Background: Osteoporosis is a bone remodeling disease characterized by an imbalance between bone formation and resorption, leading to bone fragility. Current treatments focus on bone resorption suppression but often have adverse effects. This study aimed to explore the potential of sericin, a silkworm-derived protein, as a dual-action therapeutic agent that enhances bone formation through its component L-serine and inhibits bone resorption via D-serine, which is derived from L-serine by the action of serine racemase. Methods: Cellular experiments were conducted to evaluate the effects of L-serine on osteoblast differentiation and D-serine on osteoclast inhibition. Serum levels of D-serine were measured following sericin administration in an osteoporosis animal model. μ-CT analysis assessed trabecular and cortical bone quality, and bone-related protein expression was analyzed using immunoprecipitation-based high-performance liquid chromatography (IP-HPLC). Results: L-serine significantly upregulated osteogenic markers, including alkaline phosphatase (ALP), Runx2, osterix, and Col1a1, in osteoblasts (p < 0.05). D-serine inhibited osteoclast activation by suppressing cathepsin K expression (p < 0.001). Sericin feeding elevated serum D-serine levels (p < 0.001) and upregulated bone-related proteins such as BMP-2, osterix, and Runx2. Micro-computed tomography (μ-CT) analysis revealed significant improvements in trabecular bone parameters in the OVX-sericin group, including increased trabecular bone volume (Tb.BV/TV; p < 0.05) and reduced trabecular separation (Tb.Sp; p < 0.05), compared to the OVX and OVX-amino acid groups. Cortical bone parameters, including cortical bone volume (Ct.BV/TV) and cortical area (Ct.Ar), did not significantly differ among OVX groups, but all were lower than in the sham group (p < 0.05). Conclusions: This study demonstrates that sericin modulates bone metabolism by enhancing osteoblast activity through L-serine and inhibiting osteoclastogenesis via D-serine. Sericin supplementation improved trabecular bone mass in an osteoporosis model, highlighting its potential for bone health.

Postmenopausal osteoporosis is characterized by progressive bone loss and deterioration of trabecular microarchitecture, yet safe and effective nutritional interventions remain limited. This study investigated the skeletal effects of whole sericin compared to isolated L-serine and calcium-only formulations in an ovariectomized (OVX) rat model. Forty female Sprague–Dawley rats underwent either sham surgery or OVX, followed by 8 weeks of daily oral administration with vehicle (calcium + vitamin D, NS), sericin formulation (S55), or L-serine. Sham and untreated OVX groups served as controls. Serum D-serine concentrations and femoral trabecular microarchitecture were assessed using fluorometric assays and micro-computed tomography (μCT), respectively. OVX significantly decreased bone volume fraction (BV/TV), bone mineral density (BMD), and trabecular number, while increasing trabecular separation. Sericin supplementation markedly improved BV/TV, BMD, trabecular thickness, and trabecular number, and reduced trabecular separation compared to both vehicle and untreated OVX controls. Sericin improved multiple trabecular parameters compared with L-serine. Serum D-serine levels were significantly elevated in the sericin group relative to calcium-only controls, though comparable to sham. These findings suggest that whole sericin exerts skeletal benefits beyond those attributable to its primary amino acid component, supporting its potential as a functional food ingredient for enhancing postmenopausal bone health.

Guided bone regeneration (GBR) with conventional collagen membranes may yield limited bone formation under estrogen-deficient conditions. This study evaluated whether a collagen membrane incorporating high-molecular-weight polynucleotide (PN) enhances bone regeneration in osteoporotic rats. PN (approximately 5 mg) was loaded onto a porcine collagen membrane and characterized by attenuated total reflectance Fourier-transform infrared spectroscopy, X-ray diffraction, and an in vitro release assay. Bilateral 5-mm calvarial defects were created in 30 ovariectomized female Sprague–Dawley rats and left unfilled (Control) or covered with a collagen membrane alone (Mem) or a PN-incorporated collagen membrane (PN_Mem) (n = 10 defects per group per time point). Regeneration was assessed at 4 and 8 weeks by micro-computed tomography, Masson’s trichrome staining, and immunohistochemistry for runt-related transcription factor 2 (Runx2) and bone morphogenetic protein-2/4 (BMP-2/4). PN was physically incorporated and released biphasically (approximately 50% within 8 h and 77% within 7 days). Bone volume did not differ among the groups at 4 weeks, whereas at 8 weeks it was greater in PN_Mem (5.98 ± 2.20 mm³) than in Control (1.24 ± 0.67 mm³; p < 0.0001) and Mem (2.52 ± 1.79 mm³; p < 0.001), with more Runx2-positive cells than in both groups and stronger BMP-2/4 immunoreactivity than in Control. PN incorporation enhanced the osteogenic performance of collagen membranes in this osteoporotic calvarial model; validation in clinically relevant alveolar defect models is required.