There is a wealth of new information touting the benefits of vitamin D
on bone, diabetes, cancer, cardiovascular disease and more, but it is yet to be
determined if endocrinologists are armed with adequate information to make an
informed judgment on vitamin D for their patients.
There are currently more than 1,000 ongoing studies examining the
benefits of vitamin D, according to
However, only one interventional trial, the newly launched Vitamin D and
Omega-3 Trial (VITAL), will be large enough to assess the balance of benefits
and risks of vitamin D for multiple chronic disease outcomes, but results will
not be available for 5 years.
JoAnn E. Manson, MD, DrPH, principal investigator of VITAL and
professor of medicine at Harvard Medical School, said the study has begun
enrollment and will test 2,000 IU of vitamin D per day in 20,000 U.S. men and
women during 5 years.
Vitamin D is a promising but as yet unproven nutrient for
prevention of cancer, CVD, diabetes, autoimmune diseases and other
outcomes, Manson told Endocrine Today. We should be
cautious not to jump on the bandwagon and recommend megadoses of this
supplement before VITAL and other trials can rigorously test both efficacy and
JoAnn E. Manson, MD, DrPH, is principal investigator of VITAL,
a trial that will evaluate the role of vitamin D in chronic disease prevention.
Photo courtesy of:
Brigham and Womens
Until those data are available, there are many unanswered questions
about the benefits of vitamin D: Are supplements the answer to vitamin D
deficiency? Are natural methods preferable? What are the optimal serum blood
levels of vitamin D? Is overdosing possible?
To clarify some of these questions, Endocrine Today spoke
with several leading vitamin D researchers, endocrinologists and a physician
who conducted vitamin D research at his own family practice.
From 1995 to 1999, the average number of papers with the term
vitamin D in the title or abstract was about 700 to 900 per year.
In contrast, the publication rate has drastically increased to more than 2,400
papers on vitamin D published just in 2009, according to Anthony W. Norman,
MD, distinguished professor of biochemistry and biomedical sciences at the
University of California, Riverside.
There has literally been an explosion of new data on vitamin
D, Norman told Endocrine Today.
In an Endocrine Today
Michael Kleerekoper, MD, estimated that major U.S. medical laboratories
have been performing upwards of 30,000 assays for 25-hydroxyvitamin D
As a result of the positive press surrounding vitamin D, physicians are
slowly getting on board and learning the benefits, William B. Grant,
PhD, a vitamin D researcher and founding director of the Sunlight,
Nutrition and Health Research Center (SUNARC) in San Francisco, said in an
Americans do not get enough vitamin D the benefits are
tremendous and the adverse effects are minimal, Grant said.
He referenced various studies that have shown benefits of vitamin D on
reduced risk for metabolic diseases, cancer, infectious diseases, autoimmune
diseases, CV diseases, fractures, congestive heart failure and periodontal
disease, to name a few. Most studies, however, were observational, not
James Lundblad, MD, PhD, said endocrinologists seem to be aware
of the positives associated with vitamin D.
However, they should be critical of excessive claims of
benefit, Lundblad, endocrinologist at Oregon Health & Science
University, said in an interview. There is a great deal of hype
surrounding the potential benefits of vitamin D replacement, and perhaps these
are overstated, particularly those within the range of moderate vitamin D
deficiency as defined by the newer proposed lower limit of normal of 30
Results of a study published in the Journal of the American Medical
Association in May showed an increased risk for falls and fractures tied to
a single, annual high dose of vitamin D among older women. These data go
against the plethora of other information that demonstrate benefits of vitamin
Could negative data such as these cause endocrinologists to consider
whether the benefits of vitamin D are overstated?
The list of positives for vitamin D is well-documented, but potential
negatives may not be understood. A possible danger in the absence of supporting
data is the perception that achieving even higher levels of vitamin D may
afford significant additional benefit, Lundblad said.
In my experience, providers do not routinely monitor for the
potential adverse effects of hypercalcemia, much less hypercalciuria. In my own
practice, however, I rarely see elevated vitamin D levels, and recommended
replacement regimens (up to 2,000 IU cholecalciferol per day) are well below
accepted limits, Lundblad said.
Bruce W. Hollis, PhD, director of pediatric nutritional sciences
at the Medical University of South Carolina, Charleston, has conducted vitamin
D research for more than 30 years. Fear of vitamin D overdose should not be an
area of concern for physicians because in all his years of experience he has
yet to see one, he said.
Hollis said the only known pathway to vitamin D toxicity is
hypercalciuria followed by hypercalcemia; however, he noted that neither has
been observed in larger studies on intakes up to 40,000 IU per day. Most
studies, however, have been short-term.
Our own NIH-sponsored, FDA-oversight trials have dosed pregnant
and lactating women with up to 6,000 IU per day for months and have not had a
single adverse event due to the vitamin D, Hollis said.
Also, no one has had a blood level that exceeded 100 ng/mL. Thus,
as long as a physician is not raising the level above 100 ng/mL, there will be
no problem, he added.
Several previous studies have also questioned whether excess vitamin D
causes kidney stones. A Womens Health Initiative (WHI) study in 2006
examined 36,282 women and found that those assigned to active calcium and
vitamin D had 17% more kidney stones compared with women assigned placebo (34
cases per 10,000 women vs. 29 cases per 10,000 women).
However, many experts believe it was more likely that the stones were
due to calcium rather than vitamin D in the combined supplement.
In April, the public health research organization Grassroots Health
hosted a seminar as part of its campaign to unveil the latest research on the
positives of vitamin D.
At the seminar, Hollis was part of a research team that presented data
showing that pregnant women taking vitamin D supplements during pregnancy
prevented preterm labor and births and infections. These data support previous
results that indicate vitamin D deficiency is an issue for pregnant women and
contradict popular belief in the 1950s and 1960s that vitamin D could cause
Hollis and colleagues randomly assigned 494 pregnant women at 12 to 16
weeks gestation to three treatment groups: 400 IU vitamin D per day until
delivery; 2,000 IU per day; and 4,000 IU per day. The women were evaluated
monthly for safety and potential complications such as preeclampsia,
infections, preterm labor/birth and gestational diabetes.
Carol Wagner, MD, professor of pediatrics at Medical University
of South Carolina, Charleston, and another researcher for the study, found no
adverse events related to vitamin D in any of the three arms of the study. In
fact, the greatest effects were found among women taking 4,000 IU of vitamin D
What was achieved in our high-dose group was sufficiency within
the physiologic range that is demonstrated in people who live in a sun-rich
environment with skin exposure, Wagner told Endocrine Today.
At the 13th Vitamin D Workshop in 2007 and again at a workshop in 2009,
Norman and more than 425 researchers from 32 countries concluded that although
the problem of insufficient vitamin D is globally understood, merely eating
vitamin D-rich foods is not adequate enough to solve the problem for most
adults. Wagner agreed and said studies such as this will help feed the momentum
to address a health issue of this magnitude.
Because of modern-day lifestyles and the concern for deleterious
effects of UVA, in particular, we have limited sunlight exposure that has led
to this epidemic in substrate vitamin D deficiency. Correction of that
deficiency state is sensible and can be approached with reason and careful
thought, Wagner said. All of us involved in this effort adhere to
the mantra of doing no harm.
Results of the double blind, placebo-controlled study published in the
May 12 issue of JAMA showed that 2,256 elderly women given a
single high dose of vitamin D once a year had 15% more falls and 26% more
fractures than the placebo group. This contradicts several other studies,
including the WHI study, which found that vitamin D prevented fractures.
Researchers at the University of Melbourne, Australia, assessed whether
a single, annual dose of 500,000 IU cholecalciferol administered orally to
women aged 70 years and older would improve adherence and reduce the risk for
falls and fracture over 3 to 5 years.
Anthony W. Norman
Women in the vitamin D group had 171 fractures compared with 135 in the
placebo group, and 837 women in the vitamin D group fell 2,892 times compared
with 769 women in the placebo group who fell 2,512 times.
This is a puzzling study, Norman said. He noted that only 5%
of the women included in the study had 25(OH)D levels determined. The levels
fell sharply after 3 months in the first year to a lower value, and in the
second year, the 25(OH)D levels fell to the approximate value the women had
before start of the study.
I am not sure that there can be a definitive outcome or conclusion
for this study, beyond that a single dose of 500,000 IU per year does not
maintain blood levels at a high enough level to support a major benefit in all
physiological systems that vitamin D can effect, Norman said.
Joseph Shaker, MD, an endocrinologist at Froedtert and Medical
College of Wisconsin, said the results are interesting because other studies
have shown a benefit of vitamin D in terms of muscle function and falls. In
these studies that show decreased falls with vitamin D, it is usually given at
lower, more frequent doses, such as 800 IU per day, Shaker said.
It is possible that the large dose of vitamin D given once yearly
could adversely affect the metabolism of vitamin D, Shaker said.
It is also possible that the large dose of vitamin D improved
physical performance resulting in more active patients with a greater chance to
fall. Another theory is that the high-dose vitamin D may have decreased the
rate of wintertime infections, resulting in more active patients during the
winter with increased opportunity for falls and fractures, he said.
Dave McCarthy, MD, said medical research on the high prevalence
of vitamin D deficiency motivated him to introduce the findings into his family
practice, and his patients have had a substantial reduction in influenza and
When combined with supplemental magnesium, vitamin D repletion has
dramatically changed my practice, said McCarthy, whose family practice is
affiliated with The Memorial Hospital of Belleville, Ill.
There are now very few patients with infections, and asthmatics
who are coming off medications are staying off of them. Elevations in blood
pressure now require many fewer medications, he said.
McCarthy has been employing these methods since February 2007, and
patient acceptance has been high. He said he checks each patients 25(OH)D
level and supplements to reach a target of 80 ng/mL in adults and children. Of
the first 1,500 patients McCarthy tested, 40% began with vitamin D levels less
than 20 ng/mL and 70% less than 35 ng/mL. Only 1% initially had values within
his target range.
According to McCarthy, his target range is based upon several factors:
- A lifeguard study that found vitamin D levels in the 70 ng/mL range
up to 100 ng/mL (natures level) were associated with no adverse
- Data in patients with breast cancer showing a reduction in the
incidence of new cancer with postulated 0 point at 80 ng/mL;
- Colon cancer data showing a reduction in the incidence of new cancer
(linear) with postulated 0 point at 75 ng/mL;
- More than 200 polymorphisms of the vitamin D receptor requiring
higher D levels to attain same desired outcomes;
- When a patient misses dosing, an attained level of 80 ng/mL gives the
patient an additional month of good levels off of vitamin D.
McCarthy said the optimal level of 25(OH)D still remains to be
determined with precision, as the peak effects have yet to be found.
The VITAL study is expected to shed light on the role of vitamin D in
chronic diseases prevention.
The randomized trial will test a dose of 2,000 IU per day among 20,000
eligible men aged 60 years and older and women aged 65 years and older without
a history of cancer, CVD or stroke.
In addition, the trial will assess the risk of hypercalcemia and
other biomarker changes in follow-up bloods, as well as study outcomes from
cancer to cognitive function to depression to autoimmune disorders, lead
investigator Manson said.
She and colleagues will explore whether vitamin D supplementation may be
able to reduce some of the health disparities seen by race and ethnicity. For
example, black Americans have a higher risk for vitamin D deficiency and a
greater frequency of diabetes, hypertension and certain types of cancer, she
We are excited about the potential of vitamin D to reduce this
health gap, but it is important to get answers from clinical trials before
recommending mega-doses of this supplement, she said.
On a larger scale, These low-cost supplements, if found to be
effective, have the potential of reducing the burden of chronic disease in this
country and throughout the world, Manson said.
More information about VITAL is available
Norman said it is now widely appreciated by vitamin D scientists that
50% of people in North America and Western Europe are vitamin D-insufficient,
and that in the rest of the world, two-thirds of the people are vitamin
D-insufficient or deficient.
Still, the need for further research is evident.
There is the emerging view that the relative daily intake of
vitamin D should be increased from the currently recommended 200 IU, 400 IU,
600 IU per day to a significantly higher level of 2,000 IU to 4,000 IU per day,
There is a conundrum. How can a physician of a government
recommend major increases in vitamin D intake, without appropriate
evidence-based research studies on very large groups, for example, 2,000 IU for
3 to 5 years, to ensure safety? Norman said.
Shaker said the higher doses that are now often recommended could have
unpredicted adverse effects over the long run. Unselected use of these much
higher doses may be based on over-interpretation of the literature, as well as
some of the recent information in the lay press about vitamin D.
Clearly, long-term, controlled clinical trials with vitamin D
would be useful in determining the benefits of vitamin D on multiple outcomes,
as well as determining any possible adverse effects, Shaker said.
Such studies may require a large number of patients followed for a long
period of time.
VITAL and future trials are expected to provide this information,
according to Manson.
As for the results of the high-dose falls study, Lundblad said the main
concern is that it may lead to reluctance on the part of some clinicians to
aggressively treat low vitamin D levels.
The study does, however, highlight the need for prospective,
randomized studies to reveal unanticipated consequences. The biological and
biochemical consequences of high-dose therapy are unclear but, possibly, are
related to high levels of vitamin D achieved transiently in this
experiment, Lundblad said.
If reproducible, we might rethink our strategy of relatively
high-dose episodic administration in favor of lower daily dosing,
The bottom line, according to Kleerekoper, is to be careful of the
currently available epidemiological evidence.
As he said in a slide presentation provided to Endocrine
Today, Our patients find all the new hot stuff in their morning
newspapers, the TV or their BlackBerry before you do. Neither they nor we can
put these new data into perspective; almost always you can find
conflicting conclusions. Nonetheless, we need to be aware of all of this and,
even though our time is our most precious commodity, we need to take the time
to keep up to date on these late-breaking health care statistics.
by Angelo Milone
For more information:
- Sanders KM. JAMA. 2010;303:1815-1822.
A recent study showed
negative effects of vitamin D supplementation, contradicting previous studies.
Could the benefits of vitamin D be overstated?