MOLECULAR MECHANISMS OF OSTEOTROPIC MICRONUTRIENTS IN BONE HEALING: SIGNALING PATHWAYS, REDOX HOMEOSTASIS, AND MATRIX MATURATION

Abstract

Delayed union and non-union complicate a substantial minority of fractures and are strongly associated with ageing and metabolic comorbidity, motivating close scrutiny of the biological factors that determine repair. Micronutrients have traditionally been regarded as passive structural raw materials, yet accumulating evidence shows that they act as direct molecular modulators of the healing cascade. This review reframes osteotropic micronutrients as regulators positioned along the four phases of bone repair (inflammation, soft callus, hard callus, and remodelling) and interprets their actions through a unifying three-axis framework: regulation of osteogenic and osteoclastic signalling, enzymatic support of collagen matrix synthesis and cross-linking, and preservation of redox homeostasis. Within this framework we examine the macrominerals (Ca, P, Mg), essential trace metals (Zn, Cu, Mn, Fe), redox-active and structural trace elements (Se, Sr, B, Si, F), and osteotropic vitamins (D, K, C), mapping each onto specific molecular targets, from RUNX2 and lysyl oxidase to the glutathione peroxidases and γ-glutamyl carboxylase. We then analyse the synergies, antagonisms, and characteristic deficiency signatures that arise as these nutrients converge on shared enzymatic and redox hubs, underscoring that their effects are dose-dependent, ratio-sensitive, and phase-specific rather than simply additive. Finally, we consider the translational implications for bioavailability and for phase-matched, multi-element delivery systems, including biopolymer-stabilised nanocarriers, that may convert this mechanistic understanding into nutrition-based adjuncts to fracture management.