Shedding Light on the Controversy Over Vitamin D

Calcitriol is an extremely potent, active molecule. In fact, Anthony Norman, PhD, Distinguished Professor of Biochemistry and Biomedical Sciences at the University of California, Riverside, refers to calcitriol as "hormone D." Dr Norman, who has studied vitamin D for more than 40 years, notes that more than 30 tissues in the body have receptors for calcitriol (Table 1). Each tissue that is equipped with these receptors is known to have or is suspected of having a response to calcitriol.

A brief history. In the past, sun exposure was the main source of vitamin D for most people. Humans are usually able to manufacture at least 1000 IU of vitamin D with just minutes of exposure to midday sun-- although this varies considerably with skin color, latitude, and time of year. The only naturally occurring food source that supplies substantial quantities of the vitamin is cold-water ocean fish (the chief source of vitamin D for the Inuit and other peoples of the far north, where the weakness of the sunlight makes production of vitamin D in the skin difficult or impossible). Food sources of vitamin D are listed in Table 2.

When the industrial revolution dramatically reduced people's sun exposure, rickets became common in smog-covered factory towns. After the discovery that severe vitamin D deficiency was the cause of rickets, milk and other food products began to be fortified with the vitamin. These fortified foods provided most people with enough of the vitamin that rickets quickly became a scourge of the past. However, as recent research increasingly demonstrates, the absence of rickets does not necessarily mean a person is receiving all the vitamin D he or she needs for optimal health.

BONES AND BEYOND: THE VARIED HEALTH EFFECTS OF VITAMIN D

Skeletal health. The role of vitamin D in calcium metabolism is well established. Calcitriol, which is produced from vitamin D, plays a vital role in the growth and maintenance of bones. Among the causes of a noticeable reemergence of rickets in recent years are prolonged exclusive breast-feeding without vitamin D supplementation and extensive use of sunscreens and increased use of day care, resulting in decreased outdoor activity and sun exposure among children.²

The role of vitamin D/calcitriol in maintaining bone health goes beyond the prevention of rickets, however. Dr Norman points out that a painful and debilitating bone disease, renal osteodystrophy, can develop in patients with kidney failure who receive dialysis. Calcitriol both cures and prevents renal osteodystrophy. He also notes that in more than 15 countries (although not in the United States), calcitriol is an approved treatment for osteoporosis.

Muscle strength. Several recent studies have shown a significant association between falls in the elderly and vitamin D deficiency.^3,4 Although this might at first seem to be just another example of the correlation between vitamin D and bone health, the study authors think a more likely explanation is that vitamin D plays an important role in the maintenance of muscle mass and strength. It was probably compromised muscle function secondary to vitamin D deficiency that led to more frequent falls. Dr Norman notes that one of the early effects of vitamin D supplementation is an improvement in muscle strength. However, the exact mechanism of action for this effect is not known.

Cancer prevention and treatment. A possible role in cancer prevention is one of the most publicized--although still controversial--issues in vitamin D research. The lower rates of cancers of the prostate, breast, colon, and other organs in people who live at latitudes that receive more direct sunlight suggest a link between vitamin D and these cancers (Figure).⁵

Marianne Berwick, PhD, MPH, Professor of Epidemiology at the University of New Mexico has done extensive research on melanoma, including research into the interplay of ultraviolet (UV) exposure, vitamin D, and development of skin cancer. She points out that calcitriol has been shown both in vitro and in animals to inhibit cell proliferation and promote cell differentiation--both mechanisms that would help thwart the development of tumors. However, she thinks more data are needed before any claim to prevent cancer is made. Dr Norman notes that the role of vitamin D in cancer prevention--and even treatment--is a very active area of research; currently the NIH is funding studies on the vitamin's role in breast cancer, colon cancer, and leukemia.

Immune system health. Two of the most important types of cells that have vitamin D receptors are B and T lymphocytes. This, says Dr Norman, is evidence that calcitriol plays a key role in the development of the immune system. There is mounting evidence--both epidemiologic and laboratory--that vitamin D helps prevent the development of autoimmune diseases such as multiple sclerosis and type 1 diabetes.^6,7

Most recently, researchers at Harvard University and the University of California, Los Angeles, shed light on the complex mechanism by which calcitriol helps the body fight tuberculosis (TB).⁸ Their work, although still limited to the laboratory, helps explain why TB treatment in the pre-antibiotic era often consisted of exposing patients to sunlight high in the mountains--and may also explain why people of African descent (whose skin produces less vitamin D) are more susceptible to TB than those of European descent.

HOW MUCH VITAMIN D DO PATIENTS NEED?

Many scientists argue that the guidelines governing intake of the vitamin need significant revision. The current guidelines, which with only a few minor alterations date back about 50 years, recommend a daily intake of vitamin D of 200 IU for most persons up to age 50 years (400 IU for those aged 51 to 70 years, and 600 IU for those older than 70 years).⁹ Dr Norman notes that experts are increasingly recommending a daily intake of 800 to 1000 IU, with some advocating 2000 IU/d.

In addition to calls for increases in the US Food and Nutrition Board's recommended "adequate intake," many experts now support measurement of serum levels of circulating calcidiol as a more accurate method than daily intake for ascertaining vitamin D sufficiency. However, the optimal level of serum calcidiol is hotly contested. Currently, levels in the range of 10 to 55 ng/mL are considered normal. A number of researchers are now suggesting that levels in the lower end of this range actually represent a state of vitamin D insufficiency.

Dr Norman believes that a level of 20 to 30 ng/mL is probably necessary for optimal health. While stressing that he is not a physician, he believes it would be prudent to monitor serum calcidiol levels in certain patients (adolescents, women of all ages, and the elderly). For those in whom insufficiency is detected, he recommends supplementation to bring their levels up to 20 to 30 ng/mL.

Although some researchers have recommended the adoption of higher normal ranges, neither Dr Norman nor Dr Berwick thinks that the evidence is robust enough yet to support recommendations of more than 30 or 40 ng/mL. In addition, Dr Berwick points out that there are significant inconsistencies in the measurements of different laboratories; she feels that a more reliable and standardized method of measurement is urgently needed.

THE SUNLIGHT CONTROVERSY

Perhaps no issue involving vitamin D has provoked so much controversy as the question of what source of the vitamin to recommend to patients. Recent dramatic increases in the incidence of skin cancer--especially melanoma--make many experts leery of recommending sun exposure.

Sunlight's role in melanoma. Dr Berwick notes that the relationship between sun exposure and melanoma is more complex than the linear dose-response relationship seen with the less deadly squamous cell carcinoma. Rather than total cumulative exposure, intermittent intense sun exposure--especially in the first 10 years of life--appears to be implicated in melanoma.¹⁰

In addition, sunscreens, although very successful at preventing sunburn (and at blocking the synthesis of vitamin D), have been less successful at reducing the incidence of melanoma. Dr Berwick says that this is because melanoma appears to be caused, at least in part, by UVA rays that penetrate to the deepest layer of skin. Until recently, most sunscreens have not been effective at blocking light in this spectrum. Furthermore, few people apply sunscreens as frequently or thickly as needed to create melanoma-preventing blockage. Finally, because even thinly applied sunscreens usually do prevent sunburn, their use may lead people to prolong their time in the sun. Thus, caution with regard to sun exposure would appear to be key to reducing melanoma risk.

A slight wrinkle in this conclusion is offered by Dr Berwick's recent research, which suggests that vitamin D--including that produced by sunlight on skin--may exert an inhibitory effect on melanoma similar to that postulated for other cancers. There is some evidence that a diet rich in vitamin D protects against the development of melanoma.¹¹ In addition, solar elastosis and other measures of sun exposure were found to be inversely associated with death from melanoma.¹² Although sun exposure does not prevent the development of melanoma, it may protect against its progression.

WHAT TO TELL PATIENTS

How best to obtain an adequate amount of vitamin D? Both Dr Norman and Dr Berwick recommend a combination of sun exposure and dietary supplementation--although their rationales are somewhat different. Dr Norman believes a conservative approach to sun exposure is crucial to prevent increases in skin cancer risk. Dr Berwick's stance is more of a fallback position. She feels that there simply are not enough good data to support relying principally on sunlight for vitamin D. She also notes that calculating the precise amount of unprotected sun exposure one needed (with proper accounting for all the variables involved--latitude, time of year, time of day, skin color, and age) and then remembering to cover up when the allotted unprotected time was up would be complex and impractical.

Although Dr Norman approves of limited unprotected sun exposure (20 minutes on the cheeks and arms 3 times a week at the latitude of Boston, with reduced amounts in more southern locations) as a means of obtaining reasonable amounts of vitamin D, he feels that dietary supplementation is essential for most people. Most multivitamins contain vitamin D, and milk and a few other foods are supplemented with D. However, to obtain the amount of the vitamin he feels is needed to produce adequate serum levels, a person would have to take several multivitamin tablets (and risk excessive intake of other vitamins) or drink an impractical amount of fortified milk or orange juice. Although their quality cannot be relied on, potent vitamin D supplements are available in some health food stores.

In addition, he stresses the importance of supplementing with vitamin D₃ rather than D₂, which is a far less potent form of the vitamin. (An FDA-approved formulation of vitamin D₂ has been available for many years, and this is still sometimes prescribed for infants who are vitamin D-deficient. However, 2.5 to 3 times as much of the agent is needed [in both children and adults] to have the effect supplied by an appropriate amount of vitamin D₃.) Although many manufacturers have switched to using D₃, often it is impossible to tell what form of vitamin D a particular capsule or foodstuff contains. Currently, there is no FDA-approved 1000-IU vitamin D₃ supplement available in the United States.

Dr Berwick thinks that we don't yet know enough to say specifically how much vitamin D people need. However, she notes that supplementation is important in persons who are most likely to be vitamin D-insufficient. Like Dr Norman, Dr Berwick favors supplementation with vitamin D₃ rather than with D₂.

With regard to sun exposure, Dr Berwick urges caution but also logic: "Tell patients to exercise prudence in the sun, but also to enjoy it. I think you can tell patients--depending on their skin type, of course--that 15 to 20 minutes of unprotected sun in the middle of the day is probably good for them and won't hurt them. Although you need to wear sunscreen if there is a chance you might get sunburned, I don't think people need to wear sunscreen 365 days a year." She recommends more sun exposure for patients with darker skin. These patients have a lower risk of melanoma and greater likelihood of vitamin D insufficiency or deficiency. "Just try to give patients confidence in their own good sense," she says.