Less sun means more disease -Grant, Holick, Cannell, et al

ISSN 2072-6643

www.mdpi.com/journal/nutrients

Review

Emphasizing theHealth Benefits of Vitamin D for Those with NeurodevelopmentalDisorders and Intellectual Disabilities

William B. Grant^1,* ,Sunil J. Wimalawansa²,Michael F. Holick³, John J. Cannell⁴,
Pawel Pludowski⁵, Joan M. Lappe⁶,Mary Pittaway⁷ and Philip May⁸

¹    Sunlight, Nutrition, and Health Research Center, P.O.Box641603, San Francisco, CA 94164-1603, USA

²    Department ofMedicine & Endocrinology, Cardio MetabolicInstitute, Somerset, NJ08873, USA; E-Mail: [email protected]

³    Department ofMedicine, Section of Endocrinology, Nutrition, and Diabetes, and the Vitamin D,Skin, and Bone Research Laboratory, Boston University Medical Center, Boston,MA 02118, USA; E-Mail: [email protected]

⁴    Vitamin D Council and San Luis Obispo IntegrativeMedicine, San Luis Obispo, CA 93401, USA; E-Mail: [email protected]

⁵    Department ofBiochemistry, Radioimmunology, and Experimental Medicine, The Children’sMemorial Health Institute,04-730 Warsaw, Poland; E-Mail: [email protected]

⁶    Creighton University School of Medicine, Omaha, NE68131, USA; E-Mail: [email protected]

⁷    Global Clinical Advisor-HealthPromotion, Special Olympics International and Affiliate Faculty,College of Education and Human Sciences, University of Montana, Missoula, MT59812, USA; E-Mail: [email protected]

⁸    InternationalFoundation for Chronic Disabilities, Inc., P.O. Box 166, Oxford, NJ 07863, USA;E-Mail: [email protected]

*   Author to whom correspondence should be addressed; E-Mail:[email protected]; Tel.:1-415-409-1980.

Received:23 October 2014 / Accepted: 5 February 2015 /Published:

Abstract: People with neurodevelopmental disorders and intellectual disabilitieshave much greater health care needs. Mainly staying indoors, such peoplegenerally have low 25-hydroxyvitamin D(25(OH)D) concentrations. The Vitamin D Task Force of the AmericanAcademy of Developmental Medicine and Dentistry (AADMD) reviewed the evidenceof25(OH)D concentrations that benefit thehealth of persons with developmental disabilities. Maintaining recommendedoptimal serum 25(OH)D concentrations year long will benefit skeletaldevelopment in infants, children, and adolescents, and benefit musculoskeletalhealth and neuromuscular coordination in adult patients, and decrease risk offalls. Maintaining optimal concentrations decreases risks and severities of autoimmune diseases, cardiovascular disease,many types of cancer, dementia, types 1 and 2 diabetes mellitus, andrespiratory tract infections. Other benefits include improved dental andoral health and improved physical performance. The Task Force recommends that25(OH)D concentrations for optimal health to be in the range of 75 to 125 nmol/L, which can be achieved using between 800 to 4000IU/d vitamin D₃ and sensible exposure to solar UVB radiation. Thepaper also discusses the potential risks of higher 25(OH)D concentrations, theevidence from and limitations of randomized controlled trials, and therecommendations by various groups and agencies.

Keywords:autism; bone health; cancer; cardiovascular disease; developmentaldisabilities; Down syndrome; fractures; intellectual disabilities; vitamin D;25-hydroxyvitamin D

1. Introduction

People with neurodevelopmentaldisorders and intellectual developmental disabilities (IDD), or medicallycomplex developmental disabilities (MCDD), require much greater health carethan other patient populations. According to the American Academy ofDevelopmental Medicine and Dentistry (AADMD), the most commonly diagnosed neurodevelopmental disorders are Down syndrome, fetalalcohol spectrum disorder, fragile X syndrome, cerebral palsy, autism, andintellectual disability of unknown origin ^[1]. The Canadian consensus guidelines for adults with developmentaldisabilities ^[2] summarize these and related issues for such people inCanada.

People with MCDD are prone tohaving low blood concentrations of 25-hydroxyvitamin D (25(OH)D) for severalreasons, including generally staying indoors or excessive use of sunscreens,propensity to obesity, and taking various medications ^[3]. These peopletherefore have higher rates of osteopenia andosteoporosis ^[4], chronic diseases, [5–8], respiratory infections ^[9], andpoorer oral health ^[10] than community-dwelling individuals. Evidencesuggests that vitamin D offers several health benefits, including reduced riskof falls and fractures, several types of cancer, cardiovascular disease,cognitive decline, dementia, diabetes mellitus, respiratory and other types ofinfections, and many other conditions and diseases ^[11].

In light of the rapidlyadvancing understanding of vitamin D’s importance for optimal health, AADMDcommissioned its Vitamin D Task Force to review evidence of vitamin D’s healthbenefits and recommend strategies to manage vitamin D deficiency among the MCDDcommunity. Since those in the MCDD community are living longer now ^[12], thetask force considered the effects of vitamin D for all age groups.

2. Approach and Rationale

In carrying out this charter,task force members used PubMed.gov and other databases to review the literatureon the health conditions of people with MCDD as well as on vitamin D’s healthbenefits. Members used the following search terms: vitamin D and intellectualdisabilities, developmental disabilities, many diseases; developmentaldisabilities or intellectual disabilities and health outcomes. Many findingssupporting vitamin D’s role in reducing risk of disease come from observationalstudies that determined health outcomes from studies measuring blood 25(OH)Dconcentrations at time of enrollment ordiagnosis. One can raise 25(OH)D concentrations by either UVB exposure or oralvitamin D intake. Thus, it is possible that 25(OH)D concentrations are,in part, an index of solar UVB exposure that includes effects other thanvitamin D production.

Concern has been raised that25(OH)D concentration-health outcome relations could be due to reversecausation, that is, that having disease affects 25(OH)D concentrations, sincefew randomized controlled trials (RCTs) havesupported the findings of observational studies in general. The reason for thisis thought to be largely because of trial design. Most vitamin D RCTs were based on the pharmaceutical drug model and assumethat the only source of the agent is through the trial and that a lineardose-response relation exists; neither assumption is valid for vitamin D ^[13].In addition, many trials used little vitamin D (400–1000 IU/day), did notmeasure 25(OH)D concentrations at time of enrollment or end, and enrolledmostly people with 25(OH)D concentrations near or above 50 nmol/L.Thus, one would not expect such studies to find significant benefits. Thus, for now, observational studies—especially inthe form of meta-analyses—appear to offer the best information on thelink between vitamin D and many health outcomes ^[11,14].

We intend these guidelines to prevent chronic and infectious diseases,not treat them, and several papers discussed here based their vitamin Dguidelines and recommendations largely on observational studies.

3. Findings

The first task was to determinewhat conditions and diseases are more common among those with MCDD. Table 1shows representative findings for several vitamin D-sensitive diseases. Ratesfor many chronic diseases are approximately twice those for community-dwelling,non-MCDD individuals. Table 2 gives the definitions of the acronyms regardingdisabilities.

Table 1.Representativefindings regarding disease rates among those with developmental and/orintellectual disabilities.

DD,developmental disabilities; ID, intellectual disability;IDD, intellectual and developmental disabilities;OR, odds ratio.

Table2. Definitions

Respiratorytract infections (RTIs) are common among those withdevelopmental disabilities ^[19,24] because they:(1) often live together ingroup homes or institutions, where RTIs can spreadrapidly; and (2) generally have low serum 25(OH)D concentrations due partly tostaying largely indoors. Also, some medicinesgiven to this population, such as anticonvulsant drugs, glucocorticoids,and AIDS medications, reduce serum 25(OH)D concentrations ^[25].

Similarly, the MCDD communityhas low serum 25(OH)D concentrations for several reasons.
They stay mostly indoors and so producelittle vitamin D from solar ultraviolet-B (UVB), are often obese, andtake medications that lower 25(OH)D concentrations ^[26]. They also areunlikely to take vitamin supplements. Table 3 presents findings regarding serum25(OH)D concentrations for those with ID or primarily older people living innursing homes.

Table 3.Blood 25(OH)D concentrations among those with ID.

ID, intellectual disability.

3.1.Conditions and Diseases That Vitamin D MightPrevent and Treat

3.1.1. Bone Metabolism, Falls and Fractures

Vitamin D was first known as the substance that prevented rickets.Although doctors in the 19th century knew that lack of sunlight was a riskfactor for rickets, research did not identify vitamin D as the compound thatprevented rickets until the early 20th century ^[30]. Vitamin D preventsrickets by mediating calcium absorption in the intestines as well as calciummetabolism.

A 2010 study regarding vitaminD deficiency and bone mineralization involved examining bones from vehicularaccident victims in Germany. Both blood and bone samples were obtained atautopsy. That study defined osteomalacia as apathologic increase in osteoid volume per bone volumegreater than 2%. People with serum 25(OH)D concentration<75 nmol/L met that criterion, but no one with serum 25(OH)Dconcentrations >75 nmol/L did ^[31].

Avoiding falls and fracturesinvolves both strong bones and good neuromuscular control. Postural sway islinked to increased risk of falls, and sway was more prevalent in those withserum 25(OH)D concentrations below 30 nmol/L ^[32]. Astudy in The Netherlands found that weekly treatment with 8400 IU of vitamin D₃ reduced posturalsway in those with elevated sway at enrollment ^[33]. A meta-analysis ofvitamin D supplements showing reduced risk of falls for elderly peoplesuggested that vitamin D’s effect may be due to improved neuromuscular functionwith vitamin D supplementation ^[34].A pooled analysis of fractures withrespect to vitamin D supplementation among those older than 65 years found that“By quartiles of actual intake, reduction in the risk of fracturewas shown only at the highest intake concentration (median, 800 IU daily;range, 792 to 2000), with a 30% reduction in the risk of hip fracture (hazardratio (HR), 0.70; 95% CI, 0.58, 0.86) and a 14% reduction in the risk of any nonvertebral fracture (HR, 0.86; 95% CI, 0.76, 0.96)” ^[35].

The Endocrine Societyrecommends serum 25(OH)D concentrations above 75 nmol/Lto reduce risk of falls and fractures ^[36]. People with MCDD often have osteomalacia ^[37]andosteopenia ^[38],which has been treated with bisphosphonates ^[38].However, a DXA machine, which measures bone mineral density, cannot distinguishlow bone mineral density caused by osteoporosis from that caused by osteomalacia. Treating osteomalaciawith a bisphosphonate could precipitate severe oreven lethal hypocalcemia. In an observational studyof patients associated with two U.S. hospitals, favorable response to bisphosphonates was better at higher 25(OH)Dconcentrations: nonresponder rates were 79% for thosewith 25(OH)D concentrations <75 nmol/L, 50% forthose with 25(OH)D concentrations of 75–100 nmol/L,and only 33% for those with 25(OH)D concentrations >100 nmol/L^[39].

To maintain calciumconcentration in the blood, the body takes calcium from the intestines or bonesaccording to the balance between parathyroid hormone (PTH) and1,25-dihydroxyvitamin D ^[40].
The 25(OH)D concentration–PTH relation has an inverse relation out to at leasta serum 25(OH)D concentration of 150 nmol/L ^[41].Increased PTH concentrations are associated with increased mortality rates,vascular and valvular calcification, renal failure,heart failure, and cardiovascular disease ^[40].

However, other factors—such asintake of vitamins C and K as well as calcium and magnesium ^[42], proteinintake ^[43], and exercise ^[44,45]—also affect bone strength.

3.1.2. Physical Functioning

Since 25(OH)D concentrationsaffect muscles and neuromuscular control ^[32], we can reasonably expectconcentrations to also affect physical functioning. A study of two cohorts ofelderly people living in Amsterdam examined the relation between serum 25(OH)Dconcentrations and functional limitations. The study included six functions:walking up and down staircases, dressing and undressing oneself, sitting downand standing up from a chair, cutting one’s toenails, walking outside for 5minutes without resting, and using one’s own or public transportation. After 3years of follow-up, those aged at least 65 years at enrollment and with serum25(OH)D concentrations <75 nmol/L showed morefunctional limitations (at least two more), whereas those aged 55–65 years atenrollment had more functional limitations after 6 years of follow-up thanthose with concentrations X05;75 nmol/L ^[46].

3.1.3. Infectious Diseases

Vitamin D fights bacterial andviral infectious diseases in at least two ways. One is by inducing cathelicidin (also known as LL-37), a polypeptide withantimicrobial and antiendotoxin properties, and defensins ^[47]. The other is by shifting cytokineproduction toward diseases less prone to cause inflammation ^[48,49].

3.1.4. Type A Influenza

The seasonal variation ofinfluenza formed the basis of Cannell’s UVB–vitaminD–influenza hypothesis ^[50]. Two RCTs supported thishypothesis, one involving black postmenopausal women with a baseline mean25(OH)D concentration of 48 nmol/L ^[51], the otherinvolving schoolchildren in Japan ^[52]. In the black postmenopausal womenstudy, for 312 person-years of taking a placebo with baseline 25(OH)D concentrations 47±21 nmol, 30colds or influenza cases occurred; for 208 person-years of taking 800 IU/day vitamin D₃, 8colds or influenza cases occurred; for 104 person-years of taking 2000 IU/dayvitamin D₃, one cold or influenza case occurred. In the Japan study,supplementation with 1000 IU of vitamin D₃ per day reduced risk oftype A influenza by 67% but did not affect that of type B influenza.

3.1.5. Acute Respiratory Tract Infections,Asthma, and Chronic Obstructive Pulmonary Disease

A June 2013 meta-analysis ofthe 11 RCTs on vitamin D and RTIsassociated vitamin D supplementation with an OR of 0.64 (95% CI, 0.49, 0.84).That analysis also noted that once-daily dosing yielded better effects thanbolus dosing (odds ratio = 0.51 vs. 0.86; p = 0.01) ^[53].Thisstudy supports daily rather than weekly or monthly dosing. Studies have alsoassociated higher 25(OH)D concentrations and vitamin D supplementation withreduced effects of asthma [54–56] andchronic obstructive pulmonary disease ^[57,58]. A meta-analysis of results ofvitamin D trials found a statistically significant reduction (relativerisk (RR) 0.41, 95% CI, 0.27, 0.63) in asthmaexacerbation with vitamin D therapy ^[59].

3.1.6. Insulin Resistance

In insulin resistance, cells donot respond to insulin, causing high blood sugar. A vitamin D RCT involvinginsulin-resistant South Asian women living in New Zealand with baseline 25(OH)Dconcentrations below 50 nmol/L gave half the women4000 IU of vitamin D₃ per day and placebos to the other half.Participants reaching serum 25(OH)D concentrations of 80–120 nmol/L showed significantly improved insulin sensitivity ^[60].

3.1.7. Type 2 Diabetes Mellitus

Mounting evidence indicatesthat vitamin D reduces risk of developing type 2 diabetes mellitus (T2DM), forwhich insulin resistance is a risk factor. Several observational studies foundthat people with higher serum 25(OH)D concentrations had reduced risk ofdeveloping T2DM. A meta-analysis of 18studies found that the RR dropped from 1.0 (95% CI, 0.9, 1.1) at 33 nmol/L to 0.67 (95% CI, 0.45, 0.73) at 100 nmol/L ^[61]. Some caution regarding this finding is inorder because a recent study found that after adjustment for body mass index,the inverse correlation between incidence of T2DM and baseline 25(OH)Dconcentration was no longer significant ^[62]. An open-label prospective studyin India involving prediabetic individuals with meanage of 48 years followed for a mean of 28±9 months found that having meanbaseline 25(OH)D concentration of 95 nmol/L or beingsupplemented with sufficient vitamin D to raise the final 25(OH)D concentrationto 89 nmol/L significantly reduced the conversion todiabetes mellitus compared with baseline or final 25(OH)D concentration of 45 nmol/L ^[63]. A study in Israel found a beneficial effectof supplementation with 1000 IU of vitamin D per day for patients with T2DM for12 months in improving the central aortic augmentation index, therebyalleviating some cardiovascular damage ^[64].

3.1.8. Cardiovascular Disease

Strong evidence fromprospective observational studies indicates that serum 25(OH)D concentrationsare inversely correlated with cardiovascular disease (CVD). A meta-analysis of16 studies found that the RR of CVD was 2.2(95% CI, 1.7, 2.8) for 20 nmol/L, dropping to 1.0(95% CI, 0.8, 1.2) at 75 nmol/L ^[65]. The RR for lowvs. high serum 25(OH)D concentration from these studies was 1.52 (95% CI,1.30, 1.77). RCTs on those with low 25(OH)Dconcentrations at enrollment found beneficial effects of vitamin D supplementation.In the Women’s Health Initiative Study, 400 IU of vitamin D₃ plus1500 mg of calcium supplementation per day was associated with increasedhigh-density lipoprotein cholesterol and lower low-density lipoproteincholesterol and triglycerides ^[66]. The improvements in lipid profiles weremost pronounced for those with 25(OH)D concentrations above 100 nmol/L. However, vitamin D RCTsconducted on healthy community-dwelling populations found no beneficial effectof vitamin D supplementation on risk of CVD ^[67]. Respiratory infections suchas influenza can trigger CVD events such as acute myocardial infarction ^[68],suggesting another way vitamin D might reduce risk of CVD.

3.1.9. Alzheimer’s Disease

Evidence is mounting thatvitamin D deficiency is an important risk factor for Alzheimer’s disease (AD).A prospective study in Denmark associated low 25(OH)D concentrations with abouta 20% increased risk of both AD and vascular dementia over a 30-year follow-up ^[69].Cardiovascular risk factors contribute to risk of AD ^[70]. As just discussed,vitamin D deficiency is a risk factor for CVD. In early 2014, Gezen-Ak and colleagues reviewed evidence that vitamin Ddeficiency is an important risk factor for AD. The evidence includes thatvitamin D plays roles in protecting the central nervous system, regulating calcium homeostasis, attenuating oxidative stress,and enhancing immune response ^[71].Another recent paper suggested that vitaminD supplements could be used in therapy for those with AD ^[72]. A recentcohort study in the U.S. involving 658 elderly people monitored for a mean of5.6 years found a multivariate-adjusted HR for incident AD of 2.22 (95%CI,1.02, 4.83) for those with 25(OH)D <25 nmol/Lcompared with those with 25(OH)D >50 nmol/L ^[73].

3.1.10. Autism Spectrum Disorder

Evidence increasingly indicatesthat vitamin D deficiency plays an important role in risk for and progress ofautism spectrum disorder. Cannell proposed thevitamin D–autism hypothesis in 2008 ^[74]. An ecological study of autism prevalencerates for those aged 6–17 years in the United States found significant inversecorrelations with solar UVB doses, a proxy for vitamin D production ^[75].Researchers in 2014 proposed that a mechanism linking vitamin D deficiency torisk of autism was that vitamin D regulates serotonin synthesis both inside andoutside the brain ^[76]. They also indicated that increasing 25(OH)D concentrations might ameliorate some symptoms ofautism. A recent paper reviewed the evidence that vitamin D reduces riskof autism spectrum disorder ^[77]. Treating those with autism spectrum disorderwith vitamin D may reduce symptoms of autism ^[78,79].

3.1.11. Attention Deficit–Hyperactivity Disorder

People with ID have anincreased risk of attention deficit hyperactivity disorder (ADHD) ^[80].
Two recent papers reported that people with ADHD have lower 25(OH)Dconcentrations than control subjects ^[54,81]. Preliminary evidence indicatesthat increasing 25(OH)D concentrations can reduce symptoms of ADHD ^[82].

3.1.12. Cancer

Evidence that vitamin D reducescancer risk comes from several study types. Ecological studies based ongeographical variations of solar UVB and cancer incidence or mortality ratesfurnish good evidence for about 15 cancers ^[83,84]. Observational studies basedon serum 25(OH)D concentrations offer good evidence that vitamin D reduces riskof colorectal and breast cancer ^[85,86] and aggressive prostate cancer ^[87]. RCTs offersome evidence that vitamin D reduces risk of cancer [88–90], although vitaminD RCTs to date have not been well designed orconducted ^[13]. As Ref. ^[13] outlines, vitamin D RCTsshould start with an understanding of the 25(OH)D concentration–health outcomerelation, measure the 25(OH)D concentration of the prospective participants,include only those whose 25(OH)D concentration is near the lower end of therelation, supplement them with enough vitamin D to raise the concentration tothe upper end of the relation, and then remeasure25(OH)D concentrations. Most vitamin D RCTs to datedid not measure baseline 25(OH)D concentrations; those doing so did not rejectthose with higher 25(OH)D concentrations. Also, until recently, the vitamin D₃supplementation was 400 IU/day, although it is rising to 1000–4000 IU/day.Also, for those diagnosed with breast cancer, colon cancer, lung cancer, andlymphoma and who have higher 25(OH)D concentrations, survival rates are muchhigher ^[91].

3.1.13. Oral Health

Vitamin D’s role in reducing risk of dental caries has been known since1928 with a study of vitamin D supplementation in boys in Sheffield,England ^[92]. The effect was originally thought to be due to better calciummetabolism but has now been linked more strongly to antimicrobial propertiesthrough
vitamin D’s induction of cathelicidin^[93]. Several geographical ecological studies in the mid-20th centuryinversely correlated solar UVB doses and dental caries ^[93]. Further evidencecomes from controlled trials of vitamin D supplementation and observation ofcaries incidence. A 2012 review of 24 controlled clinical trials encompassing2827 participants found a pooled relative-rate estimate of supplemental vitamin D of 0.53 (95% CI, 0.43, 0.65) ^[94]. Although many ofthese trials were not modern RCTs, results among them were consistent, givingcredibility to the findings. Studies have also linked vitamin Ddeficiency to periodontal disease [95–97]. A recent study in Saudi Arabiafound that for older men, “total vitamin D intake X05;800 IU was associated with lower odds of severe periodontaldisease (OR = 0.67, 95% CI, 0.55, 0.81) and moderate-to-severe ABL (OR =0.54, 95% CI, 0.30, 0.96) relative to intake <400 IU/day” ^[98].

3.1.14. Other Health Outcomes

Evidence also indicates thatvitamin D reduces risk of cognitive decline ^[99], hypertension ^[100], andnonspecific pain ^[101,102]. These associations are still the subject ofongoing research, but they do offer additional reasons to recommend higher25(OH)D concentrations for people with MCDD.

3.1.15. All-Cause Mortality Rate

A recent meta-analysis of 32observational studies found increased HR for 25(OH)D concentrations below 90 nmol/L ^[103]. The HR for <25 nmol/Lwas 1.90 (95% CI, 1.63, 2.23), that for 25–48 nmol/Lwas 1.58 (95% CI, 1.36, 1.84), and that for 50–73 nmol/Lwas 1.23 (95% CI, 1.06, 1.24). Another meta-analysis found significant RRs for low vs. high 25(OH)D concentration inobservational studies ranging from 1.14 (95% CI, 1.01, 1.29) to 1.60 (95% CI,1.32, 1.94), with the exception of secondary preventioncohorts for noncardiovascular, noncancerdeath, for cancer, cardiovascular, other, and all-cause mortality rates ^[104].

3.1.16.Health Outcomes in Relation to 25(OH)D Concentrations

Table 4 presents 25(OH)Dconcentrations above which little additional benefit is found. Several values are based on meta-analyses of 25(OH)Dconcentration–health outcome relations from observational studies suchas those for breast cancer ^[85], cardiovascular disease ^[65], T2DM ^[61], andall-cause mortality rate ^[103]. Others are based on a variety of studies,including clinical, cohort, and prospective studies, and guidelines byorganizations. These results are in line with those reported by Spedding, generally 75–100 nmol/L^[105].

Table 4.Findings regarding 25(OH)D concentrations related to health conditions fromobservational studies.

The U.S.Department of Health and Human Services is developing more coordinated and comprehensive approaches to prevent and treatdisease in persons with multiple chronic conditions ^[113].
We hope that these approaches will include increasing 25(OH)Dconcentrations.

From the relationships betweenhealth outcomes and 25(OH)D concentrations, one can estimate the beneficialeffects of increasing 25(OH)D concentrations. Table 5 presents findings fromseveral studies, primarily meta-analyses of observational studies. Increasingfrom 38 to 75 nmol/L reduces average adverse healthoutcomes by 27%,whereas increasing to 100 nmol/Lreduces outcomes by 36%.

Table 5.Estimated reductions in disease rates by increasing 25(OH)D concentrations.

A few reportsfound adverse health effects for higher 25(OH)D concentrations, the most importantbeing hypercalcemia,which generally does not occur for 25(OH)D concentrations below 500 nmol/L ^[117]. Achieving this concentration ishighly unlikely unless someone takes more than 50,000 IU of vitamin D daily fora prolonged period or mistakenly overdoses with high-concentration vitamin Dsupplements with 1million IU of vitamin D ^[118]. We discuss findings of J- orU-shaped 25(OH)D concentration–health outcomes later.

3.2. Reviews of Vitamin D Benefits, Requirements,Recommendations

Several health organizationsand vitamin D working groups have reviewed the evidence of health benefits ofvitamin D and recommended desirable serum 25(OH)D concentrations and vitamin D₃supplementation. Many molecular mechanisms of vitamin D’s action are well known^[119]. Table 6 summarizes recommendations for those likely to be vitamin Ddeficient. The general consensus of these recommendationsis that serum 25(OH)D concentrations should be at least 75 nmol/Land up to 125 nmol/L and that reaching theseconcentrations takes about 1000–2000 IU of vitamin D₃ per day. Arecent paper also analyzed optimal concentration on the basis of three diversefindings (zero correlation between 25(OH)D and PTH above a threshold, supportof lactation, and ancestral values), concluding that 100–130 nmol/L was optimal and could beachieved with all-source inputs of 4000–6000 IU per day ^[13].The task forceconsidered input from these organizations and working groups in makingrecommendations for people with MCDD.

Table 6.Vitamin D recommendations by organizations and groups.

ESCEO, European Society for Clinical andEconomic Aspects of Osteoporosis and Osteoarthritis; UL, upper limit.

3.2.1. Institute of Medicine Report

The Institute of Medicine (IOM)issued a report in 2010 on dietary requirements for calcium and vitamin D forpeople living in North America. Its recommendations for vitamin D intake toachieve a serum 25(OH)D concentration of 50 nmol/Lwere 400 IU/day for infants younger than 1 year, 600 IU/day for those aged 1–70years, and 800 IU/day for those aged ³71years ^[126]. The abstract of that paper stated, “The Committee concluded that available scientific evidence supports akey role of calcium and vitamin D in skeletalhealth, consistent with a cause-and-effect relationship and providing a soundbasis for determination of intake requirements. For extraskeletaloutcomes, including cancer, cardiovascular disease, diabetes, and autoimmunedisorders, the evidence was inconsistent, inconclusive as to causality, andinsufficient to inform nutritional requirements. Randomized clinical trialevidence for extraskeletal outcomes was limited and generally uninformative”. The vitamin Dresearch community severely criticized the IOM report. For example, “TheIOM recommendations for vitamin Dfail in a major way on logic, on science, and on effective public healthguidance. Moreover, by failing to use a physiological referent, the IOM approach constitutes precisely the wrong model fordevelopment of nutritional policy”^[127]. The only evidence that the IOMcommittee found acceptable as a basis for policy recommendations was from RCTs and observational studies regarding bone health. Amongother things, IOM misinterpreted the observational study it used to set the25(OH)D concentration to50 nmol/L; the authors of thestudy concluded from the data that 75 nmol/L was theappropriate concentration ^[31].

The levels of evidence forevidence-based medicine place systematic reviews of RCTsat the top but permit observational studies and mechanism-based reasoning inthe absence of RCTs ^[128].
The recommendations in Table 6 were based largely on observational studies andmechanisms. As noted, vitamin D RCTs have in generalbeen poorly designed. A recent paper argued that absence of supportive vitaminD RCTs should not undermine the observational studiesfinding beneficial effects ^[129]. The IOM report also noted that “Guidelinesregarding the use of serum markers of vitamin D status for medical managementof individual patients and for screening were beyond the scope of theCommittee’s charge, and evidence-based consensus guidelines are not available.However, these issues should be addressed by appropriate federal agencies andprofessional organizations in light of the findings in this report.” Most ofthe recommendations in Table 6 were done by professional organizations for thebenefit of those they serve. For example, one stated, “The objective was toprovide guidelines to clinicians for theevaluation, treatment, and prevention of vitamin D deficiency with an emphasison the care of patients who are at risk for deficiency” ^[36].

Finally, since the IOM report was published (29 November,2010), 13,535 publications with vitamin D inthe title or abstract have been published at PubMed.gov as of  23 February, 2015, compared with 27,775published before that date. This paper cites many of these publications.
Until about 2000, most papers published on the use of vitamin D in clinicaltrials was related to musculoskeletal effects; now, however, the evidence ofbenefits for nonskeletal effects is still accruing.The IOM listed 4000 IU/day vitamin D as the upper limit of supplementation. However,they noted that no adverse effects had been reported for less than 10,000IU/day (see ^[130]). A recent paper studied the dose–response relation for25(OH)D and serum calcium as a function of vitamin D supplementation. For dailydoses of 10,000 IU/day, the mean 25(OH)D concentration was above 150 nmol/L (155 nmol/L) only for theunderweight group; for the obese group, the mean concentration was 110 nmol/L ^[131]. Serum calcium was nearly unchanged for up to20,000 IU/day.

3.2.2. U- and J-Shaped 25(OH)D Concentration–HealthOutcome Relations

Several observational studiesreported a J- or U-shaped 25(OH)D concentration–health outcome relation withthe following factors: all-cause mortality ^[132,133]; adverse cardiac and cerebrovascular events in cardiac surgery ^[134]; frailty ^[135];hospital mortality ^[136]; and immunoglobulin E ^[137]. The mortality ratefindings are not supported in a meta-analysis of 32 studies ^[103]. Suchstudies have been cited to warn against supplementing with too much vitamin Dor raising 25(OH)D concentrations too high. However, most of these studies areon elderly people and the highest 25(OH)D quintile was generally above 100 nmol/L, a value generally reached in the U.S. and Europethrough vitamin D supplementation. None of those studies seems to have askedparticipants when they started taking supplements. For frailty, although aU-shaped relation emerged for older women, a nearly linear inverse 25(OH)Dconcentration-frailty relation was present for men ^[138]. The differencebetween men and women is consistent with the fact that women are often advisedto start taking vitamin D supplements after menopause, and that taking vitaminD late in life cannot overcome all the adverse effects of low 25(OH)Dconcentrations earlier in life. No mechanisms have been proposed to explainmost of the J- or U-shaped relations.

A recent paper reporting anobservational study of inflammation with respect to 25(OH)D concentrationstated, “On the other hand, the U-shaped association may be an artifact, determinedby the small proportion of subjects with 25(OH)D in the target range (25(OH)DX05;30 ng/mL: 13.1% of subjects; 25(OH)D X05;40ng/mL;3.0% of subjects). The majority of our study population (76.3%)had25(OH)D concentrations <25 ng/mL, a range in whichhs-CRP decreased with increasing 25(OH)D.Additionally, we cannot exclude that subjects with high 25(OH)D concentrationshad not acknowledged taking vitamin D supplements in the SHIP examination,which might have biased the analyses. Overall, there is no final explanationfor the U-shaped association between 25(OH)D and hs-CRPin our study population and we suggest assessing it in future studies” ^[139].

Another recent paper examinedwhether 25(OH)D concentrations >100 nmol/L reduced1,25-dihydroxyvitamin D concentrations to account for the U-shaped relation forpostoperative recovery after cardiac surgery; the answer was no ^[140].However, that paper noted that impaired kidney function as measured byestimated glomerular filtration rate is associatedwith lower conversion of 25(OH)D to 1,25(OH)₂D, which could accountfor some adverse effects associated with higher 25(OH)D concentrations. Reportsthat seem most credible—both for 25(OH)D >125 nmol/L—revealedincreased immunoglobulin E, a marker of allergic responses^[137], as well as reduced cognitive performance ^[141]. Men had increased riskof hypogonadism for 25(OH)D concentrations >100 nmol/L ^[142]. However, these reports need furtherconfirmation.

3.2.3. Reports of Adverse Events Associated withHigh dose Vitamin D

One of the dangers of vitamin Dsupplementation is risk of hypercalcemia or bloodcalcium levels that are too high. Vitamin D intoxication can result in anelevated serum calcium and serum phosphorus level. Constitutional symptomsinclude confusion, nausea, constipation, polyuria andpolydipsia, decreased heart rate and arrhythmias. ^[143].The long-term consequences include soft tissue calcification of the bloodvessels, nephrocalcinosis and kidney stones.Generally, hypercalcemia does not occur for vitamin Dsupplementation less than 40,000 IU/day^[144]. However, sometimes high 25(OH)Dconcentrations are reached by accident, such as a manufacturing and labelingerrors ^{[118,143,145]}. “Hydration, diuretics and prednisone induced aprogressive reduction of calcium levels”^[143]. It can take several months to ayear for 25(OH)D concentrations to return to normal, although hypercalcemia disappeared below 25(OH)D concentrations of1000 nmol/L in one study ^[118].

3.2.4. Reverse Causality

Concern has been raised that25(OH)D concentration–health outcome relations found in observational studiescould be due to reverse causation, that is, that having disease affects 25(OH)Dconcentrations. This concern has been raised in large part since vitamin D RCTs generally have not confirmed the findings ofobservational studies ^[146]. This effect is most likely to be found incross-sectional studies of disease prevalence, and most authors are careful toacknowledge this possibility. However, reverse causation is not thought toaffect prospective studies with long follow-up times, especially if health outcomes occurring in the first year or twoare omitted. Those outcomes might be due to undiagnosed disease, sinceit is assumed that the health outcome developed after measurement of 25(OH)D concentration. However, reverse causationmight affect case–control studies in which 25(OH)D concentrations aremeasured near time of diagnosis.

Breast cancer is one healthoutcome for which reverse causality is often claimed for case-control studiessince nested case-control studies do not find significantinverse correlations with 25(OH)D concentrations for follow-up times longerthan 3 years ^[86]. A recent paper argues that case-control studies do not showevidence of reverse causality for breast cancer since the 25(OH)Dconcentration-incidence relations for 10 studies overlay each other very well ^[107].One of the 10 studies included in the meta-analysis used 25(OH)D concentrationsmeasured about 1year before diagnosis and had similar findings to the otherstudies, which measured 25(OH)D concentrations shortly after diagnosis. Thereason for the disparity between case-control studies and nested case-controlstudies is attributed to the rapid development of breast cancer tumors. Breastcancer screening is recommended annually, whereas colorectal cancer screeningis recommended every 10 years.

3.2.5 Randomized Controlled Trials

Several recent papers havepointed out that vitamin D RCTs do not support thefindings of observational studies ^[67,146,147]. In response to the paper by Autier ^[146], three of us analyzed all the RCTs examining the effect of vitamin D on biomarkers ofinflammation. Half of the trials with baseline 25(OH)D concentration <48 nmol/L resulted in significant inverse correlations between
vitamin D supplementation and inflammation, whereas only 25% of those withhigher baseline 25(OH)D concentrations did ^[148]. One problem with mostvitamin D RCTs conducted to date is that they havelargely been based on guidelines for pharmaceutical drugs, which assume thatthe trial is the only source of the agent and that a linear dose–responserelation is in effect. Vitamin D satisfies neither assumption since UVBexposure, diet, and supplements are common sources of vitamin D. Another problemis that those conducting the trialsgenerally did not design the trials to evaluate the 25(OH)Dconcentration-health outcome relation. In a recent paper, Heaneyoutlined guidelines for trials of nutrients such as vitamin D.

The important steps include starting with an understanding of the25(OH)D concentration-health outcome relation, measuring 25(OH)D concentrationsof potential participants, enrolling only those with 25(OH)Dconcentrations near the low end of the relation, supplementing them with enoughvitamin D to raise 25(OH)D concentrations to near the upper end of quasi-linearregion of the relation, remeasuring25(OH)D concentrations, and ensuring thatimportant cofactors have been optimized ^[13]. Very few vitamin D RCTs conducted to date satisfy these guidelines; thus, fewfound significant effects. Also, some question exists of whether the trialswere conducted at the right age and for a long enough period.

3.2.6. Vitamin D₃ (cholecalciferol)vs. Vitamin D₂ (ergocalciferol)

Vitamin D₃ (cholecalciferol) is synthesized in human skin, whereasvitamin D₂ (ergocalciferol) comes fromyeast and fungi. Most vitamin D supplements are vitamin D₃. Reportsof the effectiveness of the two types conflict. In a study supplementinghealthy adults with 50,000 IU of vitamin D₂ or D₃,vitamin D₃ was 87% more potent in raising and maintaining 25(OH)Dconcentrations ^[149].

A 2012 study with 50,000 IU ofvitamin D₂ supplementation every other week increased total serum25(OH)D concentration from 78 to 120 nmol/L butlowered 25(OH)D₃ concentration from 68 to 35 nmol/L^[150]. The most recent study found that treating those with T2DM with 50,000IU of  vitamin D₂per day for10 days yielded increases comparable to those taking 40,000 IU of vitamin D₃daily for 10 days ^[151]. Heavierpeople require larger vitamin D doses ^[152]. A meta-analysis of all-causemortality rate from vitamin D supplementation trials found a RR of 0.89 (95%CI, 0.80, 0.99) for trials using vitamin D₃ and 1.04 (95% CI, 0.97,1.11) for trials using vitamin D₂^[104]. In other words,
vitamin D₃ significantly reduced risk of death, whereas vitamin D₂did not.

Another consideration is that 50,000-IU vitamin D₂ capsulescan be prescribed, but 50,000-IU vitamin D₃ capsules cannot.However, prescription-grade vitamin D₃ is available at lower costthan vitamin D₂ (Bio-Tech Pharmacal, Fayetteville, AR, USA). Vitamin D capsules of50,000 IU can be given once per month, a daily average of 1640 IU.Alternatively, for example, 20,000 IU per week could be given, a daily averageof 2860 IU. Since 25(OH)D has a half-life in the blood of 4–6 weeks, suchdosing is acceptable.

3.2.7. Diet and 25(OH)D Concentrations

Few foods contain vitamin D.The primary food sources of vitamin D in the United States are fatty fish and vitaminD-fortified milk or other foods; however, many other countries do not fortifyany food with vitamin D. In the United States, the mean daily vitamin D intakefrom food for adults is about 250 IU ^[153].However, some diets provide more vitamin D than others. A UK study found thatmeat eaters had 25(OH)D concentrations 20 nmol/Lhigher than those of vegans ^[154]. Fish eaters had slightly lowerconcentrations than those of meat eaters, whereas vegetarians, who may eat milkand eggs, had concentrations about halfway between those of meat eaters andvegans. Meat evidently has vitamin D as 25(OH)D, which tests generally do notmeasure. Diet has important effects on health, but the amount of vitamin Dderived from food is not enough to raise 25(OH)D concentrations to recommendedvalues.

3.2.8. Testing Serum 25(OH)D Concentrations

Since the recommendations areprimarily for serum 25(OH)D concentrations, those with MCDD should have theirserum 25(OH)D concentrations tested before beginning supplementation as well asafter 6 months to see whether the dose is correct, then annually thereafter.Achieved 25(OH)D concentrations vary considerably with respect to oral vitaminD intake ^[155]. Taking vitamin D₂ and vitamin D₃ alsoyields different 25(OH)D concentrations. Apparently, some individuals can takeup to 1 year to obtain a steady-state serum level of 25(OH)D, so a 3- or6-month level is not necessarily the maximum obtainable.

However, 25(OH)D assays stillhave some problems. Several approaches for measuring 25(OH)D concentrationsexist, including immunoassays, high-performance liquid chromatography, andliquid chromatography–tandem mass spectrometry. Liquidblood or dried blood spots can also be used. Recent reports compared automatedimmunoassays with liquid chromatography-tandem mass spectrometry methods ^[156,157].Both methods have generally good reproducibility and low bias. Other assays didnot compare well. Thus, investigating the assay used to measure 25(OH)Dconcentration is important.

The international Vitamin D External Quality Assessment Scheme sendsblood samples to laboratories throughout the world to check measurementaccuracies. By 2011, intralaboratory imprecision wasdown to 15% ^[158]. From a clinical point of view, a good policy would probablybe to ask the assay company for accuracy andrepeatability values of 25(OH)D measurements and whether vitamin D₂and vitamin D₃ are measured separately or together.

4. Conclusions

This review summarizes evidencethat vitamin D has important health benefits for those with MCDD as well asothers. The vitamin D recommendations by health organizations and vitamin Dresearchers are that 25(OH)D concentrations for optimal health are in the rangeof 75 to 100 or 125 nmol/L (30 to 50 ng/mL) and that to reach these concentrations takes 800 to4000 IU/d vitamin D₃. However, since solar UVB exposure is thenatural way to obtain vitamin D₃, and since there appear to beadditional health benefits associated with solar UV exposure, sensible solarUVB exposure should also be considered when the sun is high enough that one'sshadow is shorter than one's height. We hope that physicians who treat thosewith MCDD will incorporate vitamin D supplementation in their practice.Tracking results of vitamin D supplementation, either formally or informally,would also be advisable.

Author Contributions

PM conceived the idea for thereview. WBG led the preparation of the paper. JJC, WBG, MFH, JML, PM, MP, PP,and SJW contributed ideas and/or papers for consideration. WBG and SJW wrote thepaper.

Conflicts of Interest

WBG receives funding fromBio-Tech Pharmacal (Fayetteville, AR, USA) and MediSun Technology (HighlandPark, IL, USA). JJC is director of the Vitamin D Council, earns royalties fromPurity Products Inc., and is on the Scientific Advisory Board for OPKOHealth Inc. The other authors declare no conflict of interest.

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