The trials and tribulations of vitamin D: time for the ‘sunshine’ vitamin to come in out of the cold – or just more broken promises?

Abstract

We are presently faced with the competing notions of modern life being a ‘state of vitamin D depletion’, implying a widespread need to supplement with vitamin D, or, the opposite view, which is that the present evidence can only support at best selective targeted vitamin D intervention. This is important as there is evidence that over the last 40–50 years there were downwards global trends in serum 25(OH)D concentrations, while individual consumption of vitamin D as supplements rose. For this reason and many others, a large population-based interventional study, the VITAL trial, was designed to try to establish the health value of vitamin D supplementation. VITAL is a huge primary prevention trial looking at the effects of vitamin D repletion in preventing cancer and cardiovascular disease in a fundamentally healthy population. This may seem an unusual approach given that what we mostly know about vitamin D is that is has some effects on the skeleton. This review looks to explore current knowledge about vitamin D in health and disease, and at how this is now undergoing significant reappraisal and revision. We will carefully critique the VITAL study design to see if it will allow for the construction of the detailed portfolio of clinical evidence so urgently needed to allow us better to understand role of vitamin D supplementation in health and disease.

Keywords::

• bone cancer
• cardiovascular disease
• repletion
• UV light
• VITAL study
• vitamin D

Financial & competing interests disclosure

D Goldsmith has received speaking and consulting honoraria from Abbvie, Amgen, Genzyme/Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Vitamin D3 is synthesized in the skin, mainly during the summer period, following skin exposure to solar ultraviolet radiation, or it is obtained from food, especially from ingestion of fatty fish.

• The active metabolite 1,25(OH)2D has pleiotropic effects through the intracellular VDR and vitamin D-responsive elements of many genes, leading to increased or decreased gene expression of, for example, calcium binding protein or osteocalcin, and rapid nongenomic effects through a membrane receptor and second messengers.

• The primary function of vitamin D may well be vigorously to defend normocalcemia, using bowel, kidney and bone to regulate uptake, excretion and storage, respectively.

• With the increased frequency with which vitamin D status is now assessed, in a diverse group of patients, it is now appreciated that, alongside the classical skeletal ‘rickets’ disease paradigm of vitamin D deficiency, there is a nonclassical paradigm of associations seemingly unrelated to the skeletal manifestations.

• With the recent increase in measurement of serum 25(OH)D concentrations, and research into the actions of vitamin D, the full extent of its insufficiency and/or deficiency has come to light, with estimations suggesting that as many as one billion people worldwide are actually deficient.

• At the moment, there is no dietary recommendation for vitamin D intakes in healthy adults in the UK as the population is assumed to obtain sufficient vitamin D through sun exposure, but this has been proven to not be the case as, for at least 6 months of the year, there can be no UVB-driven skin synthesis of vitamin D in the UK and at higher latitudes.

• The primary aims of VITAL are to test whether vitamin D3 or marine Ω-3 fatty acid supplementation reduces the risk for total cancer and major cardiovascular disease events (a composite endpoint of myocardial infarction, stroke and cardiovascular mortality) – however, the choice of trial methodology to employ two therapeutic interventions in parallel is a traditional one but may yet prove to be controversial when the results are known in 2017.

• We feel that VITAL will be a true landmark study as an example of trying to provide evidence at a high level to support public health benefits – we feel it is important to wait for its completion before making any major changes to our current practices on vitamin D screening and supplementation, imperfect though they may be now.

Notes