Vitamin D3

Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are the main forms of vitamin D, and both are converted into the active form, 1,25-dihydroxyvitamin D, by two hydroxylations in the liver, kidney and other tissues such as the pancreas and immune cells. ^[1] Cholecalciferol is the main dietary form of vitamin D, and ergocalciferol appears to be absorbed with similar efficiency. ^[2] Cutaneous vitamin D synthesis depends on UVB exposure, and sun exposure in moderation is the major source of vitamin D for most humans. ^{[3] [4]} Very few foods naturally contain vitamin D, and nutrition surveillance data from various countries show habitual intakes much lower than recommendations. ^{[4] [5]} Its circulating hepatic metabolite, 25-hydroxyvitamin D (calcifediol), is a non-active precursor regarded as a pre-hormone. ^[6] Low status is common: one review reports that 25% of the U.S. population and 60% of Central Europeans have serum 25(OH)D levels below 20 ng/mL. ^[7] Oral administration is the preferred route, and cholecalciferol is the favored form for supplementation because of its safety and minimal monitoring requirements, while calcifediol may be used in certain conditions and calcitriol is reserved for disorders in which the active metabolite is not readily produced. ^[8]

The active metabolite 1,25(OH)2D is the ligand for the vitamin D receptor (VDR). ^[9] Its main effect is to stimulate intestinal calcium absorption, and its effects on bone are primarily indirect, mediated by intestinal calcium transport and serum calcium and phosphate homeostasis. ^{[10] [9]} Vitamin D deficiency causes secondary hyperparathyroidism and bone loss leading to Osteoporosis and fractures, mineralization defects that may progress to osteomalacia, and muscle weakness that contributes to falls. ^{[10] [11]} Vitamin D status is related to bone mineral density and bone turnover, and supplementation may decrease bone turnover and increase bone mineral density. ^[10] The VDR and vitamin D metabolic enzymes are widely expressed, and genetic, cellular and animal studies suggest extraskeletal effects on cell proliferation, immune and muscle function, and vascular and metabolic properties.

A meta-analysis of 52 randomised trials with 75 454 participants found that vitamin D supplementation was not associated with all-cause mortality (risk ratio 0.98) but reduced cancer death (risk ratio 0.84). ^[13] For fractures, a meta-analysis of 33 randomized trials (51 145 community-dwelling adults older than 50 years) found no association between vitamin D, calcium or both and the risk of hip fracture. ^[14] In contrast, a National Osteoporosis Foundation meta-analysis of trials including 30,970 participants found that calcium plus vitamin D reduced total fractures by 15% and hip fractures by 30%. ^[15] In care-facility residents with low vitamin D levels, a Cochrane review found that vitamin D supplementation probably reduces the rate of falls (rate ratio 0.63) but probably makes little or no difference to the risk of falling (risk ratio 0.99). ^[16] In a meta-analysis of 39 randomized trials (2982 people with Type 2 Diabetes), vitamin D supplementation lowered

Optimal 25(OH)D levels remain debated, recommendations vary between societies, and the lack of assay standardization complicates the interpretation of available studies. ^{[8] [20]} Bone-centric guidelines target a 25(OH)D concentration of 20 ng/mL (50 nmol/L) with daily doses of 400 to 800 IU, whereas guidelines focused on pleiotropic effects target 30 ng/mL (75 nmol/L) with doses between 400 and 2000 IU/day. ^[21] Some authors, drawing mainly on prospective cohort studies, advise raising levels above 30 ng/mL with 2000 IU/day of vitamin D3, and the 2011 Endocrine Society guideline gave a preferred range of 40 to 60 ng/mL. ^{[7] [19]} For older adults, an international consensus sets the goal above 50 nmol/L and advises avoiding levels below 30 nmol/L, the threshold (30 nmol/L or 12 ng/mL) that another review defines as severe deficiency. ^{[22] [23]} The 2024 Endocrine Society guideline found no clear evidence defining an optimal 25(OH)D target for disease prevention and suggests against routine 25(OH)D testing in the populations it considered, whereas the 2011 guideline recommended testing in patients at risk for deficiency.