Vitamin D deficiency is frequent and has been associated with fatigue in uncontrolled trials.

This is the first double-blind placebo-controlled clinical trial to investigate the efficacy of per os vitamin D3 (cholecalciferol) in treating fatigue among otherwise healthy persons with low serum 25-hydroxyvitamin D (25(OH)D) levels.

We enrolled 120 individuals (mean age 29 ± 6 years, 53% women) presenting with fatigue and vitamin D deficiency (serum 25(OH)D < 20 μg/L).

Participants were randomized to a single oral dose of 100,000 units of vitamin D or placebo.

The primary endpoint was intra-individual change in the fatigue assessment scale (FAS) at 4 weeks after treatment.

The mean age of the participants was 29 ± 6 years, 53% were women. Mean FAS decreased significantly more in the vitamin D group (−3.3 ± 5.3; 95% confidence interval [CI] for change −14.1 to 4.1) compared with placebo (−0.8 ± 5.3; 95% CI for change −9.0 to 8.7); (P = 0.01). Amelioration of fatigue was reported more frequently in vitamin D than in placebo group (42 [72%] vs. 31 [50%]; P = 0.01; odds ratio [OR] 2.63, 95% CI for OR 1.23–5.62). Among all participants, improvement in fatigue score correlated with the rise in 25(OH)D level (R = −0.22, P = 0.02).

Vitamin D treatment significantly improved fatigue in otherwise healthy persons with vitamin D deficiency.

Daily vitamin D supplementation is often inadequate in treating vitamin D deficiency due to poor compliance. A single, large dose of vitamin D given at timed intervals may be an alternative strategy.

We conducted a systematic literature review to investigate the efficacy of a single large bolus dose to treat vitamin D deficiency. We identified 2,243 articles in PubMed using the terms “high dose vitamin D,” “single dose vitamin D,” “bolus vitamin D,” or “annual dose vitamin D.” Review articles, cross-sectional studies, nonhuman studies, responses to other articles, and non-English articles were excluded. Manuscripts were also excluded if the study: (1) did not use oral cholecalciferol or ergocalciferol, (2) used vitamin D analogs, (3) enrolled participants under age 18 years, (4) administered doses <100,000 international units (IU) (2.5 mg), or (5) administered >1 dose per year. References of eligible manuscripts and the Cochrane databases were also searched. Two independent reviewers identified eligible manuscripts, and a third reviewer evaluated disagreements. Thirty manuscripts were selected using these criteria.

Large, single doses of vitamin D consistently increased serum/plasma 25-hydroxyvitamin D (25[OH]D) concentrations in several vitamin D-sufficient and -deficient populations. Vitamin D3 doses ≥300,000 IU provided optimal changes in serum/plasma 25(OH)D and parathyroid hormone (PTH) concentrations. Vitamin D supplementation also impacted bone health and extraskeletal endpoints.

This review recommends that vitamin D3 be used for supplementation over vitamin D2 and concludes that single vitamin D3 doses ≥300,000 IU are most effective at improving vitamin D status and suppressing PTH concentrations for up to 3 months.

Lower doses, however, may be sufficient in certain populations.

Vitamin D doses >500,000 IU should be used judiciously in order to minimize adverse events.

For the purpose of this review, megadoses of vitamin D were defined as the administration of doses greater than 100,000 IU. In addition, fractional doses that exceed 100,000 IU of vitamin D should be considered as megadoses.

Hypovitaminosis D is a widespread problem. The role of vitamin D in bone metabolism and its influence on the risk of falls and fractures is clear. It seems that doses of 800 to 2000 IU daily are effective in maintaining serum levels above 30 ng/mL. The ideal dose for vitamin D supplementation should be individualized according to the serum levels and risk factors of each patient. For years it has been discussed whether the use of high doses of vitamin D, called megadoses, could be effective in maintaining adequate serum levels, reducing the risk of falls and hence fractures. The results of research studies make it clear that megadoses of vitamin D would have an opposite effect from what would be expected of them. The information presented shows that the Megadoses increase the risk of falls, fractures and toxicity, so this form of supplementation would not be the most appropriate. The daily dosage according to the needs of each patient seems to be safer and more effective.