Introduction

Vitamin D is classified amongst nutrients as a fat-soluble vitamin, which is consumed from food, including fortified food or supplements. It can also be synthesized by exposure of the skin to sunlight. Vitamin D facilitates absorption and retention of calcium and phosphorus both of which are critical for bone and teeth formation. Many organs and tissues have vitamin D receptors, which suggest important roles in the body beyond bone and research has shown that vitamin D regulates inflammation and immune function with potentially beneficial effects on the health of the brain, the cardiovascular system, the endocrine system, and other metabolic pathways. Few foods contain vitamin D. Oily fish, butter, liver, eggs, milk, and fortified foods including some breakfast cereals and spreads are the main dietary sources. Whilst most of the requirement for vitamin D is considered to come from casual exposure to sunlight, there is considerable debate on the sufficiency of sunlight to achieve acceptable blood levels of vitamin D because a significant proportion of the population does not achieve adequate skin exposure. Studies from many countries, including those in sunnier regions, such as Southern Europe, the Middle East and Australia demonstrate low vitamin D levels in a high proportion of the populations. Because so few foods contain vitamin D, supplementation with vitamin D should be recommended to bridge this gap.

In this paper we consider the magnitude of the vitamin D gap and its impacts on health and disease. We also outline how the gap can be bridged, discussing the role of foods, sunshine and supplements, explaining why supplements are the most achievable way forwards.

What is the vitamin D gap?

Many countries and organisations globally make recommendations for vitamin D intake for infants and children, adults, older people and in pregnancy and breastfeeding (see Table 1).

Table 1: Current selected vitamin D supplementation guidelines.

Recommendations for intake are based on achieving specific serum concentrations of 25 hydroxyvitamin D (25(OH)D), which is considered to be the best marker of vitamin D status. Most guidelines unanimously agree that serum concentrations of 25(OH)D of <25nmol/litre should be avoided at all ages across a population. However, there is no consensus globally on the concentrations of serum 25(OH)D concentrations reflecting vitamin D sufficiency. Recommendations from different countries and even organisations in the same country for sufficiency of vitamin D vary for serum 25(OH)D from 25 to > 100 nmol/litre. The recommended daily dose considered to be required to achieve these specific serum concentrations also varies.

The UK recommends a dose of 10 mcg daily to achieve a serum concentration of 25(OH)D of at least 25nmol/litre [1]. The European Food Safety Authority (EFSA) [4], the United States Institute of Medicine (IOM) [12] and Health Canada [11] recommend a dose of 15mcg for adults to achieve a serum concentration of 50nmol/litre. Higher doses are often recommended for older people e.g. 20mcg daily for adults > 70 years in the US and Canada.

Organisations with a specific health remit for example the European Menopause and Andropause Society (EMAS) [5] and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) [7] recommend 20-50mcg and 20-25mcg respectively for postmenopausal women. The National Osteoporosis Foundation (NOF) [15] recommends a daily dose of 20-25mcg, whilst the US Endocrine Society [13] recommend that obese children and adults take 2-3 times the dose recommended for their healthy weight peers. In one recent trial the effect of vitamin D in terms of vitamin D biomarkers was blunted in obese patients [20]

Whatever the recommendations for vitamin D intake, it is clear that vitamin D deficiency is prevalent throughout the world even in sunnier countries, including Australia, where it was once assumed that sunlight was sufficient to prevent this deficiency [21] A pooled analysis of 7.9 million people globally found that, 15.7%, 47.9% and 76·6% of participants had serum 25-hydroxyvitamin D levels less than 30, 50, and 75 nmol/l, respectively [22]. With regards to the UK the Scientific Advisory Committee on Nutrition (SACN) [1] set a Reference Nutrient Intake (RNI) of 10 mcg daily to achieve a vitamin D serum concentration above 25 nmol/litre in those aged 4 years and upwards.

The UK National Diet and Nutrition Survey (NDNS) time trend analysis show that intakes have changed little over the past decade with average daily intakes of 2-3 mcg from food alone [23] showing a substantial gap in actual vs recommended intakes. In 2016 the UK government changed its advice to recommend that everyone considers taking a 10mcg daily vitamin D supplement.

The latest NDNS data (years 2016-2019) show that one in five people in the UK are deficient in vitamin D [23] This applies to 10% of children aged 4-10 years (boys 8%; girls 13%); 26% of 11–18-year-olds (boys 15%; girls 39%); 17% of adults aged 19-64 years (men 16%; women 19%) and 13% of adults > 65 years (men 13%; women 13%). In addition, a study in UK primary care found that amongst 210,502 patients who had a vitamin D test, one third were deficient (with deficiency identified as a blood level below 30nmol/litre). Deficiency among ethnic minority groups ranged from 43% among those of mixed ethnicity to 66% in Asians [24].

Studies of the UK Biobank Cohort looking at ethnic minorities have confirmed the huge differences in vitamin D status with Black and Asian populations more at risk of a vitamin D status < 25nmol/litre than white populations [25,26]. In addition, South Asian populations have less seasonal variation in vitamin D status as they have all year-round low vitamin D status [27]. Looking at the European perspective where the target level of 25(OH)D is >50nmol/litre, data suggest that 10mcg daily of vitamin D would allow only approximately 50% of the UK population to achieve the higher level, if that level were to be recommended, and that 25mcg vitamin D daily would be required to achieve the target level of > 50nmol/litre in 97.5% of the population.

In Ireland a similar picture emerges. An Irish epidemiological study [28] found that 10-40% of the Irish population had vitamin D levels below the US threshold of 25(OH)D of <30nmol/litre, which was more pronounced in the winter months.

Vitamin D deficiency (<30nmol/litre) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L)) is found in >10% of Europeans [29]. A systematic review of 107 studies representing 633,093 individuals in Southern Europe found that of one-third of the studies reported mean 25(OH)D concentrations below 50 nmol/L and approximately 10% reported mean serum 25(OH)D concentrations below 25 nmol/L. Women, infants and adolescents had a higher prevalence of low vitamin D status [30].

A survey of a representative population in Australia found that 20 % of participants (19 % men; 21 % women) were classified as vitamin D deficient (<25nmol/litre 25(OH)D), with a further 43 % classified as insufficient (45 % men; 42 % women) (50-75nmol/litre) [31].

Why does the vitamin D gap matter?

Health risks from low vitamin D status

Vitamin D is essential for calcium absorption and bone mineralisation which is positively associated with bone mineral density. However, vitamin D has actions on bone independent of its ability to absorb calcium. It is a major bone regulatory hormone, whose renal metabolite, 1,25(OH)2D3 has effects on bone through facilitating the development and differentiation of the osteoblasts [32].

Good bone health is essential for consolidation of bone mass in adulthood and reduction in risk of osteoporosis later life. Many of the vitamin D guidelines globally (e.g., the UK, wider Europe, Australia and New Zealand, Canada and the US) are based on vitamin D (sometimes with additional calcium) requirements for bone health. (see Table 1). For adults, recommendations for bone health range for adults under 70 years  from 10 mcg (e.g., UK, Nordic Countries, Australia and New Zealand) 15mcg (e.g., EFSA, Canada, the US) and 20mcg (e.g., Germany, Austria and Switzerland). For adults > 70 years, Australia and New Zealand recommends 15 mcg, Canada and the US, 20mcg and the Nordic Countries recommend 20mcg for people of >74 years. Ireland recommends 15mcg daily for healthy older adults and 20mcg daily where there is no or limited exposure to sunlight. For bone health, some authorities recommend higher doses for people who are obese (e.g., the US Endocrine Society recommends 2-3 times the dose of vitamin D for people of healthy weight).

Nutritional rickets and osteomalacia represent the most serious sequelae of vitamin D deficiency. The risk of developing rickets/osteomalacia is increased at a 25(OH)D concentration of ≤ 30 nmol/L. This threshold may vary depending on other conditions such as calcium and phosphate nutrition, parathyroid hormone (PTH) levels, and season. Nutritional rickets remains a global problem, particularly in the Middle East and African countries. However, rickets occurs in the UK, albeit with a low incidence, but with serious complications and deaths especially amongst Black and South Asian children under 5 years [33]. Nutritional rickets also persists in Canada [34], Australia [35], New Zealand [36] and the United States [37].

However, low vitamin D status has other far-reaching impacts on bone health. Low vitamin D status (<50nmol/litre) accelerates bone turnover, bone loss and osteoporotic fracture [38]. A systematic review of 28 studies in 61,744 people found that the risk of hip fractures was 1.8 times as high in those with low vs high 25(OH)D levels. The risk of hip fracture was 2.16 (1.49-3.11, P ≤ 0.001) in case-control studies; 1.52 (1.29-1.79, P = 0.001) in cohort studies; and 1.1 (1.18-1.70, P ≤ 0.001) in case-cohort studies [39].

 Low vitamin D status is also associated with fracture in younger people. A recent study in US military personnel (mean age 20 years) showed that lower 25(OH)D status was associated with higher risk of stress fracture [40]. A cross-sectional US study including 165 participants (83 men, 82 women, 18-30y) who self-identified as Asian, Black, or White measured bone microarchitecture and strength of the distal radius and tibia. In this study 43.6% of participants had low 25(OH) D (< 50nmol/ml) with greater prevalence in Asian (38.9%) and Black (43.1%) compared with White (18.0%) participants (p<0.001). Lower 25(OH) D was associated with worse bone outcomes at the distal radius and tibia at the time of peak bone mass, warranting paying further attention to vitamin D status in young adults [41].

Both skeletal muscle atrophy and poor muscle function are consequences of low vitamin D status [42] This is likely because vitamin D deficiency reduces oxygen consumption and causes disruption of mitochondrial function [43]. Hand grip strength is higher in those with 25(OH)D levels from 30 to <50 nmol/L and ≥50 to ≤125 nmol/L than in people who are deficient [44]. Poor muscle function increases the risk of falls and low vitamin D status has been linked with poor gait and balance in older people [45] as well as falls [46]. Vitamin D deficiency is also associated and with poor sports/athletic function [47,48].

Vitamin D has key roles in immune function [49,50]. Low vitamin D (<25nmol/litre) reduces the number of lymphocytesand the immune capability of macrophages lowering their ability to kill pathogens, altering integrity of the respiratory and gastrointestinal epithelium,and impairing T and B cell (T & B Cells are a types of white blood cells that protect immune function) movements in the intestine with a reduced number and activity of NK (natural killer) cells and impaired innate immunity. Low vitamin D status is linked with various autoimmune conditions such as type 1 diabetes, systemic lupus erythematosus (SLE) and rheumatoid arthritis [51].

Vitamin D also appears to influence the gut microbiota. This is likely one mechanism by which vitamin D affects immune function and hence its extra-skeletal functions. Evidence from a recent systematic review of 25 studies (14 interventional (1511 subjects) and 11 observational (4618 subjects) found that vitamin D supplementation significantly changed the gut microbial population particularly Firmicutes, Actinobacteria and Bacteroidetes phyla. Firmicutes were correlated with serum 25(OH)D. Dietary vitamin D also appears to induce a shift in bacterial composition and/or affects the species’ richness. Veillonellaceae and Oscillospiraceae families, in the Firmicutes phylum, more frequently decreased with both increasing levels of 25(OH)D and vitamin D supplementation [52]. 

Low serum vitamin D levels are associated with increased risk of respiratory tract infection in several studies. Cross-sectional data from 6,789 participants in the nationwide 1958 British birth cohort [53] indicated that the prevalence of respiratory infections had a strong seasonal pattern in the opposite direction to the pattern for 25(OH)D concentrations. Each 10 nmol/l increase in 25(OH)D was associated with a 7 % lower risk of infection (95 % CI 3, 11 %) and improved lung function. A 2019 systematic review [54] of epidemiological studies also found an increased risk of upper and lower respiratory tract infections with low serum vitamin D levels.

Low serum vitamin D has been linked with increased risk from COVID-19. A meta-analysis of 31 peer-reviewed observational studies (14262 subjects) identified a positive trend between serum 25(OH)D level <50 nmol/litre and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant [55]. A retrospective study involving 1226 participants across two East Sussex NHS Trust hospitals suggests a similar mortality from COVID-19 irrespective of 25(OH)D levels [56]. However, low vitamin D levels have been associated with Long COVID in COVID-19 survivors [57].

Vitamin D status is linked with cardiometabolic disease. In a 2018 cohort study higher vitamin D was associated with a lower risk of type 2 diabetes [58]. In the UK Biobank study, a similar inverse association was more prominent in people with healthier sleep patterns (i.e., less frequent day time sleeping) [59]. Low plasma vitamin D is linked with insulin resistance [60]. Serum 25(OH)D levels are inversely associated with an increased risk of coronary heart disease (CHD) and the association was more evident in people with poor sleep patterns [61]. In a meta-analysis of 40 studies, serum 25(OH)D concentrations were not only associated with increased total cardiovascular events and cardiovascular mortality, but also with increased risk of heart failure, myocardial infarction and CHD [62]. A meta-analysis of four prospective studies found that in people with one stroke, low vitamin D levels were associated with a higher risk of recurrent stroke [63]. Other non-skeletal conditions with which low vitamin D status is associated include depression [64] and poor sleep [65].

Supplementation studies

Given the links between low vitamin D status and both musculo-skeletal and non-skeletal conditions, it is important to clarify the impact of vitamin D supplementation on these same conditions. Table 2 presents summary data by health condition from key randomised controlled trials (RCTs) and meta-analyses over the past 10 years. Whilst findings from RCTs are often used to infer causation, it is important to consider that epidemiological studies evaluate links across longer time frames, without such large differences in vitamin D intake and can better represent a real-life context. With supplementation studies both the starting 25-hydroxyvitamin D [25(OH)D] level and the dose of vitamin D administered are important. Where studies show limited effect of supplementation, it is possible that participants were vitamin D replete at the start of the study, suggesting that the key requirement with vitamin D supplementation is to avoid vitamin D deficiency.

With regards to bone health and bone density, many studies indicate a positive effect of vitamin D supplementation on bone density [66-68] but inconsistencies exist across a few studies [69]. Again, findings with regards to falls and fractures are inconsistent, but vitamin D supplementation in doses of 800-1000 IU (20-25mcg) daily with adequate calcium intake can decrease the incidence of fractures in elderly, vitamin D deficient subjects [70,71]. In terms of falls, vitamin D supplementation is most effective with moderate doses of vitamin D given to older people who are vitamin D deficient [72,73]. In summary, older adults with serum 25(OH)D levels <50nmol/L are likely to have fewer falls if supplemented with 800-1000 IU (20-25mcg) per day of vitamin D. Similarly, older adults with poor muscle function, including sarcopenia, improve their muscle function with supplementation, but with moderate doses of 800-1000 IU (20-25mcg daily). Improved hand grip strength was demonstrated in one study [74]. Vitamin D supplementation has been shown to reduce joint pain in osteoarthritis of the knee but without impact on progression of the condition [75-77].

Turning to extra-skeletal conditions, vitamin D supplementation has been shown to reduce risk of acute respiratory tract infection in daily doses of 400-1000 IU(10-25mcg) in people who are deficient in vitamin D [78-80].Vitamin D supplementation also showed efficacy in treatment of respiratory tract infection in a meta-analysis of 18 studies (3648 participants) and although the analysis was restricted to the highest quality studies, just a small benefit was found. As a result, further research is needed.

With regards to COVID-19 the UK CORONAVIT study showed no benefit of vitamin D supplementation on risk of COVID-19 [81]. Some studies have shown a benefit of vitamin D supplementation in patients who already have COVID-19. A meta-analysis of five clinical trials including 1400 patients found that vitamin D administration in large daily or weekly doses resulted in reduced risk of death and admission to intensive care unit (ICU) [82].

Supplementation studies evaluating vitamin D in cardiometabolic conditions have shown inconsistent findings, but as the number of clinical trials have increased, more recent meta-analyses have demonstrated positive findings particularly in terms of blood lipids and insulin parameters and in reducing the risk of type 2 diabetes [83-90].

Studies evaluating vitamin D supplementation in depression [91,92] and sleep [93] have shown promising findings with more research required to confirm these outcomes. Evidence also exists that vitamin D supplementation can significantly shift the gut microbiota [94] which may have a beneficial effect on immune function and contribute to the emerging positive findings for vitamin D in cardiovascular and metabolic health and brain health.

Table 2: Vitamin D randomized controlled trials and meta-analyses.