Revisiting the Role of Vitamin D in Fracture Prevention in the Era of Mega-Trials

For decades, vitamin D has been a cornerstone of preventive medicine. However, recent large-scale randomized controlled trials have failed to replicate the broad benefits previously observed in epidemiological studies, particularly with respect to fracture and fall prevention in vitamin D-replete populations. Moreover, growing evidence suggesting an increased fall risk associated with high-dose bolus administration has necessitated a re-evaluation of safety assumptions. This review synthesizes these discordant findings to propose a framework grounded in precision medicine. We explore the ‘divergent threshold’ hypothesis, whereby a serum 25-hydroxyvitamin D level of 20 to 30 ng/mL may be sufficient for skeletal health, whereas a higher threshold of 40 to 50 ng/mL appears necessary to achieve metabolic benefits, such as diabetes prevention in non-obese individuals. Ultimately, we advocate a shift away from a ‘one-size-fits-all’ paradigm toward targeted strategies that maximize efficacy while minimizing the risks associated with excess supplementation.