VITAMIN D: IRRATIONAL EXUBERANCE?

April 20, 2011 - By Alan R. Gaby, M.D.

During the past decade it has become clear that vitamin D deficiency is relatively common among the general population. Potential consequences of low vitamin D status include accelerated bone loss, an increased risk of falls among the elderly, decreased resistance against influenza and other types of infection, an possibly an increased risk of developing cancer and certain autoimmune diseases. In addition, evidence has accumulated that the amount of vitamin D needed to prevent a deficiency is higher than previously believed. Whereas 400 IU/day had long been thought to be sufficient for most people, it is now known that 800 IU/day is needed to slow the progression of osteoporosis and to prevent falls.

In recent years, a number of researchers have recommended a redefinition of vitamin D deficiency, and many laboratories have changed their reference range for serum 25-hydroxyvitamin D (25[OH]D) to comply with that recommendation. Historically, the lower limit of normal for 25(OH)D has been 10-15 ng/ml (25-37.5 nmol/L), depending on the laboratory. Many laboratories are now defining vitamin D deficiency as a serum 25(OH)D level < 20 ng/ml (< 50 nmol/L), and vitamin D insufficiency (mild vitamin D deficiency) as a level < 30 ng/ml (< 75 nmol/L).¹ It has also been suggested that increasing serum 25(OH)D to an "optimal" level could improve a wide range of health outcomes, including better bone and dental health, fewer falls and fractures, and possible protection against cancer and autoimmune disease. A review article concluded that a protective effect began at a 25(OH)D concentration of 30 ng/ml (75 nmol/L), and that the best outcomes were seen in people with levels of 36-40 ng/ml (90-100 nmol/L).²

If one accepts these new laboratory criteria, then inadequate vitamin D status emerges as a major epidemic, being present in 40-50% of participants in many studies. Moreover, the amount of supplemental vitamin D needed to achieve "adequate" or "optimal" vitamin D status is well above 800 IU/day in many cases. For example, it has been estimated that only 50% of people who take 1,000 IU/day of vitamin D will attain a serum 25(OH)D level of 30 ng/ml (75 nmol/L). The estimated dosage needed to achieve a level of 30-32 ng/ml (75-80 nmol/L) in nearly all healthy adults has ranged from 1,644 IU/day to more than 3,440 IU/day in different studies.^3,4 Even larger doses would be needed to achieve an "optimal" level of 36-40 ng/ml (90-100 nmol/L). Based on these findings, some practitioners are recommending long-term supplementation with 2,000, 5,000, or even 10,000 IU/day of vitamin D for many of their patients.

A recurring theme in nutritional medicine is that the dosages of various nutrients needed to promote optimal health are often greater than the amounts needed to prevent a frank deficiency. The same is almost certainly true with respect to vitamin D. However, considering that a substantial minority of the population would need to consume potentially toxic doses of vitamin D in order to achieve a serum 25(OH)D level of at least 30 ng/ml (75 nmol/L), the evidence supporting the benefit and safety of high-dose vitamin D warrants scrutiny.

After reviewing the available research, I have reached several conclusions. First, serum 25(OH)D is not an entirely reliable indicator of vitamin D status. Second, an increase in the lower end of the reference range for serum 25(OH)D may not be appropriate for some populations and some individuals. Third, the evidence supporting the benefit of pushing serum 25(OH)D to an "optimal" level is weak. Fourth, the evidence supporting the long-term safety of vitamin D in doses greater than 2,000 IU/day is weak. Of particular concern is the possibility that long-term use of high doses might promote the development of atherosclerosis or kidney stones. Fifth, the physiological effects of sunlight exposure differ from those of vitamin D supplementation. One implication of that fact is that vitamin D supplementation may not duplicate the beneficial effects of sunlight exposure. Moreover, evidence regarding the safety of vitamin D synthesized in the skin might not apply to orally administered vitamin D.

These conclusions do not negate the observations that large doses of vitamin D have been safe and effective for some patients (such as patients with malabsorption, prostate cancer, or drug-induced vitamin D deficiency). However, routine use more than 2,000 IU/day of vitamin D for the sole purpose of achieving a target 25(OH)D level may be unwarranted. The evidence that has led me to these conclusions is reviewed below.

Assessment of Vitamin D Status

Although 1,25-dihydroxyvitamin D (1,25[OH]2D) is the biologically active form of vitamin D, serum 1,25(OH)2D is not a reliable indicator of vitamin D status. That is because vitamin D deficiency results in a compensatory increase in the concentration of parathyroid hormone, which increases the renal production of 1,25(OH)2D. Consequently, serum 1,25(OH)2D levels are often normal or elevated in people with vitamin D deficiency.⁵

The serum vitamin D concentration is also not a reliable indicator of vitamin D status, because its serum half-life is only about 24 hours. Therefore, serum vitamin D levels are dependent largely on recent vitamin D intake and recent sunlight exposure. In contrast, the serum half-life of 25(OH)D is about 3 weeks, which makes this metabolite more reliable than vitamin D itself as an indicator of long-term vitamin D exposure. For that reason, the serum concentration of 25(OH)D is generally considered to be the "gold standard" for assessing vitamin D status.

Reliability of serum 25(OH)D

Metallurgically speaking, however, the reliability of serum 25(OH)D as an indicator of vitamin D status might more aptly be characterized as bronze, rather than gold, even though it is currently the best assessment method available. One problem with this test is that substantial variations have been encountered from one laboratory to another and with the use of different methods of assessment. For example, of 42 serum 25(OH)D measurements made by a laboratory that used an in-house radioimmunoassay, only 17% were reported as < 32 ng/ml (< 80 nmol/L). In contrast, 90% of a group of nearly identical samples sent to a laboratory that used a commercially available radioimmunoassay were reported as < 32 ng/ml.⁶

Another complicating factor is that 25(OH)D is only one of more than 50 vitamin D metabolites that have been identified. Although little is known about many of these metabolites, at least one (not including 1,25[OH]2D) appears to have biological activity, a point that is discussed below. It would not be surprising if some of these compounds were able to bind to vitamin D receptors or to compete with vitamin D, 25(OH)D, or 1,25(OH)2D as substrates for enzymes involved in vitamin D metabolism. True vitamin D status (as it relates to the regulation of calcium and phosphorus metabolism and to various other biological roles of the vitamin) might therefore be a function of complex interactions between many different vitamin D metabolites. If that is the case, then different individuals could have different serum 25(OH)D "set points" for adequate or optimal vitamin D status, based on factors such as individual differences in the synthesis and degradation of various vitamin D metabolites, and differences in the binding affinity of these metabolites to vitamin D receptors. Considering that the serum level of 1,25(OH)2D itself (the major active form of vitamin D) does not always reliably reflect vitamin D status, one should not necessarily expect that serum levels of its precursor molecule (25[OH]D) would provide more than a rough approximation of vitamin D status. While very low and very high 25(OH)D levels would seem to be reliable indicators of vitamin D deficiency and excess, respectively, basing clinical decisions on serum 25(OH)D levels between those extremes may not always be appropriate.

High-dose vitamin D and serum 25(OH)D

Serum 25(OH)D may be a less reliable indicator of vitamin D status when large doses of the vitamin are being given than when smaller doses are being used. That is because at dosages below 2,000 IU/day, the rate of conversion of vitamin D to 25(OH)D is proportional to the amount of vitamin D administered. However, at higher dosages, hepatic 25-hydroxylases become saturated, and the conversion of vitamin D to 25(OH)D does not increase linearly with increasing vitamin D doses. Instead, large quantities of vitamin D are stored as the native compound, presumably in body fat, and are slowly released to be converted to 25(OH)D. This increase in body stores of vitamin D is not reflected in serum measurements of 25(OH)D.⁷

Serum 25(OH)D and parathyroid hormone

As serum 25(OH)D levels increase, parathyroid hormone levels tend to decline. Therefore, it is conceivable that measuring serum parathyroid hormone in combination with 25(OH)D would provide a better picture of vitamin D status than would measuring 25(OH)D alone. However, numerous factors influence parathyroid levels, and variations in serum 25(OH)D levels have been found to explain at most only 13% of the variation in parathyroid hormone levels.^8,9 For that reason, the serum parathyroid level may not provide reliable information about vitamin D status in patients with borderline-low serum 25(OH)D levels. Moreover, the high cost of the parathyroid hormone test precludes its routine use.

New Definitions of Deficiency and "Optimal" Status: Are They Valid?

The normal range for serum 25(OH)D was originally derived from people who had little sunlight exposure. Therefore, a normal serum 25(OH)D level does not necessarily indicate adequate vitamin D status. In recent years, some investigators have redefined vitamin D deficiency according to biochemical parameters such as parathyroid hormone levels and fractional calcium absorption. In population studies, as serum 25(OH)D levels increased, parathyroid hormone levels tended to decline and fractional calcium absorption tended to increase. Individuals might be considered vitamin D-sufficient when a further increase in their serum 25(OH)D level does not result in further changes in parathyroid hormone levels or in fractional calcium absorption. Based on population studies that examined these biomarkers, it has been suggest that vitamin D deficiency should be defined as a serum 25(OH)D level < 20 ng/ml (< 50 nmol/L) and vitamin D insufficiency (mild vitamin D deficiency) should be defined as a level < 30 ng/ml (< 75 nmol/L).

Examining the new definition of deficiency

As noted above, correlations (albeit weak) have been observed between 25(OH)D, parathyroid hormone,^3,4 and fractional calcium absorption.¹¹ However, in the absence of severe vitamin D deficiency, these associations do not seem to apply to all population groups, nor to all individuals within population groups. In one study, serum 25(OH)D and parathyroid hormone levels were measured in 93 young non-overweight adults living in Hawaii. Their mean sun exposure was 29 hours per week, and their mean sun exposure index (hours per week of total body exposure with no sunscreen used) was 11.1 hours. The proportion of subjects who had a serum 25(OH)D level < 30 ng/ml (< 75 nmol/L) was 25-51% (depending on the assay method used), and 3-8% of the individuals had a level < 20 ng/ml (< 50 nmol/L). Of note, there was no correlation between serum 25(OH)D and parathyroid hormone levels,¹² which further calls into question the basis upon which the new definitions of vitamin D deficiency and insufficiency were created.

The finding that vitamin D deficiency and insufficiency are so common among healthy young people with heavy sun exposure suggests either that the cut-off levels for 25(OH)D used to define deficiency and insufficiency are inappropriately high for some population groups or that serum 25(OH)D is not always a reliable indicator of vitamin D status (as discussed above). Thus, while some individuals may have inadequate vitamin D status despite having a serum 25(OH)D level greater than 15 ng/ml, others may have adequate vitamin D status despite having a serum 25(OH)D level less than 20-30 ng/ml (50-75 nmol/L).

Of note, in the late 1990s the standard radioimmunoassay for 25(OH)D was changed by the manufacturer by introducing an antibody that improved binding. The new assay procedure decreased measured values by approximately 4 ng/ml (10 mmol/L), which means that values measured by the new method are 4 ng/ml (10 mmol/L) lower than those measured by the old method.¹³ The fact that the new cut-off points for vitamin D deficiency and insufficiency were based in part on studies conducted prior to the late 1990s could explain to some extent why those cut-off points appear to be inappropriately high in some instances (such as the study cited above, conducted in Hawaii in 2007).

Examining the new definition of optimal

With regard to the concept of optimizing 25(OH)D levels in order to reduce the incidence of certain chronic diseases, the supporting evidence has been derived largely from observational studies, in which associations were found between serum 25(OH)D levels and health outcomes. Of note, not all studies found such an association, and the reported protective effect of higher 25(OH)D levels might be explainable at least in part by a failure to control for confounding factors such as age, body mass index, seasonal variation of 25(OH)D levels, and co-morbidities.¹⁴ Additional supporting evidence has come from randomized controlled trials in which vitamin D-supplemented participants who achieved higher serum 25(OH)D levels had better outcomes than vitamin D-supplemented participants whose 25(OH)D levels were lower.

Both of these lines of evidence have limitations. In the observational studies, high serum 25(OH)D levels presumably resulted mainly from abundant sunlight exposure, since very few people ingest enough vitamin D from diet and supplements to achieve 25(OH)D levels of 90-100 nmol/L. People who spend a lot of time in the sun may differ in many respects from people who avoid the sun, and some of these differences could impact health. Even if sun exposure per se produces health benefits, the effect might not be due entirely (or even primarily) to vitamin D. For example, corticotropin-releasing hormone, which is produced by sun-exposed skin, plays a role in regulating endocrine, cardiovascular, gastrointestinal, metabolic, and immune function; and increased synthesis of this hormone might have positive effects on various aspects of health.¹⁵ Other beneficial effects of sunlight might result from stimulation of the hypothalamic-pituitary axis through the retina.

The findings from randomized controlled trials also do not necessarily indicate that the reason participants had better outcomes was that they achieved higher 25(OH)D levels. A higher serum 25(OH)D response to vitamin D supplementation may simply reflect efficient nutrient absorption in general, a factor that could improve outcomes irrespective of vitamin D status. In addition, the effect of vitamin D supplementation on serum 25(OH)D levels is presumably influenced by the efficiency with which hepatic enzymes hydroxylate vitamin D. Four different cytochrome P450 enzymes are thought to be capable of hydroxylating vitamin D.¹⁶ Since cytochrome P450 enzymes also play a role in detoxifying xenobiotic chemicals, people who achieve high 25(OH)D levels in response to vitamin D supplementation may have more robust detoxification mechanisms than those whose serum 25(OH)D response is less pronounced. Moreover, hydroxylase enzymes play a role in the synthesis of dehydroepiandrosterone (DHEA) and estriol, both of which may have beneficial effects on human health. Therefore, the achievement of a high serum 25(OH)D level in response to vitamin D supplementation may be just a marker for the presence of other health-promoting biochemical capabilities.

Adverse Effects of Vitamin D

Tolerable Upper Intake Levels (ULs)

The Food and Nutrition Board of the Institute of Medicine has established a Tolerable Upper Intake Level (UL) of 1,000 IU/day for children less than 6 months of age, 1,500 IU/day for children aged 6-12 months, 2,500 IU/day for children aged 1-3 years, 3,000 IU/day for children aged 4-8 years, and 4,000 IU/day for older children and adults. The ULs for vitamin D are based on amounts that can apparently be consumed indefinitely by healthy people without causing hypercalcemia.

Are dosages above the ULs safe?

Some investigators have argued that the ULs are excessively conservative, and that 10,000 IU/day is a safe level of intake for most adults.¹⁷ This argument is based on two main points. First, with the exception of one study, hypercalcemia has not been observed in studies in which doses up to 10,000 IU/day were given. Second, whole-body sunlight exposure results in the production of at least 10,000 IU/day of vitamin D; and people who obtain large amounts of sun exposure do not exhibit signs of vitamin D toxicity or other long-term adverse effects (other than photoaging of the skin and skin cancer).

However, the contention that the UL for adults should be raised to 10,000 IU/day has four important weaknesses. First, studies of high-dose vitamin D supplementation were of relatively short duration. Second, the absence of hypercalcemia from a given dosage of vitamin D is not proof of safety. Third, it is not clear whether human skin really can synthesize as much as 10,000 IU/day of vitamin D. And fourth, the physiological effects of sunlight exposure differ from those of orally administered vitamin D; consequently, it may be inappropriate to compare the safety of these different methods of obtaining vitamin D.

Questions regarding long-term safety

The studies in which 10,000 IU/day of vitamin D was administered lasted a maximum of 20 weeks. Because vitamin D can accumulate with continued administration, studies lasting 20 weeks or less are not sufficient to establish the long-term safety of high doses.

Furthermore, the absence of hypercalcemia from a particular dosage of vitamin D does not necessarily indicate that that dosage is safe. The human body tightly regulates serum calcium levels by several different mechanisms, and it is likely that hypercalcemia occurs only after all calcium-regulating mechanisms have been overwhelmed. One way in which the body prevents hypercalcemia is by increasing urinary calcium excretion. High vitamin D intake might therefore increase the risk of developing kidney stones, even if serum calcium levels remain normal. In one study, 3 of 45 elderly individuals who received 5,000 IU/day of vitamin D3 for 12 months showed evidence of hypercalciuria, and mean urinary calcium excretion increased in the group as a whole.¹⁸ In contrast, other studies found that supplementation with 4,000 IU/day of vitamin D3 for 2-5 months¹⁹ or 280,000 IU of vitamin D3 once a week for 6 weeks²⁰ had no effect on serum or urinary calcium levels. While vitamin D-induced hypercalciuria appears to be uncommon, it would be prudent to monitor both serum and urinary calcium levels in patients being treated with large doses of vitamin D for long periods of time, particularly if they are also taking a calcium supplement.

Atherosclerosis and arterial calcification might also result from long-term consumption of large amounts of vitamin D. Swine fed vitamin D3 at a level of 12,500 IU per pound of diet (equivalent to about 11,500 IU/day for humans²¹) developed pathological changes in the thoracic aorta that were indistinguishable from those found in the thoracic aorta of humans undergoing coronary bypass surgery.²² Even a modest increase in vitamin D3 intake²³ (from 331 IU/kg of diet to 2,200 IU/kg of diet) exacerbated coronary atherosclerosis in swine consuming a diet high in saturated fat.²⁴ A vitamin D dosage of 2,200 IU/kg of diet is equivalent to only 917 IU/day for humans.²⁵

Can human skin produce 10,000 IU/day of vitamin D?

Vieth has argued that 10,000 IU/day of vitamin D is safe for the general population. This argument is based in part on the assertion that whole-body sunlight exposure results in the production of at least 10,000 IU/day. One study used to support that assertion found that, in elderly vitamin D-deficient volunteers, exposure of 5% of body surface area to ultraviolet irradiation 3 times a week for 12 weeks increased serum 25(OH)D levels about the same amount as oral administration of 400 IU/day of vitamin D.25 Vieth assumed that whole-body irradiation would result in the production of 20 times as much vitamin D (i.e., 8,000 IU/day) as would irradiation of 5% of body surface area. Younger individuals, who have a greater capacity to synthesize vitamin D in the skin, would presumably manufacture even more than 8,000 IU/day. However, there is no clear evidence that one can extrapolate the effects of irradiating 5% of the skin to the effects of irradiating the entire body.

Another study found that a one-time exposure of young adults to 1 minimal erythemal dose of simulated sunlight (i.e., the minimum amount that produces redness of the skin) was equivalent to oral administration of 10,000-25,000 IU of vitamin D2, as determined by changes in circulating vitamin D levels. However, results from a single-dose study are of doubtful relevance to long-term vitamin D homeostasis, because repeated exposure of the skin to sunlight results in photodegradation of the vitamin D that has not yet escaped into the circulation.²⁶ Thus, the net amount of vitamin D produced on subsequent days of sun exposure may be substantially less than the amount produced on the first day. Even if repeated sunlight exposure does result in the production of relatively large amounts of vitamin D, it would not necessarily indicate that such doses are safe when administered orally (see below).

Sunlight exposure and oral vitamin D are not the same

At least one of the photodegradation products of vitamin D (5,6-trans-vitamin D)(30) has demonstrated biochemical effects similar to those of 1,25(OH)2D in rats, although 5,6-trans-vitamin D is 20-40 times less potent than 1,25(OH)2D.²⁷ As a weak vitamin D agonist, 5,6-trans-vitamin D might compete with 1,25(OH)2D for binding to vitamin D receptors, and thereby function as a regulator of vitamin D activity. Thus, human skin apparently possesses mechanisms not only to prevent the release of excessive amounts of vitamin D into the circulation (as noted above), but also to modulate the action of vitamin D.

In addition to producing vitamin D degradation products, sun-exposed skin synthesizes corticotropin-releasing hormone (CRH).13,²⁸ CRH, which is better known as a hypothalamic hormone, has a wide range of physiological effects, some of which might modulate the actions of vitamin D. Furthermore, studies in animals have shown that stimulation of the retina by ultraviolet light directly influences hypothalamic and pituitary function.²⁹

Some of these sunlight-induced responses in the skin and retina might decrease the deleterious effects of vitamin D. Since there is no evidence that any of these ancillary effects of sunlight exposure occur with oral administration of vitamin D, one cannot draw conclusions regarding the safety of ingested vitamin D from data on the safety of vitamin D synthesized by the skin.

Safe and Effective Vitamin D Levels: What to Make of It All

The available evidence suggests that currently recommended vitamin D intakes are not sufficient to promote optimal health. A number of studies have shown that supplementing with 800 IU/day of vitamin D provides greater benefit than supplementing with 400 IU/day. I frequently recommend 800-1,200 IU/day of supplemental vitamin D, and sometimes more, depending on age, body mass index, skin color, and amount of sunlight exposure. However, the safety and efficacy of giving healthy people large doses of vitamin D (such as more than 2,000 IU/day) for the sole purpose of reaching a target serum 25(OH)D level have not been established. For patients with potentially vitamin D-responsive diseases and for those who are at increased risk of developing these diseases, the potential benefits of high-dose vitamin D should be weighed against the risks.

Vitamin D from sunlight

Throughout most of human history, vitamin D was obtained almost exclusively from cutaneous biosynthesis, since typical diets contained little or no vitamin D. Because of its multiple and complex physiological effects, sunlight exposure may be the preferred method of obtaining vitamin D. Of note, John Denver attributed his happiness to sunshine on his shoulder, not to vitamin D pills.

According to one investigator, exposure of the arms and legs or the hands, arms, and face to sunlight for 5-15 minutes two to three times a week between 10 a.m. and 3 p.m. during the spring, summer, and autumn usually results in adequate vitamin D production by individuals with skin type II (fair skinned) or III (darker Caucasian). That amount of sunlight exposure is 25% of what would cause a minimal erythemal response. After the initial 5-15 minutes of sunlight exposure, application of a sunscreen with a sun protection factor (SPF) of at least 15 is recommended.³⁰ While it appears that many people can maintain adequate vitamin D status with fairly modest levels of sunlight exposure, the risks and benefits of sun exposure should be assessed on an individual basis.

Alan R. Gaby, M.D., received his undergraduate degree from Yale University, his M.S. in biochemistry from Emory University, and his M.D. from the University of Maryland. He was in private practice for 17 years, specializing in nutritional medicine. He is past-president of the American Holistic Medical Association and gave expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. He is the author of Preventing and Reversing Osteoporosis (Prima, 1994), and The Doctor’s Guide to Vitamin B6 (Rodale Press, 1984), the co-author of The Patient’s Book of Natural Healing (Prima, 1999), and has written numerous scientific papers in the field of nutritional medicine. He has been the contributing medical editor for the Townsend Letter for Doctors since 1985, and contributing editor for Alternative Medicine Review since 1996. Over the past 25 years, he has developed a computerized database of more than 25,000 individually chosen medical-journal articles related to the field of natural medicine. He was professor of nutrition and a member of the clinical faculty at Bastyr University in Kenmore, WA from 1995 to 2002.

Over the past 30 years, he has developed a computerized database of more than 26,000 individually chosen medical journal articles related to the field of natural medicine. He was professor of nutrition and a member of the clinical faculty at Bastyr University in Kenmore, WA, from 1995 to 2002. He is Chief Science Editor for Aisle 7 (formerly Healthnotes, Inc). He has appeared on the CBS Evening News and the Donahue Show. In 2010, Dr. Gaby completed a 30-year project, a textbook of nutritional medicine, which is schedule for release in November.

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21. A 2,000-kcal diet providing 30% of total energy from fat would weigh 0.417 kg or 0.92 pounds (dry weight).

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28. Slominski A, Baker J, Ermak G, et al. Ultraviolet B stimulates production of corticotropin releasing factor (CRF) by human melanocytes. FEBS Lett 1996;399:175-176.

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