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. Breast milk is a very poor source

of vitamin D and if sun exposure is limited, serious deficiencies can develop. A

rebound is in fact being seen in the incidence of rickets [8], even in the US.

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

 

 

 

 

REFERENCES

 

Holick, M. F., " Vitamin D: A millenium perspective, " J Cell Biochem., vol. 88,

no. 2, pp. 296-307, Feb.2003.

Oppenheimer, S., The Real Eve. Modern Man's Journey Out of Africa New York:

Carroll & Graf Publishers, 2003.

Harding, R. M., Healy, E., Ray, A. J., Ellis, N. S., Flanagan, N., C.,

Dixon, C., Sajantila, A., Jackson, I. J., Birch-Machin, M. A., and Rees, J. L.,

" Evidence for variable selective pressures at MC1R, " Am J Hum.Genet., vol. 66,

no. 4, pp. 1351-1361, Apr.2000.

Jablonski, N. G. and Chaplin, G., " The evolution of human skin coloration, " J

Hum.Evol., vol. 39, no. 1, pp. 57- 106, July2000.

Zittermann, A., " Vitamin D in preventive medicine: are we ignoring the

evidence?, " Br.J Nutr, vol. 89, no. 5, pp. 552-572, May2003.

Holick, M. F., " Vitamin D: the underappreciated D-lightful hormone that is

important for skeletal and cellular health, " Curr Opin Endocrinol Diabetes, vol.

9 pp. 87-98, 2002.

Trang, H. M., Cole, D. E., Rubin, L. A., Pierratos, A., Siu, S., and Vieth, R.,

" Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently

than does vitamin D2, " American Journal of Clinical Nutrition, vol. 68, no. 4,

pp. 854-858, Oct.1998.

Abrams, S. A., " Nutritional rickets: an old disease returns, " Nutr Rev., vol.

60, no. 4, pp. 111-115, Apr.2002.

Vieth, R. and Fraser, D., " Vitamin D insufficiency: no recommended dietary

allowance exists for this nutrient, " CMAJ., vol. 166, no. 12, pp. 1541-1542,

June2002.

Webb, A. R., Kline, L., and Holick, M. F., " Influence of season and latitude on

the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and

Edmonton will not promote vitamin D3 synthesis in human skin, " Journal of

Clinical Endocrinology Metabolism, vol. 67, no. 2, pp. 373-378, Aug.1988.

McKenna, M. J. and Freaney, R., " Secondary hyperparathyroidism in the elderly:

means to defining hypovitaminosis D, " Osteoporos.Int., vol. 8 Suppl 2 pp. S3-S6,

1998.

Brustad, M., Braaten, T., and Lund, E., " Predictors for cod-liver oil supplement

use--the Norwegian Women and Cancer Study, " Eur.J Clin Nutr, vol. 58, no. 1, pp.

128-136, Jan.2004.

Need, A. G., Horowitz, M., Morris, H. A., and Nordin, B. C., " Vitamin D status:

effects on parathyroid hormone and 1, 25-dihydroxyvitamin D in postmenopausal

women, " American Journal of Clinical Nutrition, vol. 71, no. 6, pp. 1577-1581,

June2000.

Vieth, R., " Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and

safety, " American Journal of Clinical Nutrition, vol. 69, no. 5, pp. 842-856,

May1999.

Heaney, R. P., Dowell, M. S., Hale, C. A., and Bendich, A., " Calcium absorption

varies within the reference range for serum 25-hydroxyvitamin D, " J Am Coll

Nutr, vol. 22, no. 2, pp. 142-146, Apr.2003.

Basha, B., Rao, D. S., Han, Z. H., and Parfitt, A. M., " Osteomalacia due to

vitamin D depletion: a neglected consequence of intestinal malabsorption, " Am J

Med, vol. 108, no. 4, pp. 296-300, Mar.2000.

Vieth, R., Chan, P. C., and MacFarlane, G. D., " Efficacy and safety of vitamin

D3 intake exceeding the lowest observed adverse effect level, " American Journal

of Clinical Nutrition, vol. 73, no. 2, pp. 288-294, Feb.2001.

Vieth, R., " Problems with direct 25-hydroxyvitamin D assays, and the target

amount of vitamin D nutrition desirable for patients with osteoporosis, "

Osteoporos.Int., vol. 11, no. 7, pp. 635-636, 2000.

Calvo, M. S. and Whiting, S. J., " Prevalence of vitamin D insufficiency in

Canada and the United States: importance to health status and efficacy of

current food fortification and dietary supplement use, " Nutr Rev., vol. 61, no.

3, pp. 107-113, Mar.2003.

Thomas, M. K., Lloyd-Jones, D. M., Thadhani, R. I., Shaw, A. C., Deraska, D. J.,

Kitch, B. T., Vamvakas, E. C., Dick, I. M., Prince, R. L., and Finkelstein, J.

S., " Hypovitaminosis D in Medical Inpatients, " The New England Journal of

Medicine, vol. 338, no. 12, pp. 777-783, Mar.1998.

Nesby-O'Dell, S., Scanlon, K. S., Cogswell, M. E., Gillespie, C., Hollis, B. W.,

Looker, A. C., Allen, C., Doughertly, C., Gunter, E. W., and Bowman, B. A.,

" Hypovitaminosis D prevalence and determinants among African American and white

women of reproductive age: third National Health and Nutrition Examination

Survey, 1988-1994, " American Journal of Clinical Nutrition, vol. 76, no. 1, pp.

187-192, July2002.

Tangpricha, V., Pearce, E. N., Chen, T. C., and Holick, M. F., " Vitamin D

insufficiency among free-living healthy young adults, " Am J Med, vol. 112, no.

8, pp. 659-662, June2002.

Passeri, G., Pini, G., Troiano, L., Vescovini, R., Sansoni, P., Passeri, M.,

Gueresi, P., Delsignore, R., Pedrazzoni, M., and Franceschi, C., " Low vitamin D

status, high bone turnover, and bone fractures in centenarians, " J Clin

Endocrinol.Metab, vol. 88, no. 11, pp. 5109-5115, Nov.2003.

Plotnikoff, G. A. and Quigley, J. M., " Prevalence of severe hypovitaminosis D in

patients with persistent, nonspecific musculoskeletal pain, " Mayo Clin Proc.,

vol. 78, no. 12, pp. 1463-1470, Dec.2003.

Vieth, R., Cole, D. E., Hawker, G. A., Trang, H. M., and Rubin, L. A.,

" Wintertime vitamin D insufficiency is common in young Canadian women, and their

vitamin D intake does not prevent it, " Eur.J Clin Nutr, vol. 55, no. 12, pp.

1091-1097, Dec.2001.

Holick, M. F., " McCollum Award Lecture, 1994: vitamin D--new horizons for the

21st century, " American Journal of Clinical Nutrition, vol. 60, no. 4, pp.

619-630, Oct.1994.

Holick, M. F., " Too little vitamin D in premenopausal women: why should we

care?, " American Journal of Clinical Nutrition, vol. 76, no. 1, pp. 3-4,

July2002.

Rucker, D., Allan, J. A., Fick, G. H., and Hanley, D. A., " Vitamin D

insufficiency in a population of healthy western Canadians, " CMAJ., vol. 166,

no. 12, pp. 1517-1524, June2002.

Utiger, R. D., " The Need for More Vitamin D, " The New England Journal of

Medicine, vol. 338, no. 12, pp. 828- 829, Mar.1998.

Heaney, R. P., " Vitamin D: how much do we need, and how much is too much?, "

Osteoporos.Int., vol. 11, no. 7, pp. 553-555, 2000.

Munro, I., " Derivation of tolerable upper intake levels of nutrients, " American

Journal of Clinical Nutrition, vol. 74, no. 6, pp. 865-867, Dec.2001.

Guillemant, J., Le, H. T., Maria, A., Allemandou, A., Peres, G., and Guillemant,

S., " Wintertime vitamin D deficiency in male adolescents: effect on parathyroid

function and response to vitamin D3 supplements, " Osteoporos.Int., vol. 12, no.

10, pp. 875-879, 2001.

Trivedi, D. P., Doll, R., and Khaw, K. T., " Effect of four monthly oral vitamin

D3 (cholecalciferol) supplementation on fractures and mortality in men and women

living in the community: randomised double blind controlled trial, " BMJ, vol.

326, no. 7387, pp. 469, Mar.2003.

Heaney, R. P., Davies, K. M., Chen, T. C., Holick, M. F., and Barger-Lux, M. J.,

" Human serum 25- hydroxycholecalciferol response to extended oral dosing with

cholecalciferol, " American Journal of Clinical Nutrition, vol. 77, no. 1, pp.

204-210, Jan.2003.

Vieth, R., Pinto, T. R., Reen, B. S., and Wong, M. M., " Vitamin D poisoning by

table sugar, " Lancet, vol. 359, no. 9307, pp. 672, Feb.2002.

Koutkia, P., Chen, T. C., and Holick, M. F., " Vitamin D intoxication associated

with an over-the-counter supplement, " The New England Journal of Medicine, vol.

345, no. 1, pp. 66-67, July2001.

Holick, M. F., " Vitamin D: importance in the prevention of cancers, type 1

diabetes, heart disease, and osteoporosis, " American Journal of Clinical

Nutrition, vol. 79, no. 3, pp. 362-371, Mar.2004.

Martinez, M. E., Giovannucci, E. L., Colditz, G. A., Stampfer, M. J., Hunter, D.

J., Speizer, F. E., Wing, A., and Willett, W. C., " Calcium, vitamin D, and the

occurrence of colorectal cancer among women, " JNCI Cancer Spectrum, vol. 88, no.

19, pp. 1375-1382, Oct.1996.

Baron, J. A., Beach, M., Mandel, J. S., van Stolk, R. U., Haile, R. W., Sandler,

R. S., Rothstein, R., Summers, R. W., Snover, D. C., Beck, G. J., Bond, J. H.,

and Greenberg, E. R., " Calcium supplements for the prevention of colorectal

adenomas. Calcium Polyp Prevention Study Group, " The New England Journal of

Medicine, vol. 340, no. 2, pp. 101-107, Jan.1999.

Zheng, W., Anderson, K. E., Kushi, L. H., Sellers, T. A., Greenstein, J., Hong,

C. P., Cerhan, J. R., Bostick, R. M., and Folsom, A. R., " A prospective cohort

study of intake of calcium, vitamin D, and other micronutrients in relation to

incidence of rectal cancer among postmenopausal women, " Cancer Epidemiology

Biomarkers Prevention, vol. 7, no. 3, pp. 221-225, Mar.1998.

Kampman, E., Slattery, M. L., Caan, B., and Potter, J. D., " Calcium, vitamin D,

sunshine exposure, dairy products and colon cancer risk (United States), " Cancer

Causes Control, vol. 11, no. 5, pp. 459-466, May2000.

Peters, U., McGlynn, K. A., Chatterjee, N., Gunter, E., Garcia-Closas, M.,

Rothman, N., and Sinha, R., " Vitamin D, Calcium, and Vitamin D Receptor

Polymorphism in Colorectal Adenomas, " Cancer Epidemiology Biomarkers Prevention,

vol. 10, no. 12, pp. 1267-1274, Dec.2001.

Grau, M. V., Baron, J. A., Sandler, R. S., Haile, R. W., Beach, M. L., Church,

T. R., and Heber, D., " Vitamin D, calcium supplementation, and colorectal

adenomas: results of a randomized trial, " J Natl.Cancer Inst., vol. 95, no. 23,

pp. 1765-1771, Dec.2003.

Wu, K., Willett, W. C., Fuchs, C. S., Colditz, G. A., and Giovannucci, E. L.,

" Calcium intake and risk of colon cancer in women and men, " JNCI Cancer

Spectrum, vol. 94, no. 6, pp. 437-446, Mar.2002.

Martinez, M. E., Marshall, J. R., Sampliner, R., Wilkinson, J., and Alberts, D.

S., " Calcium, vitamin D, and risk of adenoma recurrence (United States), " Cancer

Causes Control, vol. 13, no. 3, pp. 213-220, Apr.2002.

Jacobs, E. T., Martinez, M. E., and Alberts, D. S., " Research and public health

implications of the intricate relationship between calcium and vitamin D in the

prevention of colorectal neoplasia, " J Natl.Cancer Inst., vol. 95, no. 23, pp.

1736-1737, Dec.2003.

McCullough, M. L., Robertson, A. S., Rodriguez, C., Jacobs, E. J., Chao, A.,

Carolyn, J., Calle, E. E., Willett, W. C., and Thun, M. J., " Calcium, vitamin D,

dairy products, and risk of colorectal cancer in the Cancer Prevention Study II

Nutrition Cohort (United States), " Cancer Causes Control, vol. 14, no. 1, pp.

1-12, Feb.2003.

Lieberman, D. A., Prindiville, S., Weiss, D. G., and Willett, W., " Risk factors

for advanced colonic neoplasia and hyperplastic polyps in asymptomatic

individuals, " JAMA: The Journal of the American Medical Association, vol. 290,

no. 22, pp. 2959-2967, Dec.2003.

Lamprecht, S. A. and Lipkin, M., " Chemoprevention of colon cancer by calcium,

vitamin D and folate: molecular mechanisms, " Nat.Rev.Cancer, vol. 3, no. 8, pp.

601-614, Aug.2003.

Grant, W. B., " An ecologic study of dietary and solar ultraviolet-B links to

breast carcinoma mortality rates, " Cancer, vol. 94, no. 1, pp. 272-281,

Jan.2002.

Freedman, D. M., Dosemeci, M., and McGlynn, K., " Sunlight and mortality from

breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite

death certificate based case-control study, " Occupational and Environmental

Medicine, vol. 59, no. 4, pp. 257-262, Apr.2002.

Janowsky, E. C., Lester, G. E., Weinberg, C. R., Millikan, R. C., Schildkraut,

J. M., Garrett, P. A., and Hulka, B. S., " Association between low levels of

1,25-dihydroxyvitamin D and breast cancer risk, " Public Health Nutr, vol. 2, no.

3, pp. 283-291, Sept.1999.

Shin, M. H., Holmes, M. D., Hankinson, S. E., Wu, K., Colditz, G. A., and

Willett, W. C., " Intake of dairy products, calcium, and vitamin d and risk of

breast cancer, " J Natl.Cancer Inst., vol. 94, no. 17, pp. 1301-1311, Sept.2002.

John, E. M., Schwartz, G. G., Dreon, D. M., and Koo, J., " Vitamin D and Breast

Cancer Risk: The NHANES I Epidemiologic Follow-up Study, 1971-1975 to 1992, "

Cancer Epidemiology Biomarkers Prevention, vol. 8, no. 5, pp. 399-406, May1999.

Chen, T. C. and Holick, M. F., " Vitamin D and prostate cancer prevention and

treatment, " Trends Endocrinol Metab, vol. 14, no. 9, pp. 423-430, Nov.2003.

Ahonen, M. H., Tenkanen, L., Teppo, L., Hakama, M., and Tuohimaa, P., " Prostate

cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland), "

Cancer Causes Control, vol. 11, no. 9, pp. 847-852, Oct.2000.

Luscombe, C. J., Fryer, A. A., French, M. E., Liu, S., Saxby, M. F., Jones, P.

W., and Strange, R. C., " Exposure to ultraviolet radiation: association with

susceptibility and age at presentation with prostate cancer, " Lancet, vol. 358,

no. 9282, pp. 641-642, Aug.2001.

Chen, T. C., Wang, L., Whitlatch, L. W., Flanagan, J. N., and Holick, M. F.,

" Prostatic 25-hydroxyvitamin D- 1alpha-hydroxylase and its implication in

prostate cancer, " J Cell Biochem., vol. 88, no. 2, pp. 315-322, Feb.2003.

Kristal, A. R., Cohen, J. H., Qu, P., and Stanford, J. L., " Associations of

Energy, Fat, Calcium, and Vitamin D with Prostate Cancer Risk, " Cancer

Epidemiology Biomarkers Prevention, vol. 11, no. 8, pp. 719-725, Aug.2002.

Berndt, S. I., Carter, H. B., Landis, P. K., Tucker, K. L., Hsieh, L. J.,

Metter, E. J., and Platz, E. A., " Calcium intake and prostate cancer risk in a

long-term aging study: the Baltimore Longitudinal Study of Aging, " Urology, vol.

60, no. 6, pp. 1118-1123, Dec.2002.

Giovannucci, E., Rimm, E. B., Wolk, A., Ascherio, A., Stampfer, M. J., Colditz,

G. A., and Willett, W. C., " Calcium and fructose intake in relation to risk of

prostate cancer, " Cancer Research, vol. 58, no. 3, pp. 442- 447, Feb.1998.

Walsh, P. C., " Calcium intake and prostate cancer risk in a long-term aging

study: The Baltimore Logitudinal Study of Aging, " J Urol., vol. 170, no. 1, pp.

312, July2003.

Qin, L. Q., Wang, P. Y., Kaneko, T., Hoshi, K., and Sato, A., " Estrogen: one of

the risk factors in milk for prostate cancer, " Med Hypotheses, vol. 62, no. 1,

pp. 133-142, 2004.

Mezquita-Raya, P., Munoz-Torres, M., Luna, J. D., Luna, V., Lopez-Rodriguez, F.,

Torres-Vela, E., and Escobar-Jimenez, F., " Relation between vitamin D

insufficiency, bone density, and bone metabolism in healthy postmenopausal

women, " J Bone Miner.Res., vol. 16, no. 8, pp. 1408-1415, Aug.2001.

Dawson-Hughes, B., Harris, S. S., Krall, E. A., and Dallal, G. E., " Effect of

Calcium and Vitamin D Supplementation on Bone Density in Men and Women 65 Years

of Age or Older, " The New England Journal of Medicine, vol. 337, no. 10, pp.

670-676, Sept.1997.

Feskanich, D., Willett, W. C., and Colditz, G. A., " Calcium, vitamin D, milk

consumption, and hip fractures: a prospective study among postmenopausal women, "

American Journal of Clinical Nutrition, vol. 77, no. 2, pp. 504-511, Feb.2003.

Nguyen, T. V., Center, J. R., and Eisman, J. A., " Osteoporosis: underrated,

underdiagnosed and undertreated, " Med J Aust., vol. 180, no. 5 Suppl, pp.

S18-S22, Mar.2004.

Rostand, S. G., " Ultraviolet light may contribute to geographic and racial blood

pressure differences, " Hypertension, vol. 30, no. 2 Pt 1, pp. 150-156, Aug.1997.

Krause, R., Buhring, M., Hopfenmuller, W., Holick, M. F., and Sharma, A. M.,

" Ultraviolet B and blood pressure, " Lancet, vol. 352, no. 9129, pp. 709-710,

Aug.1998.

Pfeifer, M., Begerow, B., Minne, H. W., Nachtigall, D., and Hansen, C., " Effects

of a short-term vitamin D(3) and calcium supplementation on blood pressure and

parathyroid hormone levels in elderly women, " Journal of Clinical Endocrinology

Metabolism, vol. 86, no. 4, pp. 1633-1637, Apr.2001.

Kristal-Boneh, E., Froom, P., Harari, G., and Ribak, J., " Association of

calcitriol and blood pressure in normotensive men, " Hypertension, vol. 30, no.

5, pp. 1289-1294, Nov.1997.

Cappuccio, F. P., Meilahn, E., Zmuda, J. M., and Cauley, J. A., " High blood

pressure and bone-mineral loss in elderly white women: a prospective study.

Study of Osteoporotic Fractures Research Group, " Lancet, vol. 354, no. 9183, pp.

971-975, Sept.1999.

" Vitamin D supplement in early childhood and risk for Type I (insulin-dependent)

diabetes mellitus. The EURODIAB Substudy 2 Study Group, " Diabetologia, vol. 42,

no. 1, pp. 51-54, Jan.1999.

Stene, L. C., Ulriksen, J., Magnus, P., and Joner, G., " Use of cod liver oil

during pregnancy associated with lower risk of Type I diabetes in the

offspring, " Diabetologia, vol. 43, no. 9, pp. 1093-1098, Sept.2000.

Hypponen, E., Laara, E., Reunanen, A., Jarvelin, M. R., and Virtanen, S. M.,

" Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study, " Lancet,

vol. 358, no. 9292, pp. 1500-1503, Nov.2001.

Gartner, L. M. and Greer, F. R., " Prevention of rickets and vitamin D

deficiency: new guidelines for vitamin D intake, " Pediatrics, vol. 111, no. 4 Pt

1, pp. 908-910, Apr.2003.

Zella, J. B. and DeLuca, H. F., " Vitamin D and autoimmune diabetes, " J Cell

Biochem., vol. 88, no. 2, pp. 216- 222, Feb.2003.

Merlino, L. A., Curtis, J., Mikuls, T. R., Cerhan, J. R., Criswell, L. A., and

Saag, K. G., " Vitamin D intake is inversely associated with rheumatoid

arthritis: results from the Iowa Women's Health Study, " Arthritis Rheum., vol.

50, no. 1, pp. 72-77, Jan.2004.

Kreiter, S. R., Schwartz, R. P., Kirkman, H. N., Jr., Charlton, P. A.,

Calikoglu, A. S., and Davenport, M. L., " Nutritional rickets in African American

breast-fed infants, " J Pediatr., vol. 137, no. 2, pp. 153-157, Aug.2000.

American Academy of Pediatrics. Pediatric Nutrition Handbook. 275-277. 1998.

" Ultraviolet light: a hazard to children. American Academy of Pediatrics.

Committee on Environmental Health, " Pediatrics, vol. 104, no. 2 Pt 1, pp.

328-333, Aug.1999.

Shaikh, U. and Alpert, P. T., " Practices of vitamin D recommendation in Las

Vegas, Nevada, " J Hum.Lact., vol. 20, no. 1, pp. 56-61, Feb.2004.

Munger, K. L., Zhang, S. M., O'Reilly, E., Hernan, M. A., Olek, M. J., Willett,

W. C., and Ascherio, A., " Vitamin D intake and incidence of multiple sclerosis, "

Neurology, vol. 62, no. 1, pp. 60-65, Jan.2004.

Zhang, S. M., Hernan, M. A., Olek, M. J., Spiegelman, D., Willett, W. C., and

Ascherio, A., " Intakes of carotenoids, vitamin C, and vitamin E and MS risk

among two large cohorts of women, " Neurology, vol. 57, no. 1, pp. 75-80,

July2001.

Johansson, S. and Melhus, H., " Vitamin A antagonizes calcium response to vitamin

D in man, " J Bone Miner.Res, vol. 16, no. 10, pp. 1899-1905, Oct.2001.

Holick, M. F., " Vitamin D deficiency: what a pain it is, " Mayo Clin Proc., vol.

78, no. 12, pp. 1457-1459, Dec.2003.

 

 

 

This article was first published in International Health News Isuues 147 and 148

(May/June 2004)

_________________

JoAnn Guest

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