Vitamin K Status and Skeletal Fragility: Differential Associations of Osteocalcin Carboxylation States with Bone Strength, Geometry and Microarchitecture

Background: The contribution of specific nutritional biomarkers to skeletal fragility remains poorly understood, in part because most studies include participants with metabolic conditions that obscure nutrient-specific effects. We aimed to examine incremental contribution of six pathway-specific nutritional biomarkers. Methods: In a prospective cross-sectional case–control design, 108 patients undergoing arthroplasty were enrolled (hip-fracture, n = 63; non-fracture, n = 45), and bone biopsies and blood specimens were collected intraoperatively. Circulating biomarkers reflecting vitamin K, one-carbon metabolism, antioxidant nutrients (vitamins E and C), protein and zinc status were measured. Bone outcomes included remodelling markers, trabecular microarchitecture and bone strength. Hierarchical regression was used to quantify the incremental contribution of nutritional biomarkers beyond clinical covariates with a priori outcome selection. Results: Bone remodelling markers did not differ between groups after covariate adjustment, indicating that fractures in this cohort were characterised by deficits in bone strength and quality rather than elevated systemic remodelling activity. Among six nutritional pathways tested, only vitamin K-dependent biomarkers showed consistent independent associations with bone outcomes, suggesting a degree of pathway specificity. Critically, carboxylated (cOC), undercarboxylated (ucOC) and fully uncarboxylated (unOC) osteocalcin fractions showed differential associations reflecting their distinct biological roles: cOC was independently associated with greater bone strength (section modulus, femoral neck width and cortical shaft thickness; p < 0.05) and lower trabecular separation (Tb.Sp); ucOC was associated with higher Tb.Sp (p = 0.004); and unOC was positively associated with cortical bone instability (buckling ratio, p = 0.003) and explained 17% of the variance in the bone resorption marker (p < 0.001), consistent with a shift towards bone loss. Vitamin K2-7 was negatively associated with hip axis length (p = 0.021). Conclusions: These findings identify vitamin K-dependent carboxylation as a mechanistically specific and modifiable factor associated with skeletal fragility beyond bone mineral density, with distinct skeletal consequences across osteocalcin carboxylation states.