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 safe9-11 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
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.
Emanuele Rocco Villani1, Graziano Onder1, Luca Pellizzari2
1 Centre for Ageing Medicine, A. Gemelli Polyclinic, Catholic University of the Sacred Heart, Rome
2 Geriatrics A, Integrated University Hospital, Verona
- Secosteroids - an overview. ScienceDirect Topics, https://www.sciencedirect.com/topics/neuroscience/secosteroids
- AIFA. L’uso dei farmaci in Italia - Rapporto OsMed 2017 http://www.aifa.gov.it/content/luso-dei-farmaci-italia-rapporto-osmed-2017
- Cashman K. Vitamin D deficiency: defining, prevalence, causes, and strategies of addressing. Calcif Tissue Int 2019; DOI:10.1007/s00223-019-00559-4. CDI
- Cantorna M, Snyder L, et al. Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients 2015;7:3011-21. CDI
- Arababadi M, Nosratabadi R, et al. Vitamin D and toll like receptors. Life Sci 2018;203:105-11. CDI
- Theodoratou E, Tzoulaki I, et al. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 2014;348:g2035. CDI
- Autier P, Mullie P, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol 2017;5:986-1004.
- Bolland M, Grey A, et al. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol 2018;6:847-58.
- Malihi Z, Wu Z, et al. Noncalcemic adverse effects and withdrawals in randomized controlled trials of long-term vitamin D2 or D3 supplementation: a systematic review and meta-analysis. Nutr Rev 2017;75:1007-34. CDI
- Straube S, Derry S, et al. Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database Syst Rev. 2015 May;6(5).
- Ferguson J, Chang A. Vitamin D supplementation for cystic fibrosis. Cochrane Database Syst Rev. 2014 May;14(5).
- Malihi Z, Wu Z, et al. Hypercalcemia, hypercalciuria, and kidney stones in long-term studies of vitamin D supplementation: systematic review and meta-analysis. Am J Clin Nutr 2016;104:1039-51. CDI
- Kearns M, Alvarez J, et al. Large, single-dose, oral vitamin D supplementation in adult populations: a systematic review. Endocr Pract 2014;20:341-51. CDI
- Vitamin D and Longevity (VIDAL) Trial: feasibility study of 1615 men and women aged 65-84 with cluster randomisation of 20 GP practices to open or double blind individual randomisation. https://www.researchgate.net/publication/329770618_Vitamin_D_and_Longevi...
- Pradhan A, Manson J. Update on the Vitamin D and OmegA-3 trial (VITAL). J Steroid