Vitamin D: Is the Need and Evidence for Supplementation Being Ignored?

[Guest guest]

Vitamin D: Is the Need and Evidence for Supplementation Being Ignored?

by William R. Ware, Ph.D.

 

Emeritus Professor of Chemistry, University of Western Ontario

INTRODUCTION

Vitamin D, the so-called sunshine vitamin, is in fact not really a

vitamin but a hormone which the body can make using sunlight.

 

Historically [1], vitamin-D deficiency was associated with the childhood

disease of rickets characterized by severe growth retardation and the

bending or bowing of the legs.

Rickets was presumably a product of the Industrial Revolution with a

high level of urbanization and child labor resulting in minimal exposure

to the sun. Severe vitamin-D deficiency also caused some young women to

have a deformed pelvis with the resultant difficulty in birthing, which

incidentally gave rise to the practice of Cesarean sections.

 

The suggestion that rickets was due to a lack of

sunlight was advanced in 1822, but it was not until 1919 that a cure

attributed to exposure to radiation from a mercury arc lamp gave strong

support to this hypothesis.

 

By the 1930s and 1940s the fortification of food with synthetically

made vitamin D was popular.

This was long before the

photochemistry of the cutaneous (in the skin) production of vitamin D

and the biochemistry and action of its metabolites were understood. With

the almost complete disappearance of rickets, there was little interest

in the possibility of residual or sub-clinical deficiency.

 

Only recently has a serum marker for the vitamin D status been

validated, and there has been renewed interest in the possibility of

vitamin D deficiency and its implications which is quite recent

and is in part due to the modern understanding of the multiplicity of

biochemical actions of vitamin D metabolites.

 

Today, research on the role of vitamin D metabolites in health and

illness has gone well beyond their role in calcium homeostasis and bone

health. They are implicated in cancer prevention,

hypertension, rheumatoid arthritis, multiple sclerosis, and early-onset

diabetes (type 1).

 

It is the nature of the human species that most of the vitamin D

required is generated by the action of the sun.

 

Natural food sources are very limited and provide only small amounts

unless large quantities of oily fish are eaten.

 

Humans are thought to have evolved in equatorial Africa and to have

migrated from this area only about 80,000 years ago [2]. The dark skin

of our ancestors is thought to have been a protective feature, reducing

the destruction of folate by UV light, protecting the sweat glands from

damage and increasing reflectivity

of solar energy [3,4].

 

Even though dark skin reduces the efficiency of vitamin D

production, our hunter-gatherer ancestors were exposed to very high

levels of UV throughout most days. Migrations eventually took groups

into the northern latitudes of Europe and Asia where the dark skin was a

disadvantage because of reduced vitamin D production due to low winter

levels of UV radiation. The lighter skin color associated with those

living in northern latitudes that subsequently evolved [3,4] provided

better utilization of solar

UV and presumably allowed greater buildup of vitamin D stores during the

summer months.

 

The effect of severe vitamin D deficiency on both children and females

of child-bearing age provides a plausible mechanism for selection and

adaptation.

 

Compelling evidence-based arguments can now be made that many

individuals have only marginal serum levels of the critical metabolite

of this vitamin, and that

deficiency is present in a significant fraction of the world's

population [1,5,6].

 

This deficiency results from inadequate sun exposure and from the

failure to eat large enough quantities of dark, oily fish and, where

available, fortified foods. This review will examine a number of

questions concerning vitamin D, its role in health, the dangers of

deficiency, the need for supplements, and the currently expanding

appreciation of its importance in biochemical processes other than those

related to calcium homeostasis.

 

SOURCES AND METABOLISM OF VITAMIN D [1,5]

 

Humans acquire vitamin D from the action of sunlight and from food. The

skin contains a cholesterol derivative, 7-dehydrocholesterol (provitamin

D), which ultraviolet light (UVB, 290-315 nm) converts to vitamin D

which is then either stored in body fat or converted in the liver to

25-hydroxyvitamin D, which we

will denote as 25(OH)D.

 

Vitamin D from dietary sources is also converted in the

liver to 25(OH)D.

 

Circulating 25(OH)D is converted, mostly in the kidney, to

another derivative, 1,25(OH)2D, also called calcitriol, or vitamin D

hormone,

which regulates serum calcium and phosphorus levels by controlling the

intestinal efficiency of absorption.

 

Many tissues and cells in the body have

receptors for vitamin D hormone, and it has been recognized for at least

two decades that this hormone is a potent inhibitor of cellular

proliferation and an inducer of cell maturation.

 

This may have very important implications in

connection with the incidence and progression of cancer. Vitamin D

hormone receptors are known to exist, for example, in breast, prostate

and colon tissue.

 

There are two forms of vitamin D, D2 and D3. Vitamin D3 is also called

cholecalciferol, whereas vitamin D2 is called calciferol or

ergocalciferol.

 

The same conversion is used for both to convert from grams to

International Units (IU), i.e. 100 IU = 2.5 micrograms (µg).

 

However, these two forms are thought to have different biological

activity, with D3 having between 1.7 and 2 times the conversion

efficiency to 25(OH)D for approximately equivalent amounts [7].

However, this area remains uncertain and it is common practice not to

differentiate between the two forms.

 

Vitamin D2 is not a natural component of

human biochemistry but can be manufactured, for example, by UV

irradiation of a lipid extracted from yeast. Thus its existence in

fortified food and therapeutic

prescriptions is mainly for the sake of synthetic convenience.

 

Supplements may contain either form, and sometimes this is not clear

from the label. Typical supplement users probably consume 200-800 IU/d.

 

Fish are the primary natural food source of dietary vitamin D (the D3

form), with 100 grams of herring or salmon providing 1000 IU or 640 IU

respectively. A

teaspoon of cod liver oil provides about 400 IU, an egg only about 100

IU [5].

 

 

For those who consume only limited amounts of these foods, fortified

foods and sunlight are the only sources. If one avoids fortified dairy

or cereal products, and in addition minimizes exposure to the sun,

deficiency becomes a real possibility.

 

Babies who are nourished exclusively by nursing must get their

vitamin D from the mother's milk or from sun.

 

 

In addition, the fear of skin cancer has promoted the extensive use of

sunscreens which essentially eliminates any solar vitamin D generation.

A

sunscreen SPF of 8 reduces vitamin D3 production by about 98% [1]!

To put these numbers in perspective, consider that an adult with white

skin

wearing a bathing suit generates about 10,000 IU of vitamin D3 in 15-30

minutes

when exposed to the summer sun [9]. This is 25-50 times what is in the

typical

multivitamin. Lengthy sun exposure does not produce toxic levels because

vitamin

D is also photolabile and as it builds up it is converted (also by UVB)

to

compounds that do not lead to bioactive metabolites.

 

It may surprise some readers to learn that in the northern latitudes

(>35°-40°N)

the amount of UVB in sunlight is low to negligible in the winter months,

except

at higher altitudes, and contrary to popular belief, sunbathing in the

winter in

Boston or Edmonton does not generate significant Vitamin D [10]. The

same is

true in latitudes below about 35°S. Even the sunny French Rivera and

Spain have

low levels of UVB in the winter. The latitude effect is caused by

increased

light scattering and ozone absorption due to the tilt of the earth's

axis. Thus

there is a large and expected seasonal variation of vitamin D status in

many

populated regions. A number of correlations of latitude with disease

incidence

have been reported which my be due to vitamin D deficiency [1]

 

ESTABLISHING DEFICIENCY AS WELL AS HEALTHY LEVELS OF VITAMIN D

 

To establish daily requirements and the prevalence of deficiency, it is

desirable to have a marker, ideally a blood marker. The concentration of

vitamin

D3 in the blood turns out to be uninformative. The consensus today is

that the

serum concentration of the metabolite 25(OH)D is the most informative

measure of

the vitamin status and should be used to define deficiency, sufficiency

and

perhaps toxicity [11]. Most labs offer this test. Given this consensus

on a

marker, the challenge is to establish a level below which deficiency

exists and

a level for optimum health, and to relate these levels to vitamin D

intake, both

orally and from sun exposure. A number of different approaches have been

used.

 

 

The level at which secondary hyperparathyroidism is evident. When

25(OH)D is

low, there is a decrease in vitamin D hormone and thus a decrease in

calcium

absorption and a lower serum calcium concentration. This causes the

parathyroid

hormone (PTH) serum concentration to increase, and this in turn

increases

vitamin D hormone production. This keeps the vitamin D hormone

concentration

nearly constant at the expense of a higher PTH level. This is called

secondary

hyperparathyroidism (primary hyperparathyroidism generally involves

parathyroid

gland tumors). Serum calcium may still be within the reference range.

The

increased PTH level causes increase bone turnover and bone loss. Thus

secondary

hyperparathyroidism has been proposed as the principal mechanism

connecting

vitamin D deficiency with the pathogenesis of decreased bone mineral

density and

the risk of hip fracture in the elderly, and this disorder can also

precipitate

or exacerbate osteoporosis [6]. As the level of 25(OH)D

continues to drop, PTH levels can double or triple. Numerous studies of

the

relationship between the levels of PTH and 25(OH)D in the blood reveal

that at

25(OH)D levels below 50 to 100 nmol/L (nM), the PTH level begins to

increase

[12-14]. There is no consensus and those trained in the physical

sciences would

be alarmed at the scatter in some of the data, but it appears that the

majority

of researchers favor a range between 75 and 100 nM as the threshold

below which

secondary hyperparathyroidism begins, and this then establishes a

threshold for

deficiency. Rickets and osteomalacia are seen at levels below about 20

nM, so

there is a big gap between the onset of hyperparathyroidism and the

level just

high enough to prevent what some call the reference disease.

Keeping in mind our sun-drenched primitive ancestors in Equatorial

Africa, some

guidance regarding healthy levels of 25(OH)D can be gleaned from the

following

data based on studies of people living and working in sun-rich

environments

[14]. Farmers in Puerto Rico were found on average to have levels of 135

nM,

whereas lifeguards in St Louis came in at 163 and lifeguards in Israel

at 148

nM. Levels over 200 nM have been found in sun-exposed individuals. Those

taking

vitamin D supplements were excluded from these studies.

Studies connecting calcium absorption with the serum levels of 25(OH)D

in

postmenopausal women suggest a level above about 80 nM is desirable

[15].

In two well accepted studies showing fracture prevention with vitamin D

and

calcium, mean 25(OH)D levels exceeded 100 nM [14].

In a clinical report [16] on 15 patients with confirmed osteomalacia,

the

average 25(OH)D level was 13.5 nM with a range of 5-35 nM. PTH was also

3 to 10

times above the reference range.

Other studies could be quoted [1,5,6] but the point is clear that levels

of

25(OH)D in the range of 75-100 nM can be justified as probably desirable

for

optimum health [6,14,17]. Note that there is some variation between

laboratories

as well as between various assay methods. The results obtained using two

 

commonly used assay methods have been found to differ, on average, by

about 30%

[18].

 

THE PREVALENCE OF VITAMIN D DEFICIENCY[19]

 

There have been a large number of studies concerning the prevalence of

low

levels of 25(OH)D, some of which are summarized below to provide an

indication

of the widespread nature of the problem. Studies generally use vitamin D

 

supplementation of 200 IU/d or more as grounds for exclusion, and

frequently set

a cut-off for deficiency at between 35 and 50 nM 25(OH)D with severe

deficiency

below 20 nM. There is no general agreement on nomenclature (deficiency,

insufficiency, hypovitaminosis D, etc.) or precise cut-off values, but

this does

not change the picture that emerges.

 

 

In a study [20] of hypovitaminosis D (low levels of vitamin D) in

medical

inpatients, 290 consecutive patients hospitalized in a general medical

service

at Massachusetts General Hospital were selected, 150 in March and 140 in

 

September (when the marker would have been expected to be at its

maximum). Using

37.5 nM as a cut- off, 57% were found to be vitamin D deficient and of

these 22%

had serum levels of 25(OH)D below 20 nM. No significant differences were

found

in the March and September groups. In a subgroup of 77 patients less

than 65

years of age without risk factors for hypovitaminosis D, 43% were

vitamin D

deficient.

Nesby-O'Dell et al [21] found that 42% of African American women in the

US aged

15 to 49 had 25(OH)D levels below 35.7 nM and were described as having

hypovitaminosis D.

Tangpricha et al [22] reported that 32% of healthy young white men and

women in

Boston aged 18 to 29 were deficient at the end of the winter of 1999,

with

levels below 50nM.

Centenarians living in Parma or Mantove, Italy (latitude 43°N) having no

acute

diseases were studied [23] and it was found that 99 out of 104 had

25(OH)D

levels below the sensitivity of the test used (<5 nM).

Plotnikoff and Quigley recently reported [24] a study of patients

presenting

with persistent musculoskeletal pain. Elderly patients refractory to the

usual

therapy had a high prevalence of vitamin D deficiency (<50nM). It is

interesting

that 90% of the 150 consecutive patients had been evaluated for their

persistent

muscuskeletal pain one year or more before the study and yet none were

tested

for vitamin D deficiency!

Vieth et al [25] describe a study involving 796 young women (18-35

years) over

one year in Toronto, Canada (latitude 43°N). During this period, the

prevalence

of low 25(OH)D of <40 nM was 25.6% for non-white, non-black subjects and

14.8%

in white women. Of the 435 women studied during the winter half of the

year, the

prevalence of low 25(OH)D was independent of vitamin D intake up to 200

IU/d.

Many more studies could be listed[1,5,6], but the point is clear.

Deficiency

appears widespread in all age groups, but especially in the elderly. If

a

cut-off of 75 nM for 25(OH)D, one threshold suggested above, had been

used in

these and other studies, the prevalence of deficiency would have been

much

higher. As might be expected, black skinned individuals have the biggest

problem

followed by Hispanics [19]. In cultures where most of the skin is

covered when

the individual is outdoors, significant to severe vitamin D deficiency

is

routinely found. Finally, it is of considerable interest that 200 IU/d

in

general had an insignificant effect of serum 25(OH)D levels, and yet

this dose

is the currently recommended adequate intake for young persons.

 

VITAMIN D INTAKE TO ASSURE THE ABSENCE OF DEFICIENCY

 

One might think that the current recommendations for vitamin D intake

were

designed to ensure adequacy. To quote Reinhold Vieth and Donald Fraser

of the

University of Toronto [9], " In fact, the current recommendations for

vitamin D

are not designed to ensure anything. They are simply based on the old,

default

strategy for setting a nutritional guideline, which is to recommend an

amount of

nutrient similar to what healthy people are eating. " The recommended

daily

allowance for vitamin D does not in fact as yet exist, and instead

recommendations are referred to as " adequate intake " (AI). The AI for

young

adults was chosen to approximate twice the average vitamin intake

reported by 52

young women in a study from Omaha, Nebraska in 1997. The use of the term

AI is

in fact an admission of the weak nature of the evidence used by the Food

and

Nutrition Board of the US Institute of Medicine. The current AI for

young adults

is 200 IU, for adults 400 IU and for the elderly, 600 IU/d. These

recommendations assume some input from solar generated vitamin D, but as

we

have seen, this is highly variable.

 

There have been a number of studies concerning the relationship between

vitamin

D intake and serum 25(OH)D levels [14]. To keep the levels of this

metabolite

above 75-100 nM, a total daily intake of about 4000 IU from all sources

is

required [14]. This translates into adequate sun exposure in the summer

months

to maintain high summer levels and build up stores of vitamin D, plus

supplements. To avoid undesirably low concentrations of serum 25(OH)D,

all

adults are encouraged by Vieth and Frazer [9] to take 1000 IU of vitamin

D3 per

day. In fact, at least 25 studies show that 800 IU/d results in an

average

25(OH)D level of <80 nM [14], and Vieth et al [17] found that 1000 IU/d

resulted

in an average 25(OH)D level of about 70 nM. Increasing the dose to 4000

IU is

predicted by Vieth et al [17] to yield an average of about 90 nM. For

housebound

elderly and others with almost no sun exposure at any season, 1000 IU/d

would

appear to be well below optimum, and 600 IU appears totally

inadequate. In connection with the AI of 400 IU/d, Holick [26] found

that even

a dose of 600 IU/d was insufficient to maintain normal 25(OH)D levels

for

nuclear submariners submerged for 3 months. The view that the AIs are

unrealistically low and that a daily oral intake of about 1000 IU/d is

indicated

has been put forward by others as well [6,27-30]. Obviously, the biggest

problem

for the concerned individual is to balance solar generation and

supplementation.

Fortunately, virtually unlimited solar generation appears safe, aside

from skin

cancer considerations.

 

TOXICITY

 

The maximum suggested dose currently is 2000 IU/d according to

guidelines from

the 1997 Food and Nutrition Board. Vieth argues in a reply to a letter

by Munro

[31] that this is unrealistically low. Toxicity has never been observed

in cases

where the high circulating 25(OH)D is derived from sunlight, and amounts

can

reach 235 nM, which is vastly more than 2000 IU could generate. If one

sunbathes

until the skin just shows a slight pink result, the estimated generation

of

vitamin D is equivalent to an oral intake of between 10,000 and 20,000

IU [14].

Therapeutic oral doses of 50,000 IU, generally D2, are available by

prescription

and are used to treat severe vitamin D deficiency. In a French study

published

in 2001 [32], three oral doses of 100,000 IU each of D3 were

administered to

male adolescents at the end of September, November and January, an

intervention

which maintained their March 25(OH)D levels at summer values of about 55

nM, as

compared to controls that dropped to 20 nM. No

side effects were observed. In a recently reported study [33], 2037 men

and 649

women received an oral dose of 100,000 IU of D3 every four months for

five years

to test the hypothesis that there would be a beneficial effect on the

incidence

of fractures as well as mortality. Both were significantly reduced and

no

adverse effects were observed. In the study by Heaney et al [34], up to

10,000

IU/d resulted in no adverse effects, including hypercalcemia, and the

subjects

were carefully monitored because of the high doses used.

 

Toxic doses of vitamin D are described as producing vitamin D

intoxication,

which is generally accompanied by high or dangerous levels of serum

calcium,

i.e. hypercalcemia. There are only a few reports in the literature. The

case of

vitamin D poisoning reported in The Lancet in 2002 involved prolonged,

accidental daily consumption by both a father and his son of >1,700,000

IU/d

(this is not a misprint) from contaminated table sugar that occurred

over a

period of seven months [35]. In another case [36] the patient presented

and was

hospitalized with symptoms of hypercalcemia of a few weeks duration and

was

found to have a serum level of 25(OH)D of over 1200 nM! Analysis of the

vitamin

D supplement provided by the patient and an additional sample obtained

from the

company involved indicated a huge manufacturing error resulting in a

daily dose

of vitamin D of between 156,000 and 2,600,000 IU/d. It is not known how

long

this dose had been taken. Other cases [35] of toxicity have involved

huge excesses of vitamin D added accidentally to milk, or where

industrial

concentrates of vitamin D were mistaken for cooking oil. Thus, it is

impossible

to make a case for toxicity even at levels well above 2000 IU/d. The

reports of

vitamin D intoxication have involved doses that were, by comparison,

astronomical.

 

VITAMIN D AND PREVENTION OF CANCER

 

The reader is also referred to the review by Hans Larsen in the IHN

Research

Report Vitamin D and Cancer. Suspicion that there was a cancer-vitamin D

 

connection was prompted by observations that the risk of some cancers

varied

with the latitude. As more became known about the metabolism of vitamin

D and

the actions of its metabolites, it was proposed that at lower latitudes

there

would be a higher circulating concentration of 25(OH)D and thus higher

concentrations of 1,25-dihydroxyvitamin D (vitamin D hormone), which was

known

to be extremely potent in inhibiting cell proliferation. The trouble

with this

simple theory was that the serum concentration of vitamin D hormone is

tightly

regulated, and its concentration does not change significantly with UV

exposure

or oral supplementation. Only 25(OH)D changes dramatically. However,

there is a

way around this objection [37]. It has been found that a number of cell

types

have the enzyme capability to convert 25(OH)D to the vitamin D

hormone, and thus serum and cellular levels of 25(OH)D could influence

the

intracellular concentration of vitamin D hormone, bypass the control

mechanisms,

and thus provide a connection between the cellular concentrations of

these two

metabolites. It is now know that a wide variety of normal tissues as

well as

various cancer cells, including breast, prostate and colon, can make

vitamin D

hormone from 25(OH)D. Epidemiologic studies designed to investigate the

cancer-vitamin D hypotheses have had mixed success. We will very briefly

examine

positive results reported for colorectal, breast and prostate cancer,

the only

sites that have received significant attention.

 

COLORECTAL CANCER. By the mid 90s there was already considerable

interest in the

connection between vitamin D, calcium and colorectal cancer, but studies

on

humans had yielded inconsistent results [38]. Over the next eight years

a number

of intervention, case control and prospective studies were reported

[39-48] with

the majority providing evidence of an inverse relationship between

vitamin D

status or intake and either primary colon cancer or the recurrence of

polyps in

the colon. In addition, an inverse risk relationship has generally but

not

always been found with calcium intake. Grau et al [43] recently

published the

results of an important trial that was in part motivated by the reported

 

association between 25(OH)D serum levels and the risk of colorectal

cancer. They

found in a randomized placebo-controlled clinical trial with both male

and

female subjects that vitamin D status strongly modified the effect of

calcium

supplementation on adenoma (polyp) recurrence. Calcium

supplementation (1200 mg/d) lowered adenoma recurrence risk only among

subjects

with 25(OH)D levels above the median of the cohort, which was about 75

nM. What

is noteworthy is the high median level of this vitamin D status marker.

The

highest value in the cohort was 91 nM. In another recently published

study,

Lieberman et al [48] examined a cohort of mostly men aged 50-75 who had

completed a colonoscopy. Advanced neoplasia was found in 329 out of 1441

 

participants. When those with advanced neoplasia were compared to the

total

cohort as a function of vitamin D intake, an inverse association was

found with

apparent dose dependence and an odds ratio of 0.61 for intakes of

greater than

about 645 IU/d. These results are consistent with those reported by

McCollough

et al [47] on participants in the Cancer Prevention Study II Nutrition

Cohort

(60,886 men, 66,883 women). Vitamin D intake in this study was

associated with

reduced risk of colorectal cancer only in men, with an adjusted rate

ratio of 0.58 for total vitamin D intake of greater than 525 IU/d and a

highly

significant trend for the rate ratio between this intake and <110 IU/d.

They

also found that calcium modestly reduced the risk of colorectal cancer.

In a

large prospective study based on two cohorts, one from the Nurses'

Health Study,

the other from the Health Professionals Follow-up Study, Wu et al [44]

reported

an inverse association between high total calcium intake (>700 mg/d) and

distal

(left sided) colon cancer, but only in participants with highest intake

of

vitamin D (median intake for the highest third the two cohorts was

between 529

and 610 IU/d). Thus the picture emerges that calcium and vitamin D work

together

in this context, and while both are implicated in the incidence of

colorectal

cancer, the risk reduction is greater at high calcium intakes and a high

vitamin

D status, either determined from intake or by measuring 25(OH)D levels.

Readers

interested in the mechanistic and genetic aspects

are referred to a review by Lamprecht and Lipkin [49].

 

BREAST CANCER. A possible connection between vitamin D and breast cancer

was

suggested over 10 years ago because of studies connecting incidence or

mortality

with the amount of solar radiation available. In the US, breast cancer

rates in

the Northeast sector are approximately twice those found in the

southwest [50].

Dietary consumption factors are very similar in the four quadrants of

the US

[50]. The connection with sunlight was confirmed in a recent study by

Freedman

et al [51] where they found that mortality for breast cancer (and colon

cancer)

was negatively associated with both residential and occupational

sunlight

exposure. Janowski et al [52] found that after adjusting for confounding

 

factors, the odds ratio for the lowest relative to the highest quartile

of

vitamin D hormone in a case control study (156 cancer cases, 184

controls) was

5.2. This is surprising, considering that serum vitamin D hormone is

normally

tightly controlled. Shin et al from Harvard in a large

prospective study based on the Nurses' Health Study data base [53] have

examined the connection between the incidence of breast cancer and

calcium and

vitamin D. It was found that both dietary calcium and vitamin D were

inversely

associated with breast cancer in premenopausal but not in postmenopausal

women.

It was, however, not possible to separate the effects of vitamin D and

calcium.

The strongest association with vitamin D was with the total intake

including

cutaneous production. This study is consistent with the NHANES I

Epidemiologic

Follow-up Study [54] where risk reductions between 0.35 and 0.75 were

found for

women who lived the US in regions of high solar radiation. This study

took into

account vitamin D intake from sunlight, diet and supplements. The

failure of

Shin et al to find a vitamin D effect in postmenopausal women is

puzzling, since

the other studies described included both pre and postmenopausal

subjects.

 

PROSTATE CANCER [55]. The north-south gradient in prostate cancer

mortality and

the greater risk for prostate cancer among dark-skinned individuals are

reminiscent of rickets and suggest that one of the causes of prostate

cancer

initiation or progression might be vitamin D deficiency. A large case

control

study reported in 2000 supports this hypothesis [56]. In a follow-up of

19,000

males, 149 prostate cancer cases were matched with 566 controls. Men

with

25(OH)D levels below the median of 40 nM had an adjusted relative risk

of l.7

compared to men with this marker above the median. Also, the prostate

cancer

risk was highest among men younger than 52 years of age (pre so-called

andropause) with low serum 25(OH)D levels. They had a relative risk of

3.5!

Another case control study [57] examined the relationship with sunlight

exposure

in some detail, and found significant odds ratios favoring the

hypothesis that

the protection from prostate cancer was exposure dependent. In recent

studies where no connection with vitamin D was found, the majority of

subjects

had intakes below 600 IU/d. Chen and Holick, [55] in their recent review

of

vitamin D and prostate cancer prevention and treatment, suggest annual

testing

of 25(OH)D levels. In connection with the basic mechanism involved, Chen

et al

[58] have recently demonstrated that primary cultures of prostate cancer

cells

and prostate cancer cell lines show a marked decrease in activity of the

enzyme

that converts 25(OH)D to vitamin D hormone, with attendant loss of the

growth-inhibitory activity of this hormone.

 

Since vitamin D and calcium are frequently taken together, the matter of

the

connection between prostate cancer and calcium arises. There have been a

number

of studies, both of supplement and dairy intake, with mixed results.

Some

indicated increased risk at high calcium intake. In a case control study

[59],

605 diagnosed prostate cancer cases were compared with randomly selected

 

controls. No effect of total calcium intake on incidence of localized

prostate

cancer was observed, with the highest quintile cut-off of >1163 mg/d.

For cancer

that had already spread outside the prostate or metastasized at the time

of

diagnosis, total calcium as a risk factor appeared above 518-850 mg/d. A

large

and very recent longitudinal (cohort) study [60] which was corrected for

a

number of confounding factors, found no connection up to a bit over 2000

mg/d.

Over 96% of the cases were Stage B (organ confined). The Health

Professionals

Follow-up Study [61] found that an intake greater than 2000 mg/d was

significantly associated with risk of advanced or metastatic cancer, but

 

calcium intake near the recommended daily intake (1000 mg/d) was not

significantly associated with total prostate cancer risk. To quote

Patrick

Walsh, a very well known urologist at Johns Hopkins Medical School, from

an

editorial in 2003 [62] concerning calcium supplements, " I have always

found this

association to be worrisome when advising patients about their dietary

intake of

calcium. I think now I can relax. Patients with moderate calcium intake

(700 to

800 mg per day) are at no increased risk. " Finally, it has recently been

 

suggested that the positive connection between high levels of milk

consumption

and prostate cancer may in fact be partly due to its estrogen content

rather

than calcium [63].

 

VITAMIN D AND OTHER HEALTH PROBLEMS

 

BONE HEALTH. There have been a large number of studies relating vitamin

D

deficiency to bone health. For example, Mazquita-Raya et al [64] showed

that

deficiency (less than 40 nM 25(OH)D) in otherwise healthy postmenopausal

women

was a common risk factor for osteoporosis associated with increased bone

 

remodeling and low bone mass. Dawson-Hughes et al [65] found that for

both men

and women over 65 years of age, supplementation with calcium (500 mg/d)

and

vitamin D (about 700 IU/d) moderately reduced bone loss over a three

year

period. Feskanich et al [66] in a study of 72,000 postmenopausal women

(Nurses'

Health Study cohort) found that adequate intake of vitamin D (highest

risk

reduction for greater than 500 IU/d) was associated with lower risk of

osteoporotic hip fractures. They found that supplementation or dark

(oily) fish

consumption was the only satisfactory preventive measures, and that

neither milk

nor a high-calcium diet appeared to reduce risk. Nguyen et al [67] in a

review

titled Osteoporosis: Underrated, Underdiagnosed and Undertreated,

examined the

evidence that vitamin D and calcium supplementation can reduce hip

fractures,

particularly in institutionalized and housebound elderly and recommended

 

supplements. Other studies could be quoted, but these, all very recent,

make the

point.

 

HYPERTENSION. Seasonal and geographic variations of blood pressure have

been

recognized for some time [68], leading to the hypothesis that variations

in

vitamin D photosynthesis results in diminished vitamin D levels and

increased

parathyroid hormone secretion which may result in higher blood pressure.

In 1998

Krause et al [69] used full-body UV radiation (3 times a week over six

weeks in

February and March) on 18 patients with untreated mild essential

hypertension

randomized to UVB or UVA (longer wavelengths—the controls) to examine

this

question. Significant decreases in systolic and diastolic BP (average 6

mm Hg,

range1- 14) were observed in the UVB but not the UVA group. In the UVB

group,

25(OH)D increased by 160% from 58 to 151 nM and there was a 15% fall in

PTH.

Serum calcium, phosphorous and vitamin D hormone levels were unchanged.

Both

groups initially were deficient, with a substantial fraction having

25(OH)D

levels below 50 nM.

 

What appears to be the first randomized, placebo-controlled double-blind

trial

investigating the effect of vitamin D and calcium supplementation on

blood

pressure was reported in 2001 [70]. The study involved elderly women.

They

received either 1200 mg calcium or 800 IU vitamin D3 per day or both for

8

weeks. Vitamin D plus calcium was found to be much more effective in

lowering BP

than calcium alone, with the former yielding a drop from 144 to 131 mm

Hg on

average for systolic and 85 to 78 for diastolic pressure. The average

initial

values of 25(OH)D were quite low (about 25 nM) and increased in the

calcium plus

vitamin D treatment to 65 nM. These studies are consistent with earlier

work

[71], including a study of the relationship between hypertension and

bone-mineral loss in elderly women [72]. The authors cautiously conclude

that

inadequate vitamin D could play a contributory role in the pathogenesis

and

progression of hypertension and thus cardiovascular disease in elderly

women.

 

DIABETES. Studies regarding Type 1 diabetes (insulin dependent diabetes)

 

describing a latitude dependence and inverse dependence of incidence on

mean

monthly sunshine hours suggest that vitamin D might play a protective

role, and

a deficiency might favor the development of this form of diabetes.

European

studies [73-75] have provided some measure of confirmation of this

hypothesis,

but in only one was there any dose information. In that study [75] large

daily

doses (2000 IU/d) during the first year of life were found to confer

protection

against the later development of Type 1 diabetes over the ten year

duration of

the study. In another study, the use of cod liver oil during pregnancy

was

associated with lower risk of Type 1 diabetes in offspring, but no dose

levels

were given. It is interesting that suspected rickets early in life was

found to

yield a risk enhancement of about 3 times for developing Type 1 diabetes

[75].

Most of these studies suffer from the failure to measure serum

25(OH)D levels, to characterize maternal vitamin D status or intake from

all

sources during the first year, or to examine dose dependence in general.

This

latter aspect is particularly critical since 2000 IU is ten times more

than

current US guidelines indicate as appropriate for children [76]. While

there has

been some work on possible mechanisms [77], most investigators suggest

that

vitamin D is acting as an immune system modulating agent which might

inhibit

autoimmune processes targeted against the beta cells of the pancreas.

Further

work, especially on the epidemiology, is clearly needed.

 

RHEUMATOID ARTHRITIS. Like Type 1 diabetes, rheumatoid arthritis (RA)

can be

considered an autoimmune disease. Vitamin D has been shown in animal

models to

have immune modulating effects, and this was part of the motivation for

a study

just reported that found vitamin D intake inversely associated with the

risk of

developing RA [78]. Almost 30,000 women aged 55-69 were followed for

about 10

years in the Iowa Women's Health Study. An adjusted relative risk of

developing

RA was 0.66 for supplement users taking 400 IU/d or more of vitamin D.

Unfortunately, the design of the study prevented clinical examination,

the

determination of serum 25(OH)D or sunlight exposure. Iowa is above 40°N

and thus

one would expect a fairly strong seasonal variation in vitamin D status

in this

age group.

 

PEDIATRIC ASPECTS IN GENERAL. The American Academy of Pediatrics (AAP)

has

recently revised their guidelines [76] regarding the prevention of

rickets and

vitamin D deficiency. Their recommendations are based on data indicating

that

200 IU/d will prevent physical signs of vitamin D deficiency and

maintain serum

levels of 25(OH)D at or above 27.5 nM [76]. Since rickets has been seen

[79] at

25(OH)D levels as high as 22 nM this is in keeping with the traditional

philosophy of recommended levels that " just avoid the disease. " The AAP

recommends as an adequate intake, 200 IU/day for the following: (a) all

breastfed infants unless they were weaned to at least 500 mL/d (about 2

cups) of

vitamin D fortified formula or milk; (b) all non-breastfed infants who

are

ingesting less than 500 mL/d of vitamin D fortified formula or milk; ©

 

children and adolescents who do not get regular sunlight exposure, do

not ingest

at least 500 mL/d of vitamin D fortified milk, or do not take a daily

multivitamin supplement containing at least 200 IU of vitamin D. Note

that

human breast milk contains about 25 IU/L, or less, and all milk and

formulas

sold in the US should have at least 400 IU/L. These guidelines do not

caution

against the low UVB in the winter sunlight at northern latitudes, nor do

they

focus on dark-skinned mothers whose children, if exclusively fed breast

milk,

account for the majority of cases of rickets currently being seen in the

US

[79]. However, the AAP in 1998 recommended 400 IU/d for deeply pigmented

 

breastfed infants or those with inadequate exposure to sunlight [80].

Establishing " adequate " sunlight exposure is difficult for both parents

and

health care providers, and there is the strong recommendation from the

AAP [81]

that childhood exposure to sunlight be severely limited because of skin

cancer

concerns and that adequate sunscreens be used at all times, thus

effectively

eliminating generation of vitamin D by this normal route. A compromise

solution,

although not suggested by the AAP guidelines, might involve limiting sun

 

exposure to that known to approximately provide adequate vitamin D

levels and

use sunscreen or protective clothing for all other exposure. It is

estimated

[80] that for infants and small children, 30 min of exposure per week in

just a

diaper, or 2 hours exposure per week if fully clothed with no hat is

sufficient.

African Americans possibly need six times as much exposure [82].

Presumably no

one is going to recommend that all children have their 25(OH)D levels

measured.

More detailed studies are clearly needed. Also the target value for

25(OH)D that

is known to be optimum for this age group appears to need investigating.

It may

very well be significantly above the AAP's 27.5 nM, especially if in

adults it

is 75-100 nM.

 

MULTIPLE SCLEROSIS. Munger et al have conducted the first large

prospective

study of vitamin D intake and the incidence of multiple sclerosis (MS),

the

results of which have just been published [83]. This study was based on

cohorts

from two Nurses' Health Studies totaling over 187,000 subjects. It was

motivated

by reports that the incidence of MS was latitude dependent and that

lesion

activity as judged by MRI studies was inversely correlated with vitamin

D

status. For those women who used supplemental vitamin D at levels equal

to or

greater than 400 IU/d, they observed a 40% lower risk of MS compared to

women

who did not use supplements. While they were unable to separate the

effect of

vitamin D from multivitamin use, an earlier study found that higher

intakes of

dietary carotenoids, vitamin C and vitamin E failed to reduce the risk

of MS in

women [84]. Thus, they favor the interpretation that involves vitamin D

status.

 

CONCLUSIONS

 

It seems clear that anyone who is not paying attention to vitamin D

status,

either for themselves or for patients, is indeed ignoring the evidence.

While

much research remains to be done, and not all studies have provided

positive

results, the number of health issues that appear to relate to vitamin D

status

provides a strong incentive for being concerned. It should be clear

that: (a)

there is considerable evidence of rather widespread vitamin D

deficiency; (b)

numerous studies indicate the importance of maintaining high levels of

serum

25(OH)D in order to optimize health; and © the importance of vitamin D

 

transcends its role in bone health and calcium metabolism. The

government

mandated fortification of dairy products and cereals is indicative of a

general

awareness in public health circles of the importance of this vitamin, at

least

as regards to bone health. But because of the variation in eating

patterns,

geographical location of residence, sun exposure, and fear of skin

cancer, becoming deficient may merely involve following the path of

least

resistance, since the alternative is to estimate intake from food and

supplements, pay attention to levels of fortification, and estimate

generation

from sunlight, actions that take effort and some knowledge. Furthermore,

there

is a common opinion among health care professionals that since rickets

is rare,

there is no vitamin D problem. There is also the commonly held opinion

that we

get everything we need from food. Neither of these positions appears

defensible.

 

 

Obviously, no one has ever taken a large group of presumably healthy

subjects,

kept their 25(OH)D levels above, say 75 nM for twenty years, and

observed the

results. Thus the vitamin D intake and 25(OH)D level for truly optimum

long-term

health is a matter of conjecture. The consensus among researchers as

regards to

the sensible level of supplementation appears to be about 1000 IU/d for

adults,

based mainly on keeping 25(OH)D levels high throughout the year. This is

to be

compared to the current recommendation of 400 IU/d with an increase to

600 IU/d

for the elderly. From what is now known about toxicity, 1000 IU/d should

not be

a cause for concern. However, the intake should not be increased by

increasing

the number of multivitamin pills taken daily, since this may produce

undesirable

levels of, for example, vitamin A, which incidentally antagonizes

calcium

response to vitamin D [85]. It should also be clear that a high level of

summer

sunlight exposure builds up stored reserves,

and the expected drop in the winter, especially in the northern (or

southern)

latitudes can be countered by supplementation. Concerns about skin

cancer can be

minimized by the practice of short but frequent exposure, e.g. 15-30 min

in full

summer sun, which can be very effective in producing a large amount of

D3,

followed by use of a sunscreen or protective clothing, although not

everyone

agrees that sunscreens are a good idea (see IHN Research Report

Sunscreens: Do

They Cause Skin Cancer, by Hans Larsen). Several reviewers and

researchers

[86,55] have suggested that 25(OH)D should be routinely measured

annually,

probably in mid-winter, in order that deficiency is not missed. This

could be

especially important for those with infrequent sun exposure, northern

latitude

residence, infrequent ingestion of fortified foods and no or low

supplementation. Finally, it appears important to also pay attention to

optimum

calcium intake in the context of maximizing the benefits of adequate

vitamin D.

 

 

 

 

CLICK HERE FOR THE LATEST RESEARCH ON VITAMIN D

 

 

 

 

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This article was first published in International Health News Isuues 147

and 148

(May/June 2004)

_________________

 

JoAnn Guest

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AIM Barleygreen

" Wisdom of the Past, Food of the Future "

 

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