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<p><b><span style='font-family:Arial'>Vitamin D Therapeutics</span></b></p>
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<p class=MsoNormal><span style='color:red'>Why Vitamin D?</span> <br>
<a href="index.html">Home</a></p>
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<p style='margin:0in;margin-bottom:.0001pt'><b style='mso-bidi-font-weight:
normal'><span style='font-family:Arial'>VITAMIN D: Deficiency, Diversity and
Dosage<o:p></o:p></span></b></p>
<p style='margin:0in;margin-bottom:.0001pt'><span style='font-size:11.0pt;
font-family:Arial'>by Andrew W. Saul<o:p></o:p></span></p>
<p><span style='font-size:10.0pt;font-family:Arial'>(Reprinted with
permission from the <i>Journal of Orthomolecular Medicine</i>, 2003; Vol. 18,
Numbers 3 and 4, p. 194-204.)<o:p></o:p></span></p>
<p><i><span style='font-size:11.0pt;font-family:Arial'>"Vitamin D
deficiency is a major unrecognized health problem." </span></i><span
style='font-size:11.0pt;font-family:Arial'>(Michael F. Holick, M.D., <st1:place
w:st="on"><st1:PlaceName w:st="on">Boston</st1:PlaceName> <st1:PlaceType
w:st="on">University</st1:PlaceType> <st1:PlaceName w:st="on">Medical</st1:PlaceName>
<st1:PlaceType w:st="on">Center</st1:PlaceType></st1:place>)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>There have been many
papers published on vitamin D. A Medline search for "vitamin D"
will yield over 32,000 matches. It is well established that insufficient
quantities of the vitamin contribute to <span class=SpellE>osteopenia</span>,
<span class=SpellE>osteomalacia</span>, and osteoporosis. However, there is
so much new interest in "boneless" applications of vitamin D that
the topic was featured in the June, 2003 Reader's Digest. (1)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Vitamin D was first
isolated from tuna fish oil in 1936, and synthesized in 1952. It is a <span
class=SpellE>prohormone</span> sterol which the body manufactures, given
sunlight, from 7-dehydrocholesterol. Vitamin D 3 (C27H44O, <span
class=SpellE>cholecalciferol</span>) is the form we and other animals make,
and what is found in fish liver oil. Oddly enough, fish cannot synthesize
vitamin D. They get theirs early in the food chain from <span class=SpellE>planktonic</span>
algae, and big fish eat little fish, and we eat them. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Vitamin D 2 (C28H44O) is
made from <span class=SpellE>ergosterol</span>, not cholesterol, and
consequently is called <span class=SpellE>ergocalciferol</span>. This is the
form that is found in plants, and that is also man-made by ultraviolet
irradiation of <span class=SpellE>ergosterol</span>, and that is usually
added to milk and found in most American supplements. Vitamin D3 is more
commonly used as a supplement in <st1:place w:st="on">Europe</st1:place>. (2)
As a curiosity, reindeer lichen contains both vitamin D2 and D3. (3)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Although D2 and D3 differ
by a single carbon atom, there is evidence that D3 is more efficiently
utilized in chicks (4) and, more to the point, in humans. "The
assumption that vitamins D2 and D3 have equal nutritional value is probably
wrong and should be reconsidered." (5)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>There are two commercial
sources of natural vitamin D3: fish liver oil and <span class=GramE>an oil</span>
extracted from wool. "If a label lists 'vitamin D3 (<span class=SpellE>cholecalciferol</span>)'
then it is from wool oil. This is considered a vegetarian source (the animal
is not harmed, just sheared), but not vegan. Fish liver oil will be in
parentheses if it is the source." (6) Animals can obtain vitamin D from
licking their fur, and in humans, rickets can be successfully treated by
rubbing cod liver oil into the skin.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>LONG-TERM SAFETY <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>As with all vitamins,
there is ongoing and ever-protracted debate about vitamin D's safety and
effectiveness. In the end, the issue really boils down to dosage. Because
vitamin D can be made in the body, given sufficient sunlight, it has been
considered more of a hormone than a vitamin. This terminology is likely to
prejudice any consideration of megadoses, and that is unfortunate. Government-sponsored
"tolerable" or "safe upper limits" (UL) for vitamin D
have been established, perhaps based as much on speculation as on available
facts. For babies under one year, that "upper limit" is 1,000 IU
(25 mcg) per day. For everyone else, including pregnant and nursing women, it
is 2,000 IU (50 mcg) per day. (7) These "safe upper limits" may be
excessively conservative. <span class=SpellE>Vieth</span> et al write,
"The 100-microg/d (4,000 IU/day) dosage of vitamin D3 effectively
increased 25(OH<span class=GramE>)D</span> to high-normal concentrations in practically
all adults and serum 25(OH)D remained within the physiologic range;
therefore, we consider 100 <span class=SpellE>microg</span> vitamin D3/d
(4,000 IU/day) to be a safe intake." (8)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Vitamin D has sometimes
been regarded as the most potentially dangerous vitamin. In his 2001 article
"Vitamin Toxicity," Mark <span class=SpellE>Rosenbloom</span>, MD,
writes that, for vitamin D, "Acute toxic dose is not established, and
chronic toxic dose is more than 50,000 IU/day in adults. In children, 400
IU/day is potentially toxic. A wide variance in potential toxicity
exists." There were no fatalities cited. (9) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>The Merck Manual's
assessment is somewhat different: "Vitamin D 1000 µg (40,000 IU)/day
produces toxicity within 1 to 4 months in infants, and as little as 75 µg
(3,000 IU)/day can produce toxicity over years. Toxic effects have occurred
in adults receiving 2,500 µg (100,000 IU)/day for several months." (10)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>The Merck Manual's lowest
"toxicity" figure for "infants" of 3,000 IU is
substantially higher than Dr. <span class=SpellE>Rosenbloom's</span>
"potentially toxic" figure of 400 IU for presumably older and
larger "children." "Potentially toxic" is very different
than "toxic." Moreover, "toxic" is very different than
"death." The choice to use the word "toxic" may serve to
convey a false impression of immediate and mortal danger. There are numerous
symptomatic warnings before serious toxic effects occur. Merck says,
"The first symptoms are anorexia, nausea, and vomiting, followed by <span
class=SpellE>polyuria</span>, <span class=SpellE>polydipsia</span>, weakness,
nervousness, and <span class=SpellE>pruritus</span>. (Eventually) renal
function is impaired. . . <span class=SpellE>Metastatic</span> calcifications
may occur, particularly in the kidneys. In <st1:country-region w:st="on"><st1:place
w:st="on">Great Britain</st1:place></st1:country-region>, so-called <span
class=SpellE>hypercalcemia</span> in infancy with failure to thrive has
occurred with a daily vitamin D intake of 50 to 75 µg (2000 to 3000
IU)." (10) Though the details and duration of intake are not stated, a
body-weight comparison suggests that if an infant weighed 10 pounds, that
would be the dose equivalent of approximately 32,000 to 48,000 IU per day for
an average adult.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>A widely-used nutrition
textbook that I taught from (11) said that 2,000 IU daily for an adult is
toxic (p 220-221). In this same textbook, on the same page, there was an
error that, by the author's own standard, could likely be fatal to the
reader's baby. A "Caution" statement on page 221 indicated the daily
vitamin D requirement for an infant as 10 MILLIGRAMS. This is 1,000 times the
correct figure, which is 10 micrograms. 10 milligrams is 400,000 IU; 10
micrograms is 400 IU. That textbook typo is a far greater mistake than any
health nut would ever make. By the next edition, the mistake had been
corrected.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>This is not an isolated
instance. As recently as July, 2003, the website of a major university
medical school (12) made the same mistake of stating milligrams (mg) instead
of micrograms (mcg). This abbreviation error, amounting to a difference of
three orders of magnitude, was present no fewer than six times in a single
article. One of the medical school's statements read, "The upper limit
of safety for vitamin D established by the Food and Nutrition Board of the <st1:place
w:st="on"><st1:PlaceType w:st="on">Institute</st1:PlaceType> of <st1:PlaceName
w:st="on">Medicine</st1:PlaceName></st1:place> is 25 mg (1000 IU) daily for
infants and 50 mg (2000 IU) for children and adults." Actually, 25 mg
would be one million IU/day, and 50 mg is two million IU/day. Mark Twain's
advice comes to mind: "Be careful in reading health books. You may die
of a misprint." Perhaps it is a testament to the safety of vitamin D
that there has never been a report of any reader deaths from medical
school-induced <span class=SpellE>hypervitaminosis</span>. Additionally, if
nutrition textbook and medical school proofreaders can confuse milligrams
with micrograms, then certainly the public can. This may serve as a practical
example of the advantage of using International Units in discussing and
labeling the fat-soluble vitamins.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>It is instructive to note
that as far back as 1939, some truly enormous doses of vitamin D were in fact
found to be far less deadly than one might expect. In several countries, most
infants, including preemies, survived 200,000 to as many as 600,000 units of
vitamin D given in a single injected or oral dose. These are incredibly high
quantities, especially when they are considered in relation to a premature
infant's body weight. (13) Pregnant women have likewise been given two huge
oral doses of vitamin D (600,000 IU) during the 7th and 8th months. (14)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>In 2003, vitamin D's
safety margins appear pretty much unchanged. This year, the British Medical
Journal published a double-blind controlled trial of 100,000 IU vitamin D3
given orally to over 2,000 elderly patients once every four months, for five
years. The authors reported, in addition to greatly reduced fracture rates,
that the high-dose therapy was "without adverse effects in men and
women." (15) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>It may be readily be
conceded that huge but occasional doses are insufficient to produce toxicity
because vitamin D is fat-soluble, stored by the body, and it takes many
months of very high doses to produce calcification of soft tissues, such as
the lung and kidneys. "Overdose," "<span class=GramE>toxic,"</span>
and "fatal" are very strong, yet very different terms that are
often used interchangeably by critics of vitamin supplementation. Most
overdoses are not toxic, and most <span class=GramE>toxicities</span> are not
fatal.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Current US Daily
Reference Intakes (DRI) for vitamin D are:<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Infants 0-12 months, 200
IU (5 micrograms) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Males and females 1-50
years, 200 IU (5 mcg) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>51-70 years, 400 IU (10
mcg)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>71 years and older, 600
IU (15 mcg) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Pregnant or nursing
women, 200 IU (5 mcg) (7)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Formerly, the US RDA for
vitamin D was only 5 mcg (200 IU) for older adults. The present
recommendations are an improvement. However, there is evidence that even
three times the DRI for an adult is inadequate if a person is not receiving
adequate sunlight. (16) DRI or RDA levels are certainly not therapeutic
levels, as the treatment of rickets generally requires a dose of 1,600 IU/day,
and may require a daily dosage of 50,000 to as much as 300,000 IU in
resistant cases. (17) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Current widely-publicized
government recommendations are probably inadequate for disease prevention.
Reinhold <span class=SpellE>Vieth</span>, Ph.D., writes, "For adults,
the 5-microgram (200 IU) vitamin D recommended dietary allowance may prevent <span
class=SpellE>osteomalacia</span> in the absence of sunlight, but more is
needed to help prevent osteoporosis and secondary hyperparathyroidism. Other
benefits of vitamin D supplementation are implicated epidemiologically:
prevention of some cancers, osteoarthritis progression, multiple sclerosis,
and hypertension. Total-body sun exposure easily provides the equivalent of
250 <span class=SpellE>microg</span> (10,000 IU) vitamin D/day, suggesting
that this is a physiologic limit. . . <span style='mso-spacerun:yes'> </span>Except
in those with conditions causing hypersensitivity, there is no evidence of
adverse effects with serum 25(OH)D concentrations <140 <span class=SpellE>nmol</span>/L,
which require a total vitamin D supply of 250 <span class=SpellE>microg</span>
(10,000 IU)/d to attain. Published cases of vitamin D toxicity with <span
class=SpellE>hypercalcemia</span>, for which the 25(OH<span class=GramE>)D</span>
concentration and vitamin D dose are known, all involve intake of greater
than or equal to 1,000 <span class=SpellE>microg</span> (40,000 IU)/d.
Because vitamin D is potentially toxic, intake of >25 <span class=SpellE>microg</span>
(1,000 IU)/d has been avoided even though the weight of evidence shows that
the currently accepted, no observed adverse effect limit of 50 <span
class=SpellE>microg</span> (2,000 IU)/d is too low by at least 5-fold."
(18)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>These figures, high
though they may seem, may actually be fairly conservative. The Nutrition Desk
Reference, Second Edition (19) states that, for vitamin D, "The
threshold for toxicity is 500 to 600 micrograms per kilogram body weight per
day." (p 40) "Toxic" in this particular instance must mean
"death," as this figure is presumably based on the US Environmental
Protection Agency's published oral LD50 for female rats of 619 mg/kg (20).
500 to 600 mcg is the equivalent of 20,000 to 24,000 IU, per kilogram body
weight per day. By comparison, this would mean that for an average (70 kg)
adult human, toxicity would occur at an astounding 1,400,000 to 1,680,000
IU/day. In ducks, it is even higher: EPA's LD 50 for mallards is greater than
2000 mg/kg, more than three times that for female rats.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Even if such figures were
not directly applicable to human beings, vitamin D must remain one of the
most non-toxic substances imaginable. It might be speculated that at least
some of the recent increase of interest in vitamin D analogs is due, in part,
to patent- and profit-driven attempts to chemically sidestep the presumed
dangers of high doses of inexpensive, natural vitamin D. If the vitamin is
non-toxic, incentive to develop pharmaceutical analogs largely disappears. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>There are, of course,
some reasonable cautions with its use. Persons with hyperparathyroidism, lymphoma,
lupus <span class=SpellE>erythematosus</span>, tuberculosis, <span
class=SpellE>sarcoidosis</span>, kidney disease, or those taking digitalis,
calcium channel-blockers, or <span class=SpellE>thiazide</span> diuretics,
should have physician supervision before and while taking extra vitamin D.
Hyperparathyroidism has been successfully managed with 50,000 to 200,000 IU
of vitamin D daily (21). When employing large doses of vitamin D, periodic
testing is highly advisable.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>DEFICIENCY<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Vitamin D deficiency is,
of course, to found in people who do not take supplements, who receive little
sun exposure, and who do not drink vitamin D fortified milk. A recent study
(22) indicates that about a quarter of supposedly bone-growing American
adolescents are likely vitamin D deficient. "Additionally, <span
class=SpellE>phenytoin</span> (<span class=SpellE>Dilantin</span>), <span
class=SpellE>primidone</span> (<span class=SpellE>Mysoline</span>), and <span
class=SpellE>phenobarbital</span> for seizures; corticosteroids; <span
class=SpellE>cimetidine</span> (<span class=SpellE>Tagamet</span>) for
ulcers; the blood-thinning drug heparin; and the <span class=SpellE>antituberculosis</span>
drugs <span class=SpellE>isoniazid</span> (INH) and <span class=SpellE>rifampin</span>
may interfere with vitamin D absorption or activity." (23) Cyclosporine
and <span class=SpellE>carbamazepene</span> also negatively interfere with
vitamin D. Vitamin D deficiency is prevalent in the elderly, who all too
commonly eat the worst diet, take the most medication, and get the least
sunlight. Furthermore, the normal aging process itself decreases the body's
ability to make vitamin D from what sunlight may be received. In any age
group, even a relatively wholesome-appearing diet heavy in cereal grains
reduces the availability of vitamin D in the body. (24) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>OSTEOPOROSIS<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>For decades, a milk-fed
(and dairy industry-educated) public has had its attention focused on calcium
and largely diverted from the "other" important
osteoporosis-preventing factor: vitamin D. Not only is vitamin D necessary
for calcium deposition in the body, it is necessary for getting calcium into
the body in the first place. "(P<span class=GramE>)<span class=SpellE>assive</span></span>
diffusion (dictated by calcium intake) is not the major mechanism by which
dietary calcium is absorbed by normal adult humans. The vitamin D-dependent
processes are more important quantitatively and thus constitute a major
determinant of calcium status. Individuals who are not exposed to sunlight
may be especially at risk." (25)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Most persons with
osteoporosis have low vitamin D levels. Along with calcium, 800 IU of vitamin
D daily has been shown in a double-blind placebo-controlled study to increase
bone density, and to reduce hip fractures by an astounding 43%. (26)
Fractures and their complications are a major cause of death in the elderly.
Up to "27% of all hip fracture victims die within six months of their
fall, usually of complications following surgery or from infections."
(27) There are over 250,000 hip fractures annually among persons over age 65,
and probably "90% of all fractures past age 60 are due to osteoporosis."
(28) Vitamin D therapy can save lives as well as bones. The fact that the DRI
of vitamin D is tripled for the elderly is an indication that this fact is
not unknown. But 600 IU of vitamin D for a 71 year old is probably too
little, and for some, too late.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Such was nearly the case
for my mother, a grand mal epileptic who took <span class=SpellE>phenytoin</span>
(<span class=SpellE>Dilantin</span>) for nearly 50 years. As she aged, she
began to fracture easily. This problem continued even after she was put on
calcium supplements accompanied by an RDA-level vitamin D supplement. But
after her vitamin D intake was raised to 2,000 IU/day, she never broke a bone
again. This is true even though she still fell from time to time, sometimes
so severely that she required inpatient care. But there were no more fractures.
Epileptics may need as much as 4000 IU daily. (29) "Interestingly,
vitamin D may offer another benefit for osteoporosis: studies have found that
when older individuals take vitamin D supplements, they have less of a
tendency to sway while standing or walking, and may therefore be less likely
to fall." (23) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>RICKETS<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Childhood rickets remains
a larger public health problem than might be expected. "Until recently,
rickets secondary to vitamin D deficiency was considered a medical oddity
rather than a clinical reality in <st1:State w:st="on">Catalonia</st1:State>
(<st1:country-region w:st="on"><st1:place w:st="on">Spain</st1:place></st1:country-region>).
However, recent data show a reemergence of the disease in the infancy.
Nutritional rickets . . . mainly affects immigrant infants and children from
Sub-Saharan Africa and <st1:country-region w:st="on"><st1:place w:st="on">Morocco</st1:place></st1:country-region>,
black or dark-skinned, fed with maternal milk alone, without vitamin D
supplementation and with little sun exposure. Systematic, preventive
supplementation with vitamin D is essential in these populations." (30)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Such is the case
elsewhere as well, such as on the sunny island of Crete, where "A full-term
male infant presented with clinical and biochemical findings consistent with
the diagnosis of congenital rickets: weak muscle tone, <span class=SpellE>craniotabes</span>,
episodes of tremor, hypocalcaemia, elevated serum alkaline <span
class=SpellE>phosphatase</span>, secondary hyperparathyroidism, decreased
25-hydroxyvitamin D and normal 1,25-dihydroxyvitamin D serum levels. The
mother's history and biochemical findings suggested nutritional vitamin D
deficiency. . . It is surprising that this case occurred in an affluent
setting, in the Mediterranean <st1:place w:st="on"><st1:PlaceType w:st="on">island</st1:PlaceType>
of <st1:PlaceName w:st="on">Crete</st1:PlaceName></st1:place>, with an
abundance of sunlight throughout the year." The authors assert that
"a high index of suspicion is required for prompt diagnosis and
treatment, thus preventing complications." (31) Seizures may be a
symptom of rickets. (32, 33, 34)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>"A high index of
suspicion" of vitamin D deficiency would be a good policy for clinicians
in the <st1:country-region w:st="on"><st1:place w:st="on">United States</st1:place></st1:country-region>
as well. Rickets has been observed in <st1:State w:st="on">Texas</st1:State>
(35) and in <st1:State w:st="on"><st1:place w:st="on">North Carolina</st1:place></st1:State>,
where "Thirty patients with nutritional rickets were first seen between
1990 and June of 1999. Over half of the cases occurred in 1998 and the first
half of 1999. All patients were African American children who were breast fed
without receiving supplemental vitamin D. . . Factors that may have
contributed to the increase in referrals of children with nutritional rickets
include more African American women breast-feeding, fewer infants receiving
vitamin D supplements, and mothers and children exposed to less sunlight. We
recommend that all dark-skinned breast-fed infants and children receive
vitamin D supplementation." (36)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Heavily pigmented skin
blocks up to 95% of UV radiation to the deepest skin layers. Additionally,
now-widespread air pollution interferes with vitamin D synthesis in two
almost paradoxical ways. Particulate pollution reduces the amount of sunlight
people may receive, and ozone depletion causes people to minimize exposure to
what sunlight there is. As people are <span class=GramE>cover</span> their
skin to avoid skin cancer, they reduce their vitamin D.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>On 4 August 2002, Reuters
News Service reported that "the number of cases of rickets in the <st1:country-region
w:st="on"><st1:place w:st="on">United States</st1:place></st1:country-region>
has crept up in recent years. Breast milk contains many valuable nutrients
but not enough Vitamin D to meet the daily requirement of 200 International
Units. Exposure to the sun's rays normally generates Vitamin D in the skin,
but applying sun block stops that process." <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>FOOD FORTIFICATION<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>With the exception of
oily fish, foods do not contain a significant amount of vitamin D. Because of
concern over mercury levels, eating the flesh of fish may not be practical
advice, and, while it contains no mercury, there is widespread dislike for
cod liver oil. Since the 1930's, vitamin D has been added to fluid milk but
not to other milk products. More recently, it has also been added to flour to
reduce rickets among immigrants to <st1:country-region w:st="on"><st1:place
w:st="on">Britain</st1:place></st1:country-region>. (10)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>It is cheap and reliable
for people to get their vitamin D from enriched foods. Iodine, iron and some
of the B-vitamins are other examples of nutrients that have been added to
foods for decades. That action should be seen for what it is: a national
policy effectively acknowledging that the masses eat so inadequately that
they are otherwise unable to avoid the most obvious clinical ramifications of
the most classic of nutrient deficiencies, including iodine-deficiency
goiter, iron-deficiency anemia, and pellagra. In the case of vitamin D, it is
a tacit statement about safety as well. With 400 IU added per quart, it is
easy for many a milk-drinking teenager to easily quadruple the DRI of 200
IU/day. Few dieticians appear worried that many people are routinely and
substantially exceeding government <span class=SpellE>DRI's</span> for
vitamin D.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Adding fluoride to public
water supplies is a similar, if less well reasoned, application of government
intervention. There has been nearly as much interest in trying to strengthen
bones with fluoride as there has been in using vitamin D. But not only does
fluoridation fail to protect bones from fracture, it actually contributes to
increased fractures. (37, 38) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Additionally, both the
National Toxicology Program and the National Cancer Institute found a
fluoride-related increase in <span class=SpellE>osteosarcoma</span> in young
males. (39) Water fluoridation isn't particularly effective in preventing
dental caries, resulting in an average of one half of one filling less per
user per lifetime. (40) <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>OBESITY<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Supplements, not
sunlight, may be necessary for overweight persons because they are less than
half as able to utilize <span class=SpellE>cutaneously</span>-synthesized
vitamin D3 compared to lean persons. Since approximately two-thirds of all
Americans are overweight or obese, this is a very significant public health
problem. "In the obese <span class=GramE>subjects</span> oral vitamin D
was more bioavailable than vitamin D from sunlight exposure . . . The authors
propose that vitamin D is being sequestered in body fat in obese persons,
giving rise to a relative deficiency which could be corrected with oral
administration of extra vitamin D." (41)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>DIVERSITY OF USES<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Controversy over vitamin
D therapy increases with the distance research moves away from the skeleton.
There is growing evidence that the "sunshine vitamin" may be vastly
more important to human health than previously thought and commonly taught.
Vitamin D metabolite (1<span class=GramE>,25</span>-dihydroxyvitamin D)
receptors (VDR), writes Michael F. Holick, M.D., "are present not only
in the intestine and bone, but in a wide variety of other tissues, including
the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin,
gonads, etc. 1,25(OH)(2)D is one of the most potent substances to inhibit
proliferation of both normal and <span class=SpellE>hyperproliferative</span>
cells and induce them to mature. . . Chronic vitamin D deficiency may have
serious adverse consequences, including increased risk of hypertension,
multiple sclerosis, cancers of the colon, prostate, breast, and ovary, and
type <span class=GramE>1 diabetes</span>." (42)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>It is noteworthy that
skin cancer may actually be prevented by what many feel causes it: sunshine.
(43, 44) <span class=SpellE>Krispin</span> Sullivan, author of Naked at Noon:
Understanding Sunlight and Vitamin D, writes: "One of the known
protectors of skin cells from pre-cancerous changes is vitamin D. For most
Americans the primary source of vitamin D is sunlight. UV-B, the only band of
light producing vitamin D, is significantly present only midday during summer
months in most of the <st1:country-region w:st="on"><st1:place w:st="on">U.S.</st1:place></st1:country-region>,
the exact time we are advised to avoid sunlight. UV-B is blocked by
sunscreen." (45) Over-exposure to sunlight does not cause vitamin D
toxicity. Persisting concerns over sun exposure are arguments in favor of its
nutritional equivalent: oral vitamin D supplementation. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>MULTIPLE SCLEROSIS<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Persons with multiple
sclerosis typically are vitamin D deficient and demonstrate dramatically
reduced bone mass. Unsurprisingly, such bone loss appears to be directly
caused by insufficient vitamin D (46) and can "be safely and
inexpensively corrected by the routine use of vitamin D supplements."
(47)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>More importantly, vitamin
D may have a key role in the progression of multiple sclerosis itself. Hayes
et al write, "(E)<span class=SpellE>xogenous</span>
1,25-dihydroxyvitamin D3, the hormonal form of vitamin D3, can completely prevent
experimental autoimmune encephalomyelitis (EAE), a widely accepted mouse
model of human multiple sclerosis (MS) . . . (T)he hormonal form of vitamin
D3 is a selective immune system regulator inhibiting this autoimmune disease.
Thus, under low-sunlight conditions, insufficient vitamin D3 is produced,
limiting production of 1<span class=GramE>,25</span>-dihydroxyvitamin D3,
providing a risk for MS. . . This theory can explain the striking geographic
distribution of MS, which is nearly zero in equatorial regions and increases
dramatically with latitude in both hemispheres. . . MS may be preventable in
genetically susceptible individuals with early intervention strategies that
provide adequate levels of hormonally active 1<span class=GramE>,25</span>-dihydroxyvitamin
D3 or its analogs." (48) Dr. Hayes adds that "Inheriting genetic
risk factors for multiple sclerosis (MS) is not sufficient to cause this <span
class=SpellE>demyelinating</span> disease of the central nervous system;
exposure to environmental risk factors is also required." (49)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>In a review article,
"Vitamin D Supplementation in the Fight Against Multiple Sclerosis (50),
Ashton F. Embry credits P. Goldberg (51, 52) with being the first to propose
that vitamin D is an important factor in the development of MS. Goldberg
"postulated that such a close correspondence between low sunlight and MS
was due to low vitamin D production in the population. Goldberg also showed
that within areas of low sunlight (e.g. <st1:country-region w:st="on"><st1:place
w:st="on">Norway</st1:place></st1:country-region>) differences in MS
prevalence could be explained by dietary factors which affect vitamin D
production. Such factors include the amount of fish eaten (increases vitamin
D) and the amount of grains consumed (reduces vitamin D levels due to the
action of <span class=SpellE>phytates</span>). To explain how vitamin D
levels were related to MS, Goldberg proposed that genetically susceptible
individuals may need larger than normal amounts of vitamin D during myelin
formation and that insufficient vitamin D during childhood might result in
defective myelin which would be susceptible to breakdown in later life.
Goldberg's ideas were completely ignored by medical researchers." <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>At least at the time they
were. Eventually it was demonstrated that vitamin D hormone could prevent or
halt not only an animal form of MS (53, 54) but there had been a clinical
study (55) showing that vitamin D, along with calcium and magnesium, reduced
the relapse rate in humans with multiple sclerosis. Frederick R. Klenner,
M.D., reported success using vitamin and mineral therapy for multiple
sclerosis over thirty years ago. (56, 57, 58)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>HEART DISEASE AND OTHER
CLINICAL USES<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Vitamin D has an
important role in cardiovascular health. (59, 60) For example, not only can
it prevent hypertension, it can help treat it. (61, 62) "Hypertension
appears to improve with vitamin D supplementation whether or not the vitamin
is deficient." (63) This is an important point. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Congestive heart failure
(CHF) may be caused by vitamin D deficiency. "Low vitamin D status can
explain alterations in mineral metabolism as well as myocardial dysfunction
in the CHF patients, and it may therefore be a contributing factor in the
pathogenesis of CHF." (64) Not surprisingly, bone loss is associated
with congestive heart failure. (65) Dilated cardiomyopathy has been linked
with rickets, both of which "responded well to supplemental calcium and
vitamin D." (66)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Scleroderma has responded
favorably to long-term oral vitamin D3 (1<span class=GramE>,25</span>-dihydroxycholecalciferol)
therapy (67) and psoriasis has been successfully treated, not only with
vitamin D analogues, but with topical vitamin D3. (68) Vitamin D deficiency
may be a contributing cause of inflammatory bowel disease, and might be an
effective treatment. (69) Over 50 years ago, lupus <span class=SpellE>vulgaris</span>
(tuberculosis of the skin) was reported successfully treated with 150,000 IU
of vitamin D daily for six to eight months. (70) <o:p></o:p></span></p>
<p><st1:City w:st="on"><st1:place w:st="on"><span style='font-size:11.0pt;
font-family:Arial'>Colon</span></st1:place></st1:City><span
style='font-size:11.0pt;font-family:Arial'> cancer is clearly related to poor
vitamin D nutrition (71, 72, <span class=GramE>73</span>). Inadequate vitamin
D levels are also associated with ovarian cancer (74), polycystic ovary
syndrome, (75) rheumatoid arthritis (76), and lupus (77). Infants receiving
vitamin D supplements show as much as an 80% reduction in type I diabetes.
(78, 79, 80, 81). A Medline search will reveal nearly 300 papers on fighting
prostate cancer with vitamin D and its derivatives, and nearly 400 in
relation to D and breast cancer.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>DEFICIENCY AND DIVERSITY:
A SUMMARY<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Vitamin D deficiency is
cause or contributor to a wide variety of diseases, many of which appear
unrelated to bone problems. So important is this vitamin for the entire
population that it is necessary for milk to be enriched with it. Most persons
do not get adequate vitamin D from sunlight, and the problem compounded for
the obese and for the elderly. For those individuals, and for any person on
any of a number of commonly prescribed medications, vitamin D supplementation
is mandatory.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Government recommended
dietary intakes of 200 to 600 IU/day are too low, according to the weight of
clinical evidence. Government "tolerable" or "safe upper
intake levels" (UL) of 1,000 to 2,000 IU/day are likewise too low, and
largely unsupported by toxicological evidence. An optimum health
recommendation of 1,000 to 4,000 IU/day, in total from all sources, is not
unreasonable for the vast majority of healthy adults. Effective therapeutic
levels for illness may be far higher. When high doses are used, appropriate
testing and monitoring is recommended. It would be unreasonable to deny a
therapeutic trial of vitamin D in cases of multiple sclerosis, scleroderma,
psoriasis, congestive heart failure, hypertension, and various forms of
cancer. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Excessive avoidance of <span
class=GramE>sunlight,</span> and sensational but unscientific dread of
relatively high-dose vitamin D side effects does more than merely set the
stage for a population of rickety children and fracture-ridden elderly.
Overestimates and outright misstatements of vitamin D's "potential
toxicity" open new marketing avenues for the development of vitamin
D-like drugs, a commercial opportunity that the pharmaceutical industry has
not overlooked.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>ON DANGERS AND DOSAGE: A
CONCLUDING COMMENT<o:p></o:p></span></p>
<p><span class=SpellE><span style='font-size:11.0pt;font-family:Arial'>Hypervitaminosis</span></span><span
style='font-size:11.0pt;font-family:Arial'> articles are popular with the
media, sometimes even making it into the pages of the Wall Street Journal. On
April 30, 1992, David <span class=SpellE>Stipp</span> reported that between
1990 and 1992, "a series of patients with vitamin D overdoses began
turning up at <st1:City w:st="on"><st1:place w:st="on">Boston</st1:place></st1:City>
hospitals." One of these patients subsequently died from drug
complications, and the case went to court. (82) "Essentially, this was a
product liability action against the producer of dairy products, specifically
milk which contained excessive amounts of Vitamin D. The plaintiff's decedent
purportedly suffered from elevated levels of Vitamin D in her bloodstream
which required medication which in turn allegedly compromised her immune
system, leading to her death." (83) This is the one and only vitamin
D-related death I could find confirmation of anywhere, and even this one was
not directly due to the vitamin, but rather to side effects of medication.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>A physiology textbook
later stated that "At least 19 cases of vitamin D toxicity were reported
in the <st1:City w:st="on"><st1:place w:st="on">Boston</st1:place></st1:City>
area during 1992. Symptoms included fatigue, weight loss, and potentially
severe damage to the kidneys and cardiovascular system. The problems resulted
from drinking milk fortified with vitamin D. Due to problems at one <span
class=GramE>dairy,</span> some of the milk sold had over 230,000 units of
vitamin D per quart instead of the usual 400 units per quart. The incident
highlighted the need for quality control in the production, and care in the
consumption, of vitamin supplements." (84)<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>Such a conclusion is
inaccurate. The incident might just as well be taken to be an unintentional
proof of vitamin safety, even in ridiculously high overdosage situations. It
is certainly noteworthy that 580 times the normal amount of vitamin D
produced, at most, one alleged fatality over a two-year period. Furthermore,
there was a total of fewer than two dozen toxicity reports, for the entire
Boston metropolitan area, after large numbers of people had been ingesting
close to a quarter of a million units of vitamin D per liter of milk day
after day, month after month, for up to two years. <span class=GramE>This
borders</span> on the extraordinary. Events such as this demonstrate that the
margin for error with vitamin D is very large indeed. Though the news
reported about the vitamin's toxicity, the real story was the vitamin's
safety. The scientific literature confirms the vitamin's value.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>References cited:<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>1. <span class=SpellE>Freinkel</span>
S. The healing vitamin. Reader's Digest. June, 2003. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>2. </span><span
style='font-size:11.0pt'><a
href="http://www.ibl-hamburg.com/prod/mg_11021_m.htm">http://www.ibl-hamburg.com/prod/mg_11021_m.htm</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>3. <span class=SpellE>Int</span>
J Circumpolar Health. 59: 26-32. 2000.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>4. </span><span
style='font-size:11.0pt'><a href="http://www.cyberlipid.org/vitd/vitd0001.htm">http://www.cyberlipid.org/vitd/vitd0001.htm</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>5. HM <span class=SpellE>Trang</span>,
DE Cole, LA Rubin, A <span class=SpellE>Pierratos</span>, <st1:place w:st="on">S
<span class=SpellE>Siu</span></st1:place> and R <span class=SpellE>Vieth</span>.
Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently
than does vitamin D2. American Journal of Clinical Nutrition, <span
class=SpellE>Vol</span> 68, 854-858, 1998.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>6. </span><span
style='font-size:11.0pt'><a href="http://www.vitamer.com/faq_ts_pygeum.html">http://www.vitamer.com/faq_ts_pygeum.html</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>7. Dietary Reference
Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Standing
Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and
Nutrition Board, <st1:place w:st="on"><st1:PlaceType w:st="on">Institute</st1:PlaceType>
of <st1:PlaceName w:st="on">Medicine</st1:PlaceName></st1:place>, Chapter 7.
National Academies Press, <st1:place w:st="on"><st1:City w:st="on">Washington</st1:City>,
<st1:State w:st="on">DC</st1:State></st1:place>. 1999.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>8. <span class=SpellE>Vieth</span>
R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding
the lowest observed adverse effect level. Am J <span class=SpellE>Clin</span>
<span class=SpellE>Nutr</span>. Feb; 73(2):288-94. 2001.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>9. </span><span
style='font-size:11.0pt'><a href="http://www.emedicine.com/emerg/topic638.htm">http://www.emedicine.com/emerg/topic638.htm</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>10. The Merck Manual of
Diagnosis and Therapy. Section 1. Chapter 3. Vitamin Deficiency, Dependency,
And Toxicity. Vitamin D Toxicity. </span><span style='font-size:11.0pt'><a
href="http://www.merck.com/pubs/mmanual/section1/chapter3/3e.htm">http://www.merck.com/pubs/mmanual/section1/chapter3/3e.htm</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>11. Williams SR.
Nutrition and Diet Therapy, 6th edition. <st1:City w:st="on"><st1:place
w:st="on">St. Louis</st1:place></st1:City>: <span class=SpellE>Mosby</span>,
1989.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>12. Northwestern
University, <st1:place w:st="on"><st1:PlaceName w:st="on">Feinberg</st1:PlaceName>
<st1:PlaceType w:st="on">School</st1:PlaceType></st1:place> of Medicine.
Nutrition Fact Sheet: Vitamin D. </span><span style='font-size:11.0pt'><a
href="http://www.feinberg.northwestern.edu/nutrition/factsheets/vitamin-d.html">http://www.feinberg.northwestern.edu/nutrition/factsheets/vitamin-d.html</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>13. Bicknell F and
Prescott F. The Vitamins in Medicine, third edition. <st1:place w:st="on"><st1:City
w:st="on">Milwaukee</st1:City>, <st1:State w:st="on">WI</st1:State></st1:place>:
Lee Foundation. p 544 and 578-591. 1953.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>14. <span class=SpellE>Marya</span>
RK, <span class=SpellE>Rathee</span> S, <span class=SpellE>Lata</span> V et
al. Effects of vitamin D supplementation in pregnancy. <span class=SpellE>Gynecol</span>
<span class=SpellE>Obstet</span> Invest. 12:155-161. 1981.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>15. <span class=SpellE>Trivedi</span>
DP, Doll R, <span class=SpellE>Khaw</span> KT. Effect <span class=GramE>of
four monthly oral vitamin D3 (<span class=SpellE>cholecalciferol</span>) supplementation</span>
on fractures and mortality in men and women living in the community: <span
class=SpellE>randomised</span> double blind controlled trial. BMJ. Mar 1<span
class=GramE>;326</span> (7387):469. 2003.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>16. <span class=SpellE>Glerup</span>
H, <span class=SpellE>Mikkelsen</span> K, <span class=SpellE>Poulsen</span>
L, et al. Commonly recommended daily intake of vitamin D is not sufficient if
sunlight exposure is limited. J Intern Med. 247:260-268. 2000.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>17. <span class=SpellE>Eguchi</span>
M and <span class=SpellE>Kaibara</span> N. Treatment of <span class=SpellE>hypophosphataemic</span>
vitamin D-resistant rickets and adult presenting <span class=SpellE>hypophosphataemic</span>
vitamin D-resistant <span class=SpellE>osteomalacia</span>. <span
class=SpellE>Int</span> <span class=SpellE>Orthop</span>. 3:257-264. 1980.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>18. <span class=SpellE>Vieth</span>
R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.
Am J <span class=SpellE>Clin</span> <span class=SpellE>Nutr</span>. May;
69(5):842-56. 1999.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>19. Garrison RH <span
class=SpellE>Jr</span> and <span class=SpellE>Somer</span> E. The Nutrition
Desk Reference, Second Edition. <st1:place w:st="on"><st1:City w:st="on">New
Canaan</st1:City>, <st1:State w:st="on">CT</st1:State></st1:place>: Keats,
1990<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>20. <span class=SpellE>Cholecalciferol</span>
(Vitamin D3) Chemical Profile 12/84. US Environmental <st1:place w:st="on"><st1:City
w:st="on">Protection Agency</st1:City>, <st1:State w:st="on">Washington</st1:State></st1:place>,
DC. Chemical Fact Sheet Number 42. December 1, 1984. </span><span
style='font-size:11.0pt'><a
href="http://pmep.cce.cornell.edu/profiles/rodent/cholecalciferol/rod-prof-cholecalciferol.html">http://pmep.cce.cornell.edu/profiles/rodent/cholecalciferol/rod-prof-cholecalciferol.html</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>21. <span class=SpellE>Woodhead</span>
JS, <span class=SpellE>Ghose</span> RR, Gupta SK. Severe <span class=SpellE>hypophosphataemic</span>
<span class=SpellE>osteomalacia</span> with primary hyperparathyroidism. Br
Med J. 281:647-648. 1980. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>22. Gordon CM et al. In
press. </span><span style='font-size:11.0pt'><a
href="http://www.philly.com/mld/philly/living/health/6119306.htm">http://www.philly.com/mld/philly/living/health/6119306.htm</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>23. <span class=SpellE>BluePrint</span>
for Health Herb Index: Vitamin D. Blue Cross and Blue Shield of Minnesota,
Inc. 2002. </span><span style='font-size:11.0pt'><a
href="http://blueprint.bluecrossmn.com/topic/topic100587894">http://blueprint.bluecrossmn.com/topic/topic100587894</a></span><span
style='font-size:11.0pt;font-family:Arial'> <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>24. Willis, M and Fairly,
A. Effect of increased dietary <span class=SpellE>phytic</span> acid on <span
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406. 1972.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>25. McCormick CC. Passive
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<p><span style='font-size:11.0pt;font-family:Arial'>26. Dawson-Hughes B,
Harris SS, <span class=SpellE>Krall</span> EA, et al. Effect of calcium and
vitamin D supplementation on bone density in men and women 65 years of age or
older. N <span class=SpellE>Engl</span> J Med. 337:670-676. 1997.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>27. <span class=SpellE>Mitric</span>
JM. Maturity News Service, November 15, 1992<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>28. <span class=SpellE>Recker</span>
RR. Osteoporosis. Contemporary Nutrition, Vol. 8, no. 5, May 1983.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>29. Christiansen C and <span
class=SpellE>Rodbro</span> P. Initial and maintenance doses of vitamin D2 in
the treatment of anticonvulsant <span class=SpellE>osteomalacia</span>. <span
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1974.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>30. <span class=SpellE>Yeste</span>
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childhood: analysis of 62 cases<span class=GramE>][</span>Article in Spanish]
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<p><span style='font-size:11.0pt;font-family:Arial'>31. <span class=SpellE>Anatoliotaki</span>
M, <span class=SpellE>Tsilimigaki</span> A, <span class=SpellE>Tsekoura</span>
T, <span class=SpellE>Schinaki</span> A, <span class=SpellE>Stefanaki</span>
S, <span class=SpellE>Nikolaidou</span> P. Congenital rickets due to maternal
vitamin D deficiency in a sunny island of Greece. <span class=SpellE>Acta</span>
<span class=SpellE>Paediatr</span>. 92(3):389-91. 2003.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>32. <span class=SpellE>Hoecker</span>
CC, <span class=SpellE>Kanegaye</span> JT. First place winner. Recurrent
febrile seizures: an unusual presentation of nutritional rickets. J <span
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<p><span style='font-size:11.0pt;font-family:Arial'>33. Johnson GH, Willis F.
Seizures as the presenting feature of rickets in an infant. Med J <span
class=SpellE>Aust</span>. May 5<span class=GramE>;178</span>(9):467 2003.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>34. <span class=SpellE>Stebbing</span>
C, <span class=SpellE>Mansy</span> S, <span class=SpellE>Kanabar</span> D.
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<p><span style='font-size:11.0pt;font-family:Arial'>35. Shah M, <span
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afflict children in north <st1:State w:st="on"><st1:place w:st="on">Texas</st1:place></st1:State>.
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<p><span style='font-size:11.0pt;font-family:Arial'>36. <span class=SpellE>Kreiter</span>
SR, Schwartz RP, <span class=SpellE>Kirkman</span> HN <span class=SpellE>Jr</span>,
Charlton PA, <st1:place w:st="on"><st1:City w:st="on"><span class=SpellE>Calikoglu</span></st1:City>
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<p><span style='font-size:11.0pt;font-family:Arial'>37. Lee JR. Fluoridation
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<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>38. Medical World News,
October 23, 1989 and November 13, 1989. Journal of the American Medical
Association, July 25, 1990, June 19, 1991 and July 24, 1991; American Journal
of Epidemiology, April 15, 1991; and the American Journal of Public Health,
July, 1990. <o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>39. Review of fluoride
benefits and risks. <st1:country-region w:st="on"><st1:place w:st="on">U.S.</st1:place></st1:country-region>
Public Health Service, February, 1991.<o:p></o:p></span></p>
<p><span style='font-size:11.0pt;font-family:Arial'>40. Fluoridation of
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<p><span style='font-size:11.0pt;font-family:Arial'>41. <span class=SpellE>Wortsman</span>
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<p><span style='font-size:11.0pt;font-family:Arial'>42. Holick MF. Vitamin D:
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<p><span style='font-size:11.0pt;font-family:Arial'>43. Key SW, Marble M.
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style='font-size:11.0pt'><a
href="http://www.dwpm.com/content/main/litigation00_news.php3">http://www.dwpm.com/content/main/litigation00_news.php3</a></span><span
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</span><a
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