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VITAMIN D AND HEALTH IN THE 21ST CENTURY: BONE AND BEYOND |
1 From the Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston
2 Presented at the conference "Vitamin D and Health in the 21st Century: Bone and Beyond," held in Bethesda, MD, October 9–10, 2003. 3 Supported in part by NIH grants M01-RR00533 and AR36963 and the UV Foundation. 4 Address reprint requests and correspondence to MF Holick, Boston University School of Medicine, 715 Albany Street, M-1013 Boston, MA 02118. E-mail: mfholick{at}bu.edu.
ABSTRACT
Most humans depend on sun exposure to satisfy their requirements for vitamin D. Solar ultraviolet B photons are absorbed by 7-dehydrocholesterol in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3. Season, latitude, time of day, skin pigmentation, aging, sunscreen use, and glass all influence the cutaneous production of vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D3. Vitamin D deficiency is an unrecognized epidemic among both children and adults in the United States. Vitamin D deficiency not only causes rickets among children but also precipitates and exacerbates osteoporosis among adults and causes the painful bone disease osteomalacia. Vitamin D deficiency has been associated with increased risks of deadly cancers, cardiovascular disease, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Maintaining blood concentrations of 25-hydroxyvitamin D above 80 nmol/L (
30 ng/mL) not only is important for maximizing intestinal calcium absorption but also may be important for providing the extrarenal 1
-hydroxylase that is present in most tissues to produce 1,25-dihydroxyvitamin D3. Although chronic excessive exposure to sunlight increases the risk of nonmelanoma skin cancer, the avoidance of all direct sun exposure increases the risk of vitamin D deficiency, which can have serious consequences. Monitoring serum 25-hydroxyvitamin D concentrations yearly should help reveal vitamin D deficiencies. Sensible sun exposure (usually 5–10 min of exposure of the arms and legs or the hands, arms, and face, 2 or 3 times per week) and increased dietary and supplemental vitamin D intakes are reasonable approaches to guarantee vitamin D sufficiency.
Key Words: Vitamin D • sunlight • cancer • diabetes • bone
INTRODUCTION
Vitamin D is taken for granted and is assumed to be plentiful in a healthy diet. Unfortunately, very few foods naturally contain vitamin D, and only a few foods are fortified with vitamin D. This is the reason why vitamin D deficiency has become epidemic for all age groups in the United States and Europe. Vitamin D deficiency not only causes metabolic bone disease among children and adults but also may increase the risk of many common chronic diseases. The goal of this review is to provide a broad prospective on the evaluation, evolution, discovery, and many biological functions of vitamin D.
HISTORY
Vitamin D is recognized as the sunshine vitamin. From an evolutionary perspective, phytoplankton and zooplankton that have existed in our oceans for >500 million years produced vitamin D when exposed to sunlight (1, 2). Although the function of vitamin D in these early life forms is not well understood, it is possible that the vitamin D photosynthetic process was used by early life forms to provide the organism with information about exposure to solar ultraviolet (UV)B (290–315 nm) radiation (1, 2).
The precursor provitamin D (either ergosterol or 7-dehydro-cholesterol), which is a relatively rigid, 4-ringed structure, is incorporated into the lipid bilayer of the plasma membrane (Figure 1
). During the production of previtamin D during exposure to solar UVB radiation, the B ring opens and becomes a less-rigid open structure, which may provide the membrane with increased permeability to various ions, including calcium. This may be why vitamin D has remained so important, throughout evolution, for the maintenance of calcium metabolism and ultimately for the evolution of life forms to develop endoskeletons and to venture onto land (1).
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); they called this disease rickets (1–3). The disease migrated to the northeastern United States, where children in New York City and Boston were raised in a similar polluted sunless environment. By 1900, the disease was so common and devastating that it was estimated that >90% of children in Leiden, the Netherlands, and 80% of children in Boston suffered from rickets (2, 3).
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In 1919, Huldschinsky (6) exposed children with rickets to a mercury arc lamp and reported the dramatic healing of rickets. In 1921, Hess and Unger (7) observed children in New York City who were exposed to sunlight on the roof of the hospital for a period of several months, and they noted effective treatment of rickets. These findings led Steenbock and Black (8) and Hess and Weinstock (9) to irradiate a wide variety of substances, including grasses and various vegetable oils; they reported that the irradiation process imparted antirachitic activity to the foods. Hess et al (10) also demonstrated that sun exposure prevented rickets in rats. This led Steenbock (11) to introduce the concept of irradiating foods with UV radiation for the treatment and prevention of rickets. Milk was initially fortified with ergosterol and irradiated for antirachitic activity. This led to the fortification of milk with synthetically produced vitamin D2. This simple fortification process essentially eradicated rickets in countries that adopted this practice. In the 1930s, vitamin D was the new miracle vitamin and many products were fortified with vitamin D2, including peanut butter, hot dogs, soda pop, and bread. Schlitz Brewery (Milwaukee, WI) introduced beer containing vitamin D2 (100 IU or 2.5 µg per 8-ounce can) and marketed it as the beer with sunny energy in both summer and winter. Europe also fortified dairy products with vitamin D2. After World War II, however, the vitamin D fortification process was not carefully monitored and large excess amounts of vitamin D were added to some milk products, causing an outbreak of vitamin D intoxication among infants and young children (12, 13). This led to the banning of vitamin D fortification of dairy products in most European countries that remains to this day. In Europe, margarine and some cereals are fortified with vitamin D.
PHOTOSYNTHESIS OF VITAMIN D
During exposure to sunlight, UVB radiation (290–315 nm) is absorbed by 7-dehydrocholesterol that is present in the plasma membranes of both epidermal keratinocytes and dermal fibroblasts (14). The energy is absorbed by the double bonds in the B ring, which results in rearrangement of the double bonds and opening of the B ring to form previtamin D3 (Figure 1
).
Once formed, previtamin D3, which is entrapped within the plasma membrane lipid bilayer, rapidly undergoes rearrangement of its double bonds to form the more thermodynamically stable vitamin D3. During this transformation process, vitamin D3 is ejected from the plasma membrane into the extracellular space (14). The vitamin D-binding protein in the dermal capillary bed has an affinity for vitamin D3 (14–16) and draws it into the circulation.
Prolonged sun exposure does not result in the production of excess quantities of vitamin D3 to cause intoxication. The reason for this is that, during sun exposure, the previtamin D3 that is formed and the thermal isomerization product vitamin D3 that does not escape into the circulation absorb solar UV radiation and isomerize to several photoproducts that are thought to have little activity on calcium metabolism (2, 3, 14, 15) (Figure 3).
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Anything that either influences the number of solar UVB photons that penetrate the skin or alters the amount of 7-dehydrocholesterol in the skin influences the cutaneous production of vitamin D3. The amount of 7-dehydrocholesterol in the epidermis is relatively constant until later in life, when it begins to decline (17, 18). A person 70 years of age exposed to the same amount of sunlight as a 20-year-old person makes 25% of the vitamin D3 that the 20-year-old person can make (Figure 4).
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30 ng/mL (Figure 5) (19).
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) (20); properly used sunscreen with a SPF of 15 reduces the capacity by >98%.
Time of day, season, and latitude also dramatically influence the cutaneous production of vitamin D3 (2, 3, 21). The reason is that, although the sun is closest to the earth in the winter, the sun's rays are entering at a more oblique angle (zenith angle) and more UVB photons are efficiently absorbed by the ozone layer, because the more oblique angle causes the UVB photons to pass through the ozone for a greater distance. In addition, with the more oblique angle there are fewer photons per unit area striking the earth. Time of day, season, and latitude all influence the zenith angle of the sun. Above 37°latitude during the months of November through February, there are marked decreases (80-100%, depending on latitude) in the number of UVB photons reaching the earth's surface. Therefore, very little if any vitamin D3 is produced in the skin during the winter.
However, below 37° and closer to the equator, more vitamin D3 synthesis occurs in the skin throughout the year. Similarly, in the early morning or late afternoon, the zenith angle is so oblique that very little if any vitamin D3 is produced in the skin even in the summer (2, 3, 21, 22). This is why it is important to have safe sun exposure between the hours of 1000 and 1500 in the spring, summer, and autumn, because this is the only time when enough UVB photons reach the earth's surface to produce vitamin D3 in the skin (2, 3, 21, 22).
Vitamin D3 is fat soluble and is stored in the body fat. Any excess vitamin D3 that is produced during exposure to sunlight can be stored in the body fat and used during the winter, when little vitamin D3 is produced in the skin. We recently determined that there was 4-400 ng/g vitamin D2 and vitamin D3 in abdominal fat obtained from obese patients undergoing gastric bypass surgery. Therefore, for obese individuals, the fat can be an irreversible sink for vitamin D, increasing the risk of vitamin D deficiency (23, 24). We observed that, when we gave nonobese and obese subjects a 50 000 IU dose of vitamin D2 orally or exposed them to simulated sunlight in a tanning bed for the same periods of time, the obese subjects exhibited increases in blood vitamin D concentrations of no more than 50%, compared with nonobese individuals (24).
SOURCES OF VITAMIN D
Very few foods naturally contain vitamin D. Oily fish such as salmon (360 IU per 3.5-ounce serving), mackerel, and sardines are good sources of vitamin D3, as are irradiated mushrooms. Although egg yolks are reported to contain vitamin D, amounts are highly variable (usually no more than 50 IU per yolk), and the cholesterol content of egg yolks makes this a poor source of vitamin D. Cod liver oil, which has been considered for >3 centuries to be critically important for bone health, is an excellent source of vitamin D3. Very few foods are fortified with vitamin D. Fortified foods include milk (100 IU per 8-ounce serving), orange juice (100 IU per 8-ounce serving) and other juice products, and some breads and cereals (22, 25).
More than 90% of the vitamin D requirement for most people comes from casual exposure to sunlight (2, 3, 22). The skin has a large capacity to produce vitamin D. Young adults exposed to 1 MED of UVB radiation in a tanning bed underwent measurement of their blood vitamin D3 concentrations, compared with their blood vitamin D2 concentrations after an oral dose of vitamin D2. Men and women in bathing suits who were exposed to a 1-MED dose of UVB radiation exhibited increases in blood concentrations of vitamin D that were equivalent to those observed with doses of 10 000-20 000 IU of vitamin D (2, 22, 26). Therefore, 1 MED is equivalent to 10-50 times the recommended adequate intakes, which are 200, 400, and 600 IU for children and adults <50 y, 51-70 y, and 
71 y of age, respectively (2, 22, 26, 27). Studies reported that exposure of 20% of the body's surface to either direct sunlight or tanning bed radiation was effective in increasing blood concentrations of vitamin D3 and 25-hydroxyvitamin D3 [25(OH)D3] among both young adults and older adults (28–33). Indeed, Chuck et al (33) suggested that the use of UVB lamps in nursing homes in Great Britain was the most effective means of maintaining blood concentrations of 25(OH)D. There appears to be a benefit of higher blood concentrations of 25(OH)D for bone health, because the bone density of teenagers and adults was directly related to their 25(OH)D concentrations (30, 32–35). We found that tanners in Boston had 25(OH)D concentrations (100 nmol/L) that were >150% higher than those of nontanners (40 nmol/L) at the end of the winter. Furthermore, the average bone density of the tanners was greater than that of the nontanners (32).
SKIN CANCER, SUNLIGHT, AND VITAMIN D
There is great concern about any exposure to sunlight causing skin damage, including skin cancer and wrinkling (35–40). Chronic excessive exposure to sunlight and sunburn incidents during childhood and young adult life significantly increase the risk of nonmelanoma basal and squamous cell carcinomas (36–39).
The most serious form of skin cancer is melanoma. It should be recognized that most melanomas occur on non—sun-exposed areas (41) and that having more sunburn experiences, having more moles, and having red hair increase the risk of the deadly disease (36).
Chronic excessive sun exposure also damages the elastic structure of the skin, increasing the risk of wrinkling (35). However, on the basis of our understanding of the efficiency of sun exposure for producing vitamin D3 in the skin, it is reasonable to allow some sun exposure without sun protection, for production of adequate amounts of vitamin D3. When adults topically applied a sunscreen properly (2 mg/cm2, ie, 1 ounce over an adult body wearing a bathing suit), the amount of vitamin D3 produced in the skin was reduced by >95% (2, 3, 22, 40). Exposure to sunlight for 5-15 min between the hours of 1000 and 1500 during the spring, summer, and autumn is usually enough exposure for individuals with skin type II or III (2, 3, 22, 42–44). This is 25% of what would cause a minimal erythemal response, ie, a slight pinkness to the skin. After this exposure, application of a sunscreen with a SPF of 15 is recommended, to prevent the damaging effects of chronic excessive exposure to sunlight.
PREVALENCE AND DETECTION OF VITAMIN D DEFICIENCY
The only way to determine whether a person is vitamin D (vitamin D represents either vitamin D2 or vitamin D3) sufficient, deficient, or intoxicated is to measure the circulating concentrations of 25(OH)D (2, 3, 22). 25(OH)D, which is produced in the liver, is the major circulating form of vitamin D (Figure 3). Its half-life in the circulation is 2 wk, and it is a measure of vitamin D status. Although 25(OH)D requires additional hydroxylation in the kidney to become active as 1,25-dihydroxyvitamin D [1,25(OH)2D] (Figure 3), serum concentrations of 1,25(OH)2D should never be used to determine vitamin D status (45–47). The reasons for this are that the half-life of 1,25(OH)2D in the circulation is <4 h, its concentrations are 1000-fold less than those of 25(OH)D, and, most importantly, as a person becomes vitamin D deficient, there is a compensatory increase in parathyroid hormone (PTH) secretion, which stimulates the kidney to produce more 1,25(OH)2D. As a person becomes vitamin D deficient and 25(OH)D concentrations decrease, 1,25(OH)2D concentrations are maintained in the normal range and sometimes are even elevated. Therefore, 1,25(OH)2D concentrations are not useful and can mislead physicians into thinking that patients are vitamin D sufficient when they can be severely vitamin D deficient (45–51).
Typically, normal ranges for assay results are considered to be the mean ± 2 SDs for a healthy population. Unfortunately, it was not appreciated that the general population is at risk of vitamin D deficiency, and so-called normal values included in the normal range often indicate vitamin D deficiency (49–51).
The upper limit of 25(OH)D concentrations for most commercial assays is 125 nmol/L (50 ng/mL). It is known that lifeguards and sunbathers can have blood concentrations of 25(OH)D of >250 nmol/L (100 ng/mL), and they are not vitamin D intoxicated. Indeed, 25(OH)D concentrations of >325 nmol/L (150 ng/mL) with associated hypercalcemia are pathognomonic for hypervitaminosis D (vitamin D intoxication) (52–55).
The lower limit of the normal range for 25(OH)D assays is also suspect. Several reports suggested that, if PTH concentrations are plotted as a function of 25(OH)D concentrations, then they begin to plateau when the 25(OH)D concentrations are 78 nmol/L (30 ng/mL) (56–59) (Figure 6). Malabanan et al (49) conducted provocative testing with vitamin D2 among healthy adults with 25(OH)D concentrations of 25-62.5 nmol/L (10-25 ng/mL). All subjects were given 50 000 units of vitamin D2 once per week for 8 wk, with calcium supplementation. The 25(OH)D concentrations increased by >100% and the PTH concentrations decreased by 22%, on average. When the baseline 25(OH)D concentrations were related to the PTH concentrations at the end of the study, it was observed that subjects with 25(OH)D concentrations of 25–37.5 nmol/L (11-15 ng/mL) and 38–30 nmol/L (16-20 ng/mL) exhibited 55% and 35% decreases in PTH concentrations, respectively, whereas healthy adults with 25(OH)D concentrations of 50 nmol/L (20 ng/mL) demonstrated no significant change. It was concluded that concentrations of at least 50 nmol/L were required to minimally satisfy the body's vitamin D requirement and that concentrations of 30 ng/mL were preferred (49, 57, 58, 60).
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Vitamin D deficiency among children not only causes overt rickets but also can prevent children from reaching their genetically programmed height and peak bone mass. For adults, vitamin D deficiency has more subtle effects on the skeleton. The secondary hyperparathyroidism mobilizes calcium from the skeleton and thus can reduce bone mineral density and ultimately precipitate or exacerbate osteoporosis. In addition, vitamin Ddeficiency causes a mineralization defect of the collagen matrix that is laid down by osteoblasts. The rubbery matrix does not provide structural support, which increases the risk of fracture. Collagen matrix that is not properly mineralized becomes hydrated, causing an outward expansion on the periosteal covering, which is highly innervated with sensory pain fibers. The consequence is that people with osteomalacia often complain of an aching in their bones (48, 59, 61–64). In addition, skeletal muscles have receptors for 1,25(OH)2D, and vitamin D deficiency not only causes muscle weakness among children with rickets but also causes muscle weakness among adults with osteomalacia (62–66). Patients often complain of aching bones and muscle discomfort. Such patients are often misdiagnosed with fibromyalgia, chronic fatigue syndrome, myositis, or other nonspecific collagen vascular diseases. It is estimated that 40-60% of patients with fibromyalgia may have some component of vitamin D deficiency and osteomalacia (22, 47, 59, 61–66). Glerup et al (59) reported that 88% of Danish Arab women with muscle weakness and pain were vitamin D deficient. More than 90% of 150 children and adults 10–65 y of age who presented with nonspecific muscle aches and bone aches and pains at a Minnesota hospital were found to be vitamin D deficient (62).
It is estimated that >50% of African Americans in the United States are either chronically or seasonally at risk of vitamin D deficiency. Nesby-O'Dell et al (67) reported that, in the third National Health and Nutrition Examination Survey, 42% of African American women 15–49 y of age were found to be vitamin D deficient at the end of the winter. Holick (22, 26) observed that 84% of African American men and women >65 y of age were vitamin D deficient at the end of the summer in Boston. The reasons for this are that African Americans often have a lactase deficiency and do not drink milk, they have markedly decreased efficiency in making vitamin D3 in their skin, and they avoid the sun because they do not want to increase their skin pigmentation. Women in Saudi Arabia and their children have high prevalences of osteomalacia and rickets, respectively, and vitamin D deficiency because of their practice of wearing clothing over the whole body and avoiding direct sunlight (68, 69).
Vitamin D deficiency is well recognized as a major health problem for adults >50 y of age (49, 70–73). Gloth et al (70) reported that 54% of community dwellers and 38% of nursing home residents were vitamin D deficient. In a hospital setting, Thomas et al (73) reported that >40% of hospitalized patients in Boston were vitamin D deficient. In an outpatient setting, 41% of 169 otherwise healthy adults 49–83 y of age were found to be vitamin D deficient throughout the year (49). Young adults, especially of African American origin, are at high risk of vitamin D deficiency (58). However, students and young adults who never see daylight and are always working or who always wear sun protection are also at risk. At the Boston Medical Center, it was observed that 32% of the students and doctors 18–29 y of age were vitamin D deficient at the end of the winter (58) (Figure 7). Even teenagers and young children are at risk. Gordon et al (74) reported that >50% of African American teenagers in Boston were found to be vitamin D deficient. Sullivan et al (75) observed that 48% of white girls 9–13 y of age were vitamin D deficient at the end of the winter and 17% were still vitamin D deficient at the end of the summer, because of the sunscreen use and complete sun protection they practiced.
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Vitamin D deficiency results in abnormalities in both calcium and phosphorus metabolism. The major function of vitamin D is to maintain serum calcium concentrations within the physiologically acceptable range. It accomplishes this by increasing intestinal calcium absorption (Figure 5). In a vitamin D-deficient state, the intestine typically absorbs 10-15% of dietary calcium (3, 22). In a vitamin D-sufficient state, 30% typically is absorbed from the diet; as much as 60-80% can be absorbed during periods of growth and pregnancy or lactation, with increased demand for calcium.
To achieve the maximal efficiency of vitamin D-induced intestinal calcium transport, the serum 25(OH)D concentrations must be at least 78 nmol/L (30 ng/mL) (60). When there is inadequate calcium in the diet, 1,25(OH)2D interacts with its receptor in osteoblasts and induces the expression of receptor activator of nuclear factor-
B ligand, which interacts with its receptor on preosteoclasts, inducing them to become mature osteoclasts (76, 77) (Figure 8). The net effect is to enhance mobilization of calcium from the skeleton to maintain serum calcium concentrations in the normal range. Vitamin D deficiency results in decreased concentrations of ionized calcium, which are immediately recognized by the calcium sensor in the parathyroid glands (78). This results in increased expression, production, and secretion of PTH. PTH helps maintain calcium metabolism by increasing tubular reabsorption of calcium in the kidney, enhancing the production of 1,25(OH)2D, and interacting with osteoblasts to increase the receptor activator of nuclear factor-B ligand system, similar to 1,25(OH)2D (Figure 8).
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NONCALCEMIC ACTIONS OF VITAMIN D
The revelation in 1979 that most tissues and cells in the body localized [3H]-1,25(OH)2D3 opened an exciting new chapter on the multitude of biological functions of vitamin D (79). It is known that 1,25(OH)2D interacts with a specific nuclear receptor similar to other steroid hormones (2, 22, 76, 79, 80). After 1,25(OH)2D enters the cell, it is transported through the microtubular network to the nucleus (81). After it enters the nucleus bound to its vitamin D receptor (VDR), it complexes with the retinoic acid X receptor to form a heterodimeric complex that seeks out specific DNA sequences known as vitamin D-responsive elements. Once the 1,25(OH)2D3-VDR-retinoic acid X receptor complex binds to the vitamin D-responsive element, a variety of transcriptional factors, including DRIP, bind to it, resulting in expression of the vitamin D-responsive gene (Figure 9) (76, 80).
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-hydroxyvitamin D3. Studies were immediately implemented to determine whether 1,25(OH)2D3 could be used to treat leukemia. The studies were disappointing, because the drug caused severe hypercalcemia and, although some of the patients experienced remission, all eventually died in a blastic phase (84).
Although 1,25(OH)2D3 was a disappointment as an antitumor agent, the one proven clinical application for the potent antiproliferative activity of 1,25(OH)2D3 was in the treatment of psoriasis. Keratinocytes have a VDR and, when they are exposed to 1,25(OH)2D3, their growth is markedly inhibited and they are induced to differentiate (85). Initial clinical trials with topical 1,25(OH)2D3 treatment demonstrated remarkable improvement in scaling, erythema, and plaque thickness, which was sustained (86–88). There were no untoward side effects. As a result, 3 analogs, including calcipotriene, 1,24-dihydroxyvitamin D3, and 22-oxo-1,25-dihydroxyvitamin D3, were developed and were demonstrated to be clinically effective for the treatment of psoriasis (87). Topical activated vitamin D treatment is the first-line therapy for psoriasis throughout the world.
1,25(OH)2D3 has been shown to have a multitude of other physiologic functions (2, 22, 76, 89, 90), including stimulation of insulin production (91), modulation of activated T and B lymphocyte function (92, 93), effects on myocardial contractility (94, 95), prevention of inflammatory bowel disease (96), and promotion of thyroid-stimulating hormone secretion (2, 3, 22). These are just a few of the many physiologic functions that have been reported for 1,25(OH)2D3 that are not related to calcium metabolism (2, 3, 22, 79, 82, 96).
VITAMIN D DEFICIENCY AND LATITUDINAL ASSOCIATIONS WITH RISKS OF CANCER AND AUTOIMMUNE DISEASES
In 1941, Apperley (97) reported his remarkable observation that people in the United States who lived at higher latitudes, such as in New Hampshire, Vermont, and Massachusetts, had overall greater risks of dying as a result of cancer, compared with men and women of similar ages who lived in southern states, such as Texas, Georgia, and Alabama. He suggested that there needed to be a reexamination of the relationship between skin cancer and other cancers, noting that "the presence of skin cancer is really an occasional accompaniment of a relative cancer immunity in some way related to exposure to solar radiation" (p. 195). Little attention was paid to this remarkable observation until the 1980s, when Garland et al(98–100) reported that both colon and breast cancer risks were higher for those living at higher latitudes in the United States. A prospective study revealed that, if 25(OH)D concentrations were <50 nmol/L (20 ng/mL), then there was a 2-fold increased risk of developing colon cancer (98). Hanchette and Schwartz (101) also demonstrated a gradient for prostate cancer, with the highest mortality rates among white men living at the highest latitudes in the United States. Since these observations, several investigators not only confirmed the observations but added to the list of cancers that may be associated with living at higher latitudes and thus may be related to vitamin D deficiency (102–105). Grant (102) examined latitudinal variations in breast cancer mortality rates in Europe and, controlling for diet, concluded that lack of UVB radiation from sunlight accounts for perhaps 25% of the breast cancer mortality rates in northern Europe (104). He also reported that both men and women with more sun exposure were less likely to die prematurely as a result of cancer (102, 104).
Interestingly, there is also a latitudinal association with increased risk of developing multiple sclerosis (106–108) and cardiovascular disease (109). Rostand (109) observed in 1979 that people who lived at higher latitudes in the United States, Europe, and Asia were more likely to have hypertension. It is well established that there is a latitudinal association with the prevalence of multiple sclerosis. People who were born below 35°N latitude and lived at or below that latitude for the first 10 years of their lives had decreased lifetime risks of developing multiple sclerosis, compared with those who were born above 35°N latitude (106, 107). There is compelling evidence that this is attributable to a decrease in UVB light exposure. One study suggested that the seasonal variation in multiple sclerosis was 50% less in the summer, compared with that in the winter (108, 110). Mahon et al (111) and Ponsonby et al (107) observed that increases in vitamin D intake were related to decreases in multiple sclerosis incidents.
Bodiwala et al (112) reported that men who worked outdoors and had increased sun exposure throughout their lifetimes had a 3–5-y "honeymoon" period before they developed prostate cancer, compared with age-matched control subjects who had little sun exposure and began developing prostate cancer at the age of 53 y. Tuohimaa et al (113) reported that the risk of prostate cancer was reduced by 50% with serum 25(OH)D concentrations of 50 nmol/L.
POSSIBLE MECHANISMS FOR THE ROLE OF VITAMIN D IN PREVENTING COMMON CANCERS, HEART DISEASE, AND AUTOIMMUNE DISEASES
There is good epidemiologic documentation that living at lower latitudes decreases the risks of many chronic diseases. It has been assumed that, because the production of vitamin D is more efficient at lower latitudes, this is the explanation for these interesting observations. In addition, there is mounting scientific evidence suggesting that increasing vitamin D intake decreases the risks of developing chronic diseases. For example, it was shown that treatment of children with 2000 IU/d vitamin D from 1 y of age decreased their risk of developing type 1 diabetes mellitus by 80% throughout the next 20 y (114). Furthermore, children from the same cohort who were vitamin D deficient at 1 y of age had a 4-fold increased risk of developing type 1 diabetes. An increase in vitamin D intake has been associated with decreased risk of developing rheumatoid arthritis (115). Exposure to tanning bed UVB radiation, which resulted in a >100% increase in blood concentrations of 25(OH)D, was effective in treating hypertension among adults. However, adults exposed to a tanning bed that transmitted only UVA radiation and did not increase blood concentrations of 25(OH)D demonstrated no effect on their hypertension (116). There is also evidence that increased intake of calcium and vitamin D decreases the risk of developing colon cancer (117).
How is it possible that vitamin D can have such a wide range of therapeutic and health-related benefits? The answer lies in the fact that the VDR is present in most cells and tissues in the body. 1,25(OH)2D is one of the most potent regulators of cellular growth in both normal and cancer cells (2, 3, 22, 26, 76, 82, 83). It has been suggested that increased vitamin D intake or increased exposure to sunlight, raising blood concentrations of 25(OH)D above 78 nmol/L (30 ng/mL), is necessary for maximal extrarenal production of 1,25(OH)2D in a wide variety of tissues and cells in the body, including colon, breast, prostate, lung, activated macrophages, and parathyroid cells. The local production of 1,25(OH)2D is thought to be important for keeping cell growth in check and possible preventing the cell from becoming autonomous and developing into a unregulated cancer cell (2, 3, 118–120).
Activated T and B lymphocytes have VDRs. 1,25(OH)2D is a very effective modulator of the immune system. In a variety of animal models, it has been demonstrated that pretreatment with 1,25(OH)2D is effective in mitigating or preventing the onset of type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, and Crohn's disease (2, 22, 90, 121–123). In addition, Li et al (124) reported that, in a mouse model, 1,25(OH)2D was an effective inhibitor of the blood pressure hormone renin.
CONCLUSIONS
Vitamin D can no longer be thought of as a nutrient necessary for the prevention of rickets among children. Vitamin D should be considered essential for overall health and well-being (Figure 10). Vitamin D deficiency and decreased exposure to solar UVB radiation have been demonstrated to increase the risks of many common cancers, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, and there are indications that they may be associated with type 2 diabetes (125, 126) and schizophrenia (127–129). The photosynthesis of vitamin D has been occurring in living organisms for > 500 million years, and it is not surprising that vitamin D has evolved into such an important and necessary hormone, which acts as an indicator of overall health and well-being. Vigilance in maintaining a normal vitamin D status, ie, 25(OH)D concentrations of 75–125 nmol/L, should be a high priority. Surveillance for vitamin D deficiency, with measurement of 25(OH)D concentrations, should be part of normal yearly physical examinations.
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ACKNOWLEDGMENTS
MFH is a consultant for Nichols Institute (San Clemente, CA).
REFERENCES
,25-dihydroxyvitamin D3. In: Norman A, Schaefer K, Herrath DV, Grigdeit H-G, eds. Vitamin D: chemical, biochemical and clinical endocrinology of calcium metabolism. New York: Walter de Gruyter, 1982:59–64.
-hydroxylase in normal and malignant colon tissue. Lancet 2001;357:1673–4.[Medline]
-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis. Steroids 2001;66:287–92.[Medline]
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 R. T. Wilson, J. Wang, V. Chinchilli, J. P. Richie, J. Virtamo, L. E. Moore, and D. Albanes Fish, Vitamin D, and Flavonoids in Relation to Renal Cell Cancer Among Smokers Am. J. Epidemiol., September 15, 2009; 170(6): 717 - 729. [Abstract] [Full Text] [PDF]
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 M. THILL, D. FISCHER, S. BECKER, T. CORDES, C. DITTMER, K. DIEDRICH, D. SALEHIN, and M. FRIEDRICH Prostaglandin Metabolizing Enzymes in Correlation with Vitamin D Receptor in Benign and Malignant Breast Cell Lines Anticancer Res, September 1, 2009; 29(9): 3619 - 3625. [Abstract] [Full Text] [PDF]
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 K. M Seamans and K. D Cashman Existing and potentially novel functional markers of vitamin D status: a systematic review Am. J. Clinical Nutrition, June 1, 2009; 89(6): 1997S - 2008S. [Abstract] [Full Text] [PDF]
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 L. M. Bodnar, M. A. Krohn, and H. N. Simhan Maternal Vitamin D Deficiency Is Associated with Bacterial Vaginosis in the First Trimester of Pregnancy J. Nutr., June 1, 2009; 139(6): 1157 - 1161. [Abstract] [Full Text] [PDF]
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K. D Cashman, J. M. Wallace, G. Horigan, T. R Hill, M. S Barnes, A. J Lucey, M. P Bonham, N. Taylor, E. M Duffy, K. Seamans, et al. Estimation of the dietary requirement for vitamin D in free-living adults >=64 y of age Am. J. Clinical Nutrition, May 1, 2009; 89(5): 1366 - 1374. [Abstract] [Full Text] [PDF]
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 D. K. Kinney, P. Teixeira, D. Hsu, S. C. Napoleon, D. J. Crowley, A. Miller, W. Hyman, and E. Huang Relation of Schizophrenia Prevalence to Latitude, Climate, Fish Consumption, Infant Mortality, and Skin Color: A Role for Prenatal Vitamin D Deficiency and Infections? Schizophr Bull, May 1, 2009; 35(3): 582 - 595. [Abstract] [Full Text] [PDF]
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 J. H. Lee, J. H. O'Keefe, D. Bell, D. D. Hensrud, and M. F. Holick Vitamin D Deficiency: An Important, Common, and Easily Treatable Cardiovascular Risk Factor? J. Am. Coll. Cardiol., December 9, 2008; 52(24): 1949 - 1956. [Abstract] [Full Text] [PDF]
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S. O'Donnell, A. Cranney, T. Horsley, H. A Weiler, S. A Atkinson, D. A Hanley, D. S Ooi, L. Ward, N. Barrowman, M. Fang, et al. Efficacy of food fortification on serum 25-hydroxyvitamin D concentrations: systematic review Am. J. Clinical Nutrition, December 1, 2008; 88(6): 1528 - 1534. [Abstract] [Full Text] [PDF]
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K. D Cashman, T. R Hill, A. J Lucey, N. Taylor, K. M Seamans, S. Muldowney, A. P FitzGerald, A. Flynn, M. S Barnes, G. Horigan, et al. Estimation of the dietary requirement for vitamin D in healthy adults Am. J. Clinical Nutrition, December 1, 2008; 88(6): 1535 - 1542. [Abstract] [Full Text] [PDF]
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 G. Jean, J.-C. Terrat, T. Vanel, J.-M. Hurot, C. Lorriaux, B. Mayor, and C. Chazot Daily oral 25-hydroxycholecalciferol supplementation for vitamin D deficiency in haemodialysis patients: effects on mineral metabolism and bone markers Nephrol. Dial. Transplant., November 1, 2008; 23(11): 3670 - 3676. [Abstract] [Full Text] [PDF]
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S.-M. Orton, A. P Morris, B. M Herrera, S. V Ramagopalan, M. R Lincoln, M. J Chao, R. Vieth, A D. Sadovnick, and G. C Ebers Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis Am. J. Clinical Nutrition, August 1, 2008; 88(2): 441 - 447. [Abstract] [Full Text] [PDF]
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 M. Misra, D. Pacaud, A. Petryk, P. F. Collett-Solberg, M. Kappy, and on behalf of the Drug and Therapeutics Committee o Vitamin D Deficiency in Children and Its Management: Review of Current Knowledge and Recommendations Pediatrics, August 1, 2008; 122(2): 398 - 417. [Abstract] [Full Text] [PDF]
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 S. Mark, K. Gray-Donald, E. E. Delvin, J. O'Loughlin, G. Paradis, E. Levy, and M. Lambert Low Vitamin D Status in a Representative Sample of Youth From Quebec, Canada Clin. Chem., August 1, 2008; 54(8): 1283 - 1289. [Abstract] [Full Text] [PDF]
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 L. A. Mucci and D. Spiegelman Vitamin D and Prostate Cancer Risk--A Less Sunny Outlook? J Natl Cancer Inst, June 4, 2008; 100(11): 759 - 761. [Full Text] [PDF]
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 J. P. Lazol, N. Cakan, and D. Kamat 10-Year Case Review of Nutritional Rickets in Children's Hospital of Michigan Clinical Pediatrics, May 1, 2008; 47(4): 379 - 384. [Abstract] [PDF]
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 J. A Simon Review: vitamin D supplementation decreases all-cause mortality in adults and older people Evid. Based Med., April 1, 2008; 13(2): 47 - 47. [Full Text] [PDF]
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A. E Millen and L. M Bodnar Preface Am. J. Clinical Nutrition, April 1, 2008; 87(4): 1079S - 1079S. [Full Text] [PDF]
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A. E Millen and L. M Bodnar Vitamin D assessment in population-based studies: a review of the issues Am. J. Clinical Nutrition, April 1, 2008; 87(4): 1102S - 1105S. [Abstract] [Full Text] [PDF]
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 K H Costenbader, D Feskanich, M Holmes, E W Karlson, and E Benito-Garcia Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women Ann Rheum Dis, April 1, 2008; 67(4): 530 - 535. [Abstract] [Full Text] [PDF]
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B. Ewers, A. Gasbjerg, C. Moelgaard, A. M. Frederiksen, and P. Marckmann Vitamin D status in kidney transplant patients: need for intensified routine supplementation Am. J. Clinical Nutrition, February 1, 2008; 87(2): 431 - 437. [Abstract] [Full Text] [PDF]
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M. K. Shea, S. L. Booth, J. M. Massaro, P. F. Jacques, R. B. D'Agostino Sr, B. Dawson-Hughes, J. M. Ordovas, C. J. O'Donnell, S. Kathiresan, J. F. Keaney Jr, et al. Vitamin K and Vitamin D Status: Associations with Inflammatory Markers in the Framingham Offspring Study Am. J. Epidemiol., February 1, 2008; 167(3): 313 - 320. [Abstract] [Full Text] [PDF]
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A. H. Lichtenstein, H. Rasmussen, W. W. Yu, S. R. Epstein, and R. M. Russell Modified MyPyramid for Older Adults J. Nutr., January 1, 2008; 138(1): 5 - 11. [Abstract] [Full Text] [PDF]
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 S. Alsafwah, S. P. LaGuardia, M. Arroyo, B. K. Dockery, S. K. Bhattacharya, R. A. Ahokas, and K. P. Newman Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients Clin. Med. Res., December 1, 2007; 5(4): 238 - 243. [Abstract] [Full Text] [PDF]
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D. M. Freedman, A. C. Looker, S.-C. Chang, and B. I. Graubard Prospective Study of Serum Vitamin D and Cancer Mortality in the United States J Natl Cancer Inst, November 7, 2007; 99(21): 1594 - 1602. [Abstract] [Full Text] [PDF]
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K. D. Cashman Diet, Nutrition, and Bone Health J. Nutr., November 1, 2007; 137(11): 2507S - 2512S. [Abstract] [Full Text] [PDF]
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A H Zargar, S Ahmad, S R Masoodi, A I Wani, M I Bashir, B A Laway, and Z A Shah Vitamin D status in apparently healthy adults in Kashmir Valley of Indian subcontinent Postgrad. Med. J., November 1, 2007; 83(985): 713 - 716. [Abstract] [Full Text] [PDF]
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 K. Rajakumar, S. L. Greenspan, S. B. Thomas, and M. F. Holick SOLAR Ultraviolet Radiation AND Vitamin D: A Historical Perspective Am J Public Health, October 1, 2007; 97(10): 1746 - 1754. [Abstract] [Full Text] [PDF]
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 E. Giovannucci Can Vitamin D Reduce Total Mortality? Arch Intern Med, September 10, 2007; 167(16): 1709 - 1710. [Full Text] [PDF]
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 A. Dawodu and C. L Wagner Mother-child vitamin D deficiency: an international perspective Arch. Dis. Child., September 1, 2007; 92(9): 737 - 740. [Full Text] [PDF]
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A F Williams Vitamin D in pregnancy: an old problem still to be solved? Arch. Dis. Child., September 1, 2007; 92(9): 740 - 741. [Full Text] [PDF]
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 E. Somigliana, P. Panina-Bordignon, S. Murone, P. Di Lucia, P. Vercellini, and P. Vigano Vitamin D reserve is higher in women with endometriosis Hum. Reprod., August 1, 2007; 22(8): 2273 - 2278. [Abstract] [Full Text] [PDF]
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M. L. Neuhouser, M. J. Barnett, A. R. Kristal, C. B. Ambrosone, I. King, M. Thornquist, and G. Goodman (n-6) PUFA Increase and Dairy Foods Decrease Prostate Cancer Risk in Heavy Smokers J. Nutr., July 1, 2007; 137(7): 1821 - 1827. [Abstract] [Full Text] [PDF]
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D. Martins, M. Wolf, D. Pan, A. Zadshir, N. Tareen, R. Thadhani, A. Felsenfeld, B. Levine, R. Mehrotra, and K. Norris Prevalence of Cardiovascular Risk Factors and the Serum Levels of 25-Hydroxyvitamin D in the United States: Data From the Third National Health and Nutrition Examination Survey Arch Intern Med, June 11, 2007; 167(11): 1159 - 1165. [Abstract] [Full Text] [PDF]
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 L. Shinchuk and M. F. Holick Vitamin D and Rehabilitation: Improving Functional Outcomes Nutr Clin Pract, June 1, 2007; 22(3): 297 - 304. [Abstract] [Full Text] [PDF]
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 G. Schwalfenberg Not enough vitamin D: Health consequences for Canadians Can Fam Physician, May 1, 2007; 53(5): 841 - 854. [Abstract] [Full Text] [PDF]
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E. de Vries, I. Soerjomataram, S. Houterman, M. W. J. Louwman, and J. W. W. Coebergh Decreased Risk of Prostate Cancer after Skin Cancer Diagnosis: A Protective Role of Ultraviolet Radiation? Am. J. Epidemiol., April 15, 2007; 165(8): 966 - 972. [Abstract] [Full Text] [PDF]
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 D. K. Houston, M. Cesari, L. Ferrucci, A. Cherubini, D. Maggio, B. Bartali, M. A. Johnson, G. G. Schwartz, and S. B. Kritchevsky Association Between Vitamin D Status and Physical Performance: The InCHIANTI Study J Gerontol A Biol Sci Med Sci, April 1, 2007; 62(4): 440 - 446. [Abstract] [Full Text] [PDF]
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K. D Cashman Vitamin D in childhood and adolescence Postgrad. Med. J., April 1, 2007; 83(978): 230 - 235. [Abstract] [Full Text] [PDF]
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R. M van Dam, M. B Snijder, J. M Dekker, C. D. Stehouwer, L. M Bouter, R. J Heine, and P. Lips Potentially modifiable determinants of vitamin D status in an older population in the Netherlands: the Hoorn Study Am. J. Clinical Nutrition, March 1, 2007; 85(3): 755 - 761. [Abstract] [Full Text] [PDF]
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E. Hypponen and C. Power Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors Am. J. Clinical Nutrition, March 1, 2007; 85(3): 860 - 868. [Abstract] [Full Text] [PDF]
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 J. Han, G. A. Colditz, and D. J. Hunter Polymorphisms in the MTHFR and VDR genes and skin cancer risk Carcinogenesis, February 1, 2007; 28(2): 390 - 397. [Abstract] [Full Text] [PDF]
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 K. L. Munger, L. I. Levin, B. W. Hollis, N. S. Howard, and A. Ascherio Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis JAMA, December 20, 2006; 296(23): 2832 - 2838. [Abstract] [Full Text] [PDF]
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E. T. Chang, K. M. Balter, A. Torrang, K. E. Smedby, M. Melbye, C. Sundstrom, B. Glimelius, and H.-O. Adami Nutrient Intake and Risk of Non-Hodgkin's Lymphoma Am. J. Epidemiol., December 15, 2006; 164(12): 1222 - 1232. [Abstract] [Full Text] [PDF]
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J. M. Hollander and J. I. Mechanick Nutrition Support and the Chronic Critical Illness Syndrome Nutr Clin Pract, December 1, 2006; 21(6): 587 - 604. [Abstract] [Full Text] [PDF]
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 B. N. Ames Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage PNAS, November 21, 2006; 103(47): 17589 - 17594. [Abstract] [Full Text] [PDF]
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 T. A. Guise Bone Loss and Fracture Risk Associated with Cancer Therapy Oncologist, November 1, 2006; 11(10): 1121 - 1131. [Abstract] [Full Text] [PDF]
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M. Visser, D. J. Deeg, M. T. Puts, J. C Seidell, and P. Lips Low serum concentrations of 25-hydroxyvitamin D in older persons and the risk of nursing home admission. Am. J. Clinical Nutrition, September 1, 2006; 84(3): 616 - 622. [Abstract] [Full Text] [PDF]
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 M. F. McCarty and K. I. Block Toward a Core Nutraceutical Program for Cancer Management Integr Cancer Ther, June 1, 2006; 5(2): 150 - 171. [Abstract] [PDF]
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 M. F. Holick, E. Giovannucci, J. Wactawski-Wende, G. L. Anderson, and M. O'Sullivan Calcium plus vitamin D and the risk of colorectal cancer. N. Engl. J. Med., May 25, 2006; 354(21): 2287 - 2288. [Full Text] [PDF]
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C. B Stephensen, G. S Marquis, L. A Kruzich, S. D Douglas, G. M Aldrovandi, and C. M Wilson Vitamin D status in adolescents and young adults with HIV infection Am. J. Clinical Nutrition, May 1, 2006; 83(5): 1135 - 1141. [Abstract] [Full Text] [PDF]
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C. M. Kemmis, S. M. Salvador, K. M. Smith, and J. Welsh Human Mammary Epithelial Cells Express CYP27B1 and Are Growth Inhibited by 25-Hydroxyvitamin D-3, the Major Circulating Form of Vitamin D-3 J. Nutr., April 1, 2006; 136(4): 887 - 892. [Abstract] [Full Text] [PDF]
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 K. M Egan Commentary: Sunlight, vitamin D, and the cancer connection revisited Int. J. Epidemiol., April 1, 2006; 35(2): 227 - 230. [Full Text] [PDF]
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 M. F. Holick High Prevalence of Vitamin D Inadequacy and Implications for Health Mayo Clin. Proc., March 1, 2006; 81(3): 353 - 373. [Abstract] [Full Text] [PDF]
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M. Monge, I. Shahapuni, L. Harbouche, P. Moriniere, N. E. Esper, Z. Massy, G. Choukroun, and A. Fournier Cinacalcet and vascular calcifications induced by calcitriol Nephrol. Dial. Transplant., February 1, 2006; 21(2): 551 - 552. [Full Text] [PDF]
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V. Tangpricha, C. Spina, M. Yao, T. C. Chen, M. M. Wolfe, and M. F. Holick Vitamin D Deficiency Enhances the Growth of MC-26 Colon Cancer Xenografts in Balb/c Mice J. Nutr., October 1, 2005; 135(10): 2350 - 2354. [Abstract] [Full Text] [PDF]
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C. E. Moore, M. M. Murphy, and M. F. Holick Vitamin D Intakes by Children and Adults in the United States Differ among Ethnic Groups J. Nutr., October 1, 2005; 135(10): 2478 - 2485. [Abstract] [Full Text] [PDF]
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M. F Holick and V. Tangpricha Reply to MA Weinstock and D Lazovich Am. J. Clinical Nutrition, September 1, 2005; 82(3): 707 - 708. [Full Text] [PDF]
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 M. M. Bachschmid and B. van der Loo A New "Sunshine" in the Vasculature? Circulation, April 5, 2005; 111(13): 1571 - 1573. [Full Text] [PDF]
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 E. Seeman and G. J. Strewler Clinical and Basic Research Papers - December 2004 Selections IBMS BoneKEy, January 1, 2005; 2(1): 1 - 5. [Full Text] [PDF]
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D. J Raiten and M. F. Picciano Vitamin D and health in the 21st century: bone and beyond. Executive summary Am. J. Clinical Nutrition, December 1, 2004; 80(6): 1673S - 1677S. [Abstract] [Full Text] [PDF]
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20 ng/mL] at the end of winter and at the end of summer. There was a significant difference in the proportions of subjects with vitamin D insufficiency between the end-of-winter and end-of-summer groups (P < 0.05). Reproduced from Am J Med 2002;112:659–62 with permission form Excerpta Medica Inc.
