Vitamin D on Trial

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March 2012 »                Features                        
Vitamin D on Trial
Prevention trials for vitamins and supplements are notoriously difficult, but some researchers aren’t giving up on finding proof that vitamin D helps ward off disease.
By Amy Maxmen |                         March 1, 2012               

                                                                                 Harry Campbell

                                                                Once a month for the next 5 years, 20,000 people across the United States will find a package containing 62 pills in their mailboxes.  As participants in a clinical trial, the recipients agreed to swallow two of the pills daily. But inevitably as the years pass, some pill packets will become buried under a stack of letters, or forgotten in a drawer.  After all, these pills contain only vitamin D, fish oil, or an inert placebo—a person doesn’t need them to make it through the day.  Plus, no one monitors who takes the pills daily and who does not.
In another study, 871 pregnant women swallow a vitamin D or a placebo pill every day for the duration of their pregnancy. Then every year for 3 years after they’ve given birth, clinicians will evaluate their children for signs of asthma, in search of clues about the relationship between the essential vitamin and the respiratory disorder. But the study is scheduled to last only 3 years, so it won’t include children who begin to wheeze at age 6, when childhood asthma most often strikes.
A better vitamin D trial might send health-care professionals out to personally deliver pills to each of the first trial’s 20,000 participants. It might also test various doses of supplements, because no one knows how much is best. The asthma trial might include more women, run for a longer period of time, and test childhood supplementation, too. But then they’d also cost millions more, and in contrast to many drug trials, Pharma isn’t footing the bill. Profits from vitamin sales pale in comparison to those of most drugs, and therefore a company would struggle to recoup the money it spent testing supplements. Unfortunately, prevention trials require large sample sizes and long-term follow-up, making them incredibly expensive. Indeed, the National Institutes of Health has granted about $32 million for these two trials alone.
But researchers aren’t giving up. With limited budgets, vitamin D investigators are working hard to keep costs down, while still giving the vitamin a fighting chance to prove itself. Deficiencies of vitamin D have been linked to cancer, diabetes, strokes, and other maladies, and at least 12 imperfect clinical trials on its preventive powers have been set in motion since 2008. And while some scientists worry their cost-trimming shortcuts will render the results useless, others remain optimistic. Perhaps this smorgasbord of trials will reveal unpredictable benefits of taking one’s vitamins.
How the Body Processes Vitamin DVitamin D is a fat-soluble prohormone that can be obtained from foods—either the few foods in which it is naturally present, such as fish, or fortified foods—as well as from dietary supplements. It is also produced endogenously when ultraviolet rays from the sun react with 7-dehydrocholesterol in the skin, converting it into the vitamin.
Vitamin D Metabolism
The forms of vitamin D that are obtained from foods and supplements (D2 and D3), as well as endogenously upon sun exposure (D3), are biologically inert. Two hydroxylation reactions are necessary to convert the vitamin to its active form. The first reaction occurs in the liver and converts the vitamin to an intermediate known as 25-hydroxyvitamin D3 (25D), or calcidiol. The second reaction occurs primarily in the kidneys, and results in the vitamin’s active form, 1,25-dihydroxyvitamin D3 (1,25D), or calcitriol.

Enticing observationsIn 2008, epidemiologist JoAnn Manson at Harvard Medical School in Boston received NIH funding to lead the largest vitamin D intervention trial yet. In observational studies, Vitamin D had shown promise for lowering the risk of a wide range of diseases, but Manson felt the field would benefit from a large clinical trial that more rigorously tested the vitamin’s power. This sentiment only grew when she analyzed about 1,000 reports on vitamin D metabolism, intake, and impact on human health as a member of a panel convened by the Institute of Medicine (IOM) in 2009. The panel decided that while the benefit of the nutrient for bones is real, helping to promote bone strength while staving off diseases such as rickets, osteomalacia, and osteoporosis, the evidence of nonskeletal benefits was inconclusive1—an uncertainty that continues to linger.2
The decision infuriated many scientists—some of whom had documented the correlation between high blood levels of vitamin D and lower rates of colorectal cancer, diabetes, asthma, influenza, multiple sclerosis, and an array of other ailments. And in many cases, researchers can point to ways the vitamin might bring about benefits. The hormone derived from vitamin D, called 1,25-dihydroxyvitamin D3, or calcitriol, can turn on or off hundreds of genes in the body, thereby participating in processes ranging from cell proliferation to immune system regulation. But the IOM panel concluded that without large-scale prevention trials confirming the ultimate result of high levels of vitamin D, it could not say for certain whether insufficiency contributes to cancer or any other nonskeletal disease.
Others argue that the correlational studies provide enough evidence to recommend that people maintain a higher concentration of vitamin D in their blood, and that difficult, expensive, and often inconclusive prevention trials, particularly those for relatively rare or unpredictable diseases, are a waste of time. “The success of the RCT [randomized controlled trial] in evaluating medical treatments has, perhaps, blinded nutritionists, regulators, and editors to the fact that it is a method ill-suited for the evaluation of nutrient effects,” Robert Heaney, an endocrinologist at Creighton University School of Medicine wrote in a 2008 commentary published in The Journal of Nutrition.3
And it seems the public isn’t waiting for clinical trial data. Spurred by headlines about its potential benefits, US consumer sales of vitamin D supplements rocketed from $50 million in 2005 to $550 million in 2010, according to estimates from the Nutrition Business Journal. Enthusiasm for the vitamin echoes among doctors and natural-food advocates, who are pushing for doses higher than the 400 to 600 International Units (IU) that the government currently recommends for maintaining healthy bones.
However, Manson, a refined woman of measured words, is acutely aware of the disappointment that has trailed the hyping of vitamins over the decades. Vitamin E, a fat-soluble antioxidant, gained a reputation for fighting cancer in the 1990s, when observational studies found that people who took supplements had lower rates of the disease.  But the buzz died out in 2008 when a 35,000-person clinical trial on vitamin E and selenium was terminated prematurely after people taking the supplements showed a slightly higher risk of developing prostate cancer than the control group. Similarly, in 1996 two large clinical trials dumbfounded fans of beta-carotene, a substance that humans convert into vitamin A after consuming it in fruits and vegetables. One trial found that it raised the risk of lung cancer and heart disease, and the other ended anticlimactically after 12 years with the conclusion that beta-carotene supplements performed no differently than placebo. “You have to look at these previous randomized trials as cautionary tales,” Manson says, “because they show that time and time again, everyone jumped on the bandwagon and then the randomized trials did not have favorable results, and in fact, the risks outweighed the benefits.”
At the same time, however, this is exactly why large-scale trials are necessary, she says. Though they aren’t perfect, such trials are the only way to discover whether vitamin D causes better health, or simply indicates it. “For example, people who are physically active tend to spend more time outdoors walking, hiking, or playing tennis. They get more sun exposure”—and thus more vitamin D—“but the real benefit might be physical activity,” says Manson. “There are so many potential confounders, and this is just one we know about.”

Infographic: Suspected Effects of Vitamin D
View full size JPG | PDF Harry Campbell

Manson designed her 5-year, $22 million study, called VITAL (VITamin D and omegA-3 triaL), to be cost effective. For a point of comparison, VITAL costs just $200 per person per year, whereas a rate of at least $1,000 is typical for many nutrient trials, Manson says. Rather than require in-person visits for all 20,000 participants, she decided to mail the participants their pills, in four randomized combinations—either 2,000 IU of vitamin D3 and 1 gram fish oil (omega-3 fatty acid), one of those plus a placebo, or two placebos—to be taken daily. In addition to reducing costs, she says this lessens the burden on busy participants. And in order to increase the chances that the trial would detect an effect, the participants are all over age 50, and therefore more likely to develop a disease. Furthermore, in addition to cancer and heart disease, VITAL investigators will assess dozens of other outcomes. They’ll learn when patients are diagnosed with cancer, diabetes, and other diseases, and in a subset of the participants, periodic clinical visits will allow doctors to measure blood sugar levels, cognitive performance, lung function, heart function, muscle strength, weight, and much more.
Delicate dosing

Time and time again, everyone jumped on the bandwagon and then the randomized trials did not have favorable results, and in fact, the risks outweighed the benefits.

—JoAnn Manson, Harvard Medical School

Scientists critical of the VITAL study question whether the daily dose of 2,000 IU is enough to distinguish the treatment group from the controls. If this were a drug trial, the placebo group would go without the drug completely. But it’s unethical to ask anyone to go without vitamin D. Doctors inform all participants that they can take up to 800 IU of vitamin D daily (the national recommendation for people over 70 years old) in addition to the pills they receive in the mail. If they do, the control group will sustain more than adequate levels. But some participants might decide to break the rules and head to the nearest corner store for high-dose supplements after being told that vitamin D may help prevent cancer and other diseases. And of course, many participants won’t follow through with taking the pills they’ve been sent in the mail. “You hope drop-ins and drop-outs will be equal on both sides, but they may not be,” warns biostatistician Gary Cutter at the University of Alabama at Birmingham.
A higher dose of vitamin D would widen the gap between the treatment and the control group, but Manson isn’t swayed. She says 2,000 IU will lift the treatment arm well above the level suggested to help protect against nonskeletal diseases, while she expects the controls to stabilize at levels sufficient for healthy bones. “Sure, we could have tested higher doses, but then right off the bat, we might have had safety issues,” Manson says. Indeed, the trials that found harm in vitamin E and beta-carotene have been criticized for testing too high a dose. Furthermore, elderly participants in two independent clinical trials fell more often when they received whopping doses of vitamin D once a year4 or once every 3 months5—although in the latter study the effect was not statistically significant.
Nonetheless, in other disease-prevention trials, investigators are gunning for better compliance and a fighting chance of showing an effect by doling out large, periodic doses of vitamin D. In the United Kingdom, a trial looking at the effect of vitamin D on respiratory infections (including the flu) is giving participants 120,000 IU of the vitamin every 2 months. And participants in the treatment arm of a vitamin D trial for type 2 diabetes prevention take an average dose of 89,684 IU once per week. Despite the rather extreme dose, none of the first 50 participants to hit the 6-month mark in the diabetes trial have had increased calcium in their blood and urine—the first sign of harm to bubble up in vitamin D studies, says lead trial investigator Mayer Davidson of Charles Drew University of Medicine and Science in Los Angeles. And those enrolled for 2 months in the UK trial also have normal blood calcium concentrations.
Davidson chose the high dose—one that some researchers call potentially dangerous—to ensure that if the nutrient does in fact affect glucose metabolism and prevent diabetes, he’s sure to catch it. Plus, the participants in the study require more vitamin D than usual because most of them are obese, and fat serves as a sink for fat-soluble vitamins. In addition to their weight, the people Davidson’s team recruited have other risk factors for diabetes: they’re African American or Latino; diabetes runs in their families; they have high blood pressure and impaired glucose tolerance or impaired fasting glucose, also called pre-diabetes; and they had low blood levels of vitamin D before the study began. Likewise, Anastassios Pittas at Tufts University plans to enroll patients at risk of diabetes in another prevention trial, in which he and his team will administer 4,000 IU of vitamin D daily.  By enrolling at-risk populations, Davidson and Pittas hope to see an effect on diabetes with just hundreds of participants within a few years’ time.
Investigators who study relatively rare diseases face the biggest challenge. In December, multiple sclerosis (MS) researchers gathered in Chicago to plot a trial to prevent the debilitating disease characterized by excessive inflammation and nerve damage. But because fewer than eight people per 100,000 in the United States acquire MS each year, hundreds of thousands of healthy individuals would need to enroll. Plus, while MS usually occurs sometime between ages 25 and 40, vitamin D’s putative protective power could begin in the womb, requiring a trial to run for decades to notice such effects. “It’s an unfortunate time to get funded for a long-term prevention trial,” says Cutter, a self-described skeptic, after attending the meeting. “We might have to do minimalist data collection and give up a lot of things we want to know. Even a 5-year study is very expensive,” he says, “and 5 years might not be enough.”
Adrian Martineau, at the Centre for Primary Care and Public Health of the Barts and The London School of Medicine and Dentistry, faces an analogous hurdle. He says that latent tuberculosis infections seem to activate less frequently in people who have plenty of vitamin D. But because latent infections only become active 5 percent of the time, a trial in the United Kingdom that randomizes 14,000 people with latent infections would still not be large enough to demonstrate the effect of supplements, he says.
Thus, the need for evidence from clinical trials places researchers who focus on tuberculosis in industrialized countries, MS, or other relatively rare disorders in a complicated position. But many researchers continue to push for such trials. George Ebers, a neurologist at the Wellcome Trust Centre for Human Genetics in the United Kingdom, for example, is sure that supplements could prevent some cases of MS, based on observational studies and experiments that show how vitamin D tames inflammation in animal models. Now he just wants a clinical trial to prove it. “It’s mainly about convincing other people at this point,” he says.
Personalized preventionOnly a few vitamin D trials have assessed nonskeletal diseases thus far, and their combined verdict is inconclusive. One of those trials, aimed at testing fractures, found that vitamin D combined with calcium helped prevent breast, lung, and colon cancers and leukemia, though the result was not one investigators had designed the trial to test, and it was determined from a small sample size. On the other hand, a randomized clinical trial, conducted as part of a large-scale and multifaceted investigation called the Women’s Health Initiative, concluded that vitamin D and calcium supplements didn’t reduce cancer incidence or mortality, and appeared to increase the risk of urinary tract stones.5 However, critics of this study point to the high rate of dropouts, and the low dose of vitamin D given to the treatment group (just 400 IU daily). And they say the urinary tract stones could be due to the calcium taken alongside vitamin D.
But the Women’s Health Initiative trial wasn’t a complete failure for proponents of vitamin D, as signals of a positive effect of the vitamin have begun to emerge from the data. For example, women in the treatment group who had not been taking vitamins before the trial began did show diminished rates of breast and colorectal cancer.6 Because investigators hadn’t designed the trial to detect this outcome a priori, however, the results need to be confirmed in a new clinical trial. That said, it brings science closer to understanding how and when vitamin D matters, says John Milner, chief of the National Cancer Institute’s Nutrition Science Research Group.
Indeed, answers may never be simple when it comes to nutrition. One reason why studies have arrived at conflicting conclusions may be that individual needs vary, says Milner.  He hopes that ongoing trials, despite their imperfections, will help unravel the contributions of genetics and diet. “There is some evidence that individuals with certain genetic variations require more vitamin D because they have an inability to absorb or metabolize vitamin D effectively,” he says. And because nutrients interact, a person’s diet also has the potential to alter the effect of supplements. Notably, unlike most clinical trials, which tend to enroll health-conscious Caucasians, the medley of vitamin D trials currently taking place has attracted a diversity of people. African Americans account for 43 percent of participants in the trial on childhood asthma and 25 percent of Manson’s VITAL trial (if all goes according to plan), while Latinos comprise 85 percent of Davidson’s type 2 diabetes trial members. This composition of participants will help researchers determine whether certain ethnicities, or even smaller subsets of individuals, are more responsive to vitamin D supplements than others—a situation that might mask any effects of the vitamin in more homogenous trials.
“In nutrition we talk about maintaining normal adequacy, but some people may require more vitamins than others, and identifying those populations will really be the future of nutrition,” says Milner. “It’s the classic ‘one size does not fit all.’ I’m hoping we can identify biomarkers that tell us who will really benefit, and who doesn’t need to worry.”
Potential trial pitfallsCritics of vitamin D trials worry about the following drawbacks common to prevention trials of nutrient supplements.

• Dose too small
• Dose too risky
• Outcomes too uncertain (an increased risk of disease, rather than the disease itself)
• Too little time
• Too few participants
• Incorrect treatment regimen
• Poor compliance
• Cherry-picked participants
  

Vitamin D prevention trials for nonskeletal disordersPrevention trials make drug trials look easy. They require more participants and a longer duration, and investigators must trust that the participants take the vitamins they’re given, and don’t decide to up their dose by buying over-the-counter supplements. Below is a list of ongoing trials that are trying to beat the odds to conclusively nail down the benefits of vitamin D for nonskeletal disorders, such as cancer, heart disease, and diabetes.

NAME OF TRIAL	PRIMARY OUTCOME	START DATE	DURATION OF TREATMENT	STATUS	NO. PARTICIPANTS/ EXPECTED ENROLLMENT	DOSE OF VITAMIN D3
NCT01169259	All cancers, heart disease, and stroke	July 2010	5 years	Recruiting participants	20,000 healthy men over 50 and women over 55	2,000 IU daily
To be announced (lingering ethical approvals have delayed the official listing of this trial)	nfections, cognitive decline, blood pressure increase, decline in muscle strength, risk of non-vertebral fractures	June 2012	3 years	Approved	2,000 men and women over 70 who have had a fracture or a fall	2,000 IU daily
NCT01052051	All cancers	Jan. 2009	4 years	Ongoing	2,332 healthy postmenopausal women over 55	2,000 IU (and 1,500 mg calcium) daily
NCT01463813	All cancers and cardiovascular disease	Jan. 2012	4 years	Approved	18,000 healthy men over 60 and women over 65	3,200 IU or 1,600 IU daily
NCT00920621	Asthma or recurrent wheeze at 3 years old	Sept. 2009	1 year	Ongoing	871 pregnant women whose babies have a family history of asthma, eczema, or allergic rhinitis	4,000 IU daily
NCT00685594	Type 2 diabetes	March 2008	5 years	Ongoing	517 adults with impaired glucose tolerance	20,000 IU per week
NCT00876928	Type 2 diabetes	March 2009	1 year	Ongoing	186 Latino and African American adults over age 40 with risk factors for diabetes	Dose determined by BMI; average dose is 89,684 IU per week
NCT01069874	Influenza and other respiratory infections	March 2010	1 year	Recruiting participants	Approx. 290 permanent residents or staff at 116 independent living units	120,000 IU once every 2 months

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Correction (March 6, 2012): The illustration, “How the Body Processes Vitamin D,” has been relabeled to correctly reflect that food products are a source of both the D2 and D3 forms of vitamin D. The Scientist regrets the error.
References

• Institute of Medicine, Dietary Reference Intakes for Calcium and Vitamin D, National Academies Press, 2011. ↩
• M. Chung et al., “Vitamin D with or without calcium supplementation for prevention of cancer and fractures: An updated meta-analysis for the US Preventive Services Task Force,” Ann Intern Med, 155:827-38, 2011. ↩
• R.P. Heaney, “Nutrients, endpoints, and the problem of proof,” J Nutr, 138:1591-95, 2008. ↩
• K.M. Sanders et al., “Annual high-dose oral vitamin D and falls and fractures in older women,” JAMA, 303:1815-22, 2010. ↩
• P. Glendenning et al., “Effect of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: A randomized controlled trial,” J Bone Miner Res, doi:10.1002/jbmr.524, 2011. ↩
• M.J. Bolland et al., “Calcium and vitamin D supplements and health outcomes: A reanalysis of the Women’s Health Initiative (WHI) limited-access data set,” Am J Clin Nutr, 94:1144-49, 2011. ↩