Vitamin D is essential for musculoskeletal health, particularly due to its involvement in the regulation of calcium and phosphorus(Reference Reid, Bolland and Grey1,Reference DeLuca2 ). Vitamin D is a unique nutrient in that it is not a vitamin, in the true sense of the word, but actually a pro-hormone, with its main source being an exposure of skin to UV rays (at 290–315 nm), not dietary intake(Reference DeLuca2). Over the past two decades, there has been mounting scientific and clinical evidence that vitamin D deficiency, defined as 25-hydroxyvitamin D (25(OH)D) concentrations below 25 nmol/l, and inadequacy, defined as 25(OH)D concentrations below 50 nmol/l, are a major public health issue across all age groups and populations, but especially amongst older people and ethnic minority groups (a group of people who identify with each other, either on the basis of a presumed common genealogy or ancestry or on similarities such as common language, history, society, culture or nation)(Reference Adams and Hewison3–Reference Darling, Hart and MacDonald7).
The two main forms of vitamin D are naturally present in a few foods and in small quantities, with ergocalciferol (vitamin D2) from plant and/or fungal sources, such as mushrooms and cholecalciferol (D3) from animal origin foods such as oily fish, butter, eggs and liver. It is important to appreciate that the vitamin D content in these food sources can vary dramatically between countries due to environmental and agricultural factors and that usual dietary intake of vitamin D-rich foods varies widely between populations(Reference DeLuca2). For instance, the vitamin D content of milk is known to be subjected to seasonal variations, presenting, as expected, higher content in summer months in comparison to wintertime. Several studies have indeed demonstrated a variation in vitamin D concentration in milk, ranging from 0⋅004 to 0⋅0014 μg/g fat, across not only different breeds of cattle, but also different locations(Reference Weir, Strain and Johnston8).
Habitual exposure of the skin to UVB radiation in sunlight (wavelength between 290 and 315 nm) converts the molecule 7-dehydrocholesterol, naturally present in the epidermis, into pre-vitamin D3(Reference DeLuca2,Reference Webb, Kift and Durkin9 ). Pre-vitamin D3 is thermodynamically unstable and is thus quickly metabolised to vitamin D3 through thermal isomerisation. Vitamin D3 then binds to vitamin-D-binding protein in the bloodstream and is transported to the liver, along with vitamin D absorbed from dietary sources (food and supplements)(Reference DeLuca2). In the liver, these molecules undergo a first hydroxylation by the cytochrome P450 enzyme CYP2R1 (25-hydroxylase) to produce the major circulating form, 25(OH)D(Reference DeLuca2). The molecule 25(OH)D undergoes further hydroxylation in the kidneys, by enzyme CYP27B1 (1α-hydroxylase), resulting in the active form of vitamin D (1α,25(OH)2D3), which is the main biological active metabolite(Reference DeLuca2).
Atmospheric conditions, such as cloud, ozone and humidity can cause absorption or deflection of much of the UV rays in sunlight before it reaches the earth's surface(Reference Hosseinpanah, Pour and Heibatollahi10,Reference Raiten and Picciano11 ). Since ozone absorbs UVB radiation, holes in the ozone layer caused by pollution could potentially enhance vitamin D levels of populations due to an increase of UVB radiation passing through these holes. Conversely, air pollution will disperse and absorb UVB radiation, reducing the availability of UVB rays reaching the ground, and consequently reducing the production of vitamin D in the skin.
In the UK, the latest data from the rolling National Diet and Nutrition Survey 2008/2009–2011/2012 provides evidence of an increased risk of vitamin D deficiency in all age/sex groups(Reference Beverley, Lennox and Prentice12). Year-round, 7⋅5 % of children aged 1⋅5–3 years and 24⋅4 % of children aged 11–18 years had serum 25(OH)D concentrations below 25 nmol/l(Reference Beverley, Lennox and Prentice12). In adults, 16⋅9 % of men and 24⋅1 % of women, aged 65 years and over, had serum 25(OH)D concentration below 25 nmol/l, with the prevalence being higher in the wintertime(Reference Beverley, Lennox and Prentice12). The recent Scientific Advisory Committee on Nutrition report published in 2016, suggests that the mean intake of vitamin D (from all sources, including supplements) for the general British population is 2–4 μg/d for ages 1⋅5–64 years and 5 μg/d for adults aged 65 years or over(13).
Why is vitamin D so important?
The biologically active vitamin D metabolite 1α,25(OH)2D3 is involved in bone formation as well as bone maturation(Reference Reid, Bolland and Grey1,Reference DeLuca2 ). Along with parathyroid hormone, it regulates calcium and phosphorus metabolism and enhances the absorption of calcium in the gut and reabsorption of filtered calcium in the kidney(Reference Reid, Bolland and Grey1,Reference DeLuca2 ). Vitamin D is, therefore, essential to help maintain muscle function and an optimal status may help reduce the risk of falls and fractures, particularly in older people. Prolonged and severe vitamin D deficiency may lead to rickets in children and osteomalacia/osteoporosis in adults(Reference Reid, Bolland and Grey1,Reference DeLuca2 ).
Although data is still largely observational, recent evidence also suggests that Vitamin D may have an important role in the pathophysiology of conditions as diverse as inflammatory and heart diseases, type I and II diabetes, various types of cancer and multiple sclerosis(Reference Adams and Hewison3,Reference Theodoratou, Tzoulaki and Zgaga14,Reference Holick15 ). However, while the essential role of vitamin D in the maintenance of calcium homeostasis ad skeletal health is well recognised, there is still a substantial lack of robust evidence, with few well-designed randomised controlled trials (RCT) to elucidate the effect of vitamin D deficiency in other non-skeletal related health outcomes.
The costs associated with vitamin D deficiency in the population are staggering, with a recent National Health Service report estimating that approximately 10 million people in England alone may have low vitamin D status, with treatment costs for vitamin D deficiency calculated to be over £70 million per year for England(Reference Scholes, Faulding and Mindell16).
Controversy: where to set the cut-point for total 25(OH)D status?
Defining vitamin D deficiency
The most common criteria used for determining the optimal serum 25(OH)D concentration for bone health in adults are the levels that result in (1) suppression of parathyroid hormone secretion; (2) greater bone mineral density; (3) lower rates of bone loss; and (4) decreased incidence of fractures and falls(Reference Vieth, Ladak and Walfish17,Reference Bouillon, Van Schoor and Gielen18 ). There is still much debate and controversy about which levels of circulating 25(OH)D should be considered to define states of deficiency, insufficiency and sufficiency, and consequently lack of consensus on a definition for optimal vitamin D status. There is, though, general agreement that circulating 25(OH)D concentrations of populations should not decrease below 25 nmol/l in order to preserve bone health(Reference Bouillon, Van Schoor and Gielen18,Reference Ross, Manson and Abrams19 ).
The UK Scientific Advisory Committee on Nutrition classifies vitamin D deficiency as 25(OH)D concentrations below 25 nmol/l(13), the Institute of Medicine in the US defines insufficiency as 25(OH)D concentrations below 50 nmol/l(Reference Ross, Manson and Abrams19) and the US Endocrine Society proposes 75 nmol/l(Reference Holick, Binkley and Bischoff-Ferrari20) as the minimum level required to prevent detrimental effects to health.
Vitamin D recommendations
Previously in the UK, a reference nutrient intake for vitamin D was set only for population groups deemed to be at high risk of deficiency, assuming that for most people the amount of vitamin D synthesised in the skin by exposure to sunlight was sufficient to reach serum 25(OH)D concentrations ≥25 nmol/l throughout the year(13). However, increasing new evidence proved this not to be the case and the new publication from the UK Government's Public Health England Department recommends a vitamin D daily intake of 10 μg for the UK population aged 4 years and over, including individuals from minority ethnic groups with darker skin(13). The Institute of Medicine and the Endocrine Society in the US recommendations are much higher than the UK reference standards, namely an RDA of 15 μg of vitamin D for individuals aged 1–70 years, increasing to 20 μg for those older than 70 years(Reference Ross, Manson and Abrams19, Reference Holick, Binkley and Bischoff-Ferrari20).
Vitamin D status worldwide
Over the past three decades, the increasing prevalence of inadequate vitamin D status has been reported in different populations worldwide(Reference Adams and Hewison3,Reference Mithal, Wahl and Bonjour5,Reference Hossein-nezhad, Holick and Heaney21–Reference Cashman, Dowling and Škrabáková23 ). The majority of the data comes from studies and national surveys in high latitude countries, which is not surprising due to the known challenges of maintaining adequate vitamin D levels in these locations, especially during winter.
A systematic review conducted in 2013, of studies published in the previous 10 years in apparently healthy individuals, reported a remarkably high prevalence of low vitamin D status (in places with available data) in all age groups, but especially in girls and women from the Middle East(Reference Palacios and Gonzalez24). More recently, emerging evidence indicates that low vitamin D concentrations are alarmingly common, also in low latitude countries, despite the abundance of sunlight(Reference Mendes, Hart and Botelho25–Reference Wacker and Holick27).
In the UK, data from the rolling National Diet and Nutrition Survey programme of 977 individuals showed a mean 25(OH)D level of 44⋅8 nmol/l in adults aged 19 years or over (Fig. 1). A recent study applying Vitamin D Standardization Program protocols to fourteen studies, combined with four previously standardised studies, from representative European populations, estimated that 40 and 13 % of 55 844 individuals had average year-round 25(OH)D concentrations below 50 and 30 nmol/l, respectively. Remarkably, dark-skinned ethnic groups were estimated to have a substantially higher prevalence of levels below 30 nm, ranging from 3- up to 71-fold, compared to white individuals(Reference Cashman, Dowling and Škrabáková23).
Fig. 1. Mean 25(OH)D (nmol/l) by country.
A multinational study conducted in 2004/2005 that included eighteen countries ranging in latitude from 64°N to 38°S, with 2606 participants, observed that low 25(OH)D concentrations were common among postmenopausal women with osteoporosis, with 64 % of this sample having levels below 75 nmol/l. Mean 25(OH)D concentration was 67 (se 0⋅75) nmol/l and values ranged from 15 to 607 nmol/l, with regional mean concentrations lowest in the Middle East (51 nmol/l, se 1⋅25) and highest in Latin America (74 nmol/l, se 1⋅5)(Reference Lips, Hosking and Lippuner4).
In the US, data from the National Health and Nutrition Examination Survey population reported a mean 25(OH)D concentration of 65 nmol/l in individuals aged 20–59 years and 62⋅5 nmol/l within those 60 years or over (Fig. 1). The number of individuals with 25(OH)D concentrations below 75 nmol/l almost doubled from 1994 to 2004, reaching a figure of nearly 75 % of the American population by 2004. Within dark-skinned populations (Black, Hispanic and Asians), the prevalence of levels below 75 nmol/l was more than 90 % in this cohort(Reference Ginde, Liu and Camargo28).
A longitudinal cohort study in South Australia (latitude 34°S) with 2413 participants, conducted between 2008 and 2010 (Stage 3 of the Nutrition, Water, Sanitation and Hygiene Study), observed an overall mean serum 25(OH)D of 69⋅2 nmol/l with 22⋅7 % of the population having concentrations below 50 nmol/l (Fig. 1)(Reference Gill, Hill and Shanahan29). Another study in Australia in 126 healthy free-living adults (aged 18–87 years) reported a prevalence of 10⋅2 and 32⋅3 % of individuals with serum 25(OH)D concentrations below 25 and 50 nmol/l, respectively, at the end of winter(Reference Kimlin, Harrison and Nowak30). Studies conducted in several different cities in Brazil found a high prevalence of 25(OH)D concentrations below 50 nmol/l, with values as high as 57⋅3 % in the city of São Paulo (latitude 23°S) (Fig. 1), 31⋅5 % in Recife (latitude 8°S), 63⋅7 % in Curitiba (latitude 25°S), with the latter study being conducted in adolescents(Reference Mendes, Hart and Botelho25,Reference Premaor and Furlanetto31,Reference Saraiva, Cendoroglo and Ramos32 ).
Strategies for improving vitamin D status in the population
Vitamin D supplementation and/or food fortification have been increasingly discussed worldwide as an effective strategy to tackle low vitamin D levels, particularly since natural food sources are limited in most countries. Vitamin D supplementation has been gaining popularity over recent years, in line with widespread claims of the preventive or therapeutic effects of vitamin D being related to a diverse range of health outcomes. Over the past 15 years, research has been dedicated to determining the best ways of improving vitamin D status of populations, either through the supplemental intake and/or food fortification, and have debated whether vitamin D2 or D3 should be the preferred source.
It was previously believed that there were no differences between vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) in their effectiveness in improving vitamin D concentrations(Reference Tripkovic, Wilson and Hart33). However, a recent randomised, double-blind, placebo-controlled food-fortification trial, conducted in 335 healthy South Asian and Caucasian European women (20–64 years) living in Southern England, has demonstrated that vitamin D3 was more effective than vitamin D2 in increasing serum 25(OH)D in the wintertime. This suggests that vitamin D3 might be the better option to optimise vitamin D status within the general population(Reference Tripkovic, Wilson and Hart33). In the trial, study participants received either a placebo, juice supplemented with 15 μg vitamin D2, biscuit supplemented with 15 μg vitamin D2, juice supplemented with 15 μg vitamin D3, or biscuit supplemented with 15 μg vitamin D3 daily for 12 weeks. Serum 25(OH)D was measured by liquid chromatography–tandem MS at baseline and at weeks 6 and 12 of the study. The findings from this relevant study suggested that both juice and biscuits are viable products for fortification strategies to effectively raise 25(OH)D concentrations.
Regarding strategies to reduce vitamin D deficiency at a population level through mandatory food fortification programmes, Finland has taken the lead by implementing a systematic national fortification programme and has shown this to be an effective approach. A voluntary food fortification policy was introduced in Finland in 2003 advising food manufacturers to add 10 μg/100 g vitamin D to fat spreads and 0⋅5 μg/100 g to milk products. National reports showed that over a period of 10 years, mean 25(OH)D concentrations increased from 47⋅6 to 65⋅4 nmol/l in adults(Reference Jaaskelainen, Itkonen and Lundqvist34). Furthermore, the prevalence of 25(OH)D concentrations below 30 nmol/l decreased from 13 to 0⋅6 %. It is worth noting that during the same survey period, reported supplement use also increased, from 11 to 41 %(Reference Jaaskelainen, Itkonen and Lundqvist34).
In this sense, another key recent project on vitamin D is the European Commission-funded ODIN project (food-based solutions for optimal vitamin D nutrition and health throughout the life cycle), a cross-disciplinary, collaborative project, including thirty partners from nineteen countries. This project aimed to develop evidence-based solutions to prevent low vitamin D status (25(OH)D) <30 nmol/l) using a food-first approach(Reference Kiely and Cashman35). The ODIN project is the first internationally standardised dataset of vitamin D status and included almost 56 000 EU residents(Reference Kiely and Cashman35). A summary overview published in 2018, reported that across a latitude of regions ranging from 35 to 69°N, 13 and 40 % had serum 25(OH)D below 30 and 50 nmol/l, respectively, with the risk of low vitamin D status higher among ethnic minorities(Reference Kiely and Cashman35). Within the ODIN project, four dose-response RCT were conducted in Northern Europe, accompanied by a series of food production studies, food-based RCT and dietary modelling experiments. The study collaborators concluded that diverse fortification strategies could safely increase population intakes and prevent low vitamin D status(Reference Kiely and Cashman35).
A review discussing the impact of urban living high latitude, urban living and ethnicity on 25(OH)D status, published in 2019, proposes a further discussion on the key role of a multidisciplinary approach on tackling vitamin D deficiency globally(Reference Mendes, Darling and Hart36). This multidisciplinary approach would bring together and apply knowledge from dietitians, nutritionists, endocrinologists, psychologists, social scientists, photobiologists, biochemists, engineers, town planners etc. This is crucial to be able to consider all the aspects involved in vitamin D status of populations, with particular relevance for ethnic minority groups(Reference Mendes, Darling and Hart36).
Vitamin D supplementation RCT have consistently demonstrated the dependence of the response to vitamin D supplements on initial vitamin D concentrations, although this factor has not been considered in most studies conducted in the past(Reference Stokes and Lammert37,Reference Heaney38 ). This is an important point to be considered when discussing the benefits of vitamin D supplements, as it might explain the various negative results from vitamin D supplementation studies that have investigated its effect on the incidence and risk of falls and/or fractures. For instance, a recent review that investigated the proportion of RCT that studied vitamin D deficient populations found that 70 % of RCT included participants with baseline 25(OH)D over 40 nmol/l and of the twenty-five large RCT (completed or ongoing), only one investigated a vitamin D deficient population, while three focused on vitamin D insufficient populations. Individuals that are vitamin D sufficient are considered unlikely to benefit from supplementation and could even potentially mask the beneficial effect to those with deficient or insufficient levels(Reference Bolland, Grey and Avenell39).
Conclusions
This narrative review has demonstrated that vitamin D inadequacy is a global public health issue and that whilst populations at higher latitudes are at greater risk of deficiency, particularly during winter, the concern is now extended to a global level. Targeting intervention strategies specific to each population, country and the ambient setting is important if benefits are to be optimised. Studies specifically designed to investigate the effect of, and requirements for, vitamin D supplements in each country or ethnic group are urgently required to contribute to an improved definition of vitamin D deficiency and more specific and efficient recommendations.
Recommendations for either supplementation or food fortification need to consider the availability of each vitamin D source (dietary intake, either from food or supplements, and endogenous production from sunlight exposure), individual characteristics and lifestyle aspects. Moreover, there are key considerations to be taken into account for the proposal of supplementation and fortification programmes. Firstly, identification of the optimum level of blood concentrations for optimal vitamin D status and recommended daily intake remains controversial, both of which are the bases for determining supplementation or fortification strategies, particularly for programmes implemented at population levels. Moreover, such programmes will also need to be tailored to incorporate culturally and geographically appropriate choices of vehicles for fortification, consider the bioavailability of the fortificant and consider current intake levels for each country and/or ethnic group targeted.
Inter-individual variability in vitamin D status could be reasonably explained by differences in the metabolism of vitamin D. The VDR gene plays an important role in Vitamin D metabolism and polymorphisms in this gene can potentially affect Vitamin D gene expression, meaning that genetic variation could explain the considerable differences in vitamin D levels among population independently of latitude and sunlight exposure(Reference Valdivielso and Fernandez40). Moreover, some research suggests that some polymorphisms in GC and CYP2R1 genes (involved in vitamin D metabolism) are associated with 25(OH)D concentrations(Reference Valdivielso and Fernandez40,Reference Hunter, De Lange and Snieder41 ). Therefore further research, with robust data from clinical trials, investigating genetic factors influencing vitamin D concentrations could be key in better understanding how to tackle vitamin D deficiency in different populations.
In the near future, climate changes are expected to affect food production and the interactions between environment, agricultural systems and livestock will have a critical impact on future diets and health outcomes. However, the extent and pathways, and potential consequences, are still mainly unclear. Future research will need to consider an approach with an interdisciplinary tactic, linking multiple interactions between environmental changes, agricultural productivity and livestock systems, with a specific focus on vitamin D availability through both food intake and photochemical production in the skin.
Additional research is still required to understand inter-individual variability in the metabolism of vitamin D and differences in response to supplementation, which may be due to genetic polymorphisms. Environmental, cultural and individual factors that influence vitamin D status, including during supplementation, need to be better elucidated. Such factors include adiposity, season, cultural and clothing habits, skin pigmentation, sun exposure and dietary habits also required further investigation to determine what extent each factor affects vitamin D status. Regarding supplementation strategies, particular issues include accessibility to vitamin D supplements and compliance/reluctance with supplement intake.
Most importantly, there is an urgent need for studies that appropriately investigate the response to supplementation or fortification considering initial concentrations of 25(OH)D to interpret the effect of changes between baseline and post-supplementation on the studied outcomes.
Collaborative efforts between academia, government and industry, including countries from several different latitudes, are required to implement effective long-term solutions to this global issue of vitamin D deficiency.
Financial Support
None.
Conflict of Interest
S. L. N. is the Research Director of D3Tex Ltd, which holds the UK and Gulf Corporation Council Patent for the use of UVB transparent material for vitamin D deficiency prevention.
Authorship
M. M. M. and S. L. N. drafted the manuscript; K. C., S. T., H. R. and S. L. N. revised the manuscript. M. M. M., K. C., S. T., H. R. and S. L. N. had primary responsibility for final content. All authors read and approved the final manuscript.
