Vitamin D Resistance: Mechanisms, Clinical Implications, and Integrative Perspectives

Vitamin D resistance describes a spectrum of conditions in which individuals fail to achieve expected biological responses to vitamin D despite supplementation and/or apparently adequate serum 25-hydroxyvitamin D [25(OH)D] concentrations and sun exposure. While rare hereditary forms such as Hereditary Vitamin D-Resistant Rickets (HVDRR) are well-characterized, emerging evidence suggests that acquired resistance may contribute to suboptimal responsiveness in a broader clinical population. Contributing factors include genetic variation in vitamin D metabolism and receptor pathways, chronic inflammation, metabolic dysregulation, micronutrient cofactor insufficiencies, and environmental exposures. This review synthesizes current understanding of vitamin D resistance mechanisms, diagnostic challenges, and implications for personalized supplementation strategies. We propose an operational definition of vitamin D resistance as a state of inadequate physiological response to vitamin D despite achieving conventionally sufficient 25(OH)D levels, best assessed using response-based markers such as PTH suppression, calcium handling, and clinical endpoints. We further outline a pragmatic, systems-based evaluation framework that incorporates endocrine, inflammatory, metabolic, medication-related, and micronutrient determinants to guide individualized dosing and monitoring.