Vitamin D and Health

using a bolus dose (I 2 =77%) compared to those administering daily supplementation (I 2 =44%).
Conclusions regarding any differences in biological activity between vitamin D 2 and D 3 could not be
drawn from this meta-analysis because of a number of limitations, including: small number and size of
studies (n=19-89); variability in 25(OH)D assay methodology (see chapter 4); differences in dose size
and frequency and in treatment and follow-up time. Additionally, the doses used in the studies were
very high and effects may be different at lower doses.
2.62 Subsequent RCTs support the suggestion that vitamin D 3 is more effective than vitamin D 2 in raising
serum 25(OH)D concentration. An RCT in New Zealand (Logan et al., 2013), conducted in winter,
compared effects of 25 µg/d (1000 IU) of vitamin D 2 , D 3 and placebo over 25 weeks on serum 25(OH)D
concentration of adults (n=95; 18-50 y). After 25 weeks, serum 25(OH)D concentrations of
participants in the placebo group were significantly lower than those in the vitamin D 2 and D 3 groups
(both p< 0.001) and was significantly lower in in the vitamin D 2 supplemented group compared with
the vitamin D 3 supplemented group (p< 0.001).
Toxicity
2.63 Vitamin D toxicity can lead to hypercalcaemia which results in deposition of calcium in soft tissues,
diffuse demineralisation of bones and irreversible renal and cardiovascular toxicity. Hypercalcaemia
can also lead to hypercalcuria (EVM, 2003) 20 .
2.64 Prolonged sunlight exposure does not lead to excess production of cutaneous vitamin D because
endogenously produced previtamin D 3 and vitamin D 3 are photolysed to inert compounds (see
paragraph 2.10). High doses of oral vitamin D supplements have, however, been shown to have toxic
effects (Vieth, 2006). Cases of vitamin D toxicity resulting from ingestion of over-fortified milk have
also been reported (Jacobus et al., 1992; Blank et al., 1995).
2.65 Animal studies suggest that plasma 25(OH)D concentrations associated with toxicity are above
375 nmol/L (Jones, 2008). Evidence on vitamin D toxicity in humans is based on anecdotal case
reports of acute accidental vitamin D 2 or D 3 intoxication resulting in 25(OH)D concentrations of 710-
1587 nmol/L and a threshold for toxic symptoms at concentrations of about 750 nmol/L (Vieth, 1990).
Hypercalcaemia has been reported at plasma concentrations above 375-500 nmol/L (Vieth, 1990;
Jones, 2008).
2.66 The mechanism of how vitamin D toxicity might arise is presently unclear. Proposed mechanisms are
based on increased concentrations of the active metabolite of vitamin D reaching the VDR in the
nucleus of target cells and causing gene over-expression. Three main hypotheses have been proposed
(Jones, 2008): plasma concentrations of 1,25(OH) 2 D are increased leading to increased cellular
concentrations of 1,25(OH) 2 D; plasma 25(OH)D concentrations exceed DBP binding capacity and free
25(OH)D enters the cell and has direct effects on gene expression; or, concentrations of a number of
vitamin D metabolites, especially vitamin D itself and 25(OH)D, exceed the DBP binding capacity,
causing release of free 1,25(OH) 2 D which enters target cells.
2.67 Effects of high intakes of vitamin D, including thresholds for risk, single-dose acute toxicity vs
sustained exposure, are considered further in chapter 7.
20 Expert Group on Vitamins and Minerals.
14