Vitamin D _ NEJMGroup_Collection

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Vitamin DTo Supplement, orNot to Supplement?

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VITAMIN D COLLECTION

Too often in medicine (and life) definitive answers prove elusive. Having some guidance allows

us to proceed down an uncertain road. Our collections are meant to provide such guidance, and

so we begin with vitamin D — a topic that confuses and confounds.

The thrust of this collection addresses topics relevant to non-specific vitamin D supplementation

in broad populations who don’t have symptoms clearly known to reflect deficiency (e.g., bone

pain not otherwise explained) or conditions known to be associated with low vitamin D levels

(e.g., gastrointestinal malabsorption). Obviously, clinicians should measure vitamin D levels in

those sorts of cases.

Observational studies have looked for — and discovered — correlations between various chronicdiseases and low vitamin D levels, but these are generally plagued by not being able to establish

causality with certainty. Short-term randomized trials have asked whether supplementation prevents

various conditions, ranging from upper respiratory infections to asthma exacerbations to progres-

sion of knee osteoarthritis. These trials have generally found no benefit from supplementation.

An ongoing trial — the VITAL study (NCT01169259) — may well settle the question of whether

to supplement routinely or not. In that study, some 26,000 people aged 50 and older are receiving

2000 IU of vitamin D daily or placebo to determine whether supplementation can lower the

incidence of cancer or cardiovascular disease. Unfortunately, the results are still about 5 years

away. So, although vitamin D’s importance to health is unquestioned, no one has shown exactly

how much the human body requires or exactly who would benefit from routine supplementation.

The collection includes articles from NEJM Journal Watch, the New England Journal of Medicine , and

Physician’s First Watch. (The editors of NEJM Journal Watch survey, summarize, and comment on

studies from a wide range of journals; Physician’s First Watch is our news arm.)

Our selection raises some questions that cannot yet be answered definitively. Nevertheless, we

believe that this material will help practicing clinicians navigate the uncertainty and controversy

surrounding vitamin D with more confidence.

— Joe Elia

Contributing writer, Physician’s First Watch

Host, Clinical Conversations

— Allan S. Brett, M.D.

Editor-in-chief, NEJM Journal Watch General Medicine

Professor of Medicine,

University of South Carolina School of Medicine

— Clifford J. Rosen, M.D.

Associate Editor, New England Journal of Medicine

Director of Clinical and Translational Research,

Maine Medical Center

July 2015

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Back to Table of Contents

Clinical Collections — Vitamin D

14 Revisiting Variability in Measurement of Vitamin D Levels On average, serum 25- hydroxyvitamin D levels differed by 5 ng/mL across two assays.

NEJM Journal Watch General Medicine Apr 10, 2012

What’s the Threshold for Serum 25-OH Vitamin D Levels below Which Thereis an Association with Lower Bone Density or Abnormalities in Bone Turnover?

15 At What Level of Vitamin D Does Fracture Risk Rise? In older men, fracture risk was elevated only among those with serum 25-hydroxyvitamin D levels


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Source: NEJM Journal Watch



What Does the U.S. Preventive Services Task Force (USPSTF) Have to Sayabout Screening for Vitamin D Deficiency in the General Population?

23 USPSTF: Evidence Is Insufficient to Recommend Routine Screening for Vitamin DDeficiency

Physician’s First Watch Jun 24, 2014

FINAL OVERVIEW AND LESSONS FROM THE CLINIC

25 NEJM Clinical Practice: Vitamin D Insufficiency New England Journal of Medicine Jan 20, 2011

32 Correspondence: Vitamin D Insufficiency New England Journal of Medicine Apr 7, 2011



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Clinical Collections — Vitamin D Source: Te New England Journal of Medicine

WHAT’S THE BOTTOM LINE ON VITAMIN D SUPPLEMENTS?

The VITAL Study may well settle the question of whether to supplement or not. In that study, some

26,000 men and women aged 50 and older are receiving vitamin D supplements or omega-3 fatty acids (or

both, or placebos) to determine whether they show a change in risk for cancer and cardiovascular disease.

Unfortunately, the VITAL Study’s results are roughly 5 years away.

The watchword here is “wait,” in the meantime we have some information to help you cope.

6

Skin

Liver

Kidney

Food(vitamins D2 and D3)

Provitamin D3 Previtamin D3

Vitamin D3

25-Hydroxylase (CYP2R1)

24-Hydroxylase(CYP24R1)

1α-Hydroxylase(CYP27B1)

25(OH)D3

Increased PTH,decreasedphosphate

FGF-23 Calcitriol

Biologic Activity

24,25(OH)2D3

– +

Sunlight

+ ––

l

:

i

i l

i

Figure 1. Synthesis and Metabolism of Vitamin D.

Vitamin D is initially generated in the skin from the non-

enzymatic conversion of provitamin D3 to previtamin D3.Dietary intake of vitamin D is usually relatively limited,

since few foods, with the exception of certain kinds of

fish, contain sizable amounts; supplements are com-

monly used. Vitamin D is either stored in adipose tis-sue or converted in the liver by the enzyme 25-hydroxy-

lase to 25-hydroxyvitamin D3 (25[OH]D3), the form

that circulates in the highest concentration and reflectssolar and dietary exposure. It is converted to the active

metabolite, 1,25-dihydroxyvitamin D (1,25[OH]2D), or

calcitriol, in the kidney, although other tissues have1α-hydroxylase enzymatic activity. The synthesis of

calcitriol is enhanced (+) by increasing levels of para-

thyroid hormone (PTH), which rise in response to lowerlevels of serum calcium. Reduced levels of serum phos-

phate can also increase (+) the production of calcitriol.

Its synthesis is suppressed (–) by the production of fi-broblast growth factor 23 (FGF-23), which is secreted

by osteocytes in the bone matrix. Calcitriol inhibits the

activity of 1α-hydroxylase (CYP27B1) and stimulates the

activity of 24-hydroxylase (CYP24R1), an enzyme that pro-motes production of 24,25(OH)

2D3, a vitamin D prod-

uct that is not biologically active. In CYP2R1, CYP27B1,

and CYP24R1, CYP denotes cytochrome P.

Source: NEJM Clinical Practice ar ticle“Vitamin D Insuff iciency” on page 26



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Vitamin D Supplementation Prevents FracturesA meta-analysis suggests benefit at a dose of >800 IU daily, but factors relating to treatment adherencecould have biased the results.

Bischoff-Ferrari HA et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 2012 Jul 5; 367:40.

( http://dx.doi.org/10.1056/NEJMoa1109617)

Heaney RP. Vitamin D — Baseline status and effective dose. N Engl J Med 2012 Jul 5; 367:77. ( http://dx.doi.org/10.1056/ NEJMe1206858)

ARTICLE SUMMARY

Clinical trials have not consistently confirmed that vitamin D supplementation in older adults prevents fractures.

To reconcile conflicting data, researchers pooled participant-level data from 11 randomized controlled trials of

vitamin D supplementation that involved 31,000 older people (age, ≥65).

In intent-to- treat analyses, vitamin D supplementation lowered risks for hip fracture (hazard ratio, 0.90; P=0.07)

and any nonvertebral fracture (HR, 0.93; P=0.03), but these reductions were not significant (for statistical rea-

sons, a P -value of 0.0125 was considered significant). However, the researchers conducted additional

analyses that incorporated treatment adherence and supplement use outside the trial: Participants in the highest

quartile of daily vitamin D intake (median, 800 IU; range, 792–2000) did have significantly lower risks for both

hip fracture (HR, 0.70) and any nonvertebral fracture (HR, 0.86) , compared with controls. In contrast, partici-

pants in the lowest three quartiles did not benefit from vitamin D supplementation. Some trials also involved

calcium supplementation, but the vitamin D findings were independent of additional calcium intake. Vertebral

fractures were not documented consistently in these trials.

COMMENT

These data suggest a threshold dose of about 800 IU of vitamin D daily for fracture prevention in older adults. The

pooling of participant-level data, plus the incorporation of information on adherence and supplement use outside

the trial, distinguish this analysis from previous ones. However, the departure from intent-to-treat analysis could

be a problem here. The subgroup with the highest vitamin D intake was compared with all controls; thus, the

analysis probably compared a high-adherence population to a mixed-adherence population and, if adherence is amarker for better health or healthier behaviors, this fact could confound the results. An editorialist adds that, for

any given dose of supplemental vitamin D, a person with baseline deficiency is more likely to benefit than a person

whose baseline vitamin D status is adequate.

— Allan S. Brett, MD

University of South Carolina School of Medicine, Columbia

NEJM Journal Watch General Medicine , published July 10,2012

WHAT CAN VITAMIN D DO, AND WHAT CAN’T IT DO?

Does Vitamin D Supplementation Lower Risk of Fractures?

Although the meta-analysis summarized below suggests that it does, the results were generally of borderline

significance — and thus not 100 percent decisive.

http://www.jwatch.org/cgi/content/full/2012/0/JW201207100000001?ijkey=fjSFnjqr7nHk.&keytype=ref&siteid=jwatchhttp://www.nejmgroup.org/http://www.jwatch.org/cgi/content/full/2012/0/JW201207100000001?ijkey=fjSFnjqr7nHk.&keytype=ref&siteid=jwatch


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When It Comes to Bone, Vitamin D Supplementation Falls ShortIn a large meta-analysis, vitamin D supplementation generally did not increase bone-mineral density.

Reid IR et al. Effects of vitamin D supplements on bone mineral density: A systematic review and meta-analysis. Lancet 2013 Oct 11;

[e-pub ahead of print]. ( http://dx.doi.org/10.1016/S0140-6736(13)61647-5 )

ARTICLE SUMMARY

Calcium supplements, which are taken by nearly half of U.S. adults for skeletal benefits, often include vitamin D.

However, the role of vitamin D supplementation itself in maintaining bone quality remains unclear: Vitamin D

supplements have not lowered fracture risk, and their effect on bone-mineral density (BMD) has varied. In a

meta-analysis, investigators combined data from 23 randomized controlled trials (4082 adult participants; 92%

women) in which BMD was a measured outcome and in which inclusion or dose of vitamin D varied. Studiesdiffered in patients’ mean baseline 25-hydroxyvitamin D level, vitamin D dose and duration, and concomitant

interventions (primarily calcium supplementation).

Patients who took vitamin D supplements had significantly greater increases in BMD at the femoral neck but not

at the total hip, lumbar spine, forearm, or total body. Vitamin D supplementation was associated with significant-

ly greater increases in BMD at the total hip in studies where mean baseline 25-hydroxyvitamin D level was 20 ng/mL do not require supplementation.

— Bruce Soloway, MD

Montefiore Medical Center, New York

NEJM Journal Watch General Medicine , published October 22, 2013

Does Vitamin D Supplementation Improve Bone Density?

http://www.jwatch.org/na32572/2013/10/22/when-it-comes-bone-vitamin-d-supplementation-falls-shorthttp://dx.doi.org/10.1016/S0140-6736(13)61647-5http://www.nejmgroup.org/http://dx.doi.org/10.1016/S0140-6736(13)61647-5http://www.jwatch.org/na32572/2013/10/22/when-it-comes-bone-vitamin-d-supplementation-falls-short


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Vitamin D Appears to Prevent Falls in Some High-Risk SubgroupsThe benefit appeared limited to those who received >800 IU of vitamin D daily.

Murad MH et al. The effect of vitamin D on falls: A systematic review and meta-analysis. J Clin Endocrinol Metab 2011 Oct;

96:2997. (http://dx.doi.org/10.1210/jc.2011-1193)

ARTICLE SUMMARY

Some, but not all, studies have shown that vitamin D supplementation reduces risk for falls in elders, presumably

through direct effects on muscle function. Researchers performed this meta-analysis of 26 randomized controlled

trials of vitamin D supplementation that reported falling as one outcome. The mean age of the 46,000 participants

was 76, 78% of participants were women, and median duration of vitamin D administration was 1 year. Baseline

risk for falling was high in these trials.

Vitamin D was associated with a significant reduction in risk for falling (odds ratio for risk of at least one fall,

0.86). In prespecified subgroup analyses, this benefit was seen primari ly in patients who also received calcium

supplementation and in those with vitamin D deficiency at baseline (but definitions of deficiency varied across

studies). Although the benefit appeared limited to those who received >800 IU of vitamin D daily (compared

with lower doses), the interaction between dose and falls did not reach statistical significance.

COMMENT

This analysis suggests that vitamin D supplementation — administered with calcium — reduces risk for falling,

particularly among older vitamin D– deficient women who are at high baseline risk for fall ing. The findings thus

support selective use of vitamin D in such patients. However, the authors believe that the quality of the evidence is

low to moderate due to publication bias, heterogeneity across studies, and several other factors.



NEJM Journal Watch General Medicine , published October 27, 2011

Does Vitamin D Supplementation Prevent Falls in Elderly People?

Based on results of some clinical trials, there is general belief that vitamin D supplements reduce risk of falls

in elderly patients — presumably through an effect on muscle function. Yet even here, the evidence is con-

troversial. For example, the meta-analysis summarized on this page suggested a statistically significant 14%

reduction in falls among patients receiving vitamin D treatment, while the meta-analysis on the next page

showed a 5% reduction that was not significant. If any benefit exists, it is likely to be relatively modest and

limited to vitamin-D-deficient patients with high baseline risk for falling.

http://www.jwatch.org/cgi/content/full/2011/0/JW201110270000006?ijkey=927IpU0ljl6WY&keytype=ref&siteid=jwatchhttp://www.nejmgroup.org/http://www.jwatch.org/cgi/content/full/2011/0/JW201110270000006?ijkey=927IpU0ljl6WY&keytype=ref&siteid=jwatch


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Clinical Collections — Vitamin D Source: NEJM Physician’s First Watch

No Effect of Vitamin D Supplements for Fall Risk

Boland MJ et al. Vitamin D supplementation and falls: a trial sequential meta-analyses. Lancet Diabetes Endocrinol 2014; 2:573.

(http://www.thelancet.com/journals/landia/article/PIIS2213-8587%2814%2970068-3/abstract)

ARTICLE SUMMARY

Vitamin D supplementation does not appear to reduce the risk for falls in older adults, a trial sequential analysisin the Lancet Diabetes & Endocrinology finds. This is contrary to guidance from the U.S. Preventive Services Task

Force.

Nearly 30,000 older adults participated in 20 randomized trials that looked at the effect of vitamin D supplemen-

tation — with or without calcium — on the risk for falls. Vitamin D supplementation did not reduce the incidence

of falls by 15% or more (the prespecified threshold for clinical relevance). Calcium also had no effect.

The authors write that there is “little justification” for using vitamin D for fall prevention. Commentators con-

clude that until a large trial is conducted among adults who are particularly vulnerable to falls, “we are left with

uncertainty about the benefits of vitamin D supplementation for reduction in fall risk.”

— Kelly Young

Physician’s First Watch , published April 24, 2014

http://www.jwatch.org/fw108748/2014/04/24/no-effect-vitamin-d-supplements-fall-riskhttp://www.nejmgroup.org/http://www.jwatch.org/fw108748/2014/04/24/no-effect-vitamin-d-supplements-fall-risk


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No Benefit of Vitamin D Supplementation for Knee OsteoarthritisA 2-year study might have been too short, but results still are discouraging.

McAlindon T et al. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with

symptomatic osteoarthritis: A randomized controlled trial. JAMA 2013 Jan 9; 309:155. (http://jama.jamanetwork.com/

article.aspx?articleid=1556148)

ARTICLE SUMMARYDisruption of normal bone architecture in knee osteoarthritis (OA), combined with certain epidemiologic obser-

vations, led investigators to study the potential benefit of vitamin D supplementation in 146 adults with knee OA

(mean age, 63; mean baseline 25-hydroxyvitamin D [25(OH)D] level, 22 ng/mL; most with knee malalignment

and moderate-to-severe joint space narrowing and sclerosis). Participants were randomized to cholecalciferol

(vitamin D3; 2000 IU daily) or placebo. Dosages in the intervention group were adjusted to achieve 25(OH)D

levels >36 ng/mL; doses as high as 6000 –8000 IU daily were required in several participants.

More than 80% of each group completed the 2-year trial, at which time knee pain was diminished slightly in both

groups. No difference was found between the groups in pain, function, or loss of cartilage volume.

COMMENT

Perhaps 2 years was too little time, or the participants’ baseline vitamin D levels were not low enough, or their os-teoarthritis was too severe to permit detection of benefit — still, epidemiologic studies published during this study

were less positive than those that inspired it in the first place. Although bone metabolism was the biological basis

for exploring the benefit of vitamin D on knee OA, an alternative explanation that merits further study is the ef-

fect of vitamin D on neuromuscular fitness (which might help protect the knee before or during the onset of OA).

— Thomas L. Schwenk, MD

University of Nevada School of Medicine

NEJM Journal Watch General Medicine , published January 15, 2013

Is There Evidence that Vitamin D Supplementation Improves Nonspecific Pain?

In one trial, supplements didn’t improve knee pain; in another trial, supplements didn’t improve diffuse

musculoskeletal pain; and in an observational study, low vitamin D levels were not highly correlated with back

or lower-extremity pain.

http://www.jwatch.org/jw201301150000002/2013/01/15/no-benefit-vitamin-d-supplementation-knee?ijkey=RlGofjRr5SA9c&keytype=ref&siteid=jwatch&variant=full-texthttp://www.nejmgroup.org/http://www.jwatch.org/jw201301150000002/2013/01/15/no-benefit-vitamin-d-supplementation-knee?ijkey=RlGofjRr5SA9c&keytype=ref&siteid=jwatch&variant=full-text


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Are Low Vitamin D Levels Associated with Nonspecific Pain?The results of two studies argue against any simple relation between diffuse pain and vitamin Ddeficiency.

Hicks GE et al. Associations between vitamin D status and pain in older adults: The Invecchiare in Chianti Study. J Am Geriatr Soc

2008 May; 56:785.

Warner AE and Arnspiger SA. Diffuse musculoskeletal pain is not associated with low vitamin D levels or improved by treatment with

vitamin D. J Clin Rheumatol 2008 Feb; 14:12.

ARTICLE SUMMARY

Observational data have suggested that vitamin D deficiency might be a common cause of otherwise unexplained

musculoskeletal pain ( Mayo Clin Proc 2003 Dec; 78:1463). In two new studies, researchers addressed this problem.

In a cross-sectional population-based study, researchers examined the relation between vitamin D status and pain

in the back, hips, knees, and feet in 958 randomly selected older adults (age, ≥65) in Italy. Women with low levels

of 25-hydroxyvitamin D (


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Measuring Serum Vitamin D Is ProblematicClinicians should be cautious about drawing conclusions from a single 25-OHD measurement.

Binkley N et al. Assay variation confounds the diagnosis of hypovitaminosis D: A call for standardization. J Clin Endocrinol Metab

2004 Jul; 89:3152-7.

Hollis BW. The determination of circulating 25-hydroxyvitamin D: No easy task. J Clin Endocrinol Metab 2004 Jul; 89:3149-51.

ARTICLE SUMMARY

Data suggest that vitamin D status is suboptimal among many adults. Accordingly, some experts advise that clini-

cians measure patients’ serum 25-hydroxyvitamin D (25-OHD) levels to guide supplementation. How accurate

are such measurements? Researchers approached this question in several ways:

• Serum from 59 postmenopausal women was sent to either of two national laboratories. In one laboratory, nearly

all levels were higher than 30 ng/mL; in the other, nearly all levels were lower than 30 ng/mL.

• Serum from each of 10 healthy young adults was sent to six different commercial and research laboratories.

One lab measured 25-OHD levels using the gold standard method (high-pressure liquid chromatography); the

other five used radioimmunoassays and chemiluminescent assays. The group’s mean 25-OHD level ranged from

17 ng/mL to 36 ng/mL, depending on the laboratory.

• These same 10 specimens were “spiked” with 20 ng/mL of additional 25-OHD; in the gold-standard lab, spiking

led to an appropriate mean 18 ng/mL increment in the serum level, but the mean increment was as small as

8 ng/mL in another lab.

COMMENT

Because of substantial variation in laboratory measurement of 25- hydroxyvitamin D levels, accurate diagnosis

of hypovitaminosis D is problematic. Until better standardization is achieved, clinicians should be cautious about

drawing conclusions from a single 25-OHD measurement. An editorialist discusses some of the reasons why

measuring vitamin D accurately is difficult. — Allan S. Brett, MD


NEJM Journal Watch General Medicine , published August 13, 2004

WHAT ABOUT VITAMIN D LEVELS?

How Accurate Are the Measurements?

We tend to assume that laboratory measurements of 25-hydroxyvitamin D are accurate, but studies show that

results can vary across labs — sometimes substantially. There’s no evidence favoring serial measurements of

vitamin D; but if that’s done, we should try to use the same lab each time, and we shouldn’t make too much

of small fluctuations in blood levels.

http://www.jwatch.org/jw200408130000002/2004/08/13/measuring-serum-vitamin-d-problematic?ijkey=gpMNVGfSLljhY&keytype=ref&siteid=jwatch&variant=full-texthttp://www.nejmgroup.org/http://www.jwatch.org/jw200408130000002/2004/08/13/measuring-serum-vitamin-d-problematic?ijkey=gpMNVGfSLljhY&keytype=ref&siteid=jwatch&variant=full-text


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Revisiting Variability in Measurement of Vitamin D LevelsOn average, serum 25-hydroxyvitamin D levels differed by 5 ng/mL across two assays.

Barake M et al. 25-hydroxyvitamin D assay variations and impact on clinical decision making. J Clin Endocrinol Metab 2012 Mar;

97:835. ( http://dx.doi.org/10.1210/jc.2011-2584)

ARTICLE SUMMARY

A 2004 study demonstrated that measurements of serum 25-hydroxyvitamin D (25[OH]D) levels are considerably

variable across different assays. Now, researchers at Lebanon’s American University of Beirut have revisited this

issue. They measured 25(OH)D levels in each of 494 adults using both a radioimmunoassay (Immunodiagnostic

Systems RIA; Boldon, U.K.) and an automated chemiluminescent immunoassay (DiaSorin Liaison; Stillwater,

Minnesota).

Mean 25(OH)D levels were significantly lower with DiaSorin Liaison than with IDS-RIA (21 vs. 26 ng/mL), and

the proportion of people with serum levels measuring


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At What Level of Vitamin D Does Fracture Risk Rise?In older men, fracture risk was elevated only among those with serum 25-hydroxyvitamin D levels


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Vitamin D Levels and Bone Loss in Older MenIn men older than 75, 25(OH)D levels lower than 20 ng/mL were associated with accelerated bone loss.

Ensrud KE et al. Serum 25-hydroxyvitamin D levels and rate of hip bone loss in older men. J Clin Endocrinol Metab 2009 Aug;

94:2773.

ARTICLE SUMMARY

Osteoporotic Fractures in Men is a prospective study of healthy aging — with a focus on osteoporosis — in

6000 older U.S. men (age, ≥65). In a previous report from that study, one quarter of participants exhibited

25 hydroxyvitamin D [25(OH)D] levels lower than 20 ng/mL. Now, the researchers report on the relation

between vitamin D levels and bone loss.

About 1300 participants underwent baseline measurement of serum 25(OH)D and bone-mineral density at the

hip, followed by repeat bone density testing about 4 years later. After adjustment for potentially confounding vari-

ables, men with baseline 25(OH)D levels


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Another Comparison of Vitamin D2 and Vitamin D

3 Supplementation

D3 was somewhat more effective in raising serum levels of total 25-hydroxyvitamin D.

Lehmann U et al. Bioavailability of vitamin D2 and D

3 in healthy volunteers, a randomized placebo-controlled trial.

J Clin Endocrinol Metab 2013 Nov; 98:4339. (http://dx.doi.org/10.1210/jc.2012-4287)

ARTICLE SUMMARY

Vitamin D that is produced naturally from sunlight exposure is vitamin D3. However, both D

3 (cholecalciferol)

and D2 (ergocalciferol) are available as supplements. In the U.S., supplemental vitamin D

2 is usually a 50,000 IU

prescription medication, whereas D3 is available over-the- counter in various doses. With D

3 supplementation,

essentially all measured serum 25-hydroxyvitamin D (25[OH]D) is hydroxylated D3

. In contrast, with D2

supple-

mentation, total serum 25(OH)D is the sum of supplemental D2 plus endogenous D

3. Some, but not all, studies

have suggested that supplemental D3 raises total serum 25(OH)D more than supplemental D

2 does.

Researchers randomized 107 healthy volunteers in a northern German community to receive daily 2000 IU doses

of vitamin D2, vitamin D

3, or placebo during winter months. At 8 weeks, the mean increase in total 25(OH)D was

significantly greater with D3 supplementation than with D

2 supplementation (18 vs. 12 ng/mL). Interestingly, the

D2 group’s 12 ng/mL increase in total 25(OH) D reflected the net result of a 20 ng/mL increase in D

2

but an 8 ng/mL decrease in D3.

COMMENT

In this study, vitamin D3 supplementation raised total serum 25-hydroxyvitamin D levels more effectively than did

vitamin D2

supplementation. D2

supplementation appeared to suppress endogenous D3

, thus offsetting some of the

expected increment in total serum 25(OH)D. The authors conclude that D3 should be used for supplementation.



NEJM Journal Watch General Medicine , published December 12, 2013

Is There Any Difference between Giving D2 or D

3 Supplements?

http://www.jwatch.org/cgi/content/full/2013/dec12_3/NA33047?ijkey=I1xcD86i8qIFM&keytype=ref&siteid=jwatchhttp://www.jwatch.org/cgi/content/full/2013/dec12_3/NA33047?ijkey=I1xcD86i8qIFM&keytype=ref&siteid=jwatchhttp://www.jwatch.org/cgi/content/full/2013/dec12_3/NA33047?ijkey=I1xcD86i8qIFM&keytype=ref&siteid=jwatchhttp://www.nejmgroup.org/http://www.jwatch.org/cgi/content/full/2013/dec12_3/NA33047?ijkey=I1xcD86i8qIFM&keytype=ref&siteid=jwatch


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Which Vitamin D Supplement Boosts Levels More — D2 or D

3?

D3 (cholecalciferol) has the edge.

Binkley N et al. Evaluation of ergocalciferol or cholecalciferol dosing, 1600 IU daily or 50,000 IU monthly in older adults.

J Clin Endocrinol Metab 2011 Apr; 96:981. ( http://dx.doi.org/10.1210/jc.2010-0015)

Heaney RP et al. Vitamin D3 is more potent than vitamin D2 in humans. J Clin Endocrinol Metab 2011 Mar; 96:E447.( http://dx.doi.org/10.1210/jc.2010-2230)

ARTICLE SUMMARY

In the U.S., vitamin D supplements are available over-the- counter as D3 (cholecalciferol; usually in 400–1000 IU

doses) and by prescription as vitamin D2 (ergocalciferol; Drisdol and others; often prescribed at 50,000 IU doses).

In previous research, D3 supplements raised blood levels of 25-hydroxyvitamin D (25[OH]D) more than D

2 did at

equivalent doses. In two new studies, researchers reach the same conclusion.

In a randomized trial, 64 older adults received daily D2 or D

3 (1600 IU) or monthly D

2 or D

3 (50,000 IU). Mean

25(OH)D levels were about 33 ng/mL at baseline. At 1 year, mean 25(OH)D levels had increased by 9 ng/mL in both

the daily and monthly D3 groups; mean levels increased by 6 and 4 ng/mL in the daily and monthly D

2 groups, re-

spectively. The increase was significantly greater with D3 than with D2.

In another randomized trial, 33 adults received 50,000 IU weekly of either D2 or D

3; mean baseline 25(OH)D was

about 28 ng/mL. After 12 weeks, increases in 25(OH)D levels were significantly greater with D3 than with D

2 (in-

crease from baseline, about 40 vs. 22 ng/mL) .

COMMENT

On average, oral supplemental vitamin D3 — the form made naturally after exposure to sunlight — raises 25(OH)

D blood levels more than does vitamin D2. The authors of the second study conclude, with good reason, that D

3

is preferable for correcting vitamin D deficiency. Note, however, that U.S. clinicians often give D2 by prescription

to vitamin D– deficient patients: One reason might be the availability of high-dose D2 capsules that can be taken

weekly or monthly; another might be a mistaken impression that prescription D2 is “stronger” than an equivalent

dose of D3.



NEJM Journal Watch General Medicine , published April 26, 2011

http://www.jwatch.org/cgi/content/full/2011/0/JW201104260000008?ijkey=nl9JitqCxFBHY&keytype=ref&siteid=jwatchhttp://www.jwatch.org/cgi/content/full/2011/0/JW201104260000008?ijkey=nl9JitqCxFBHY&keytype=ref&siteid=jwatchhttp://www.jwatch.org/cgi/content/full/2011/0/JW201104260000008?ijkey=nl9JitqCxFBHY&keytype=ref&siteid=jwatchhttp://www.nejmgroup.org/http://www.jwatch.org/cgi/content/full/2011/0/JW201104260000008?ijkey=nl9JitqCxFBHY&keytype=ref&siteid=jwatch


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Response to Oral Vitamin D Supplementation in Obese AdultsDespite a dose-response effect on average, individual responses vary widely.

Drincic A et al. 25-hydroxyvitamin D response to graded vitamin D3 supplementation among obese adults. J Clin Endocrinol Metab

2013 Dec; 98:4845. (http://dx.doi.org/10.1210/jc.2012-4103)

ARTICLE SUMMARY

On average, obese people have lower serum vitamin D levels and require higher doses of supplemental vitamin D

to correct deficiency than do nonobese people. To examine dose-response effects, researchers randomized 62

adults with high body-mass index (BMI; (30–58 kg/m2) to receive 1000, 5000, or 10,000 IU of oral vitamin D3

daily for 5 months. The study was conducted during winter months in Nebraska (when skin synthesis of vitamin

D is minimal ). At baseline, mean serum hydroxyvitamin D (25[OH]D) level was 23 ng/mL.

A dose-response effect was noted. Mean serum 25( OH)D levels increased by 12 ng/mL, 28 ng/mL, and 48 ng/mL

in the 1000, 5000, and 10,000 IU groups, respectively. However, participants varied widely in individual responses:

The ranges of increase in serum 25(OH)D in the three dosing groups were 2 to 39 ng/mL, 13 to 46 ng/mL, and 16

to 83 ng/mL, respectively. The incremental response to a given vitamin D dose varied inversely with BMI, but vi-

tamin D dose was more important than BMI in predicting response to supplementation.

COMMENT

This study provides information on the response to vitamin D supplementation in obese patients. The wide range

of individual responses might reflect genetic variability in binding proteins and in vitamin D hydroxylation. In

comparing these results to previous findings in nonobese cohorts, the authors estimate that the response to a given

vitamin D dose is roughly 30% lower in obese than in nonobese people — presumably because vitamin D is diluted

in body tissue mass.



NEJM Journal Watch General Medicine , published January 30, 2014

Is There Any Difference in the Effect of Supplements on Vitamin D Levels in Obese

versus Non-Obese People?

http://www.jwatch.org/cgi/content/full/2014/jan30_4/NA33376?ijkey=Sd9w4MhuYMvCo&keytype=ref&siteid=jwatchhttp://www.nejmgroup.org/http://www.jwatch.org/cgi/content/full/2014/jan30_4/NA33376?ijkey=Sd9w4MhuYMvCo&keytype=ref&siteid=jwatch


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Optimizing Postmenopausal Vitamin D3 Supplementation

For white women, 600 IU of vitamin D3 daily appears to be sufficient.

Gallagher JC et al. Dose response to vitamin D supplementation in postmenopausal women: A randomized trial. Ann Intern Med

2012 Mar 20; 156:425. (http://www.annals.org/content/156/6/425.full)

ARTICLE SUMMARY

Vitamin D deficiency is defined as a serum 25-hydroxyvitamin D (25[OH]D) level of


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Vitamin D–Binding Protein Levels Are Lower in Blacks than in WhitesBlack patients with low levels of total 25-hydroxyvitamin D might have normal bioavailable levels.

Powe CE et al. Vitamin D–binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013

Nov 21; 369:1991. (http://dx.doi.org/10.1056/NEJMoa1306357)

ARTICLE SUMMARY

Compared with whites, blacks have lower 25-hydroxyvitamin D levels but higher bone- mineral density and lower

risk for fragility fractures. How can we explain this apparent paradox? A new study of about 2000 middle-aged

adults in Baltimore suggests that the answer might lie in vitamin D–binding protein. Black and white participants

(about 1000 each) were closely matched for age, sex, and body-mass index.

Mean total 25-hydroxyvitamin D levels were substantially lower in blacks than in whites (16 vs. 26 ng/mL). How-

ever, the mean level of vitamin D–binding protein in blacks was half that in whites, resulting in similar levels of

bioavailable, or free, 25-hydroxyvitamin D in blacks and whites. Polymorphisms in the vitamin D– binding pro-

tein gene differed in frequency among blacks and whites; these polymorphisms explained most of the variation in

vitamin D–binding protein levels.

COMMENT

The clinical implication of this study is that 25-hydroxyvitamin D levels might not accurately reflect the bioavail-

able component. Blacks in particular are more likely to be predisposed genetically to low levels of binding protein,

resulting in low total — but sufficient bioavailable — 25-hydroxyvitamin D levels. This observation might be why

we often see bone-density preservation in blacks with low levels of total 25-hydroxyvitamin D.



NEJM Journal Watch General Medicine , published November 21, 2013

Why Are Black Patients So Often Diagnosed as Having Vitamin D Deficiency?

Although blacks tend to have lower vitamin D levels than whites, their bone densities are not (on average) lower.

Traditionally, it has been thought that the low levels in blacks are related to lower levels of synthesis in the

skin, but this study suggests that binding proteins also have a role, and that bioavailable vitamin D may in fact

be adequate in some blacks with low serum levels.

http://www.jwatch.org/cgi/content/full/2013/nov21_6/NA32739?ijkey=1xP2oO77opss6&keytype=ref&siteid=jwatchhttp://www.nejmgroup.org/http://www.jwatch.org/cgi/content/full/2013/nov21_6/NA32739?ijkey=1xP2oO77opss6&keytype=ref&siteid=jwatch


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What Did The Institute of Medicine Say about Vitamin D?

An IOM report from 2010 warned that the only health benefit firmly associated with vitamin D (and calcium

as well) is bone health.

Most people in North America, according to the analysis, receive enough vitamin D despite the fact that average

intake falls below requirements. The difference is probably made up by sunlight exposure. Elderly people living

in institutions and those with dark skin may be at higher risk for vitamin D insufficiency.

Dietary Reference Intakes for Calcium and Vitamin D

CALCIUM VITAMIN D

Estimated

Average

Requirement

(mg/day)

Recommended

Dietary

Allowance

(mg/day)

Upper-Level

Intake

(mg/day)

Estimated

Average

Requirement

(IU/day)

Recommended

Dietary

Allowance

(IU/day)

Upper-Level

Intake

(IU/day)

19–30 years old 800 1,000 2,500 400 600 4,000

31–50 years old 800 1,000 2,500 400 600 4,000

51–70 year old males 800 1,000 2,000 400 600 4,000

51–70 year old females 1,000 1,200 2,000 400 600 4,000

>70 years old 1,000 1,200 2,000 400 800 4,000

Source: Reprinted with permission from Dietary Reference Intakes for Calcium and Vitamin D, 2011 by the National Academy of Sciences, Courtesy of theNational Academies Press, Washington, D.C. (http://www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf )

http://www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdfhttp://www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdfhttp://www.nejmgroup.org/http://www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdfhttp://www.iom.edu/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf


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Clinical Collections — Vitamin D Source: NEJM Physician’s First Watch

USPSTF: Evidence Is Insufficient to Recommend Routine Screeningfor Vitamin D Deficiency

For the USPSTF recommendation statement: Le Fevre et al. Ann Intern Med 2015; 162:133.

http://annals.org/article.aspx?articleid=1938935

For the USPSTF evidence review: http://annals.org/article.aspx?articleid=1938934

And for the USPSTF grade definitions: http://www.uspreventiveservicestaskforce.org/Page/Name/grade-definitions

ARTICLE SUMMARY

The U.S. Preventive Services Task Force has concluded that the current evidence is inadequate to weigh thebenefits and harms of screening for vitamin D deficiency in community-dwelling, nonpregnant adults.

The so-called “I” statement, published in the Annals of Internal Medicine, applies to those who are being treated

in primary care settings, have no signs of vitamin D deficiency, and have no conditions for which vitamin D

supplementation may be recommended.

Based on its review of the evidence, the task force notes:

• There’s no consensus on the definition of vitamin D deficiency, nor is there agreement on the optimal blood level

of 25-hydroxyvitamin D.

• No studies have assessed the direct benefits or harms of screening for vitamin D deficiency.

• Adequate evidence suggests that treating asymptomatic adults with vitamin D deficiency offers no benefit in terms

of cancer, diabetes, or mortality outcomes. Treatment also does not affect fracture outcomes in those not at high

fracture risk.

— Amy Orciari Herman

Physician’s First Watch , published June 24, 2014

What Does the U.S. Preventive Services Task Force (USPSTF) Have to Say about

Screening for Vitamin D Deficiency in the General Population?

http://www.jwatch.org/fw108975/2014/06/24/uspstf-draft-recommendation-routine-screening-vitamin-dhttp://www.jwatch.org/fw108975/2014/06/24/uspstf-draft-recommendation-routine-screening-vitamin-dhttp://www.nejmgroup.org/http://www.jwatch.org/fw108975/2014/06/24/uspstf-draft-recommendation-routine-screening-vitamin-dhttp://www.jwatch.org/fw108975/2014/06/24/uspstf-draft-recommendation-routine-screening-vitamin-d


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FINAL OVERVIEW AND LESSONS FROM THE CLINIC

To conclude this collection, we offer a widely-cited Journal review article — now freshly annotated by the

author. This review reminds us of the lessons we’ve learned from both the bench and the clinic.



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Source: The New England Journal of Medicine



clinical practice

This Journal feature begins with a case vignette highlighting a common clinical problem.Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the author’s clinical recommendations.

An audio versionof this articleis available at

NEJM.org

Vitamin D Insufficiency

Clifford J. Rosen, M.D.

From the Maine Medical Center ResearchInstitute, Scarborough. Address reprint re-quests to Dr. Rosen at Maine Medical Cen-ter Research Institute, 81 Research Dr.,Scarborough, ME 04074, or at [email protected].

N Engl J Med 2011;364:248-54.

Copyright © 2011 Massachusetts Medical Society.

A healthy 61-year-old white woman is concerned about a low vitamin D level detectedduring an assessment of her skeletal health. Her menopause began at 54 years of age.

She has no history of falls, and there is no family history of hip fracture. She takes nomedications or supplements. Her height is 157.5 cm (5 ft 2 in.), and her weight 59.1 kg

(130 lb). The results of a physical examination are unremarkable, and the findings onlaboratory studies are normal. The T score for bone mineral density at the hip is −1.5,

and the serum level of 25-hydroxyvitamin D is 21 ng per milliliter (53 nmol per liter). What do you advise?

The Clinical Problem

Whereas frank vitamin D deficiency (serum level of 25-hydroxyvitamin D below 10 ng

per milliliter [25 nmol per liter]) has long been recognized as a medical condition

characterized by muscle weakness, bone pain, and fragility fractures, vitamin D

“insufficiency,” characterized as a serum level of 25-hydroxyvitamin D of 10 to 30 ng

per milliliter (25 to 75 nmol per liter), without overt clinical symptoms, has re-

cently become a concern on the part of physicians and patients.1 Increased atten-

tion to this new “syndrome” and its potential complications has led to a substantial

increase in testing for the metabolite 25-hydroxyvitamin D, the best clinical mea-

sure of vitamin D stores. The number of 25-hydroxyvitamin D assays performed by

one major reference laboratory increased by 50% in the fourth quarter of 2009 ascompared with the same quarter in 2008, and it is expected that several million

tests will be performed this year.2

The implications of vitamin D levels that are below the normal reference range

but not markedly reduced and the value of supplementation are incompletely un-

derstood. Vitamin D is critical for skeletal mineralization, and numerous observa-

tional studies have linked low levels of 25-hydroxyvitamin D to fractures.3-7 There-

fore it is not surprising that most observational and randomized, placebo-controlled

trials concerning vitamin D insufficiency have focused on skeletal health outcomes.

In the past several years, attention has turned to nonskeletal effects of vitamin D

insufficiency, particularly in relation to cardiovascular disease, diabetes mellitus,

cancer, and immune dysfunction.8-11 This review summarizes the current under-

standing and uncertainties regarding vitamin D insufficiency and the effects of

vitamin D supplementation on health outcomes.

Strategies and Evidence

Defining Vitamin D Insufficiency

Interpreting the import of a serum level of 25-hydroxyvitamin D in the “insuffi-

cient” range (i.e., 10 to 30 ng per milliliter) is challenging for several reasons. First,

most reference laboratories have raised the lower boundary of the normal range to

http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMcp1009570http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMcp1009570http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMcp1009570http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMcp1009570http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMcp1009570mailto:rosenc%40mmc.org?subject=mailto:rosenc%40mmc.org?subject=mailto:rosenc%40mmc.org?subject=http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMcp1009570http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMcp1009570http://www.nejmgroup.org/mailto:rosenc%40mmc.org?subject=mailto:rosenc%40mmc.org?subject=http://www.nejm.org/stoken/default+domain/ClinicalCollections-PDF/full?redirectUri=/doi/full/10.1056/NEJMra070553


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This is further

complicated by

recent studies

suggesting that

“free” 25(OH)D may

be a more accurate

measure of bioactiv-

ity, and that total

25(OH)D does notfully reflect “free”

levels.

30 ng per milliliter. Second, although there areseveral ways to measure 25-hydroxyvitamin D

(radioimmunoassays, enzyme-linked assays, andliquid chromatography with mass spectrometry),

the precision and accuracy of the assays, especial-ly in nonreference laboratories, remain problem-atic.12 Third, 25-hydroxyvitamin D levels change

with the seasons, exposure to sunlight, and di-

etary intake. For example, in northern latitudes,serum levels of 25-hydroxyvitamin D decline by20% from late summer to midwinter, whereas

30 minutes of full-body exposure to the sun dur-ing the summer rapidly generates vitamin D.Regular exposure to sunlight (depending on its

strength) can increase the serum level of25-hydroxyvitamin D.3

What does a serum 25-hydroxyvitamin D levelrepresent? Vitamin D is produced by the nonen-

zymatic conversion of provitamin D to previtaminD in the skin during exposure to sunlight emit-ting ultraviolet radiation in the narrow band of

290 to 315 nm (Fig. 1). Some vitamin D also comesfrom food sources (between 100 and 200 IU per

day). Vitamin D is converted in the liver to25-hydroxyvitamin D, a partially water-soluble

form with a shorter half-life than vitamin D thatcirculates bound to vitamin D–binding protein.About 40 to 50% of circulating 25-hydroxyvita-

min D is derived from skin conversion.1,3 The

active form of vitamin D is 1,25-dihydroxyvita-

min D, which is generated primarily in the kid-ney. It circulates in lower concentrations than

Skin

Liver

Kidney

Food(vitamins D2 and D3)

Provitamin D3 Previtamin D3

Vitamin D3

25-Hydroxylase (CYP2R1)

24-Hydroxylase(CYP24R1)

1α-Hydroxylase(CYP27B1)

25(OH)D3

Increased PTH,decreasedphosphate

FGF-23 Calcitriol

Biologic Activity

24,25(OH)2D3

– +

Sunlight

+ ––

l

:

i

i l

i

I

Figure 1. Synthesis and Metabolism of Vitamin D.

Vitamin D is initially generated in the skin from the non-

enzymatic conversion of provitamin D3 to previtamin D

3.

Dietary intake of vitamin D is usually relatively limited,since few foods, with the exception of certain kinds of

fish, contain sizable amounts; supplements are com-

monly used. Vitamin D is either stored in adipose tis-

sue or converted in the liver by the enzyme 25-hydroxy-lase to 25-hydroxyvitamin D3 (25[OH]D

3), the form

that circulates in the highest concentration and reflectssolar and dietary exposure. It is converted to the active

metabolite, 1,25-dihydroxyvitamin D (1,25[OH]2D), or

calcitriol, in the kidney, although other tissues have

1α-hydroxylase enzymatic activity. The synthesis ofcalcitriol is enhanced (+) by increasing levels of para-

thyroid hormone (PTH), which rise in response to lower

levels of serum calcium. Reduced levels of serum phos-phate can also increase (+) the production of calcitriol.

Its synthesis is suppressed (–) by the production of fi-

broblast growth factor 23 (FGF-23), which is secretedby osteocytes in the bone matrix. Calcitriol inhibits the

activity of 1α-hydroxylase (CYP27B1) and stimulates the

activity of 24-hydroxylase (CYP24R1), an enzyme that pro-

motes production of 24,25(OH)2D3, a vitamin D prod-uct that is not biologically active. In CYP2R1, CYP27B1,

and CYP24R1, CYP denotes cytochrome P.



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In addition, it

appears thatAfrican-Americans

may have

differences in

free vitamin D

as well as total.

25-hydroxyvitamin D but has much greater affin-

ity for the vitamin D receptor and is biologically

more potent. Low levels of 1,25-dihydroxyvita-

min D do not reflect low levels of 25-hydroxyvi-

tamin D but result from other causes, most com-

monly renal insufficiency and less frequently

oncogenic osteomalacia.

The serum 25-hydroxyvitamin D level is thebest indicator of overall vitamin D status because

this measurement reflects total vitamin D from

dietary intake and sunlight exposure, as well as

the conversion of vitamin D from adipose stores

in the liver.13,14 According to the National Health

and Nutrition Evaluation Survey (NHANES), in the

United States, the average dietary intake of vita-

min D (including supplements) may be as low as

200 IU per day (with differences according to

age).15 Skin-derived synthesis of vitamin D is

quite variable, depending on pigmentation, lati-

tude, season, clothing, age, sunscreen use, and

local weather conditions. Levels of 25-hydroxyvi-

tamin D are considerably lower among blacks

than among whites because of greater pigmenta-

tion in blacks. In healthy whites, serum levels of

25-hydroxyvitamin D may vary according to en-

vironmental, hormonal, genetic, and nutritional

factors.3,14 The body-mass index (BMI), for exam-

ple, is inversely related to the serum 25-hydroxy-

vitamin D level, and obese patients typically

have levels in the range of 10 to 20 ng per milli-

liter (25 to 50 nmol per liter); these differences

may be due in part to lower levels of exercise and

sunlight exposure in obese persons than leanpersons. Several conditions cause very low serum

levels of 25-hydroxyvitamin D (i.e., below 10 ng

per milliliter), including poor dietary intake of

vitamin D coupled with negligible sun exposure;

malabsorption due to inflammatory bowel dis-

ease, gluten enteropathy, gastric surgery, biliary

disease, or intestinal overgrowth; use of anti-

seizure medications (e.g., phenobarbital or phe-

nytoin); and long-term use of glucocorticoids.1,3

Defining a level of serum 25-hydroxyvitamin D

as low or insufficient depends on the level that is

defined as normal. Previously, according to the

World Health Organization, levels below 10 ng permilliliter were considered deficient and levels

below 20 ng per milliliter were classified as in-

sufficient.16 However, with the recent changes in

laboratory reference ranges, a normal level is now

typically defined as a serum level of 30 to 76 ng

per milliliter (75 to 190 nmol per liter). When that

range is used, the estimated prevalence of vita-

min D insufficiency is as high as 50 to 80% in the

general population.17,18 According to the NHANES

for 2005 and 2006, the mean 25-hydroxyvitamin

D level among several age groups was 24 ng per

milliliter (60 nmol per liter), a level considered

to be insufficient according to some standards.15

There are two rationales for setting the low endof the normal range for 25-hydroxyvitamin D at

30 ng per milliliter: one, put forward in studies

published in the past several years, suggests that

levels of parathyroid hormone (PTH) rise when

levels of 25-hydroxyvitamin D fall below 30 ng per

milliliter3,13,19; the other, proposed in earlier stud-

ies, suggests that active calcium absorption is op-

timal when the level of 25-hydroxy vitamin D is

30 ng per milliliter.20 However, both tenets are

now being questioned.14 Data indicate that the

relationship of PTH and 25-hydroxy vitamin D is

not curvilinear, and there is substantial variation

in PTH levels when 25-hydroxyvitamin D levels

are between 20 and 30 ng per milliliter. There is

no absolute threshold level of serum 25-hydroxy-

vitamin D at which PTH levels rise.13,19 Further-

more, although the information derived from

dual isotope analysis is the most accurate mea-

sure of calcium absorption, there are too few

studies to establish an absolute cutoff for levels

of 25-hydroxyvitamin D above which calcium ab-

sorption is not enhanced. Generally, peak absorp-

tion of calcium occurs at levels between 20 and

30 ng per milliliter.

Vitamin D and Bone Health

Although recent attention has focused on the non-

skeletal effects of vitamin D, it is well established

that vitamin D is critical for bone mineraliza-

tion.1,8-11 Therefore, it is not surprising that most

studies of vitamin D have assessed outcomes for

skeletal health.

Several observational studies of the associa-

tions between serum levels of 25-hydroxyvitamin

D and skeletal health have had conflicting re-

sults. A report from Ottawa on 15 studies (3 pro-

spective cohort studies and 12 case–control stud-

ies) concluded that associations between serum25-hydroxyvitamin D concentrations and fractures,

falls, and performance measures (tests of gait,

stability, and activity) among postmenopausal

women or elderly men were inconsistent.21 A more

recent report from the Agency for Healthcare

Research and Quality (AHRQ) and Tufts Medical



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More-recent meta-nalyses have confirmed

hat vitamin D alone has

ttle if any benefit on

racture risk and bone

mineral density

Reid et al. Lancet 2013).

Center, analyzing the same observational stud-

ies, concluded that there was fair, or reasonable,

evidence of an association between lower serum

concentrations of 25-hydroxyvitamin D and an

increased risk of falls among institutionalized

elderly persons.22

Randomized, controlled trials of vitamin D

supplementation have addressed its effects onskeletal outcomes, but most of these trials in-

volved supplementation with both vitamin D and

calcium, making it impossible to separate out

the effects attributable specifically to vitamin D.

The results of a 2007 meta-analysis of 29 trials

of supplementation with both calcium and vita-

min D or with calcium alone suggested that daily

supplementation with 1200 mg of calcium and

at least 800 IU of vitamin D resulted in reduced

rates of fracture and a modest increase in bone

mineral density, but the relationship between se-

rum 25-hydroxyvitamin D levels and skeletal out-comes was not assessed.23 A 2009 Cochrane

meta-analysis of 10 trials testing the effects of

vitamin D supplementation alone and 8 trials test-

ing the effects of vitamin D plus calcium showed

no significant relationship between vitamin D

supplementation alone and a reduction in the risk

of fracture.24 However, the study confirmed the

conclusion of the 2007 meta-analysis that calci-

um plus vitamin D was marginally effective in

reducing the risk of fracture in older persons as

compared with no supplementation (odds ratio,

0.89; 95% confidence interval, 0.80 to 0.99).

Despite the observational data suggestingan inverse association between serum levels of

25-hydroxyvitamin D and the risk of falls among

institutionalized elderly persons, the evidence is

inconsistent, with some studies showing a benefit

and others showing no effect of vitamin D sup-

plementation on the risk of fractures or falls in

various populations.22,25 Similarly, a randomized

study conducted by the Women’s Health Initiative

showed a nonsignificant reduction in hip frac-

tures among women receiving a total of 700 IU

of vitamin D and more than 2000 mg of calcium

per day.26 However, the high baseline intake of

calcium (an average of 1100 to 1200 mg per day)and vitamin D (approximately 300 IU per day) in

the placebo group may have limited the ability of

the investigators to detect effects of supplemen-

tation. Subgroup analyses of women over 60 years

of age and of those who adhered to their supple-

mentation regimen showed a significant reduc-

tion in hip fractures with supplementation, but

these results must be interpreted with caution.

Randomized trials of supplementation with vita-

min D2 or D

3 (with daily doses ranging from 400

to 822 IU) published after the AHRQ–Tufts analy-

sis also failed to show significant effects of vita-

min D supplementation on the risk of fracture or

falls in older populations.27,28 However, in one ofthose trials, vitamin D supplementation at a dose

of 400 IU daily improved gait speed and reduced

body sway.27

Several large observational studies have ad-

dressed the question of whether there is a thresh-

old level of 25-hydroxyvitamin D below which ad-

verse skeletal outcomes are more likely to occur.

In one study of elderly men, levels below 16 ng

per milliliter (40 nmol per liter) were associated

with a greater risk of fracture, whereas in an-

other study, men with levels below 20 ng per

milliliter had greater rates of femoral bone lossthan men with higher levels.29,30 In a longitudi-

nal study, Osteoporotic Fractures in Men (MrOs),

older men with serum levels of 25-hydroxyvita-

min D that were less than 20 ng per milliliter

had a higher risk of hip fracture than men with

higher levels.31 In a prospective study of older

women, 25-hydroxyvitamin D levels between 24

and 26 ng per milliliter (60 to 65 nmol per liter)

were associated with the lowest risk of hip frac-

ture; no additional risk reduction was noted

above that level.32 However, in a study of older

New Zealand women, levels of 25-hydroxyvita-

min D below 20 ng per milliliter were not asso-ciated with an increased risk of fracture during

5 years of follow-up.33

Vitamin D and Other Health Effects

Observational studies in large cohorts have shown

significant associations between low levels of

25-hydroxyvitamin D (i.e., below 20 ng per milli-

liter) and an increased risk of metabolic, neo-

plastic, and immune disorders such as type 1

diabetes mellitus and multiple sclerosis.7-11 The

two conditions most often connected with low

levels of vitamin D are atherosclerosis and diabe-

tes mellitus.34-36 For example, a significantly in-creased risk of type 2 diabetes has been reported

among persons with levels of vitamin D that are

insufficient (below 30 ng per milliliter), even after

adjustment for BMI and percentage of body fat.8,35

Similarly, another prospective study showed that

levels of serum 25-hydroxyvitamin D below 20 ng

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961647-5/abstracthttp://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961647-5/abstracthttp://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961647-5/abstracthttp://www.nejmgroup.org/http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961647-5/abstract


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Such a trial is under way

in non-institutionalized

elders. Called the STURD

Trial, it is sponsored by t

National Institute on Ag

(NCT02166333).

per milliliter were associated with an increased

risk of cardiovascular disease.10 However, there

are not enough data from large, randomized, con-

trolled trials to assess whether vitamin D supple-

mentation reduces the risk of chronic diseases

other than osteoporosis.

Areas of Uncertainty

The dynamics of vitamin D storage and reentry

into the circulation remain poorly understood,

particularly in obese persons.37 Optimal dosage

regimens for vitamin D remain uncertain. In

general, for every 100 IU of vitamin D taken in,

there is an increase of roughly 1 ng per milliliter

(3 nmol per liter) in the serum level of 25-hydroxy-

vitamin D; the lower the baseline level of 25-

hydroxyvitamin D, the greater the rise with vita-

min D supplementation. Most trials assessing the

association between 25-hydroxyvitamin D levelsand the risk of fractures and falls have used daily

doses of vitamin D between 400 and 1000 IU.

Data are scarce on the effects of long-term supple-

mentation with doses greater than 1000 IU per

day. In a recently published randomized, placebo-

controlled trial involving elderly persons not liv-

ing in institutions, those who received an oral

dose of 500,000 IU of vitamin D once a year for

3 years had a significantly increased rate of falls

and fractures, as compared with those who re-

ceived placebo, particularly in the first 3 months

after dosing.38 These results suggest that high

intermittent doses of vitamin D, as compared

with daily doses, may be metabolized and used

differently. Finally, data are lacking from large

randomized, controlled trials designed to deter-

mine whether vitamin D supplementation reduces

the risk of other major diseases, such as colon

cancer, for which there are observational data

suggesting a reduction in risk with supplementa-

tion. The ongoing Vitamin D and Omega-3 Trial

(VITAL; ClinicalTrials.gov number, NCT01169259),

a 5-year, randomized, placebo-controlled trial in-

volving 20,000 U.S. men and women is examin-

ing vitamin D supplementation (2000 IU per day), with or without supplementation of n–3 fatty acids,

for the primary prevention of cancer and cardio-

vascular disease.

Toxicity from vitamin D supplementation is

rare and consists principally of acute hypercalce-

mia, which usually results from doses that ex-

ceed 10,000 IU per day; associated serum levels

of 25-hydroxyvitamin D are well above 150 ng

per milliliter (375 nmol per liter).39 The tolerable

upper level of daily vitamin D intake recently set

by the Institute of Medicine (IOM) is 4000 IU.14

The long-term effects of supplementation at doses

above 4000 IU per day are not known, and risks

cannot be ruled out. Recent observational stud-ies have suggested associations between serum

levels of 25-hydroxyvitamin D above 60 ng per

milliliter (150 nmol per liter) and increased risks

of pancreatic cancer, vascular calcification, and

death from any cause,34,40,41 but the observational

nature of these studies precludes an assessment

of cause and effect. More longitudinal studies

and controlled trials are needed.

Several studies have suggested that vitamin D

supplementation may be most effective in reduc-

ing fractures and falls in institutionalized elderly

persons, in whom serum levels of 25-hydroxyvi-

tamin D are often below 20 ng per milliliter.42-44 Yet the optimal replacement dose in this popula-

tion is still not known. A large, long-term, ran-

domized trial is warranted to examine the ef-

fects of several different doses of vitamin D on

physical performance measures and the incidence

of falls and fractures in the institutionalized el-

derly population.

Guidelines from

professional societies

At an international workshop on vitamin D held

in 2007, there was agreement that most of the

world’s population is not getting an amount of

vitamin D sufficient to maintain healthy bone

mass and minimize the risk of fracture. The work-

shop members also agreed that vitamin D insuf-

ficiency decreases muscle strength and increases

the risk of falls.45 The recommendation from

that group, made on the basis of available obser-

vational data, was that the minimum desirable

serum level of 25-hydroxyvitamin D is 20 ng per

milliliter. Three years later, Osteoporosis Canada

issued a report stating that the 25-hydroxyvita-

min D level should be at least 30 ng per milliliterand that vitamin D insufficiency should be de-

fined as a level of 10 to 29 ng per milliliter.46 In

2010, the International Osteoporosis Foundation

issued a position statement on vitamin D status,

also based on observational data, recommending

a target serum level of 25-hydroxyvitamin D of

30 ng per milliliter in all elderly persons and

https://clinicaltrials.gov/ct2/show/NCT01169259?term=NCT01169259&rank=1https://clinicaltrials.gov/ct2/show/NCT01169259?term=NCT01169259&rank=1http://www.nejmgroup.org/https://clinicaltrials.gov/ct2/show/NCT01169259?term=NCT01169259&rank=1


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The U.S. Preventive Services

Task Force recently declared

that there was insufficient

evidence to supportwidespread screening with

serum 25(OH)D, thus raising

doubts about setting an

absolute level to target for

most individuals.

stating that vitamin D intakes as high as 2000 IUper day may be necessary to attain the recom-

mended level in some persons.47 In contrast, theIOM report, based on evidence from observational

studies and recent randomized trials, suggests thata serum level of 20 ng per milliliter of 25-hydroxy-

vitamin D would protect 97.5% of the population

against adverse skeletal outcomes such as frac-tures and falls.14

Conclusions a nd

Recommendations

The woman described in the vignette is a healthypostmenopausal woman with slightly low bonemineral density and a 25-hydroxyvitamin D level

of 21 ng per milli liter. Although the laboratorythat performed the measurement, and many

other laboratories, would label that level as in-sufficient, she is certainly not def icient in vita-

min D. According to the Fracture Risk Assess-ment Tool (FRAX) developed by the WorldHealth Organization, the probability that she

will sustain a hip fracture over the next 10 yearsis less than 1%. Moreover, she is not at high risk

for falls and is unlikely to have osteomalacia.48 Hence, for patients such as this one, I would

recommend an exercise program and a total cal-cium intake of 1200 mg per day. There remains

uncertainty about whether vitamin D supple-mentation is appropriate for her, and if so, what

the dose should be, although the recent IOM

guidelines recommend 600 IU daily for a post-menopausal woman who is not at high risk for

fractures or falls and 800 IU daily for persons who have a very high risk of osteoporosis or

who are older than 70 years of age.14 I wouldexplain that despite the recent focus in the me-

dia on the potential role of vitamin D in reduc-ing the risk of various chronic diseases, thishypothesis requires testing in large, randomized,

controlled trials, and vitamin D cannot current-ly be recommended for the purpose of reducing

the risk of heart disease or cancer.

Dr. Rosen reports serving as an unpaid consultant for LexiconGenetics and serving on the Vitamin D Subcommittee for theIOM, for which he received reimbursement for travel expenses.No other potential conf lict of interest relevant to this art icle wasreported.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

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