Use of Vitamin D

7/27/2019 Use of Vitamin D

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Al te rna t ive Med ic ine Review Vo lume 1 3 , Number 1 20 0 8

A b s t r a c tT h e r e c e n t d i s c o v e r y - f r o m am e t a - a n a l y si s of 1 8 r a n d o m i z e dc o n t r o l l e d t r i a l s - t h a t s u p pl e m e n t a l c h o l e c a l c i fe r o l ( v it a m i nD ) s ig n i f ic a n t l y r e d u c e s a i i -c a u s e m o r t a l i t y e m p h a si ze s them e d i c a l , e t h i c a l , a n d i e ga i i m p li c a t i o n s o f p r o m p tl y d i a g n o s i n ga n d a d e q u a t e l y t re a t i n g v i t a m i n D d e f i c i e n c y . Not o n l y ares u c h d e fi c ie n c i e s c o m m o n , a n d p r o b a b l y t h e r u l e , v i t a m i n Dd e f i c i e n c y isi m p l i c a t e d inm o s t o f th e d i s e a s e s o f c i v i l i za t i o n .V i t a m i n D'sfinal m e t a b o l ic p r o d u c t is a p o t e n t , p le i o t r o p i c , r e p a ira n d m a i n t e n a n c e , s e c o - st e r o i d h o r m o n e t h a t t a r ge t s m o r e t ha n2 0 0 h u m a n g e n e s i n aw i d e v a r i e t y o f t i ss u e s , m e a n i n g it ha sa s m a n y m e c h a n i s m s o f a c t i o n a s g e n e s it t a r ge ts . On e o f them o s t i m p o r t a n t g e n e s v i ta m i n D u p -r e g u la t e s is f o r c a t h e l i c i d i n ,a n a t u r a l l y o c c u r r i n g b r o a d - sp e c t r u m a n t i b i o t i c . N a t u r a l v i ta m i nD le v e l s , t h o s e fo u n d i n h u m a n s l i v i n g i n a s u n - r i c h e n v i r o n m e n t ,a r e b e t w e e n 4 0 - 7 0 n g / m L , le v e l s o b t a i n e d by f e w m o d e r nh u m a n s . A s s e s si n g s e r u m 2 5 - h yd r o x y - v i ta m i n D { 2 5 ( 0 H ) 0 ) ist h e o n l y w a y tom a k e t h e d i a g n o s i s a n d toa s su r e tr e a t m e n tis a d e q u a t e a n d s a fe . T hr e e t r e a t m e n t m o d a l it i e s e x is t forv i t a m i n D d e f i c i e n c y : s u n l i g h t , a r t i f i c i a l u l t r a v i o l e t B (UVB)r a d i a t i o n , a n d v i t a m i n D s u p pl e m e n t a t i o n . T r e a t m e n t o f v i t a m i nD d e f i c i e n c y ino t h e r w i s e h e a l t h y p a t i e n t s w i t h 2 , 0 0 0 - 7 , 0 0 0IU v i t a m i n D^ pe r d a y s h o u l d b e s u f f ic i e n t tom a i n t a i n y e a r -r o u n d 2 5 ( O H) D le v e l s b e t w e e n 4 0 - 7 0 n g / m L . In t h o s e w i t hs e r i o u s il ln e s s e s a s s o c i a t e d w i t h v i t a m i n Dd e f i c i e n c y , s u c ha s c a n c e r , h e a r t d i s e a s e , m u l t ip l e s c l e r o s is , d i a b e t e s , a u t i s m ,a n d a ho s t of o the r i l l n e sse s , d o se s sho u l d bes u f f i c i e n t tom a i n t a i n y e a r -r o u n d 2 5 ( 0 H ) D l e v e l s b e t w e e n 5 5 - 7 0 ng/m L V i t a m i n D - d e f ic i e n t p a t i e n t s w i t h s e n o u s il ln e s s s ho u l dn o t o n l y bes u p p l e m e n t e d m o r e a g gr e s si v e ly t h a n thew e l l ,t h e y s h o u l d h a v e m o r e f r e q u e n t m o n i t o r i n g of s e r u m 2 5 { 0 H )

Use of V itam in Din Clinical PracticeJohn J. Cannell, M D and Bruce W. Ho llis, PhD

D a n d s e r u m c a l c i u m . V i t a m i n Ds h o u l d a l w a y s b e a d j u v a n tt r e a t m e n t i n pa t i e n t s w i t h s e r i o u s il ln e s s e s a n d n e v e r r e p la c es t a n d a r d t r e a t m e n t . T he o r e t ic a l ly , ph a r m a c o l o g i c a l d o s e so f v it a m i n D( 2 , 0 0 0 l U / k g/ d a y f o r t hr e e d a y s) m a y p r o d u c ee n o u g h o f t he n a t u r a l l y o c c u r r i n g a n t i b i o t ic c a t h e l i c i d i n t o c u r ec o m m o n v i r a l r e s p ir a t o r y i n f e c t i o n s , s u c h as i n f l u e n za andt h e c o m m o n c o l d , b u t s u c h a t h e o r y a w a i t s f u r t h e r s c i e n c e .( >i /i e m M e c / R e i '2 0 0 8 ; 1 3 ( l ): 6- 2 0 )

IntroductionA recent meta-analysis of 18 randomized con-

trolled trials (RCT) found that cholecalciferol (vitaminD) significandy reduced total mortality.' Tliis discoveryis all the more remarkable because of the relatively lowdoses of vitamin D used (mean dose 528 IU (13 meg))and because the finding persisted across a number ofsubgroup analyses. In spite of tbe low doses used andthe short du ration of tbe trials, vitamin D's mortality re-duc tion was seven percent.*' Indeed , the recent discoverythat statins significantly increase 25-hydroxy-vitamin D(25(OH)D) levels raise the possibility that some - orall - of the mortality reduction of statins may be med i-ated through increases in vitamin D levels. ' ' '

Lappe et al recently reported the first RCT ofvitamin D in preventing internal cancers and found a60-percen t reduction in such cancers by increasing base-line 25 (O H )D levels from 29 ng/m L to 38 ng/niL witb1,100 IU (28 meg) per day.^ Baseline and treatment-induced serum 25(OH)D levels were strong and inde-pendent predictors of cancer risk. Lappe et als studyleft open the possibility that higher doses and higher

John J. Canne l l , M D - Director , Vi tam in D Counc i lCorrespondence address: 9100 San Gregor io R o a d , Atasc ade ro , CA 9 34 22E mai l : j jcann el l@gmai l .comBruce W, Holl is, PiiD - Professor of bioc t tem istry, m olecu lar b io logy, an dpediat r ics. M edica l Universi ty of Sout t i Caro l ina, Charleston, SC

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view Art ic leAl te rna t ive M ed ic ine Review Vo lume 1 3 , Num ber 1 20 08

treatment-induced 25 (O H )D levels might prevent evenmore cancers. (No te that 2 5( O H )D levels are reportedin the literature as either ng/mL or nmol/L; I.O ng/mLequals 2.5 nniol/L.)Besides cancer, vitamin D deficiency is associ-ated with cardiovascular disease, hypertension, stroke,diabetes, multiple sclerosis, rheumatoid arthritis, in-flammatory bowel disease, osteoporosis, periodontaldisease, macular degeneration, mental illness, propen-sity to Fall, and chronic pain/' '" A recent review pre-sented considerable evidence that influenza epidemics,and perhaps even the common cold, are brought on byseasonal deficiencies in antimicrobial peptides (AMP),such as cathelicidin, secondary to seasonal deficienciesin vitamin D." Results of an RCT support the theory,finding 2,000 IU of vitamin D/day for one year virtu-ally eliminated self-reported incidence of colds and in-fluenza (Figure 1).'^ Even the current triple childhoodepidemics of autism" (Figure 2), asthma,'"* and type 1diabetes,'^ all of which blossomed after sun-avoidanceadvice became widespread, might be the tragic andiatrogenic sequela of gestational or early childhood vi-tamin D deficiencies brought on by medical advice toavoid the sun.

Claims that vitamin D may help prevent sucha wide variety of diseases seem incredible until one re-alizes vitamin D is not a vitamin; rather, it is the onlyknown substrate for a potent, pleiotropic, repair andmaintenance, seco-steroid hormone with a single endo-crine function, but multiple autocrine functions. Previ-ously, many practitioners thought vitamin D's activitywas principally its endo crine function - the regulationof seru m calcium - and w as thu s mainly involved inbone metabolism. Indeed, the classic endocrine func-tion of vitamin D begins when the kidney hydroxylates25 (O H )D into 1,25(OH)2D, which then acts, both directly and indirectly, to maintain serum calcium.

However, in the last ten years, it has becomeclear the vitamin D steroid hormone system includemore than the classic endocrine pathway used to pre-serve calcium economy.'^ The enzyme that furtherhydroxylates 25(OH}D to 1,25(OH),D (activated vitamin D, the steroid hormone) is present in a wide variety of human tissues other than kidney. 1,25(OH)2Dis autonomously made in tissues and directly affectsnumerous cells via its autocrine, and presumed paracrine, functions.' ' Most organs show evidence ot endorgan responsiveness to 1,25(OH)^D.'*' Like all steroid

Figure 1. Incidence of Colds/Influenza After 2,000 IU Vitamin D Daily for O ne Year2 5 - 1

W i n t e r S p r i n g Su m m e r A u tu m nIn c i d e n c e o f r e p o r t e d c o l d / i n fl u e n z a s ym p to m s a c c o r d i n g to s e a s o n . T he p la c e b o g r o u pr e p o r t e d m o r e c o l d /i n f lu e n z a s y m p to m s in th e w i n t e r . O n l y o n e s u b j e c t h a d c o i d /i n f lu e n z as ym p t o m s w h il e t a k in g a h ig he r d o s e o f v i t a m i n D ( 2 0 0 0 l U/ d ).

'l ac e b o 1 8 0 0 l U/d 1 2 0 0 0 l U/dA d a p t e d f r o m : A l o i a J F, Li -N g M . E pi d e m i c i n fl u e n z a a n d v i t a m i n D . Epidemiol Infect 2007;1 3 5 :1 0 9 5- 1 0 9 6 . U se d w i th p e r m i ss io n .

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Figure 2. Tncreased Prevalence of Autism: 1992-20031 8 0 0 0 r6000 -4000 -

ide

.n

mbo

20001000

8 0 0600 -400 -200 -

Time trend of aut ism prevalence for the 50 states and Puerto Rico. (Reproduced w i th permission, FightingAut ism, http:/ /www.f ight ingaut ism.org/ idea/aut ism.php,accessed 5/8/07}

hormones, 1,25(OH),D acts as a molecular switch, ac-tivating more tha n 200 target genes, thereby regulatinggene expression. Thus, locally produced 1,25(OH) Dexists in most tissues of the body, is under auton om ousautocrine control, and has as many mechanisms ot ac-tion as genes it targets. This explains why the same sub-stance may have a role in preventing cancer, influenza,aurism, asthma, multiple sclerosis, and cardiovasculardisease, not just curing rickets and osteomalacia (Figure 3).

Such claims leave practitioners with under-standable skepticism and m ultiple questions. Is vitaminD a cure-all? When should I recommend vitamin DiHow much should I prescribe? What form of vitaminD should I use? How much do children need? Howmuch do pregnant or breastfeeding women need? Is itappropriate to use higher doses of vitamin D as adju-v:int treatment for any of the above diseases? How do Iinterpret vitamin D blood tests and which tests shouldI order? What is the risk of toxicity?

Another way to ask many o these questionsis / 'W ha t is an ideal 2 5 (O H )D level?" Levels needed tooptimise intestinal calcium absorption (34 ng/mL)'^are lower than those needed to optimize neurom uscularperformance (38 ng/mL).'" Recent pooled meta-analy-ses estimate 2 5( O H )D levels of 52 ng/m L are needed toeffect a 50-percent reduction in the incidence of breastcancer.^' Although some experts believe the lower limitof adequate 25(OH)D levels is in the low 30s,-"-' oth-ers recommend a lower limit of 40 ng/mL;^"*'^^ there iscertainly no scientific consensus.Ideal levels are unknown but are probablyclose to levels present w hen th e h um an gen ome evolvedin sub-equatorial Africa. Natural levels, such as thosefound at the end of summer in 30 young men whospent the summer working outdoors, were around 50ng/mL;^^ however, these levels are obtained by only asmall fraction of people.' ' Furthermore, despite suchsumm ertime levels, at the end of winter 25 (O H )D

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Alternative Medicine Review Voiume 1 3, Number 1 20 08Review A rt ic le

Figure 3 . Autocrine and Endocrine Functions of Vitamin D

Previtamin DSkinMiik,Orange Juice,Saimn,or Suppiements

Vitamin D 25(OH)DAutocrine

Most tissuesin the body

IPrevent and/or treat:Virai respiratory diseaseCancer, OsteoporosisHeart disease, Multiple scierosisDiabetes, Hypertension

Maintaincalciumeconomy

levels in 50 percent of these men dropped ro less than30 ng/mL, indicating a sun-induced level of 50 ng/niLat the end of summer is inadequate to maintain such alevel during wintertim e.

Ano ther way to ask the"ideal 25(O H )D " ques-tion involves understanding vitamin D's unique pliar-macokinetics. Unlike any other steroid hormo ne system,the substrate concentrations for the liver production of25(OH)D are absolutely rate limiting, lliis means theliver enzymes that initially hydroxylate vitamin D toform 2 5( O H )D and the enzyme in tissue that generates1,25(OH),D operate below their Michaelis-Mentenconstants throughout the full range o modern humansubstrate concentrations; i.e., the reactions follow first-orde r m ass action kinetics,"** Th e m ore vitamin D t hat isingested, the more is converted into 25(OH)D, and themore is converted into 1,25(OH)2D in the tissues. Thereaction appears to be uncontrolled; an aberrant, totallyunique , and po tentially dang erous situation for a steroidhormone system. Imagine, tor example, if corcisol, tes-tosterone, progesterone, or estradiol levels were entirelydependent on the intake of their substrate, cholesterol.

HolHs et al recently explained this conundrumand concluded very few humans obtain enough vitaminD even if they take several thousand units per day.^"Hollis et al studied the pharmacokinctics of the parencompound, viramin D, and its firsr metabolic product25{OH)D, in two groups; Hawaiians with significansun exposure and lactating women receiving 6,40IU of supplem ental vitamin D per day. They found25(OH)D levels had to exceed a minimum of 40 ngm L , and ofi:en 50 ng/mL, to begin to detect the parencompound in the blood and begin to normalize the kinetics of 25(OH)D production. In other words, when25 (O H )D levels > 40 ng/m L were achieved, the parencompound began to be detectable in the hlood, the reactions became saturable and controlled (like other steroid hormo ne systems), and thus levels above 40 ng /m Lappear to represent che lower limit of'normal" 25(OHD levels.

This implies virtually everyone has a chroni25(OH)D substrate deficiency, at least in the winterand the absence of the parent vitamin D compound(cholecalciferol) in the bloo d m eans all available vitaminD is used for metabolic needs and none of it is stored

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Al te rn a t iv e M e d i c i n e Re v ie w Vo lu me 1 3 , Nu m b e r 1 2 0 0 8

Figure 4. Seasonal Serum Levels of 25-hydroxyvtamn D34-3 0 -

2 8 -

2 4

20 -

16 -

12

8 -

4 -

0 L ^

i i

1Q .OCO o o on -> II Q .< Q . 0 )o O)LL

G e o m e t r i c m e a n m o n t h l y v a r i a t i o n s i n se r u m 2 5 - hy d r o x yv i t a m i n D [ 2 5 )O H )D j c o n c e n t r a t io n i n m e n ( b l u e . n =3 7 2 3 ) a n dw o m e n ( o r a n g e . n = 3 71 2 ) i n a 1 9 5 8 B r it is h (E n g l a n d , S c o t l a n d , a n d W a l e s ) b i r th c o h o r t a t a g e 45 . A d a p t e d f r o m : H yp po n e nE . P o w e r C . H yp o v i t a m i n o s i s D in B r i ti sh a d u l t s a t a g e 4 5 y: n a t i o n w i d e c o h o r t s t u d y o f d i e t a r y a n d l i f e s ty l e p r e d i c t o r s . A m JC l in N u t r 2 0 0 7 ; 8 5 :8 6 0 - 8 6 8 , f Js e d w i t h p e r m i s si o n .

Because of this, mos t individuals have chronic substratestarvation, Rmctional viramin D deficiency, and thus,per hap s, higher risk for the "diseases of civilization."Tlie ideal 25(OH)D level continues to be de-bated in scienriiic circles and consensus awaits furrherscience. How ever, do we wait for science to com plete itswork with highly seasonal 25(OH)D levels (Figure 4)tha t reflect sunligiir depr ivation, levels where vitam in Dsteroid phnrmacokinetics are aberrant, or is it sater towait with levels normally achieved by humans in a sun-rich environment, levels where vitamin D's kinetics arenormal ized (>40 ng/mL)iOnce a practitioner is comfortable with ideal25 (O H )D levels being above 40 n g/m L, the answers cothe questions posed above become fairly simple. Healthyhumans should be supplemented with enough vitaminD or exposed to enough ultraviolet B (UVB) radiationto achieve natural 25(OH}D levels (40-70 ng/mL)

year-round , whether rhey are infants, children, preg nantwomen, lactating women, healthy young adults, or theelderly. W ha t role vitamin D has in treating - ratherthan preventing - disease is largely unknown, but givenvitamin Ds genetic mechanism of action, it may have asignificant role. For example, vitamin D reduces cellularproliferation, induces differentiation, induces apoptosis,and prevents angioneogenesis, each a laudable goal incancer treatm ent. A simple risk-versus-benefit analysissuggests patients with a potentially fatal cancer (seebelow) may think it wise ro maintain 25(OH)D lev-els in the high end of natural ranges (55-70 ng/mL),ranges that assure vitamin D's kinetics are normalized.While the RCTs needed to clarify vitamin D's role inthe treatment of disease are being conducted, a strongcase already exists for adequately diagnosing and ag-gressively treating vitamin D

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Incidence of Vitamin D DeficiencyAdult vitamin D deficiency is the rule rather

than the exception in industrialized nations."'^' A highnumher of otherwise healthy children and adolescentsare also vitamin D deficient.^'^'^ Rickets, a disease ofthe industrial revolution, is being diagnosed more fre-quently,"' especially in breast-fed infants.'^ Alarmingly,given mounting animal data that gestational vitamin Ddeficiency causes subtle but irreversible brain damage inmammalian offspring,'**" severe deficiencies are com-mon in newborn infants and pregnant women, espe-cially African-Americans."" A population-based studyof 2,972 U.S. women of childbearing age found 42 per-cent of African-American women had 25(OH)D levelsbelow 15 ng/mL, and 12 percent had levels below 10

gFurthermore, the definition of vitamin D defi-

ciency changes almost yearly as research shows the lowend of ideal 25 {O H )D ranges are higher than were pre-viously thought. Tlie aforementioned prevalence stud-ies used outdated reference values for low-end 25(OH}D ranges and therefore underestimate the incidence ofvitamin D deficiency. Obviously, the higher the low endof the 25 {O H )D cutofFpoint , the higher the percentageof the population defined as deficient. Only 10 percentof the subjects in any of the above studies had 25(OH)D levels > 40 ng/mL.Vitamin D M etabolism and Physiology

Perhaps because the term "vitamin D" containsthe word "vitamin," most people wrongly assume theycan obtain adequate amounts by eating a healthy diet.Th e natural diets most hum ans consum e, however, con-tain minimal vitamin D, unless those diets arc rich inwild-caught fat ty fish, sun-dried Shitake mushrooms,or wild reindeer meat. Small amounts of vitamin D arecontained in fortified foods, such as fortified milk, someorange juices, and cereals, but such sources are minorcon tributo rs to vitamin D store s. Traditionally, the hu -man vitamin D system began in the skin, not in themout h .

Vitamin D normally enters the circulation afterUVB from sunlight strikes 7-dchydro-cholesterol in theskin, converting it to vitamin D^ or cholecalciferol (vita-min D ). W he n taken by mouth , the body metabolizesvitamin D similarly to that generated in the skin. No

matter how it arrives in the circulation, the liver read-i ly hydroxylates vi tamin D to 25(OH)D, the circulat-ing form of vitamin D. Hundreds of tissues in the bodyuse 25 (O H )D as a subst ra te to make the end-product ,1,25(OH)^D, known as activated vitamin D, a pleiotro-pic seco-steroid. If enough 2 5 (O H )D substrate is avai l-able, multiple tissues are free to autonomously produceand locally regulate the amount of steroid needed forany particular disease state.

The skin's manufacture of vitamin D is ex-traordinarily rapid and remarkably robust; productionafter only a few minutes of sunlight easily exceeds di-etary sources by an order of magnitude. Incidental sunexposure, not dietary intake, is the principal source ofvitamin D stores and is a fi.mction of skin surface areaexposed.^^^' For example, when fair-skinned peoplesun bath e in the sum me r (on e, fiiU-body, minim al ery-themal dose of UVB), they produce about 20,000 IUof vitam in D in 30 minutes,"*"* the equ ivalent o f d rink ing200 glasses of milk (10 0 I U /8 oz. glass) or taking 50standard mult ivi tamins (400 IU/tablet) to obtain thesame amount orally.

Tlie fact that 20,000 IU vitamin D can beproduced in the skin in 30 minutes of sun exposurecombined with vi tamin D's basic genomic mechanismof action, raises profound quest ions. W hy did naturedevelop a system that delivers huge quantities of a ste-roid precursor after only brief periods of sun exposure?Would natural selection evolve such a system if the re-markably high input that system achieved were unimportant? As hu man s evolved in a sun-rich environmen(sub-equatorial Africa), is modern sunlight deprivation- and the res ultan t routinely low levels of this repairand-maintenance steroid in tissues - a possible common cause of the diseases of civilization?

Factors Affecting Vitam in D LevelsFactors that can affect U V B expo sure, and thuthe skin's pro du ction of vitamin D , include latitude, season of the year, time of day, air pollution, cloud covermelanin content of the skin, use of sunblock, age, andthe extent of clothing covering the body. When the sunis low on the horizon, ozone, clouds, and particulate aipollution dcHcct UVB radiation away from the earth'surface. Therefore, cutaneous vitamin D production ieffectively absent early and late in the day and for th

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en t i re day du r ing severa l win te r t ime mon ths a t l a t i tudesabove 35 deg rees , and impai red any t ime the sk ies a repollu ted or cloudy.

T h u s , v i tamin D def ic iency is mo re c om mo nthe fu r ther po leward the popu la t ion . Fo r example , Bos -ton , Massa chus e t t s ( l a t i tud e 42 deg rees ) , has a fou r-mo n th "v it amin D win te r" cen te red a rou nd the win te r. so ls ti ce , whe n in su r t i c ien t U V B pe ne t ra te s the a t mo -sphere to t r igger sk in p roduc t ion . Th is becomes an evenlonger per iod when the fa l l and l a te win te r mon ths a reinc luded , when su f f i c ien t UVB on ly pene t ra tes a roundso la r noon . In no r thern Europe and Canada , the "v i t a -min D win te r" can ex tend fo r s ix mo n th s . Fu r the rm ore ,p roper ly app l ied sunb lock , common window g las s inho me s an d cars , an d clo thing al l effectively b lock U V Brad ia t ion - even in the summer . Those who avo id sun -l ight - at any lat i tud e - are at r isk of v i tam in D defi-ciency any t ime o the year. For example, a surpris inglyhigh incidence of v i tamin D deficiency exis ts in Miami,F lo r ida , desp i te i t s sunny wea tber and sub t rop ica l l a t i -t ude . ' ' '

Afr ican -Americans , the e lder ly , and the obeseface added risk . Because melanin in the skin acts as anef fec t ive and ever-p resen t sunscreen , dark -sk inned peo -p le need much longer UVB exposu re t imes to genera tethe same 2 5 ( O H ) D s to res as fa i r - sk inned ind ividua l s.^^Th e e lder ly mak e mu ch les s v i t amin D than 20 -year-o lds a f t e r exposu re to the same amoun t o f sun l igh t . ' ^Body fat absorb s v i tamin D, thus obe si ty is a major r iskfactor for deficiency, with obese African-Americans atan even h igber r i sk / " Anyone who works indoors , l ivesat h igher lat i tudes , wears excess ive clo th ing, regularlyuses sunb lock , is dark -sk in ned , ob ese , aged , o r wh oconsciously avoids the sun is at h igh risk for v i tamin Ddeficien cy.

Diagnosis of Vitamin D DeficiencyIn the absence of a metabolic bone disease suchas rickets, osteomalacia, or osteoporos is, most practitio-ners assume vitamin D deficiency is asymptomatic, al-though that may be changing. Complaints endemic toevery practitioner's office, such as muscular weakness, afeeling of heaviness in tbe legs, chronic musculoskeletalpain, fatigue, or easy tiring may be symptoms of vitamin[) deficiency.'*'' Suc h com plaints a re extremely com mo n,difficult to tre at, and easy to dismiss, but th ey may ind i-cate symptomatic vitamin D deficiency.

Physical examination is usually unremarkablebut may reveal undue pain on sternal or tibial pressureif deficiency is severe. Th e vast m ajority of cases app earnormal on exam, although frequent infections, autoim-mune illness, diabetes, cancer, heart disease, major de-pression, and a host of other "diseases of civilization"may be warning signs that deficiency has been presentfor many yearsr^'^^

The aged may be wheelchair-bound second-ary to vitamin D deficiency-induced myopathy, yet theytypically recover mobility after treatment.^" Tbe recentstrong association of low mood and cognitive impair-ment in the aged witb vitamin D deficiency^' suggestsdepressed mood and/or impaired cognition may be pre-senting symptom s. A blinded intervention trial found4,000 IU vitamin D per day improved the mood ofendocrinology outpatients,^^ but th ere are no nterven-tional studies of its effects on cognition.

Even without physical signs or symptoms,the physician sbould screen those at risk. Obtainingand properly interpreting a serum 25(OH)D level isthe only way to make the diagnosis. A 25(OH)D levelshould be obtained at least twice yearly on any patientat risk, once in the early spring for the nadir and oncein the late summer for a peak level. ' ' ' We recommend25(OH)D levels be kept above 40 ng/mL year-round(Figure 5).

It is crucial to remember tbat serum1,25(OH)^D levels play no role in diagnosing vita-min D deficiency. The kidney tigbtly controLs scruml,25{O]ri)^D levels, which are often normal or evenelevated in vitamin D deficiency. Tlierefore, a patientwitb normal or high 1,25(OH)^D serum levels but low25(OH)D levels is vitamin D deficient despite high se-rum levels of the active horm one . Practitioners w ho relyon serum 1,25(OH),D levels to make the diagnosis ofvitamin D deficiency will routinely miss it.^^Tre atm ent of Vitamin D Deficiency

Three op tions exist for treatme nt of vitamin Ddeficiency: sunlight, artificial UVB light, and vitaminD supplements. An exposure of 10-15 minutes of full-body summer noon-day sun or artificial UVB radiation(such as tanning beds) will input more than 10,000 IUof vitamin D into the systemic circulation of most light-skinned adults. One or two such exposures per week

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Figure 5* Ranges of Serum 25(OH)D

150ng/mLlOOng/mL

70ng/mL

40ng/mL

Ong/mL.

Toxic > 150ng/mL

Excessive > lOOng/mL

Ideal >40-70ng/mL

Deficient < 40ng/mL

Author's recommendations for serum25(OH) vitamin D levels.

should maintain 25{OH)D levels in an ideal range, butadequacy should be assured by 25(OH)D blood levels.Those who choose UVB light for vitamin D repletion,from either sunlight or artificial sources, should avoidsunb urn, which is associated with malignant m elanom a.Furthermore, they should understand that regular UVexposure ages the skin and increases the risk of non-melanoma skin cancers.

Tlie treatment of choice for vitamin D deficien-cy is vitamin D, cholecalciferol, also known as vitaminD . Ora l vitamin D treatm ent is more challenging thantreatm ent w ith U V B light for several reasons. First, un-expectedly high doses of vitamin D are usually neededto achieve adequate serum 2 5 (O H )D levels. On e of theproblems with vitamin D terminology is the archaicmethod used to express dose, international units or IU.One thousand IU of vitamin D sounds like a lot; in fact,it is only .025 mg or 25 micrograms; i.e., one meg is 40IU. Second, the amo unt of vitamin D needed varies withbody weight, body fat, age, skin color, season, latitude,and su nning habits. Third, unlike sun expo sure, toxicityis possible with oral supplementation - although it isextraordinarily rare.

Cholecalciferol is available over-the-counterand via the Internet in 400, 1,000, 2,000 and (recently)5,000, 10,000, and 50,0 00 IU capsules. Supp leme nta-tion with 1,000 IU per day will usually result in abouta 10-ng/mL elevation of serum 25(OH)D when givenover 3-4 months. Therefore, a normal weight, healthyadult with an initial level of 10 ng/mL would gener-ally require about 2,000 IU per day to achieve a level of30 ng/mL in the absence of cutaneous UVB exposureHowever, its kinetics are not linear; 1,000 IU per daywill substantially raise low baseline levels but a similardose will not increase higher baseline levels by a simi-lar increment (that is, 2,000 IU per day may not raise30 ng/mL to 50 ng/mL). In the absence of significantUVB exposure, input from diet and supplements ofapproximately 1,000 IU (25 meg) per day for every 15kg of body weight may be needed; i.e., an obese 150-kgadult may require up to 10,000 IU per day to achievea 25(OH)D level of 50 ng/mL. Patients with seriousdiseases may need more if the metabolic clearance of25 (O H )D is increased (see below).

The only prescription vitamin D preparationavailable in the United States is the vitamin D analogueergocalciferol (vitamin D^), available as 50,000 IU (1.25mg) capsules. However, ergocalciferol is not human vi-tamin D, it may be a weaker agonist, it is not normallypresent in humans, and its consumption results in metabolic by-produc ts no t normally found in humans.' ' ' ' It isalso less effective than cholecalciferol in raising 25(OH)D levels."-^"^

Recently, 50,000 IU capsules of vitamin D^became available in retail outlets. Grey at al treated 21vitamin D-deficient patients with 50,000 IU cholecalciferol weekly for four weeks, the n 5 0,00 0 IU mo nthlyfor one year." Blood levels rose from a mean of 11 ng/mL at baseline to 30 ng /m L at six month s and to 31 ng/mL at one year, indicating monthly doses of 50,000 IUof vitamin D do not achieve natural 25 (O H )D levelsand such levels do not continue to rise after six monthof such treatment. If such intermittent high doses ofcholecalciferol are used, maintenance requirements areprobably 50,000 IU every 1-2 weeks in most adultsalthough such supplementation studies have not beendone.

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Cod liver oil contains a variable amount ofvitamin D, but usually contains high amounts of vita-min A. Consumption of pre-formed retinols, even inamounts consumed in multiviraniins, may be causinglow-grade, but widespread, bone toxicity,^** Vitamin Aantagonizes the a ction of vitamin D, " and high retinolintake thwarts vitamin D's protective effect on distalcolorectal adenoma.' '" The authors do not recommendcod liver oil.

Neither the regular consumption of officiallyrecomm ended am ounts of vitamin D (e.g., 40 0 IU in amultivitamin), nor the regular consumption of vitaminD fortified foods (e.g., 100 IU per 8 0 2. glass of milk),effectively prevent vitamin D deficiency.^''^'' Furrber-more, 2,000 IU/day tor one year failed to achieve a 32ng/niL target 25 (O H )D concentration in 40 percent of104 African-American women studied.*"' The admin-istration of 4,000 IU/day for more than six monthsto middle-age Canadian endocrinology outpatientsresulted in average 25(OH)D levels of 44 ng/mL andproduced no side effects otber than improved mood.^^Heaney estimates 3,000 IU/day is required to assuretbat 97 percent of Americans obtain levels greater than35 ng/mL.^' Healthy adult men utilize up to 5,000 IUof vitam in D per day, if it is available.'"''

In general, tbe more a patient weighs, the morevitamin D will be required, and large amou nts of bodyfat further increase requirements. Not only are baseline25(OH)D levels lower in the obese, tbe obese lequirehigher doses of oral supplements or UV radiation thanlean individuals in order to obtain the same increasesin 25(OH)D blood levels.^^ Fat malabsorption syn-dromes may increase oral requirements or necessitatethe use of ultraviolet radiation. Advancing age impairsthe skin's ability to make vitamin D, so older personsgenerally need higher supplem ental doses than youngerones. Tlierefore, dark-skinned, large, obese, or older pa-tients ftren require higher maintenance doses than fair-skinned, small, thin, or younger ones. Loading dosesof 50,000 IU (1.25 mg) of cholecalciferol per day for aweek, or at tbe most two, are sate to use before begin-ning maintenanc e therapy.

Cytochrome P-450 enzymes are responsibleht both the initial metabolism and subsequent catabo-lism of vitamin D. Therefore, drugs dependent on cy-tochrome P-450 enzymes - and there are many - may

affect vitamin D metabolism. What clinically relevantinteractions these substances - including cardiac drugs,crythro myc ins, psych o tropics, and even grapefruit juice- have on the metab olism of vitamin D is an area await-ing further research. Of the research done on drug/vi-tamin D interactions, anticonvulsants, corticosteroids,cimeridine, anti-tuberculosis agents, theophylline, andorlistat may lower 25(OH)D levels, while thiazide di-uretics and statins increase 25(OH)D levels,^'^^ Pa-tients on medications of any kind sh ould have frequenttesting of 25{OH)D levels when being treated withdoses above 2,000 IU per day.

Tlie authors recommend parents supplementbreast-fed infants with at least 800 IU of vitamin Ddaily, while formula fed infants need 400 IU per day.Infants and toddlers may be at extremely high risk ofdeficiency during weaning. Around 12-18 months,many stop drinking vitamin D-fortified infant formulaand begin con sum ing unfortified juices , which - inter-estingly - is also the time many au tistic children rapidlydeteriorate. Toddlers and young children who do notget regular sun exposure should take 1,000-2,000 IUdaily year-round, depending on body weight, keepingin mind tbat current Food and Nutrition Board recom-mendations state doses up to 2,000 IU per day are safefor children over tbe age of one. In the Stimmer, childrenwho spend time in the sun without wearing sunblockwill need little or none. Paren ts can easily open 1,000IU capsules containing powdered vitamin D and dis-solve the co nten ts in juice or food for easy delivery tochildren and infants.

Vitamin D deficiency in pregnancy is an on-going epidemic/'** and animal evidence continues toaccumulate that maternal vitamin D deficiency perma-nently injures fetal brains.' ' ^'* Pre gn an t w om en - orwomen thinking of becoming pregnant - should bave25(OH)D levels checked every three months and beadequately treated, often with 5,000 IU or more perday, as outlined above. Lactating women require evenmore, up to 7,000 IU per day, to assure breast milk isa rich source of vitamin D."' Infants being breast fedby supplementing mothers will not require additionalsupplementation, but will require adequate supplemen-tation during and after weaning.

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Treatment of DiseaseBy far the mosr common reason to treat with

vitamin D is osteoporosis, but the dose needed remainscontroversial because the lowest effective dose (800 IU/day) is known, bur the ideal dose is not.'^ Currently, vir-tually all of the evidence that vitamin D is an effectiveadjuvant for the treatm ent of other serious medical con-dirions is anecdotal, implied by epidemiological studies,from open trials, or inferred from vitamin D's mecha-nism of action. For example, there is an anecdotal reportthat pharmacological doses of vitamin D are effectivein treating - not jus t preventing - viral respiratory in-fections.^' Doses of 2,000 IU/kg body weight for threedays (200,000 IU per day for three days for a 100-kgadult) may seem excessive to those unfamiliar with vita-min D's pharmacology and toxicity. hi fact, such dosesare common in many parts of the world simply to pre-vent or treat vitamin D deficiency.

For example, single injections of 600,000 IU(15 mg) vitamin D raised 25(OH)D levels from 2 ng/mL to 22 ng/mL at two weeks and to 27 ng/mL at sixweeks in 10 elderly subjects, with no evidence of toxic-ity.'"* Indeed, a single injection of 600,000 IU of vita-min D is not only safe; such doses were recently recom-men ded in the autu mn for th e elderly, simply to preventwintertime vitamin D deficiency.'^ Likewise, there wasno evidence of toxicity in young men taking 50,000 IUof vitamin D pe r day for six weeks (altho ugh such a dosewould become toxic if taken over a longer period).'^ In32 severely vitamin D-deficient elderly patients, 50,000IU /da y for 10 days showed no evidence of toxicity an donly raised 25(OH)D levels by an average of 5 ng/mLthree months after administration. In no patient didlevels increase more than 11 ng/m L at three m on th s. '

Treatment of colds and influenza with phar-macological doses of vitamin D may only be the tip ofthe infectious disease iceberg. As Aloia and Li-Ng havepointed out, '^ it is intriguing that vitamin D-sensitiveantimicrobial peptides (AMP) inhibit the HIV virusand there is evidence that vitamin D plays a role inHIV/'^ Invasive pneumococcal disease, meningococcaldisease, and group A streptococcal disease are morecommon when vitamin D levels are lowest (winter)'"^'^'and all three bacteria are sensitive to AMP,^^ *' raisingthe possibility that pharmacological doses of vitaminD would be an effective adjuvant treatment. In fact, the

dramatically increased production of AMPs by vitaminD and the broad spectrum of action of AMP make i treasonable to hypothesize that pharmacological dosesof vitamin D are effective adjuvants in treating a largenumber of infections.

In a recent report, 12 patients in active phasesof multiple sclerosis were treated with progressively in-creasing weekly doses of vitamin D^ (the equivalent ofstarting with 4,000 IU p er day and increasing to 40,000IU per day) and calcium.^^ Mean serum concentrationsof 25(OH)D init ial ly were 31 ng/mL and rose to amean of 154 ng/niL at the end of 28 weeks, with noabnormalities in serum or urine calcium detected in the12 subjects. The number of MS lesions per patient onbrain scan decreased from an initial mean of 1.75 at thebeginning to a mean of 0.83 (p=0.03) at the end of thestudy. However, doses of 40,000 IU per day may causetoxicity if given for longer pe riod s; certainly, such d osesflirt with toxicity. Doses of 10,000 IU per day may wellhave achieved the sam e result with out the risk of toxicity.

Both epidemiological evidence and vitamin D'smechanism of action suggest it may have a treatment effect in early cancer. For example, a study of recurrencefree survival in early-stage, non-small-cell lung cancepatients found those with the highest vitamin D inpuhad double the five-year recurrence-free survival andmuch better overall survival than those with the lowest.*"" This strongly implies a vitamin D treatment effeci.e., untreated vitamin D deficiency in non-small-cellung cancer patients is a risk factor for early death.

Season of diagnosis has a survival effect onnumerous cancers; i.e., cancer patients live longer if thediagnosis is made in the summer rather than the winj.gj._H/,88 A.lthough no one has proven vitamin D causethis summer-season treatment effect, viramin D's anticancer mechanism of action Is basic to all cancers. Thusit is reasonable to hypothesize a general cancer treatment effect, at least in cancer's early stages, when aberrant cells are more likely to retain both rhe vitamin Dreceptor and the enzyme needed to activate vitamin D.

Practitioners who treat type-2 diabetic or hypertensive patients with physiological doses of vitaminD should be prepared for the possibility of cither hyp oglycemia or hypotension, especially after several month

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ot treatment. Theoretically, such doses of vitamin Dshould eventually lower both blood sugar and bloodpressure, although blood sugars may worsen for severalweeks after initiation or increase of vitamin D. Shouldeither hypoglycemia or hypotension occur, the diabeticand/or hypertensive medication should be lowered, notthe vitamin D.

Althou gh mod ern science knows little or noth-ing ab ou t the m etabolic clearance of vitamin D in differ-ent disease states , it is reasona ble to predic t tha t vitam inD is cleared more rapidly in some disease states. For ex-ample, patients witli diabetes, HIV , or cancer may rap -idly use 25(OH)D as substrate to make large amountsof 1,25(OH),D to fight their disease. Tlierefore, a pa-tient with cancer may require significantly higher dosesof vitamin D to maintain 2 5( O H )D levels of 55-70 ng /mL than a healthy adult of similar weight and body fat.Practitioners should supplement such patients (assum-ing they are not hypercalcmie) to high natural levels,even if it means taking 10,000 IU or more per day.Frequent monitoring of 25{OH)D and calcium levelsshould guide dosing in patients with cancer and otherserious illnesses, and such treatment should be adjunc-tive and never take the place of standard treatm ent.

Tlie authors believe that those who claim thelack of RC Ts sh ow ing vitamin D's effectiveness as adju-vant cancer treatm ent means it should never be so usedmiss an important point. For example, recent studiesshow a high incidence of vitamin D deficiency in pa-tients undergoing treatment for cancer.*^' Even at theend of summer, 48 percent of cancer patients in Bostonhad levels less than 20 ng/mL.'*'' In another study, 72percent of 60 cancer patients had 25(OH)D levels lessthan 30 ng/mL, and virtually none had natural levels.'^"A 1998 study of inpatients at Massachusetts GeneralHospital found 57 percent had 25(OH)D levels lessthan 15 ng/mL.'"

Thus , the question should not be, "Should can-cer (or multiple sclerosis, septic, cardiac, HIV, or hepa-titis B) patients be treated with vitamin Di'"'Tlie betterquestion is, "Should practitioners routinely screen andaggressively treat vitamin D deficiency in patients withserious or potentially fatal illnesses, or should such pa-tients combat their disease vitamin D deficient?" As ref-erenced above, the vast majority of such patients prob-ably expire severely vitamin D deficient.

Vitamin D ToxicityVitamin D toxicity is exceedingly rare and few

practitioners ever see it,'^^ although that could changewith the recent availability of 50,000 IU capsules. Tox-icity is secondary to the unbridled effects of hypercal-cemia. In chronic toxicity, first urine calcium and thenserum calcium will begin to gradually increase when25(OH)D levels exceed some level above 150 ng/mL.Such levels must be associated with hypercalcemia inorder to indict vitamin D. Chronic vitamin D toxicityresults when hypercalcemia goes undetected and calci-fies internal organs, especially the kidneys. In order toproduce hypercalcemia, most adults would have to takein excess of 10,000 IU per day for many m ont hs or evenyears. Most patients with vitamin D toxicity recoverfully by simply stopping the vitamin D and practicingstrict sun-avoidance.

Credible evidence of vitamin D toxicity inthose chronically consuming 10,000 IU of supplemen-tal cholecalciferol daily is absent in the litera ture. In fact,the litera ture c onta ins few cases of cholecalciferol tox ic-ity from supplement use; virtually all the reported casesof hypercalcemia are from faulty industrial production,labeling errors, dosing errors, and p atients treated med i-cally with pharmacological doses of ergocalciferol.

Tlie current Adequate Intakes and Upper Lim-its are for medically unsupervised intake by adults andchildren, set by the Institute of Medicine's Food andNutrition Board (FNB) in 1997, and do not apply tomedically supervised treatment. Surprisingly, the FNBsays Adequate Intake is the same 200 IU/day for thesmallest infant as it is for the largest pregnant woman.Likewise, the FNB 's Upp er Limit for both one-year-oldchildren and forty-year-old adults is 2,000 IU/day, alimit based on old and faulty literature.'" The currentofficial reco mm end ation s are illogical; for exam ple, howcan 200 IU/day be the adequate intake for both a 3-kginfant and a 60-kg pregnant w oman, and 2,000 IU/ daybe the Uppe r Lim it for both a 10-kg child and a 150-kgadult?

Although a 2,000-IU Upper Limit is prob-ably approp riate for infants an d young children, such alimit in older children, adolescents, and adults has theeffect of both limiting effective treatment of vitamin Ddeficiency and impairing dose-appropriate interven-tional research. However, the current 2,000-IU per dayUpper Limit does not impair a practitioner's ability to

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treat v itamin D deficiency with high er doses jus t as thecomparable Upper Limit for calcium does not impairthe pra ctition ers ability to treat hypocalcemia w ith cal-cium doses above the Upp er L imit once hypocalcemia isproperly diagnosed.

Practitioners who use doses above 2,000 IUper day should periodically monitor serum 25(OH}Dlevels, especially if patients are on other medications.Periodic monitoring will also educate the practitio-ner not only to the safety of supplementation, but tothe surprisingly high oral dose required to achieve andmaintain adequate se rum 2 5( O H }D levels, especially inthe fall and winter.

Absolute and Relative C ontraindicationsto TreatmentTlie only absolute contraindication to vitamin

D supplementation is vitamin D toxicity or allergy tovitamin D, although no reports in the literature werefound of acute allergic reactions to vitamin D supple-me nts. Con traindication s to sunlight or artificial U Vradiation include a number of dermatolgica! condi-tions (porphyrias, xeroderma pigmentosum, albinism),as well as various photosensitisers (sulfonamides, phe-nothiazines, tetracyclines, psoralens). Previous skincancers, especially cutaneous melanoma, are contra-indications to excessive UV exposure, although a recentstudy found reduced mortality in melanoma patientswho continued exposure to sunlight. ' ' ' ' Nevertheless,oral treatment is recommended for patients who havehad any type of skin cancer.

Although the liver initially metabolizes vitaminD, liver disease is not a contraindication to treatm ent ofdeficiency. The liver conserves the ability to hydroxylatevitamin D despite advanced liver disease.'*' A recentstudy of patients with advanced noncholestatic chronicliver disease recommended treatment of concomitantvitamin D deficiency after finding serum 25(OH)Dlevels of less than 10 ng/mL predicted coagulopathy,hyperbilirubinemia, hypoalbuminemia, anemia, andthrombocy topen ia.*

Vitamin D hypersensitivity syndromes - ohenconfused with vitamin D toxicity - occur when extra-renal tissues produce 1,25(OH).,D in an unregulatedmanner, causing hypercalcemia."*^ These syndromes

are diagnosed by measuring serum calcium (elevated)25 (O H )D (normal or low) , and 1,25(OH),D (elevated). Vitam in D hypersensitivity syndrome s can occur Insome of the granuiomatous diseases (especially sarcoi-dosis and tuberculosis), and in some cancers (especiallynon-Hodgkins lymphoma and oat cell carcinoma of thelung). Such conditions may be unmasked by vitamin Dtreatment; for example, sarcoidosis may become clini-cally evident after summer sun exposure.

Therefore, hypercalcemia is a relative contra-indication to vitamin D, sunlight, and artificial UVB radiation. Tlie practitioner should carefully evaluate anyhypercalcmie patient for the cause of hypercalcemiaOnce the cause is clear, should the practitioner decideto treat concomitant vitamin D deficiency - despite thehypercalcemia - it should only be if the hypercalcem ia imild to mod erate ( < 12 nig/dL) and should proceed cautiously, with frequent monitoring of clinical conditionurine and serum calcium, 25 (O H )D , and 1,25(OH).,DVitamin D, especially in large doses, could theoreticallyprecipitate a worsening clinical course in such p atientsSummary

Vitamin D deficiency is endemic and is associated with numerous diseases. Understanding vitaminD's physiology and having a high index of suspicion arkeys to determining the diagnosis. Serum 25(OH)Dlevels less than 40 ng /m L are seldom found in those living in a sun-rich environment and such levels are needed to assure normalization of the pharmacokinetics ovitamin D . Tre atm ent with sun light or artificial U V Bradiation is simple but increases the risk of non-melanoma skin cancers and ages the skin. Sun bur n increasethe risk of malignant melanoma. Adequate oral supplementation will require doses that might make a practitioner initially uncomfortable, as physiological doseof vitamin D, in the absence of sun exposure, probablrange between 400 IU/day for premature infants t10,000 IU/day for the morbidly obese.

Treatment of vitamin D deficiency in otherwise healthy patients must be individualized due to thnum erous factors affecting 2 5( O H )D levels, and doseshould be adequate to maintain serum 25 (O H )D levelbetween 40-70 ng/niL. Patients with chronic diseaseassociated with vitamin D deficiency, especially interna

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cancers, should be supplem ented with doses adequate tomaintain 25{OH)D levels in the higher normal range,55-70 ng/mL. Caution is required in any patient withhypercalcemia. Tlie use of short-term pharmacologicaldoses of vitamin D as treatm ent ior the comm on cold orflu - 2,000 IU /k g/ da y for several days - while theore ti-cally promising, awaits further study.References1. Autier P, Gandini S. Vitamin D supplementation andtotal monaliry: a meta-analysis of ramiomized concroiledtrials. Afch Imcm Med 2 0 0 7 ; 1 6 7 : 1 7 3 0 - I 7 3 7 .2. Stiidcr M, BricI M, Leimenstol! B. ec al. Effect of differentancilifiidemic agents and diets on mortaliry: a systematicreview. Arch U itcrn Med 2005;165:725-730 .3. Perez-Castr i l lon J L, Vega G, Abad L, et al. Effects ofAtorvastatin on vitamin D levels in patients with acuteischmie heart disease. AmJ Cniiol 2007;99:903-905 .4. AloiaJF, Li 'Ng M, Pollack S. Stat ins and vitamin D, Am ]

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Lappe J M , Travers-Gustafson D, Davies KM , et al. VitaminIJ and calcium supplementation reduces cancer risk: resultsofa randomized tr ial . Am] Clin N u r r 2 0 0 7 ; 8 5 : 1 5 8 6 - 1 5 9 1 ,Holick MF. High prevalence of vitamin D inadequacy andimplications for health. Mayo Clin Proi 2 0 0 6 ; 8 1 : 3 5 3 - 3 7 3 .Pcterlik M, Cross HS. Vitamin D and calcium deficitspredispose for multiple chronic diseases. FAVJ Clin nveu2005:35:290-304 .Holick MF. Sunlight and vitamin D for bonehealth and prevention of autoimmune diseases,cancers, and cardiovascular disease. A)ii / Cl'm Nutr2 0 0 4 : 8 0 : 1 6 7 8 S - 1 6 8 8 S .Zit ter man n A . Vitamin D in preventive medicine: are weignoring the evidence-" Br J Nutr 2003:89:552-572 .Petcrl ik M, Cross H S . Dysfunction of the vitaminD endocrine system as common cause for multiplemalignant and other chronic diseases. Antkancer Res2006:26:2581-2588 .Canne l l J J , Vie th R , U m ha uJ C et a l. Ep idemic in fluenzaand vitamin D. Ej'uiemiol H > r r 2 0 0 6 ; 1 3 4 : U 2 9 - 1 1 4 0 .Aloia J, Li-Ng M. Re: epidemic influenza and vitaminD.H> . ffn i [ /> ft2 0 0 7;1 3 5:1 0 95-1 0 96; a u tho r r e p l y1 0 97-1 0 98 .Cannell J | . Autism and vitamin D. Med Hypotheses 2 0 0 7 ;Oct 24 [Epub ahead of print]Litonjua AA, Weiss ST. Is vitamin D deficiency toblame for the asthma ep idemici / Allergy CUn Lnmunot2 0 0 7 ; 1 2 0 ; 1 0 3 I - 1 0 3 5 .Hypponen E, Laara E, Reunanen A. et al. Intake of vitaminD and risk of type 1 diabetes: a birth -coh ort study. Lancet2OOl;358:15OO-15O3.Hean ey R P. Long-latency deficiency disease: insight.s fromcalcium and vitamin D. AmJ Clin Nutr 2 0 0 3 : 7 8 : 9 1 2 - 9 1 9 .Lips P. Vitamin D physiology. Prog Biophys Mol Biol2 0 0 6;92 :4-8 .

18 . Dusso A S, Brown AJ, Slatopolsky E. Vitamin D. Am JPbysiol Renal Physiol 2005:289:F8-F28 .

19. Heaney RP, Dowell M S, Hale CA , Bendich A. Calciumabsorption varies within the reference range for serum25-hj'droxyvitamiii D.J Am Coll Nii r r 2003:22:142-146 .20. Bischoff-Ferrari HA, Dietrich T. Orav EJ, et al. Higher25-hydroxyvitamin D concentrat ions are associated withbetter lower-extremity function in both active and inactivepersons aged > or =60 y. AmJ Clin Nuir 2004 :80 :752-758 .21 . Garland C F, Gorh am ED , Moh r SB, et al. Vitamin Dand p revention of breast cancer: pooled analysis. J SteroidBiochcm Mol Biol 2007;l0^:708-7l\.22. Holick MF. Vitamin D deficiency. N EnglJ Med2007:357:266-28 L23 . Heaney R P. The vitamin D requirement in health anddisease . / Steroid Riochcm Mol Hiol 2 0 0 5 : 9 7 : 1 3 - 1 9 .24 . Bischoff-Ferrari H A , Giovannucci E, Willet t W C ,

et al. Estimation of optimal serum concentrat ions of25-hydroxyvitamin D for multiple health outcome s. Am JClin Nutr20Q6;84:8'28.25. CannellJJ , Hols BW, Zasloff M, Heaney RP. Diagnosisand treatment of vitamin D deficiency. Expert OpinPharmacother 2008;9:107'lis.26. Barger-Lux Mj, Heaney RP. Effects of above averagesummer sun exposure on serum 25-hydroxyvitaminD and calcium absorption.J Clin Endocrinol Metab2 0 0 2 : 8 7 : 4 9 5 2 - 4 9 5 6 .27. Vieth R. What is the optimal vi tamin D status for healthi

Prog Biophys Mol Biol 2006;92;26-32 .28. Vieth R. The pharmacology of vitamin D , includingfortification strategies. In: Feldman D, PikeJW,Glor ieux F H, eds . Vitamin D. San Diego, CA: Elsevier;2 0 0 5 : 9 9 5 - 1 0 1 5 .

29. Hollis BW, Wagner CL, Drezner MK, Binkley NC.Circulat ing vitamin D3 and 25-hydroxyvitamin Din humans: an important tool to define adequatenutri t ional vi tamin D status. J Steroid BiocheinMitl Biol2 0 0 7 : 1 0 3 : 6 3 1 - 6 3 4 .30. Heaney RPr The case for unproving vitamin D statu s.JSteroid Biochem Mol Riol 2 0 0 7 : 1 0 3 : 6 3 5 - 6 4 1 .31 . Chapu y M C, Preziosi P, Maam cr M . et al . Prevalence ofvitamin D insufficiency in an adult normal population.

Osteoporos In t 1 9 9 7 ; 7 ; 4 3 9 - 4 4 3 .32. Lamberg-Allardt CJ, Outi la TA. Karkkainen MV , et al.Vitamin D deficiency and bone health in healthy adults inFinland: could this be a concern in other parts of Europei_/Bone Miner Res 2OO1;I6:2O66-2O73.

33. Rucker D. Allan JA, Fick GH. Hanley DA. Vitamin Dinsufficiency in a population of healthy western Canadians.C M A J 2 0 0 2 : 1 6 6 : 1 5 1 7 - 1 5 2 4 .34 . Roth DE, Mar tz P, Yeo R, et al. Are nationa l vitam in Dguidelines sufficient to maintain adequate blood levels inchildren^ CanJ PuiAii Health 2 0 0 5 : 9 6 : 4 4 3 - 4 4 9 .35. Gordon CM, DePeter KC, Fetdman HA, et al . Prevalenceof vitamin D deficiency among healthy adolescents. ArchPediatr Adolesc Mcd 2004a58:53l-5^7.

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51. Wilkins CH , SheUne Yl, Roe CM, et al. Vitamin Ddeficiency is associated with low m ood and worse cognitiveperformance in older adults. Am ] Geriatr Psychiatry2006; 14:1032-1040.52. Vieth R, Kimball S, Hu A, Walfish P G. Randomizedcomparison o the effects of the vitamin D3 adequateintake versus 100 meg (4000 IU) per day on biochemicalresponses and the wellbeing of patients. NutrJ 2004;3:8.53 . Holick MF. The vitamin D epidemic and its healthconsequences.; Nutr 2005:1 35:2739S-2748S.54. Houghton LA, Vieth R. Tlie case against ergocalciterol(vitamin D2) as a vitamin supplement. Aiii / Cili-i iVufr2006:84:694-697.55. Trang HM , Cole DE, Rubin LA, et al. Evidence thatvitamin D3 increases serum 25-hydroxyvitamin Dmore efficientiy than does vitamin D 2. Am ] Cltn Nutr1998:68:854-858.56. Armas LA, Holtis BW, Heaney RP. Vitamin D2 is muchless effective than vitamin D 3 in hum ans. J CIM EndocrinoMetrti .2004;89:5387'5391.57. Grey A, LucasJ, Horne A, et al. Vitamin D repletionin patients with primary hyperparathyroidism andcoexistent vitamin D insufficiency./ Clin Endocrinol Met2005:90:2122-2126.58. P enniston KL, Tanumihardjo SA . The acute andchronic toxic effects of vitamin A.AmJ Clin Nutr2006:83:191-201.59. Rohde CM . DeLuca H F. All-trans retinoic acidantagonizes th e action of calciferol and its activemetabolite, 1,25-dihydroxycholecaIciferol, in rats../ Nutr2005:135:1647-1652.60. Oh K, Willett WC:, Wu K. et al. Calcium and vitamin Dintakes in relation to risk of distal colorectal adenom a inwomen. Am j/iiiemD /2007;16 5:l 178-1186.6 1. Vieth R, Cole D E, Hawker GA , et al. Wintertime vitaminD insufficiency is common in young Canadian women, andtheir vitamin D intake does not prevent it. Eur J Clin Nutr2001:55:1091-1097.62. Brot C, Vesterganrd P, Kolthofi N, ct al. Vitamin [) statusand its adequacy in healthy Danish perimenopausal womenrelationships to dietary- intake, sun exposure and scrumparathyroid hormone. Brj Nutr 2001i86:S97-Sl03 .63 . Aloia J F, Talwar SA, Pollack S, Yeh J. A randomizedcontrolled trial of vitamin D3 .supplementation in AfricanAmerican women. ArW; hitern Meii 2005;]65:16]8-162364. Heaney RP, Davies KM, Chen T C, et al. Human serum25-hydroxycholecalciferoi response to extended oral dosingwith cholecalciferol. AtnJ Clin Nutr 2003;77:204-210.65. Wortsman J, Matsuoka LY, Chen T C, et al. Decreasedbioavaability of vitamin D in obesity. Am J Clin Nutr2000;72:690-693.66. Valsamis H, Arora SK, Labban B, McFarlane S.Antiepiieptic drugs and bone metabolism. Niiir Metab(LoMii) 20 06 :3:3 6 .67. Epstein S. Schn eidet AE . Drug and hormon e effectson vitamin D m etabolism. In: Feldman D, Pike JW,Glorieux FH, eds. Vitamin D . San Diego, CA: Elsevier;2005:1253-1291.

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Ryan M A, Akinhi H T, Serrano AG , et al. Antimicrobialactivity of native and synthetic surfactant protein Bpeptides.J mmwwl 2006:176:416-425.Kimball SM, Ursell MR, O'Connor P. Vieth R. Safety ofvitamin D3 in adults with m ultiple sclerosis. Am J ClinNHir 2007:86 :645-6 51.Zhou W, Suk R, Liu G, et al. Vitamin D is associatedwith improved survival in early-stage non-small celllung cancer patie nts. Cancer Epidemiol Biomarkers Prev2005:14:2303-2309.Porojnicu A , Robsahm TE , BergJP, Moan J. Season ofdiagnosis is a predictor of cancer survival. Sun-inducedvitamin D may be involved: a possible role of sun-inducedvitamin D.^ Steroid Biocbein Mol Biol 2007; 103:675-678.Lim HS, Roychoudhuri R, Peto J, et al. Cancer survival isdependent on season of diagnosis and sunlight exposure. IntyCiimvr 2006; 119:1530-1536.Tangpricha V, Colon NA, Kaul H, et al. Prevalence ofvitamin D deficiency in patien ts attending an outpatientcancer care clinic in Boston. Endocr Pract 2004:10.292-293.Plant AS, Tisman G. Frequency of combined deficiencies ofvitamin D and holotranscobalamin in cancer patients. NutrC^m-n 2006:56:143-148.Thomas MK, Lloyd-Jones DM, Tliadhani Rl. et al.Hypovitaminosis D in medical inpatients. N EnglJ Med1998:338:777-783.Vieth R. Vitamin D supplementation, 25-hydroxyvitaminD concentrations, and safety. Am] Clin Nutr1999:69:842-856 .Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessmentfor vitamin D. AmJ C U n Nutr 2007;83:6-18.Berwick M, Armstrong BK, Ben-Porat L, et al. Sunexposure and m ortality from melanoma._/ Nati Cancer Imt2005;97:195-199.Davies M, BerryJL, Mee AP. Bone disorders associatedwith gastrointestinal and hepatobiiiary disease. In: FeldmanD, Pike JW, Glorieux EH , eds. Vitamin D. San Diego, CA:Elsevier; 2005:129 3-1311.Fisher L, Eisher A. Vitamin D and parathyroid hormone inoutpatients with noncholestatic chronic liver disease. ClinCastroettterol Hepatol 2007:5:513-520.Sharma OP. Hypercalcemia in granulomatous disorders: aclinic-il review. Curr Opin Pulm Me 2000:6:442-447.

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