with molecular docking simulations was executed to identify bioactive constituents of Angelica sinensis with therapeutic potential. Proteomic interrogation identified CST3, A2M, CD44, CDH13, CETP, and VWF as candidate pathogenic mediators in OP+PD pathogenesis. In our hands, gene set enrichment analysis revealed that PI3K/Akt signaling functions as a principal mediator of OP+PD disease progression. Quantitative reverse-transcription PCR-based validation confirmed significant CD44 upregulation in both clinical and experimental OP+PD cohorts. In vivo modulation via CD44 suppression significantly restored periodontal tissue integrity, reduced inflammatory cell infiltration, and strengthened alveolar bone microarchitecture in OP mice, concomitant with PI3K/Akt pathway inhibition. Network pharmacology revealed glycitein as the primary bioactive phytochemical in Angelica sinensis, with CD44 identified as its central molecular target. Glycitein improved alveolar bone structure in OP+PD mice, increasing bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone mineral density (BMD), and reducing trabecular number (Tb.N), bone surface-to-bone volume ratio (BS/BV), indicating healthier bone quality, mechanistically attributed to CD44 signaling axis attenuation.