photobiology of vitamin D

vitamin D is not by the strict definition a vitamin because it can be synthesized in

the skin by the action of sunlight. therefore, factors that limit exposure of the skin to
sunlight may play a major role in determining a person's vitamin D status.

photosynthesis of previtamin D3, in human skin

7-dehydrocholesterol (7-DHC, provitamin D3), the immediate precursor of

cholesterol, is present in the viable epidermis and dermis. during exposure to
sunlight, 7-DHC absorbs sunlight (photons) with energies of between 290 and 315
nm (ultraviolet B radiation, UVB). this process causes a transformation of 7-DHC to
previtamin D3 (fig. 27-1) (holick, 1994). after previtamin D3 is made, it undergoes
an internal transformation of its double bonds that is stimulated by the body's
temperature to form vitamin D3, its three-dimensional structure changes,
facilitating vitamin D3's translocation from the skin ceel into the blood stream. once
in the blood stream, it is bound to a specific vitamin D-binding protein commonly
known as an globulin.

sunlight-mediated regulation of vitamin D3, synthesis in the skin

it is not possible to make an intoxicating amount of vitamin D3 in the skin due to

prolonged exposure to sunlight. the reason for this is that once previtamin D3 is
photosynthesize in the skin, it can either be converted to vitamin D3 or, if exposed
to sunlight, be degraded into biologically inert photoproducts known as lumisterol
and tachysterol (fig. 27-1) (holick, 1994). vitamin D3 is also exquisitely sensitive to
photodegradation by sunlight (webb et al. 1989). therefore, if vitamin D3 does not
exit from the skin into the circulation before being exposed to sunlight, it is
degraded by sunlight into supersterol I, supersterol II, and 5,6-trans-vitamin D3
(fig.27-1).

effect of melanin pigmentation on the cutaneous production of previtamin

D3

loomis (1967) popularized the theory that melanin pigmentation in humans evolved
to protect people who lived at or near the equator from producing excessive,
intoxicating amounts of vitamin D3. he further speculated that as peoples migrated
north and south of the equator they lost their skin pigmentation in order to promote
an adequate amount of vitamin D3 synthesis in their skin to protect their bones
from developing rickets and osteomalasia. melanin is an excellent sunscreen that
absorbs the ultraviolet radiation from sunlight. therefore, melanin competes with 7-
DHC in the skin for the UVB photons. as a result, increased skin pigmentation
decreases the production of previtamin D3 in the skin (clemens et al., 1982).

we have previously found that blacks with very dark skin pigmentation require
tenfold longer exposure to simulated sunlight to make the same amount of vitamin
D3 in their skin as does a light-skinned white (clemens et al., 1982). because
sunlight prevents an excessive production of either previtamin D3 or vitamin D3 in
the skin by causing the photodegradation of excessive amounts of these
compounds, it is unlikely that melanin pigmentation evolved for the purpose of
preventing vitamin D3 intoxication due to excessive exposure to sunlight of peoples
who live near the equator. it is, however, intriguing to consider the possibility that
skin pigmentation gradually disappeared in peoples that migrated north and south
of the equator in order to promote an adequate production of vitamin D3 in the skin.
this concept remains a theory and has not been proved. however, it should be noted
that blacks who line in northern europe,where food is not fortified with vitamin D as
it is in the united states, do not suffer from a higher incidence of rickets and
osteomalacia caused by vitamin D deficiency when campared with northern
european whites.

Environmental effects on the production of vitamin D3

The time of day, season of the year, and latitude have dramatic effects on the
amount of solar UVB radiation that reaches the earths surface. In winter, vitamin
producing UVB photons pass through the ozone layer at an oblique angle and are
absorbed by the ozone in great numbers. More UVB photon are able to penetrate
the ozone layer in the spring, summer, and fall months because the sun is directly
overhead. At latitude 42o N (Boston), sunlight is incapable of producing vitamin D3
in the skin from November through February. Ten degrees north of boston (52 o N,
edmonnton, Canada), this period is extended to include October and march (fig.27-
2) (webb et al.,1988).

Because casual exposure to sunlight provides most of our vitamin D requirement,

the inability of the sun to produce vitamin D3 in northern and southern latitudes
during the winter may require the elderly to take a vitamin D supplement to prevent
vitamin D deficiency. For children and young adults, the cutaneous production of
vitamin D3 during the spring, summer, and fall is adequate to produce enough for
storage in the fat that can be used during the winter months.

Exposure to sunlight at lower latitudes such as iin los angles (24 o N), Puerto rico (18o
N), and Buenos aires (34o S), results in the cutaneous production of vitamin D3
during the entire year. During the summer in boston, exposure to sunlight from the
hours of 7 A.M to 5 P.M. estern standard time (EST) result in sufficient UVB photons
to produce previtamin D3 in the skin. I the spring and fall months, vitamin D
production commences at approximately 9 A.M an cease after 3 P.M EST.

Effect of aging on the cutaneous production of vitamin D3

Aging affects many different metabolic processes. Therefore, it is not surprising that
aging also decreases the capacity of human skin to produce vitamin D3. Aging
decreases the concertation of 7-DHC n the epidermis and thereby reduces the
capacity of the skin to produce vitamin D3 by approximately 75% by age 70 years
compared with younger adults (fig. 27-3) (holick et al., 1989).

Effects of sunscreen use and clothing on the cutaneous production of

vitamin D3

The pulic is now very much aware that chronic excessive exposure to sunlight can
increase the risk of skin cancer and cause photoaging of the skin. This has led to the
general recommendation thet people of races that sunburn should always wear a
sunscreen before going outdoors (Gilchrest, 1993). Commercial sunscreens work by
bsorbing solar UVB radiation, and some product s also absorb some or all of the
solar ultraviolet A (320 to 400 nm) radiation. Thus, sunscreens act like melanin and
prevent these high-energy photons from having adverse effects on the skin.

Sunscreen use has been proved to decrease the risk of some forms of skin cancer,
including squamous cell carcinoma, and to reduce photodamage that causes
photoaging of the skin. However, since the solar radiation that is responsible for
causing the damaging effects to the skin is the same radiation that causes the
cutaneous production of vitamin D3. It is not surprising that the topical application
of a sunscreen can diminish or completely prevent the vitamin D3 production in the
skin. When a young adult expose the whole body to simulated sunlight that causes
a minimal sunburning (1 minimal erythernal dose; MED), the amount of vitamin D3
that is produced in the skin and enters the circulation is equivalent to taking
between 10.000 and 25,000 IU of vitamin D orally.

When healthy young adult volunteers applied a sunscreen preparation with aa sun
protection factor of 8 (SPF-8) before being exposed to a whole body dose of 1 MED
of simulated sunlight, plasma levels of vitamin D did not rise above the baseline
value (fig. 27-4). To further investigate the impact of sunscreen use on the
cutaneous production of vitamin D3, 10 volunteers who wore typical clothing for a
summer day (short-sleeved blouse or shirtand short) topically applied a sunscreen
with an SPF of 25 only to the face or to unclothed ares with the exception of the
face. Twenty-four hours after exposure to 0.9 MED of simulated sunlight, a small in
crease in the circulating concentration of vitamin D3, from 3.0 1.0 (mean SEM)
to 4.4 + 1.0 ng/mL of serum, was noted in the volunteers who exposed only their
faces. When the face was covered and the arms and legs were exposed there was a
significant increase in the serum vitamin d level: from 1.9 0.3 to 0.8 ng/mL.

Clothing absorbs most ultra violet radiation; therefore, covering the sskin with most
types of clothing will prevent the cutaneous production of vitamin D3(matsuoka et
al., 19920 (fig. 27-5). People of cultures such as Bedouins living in the negev desert,
who are require to have most of the skin surface covered by clothing, are prone to
develop vitamin D deviciency (taha et al. 1984).

It is recommended that children and young adults always wear a sunscreen with an
SPF of at least 15 to prevent the consequences of chronic excessive exposure to
sunlight. There is no need to be concerned about the effet of sunscreen use on
preventing the cutaneous production of vitamin D3 in this population because it is
unlikely that they will always wear a sunscreen or use the proper amount of the
agent before going outdoors. However , there is reason for concern with regard to
elderly people, who often depend on sunlight for their vitamin D requirement . if
they limit their outdoor activities ad apply a sunscreen properly before going out,
they can substantially reduce or even prevent the production of vitamin D3 and
develop a subclinical vitamin D deficiency (holick, 1994).

Food sources of vitamin D and the recommended dietary allowances

Naturally occurring vitamin D is rare in foods. Vitamn D is used to refer to either

vitamin D2 or vitamin D3, both of which can be converted to active vitamin D
metabolites. Vitamin D2 originates from the yeast and plant sterol ergosterol,
whereas vitamin D3 originates from 7-DHC in animanls. The major structural
difference between vitamin D2 and vitamin D3 is in the side chain. Unlike vitamin
D3, vitamin D2 has a double bond between carbons 22 and 23 and a methyl group
on carbon 24.

The major natural sources of vitamin D are fatty fish like mackerel and salmon and
fish oils, including cod and tuna liver oils. The major dietary sources of vitamin D are
food fortified with vitamin D2 or D3. Milk has been fortified with vitamin D in the
united states since the 1930s. more recently, some cereals and breads have been
fortified with vitamin D. other dairy products, including ice cream, cheeses, and
yogurt, are not fortified with vitamin D.

The vitamin D content in milk, however, is variable. Several recent studies suggest
that in the united states and western Canada, up to 80% of samples tested did not
contain between 400 and 600 IU/quart (10 an 15 g/quart) of vitamin D. almost 50%
of the samples did not contain 50% of the vitamin D stated on the label, and
approximately 15% of the skim milk sample contained no detectable vitamin D
(holick,1994). Multivitamin preparation containing vitamin D were found to be a
good source of vitamin vitamin D and contained between 400 and 600 IU (10 an 15
g/quart) of vitamin D per tablet; pharmaceutical preparations labeled as 50,000 IU
(1250 g) of vitamin D2 contained the stated amount 10%. Although the 1980
and 1989 RDAs for vitamin D were set at 5 g/day for adults, there is mounting
evidence that in the absence of sunlight the actual requirement for vitamin D in
adults may be as much as 15 to 20 g/day (dawson-hughes et al., 1991 ; holick,
1994). This is now reflected in the recently released dietary reference intakes for
vitamin D (institute of medicine, 1997). Although a new RDA was not established,
the adequate intake (AI) for vitamin D was set at 5 g/day for individuals 50 years of
age and younger but at 10 g/day for adults 51 to 70 years of age and at 15 g/day
for adults more than 70 years of age.

Vitamin D in bone health

Vitamin D plays a critical role in mineralization of the bone, and bone disorders
result from inadequate circulating levels of the biologically active metabolite of
vitamin D. vitamin D acts to maintain the plasma calcium and phosphate
concentration so that skeletal mineralization occurs.

Rickets and osteomalacia

Vitamin D deficiency causes rickets in children (holick, 1994). Before the epiphyseal
plates close, vitamin D deficiency causes a disorganization and hypertrophy of the
chondrocytes at the mineralization front as well as a mineralization defect,resulting
in short stature and bony deformities that are characteristic of vitamin D deficiency
rickets (fig. 27-6). In adults the epiphyseal plates are closed, thereby preventing
many ao the bony deformities seen in rachitic children. Vitamin D deficiency in
adults causes osteomalacia. Osteomalacia is a very significant metabolic bone
disease, especially in elderly people. Adults with vitamin D deficiency have a
mineralization defect in the skeleton that results in poor mineralization of the
collagen matrix (osteoid). Although this does not cause bony deformities, it can
cause severe osteopenia (a decrease in the opacity of the skeleton a seen by x-ray).
This mineraliation defect can lead to increased risk of sskeletal fractures (aaron et
al., 1974). In addition, for unexplained reasons osteomalacia can also cause
localized or generalized, unrelenting deep bone pain.

Consequences of vitamin D deficiency

The major function of vitamin D in maintaining a healthy skeleton is to maintain the

serum calcium and phosphate concentrations within their physiological ranges to
keep the calcium X phosphorus [e.g., (serum Ca of 10.0 mg/100 mL) X (serum P of
4.0 mg/100 mL) = 40] high enough for skeletal mineralization. ( see chapter 28 for
more information on calcium and phosphorus).

As the body becomes vitamin D deficient, the efficiency of intestinal calcium

absorption decreases from the usual 30% to 50% to no more than 15%. This results
in a decrease in the ionized calcium concentration in the blood, which signals the
calcium sensor in the parathyroid glands to increase the production and secretion of
parathyroid hormone (PTH) (fig. 27-7). PTH, in turn, tries to conserve calcium in the
kidney by increasing renal tubular reabsorption of calcium. Wit vitamin D, PTH helps
mobilize monocyte-like stem cells to become active bone calcium resorbing
multinucleated giant cells known as osteoclasts, which can cause erosion of the
skeleton, cusing or exacerbating osteoporosis (fi. 27-7). Although PTH perfoms an
invaluable function in retaining calcium in the kidney, it also induces a leaking of
phosphate into the urine, which results in hypophosphatemia. Thus, patients with
subclinical vitamin D deficiency often have a normal serum calcium concentration
with a low or lownormal serum phosphorus concentration. Patients with long-
standing vitamin D deficiency have low serum concentrations of both calcium and
phosphorus. This results in a substantial decrease in the calcium X phosphorus
product, resulting in the defect in bone matrix mineralization that leads to rickets in
children and osteomalcia in adults. The hallmarks for vitamin D insufficiency and
deficiency are a low-normal (between 10 and 20 ng/mL) and a low or undetectable
(less than 10 ng/mL) serum concentration of 25-hydroxy-vitamin D (25-OH-D),
respectively.

There is ample clinical evidence that increasing dietary calcium intake to at least
1000 mg/day, along with supplementation of at least 10 to 10 g of vitamin D
daily,will decrease vertebral and nonvertebral fractures and increase bone mineral
density (chapuy et al., 1992). During the winter in new England, when sunlight loses
its ability to produce vitamin D3 in the skin, there is marked loss of bone mineral
density of the hip and spine that is related to a decrease in circulating levels of 25-
OH-D and an increase in PTH levels (fig.27-8) (rosen et al., 1994).

Vitamin D metabolism and function

In the body, vitamin D undergoes two hydroxylation reactions that convert it to the
biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. this active form of
vitamin D acts on target tissues, especially intestine and bone. It acts to regulate
calcium absorption and bone mineral mobilization in order to maintain calcium
homeostasis.

Metabolism

Vitamin D2 and vitamin D3 that are used to fortify foods are ingested, mixed with
other lipids, up by enterocytes, and incorporated into chylomicrons are released by
the enterocytes and enter the lymphatic system, which drains into the venous blood
stream. Ultimately, this vitamin D (in chylomicron remants) reaches the liver, where
it is hydroxylated and again enters the circulation bound to vitamin D-binding
protein. Vitamin D3 that is synthesized in the skin enters the circulation and is
bound to the vitamin D-binding protein.

Both vitamin D2and vitamin D3 in the circulation are taken up by the liver and
hydoxylated on carbon 25 to produce 25-OH-D (see fig.27-7). 25-OH-D is the major
circulating form f vitamin D, and it is present in the circulation bound to the vitamin
D-binding protein. It is 25-OH-D that is measured in te blood to determine the
vitamin D status of a patient. The hepatic vitamin D 25-hydroxylase is not tightly
regulated; therefore, any increase in vitamin D intake or in the cutaneousproduction
of vitamii D3leads to an increase in the circulating concentration of 25-OH-D. that is
the reason why 25-OH-D is so valuable as a marker for determining the vitamin D
status of a patient. Low or undetectable circulating concentration of 25-OH-D are
diagnostic of vitamin D deficiency, and 25-Oh-D levels that are two to three times
the upper limit of the normal range (normal range, 10 to 55 ng/mL of serum) are
diagnostic for vitamin D intoxication (holick et al., 1994).
Once 25-OH-D is made, it enters the circulation, and most of it is bound to the
vitamin D-binding protein. The unbound form of 25-OH-D enters the kidney tubular
cells, where it is hydroxylated on carbon 1 to form 1,25(OH) 2D (see fig.27-7). 1,25
(OH)2D in considered to be the biologically active form of vitamin D that is
responsible for carrying out most if not all of the biological functions of vitamin D.
the major function of 1,25(OH)2D is to increase the efficiency of intestinal calcium
absorption, thereby increasing the utilization of dietary calcium (see fag.27-7).
1,25(OH)2D can increase the efficiency of intestinal calcium absoption from a basal
level of 20% to 300% up to 80%.

Regulation of 25-hydroxyvitamin D metabolism

The major factor that regulates the metabolism of 25-OH-D to 1,25(OH) 2D is PTh
(see fig. 27-6). The exact mechanism by which PTH stimulates the kidneys
production of 1,25(OH)2D is not well characterized. However, there is evidence that
the hypophosphatemic effect of PTH on the kidney may be responsible for
increasing the renal production of 1,25(OH) 2D (holick et al., 1994). Indeed,
hypophosphatemia and hyperphosphatemia are associated with increased and
decreased circulating concentrations of 1,25(OH) 2D, respectively. A variety of other
hormones associated with growth and development of the skeleton or calcium
regulation, including growth hormone and prolactin, indirectly increase the renal
production of 1,25(OH)2D.

It is recognized that elderly people often lose their ability to adapt to a low calcium
diet by increasing their efficiency of intestinal calcium absorption (Ireland and
fordtran, 1973). Although the exact mechanism is not fully understood, there is
evidence that the ability of the kidney to upregulate the production of 1,25(OH) 2D
by PTH is no longer operative (slovik et al., 1981; riggs et al., 1981).

Extrarenal production of 1,25-dihydroxyvitamin D

Although the kidney is the major site for 1,25(OH) 2D production, during pregnancy
the placenta also has the capacity to make it. This apparently is important during
the last trimester of pregnancy, when circulating levels of 1,25(OH) 2D are increased
to enhance the efficiency of intestinal calcium absorption of the mother to meet the
increased need of the fetus for calcium ti mineralize its skeleton.

There is mounting scientific evidence that other cells have the capacity to produce
1,25(OH)2D. however, it is believed that the local production of 1,25(OH) 2D is used
in an autocrine or paracrine manner and does not ccintribute to the circulating
concentration of 1,25(OH)2D. although the exact biological function of 1,25(OH) 2D in
tissues not responsible for calcium metabolism, such as circulating monocytes, skin
cells, and bone cells, is not well understood, it is recognized that 1,25(OH) 2D is a
potent inhibitor of cellular proliferation and a sstimulator of differentiation (hollick,
1994).
Biological functions of 1,25-dihydroxyvitamin D

The major biological function of vitamin D is to maintain calcium homeostasis in

order to maintain cellular metabolic processes and neuromuscular functions. The
principal biological function of 1,25(OH)2D is to increase the efficiency of intestinal
calcium absorption. 1,25(OH)2D directly affects the entry of calcium through the
plasma membrane of the intestinal absorptive cell, thereby enhancing the
movement of calcium through the cytosol and across the basolateral membrane of
the enterocyte into the circulation. 1,25(OH)2D alters the flux of calcium across the
intestinal absorptive cell by increasing the production and activity of several
proteins in the small intestine, including calcium-binding protein (calbindin), alkaline
phosphatase, low-affinity calcium dependent ATPase, calmodulin, brush border
actin, and brush border proteins with molecular masses of 80 to 90 kDa. Although
the exact function of calbindin is not well understood, it is specifically induced by
1,25(OH)2D and is thought to be one of the major proteins responsible for
alterations in the flux of calcium across the gastrointestinal mucosa. When
1,25(OH)2D is given as a single intravenous does to vitamin D-defient animals, it
causes a biphasic response. Within the first 2 hours there is a rapid increase in the
flux of calcium across the gastrointestinal mucosa that peaks by 6 hours; another
response begins after 12 hours and peaks after 24 hours.

1,25(OH)2Dalso increase the efficiency of intestinal phosphorus absorption in the

jejunum and ileum of the small intestine. Because dietary phosphate is often
plentiful and at least 40% of dietary phosphorus is aabsorbed passively, the role of
1,25(OH)2D in enhancing phosphorus absorption is less critical.

When dietary sources of calcium are inadequate to maintain calcium homeostasis,

1,25(OH)2D will call upon the bone to mobilize its calcium reserves. 1,25(OH) 2D
accomplishes this by stimulating monocytic stem cells in the bone marrow to
differentiate into bone-resorbing mature osteoclast. Once the osteoclast have
matured they no longer respond to 1,25(OH) 2D. it is beleved that 1,25(OH)2D,
through its action on osteoblast, enhances the production of osteoclast-sensitive
cytokines and hormones such as interleukin-6 (IL-6) and interleukin-12 (IL-12),
which in turn regulate osteoclastic activity. Therefore, 1,25(OH) 2D may indirectly
regulate mature osteoclast function by this mechanism.

Mature osteoblast in the bone possess vitamin D receptors and are responsive to
1,25(OH)2D. 1,25(OH)2D increase the expression of alkaline phosphatase,
osteopontin, and ostecalcin, as well as a variety of cytokines in the cells. It is likely
that 1,25(OH)2D plays an important role in the bone remodeling process. However,
1,25(OH)2D does not directly induce bone to mineralize. Instead, 1,25(OH) 2D
promotes the mineralization of osteoid laid down by osteoblast by maintaining
extracellular calcium and phosphorus concentrations within the normal
supersaturating range, which results in the passive deposition of calcium,
hydroxyapatite into the bone matrix.
Metabolism of 1,25-dihydroxyvitamin D

1,25(OH)2D is metabolized in its target tissues-the intestine, bone, kidney, as well as

in the liver. It undergoes several hydroxylations in the side chain, resulting in the
cleavage of the side chain between carbons 23 and 24, forming the biologicaly
inert, water-soluble calcitroic acid. Both 25-OH-D and 1,25(OH) 2D undergo a24-
hydroxylation to form 24,25-dihydroxyvitamin D, respectively. These metabolites are
considered to be biologically inert and arethe first step in the biodegradation of 25-
OH-D and 1,25(OH)2D. more than 40 different metabolites of vitamin D have been
identified to date, but 1,25(OH)2D is believed to be responsible for most, if not all, of
the biological actions of vitamin D on calcium and bone metabolism (deluca, 1938;
bouillon et al., 1995).

Molecular biology of vitamin D

Vitamin D is lipophilic, as its is active form. Therefore, the mechanism of action of

1,25(OH)2D is similar to the action of other small hydrophobic hormones that act
via nuclear receptors, such as retinoic acid, thyroid hormone, estrogen, and
glucocorticoids. All target tissues for vitamin D contain a nuclear receptor for
1,25(OH)2D, known as the vitamin D receptor (VDR). The VDR recognizes
1,25(OH)2D 1000 times better than it recognizes 25-OH-D. it is the unbound (ree)
1,25(OH)2D that enters into the target cell where it is recognize by the VDR.
Althought the exact machanism is not completely clarified by which 1,15(OH)2D
interacts with its receptors and causes activation of transcription of specific genes,
a sequence of events is required before 1,25(OH)2D can carry out its biological
functions.

One 1,25(OH)2D enters the cells, it eventually finds its way to the nucleus,
where it is boundto its VDR. The VDR+1,25()H)2D complex, in turn, binds a retinoic
acid x-receptor (RXR) to form a heterodimeric complex (Pixe, 1991; Darwish and
DeLuca, 1993). This heterodimeric complex interacts with a specific vitamin D-
responsive element (VDRE) within the DNA. The DNA-binding motif for VDR, which is
present in the N-terminal part of the molecule, contains two zinc finger motifs that
interact with the DNA in the VDRE (Fig.27-9). The VDRE is composed of two
tandemly repeated hexanucleotide sequence separated by three base pairs. This
interaction ultimately leads in osteoblast are to an increase or a decrease in the
transcription of the vitamin D-responsive genes and a change in the rate of
synthesis of new mRNAs.

The best-charecterized proteins that are induced by 1,25(OH)2D in osteoblast

are osteocalcin, osteopontin, and alkaline phosphates. The major gene product
produced in the small intstine by 1,25(OH)2D is the calcium-binding protein
calbindin (Wasserman et.,al 1984).

BIOLOGICAL FUNCTIONS OF 1,25(OH)2 IN NONCALCEMIC TISSUES

 A wide variety of tissues, and cells, including the barain, gonads, breast, skin,
mononuclear cells, and activated B and T lymphocytes, possess VDR. The first
insight into the biological action of 1,25(OH) 2D in noncalcemic tissues was the
observation that promyelocytic leukemic cells with a VDR transformed into mature,
biochemically functioning macrophages after being treated with 1,25(OH) 2D (Tanaka
et al.,1982). It is now recognize that 1.25(OH) 2D can inhibit the proliferation an
induced terminal differentiation of a variety of normal and tomur cells, possibly by
directly or indirectly altering transcription of cells growth regulatory genes such as
c-myc, c-fos, and c-sis (Fog.27-9). 1,25(OH)2D has not been found usefull for
treating a variety of malignant disorders, probably because clones of cell that have
a defective receptor the dominant tumor cell type, resulting in malignant cells that
are ni longer responsive to the antiproliferative activity of 1.25(OH) 2D (Koeffler et
al., 1985). However, there is one clinical application for the antiproliferative activity
of 1.25(OH)2D and its analogs. Because epidermal cells possess a VDR, it was
reasoned that patients with the hyperproliferative skin disorder might benefit from
either topical or oral 1.25(OH)2D therapy. A multitude of studies have now
demonstrated the therapeutic efficacy of 1.25(OH) 2D and its analogs for treating the
hyperproliferative skin disorder (psoriasis) that cause redness, scaling, and raised
lesions. This has led to the development of an analog, calcipotriene (Dovonex),
which is highly effective when applied topically for the treatment of psoriasis. Unlike
other treatments for psoriasis, there is no evidence that the topical application of
calcipotriene has any significant undesirable side effects (Kregvalle, 1989; Perez et
al., 1996).

RECOMMENDATIONS FOR SATISFYING THE VITAMIN d REQUIREMENT FOR

MAXIMUM BONE HEALTH

Vitamin D envolved as a calciotropic hormone responsible for maintaining the

blood calcium and pjosphorus whitin the normal physiological range. Only when the
bodys need for calcium to maintain metabolic function is satisfied is any additional
calcium that is absorbed throught the intestine deposite into the skeleton.

Vitamin D deficiency is a sighnificant helath problem, especially for elderly

people. Because most of our vitamin D comes from casual exposure to sunlight, it is
important to recognize that adults over the age of 50 years should consider being
exposed to suberythermal (not cauing sunburn) doses of sunlight to provide their
bodies with the vitamin D requirement. In boston, it has been recommended for
middle-aged and older adults that exposure of hands, face, and arms two to three
times a week to suberythermal doses of sunlight (approximately 5 to 15 minutes a
day depending on the skins sensitivity to sunlight) is adequate to provide sufficient
amounts of vitamin d3.

Vitamin d3 that is produced in the skin is stored in the body fat; therefore, the
vitamin d3 that is produced in the spring, summer, and fall can be stored and is
available during the winter when the sun is incapable of producing vitamin d3 in the
skin. This is the reason why children and the most adults do not become vitamin d-
deficient during the winter month in far northern and southern latitudes. Because a
topical application of a sunscreen can essentially prevent the producition of vitamin
d3 in the skin, people who wish to stay outdoors for long periods of time should be
exposed only to suberythermal amounts of sunlight for their vitamin d3 and then
apply a sunscreen with a SPF of 15 or greater to prevent the consequences of
chronic excessive exposure to sunlight. Children and young adults should always
wear a sunscreen before going outdoors to help. Prevents skin demage and skin
cancer. Because children and young adults will not always wear a sunscreen over all
sun-expoosed areas, they are still able to produced enough vitamin D from sun
exposure to satisfy their bodys requirement.

Although milk, some cereals, and bread products may contain vitamin D, this
is highly variable and shouls not be depended on as the only source of the vitamin.
A multivitamin tablet that contains 10 (400 IU) of vitamin D is an excellent source
and will help maintain circulating concentrations of 25-OH-D. However, in the
absence of any sunlight, a multivitamin may not be adequate to maintain normal
vitamin D status (Holick< 1994). Adults 51 years and older who have little exposure
to sunlight likely require at least 10 to 15 g of vitamin D daily to satisfy the bodys
requirement. Vitamin D deviciency can be corrected by administering an oral dose
of 500,000 IU (1250g) vitamin d2 once a week for 8 weeks. The serum 25-OH-D
level can be expected to increase from less than 15 ng/mL. This treatment will
maintain a normal vitamin D status for at least 2 to 4 month. After the 8 weeks,
patients can be placed on a multivitamin containing 400 IU (10 g) of vitamin D,
which shouls help maintaince their vitamin D status. An adequate source of calcium
in combination with vitamin D from sunlight and/or a multivitamin containing
vitamin D is essential for guaranteeing a healthy skeleton throughout life