Review
Vitamin D status and ill health: a systematic review

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Summary

Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, 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. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

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

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