ReviewVitamin D status and ill health: a systematic review
Introduction
Vitamin D is a prohormone that has a key role in calcium and phosphate balance and bone structure. In the past decade, vitamin D has been the focus of keen interest because, beyond these known effects, data from ecological and observational studies have shown associations between low concentration of serum 25-hydroxyvitamin D (25[OH]D; usually used as a proxy for an individual's vitamin D status) and increased risk of cancer, cardiovascular diseases, disorders of glucose metabolism, neurodegenerative diseases, and death.1
Many factors, such as season, ageing, latitude, adiposity, physical activity, smoking, and diet (appendix p 2), can affect the link between 25(OH)D and health outcomes, but because of the number of factors and inaccuracies in their measurement, observational studies might not be able to control fully for their confounding effects. Furthermore, the list of disorders associated with low 25(OH)D has continuously increased. These issues have raised the question of whether low 25(OH)D might be the result, rather than the cause, of physiological disturbances involved in some diseases.2
Observational research is not sufficient to support the notion that a person's health would benefit from increases in 25(OH)D concentration—eg, through supplementation. Such claims must be supported by evidence from randomised controlled trials. If the health benefits of high 25(OH)D concentrations shown by data from observational studies are not reproduced in randomised trials, then the relation between 25(OH)D and disorders is probably the result of confounding or physiological events involved in these disorders.
Reports from the International Agency for Research on Cancer (IARC)3 and the US Institute of Medicine4 concluded that insufficient evidence linked 25(OH)D and most non-skeletal health disorders. However, the two reports did not provide hypotheses for why so many disorders were associated with low 25(OH)D concentrations. In this systematic review, we compare the observational and experimental data relating 25(OH)D concentrations to non-skeletal disorders in adults, aiming to formulate hypotheses that can integrate findings.
Section snippets
Search strategy and selection criteria
We searched PubMed and Embase for articles published in English from inception to Dec 31, 2012, including articles published online ahead of publication. We focused on individuals aged 18 years or older. To define the exposure, we used the following key words: “vitamin”, “vitamin D”, “25-hydroxyvitamin D”, “25(OH)D”, “cholecalciferol”, “ergocalciferol”, “calcidiol”, “calcitriol”, and “vitamin D receptors”. For disorders, we used keywords related to all-cause mortality, and to the incidence,
Study inclusion
Our systematic review included about 290 prospective cohort studies (279 on disease occurrence and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status (figure 1).
Observational prospective studies
The 20 most recent meta-analyses and pooled analyses provided summary relative risks for 208 prospective studies, some of which might have been included in different meta-analyses because they addressed several
Discussion
Prospective studies generally documented moderate to strong decreases in: cardiovascular disease, serum lipid concentrations, serum markers of inflammation, glucose metabolism disorders, weight gain, infectious diseases, mood disorders, declining cognitive function, and impaired physical functioning associated with increasing 25(OH)D. By contrast, intervention studies with vitamin D supplementation had little to no effect on these disorders.
Results of prospective studies did not suggest a
25(OH)D concentrations as a result of ill health
The absence of an effect of vitamin D supplementation on disease occurrence, severity, and clinical course leads to the hypothesis that variations in 25(OH)D concentrations would essentially be a result, and not a cause, of ill health. Decreases in vitamin D status would be a biological marker of deteriorating health—characterised by accumulation and severity of disorders driving 25(OH)D to low concentrations (figure 3). Results of observational studies support this hypothesis. For instance, in
Conclusions
Many prospective studies have shown associations between low 25(OH)D concentrations and a wide range of acute and chronic health disorders. However, an equally similar number of randomised trials have not confirmed that raising of 25(OH)D concentrations can modify the occurrence or clinical course of these disorders. Hence, associations between 25(OH)D and health disorders reported by investigators of observational studies are not causal. Low 25(OH)D could be the result of inflammatory
References (63)
- et al.
Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial
Am J Clin Nutr
(2007) - et al.
Low serum concentrations of 25-hydroxyvitamin D in older persons and the risk of nursing home admission
Am J Clin Nutr
(2006) - et al.
Cigarette smoking and inflammation revisited
Respir Physiol Neurobiol
(2013) - et al.
A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study
Eur J Cancer
(2011) - et al.
The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty
Am J Clin Nutr
(2011) - et al.
Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies
Lancet
(2007) - et al.
Non-steroidal anti-inflammatory drugs and melanoma risk: large Dutch population-based case-control study
J Invest Dermatol
(2009) - et al.
Long-term use of nonsteroidal anti-inflammatory drugs decreases the risk of cutaneous melanoma: results of a United States case-control study
J Invest Dermatol
(2011) - et al.
The cure of ageing: vitamin D–magic or myth?
Postgrad Med J
(2010) - et al.
Vitamin D: some perspective please
BMJ
(2012)
The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know
J Clin Endocrinol Metab
Prospective study of predictors of vitamin D status and cancer incidence and mortality in men
J Natl Cancer Inst
Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis
Diabet Med
Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis
J Clin Endocrinol Metab
Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. Document CPMP/EWP/1080/00 Rev. 1, Committee for Medicinal Products for Human Use (CHMP)
Vitamin D insufficiency
N Engl J Med
Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women's Health Initiative calcium-vitamin D randomized controlled trial
J Gerontol A Biol Sci Med Sci
Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis
Proc Nutr Soc
Vitamin D supplementation for prevention of mortality in adults
Cochrane Database Syst Rev
Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials
J Clin Endocrinol Metab
A systematic review: Influence of vitamin D supplementation on serum 25-hydroxyvitamin D concentration
J Clin Endocrinol Metab
Randomized clinical trials: perspectives on some recent ideas
N Engl J Med
Response to comment on: Davidson et al. High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D
Diabetes Care
Do we need to take calcium with vitamin D supplements to prevent falls, fractures, and death?
Curr Opinion Clin Nutr Metab Care
25-hydroxyvitamin D levels and the risk of mortality in the general population
Arch Intern Med
Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality
Arch Intern Med
Vitamin D status and the risk of cardiovascular disease death
Am J Epidemiol
Interventions for preventing falls in older people living in the community
Cochrane Database Syst Rev
Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects
Intern Emerg Med
Low vitamin D levels correlate with the proinflammatory state in type 1 diabetic subjects with and without microvascular complications
Am J Clin Pathol
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