Vitamin C as an Epigenetic Gatekeeper of Osteogenesis and Skeletal Health – a New Perspective on an Ancient Molecule

Abstract Vitamin C has been long recognized as an important nutrient for skeletal biology, historically attributed to its role in collagen synthesis and connective tissue integrity. Recent studies, however, reveal vitamin C as a critical epigenetic regulator of cellular differentiation. As a required cofactor for α-ketoglutarate-dependent dioxygenases, vitamin C controls the enzymatic activity of a broad array of histone and DNA demethylases, thereby modulating chromatin accessibility and driving cell-specific gene expression. This review provides a novel, integrated perspective that directly links vitamin C’s epigenetic functions to osteogenesis and skeletal health, highlighting experimental evidence that redefines its role beyond collagen maturation and antioxidant defense, and elucidating its sex-dimorphic effects. Importantly, inadequate vitamin C status remains widespread across diverse socioeconomic groups even in Western countries, with low vitamin C intake associated to higher risk of osteoporosis and fractures in the elderly. Viewed through the dual lenses of epigenetic-mechanistic function and clinical relevance, vitamin C emerges as a central epigenetic determinant of skeletal health and a safe, low-cost, and scalable adjuvant to complement current bone therapies. Integrating nutrient epidemiology, clinical data and epigenetic-mechanistic insights may enable targeted interventions to enhance skeletal resilience, particularly in vulnerable populations.