Colostrum Whey Protein Attenuates Osteoporosis via Osteogenic Stimulation, Anti-Resorptive Effects, and Hepatic-Bone Axis Modulation

Osteoporosis, a prevalent skeletal disorder aggravated by estrogen deficiency, is a major global health concern that presents significant clinical challenges, particularly for postmenopausal women. This study evaluates the therapeutic potential of colostrum whey protein (CWP) in mitigating estrogen deficiency-induced osteoporosis through both <em>in vivo</em> (ovariectomized murine model) and <em>in vitro</em> (osteoblast culture) approaches. In ovariectomized (OVX) mice, CWP administration increased bone mineral density (BMD) by 45%, elevated trabecular number (Tb.N) by 38%, restored trabecular thickness (Tb.Th), and reduced trabecular separation (Tb.Sp) by 40%. Histomorphometric analysis confirmed enhanced trabecular structure, collagen restoration, and reduced osteoclast activity. CWP also restored bone metabolism by increasing alkaline phosphatase (ALP) and osteoprotegerin (OPG) levels, while decreasing receptor activator of nuclear factor kappa-B ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP) levels. Mechanistic studies showed that CWP modulated the hepatic-bone axis through suppression of PP2ACα and induction of lecithin-cholesterol acyltransferase (LCAT), facilitating cholesterol transport. Furthermore, CWP upregulated osteogenic markers (bone morphogenetic protein-2 (BMP-2), runt-related transcription factor-2 (RUNX-2), and activated MAPK, BMP/Smad, and WNT/β-catenin signaling pathways, promoting osteoblast proliferation, differentiation, and mineralization<em> in vitro</em>. These findings highlight CWP’s dual role in enhancing bone formation and inhibiting resorption through both local (osteoblast activation) and systemic (hepatic-bone axis modulation) mechanisms. Collectively, CWP emerges as a promising multi-target therapeutic candidate for osteoporosis, bridging bone remodeling and metabolic crosstalk. Additional translational studies are warranted to validate its clinical efficacy.