Calcifediol (25-hydroxyvitamin D3)

Calcifediol is 25-hydroxyvitamin D3, the liver metabolite of vitamin D3 and the form measured in blood tests. Taken orally it bypasses hepatic 25-hydroxylation, so it raises serum 25(OH)D faster (days rather than weeks), more predictably, and with roughly 3× the potency per microgram of cholecalciferol (Quesada-Gomez & Bouillon 2018 review; Vaes 2018 RCT; Pérez-Castrillón 2021/2023 phase III–IV trials of monthly 266 mcg calcifediol vs 25,000 IU cholecalciferol). A 2025 meta-analysis (Bouden et al.) found mixed head-to-head results across studies, so the potency advantage is not uniform. Evidence for hard clinical outcomes (fracture, falls, mortality) specific to calcifediol is thinner than for vitamin D3 — the case rests on biomarker superiority plus one gait-speed RCT (Meyer 2015). It is useful where fast repletion is wanted or in fat malabsorption/liver disease. No UL is defined; because it is more potent and skips the liver's regulatory step, chronic intake well above 20 mcg/day carries a higher hypercalcaemia risk than equivalent-looking D3 doses. Do not stack with high-dose vitamin D3 without monitoring 25(OH)D.

Moderate clinical evidence. Multiple RCTs show faster/higher 25(OH)D vs cholecalciferol (~3× potency per mcg; Vaes 2018, Pérez-Castrillón 2021); outcome data limited to biomarkers and one gait-speed RCT — hard endpoints not established