1. January 2015 3
30 minutes three days a week had less metabolic cost
for walking than their walking counterparts. This
improved metabolic efficiency protected them from
the age-related decline in “walking economy,” keeping
the runners like young (sedentary) adults, whereas
older walkers followed the same downward trend in
efficiency as older sedentary adults. The authors tie
this research into work showing that intense training
in older adults can increase muscular efficiency and
stop antagonistic muscle firing, two of the mechanisms
that are thought to be related to making runners less
metabolic cost for walking. So, it seems, this study
showed some quantifiable clinical effects, and there
was a plausible mechanism, perhaps enough for
clinicians to raise their eyebrows and give this serious
consideration.
Of course, as the authors mentioned, this trial
should be expanded in size, and its methodology
improved (beyond simply a cross-sectional analysis)
to definitively change the way we approach exercise
recommendations in this demographic. Until then,
it is a reminder to continually address this aspect of
whole person care; to reiterate the importance of some
form of activity for all patients; and to explore that an
increased intensity, when it can be safely done, may
have some benefits for older adults above and beyond
walking. n
REFERENCES
1. Office of Disease Prevention and Health Promotion. Physical Activity
Guidelines. Available at: www.health.gov/paguidelines. Accessed Dec.
16, 2014.
2. Centers for Disease Control and Prevention. Healthy weight — it’s
not a diet, it’s a lifestyle. Available at: www.cdc.gov/healthyweight/
physical_activity/index.html?s_cid=govD_dnpao_006. Accessed
December 18, 2014.
3. Wen CP, et al. Minimum amount of physical activity for reduced mor-
tality and extended life expectancy: A prospective cohort study. Lancet
2011;378:1244-1253.
DIETARY SUPPLEMENTS
ABSTRACT & COMMENTARY
Vitamin D Supplementation:
What’s the Verdict?
By Luke Fortney, MD
Wellness Programs Medical Director, Meriter Medical Group, Madison, WI
Dr. Fortney reports no financial relationships relevant to this field of study.
SYNOPSIS: Large-scale observation data indicate an inverse association with circulating vitamin D levels and risk of death due to all causes,
particularly cardiovascular and cancer-related death, while supplementation with vitamin D3 appears to reduce overall mortality among
older adults.
SOURCE: Chowdhury R, et al. Vitamin D and risk of cause specific death: Systemic review and meta-analysis of observational cohort and
randomised intervention studies. BMJ 2014;348:g1903. doi: 10.1136/bmj.g1903.
For the past 20 years, vitamin D has slowly and
steadily gained interest among the lay public and
researchers alike. Unlike the popular histories of
other vitamin supplements,1
vitamin D has shown
consistent and growing promise as an efficacious
health intervention for reduction of cardiovascular and
cancer-related death. More recently, this large systemic
review and meta-analysis of 73 observational cohort
studies involving nearly 900,000 participants, and of
22 randomized controlled trials (RCT) including more
than 30,000 participants, supports the argument that
that vitamin D is important for health and prevention.
The authors of this review conclude that there is an
inverse association of 25-hydroxyvitamin D serum
levels with risks of death due to cardiovascular disease,
cancer, and other causes. Similarly, supplementation
Summary Points
• Older runners have 7-10% less metabolic
cost for walking than older walkers.
• It is possible that running increases muscle
strength and reduces antagonistic muscle acti-
vation, accounting for some of this decreased
metabolic cost.
• These results have implications for exercise
training, and forestalling the morbidity that
occurs with impaired walking performance.

2. 4 Integrative Medicine Alert
with vitamin D3 also appears to reduce overall
mortality among the elderly. What remains unknown
is whether supplementation of vitamin D2 vs D3, in
what groups of people, at what stage of the lifecycle,
for how long, and at what optimal dose, may most
favorably effect morbidity and mortality outcomes.
n COMMENTARY
This large review and meta-analysis contributes further
evidence in favor of addressing vitamin D deficiency
(< 20 ng/mL) and insufficiency (20-30 ng/mL) among
most adults. In looking at 73 cohort studies comparing
low and normal vitamin D serum levels, as well as 22
randomized, controlled trials where vitamin D was
given alone vs placebo, the authors of this large and
thorough review report encouraging findings that
suggest moderate but significantly meaningful risk
reduction for all-cause mortality that may actually
be on par with other health risks such as smoking,
alcohol consumption, and physical inactivity.
Stepping back to look at the history of vitamin D
begins in the 19th century when vitamin D deficiency
was identified as a cause of rickets, particularly in
children living in industrialized urban areas. This
observation lead to a responsive public health
movement that began supplementing various foods
with vitamin D, which in turn resulted in decreased
health problems from vitamin D deficiency. More
recently, however, low vitamin D has been linked
with other conditions among people of all ages,
but especially the elderly, poor, and chronically ill.
However, more current research continues to show
that many young healthy individuals without any
identifiable risk factors were still found to have very
low levels of circulating vitamin D.2
The physiology and pathogenesis of vitamin
D metabolism and deficiency is complex and
involves multiple steps worth reviewing briefly (see
Figure). Activation begins with ingestion of either
ergocalciferol (D2 extracted from irradiated yeast and
plant sterols) or cholecalciferol (D3 obtained from oily
fish), or by UVB irradiation of 7-dehydrocholesterol
in the skin. These precursors then circulate to the liver,
where they are hydroxylated into 25-hydroxyvitamin
D (the preferred clinical laboratory test for vitamin
D). From there, 25-hydroxyvitamin D circulates to
the kidneys, where it is further hydroxylated into 1,25
dihydroxyvitamin D, which is the most metabolically
active form in the body.
Feedback loops involving absorption of calcium in the
intestines and calcium detection by the parathyroid
glands also play a key role in activating, mobilizing,
and maintaining vitamin D levels, which is important
for a host of biological processes such as cellular
growth and regulation among many others. What’s
more, there are approximately 3000 different binding
sites for vitamin D throughout the human genome,
and receptors are present in all human tissues,
indicating a wide range of known and yet unknown
functions.3
Risk factors for vitamin D deficiency
include age > 65 years, breastfeeding mothers, darkly
pigmented skin, insufficient sunlight exposure, certain
medications (e.g., antipsychotics, anticonvulsants, and
glucocorticosteroids), obesity, physical inactivity, liver
and kidney disease, other chronic illnesses, and low
socioeconomic status.4
What has been less clear in the past 10 years is what
role vitamin D plays in various other conditions such
as depression, chronic pain, cancer, hypertension,
diabetes, acute respiratory infections, and other
infections. Other clinical questions include who should
be screened for vitamin D deficiency/insufficiency, at
what times of the life cycle, and how often.
Returning to the review by Chowdury et al, the
strengths of this meta-analysis are numerous. First,
it sheds light on some of the most important public
health questions regarding vitamin D, namely: 1)
are low levels associated with any significant risk of
premature death; 2) does supplementing with vitamin
D improve mortality in meaningful ways; and 3) what
form of vitamin D (e.g., D2 or D3) is preferred?
This review is also large and broad. It included
analysis of more than 900,000 participants from both
an observational cohort-controlled perspective, as
Summary Points
• There appears to be a significant deleterious
role of low vitamin D levels in all-cause mor-
tality, while supplementation with vitamin D3
appears to be superior to D2 in prevention of
all-cause mortality among older adults.
• Overall evidence from almost 900,000 par-
ticipants in 26 different countries reveals an
inverse association of circulating vitamin D lev-
els with risk of all-cause mortality, particularly
death from cardiovascular disease and cancer.
• Supplementation with vitamin D3 vs D2 ap-
pears to significantly reduce overall mortality
among older adults.
• Despite associations with vitamin D and mor-
tality outcomes, highly convincing evidence
for widespread vitamin D supplementation is
currently lacking and further research is still
needed.

3. January 2015 5
well as the gold standard of 22 RCTs that compared
vitamin D supplementation alone vs placebo or no
treatment while controlling for obvious confounding
variables. While the downfall to many meta-analyses
is determining what studies to include and exclude,
this review is clear and convincing in identifying the
criteria used for inclusion and quality.
To start, more than 2700 studies were identified and
considered. After initial screening by two separate
and independent investigators, a final consensus on
only 95 of these was reached by involving a third
investigator. These studies were selected based on
strict inclusion criteria. Study-specific relative risks
were then determined and analyzed using random
effects models, and finally grouped by study and
population characteristics to finalize the results. This
methodological approach is very appropriate in this
setting, given the variability of participants (e.g., older
vs younger), sample sizes, and overall effects. For
comparison with previous reviews, this meta-analysis
involved 10 times as many participants and three times
as many mortality outcomes.
Overall, the principle findings from this review
generally concur with and advance those findings
from previous research studies. Unlike preceding
reviews, however, this large and rigorous analysis
only included RCTs that administered vitamin D,
thus controlling for effects from other supplements
and vitamins. This review also used pre-selected
vitamin D cutoffs before making any conclusions. In
comparing the bottom one-third and top one-third
of reported circulating 25-hydroxyvitamin D levels
among participants, there was a relative risk (RR) of
1.35 (95% confidence interval, 1.13-1.61) for death
from cardiovascular disease and 1.14 (1.01-1.29) for
death due to cancer for those participants with the
lowest serum levels of vitamin. Additionally, the RR
for non-vascular, non-cancer death and for all-cause
mortality was 1.30 (1.07-1.59) and 1.35 (1.22-1.49),
respectively (P values > 0.05 for all). These findings
are of particular importance given that heart disease,
cancer, and stroke are the number 1, 2, and 4 causes
of death, respectively, in the United States, according
to the Centers for Disease Control and Prevention,
accounting for more than 1.2 million deaths annually.5
By using population prevalence estimates of vitamin D
deficiency from this study, this means that 12.8% of all
deaths in the United States annually can be attributed
to vitamin D deficiency. In other words, each 10 ng/
mL decline of serum vitamin D concentration was
Figure 1: Physiology and Pathogenesis of Vitamin D Metabolism and Deficiency
7-dehydrocholesterol in skin Dietary vitamin D2
or D3
290 to 315 nm
of UVB radiation
Pre-vitamin D3
25-hydroxyvitamin D
1,25 dihydroxyvitamin D (activated)
Promotes calcium absorption
via intestines
Increased serum calcium
Liver
Adds OH Activates
kidneys
Activates
parathyroid
hormone
Increased
parathyroid
hormone
Low serum
calcium
Low serum
phosphorus
Adds OH

4. 6 Integrative Medicine Alert
associated with a 16% increased risk of all-cause
mortality.
Compared with other known risk factors of chronic
disease and death, the risk of death due to low
circulating vitamin D levels in the United States
appears to be substantial at 13% vs 20% for smoking,
11% for physical inactivity, and 9% for alcohol
consumption. It should also be pointed out that: 1)
most of the studies included in this review were also
controlled for variable lifestyle and diverse population
characteristics (e.g., low socioeconomic status,
insufficient sunlight exposure, poor diet, obesity, etc.);
and 2) pooled estimates remained unchanged when
further stratified and adjusted for these various lifestyle
factors that could have affected the results.
The authors appropriately point out that caution
should nonetheless be used before drawing firm
conclusions, in that most vitamin D studies have
only involved older individuals with a generally
higher rate of death due to comorbidities anyway,
and are relatively brief in terms of intervention and
observation timelines (generally 1 year or less).
They also emphasize the need for future RCTs over
substantially longer timeframes that involve non-
institutionalized general populations of significant
scale and diversity. It still remains unknown what
dose, type, and duration of supplementation may
be needed to better understand the broader range of
associated morbidity and mortality outcomes.
Before too much excitement is elicited from the
conclusions of this meta-analysis, it should be noted
that another recent, very large systematic review
concluded that despite the encouraging associations
between vitamin D and mortality outcomes, firm
universal conclusions and recommendations cannot
yet be made.6
Finally, the question of D2 vs D3 supplementation,
in terms of health benefit and disease prevention,
has long been unclear and debated. While the RCT
aspect of this review indicated no improved mortality
among older adults when given vitamin D, further
stratification of the data reveal an interesting and
encouraging trend. Supplementation with D3 was
found to significantly reduce all-cause mortality
by 11% (CI, 0.80-0.99, P < 0.05) compared to no
overall mortality effect or protection from D2. This
finding may be explained in part due to the fact that
D2 is less potent and biologically active than D3.7
Another possible explanation is the observation
that, in the absence of concomitant use of calcium
supplementation with D2, there is an accompanying
lower 25-hydroxyvitamin D concentration compared
to D3.8
Nonetheless, more work is needed to identify what
form of vitamin D supplementation is most efficient,
cost-effective, efficacious, and safe before additional
widespread supplementation recommendations can be
made. For the time being, the benefits appear to greatly
outweigh the risks for vitamin D supplementation,
when used appropriately. However, vitamin D toxicity
(> 150 ng/mL) can result from taking too much
vitamin D for too long (> 10,000 IU of D3 or
> 50,000 IU of D2 daily for > 3 months). Taking more
than 300,000 IU of vitamin D in 24 hours can also
be dangerous due to significant increases in serium
calcium levels. (See www.vitamindcouncil.org for more
information on vitamin D toxicity)
Recent guidelines from the National Institutes of
Health and the Institute of Medicine recommend
supplementing with 600-800 IU of vitamin D3 daily
for adults,9
while other medical conditions (e.g.,
eczema and heart disease) may require 1000-2000 IU
daily.10
Recognizing that there is a dose-dependent
increase of skin cancer risk with unprotected sunlight
exposure, a more natural form of boosting vitamin
D involves exposing the skin to sunlight (UVB) for
10-15 minutes a day for fair skinned people or up to
1-2 hours a day for very dark skinned people. More
specific information on sunlight therapy for vitamin
D production regarding skin types, latitude location,
time of day, and time of year can be found at www.
vitamindcouncil.org online. n
REFERENCES
1. Slatore CG, et al. Long-term use of supplemental multivitamins, vita-
min C, vitamin E, and folate does not reduce the risk of lung cancer.
Am J Respir Crit Care Med 2008;177:524-530.
2. Tangpricha V, et al. Vitamin D insufficiency among free-living healthy
young adults. Am J Med 2002;112:659-662.
3. Ramagopalan SV, et al. A ChIP-seq defined genome-wide map of
vitamin D receptor binding: Associations with disease and evolution.
Genome Res 2010;20:1352-1360.
4. Bordelon P, et al. Recognition and management of Vitamin D defi-
ciency. Am Fam Physician 2009;80:841-846.
5. Centers for Disease Control and Prevention. Leading Causes of
Death. Available at: http://www.cdc.gov/nchs/fastats/leading-causes-of-
death.htm. Accessed Dec. 10, 2014.
6. Theodoratou E, et al. Vitamin D and multiple health outcomes: Um-
brella review of systematic reviewed and meta-analyses of observa-
tional studies and randomised trials. BMJ 2014;348:g2035.
7. Armas LA, et al. Vitamin D2 is much less effective than vitamin D3 in
humans. J Clin Endocrinol Metab 2004;89:5387-5391.
8. Autier P, et al. A systematic review: Influence of vitamin D supplemen-
tation on serum 25-hydroxyvitamin D concentration. J Clin Endocrinol
Metab 2012;97:2606-2613.
9. National Institites of Health. Office of Dietary Supplements. Vitamin D.
Fact Sheet for Health Professionals. Available at: http://ods.od.nih.gov/
factsheets/VitaminD-HealthProfessional/. Accessed Dec. 14, 2014.
10. Mayo Clinic. Vitamin D. Available at: http://www.mayoclinic.org/
drugs-supplements/vitamin-d/dosing/hrb-20060400. Accessed Dec.
14, 2014.