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The future of vitamin D supplementation

The first high performance topical Vitamin D3

product to hit the market.

Only 15 years ago, doctors, scientists and the

educated laymen thought of "vitamin D" as the "anti-

rachitic vitamin", almost exclusively. The prevention

of rickets, a defective mineralization of bones before

epiphyseal closure in immature mammals that leads

to fractures and deformity and post-menopausal

bone loss (osteoporosis) is still among the most

immediate health benefits of vitamin D

supplementation and / or adequate sun exposure.

And still, the list of recently discovered and emerging

beneficial effects of vitamin D on the endocrine,

immune and musculoskeletal system continues to

grow.

You don't want to risk being deficient

Low levels of the vitamin D metabolite 25-OHD

(<30ng/mL) have been linked to osteoporosis,

cardiovascular disease, stroke, autoimmune diseases

and cancer (see Figure 2).

Table 1: Serum25(OH)D range (ng/mL) according to 25 experts Souberbille et al. questioned for their 2010 analysis of practical implications of recent insights into the role of vitamin D in musculoskeletal health, cardiovascular disease, autoimmunity and cancer (Souberbille. 2010).

No wonder that the group of published scientists who

were surveyed for a 2010 paper on practical

recommendations for the clinical practice agreed that

25OHD levels below 30ng/mL (>75 nmol/L) require

immediate action on part of practicing physicians (see

Table 1).

Good sources of vitamin D are scarce

The most abundant source of vitamin D for humans is

exposure to sunlight (Holick. 2003). From an

evolutionary perspective, foods are rather an

alternative source of vitamin D. Most of the foods in

our diets contain relatively little vitamin D.

In fact, oily fish, like salmon, mackerel, herring, and

grandma's cod liver oil are among the few food items

that contain significant amounts of vitamin D. Yet

while 3.5 ounces of while wild-caught salmon contain

on average 500–1000 IU vitamin D, the same amount

of its farmed counterpart contains only 100–250 IU

vitamin D per serving (Chen. 2007).

25(OH)D range No. of experts

30–100 20 30–150 1 30–80 1 30–50 2 40–100 1

Oily fish like mackerel are among the few food items that contain significant amounts of dietary vitamin D. No wonder! We are after all supposed to produce all the vitamin D we need in the skin!

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It is thus only logical that the food industry is trying

to make up for the lack of vitamin D in its products

by fortifying milk, juice products, breads, yogurts,

and cheeses.

Still, the latest evidence from epidemiological

studies indicates that the amount of vitamin D the

average Westerner gets from his / her diet is not

enough to keep his / her levels of 25-OHD in the

aforementioned range of 30-100ng/mL.

The downsides of low vitamin D levels are making

the evening news

Frightening reports about the involvement of low

vitamin D levels in the etiology of almost all diseases

of civilization are in the news on an almost weekly

basis.

As a consequence of the rising awareness of the ill

health effects of low vitamin D levels, supplements

containing anything from 400 IU to 50,000 IU vitamin

D3 have become best-sellers at US and European

drugstores; and that despite the fact that the results

of randomized controlled trials draw a very

ambiguous image of the net health benefits of these

products:

Scientists are still debating the potential causes of

the confusing study results. Next to genetic

polymorphisms, researchers are also looking at

the route of administration and the role of

vitamin D binding proteins (Chun.2013).

Does only free vitamin D matter? Probably not.

Chun et al., for example, argue that the 99.9% of

25(OH)D that circulates bound to vitamin D binding

(VDBP) protein and or other carriers could have

little to no influence on the "non-classical actions

of vitamin D" (Chun. 2013). If this hypothesis was

accurate, this would imply that a simple increase in

25-OHD, as it has been shown in response to

dosages as low as 1,000IU of vitamin D3 per day will

exert its beneficial effects on metabolic (diabetes,

obesity, hyperlipidemia), immune (rheumatoid

arthritis, multiple sclerosis, asthma, etc.),

cardiovascular (stroke, CAD, CVD, etc.) and

musculoskeletal health (sarcopenia, bone loss,

etc.), only, if the 25-OHD is free and not bound by

VDP or other carriers.

A similar mechanism has already been proposed

for other hormones and is, just as it is the case for

vitamin D, highly controversial. And there are in

fact more than a handful of arguments against the

"free vitamin D hypothesis". Decreasing vitamin D

binding protein levels with age, for example, are

associated with a significantly increased risk of

vitamin D deficiency (Yousefzadeh. 2014). A similar

association has been found for fatty liver disease

(Malham. 2011) and type I diabetes (Blanton.

2011). Moreover, high levels of bound vitamin D

have been associated with decreased pancreatic

cancer and prostate cancer risks (Weinstein. 2012

& 2013) – a result that appears to be logical in view

of the reduced biological activity of vitamin D

analogues with an artificially binding affinity for

vitamin D binding protein (Bouillon. 1991).

To finally answer the question if the amount of

free 25(OH)D is a better marker of vitamin D

activity we need more relevant data, data which

Figure 1: Figure 2: A Schematic representation of the major causes for vitamin D deficiency and potential health consequences (Holick. 2010)

"Despite a few hundred systematic reviews

and meta-analyses, highly convincing evidence

of a clear role of vitamin D does not exist for any

outcome " (Theodoratou. 2014)

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could have a major impact on our understanding of

the optimal route of vitamin D supplementation, as

well.

Different binding- and pharmacokinetics - The

topical advantage

Scientists have been wondering for decades about

the potential pharmacokinetic differences

between endogenously produced vitamin D from

the skin and the various forms of vitamin D in our

diet.

In 1993 Haddad et al. published a paper in which

they were able to show that dietary vitamin D will

bind preferentially to other carriers than vitamin D

binding protein (VDBP), such as chylomicron

remnants or low density lipoprotein (LDL). The

resulting vitamin D complexes are either stored

(Holmes. 1983), as it appears to be the case in the

fat tissue of obese individuals (Vimaleswaran.

2013) or taken up through liver membrane

receptors and thus no longer available for the

health-relevant interactions with vitamin D

receptors on other organs (Haddad. 1993).

These pharmacokinetic differences and their

consequences, such as the 2x higher half-life for

cutaneously vs. orally delivered vitamin D (Wacker.

2013) and differences in vitamin D vitamin D

receptor interactions, are what makes topical

vitamin D supplements so interesting.

Before our product developers at Super Human RX

could make the important step from theory to

practice, two important questions still had to be

answered:

1. Is the topical delivery of vitamin D

feasible and effective?

2. Does the topical delivery of vitamin D

entail hitherto unknown health-risks?

Figure 2: In contrast to dietary vitamin D, which is preferentially bound by chylomicrons and taken up by the liver and / or other tissues for storage, topical vitamin D binds almost exclusively to vitamin D binding protein, which enhances its ability to interact with target organs.

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The topical delivery of vitamin D is feasible and

effective

In answering question #1, i.e. whether the topical

delivery of vitamin D can effectively increase the

serum levels of 25OHD and thus prevent the

previously discussed ill-health effects that have

been associated with low vitamin D levels, we can

resort to a very recent study from the University of

Dammam and the King Fahd University Hospital in

Saudi Arabia.

Although, or rather because Saudi Arabia is a

country with lots of sun, its citizens get little to no

sun exposure. This is particularly true for women of

whom more than 80% are classified as vitamin D

deficient – independent of seasonal variability

(Kanan. 2013).

As the results of the randomized-controlled trial by

Sadat-Ali et al. shows, this is a problem which could

easily be fixed if all the women used the topical

vitamin D cream (5,000IU/day) the researchers

used tested on 50 initially vitamin D deficient

female study participants, all of whom reached

sufficient vitamin D levels after only 90 days of

treatment (see Figure 3).

The topical delivery of vitamin D is safe

In said peer-reviewed study from the March issue

of the International Journal of Biomedical Science,

the researchers didn't just confirm that the

administration of vitamin D through the skin "is

possible" and "efficacious". They were also able to

show that it is "safe" (Sadat-Ali. 2014). A fact that

has been called into question by Michael Holick in

the early 1980s.

In a 1982 patent Holick issued (US. Pat. No.

4,310,511; issued Jan. 12, 1982), he indicated that

dermal uptake was inefficient and that there could

be an "uncontrolled increase in absorption of

vitamin D, with concomitant loss of concentration

control, and the appearance of side effects such as

vitamin D toxicity". A claim that was put into

question roughly 18 years before the previously

cited study by Sadat-Ali et al. was published.

In the patent application for a "method of

delivering a nutritional or therapeutic’ amount of

vitamin D to the blood of a mammal", who is still

doing research in the field of vitamin D

supplementation at the University of Toronto,

points out that the earlier assumption was based

on an incomplete understanding of the processes

which govern the regulation and synthesis of

vitamin D.

In said patent, Vieth also presents data from early

animal experiments in which he was able to show

that the "application to bare skin of a nutritionally

effective amount of vitamin D dissolved in a

suitable, pharmaceutically acceptable carrier, will

produce an increase in 25-hydroxyvitamin D close

to the increase attainable with the same dose given

directly into the stomach." And that in spite of the

fact that ethyl alcohol, the carrier Veith used, is

vastly inferior to DMSO which is used as a carrier in

Primal D.

The data in Figure 4 confirms that Vieth's

statements are more than marketing claims. His

test-solution did in fact allow for a similar

absorption of vitamin D3 through the skin as the

classic intravascular (injection) or gastric (oral

supplement) routes for vitamin D delivery.

Figure 3: Pre- and post-treatment serum 25-OHD levels in 50 female medical students after 90 days of daily application of topical vitamin D (Sadat Ali. 2014).

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Vieth's data does also confirm that the

subcutaneously administered vitamin D3 is

released only gradually into the blood stream,

where it reaches its peak levels 2 days after the

administration and thus at a time point, when the

vitamin D3 levels that peaked rapidly after the

intravascular injection and/or direct instillation

into the stomach have already declined by more

than 50%.

No wonder, the dreaded changes in calcium

metabolism of which Holick speculated that they

may entail a significant toxicity risk are significantly

more pronounced in response to the oral,

compared to the topical application of vitamin D at

similar doses. A significant health risk, i.e. the

potential of calcification of the kidneys as a

consequence of an increase in urinary calcium

excretion doesn't exist for either of the two ways

of administration, though.

The gist – The Top 3 Advantages of Primal D

Precise, individualized dosing

With Primal D you decide how much vitamin D you

want to apply without having to buy a new product.

Your vitamin D test came out extremely high? No

problem, with Primal D you can always adjust your

daily dose.

Sustained release of vitamin D via the natural

route, through the skin

Just like cutaneously produced vitamin D, topically

applied vitamin D will hit your blood stream much

slower than oral vitamin D. The ensuing long-lasting

elevation of vitamin D promotes vitamin D receptor

interactions on target organs rather than vitamin D

uptake and storage by the liver and fat depots (Holmes.

1983; Haddad. 1993; Sadat-Ali. 2014).

Reliable, scientifically proven ability to increase

25-OHD levels w/ out toxicity issues

In contrast to oral vitamin D supplements, topical

vitamin D will effectively increase the level of

circulating 25-OHD into the normal range of >30ng/mL,

even if you suffer from reduced bile-flow, liver

problems, digestive problems, reflux disease, irritable

bowel disease or the consequences of gastric bypass

surgery (Basha. 2000; Holick. 2007; Aarts. 2011;

Ulitsky. 2011)

Due to the sustained delivery and reduced peak serum

levels of vitamin D3 the use of Primal D is associated

with an even lower toxicity risk than regular vitamin D

supplements at similar doses.

Figure 4: Fraction of the vitamin D3 given to rats, that was measured in the serum at various times up to 3 weeks after one dose of [14C] vitamin D3 was given either by direct injection into the circulation, by direct instillation into the stomach through a feeding tube, or by application to a shaved area of skin (Vieth. 1996)

Figure 4: Ratio of calcium to creatine in response to dermal vs. gastric (oral) administration of increasing doses of vitamin D. Significant elevations would be a sign of vitamin D intoxication and / or hyperparathyroidism (Vieth. 1996)

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References:

Aarts, Edo, et al. "Vitamin D absorption:

consequences of gastric bypass surgery."

European Journal of Endocrinology 164.5

(2011): 827-832.

Basha, Bassem, et al. "Osteomalacia due to vitamin

D depletion: a neglected consequence of

intestinal malabsorption." The American journal

of medicine 108.4 (2000): 296-300.

Bouillon, Roger, et al. "Vitamin D analogs with low

affinity for the vitamin D binding protein:

enhanced in vitro and decreased in vivo

activity." Journal of Bone and Mineral Research

6.10 (1991): 1051-1057.

Chun, Rene F., et al. "Vitamin D and DBP: the free

hormone hypothesis revisited." The Journal of

steroid biochemistry and molecular biology

(2013).

Holick, Michael F. "Sunscreen compositions

containing Δ. sup. 5, 7 steroidal dienes." U.S.

Patent No. 4,310,511. 12 Jan. 1982.

Holick MF. "Vitamin D: A millennium perspective."

J Cell Biochem 2003;88:296–307.

Holick, Michael F. "Vitamin D deficiency." New

England Journal of Medicine 357.3 (2007): 266-

281.

Holick, Michael F., and Tai C. Chen. "Vitamin D

deficiency: a worldwide problem with health

consequences." The American journal of clinical

nutrition 87.4 (2008): 1080S-1086S.

Holick, Michael F. "The vitamin D deficiency

pandemic: A forgotten hormone important for

health." Public Health Rev 32.1 (2010): 267-83.

Holmes, Ross P., and Fred A. Kummerow. "The

relationship of adequate and excessive intake of

vitamin D to health and disease." Journal of the

American College of Nutrition 2.2 (1983): 173-

199.

Are you really getting enough sun?

It’s often said that spending as little as 30 minutes of whole-body sun exposure will produce 10,000 IUs of vitamin D3. This is a misconception. 7-dehydrocholesterol is synthesized to Previtamin D3 by UV light. The Previtamin D3 must still convert to D3. This does not always occur for a variety of reasons.

For instance, the skin has a feedback loop and when large amounts of D3 are being synthesized it begins to degrade faster than it synthesizes it to maintain equilibrium. Another issue may be that Previtamin D3 can be washed out of the skin before it even converts into D3 if you don’t allow it to stay put long enough. One such study indicated that this can occur from swimming while sun bathing or showering immediately after sun bathing. While this is just one study and many among the scientific community feel it’s not conclusive there appears to be some evidence that not all sun exposure will lead to a surge in D3 levels.

So even if you’re not sun-phobic you may be surprised to find that all your time gardening or sun bathing is not having the effect you want on your D3 levels. And if you are sun-phobic and slather sunscreen on at every possible opportunity you’ll be surprised to know that a sunscreen with an SPF of as little as 8 will reduce D3 synthesis by a whopping 95%.

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Kanan, Raed M., et al. "Year-round vitamin D

deficiency among Saudi female out-patients."

Public health nutrition 16.03 (2013): 544-548.

Malham, Mikkel, et al. "Vitamin D deficiency in

cirrhosis relates to liver dysfunction rather than

aetiology." World journal of gastroenterology:

WJG 17.7 (2011): 922.

Sadat-Ali, Mir, et al. "Topical Delivery of Vitamin

D3: A Randomized Controlled Pilot Study."

International journal of biomedical science: IJBS

10.1 (2014): 21.

Souberbielle, Jean-Claude, et al. "Vitamin D and

musculoskeletal health, cardiovascular disease,

autoimmunity and cancer: Recommendations

for clinical practice." Autoimmunity reviews

9.11 (2010): 709-715.

Theodoratou, Evropi, et al. "Vitamin D and multiple

health outcomes: umbrella review of systematic

reviews and meta-analyses of observational

studies and randomised trials." BMJ: British

Medical Journal 348 (2014).

Ulitsky, Alex, et al. "Vitamin D Deficiency in Patients

With Inflammatory Bowel Disease Association

With Disease Activity and Quality of Life."

Journal of Parenteral and Enteral Nutrition 35.3

(2011): 308-316.

Vieth, Reinhold W. "Topical administration of

vitamin D to mammals." U.S. Patent No.

5,532,229. 2 Jul. 1996.

Vimaleswaran, Karani S., et al. "Causal relationship

between obesity and vitamin D status: bi-

directional Mendelian randomization analysis of

multiple cohorts." PLoS medicine 10.2 (2013):

e1001383.

Wang, Yi, et al. "Vitamin D Binding Protein Affects

the Correlation of 25 (OH) D and Frailty in the

Older Men." International journal of

endocrinology 2014 (2014).

Weinstein, Stephanie J., et al. "Impact of circulating

vitamin D binding protein levels on the

association between 25-hydroxyvitamin D and

pancreatic cancer risk: a nested case–control

study." Cancer research 72.5 (2012): 1190-

1198.

Weinstein, Stephanie J., et al. "Circulating 25‐

hydroxyvitamin D, vitamin D‐binding protein

and risk of prostate cancer." International

Journal of Cancer 132.12 (2013): 2940-2947.

White, Peter, and Nancy Cooke. "The

multifunctional properties and characteristics

of vitamin D-binding protein." Trends in

Endocrinology & Metabolism 11.8 (2000): 320-

327.

Yousefzadeh, Pegah, Sue A. Shapses, and Xiangbing

Wang. "Vitamin D Binding Protein Impact on 25-

Hydroxyvitamin D Levels under Different

Physiologic and Pathologic Conditions."

International journal of endocrinology 2014

(2014).