Vitamin D: An important ally?

Vitamin D is commonly referred to as a group of hormone function secosteroids, of which the metabolically active form is 1,25-OH.¹
Vitamin D is one of the drugs that has undergone the largest increase in prescription in recent years in Italy, rising from 6.2% in 2013 to 12.6% in 2017.²
The prevalence of vitamin D deficiency in all countries is well known³ and various observational studies have associated low plasma concentrations of vitamin D with problems of the locomotor system (osteoporosis, fractures, muscle strength, falls) and chronic non-skeletal diseases such as cancer, cardiovascular diseases, infectious diseases, autoimmune diseases and mortality. Vitamin D plays both an immunomodulatory role and a protective role against oxidative stress and mitochondrial damage.^4,5 Therefore, it is not surprising that vitamin D deficiency is among the factors that contribute to increasing the incidence and severity of certain infectious diseases, autoimmune diseases and a number of age-related common diseases, as the role of oxidative stress in these diseases (e.g. in diabetes mellitus and other metabolic diseases or cardiovascular diseases) is well known. In addition, from a cardiovascular point of view, vitamin D deficiency is associated with endothelial dysfunction and atherosclerosis with a consequent role in left ventricular hypertrophy, essential hypertension and ultimately was associated with increased cardiovascular mortality.
However, these data do not translate into evidence on the clinical benefit of vitamin D supplementation. Vitamin D is now a key treatment for the prevention of bone fractures in people with osteoporosis, however its use in the prevention or treatment of other diseases is much discussed.

What the reviews say

In particular, three systematic reviews published in recent years have questioned the real effectiveness of this drug. In 2014, Theodoratou and colleagues⁶ carried out an "umbrella" review analysing 107 systematic reviews of the effectiveness of vitamin D supplementation on various health outcomes, showing that vitamin D alone does not have significant effects on bone density and the risk of fractures or falls. In this study, however, the effect of a high or low dosage of vitamin D on the results was not analyzed.
More recently, Autier and colleagues⁷ have studied the effects of vitamin D supplementation on non-bone outcomes, through a systematic review of meta-analysis and clinical trials. This study concluded that vitamin D supplementation reduces mortality for all causes by 3% (95% IC 1%-6%) and mortality for cancer by 12% (95% IC 2%-22%) in the adult or elderly population, but has no effect on the risk and progression of cardiovascular disease, diabetes, depression, muscle function, tuberculosis and colorectal cancer. In addition, this study found an effect of vitamin D on the prevention of infectious diseases of the upper respiratory tract of 12% (IC 95% 4%-19%).
Finally, in 2018, Bolland and colleagues⁸ analyzed the effect of vitamin D supplementation on musculoskeletal conditions, through a sequential analysis of clinical trials, showing that such supplementation has no effect on the prevention of fractures or falls and has no significant effect on bone density. The concomitant administration of calcium does not seem to reduce the risk of fractures in the population living at home, but instead seems effective in the institutionalized population. This study also did not document any difference between low and high-dose supplementation.

Safety of treatment

None of these studies focused on the safety of vitamin D treatment. However, most studies in the literature agree that treatment is safe^9-11 and few studies have highlighted some issues. In particular, it has been documented that treatment with vitamin D is associated with hypercalcemia and hypercalciuria, but not with an increased risk of kidney stones.
These effects appear to be independent of the dose of vitamin D used.¹² In addition, a meta-analysis that studied the effects of taking high doses (>100,000 IU) of vitamin D in single administration showed an increase in gastrointestinal symptoms (vomiting), hypercalciuria and hypercalcemia after administration.¹³

Prospects

For completeness, it should be noted that large clinical trials are currently underway that are exploring other possible actions of vitamin D. These are the Vitamin D and Longevity Trial (VIDAL) in the UK¹⁴ and the Vitamin D and Omega-3 Trial (VITAL) in the US¹⁵.
In conclusion, the effect of vitamin D in relation to complex processes such as ageing, chronic vascular and infectious diseases, neoplasms and functional parameters cannot yet be quantified. As noted by the above mentioned meta-analyses, the evidence in favour of vitamin D supplementation is scarce and not definitive, it is likely that the benefit of vitamin D supplementation has been overestimated and the prescriptive appropriateness not respected.