European Journal of Clinical Nutrition (2011) 65, 986993

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REVIEW

Vitamin D: the light side of sunshine

RS Mason, VB Sequeira and C Gordon-Thomson
Department of Physiology, Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia

Under normal circumstances, vitamin D is mainly obtained from skin through the action of ultraviolet B irradiation on 7-dehydrocholesterol. It is further metabolized to 25-hydroxyvitamin D (25OHD), the major circulating vitamin D compound, and then to 1,25-dihydroxyvitamin D, the hormonal form. The major function of vitamin D compounds is to enhance active absorption of ingested calcium (and phosphate). This assists in building bone at younger ages and ensures that despite obligatory urinary losses, bone does not need to be resorbed to maintain blood calcium concentrations. Vitamin D compounds appear to have direct effects to improve bone and muscle function, and there is good, although not entirely consistent, evidence that supplemental vitamin D and calcium together reduce falls and fractures in older individuals. On the basis of calcium control and musculoskeletal function, target levels for 25OHD in blood are at least 5060 nmol/l and there may be a case for higher targets of 7580 nmol/l. There are vitamin D receptors in most nucleated cells and some evidence, although not consistent, that adequate vitamin D levels may be important in reducing the incidence of, or mortality from, some cancers and in reducing autoimmune disease. Adequate vitamin D may also allow for a normal innate immune response to pathogens, improve cardiovascular function and mortality and increase insulin responsiveness. Vitamin D levels are maintained better in the presence of adequate calcium intakes, more exercise and less obesity. Genetic variation may have an effect on vitamin D blood levels and response to treatment with vitamin D.

European Journal of Clinical Nutrition (2011) 65, 986993; doi:10.1038/ejcn.2011.105; published online 6 July 2011
Keywords: vitamin D; sunlight; non-classical effects; calcium; deficiency

Introduction
Although observations in people with severe vitamin D deficiency meant that vitamin D was well known for its importance in gut calcium absorption and bone and muscle function, more recent studies indicate that even lesser degrees of vitamin D deficiency may result in suboptimal bone and muscle characteristics and increase the risk of falls and fractures in older people. Moreover, receptors for vitamin D are found in nearly all nucleated cells. There is emerging evidence that suboptimal vitamin D status contributes to suboptimal function of many body systems. This evidence, to date, is not conclusive, and even the definition of optimal vitamin D status is a source of considerable controversy.

Vitamin D production in skin

Under normal circumstances, most vitamin D is derived from the action of ultraviolet (UV) light on substrate
Correspondence: Professor RS Mason, Department of Physiology, Physiology and Bosch Institute, University of Sydney, Anderson Stuart Building, Sydney, New South Wales 2006, Australia. E-mail: rebeccam@physiol.usyd.edu.au Received 7 March 2011; accepted 11 April 2011; published online 6 July 2011

7-dehydrocholesterol in skin. Low wavelengths of UVB (290315 nm) are absorbed by 7-dehydrocholesterol, converting it into previtamin D. At body temperature, previtamin D converts to vitamin D, but the process takes several hours. Continued irradiation converts previtamin D or vitamin D into several products termed over-irradiation products (Holick, 1981), which have little effect on calcium metabolism but may have other functions in skin (Mason et al., 2010). One difficulty in advising optimal sun exposure to maintain vitamin D levels is that there needs to be a balance between some sun exposure to make vitamin D and the need for sun avoidance or protection to reduce risks of skin cancer. This is further complicated because there is limited data on the relationship between sun exposure and vitamin D synthesis and because the amount of UV needed varies with latitude, altitude, time of day, season of the year, cloud cover, as well as skin pigmentation and other factors, such as clothing and sunscreens (Webb and Engelsen, 2006; Springbett et al., 2010). A biological end point of UV irradiation that can be assessed with reasonable convenience is minimal erythemal dose, the amount of UV required to just cause faint redness of skin. It is possible, under limited circumstances, to use minimal erythemal dose as a guide to a vitamin D dose. The limitation is that the UV action spectra for erythema and vitamin D production are similar only

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at low wavelengthsbelow 315 nm (Webb and Engelsen, 2006). No vitamin D is produced by UVA, for example, which makes up the bulk of UV in sunlight at the earths surface, but it is possible to develop erythema from UVA exposure. Hence, the general recommendation that exposure of around 18% of body surface (face, hands and arms, or legs) to one-third of a minimal erythemal dose of UV should produce around 1000 IU (25 mg) of vitamin D has some basis in the experimental literature (Holick, 2002; Rhodes et al., 2010), but only if the times of exposure are around midmorning to mid-afternoon in summer and around noon in winter. Even then, in winter, no vitamin D is able to be produced at high latitudes 4421 North or South (Webb and Engelsen, 2006). Complex tables, based on measurements of the exposure times to produce 1/3 of a minimal erythemal dose in people with white skin at various latitudes and different times of day in different seasons, have been produced (Diamond et al., 2005; Webb and Engelsen, 2006). In practice, this information is difficult advice to convey to health practitioners or the public. Simplification is desirable. Advice along the following lines might be helpful: In summer, go outside for a walk with your sleeves rolled up around midmorning or mid-afternoon for around 68 min, most days. In winter, try to get out at lunchtime most days for about 740 min or so depending on the latitude (Diamond et al., 2005; Webb and Engelsen, 2006). Walk briskly so that you can roll your sleeves up a bit. Although this is not practical for everyone, the idea of going outside to get a bit of exercise, perhaps to clear the mind and improve peoples mood, is a goal worth considering. Sun exposure can produce DNA damage and immunosuppression, leading to skin cancers, but there is some evidence that small amounts of sun damage are relatively better repaired (de Winter et al., 2001). This, together with the observation that previtamin D and vitamin D are broken down with continued UV, suggests that little but frequent might be appropriate sun advice for vitamin D production with less likelihood of sun damage. As it happens, vitamin D compounds topically applied to skin reduce UV-induced DNA damage (Damian et al., 2010) through, what appears to be, a non-classical steroid hormone pathway (Mason et al., 2010). Furthermore, there is evidence that vitamin D compounds active in photoprotection, including the hormone 1,25dihydroxyvitamin D, are made in skin from vitamin D and over-irradiation products (Mason et al., 2010). These observations suggest that sun damage would be worse if vitamin D and its metabolites, including those from over-irradiation products, were not formed in skin (Mason et al., 2010). Blanket advice is not suitable for everyone. As the pigment melanin absorbs UVB, less vitamin D is made in people with pigmented skin in most, although not all, studies, and those with darker skin may need 36 times longer UV exposures compared with those with lighter skin (reviewed in Springbett et al., 2010). People who wear modest dress for religious or cultural reasons are also at risk of vitamin D deficiency (Grover and Morley, 2001; Springbett et al., 2010). The skin of older people is thinner (Need et al., 1993), which may explain the lower concentrations of 7-dehydrocholesterol reported and the lower vitamin D produced after UV in some (Holick et al., 1989), although not all studies (Springbett et al., 2010). A larger factor is reluctance of older people to go out into the sun, particularly people in aged care facilities, partly because of preference, lack of access to sunny spaces and frailty (Durvasula et al., 2010). Sunscreens, applied properly in a laboratory, reduce UVB penetration and reduce vitamin D production substantially (Matsuoka et al., 1987). Evidence from real-world studies suggests that use of sunscreens makes relatively little difference to vitamin D levels, partly because sunscreens tend to be inadequately applied in practice and partly because people applying sunscreens are likely to be actually going out in the sun (Springbett et al., 2010). On balance then, sun protection is advisable for people who are likely to experience sun damage (Green et al., 2010).

Dietary sources of D
Most natural foods are a poor source of vitamin D, providing o10% of daily requirements. Oily fish, particularly from the wild, is a reasonable source (25 mg/100 g) as are wild mushrooms or mushrooms pulsed with UV (30100 mg/100 g; Holick, 2007). There is a little vitamin D in eggs and meat and some in fortified foods, such as cereals, margarine and milk, although the levels of fortification vary from country to country. Fish liver has not only high levels of vitamin D but also high levels of vitamin A, which interfere with vitamin D activity (Jenab et al., 2010) and have adverse effects on bone. Animal sources of vitamin D provide vitamin D3 or cholecalciferol, formed from 7-dehydrocholesterol, as discussed above. Irradiation of the plant compound ergosterol produces vitamin D2 or ergocalciferol. These compounds differ by only a double bond in the side chain, and metabolism and actions are fairly similar in humans, although not in birds and some primates. There is some evidence that vitamin D2 may not raise blood 25-hydroxyvitamin D (25OHD) levels or be stored to the same extent as vitamin D3, even using assays that detect both forms equally (Heaney et al., 2011), but this is not a universal finding (Holick et al., 2008).

Metabolism
Once produced in skin or absorbed from the gut, vitamin D is carried in blood on vitamin D-binding protein to the liver where it undergoes 25-hydroxylation to form 25OHD, the major circulating metabolite of vitamin D. Some other tissues, such as skin, are also capable of 25-hydroxylation (Lehmann et al., 2001). Vitamin D input is largely reflected in blood 25OHD concentrations (Mason and Posen, 1979), European Journal of Clinical Nutrition

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and it is blood 25OHD that is used as a measure of vitamin D status (Holick, 2002, 2007; Diamond et al., 2005). The active hormone 1,25-dihydroxyvitamin D, also known as calcitriol, is made in the kidney for export into blood (Lawson et al., 1971; Holick, 2002, 2007). The 1a-hydroxylase enzyme that produces calcitriol is expressed by many tissues, but the calcitriol produced by non-renal tissues has mainly local effects (Holick, 2007). High levels of calcitriol may be produced by activated macrophages in conditions such as sarcoidosis so that it escapes into the bloodstream and causes hypercalcemia (Mason et al., 1984). Although kidney production of calcitriol is very tightly regulated by calcium via parathyroid hormone, by phosphate and during growth and pregnancy, extrarenal calcitriol production is far more substrate dependent and responsive to local factors (Atkins et al., 2007). This may be part of the reason why blood concentrations of 25OHD are so important (Figure 1). Both calcitriol and 25OHD undergo catabolism (Figure 1). Calcitriol is metabolized in most cells by 24-hydroxylase, expression of which is induced by calcitriol, to 1,24,25trihydroxyvitamin D and to further degradation products such as calcitroic acid (Reddy and Tserng, 1989). The 25OHD is converted to highly polar metabolites and excreted into bile, with little evidence of a clinically relevant enterohepatic circulation (Clements et al., 1984). Metabolic inactivation of 25OHD through this pathway is increased with low calcium intakes or absorption and high levels of parathyroid hormone and calcitriol (Clements et al., 1987a, b; Davies et al., 1997). of calcium in most foods and calcium absorption is not particularly efficient; hence, active calcium absorption is important to offset obligatory calcium losses, mostly in urine (Nordin, 1997; Nordin and Morris, 2010). Urine calcium losses are increased after the menopause (Aloia et al., 2010). To maintain neutral calcium balance, ingested calcium needs to be 10001300 mg/day (the higher value in older women; Nordin, 1997). As blood calcium concentrations are maintained within narrow limits, through the actions of parathyroid hormone together with vitamin D, if not enough calcium enters the blood from the gut to make up for urine and other losses, then bone is resorbed to release calcium to the extracellular fluid and blood. Any tendency for serum calcium to decrease is detected by calcium-sensing receptors in the parathyroid gland and elsewhere, and results in increased levels of parathyroid hormone and increased bone resorption (Jesudason et al., 2002). Secondary increases in parathyroid hormone (secondary hyperparathyroidism) are seen even with mild levels of vitamin D deficiency25OHD concentrations below 50 nmol/l (Malabanan et al., 1998). In mild-moderate vitamin D deficiency (412.5o50 nmol/l), there is still sufficient substrate 25OHD to produce calcitriol in the kidney under the control of parathyroid hormone; hence, blood calcium and phosphate concentrations are normal and the bone is still normally mineralized, although parathyroid hormone levels are high, as are bone resorption and turnover markers (Holick, 2007). Bone mass, measured as bone mineral density or total body calcium content, is reduced with mild-moderate D-deficiency, both in younger people (Winzenberg et al., 2011) and older individuals (Kuchuk et al., 2009). Mild-moderate vitamin D deficiency also impairs coordinated muscle function (Bischoff-Ferrari et al., 2004; Wicherts et al., 2007). The combination of impaired muscle function and reduced bone increases the risks of falls and fractures, particularly in older (465 years) people. Severe vitamin D deficiency (o12.5 nmol/l) results in very much reduced gut calcium absorption, as there is insufficient substrate 25OHD to produce adequate calcitriol (Aloia et al., 2010). Bone resorption is also reduced, as some vitamin D is needed to permit parathyroid hormone to promote bone resorption. As a result, serum calcium concentrations become low. Serum phosphate concentrations also decrease, because the now very high levels of parathyroid hormone lead to pronounced urinary phosphate wasting. Without sufficient calcium, phosphate and vitamin D, bone mineralization is impaired. There are increased areas of unmineralized bone matrix (osteoid), a hallmark of osteomalacia. If growth plates are still present, as in children, the impaired mineralization causes disorganization and hypertrophy of the growth plate and rickets, resulting in impaired longitudinal growth and bone deformity (Holick, 2006; Munns et al., 2006). At all ages, muscle weakness, especially of proximal muscles, is usually clinically evident with severe vitamin D deficiency and bones may be painful with pressure (Lips et al., 2008).

Actions on calcium, phosphate, bone and muscle

One of the main functions of the vitamin D hormone, calcitriol, is to increase active calcium absorption from the gut (Holick, 2002, 2007; Aloia et al., 2010). There is not a lot

Figure 1 Vitamin D production, metabolism and catabolism. See text for details.

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Non-classical effects of vitamin D

There is now a large range of adverse health effects associated with lower vitamin D status (Holick, 2007). Although much of the evidence to date is epidemiological, showing associations rather than causation, in some cases, there is also good data from animal models and experimental studies showing plausible mechanisms. Good cohort studies in Scandinavia, for example, have shown a link between vitamin D supplementation in infancy and reduced risk of type I diabetes 30 years later, with evidence of rickets conversely associated with a 2.6-fold increase in diagnosis of type 1 diabetes at that time (EURODIAB, 1999; Hyponnen et al., 2001; Stene et al., 2001). Given the natural history of type 1 diabetes, it is unlikely that randomized controlled trials (RCTs) could be designed to be practical or consistent with normal ethics; hence, this type of evidence in humans may be the best available in the foreseeable future. In non-obese diabetic mice, the mouse model susceptible to type 1 diabetes, D-deficiency results in earlier and greater incidence of disease onset (Mathieu et al., 2004). There are several studies indicating that calcitriol modulates the immune system, in particular suppressing pathways associated with autoimmunity (van Etten and Mathieu, 2005). Other autoimmune diseases linked with low vitamin D include multiple sclerosis, inflammatory bowel disease, asthma and rheumatoid arthritis (Souberbielle et al., 2010). As far back as 1981, calcitriol was shown to be required for insulin release from the pancreas (Norman et al., 1980). Several studies have demonstrated an association between vitamin D status and insulin resistance in young (Chiu et al., 2004) and older individuals (Need et al., 2005), but there have been mixed results of RCTs using vitamin D to improve insulin sensitivity (Pittas et al., 2007) and (von Hurst et al., 2010). This topic is reviewed elsewhere in this series. Low vitamin D status has also been linked to hypertension, increased cardiovascular mortality and overall mortality (Autier and Gandini, 2007; Dobnig et al., 2008; Melamed et al., 2008), although again, RCTs designed for these outcomes are mostly lacking or inconsistent. There is good experimental evidence that adequate circulating 25OHD is needed to produce antimicrobial peptides, such as cathelicidin, at least in human cells (Liu et al., 2006) and reviewed in White (2010). This may explain a beneficial effect of vitamin D in patients with tuberculosis, although responsiveness to vitamin D treatment may depend on vitamin D receptor genotype (Martineau et al., 2011). A major area of interest is the possibility that higher vitamin D status is associated with reduced incidence of and/or reduced mortality from a range of cancers (Giovannucci et al., 2006). A relationship between higher sun exposure and associated higher skin cancer rates but lower incidence of internal cancers was described in a study of US Navy personnel in 1937 (Peller and Stephenson, 1937). Apperly (1941) demonstrated that mortality from cancer was reduced at lower latitudes. It was not until 1980 that Garland

and Garland (1980) proposed that low vitamin D might increase the risk of colon cancer. Since then, a large number of epidemiological studies have been carried out, some of them prospective, but the results are not really consistent, except for colorectal cancers (IOM, 2011). Interestingly, in colorectal cancer, higher calcium intakes also are associated with lower colorectal cancer risk (Jenab et al., 2010). A recent meta-analysis of epidemiological studies found evidence for reduced incidence of colorectal cancer with higher 25OHD levels, with limited evidence for breast cancer and no link with prostate cancer (Gandini et al., 2010). In prostate cancer, a U-shaped curve has been described with higher incidence at both low and high 25OHD levels (Tuohimaa et al., 2004). The problem with these sorts of studies is that prospective studies may be desirable, because after diagnosis, there may be changes in lifestyle that lead to lower vitamin D status. On the other hand, a single estimation of 25OHD, which might be taken at any season, may not reflect values over the several years that it takes for a tumor to develop. Apart from incidence, there is some evidence that higher vitamin D status may lead to better cancer outcomes, that is, reduced mortality. This has been described in colon cancer (Giovannucci et al., 2006) and somewhat surprisingly in melanoma, where evidence of higher sun exposure, seen as solar elastosis in sites adjacent to the tumor, or higher 25OHD concentrations soon after diagnosis are both associated with better 5-year survival (Berwick et al., 2005; Newton-Bishop et al., 2009). Various vitamin D receptor polymorphisms have been associated with melanoma thickness, a major predictor of prognosis (Hutchinson et al., 2000; Santonocito et al., 2007), and with altered likelihood of metastasis (Halsall et al., 2004). Certainly, there is considerable evidence from animal studies that lower vitamin D status increases the incidence of tumors induced with a variety of carcinogens and reduces survival after implantation of tumors (reviewed in Kasukabe et al., 1987; Studzinski and Moore, 1995; Ooi et al., 2010). Moreover, several anticancer mechanisms of calcitriol have been demonstrated, including local production of calcitriol by tumor cells (Frankel et al., 1983), with calcitriol resulting in increased tumor cell differentiation (Mason et al., 1988), increased tumor cell apoptosis (Ravid et al., 1999) and reduced tumor-induced angiogenesis (Majewski et al., 1996). There are, however, limited RCTs that have reported to date on whether vitamin D supplementation reduces cancer incidence or mortality. One study, frequently quoted, showed a beneficial effect of higher 25OHD concentrations on cancer incidence over 5 years with both vitamin D and calcium supplements (Lappe et al., 2007). Vitamin D status increased from 71 to 96 nmol/l in those patients who were given vitamin D, but cancer was a secondary outcome; hence, risk factors were not necessarily adjusted appropriately before randomization and the patient numbers were relatively small, at around 400 per group. A number of other trials are underway, but not yet reported. European Journal of Clinical Nutrition

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Factors, other than input, that affect vitamin D status

Although vitamin D is stored in fat, it is not clear whether there is much release of vitamin D from fat, as obesity is associated with lower vitamin D levels for a given input (Wortsman et al., 2000). Little is known about storage of 25OHD, although there is some in muscle (Clements and Fraser, 1988; Heaney et al., 2009). In many studies, exercise is associated with better vitamin D status (for example, Giovannucci et al., 2006). Although this may be due to outdoor exercise and better sun exposure, this may not be the entire explanation (Scragg et al., 1992). Exercise may improve storage or retrieval, as in at least one trial, an indoor exercise program resulted in improved 25OHD concentrations (Bell et al., 1988). There is some evidence that accelerated catabolism of 25OHD and calcitriol is induced by agents such as phenytoin and phenobarbital, which induce P450 enzymes (Gough et al., 1986). Although a major function of vitamin D is to enhance active absorption of ingested calcium, calcium intakes also affect rates of vitamin D degradation. Low calcium intakes accelerate the degradation of vitamin D, as noted earlier (Clements et al., 1987b). The mechanism appears to involve raised parathyroid hormone levels in response to low calcium intakes, and probably the ensuing elevated levels of calcitriol, which enhance the activity of degradative pathways. Removal of the parathyroid gland in patients with primary hyperparathyroidism increased the half-life of 25OHD from 36 to 50 days (Clements et al., 1987a). Administration of calcium to normal subjects and patients, even without additional vitamin D, has been reported to improve vitamin D status (Berlin and Bjorkhem, 1988; Pfeifer et al., 2000). Increased dairy intake is associated with reduced risk of low 25OHD in immigrant Asian populations (Brock et al., 2007). Reduced absorption of calcium may be the explanation for low vitamin D levels in malabsorbers (Davies et al., 1997), as there is little evidence of an enterohepatic circulation for vitamin D (Clements et al., 1984). Notably, most of the meta-analyses on falls and fractures conclude that these are best reduced by combinations of vitamin D and calcium than either agent alone (Latham et al., 2003; Boonen et al., 2007; Tang et al., 2007; Avenell et al., 2009; Bischoff-Ferrari et al., 2009; DIPART, 2010; Lips, 2010; IOM, 2011). In nearly all the trials of specific antifracture agents, such as bisphosphonates, selective estrogen response modifiers, parathyroid hormone and strontium ranelate, all subjects were given calcium and vitamin D supplements, as well as the test agent or placebo (Adami et al., 2009). The efficacy of these agents in the absence of vitamin D and calcium is unclear. Recent studies indicate that polymorphisms in the gene for vitamin D-binding protein, 7-dehydroreductase (the enzyme that produces 7-dehydrocholesterol in skin), the gene that probably hydroxylates vitamin D to produce 25OHD and possibly in the gene encoding 24-hydroxylase, European Journal of Clinical Nutrition

the enzyme that degrades 25OHD and calcitriol, affect vitamin D (25OHD) levels. The degree of difference described is around the same order as the summerwinter difference (Ahn et al., 2010; Wang et al., 2010).

Vitamin D sufficiency
Vitamin D status is determined by 25OHD concentrations in blood. Conservatively, a level of 5060 nmol/l is considered the target for vitamin D sufficiency (Diamond et al., 2005; IOM, 2011; Nowson et al., in preparation). Above these 25OHD concentrations, there is no further suppression of parathyroid hormone when subjects are given additional vitamin D and calcium (Malabanan et al., 1998), there is not much further improvement in muscle function (BischoffFerrari et al., 2004; Wicherts et al., 2007), not much further increase in bone density (Ooms et al., 1995) and not much further reduction in bone turnover markers (Jesudason et al., 2002). Nevertheless, there is some push for a higher target value of closer to 7580 nmol/l, in part, because optimal 25OHD levels to achieve a reduction in falls and fractures may be 460 nmol/l (Dawson-Hughes et al., 2010) and because one study of impaired mineralization in cadavers indicated optimal bone at 475 nmol/l (Priemel et al., 2010). The higher target levels are also supported, in part, by some limited studies on non-classical effects, including improved insulin resistance (von Hurst et al., 2010) and reduced incidence of some cancers (Giovannucci et al., 2006; Lappe et al., 2007; Heaney and Holick, 2011). Ideally, the 5060 nmol/l value should be the minimum at the end of winter (van der Mei et al., 2007); hence, 25OHD concentrations at the end of summer should be higher to allow for decreases in winter.

Groups at high risk of D-deficiency

Reduced sun exposure or reduced penetration of UVB due to absorption by melanin or clothing increases the risks of vitamin D deficiency (Springbett et al., 2010). As noted earlier, older people are at particular risk of vitamin D deficiency, in part, due to reduced sun exposure, possibly reduced ability to synthesize vitamin D in skin and possibly due to low calcium intakes associated with generally poor appetite (Sambrook et al., 2011). Moreover, at major risk of D-deficiency are those who have dark skin, particularly if they wear modest dress (Grover and Morley, 2001; Springbett et al., 2010). As 25OHD is transferred to the fetus from the mother (Clements and Fraser, 1988), with little in breast milk, infants of dark-skinned and modestly dressed mothers are at high risk of failure to thrive and rickets (Holick, 2006; Munns et al., 2006). Immunosuppression greatly increases the risks of skin cancer (Dixon et al., 2010); hence, people on immunosuppressive therapy after transplantation or for other reasons are instructed to avoid the sun. People with fair skin may also be at risk of D-deficiency due to sun avoidance (Glass

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et al., 2009). People who have a significant chronic illness or disability, shift workers or even people who work predominantly indoors have less sun exposure and are at increased risk of inadequate vitamin D (van der Mei et al., 2007). For many groups, advice to increase sun exposure is neither appropriate nor practical. For those people, supplements may be reasonable. On the other hand, mass medication of the population is not appropriate or desirable. For much of the otherwise healthy population, whose lifestyle may prevent adequate sun exposure, some simple messages about going out for brief periods, mid-morning or afternoon in summer, or for longer, around mid-day in winter, as discussed earlier, may assist in raising vitamin D levels, without too many negative risks of skin damage. Adequate calcium intake through low-fat dairy products or fortified soy products and adequate exercise are useful general advices that may also assist in the maintenance of vitamin D status. Indeed, vitamin D, calcium and exercise are needed to promote healthy bone and muscle function at all ages. It is possible to argue that their importance increases from the lead up to menopause in women and toward older age in men, as there are higher risks of falls and fractures with increasing age. Definitive evidence from RCTs is not yet available for non-classical effects of vitamin D, and for a variety of reasons, as discussed earlier, such trials may not even be possible (Heaney and Holick, 2011). Given the emerging evidence that maintaining a good vitamin D status may have other health benefits as well, a prudent person might well add this to their healthy living activities.
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Conflict of interest
The authors declare no conflict of interest.

Acknowledgements
This work has been supported, in part, by funding from the National Health and Medical Research Council of Australia, New South Wales Cancer Council and The University of Sydney. Project funding has also been received from Nestle Australia. Research funding has been received from Nestle Australia and from Servier, France (for unrelated work). Honoraria have been provided by Servier, Australia, Nestle, Australia, the Australian Mushroom Growers Association and Bayer Healthcare Australia.

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