Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19

Abstract

The value of vitamin D supplementation in the treatment or prevention of various conditions is often viewed with scepticism as a result of contradictory results of randomised trials. It is now becoming apparent that there is a pattern to these inconsistencies. A recent large trial has shown that high-dose intermittent bolus vitamin D therapy is ineffective at preventing rickets - the condition that is most unequivocally caused by vitamin D deficiency. There is a plausible biological explanation since high-dose bolus replacement induces long-term expression of the catabolic enzyme 24-hydroxylase and fibroblast growth factor 23, both of which have vitamin D inactivating effects. Meta-analyses of vitamin D supplementation in prevention of acute respiratory infection and trials in tuberculosis and other conditions also support efficacy of low dose daily maintenance rather than intermittent bolus dosing. This is particularly relevant during the current COVID-19 pandemic given the well-documented associations between COVID-19 risk and vitamin D deficiency. We would urge that clinicians take note of these findings and give strong support to widespread use of daily vitamin D supplementation.

Keywords: COVID-19; dosing; efficacy; maintenance; vitamin D.

© Royal College of Physicians 2021. All rights reserved.

Figures

Fig 1.

The complexity of vitamin D metabolism. D2 is from plant sources via ultraviolet action on ergosterol and D3 from animal sources via ultraviolet action on 7-dehydrocholesterol. Activation is via 25-hydroxylation in the liver followed by 1α-hydroxylation (CYP27B1) in kidneys, immune cells and many epithelia, to 1,25(OH)2D. Increased FGF23 suppresses 1α-hydroxylation. Free 25(OH)D appears to be preferentially taken up by monocytes,19 so the reduction in DBP in illness may have a protective effect via increased availability of free 25(OH)D. Either 25(OH)D or 1,25(OH)2D can be degraded via 24-hydroxylation (CYP24A1) to 24,25(OH)D or 1,24,25(OH)3D respectively.

Fig 2.

Alterations in (a) serum concentration of 24,25(OH)2D, (b) serum concentration of 25(OH)D, (c) ratio of 24,25(OH)2D / 25(OH)D, and (d) serum concentration of cholecalciferol following a single dose of 150,000 IU vitamin D3 (open circles) and daily dose of 5000IU for 28 days (black triangles). The bars represent standard deviations. P values are for comparison of values in daily and single dosing groups at corresponding time points. It can be seen that single high-dose bolus vitamin D induces an increase in the inactivating 24-hydroxylase activity that lasts for around 4 weeks. Reproduced with permission from Ketha et al.

Fig 3.

Changes in serum FGF23 after a single bolus of ergocalciferol (vitamin D2) 300,000 IU intramuscularly in 45 subjects with vitamin D deficiency/insufficiency. FGF23, which inhibits 1α-hydroxylase activity, is increased by 50% (P<0.01) 3 months after the bolus. Reproduced with permission from Turner et al.