VITAL Study: lights and shadows

Giovanni Adami

Rheumatology Unit University of Verona

DOI 10.30455/2611-2876-2023-1e

Vitamin D is a fat-soluble hormone that plays a key role in regulating calcium absorption in the intestine. Cholecalciferol is converted into calcifediol by the liver enzyme 25-hydroxylase and subsequently, under the control of the parathormone (PTH), by the kidney enzyme 1-25-hydroxylase into the biologically active form, calcitriol. Because calcitriol directly regulates the absorption of elemental calcium from the gut, it is therefore essential to ensure an adequate substrate for bone formation.

Under conditions of low vitamin D levels, calcium absorption in the intestine is reduced and the calcium required for blood homoeostasis is drawn from the skeleton under the influence of PTH. Therefore, as is well known in physiology, severe vitamin D deficiency leads to the development of osteomalacia (in adults) and rickets (in children).

The earliest clinical/historical confirmation of vitamin D’s fundamental role in the development of osteomalacia and in bone metabolism comes from ancient finds of skeletons of individuals with deformities and multiple bone fractures as well as from empirically garnered evidence.

It is also well known that populations living above the 37th parallel are at higher risk of developing rickets/osteomalacia. Humans are able to synthesise vitamin D3 through photochemical conversion. Ultraviolet B radiation leads the conversion of 7-dehydrocholesterol into cholecalciferol by the skin. However, in the earth’s northern and southern regions UVB radiation with the wavelength required for vitamin D synthesis does not reach the surface. It has also been found that when rachitic children are exposed to the sun their clinical picture improves until complete recovery.

Vitamin D, which is present in moderate amounts in animal fats, can also be absorbed from the diet. Among Scandinavian populations, it has been shown that the risk of vitamin D deficiency was particularly high for those who lived inland and therefore had a diet low in or even devoid of fish, which is the main animal source of dietary vitamin D. For centuries, cod liver, which is extremely 

rich in vitamin D, has protected Nordic populations from developing osteomalacia or rickets.

It has therefore been widely accepted that vitamin D is a fundamentally important nutrient/hormone for bone health. In recent years, evidence for this assertion has been further strengthened. There have been many studies published, especially observational but also interventional investigations, that confirm the importance of vitamin D and, in particular, that emphasise the marked deleterious effect of low levels of vitamin D or its deficiency on bone.

Interestingly, observational studies conducted on populations at risk of fracture are essentially all in agreement in pointing out the negative role of vitamin D deficiency in increased fracture risk. In contrast, the data from interventional studies has introduced a fair amount of uncertainty. Indeed, some clinical trials were unable to demonstrate a positive effect of vitamin D on the reduction of fracture risk. Nevertheless, although these studies were conducted with extreme scientific rigour and on large populations, their limitations should not be disregarded. Therefore, we cannot, we must not allow them to negatively influence our clinical choices 3. Specifically, I will focus on the inherent weaknesses of the recent “Vitamin D and OmegA-3 TriaL (VITAL)” randomised clinical trial whose ancillary study results on fragility fractures, were recently published.


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