Vitamin and Hormone D on Diseases

This is the conclusion from a most informative analysis by Anthony W. Norman in AJCN Vol 88 No 2 pages 4915-4995.

"Conclusions

1.  Recent research has shown that vitamin D₃'s biological sphere of influence is much broader than researchers originally thought, as shown by the tissue distribution of the VDR, from mediating only calcium homeostasis (intestine, bone, kidney, and parathyroid) to functioning as a pluripotent hormone in 5 physiologic arenas in which researchers have clearly identified additional biological actions of 1α,25(OH)₂D₃ through the VDR. These physiologic arenas are the adaptive immune system, the innate immune system, insulin secretion by the pancreatic β cell, multifactorial heart functioning and blood pressure regulation, and brain and fetal development. 
2. ) Researchers have also expanded the parent vitamin D₃'s nutritional sphere of influence from a focus on bone health to include 5 additional physiologic systems. 
3. ) The nutritional guidelines for vitamin D₃ intake must be carefully reevaluated to determine the adequate intake (balancing sunlight exposure with dietary intake) to achieve good health by involving all 36 target organs rather than just the first 4 target organs (intestine, kidney, bone, and parathyroid gland) that are considered for calcium homeostasis.

Corollary- 
Given that vitamin D₂ is significantly less biologically active (33%-50%) over time in humans than is vitamin D₃ (7), its biological use as a dietary supplement in the United States should be discontinued and its use in a high-dose form [eg, 500 000 IU/mL of ergocalciferol (vitamin D₂)] in clinical studies (73, 74) and as described in the Physicians Desk Reference (75) should be replaced by a new formulation of (lower) high-dose vitamin D₃."

Vitamin D on Immunity 

This issue is very critical to a number of diseases. Vitamin D participates in the production of LL-37. This element has a role to play against pathogens attacking the body. This reference has a lot of facts and studies on vitamin D actions. Copied next from the preceding reference is an interesting take on vitamin D and colon health through the vitamin D receptor, VDR. 

"The accumulating evidence suggests that in the intestinal tract, the byproducts of gut microbes could be important for communicating with the epithelial cells, thus modulating the expression of the cathelicidin gene. This may be important for establishing a moustached barrier to prevent contact of microbes and pathogens with the intestinal epithelium. This is nicely demonstrated by the ability of short-chain fatty acids such as sodium butyrate that are produced by fermentation of fiber by microbes in the colon to induce expression of the cathelicidin [92]. The vitamin D pathway has been implicated in this induction [117]. The production of secondary bile acids by microbes may modulate cathelicidin expression in the colon via the VDR. One could speculate that the selective force for placing the cathelicidin gene under the regulation of the VDR was so its expression could be regulated by both vitamin D and xenobiotic factors (Figure 4).

A recent study indicates that the VDR may act as a receptor for additional nutritional ligands, including curcumin and polyunsaturated fats such as α-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AA) [118]. The in vivo relevance of these findings remains to be elucidated, but it is intriguing to consider that numerous nutritional compounds may modulate the expression of VDR target genes such as antimicrobial peptides."

LL-37 is significant to vitamin D levels and functions for the immune system. Here is a reference with greater insights. Copied next are the abstracts on Results and Conclusions of last reference.

Results

Critically ill subjects had significantly lower plasma 25(OH)D concentrations (storage vitamin D form) compared to healthy controls. Mean plasma LL-37 levels were significantly lower in critically ill subjects compared to healthy controls. Vitamin D binding protein (DBP) levels in plasma were significantly lower in critically ill subjects with sepsis compared to critically ill subjects without sepsis. There was a significant positive association between circulating 25(OH)D and LL-37 levels.

Conclusion

This study demonstrates an association between critical illness and lower 25(OH)D and DBP levels in critically ill patients as compared to healthy controls. It also establishes a positive association between vitamin D status and plasma LL-37, which suggests that systemic LL-37 levels may be regulated by vitamin D status. Optimal vitamin D status may be important for innate immunity especially in the setting of sepsis. Further invention studies to examine this association are warranted.

Vitamin D Functions

Let's get clear, vitamin D is more than a vitamin. And not a true vitamin at all. It's actions are like a hormone, which it is, but first here is what you need to know about this "vitamin" hormone. 

• Vitamin D operates in the body in a number of different forms.
• Sunlight acts on cholesterol in the blood near the skin turning it into a pre-vitamin D form.
• The Liver turns this pre-vitamin D form into the storage form mentioned next.
• There is a long term storage form found in the blood as 25-OHD3, the one Doctors measure.
• Both low levels and high levels of this measured storage form of vitamin D can be associated with adverse results. ref ref** <article on same study from Harvard Medical
• CRITICAL POINT: Storage form vitamin D can be found either bound wtih a strong vitamin D binding protein, (VDBP) or in a free or weakly bound abumin form.
• The free form of the storage Vitamin D is associated with bone density while the total that includes the form bound with VDBP is not.
• But, VDBP levels appear to be related to some cancers.
• Both forms need to be measured for proper information to handle conditions. (see below)
• The Kidneys produce an enzyme that converts the storage form into the short lived hormone form, 1,25 (OH)2 D3, when it is needed.
• This hormone form is reponsible for the majority of vitamn D functions.
• The hormone form of vitamin D combines with a form of vitamin A, retinoic X receptor, RXR, before this new compound attaches to Vitamin D Receptors, VDR, on certain cell walls to elicit gene transcription to build proteins that are the carriers of actions attributed to active hormone vitamin D.
• Vitamin D is also available as a supplement in the vegetarian form made from irradiated ergosterol from mushrooms. This form is vitamin D2. The natural sunlight and fish oil forms are vitamin D3. Vitamin D2 is not as long-term effective as D3 and should not be used. A lichen "plant" source of D3 is available.
• The level of free calcium, calcium ions, in the blood is the trigger to start this conversion process.
• The parathyroid gland hormone PTH is the element to carry out this process and it acts until the exact blood calcium ion level is achieved.
• The actions accorded to vitamin D are from the hormone form.
• PTH activates the conversion of the storage form into the 1000 times stronger acting hormone vitamin D form. 
• The chief function of the hormone form of Vitamin D is to direct certain actions to help PTH maintain the proper calcium ion blood level.
• This process also helps Vitamin D assist bones by absorbing minerals, but vitamin D also has immune system work in fighting infections and microbes by building LL-37. ref ref
• The storage form does have benefits, but it only exhibits vitamin D actions after it is converted to the hormone form in the blood and also in certain cells and tissues.
• A third form of Vitamin D formed from 25-OHD3 is called 24R,25(OH)2D3. 
• 24R,25 (OH)2D3 is a breakdown metabolite of vitamin D and may have opposing (and/or synergistic) effects on 1,25(OH)2D3 in bone building. Quite possibly, 24R,25(OH)2D3 works to mature matrix cells so that the hormone form of Vitamin D can go to work on them. In this way it could act as a control mechanism for hormone vitamin D actions. As part of this control, it may also speed the destruction of and elimination of the active hormone form of vitamin D when it senses job complete, blood calcium level control.
• Both 25-OHD3 and 24R,25(OH)2D3 might need to be known for optimal D level measurements. 
• (New) Vitamin D Binding Protein, VDBP ratio to 25-OHD3, is another controlling factor for vitamin D actions by limiting bioavailable of 25-OHD3 for processing and functions (see below). ref
• VDBP is really a mis-named element. It has many other functions which is why taking excess vitamin D could bind up too much VDBP and potentially limit VDBP actions in other areas (although this is rare since VDBP amounts are almost always sufficient). ref
• Vitamin D bound to VDBP is not at that moment available for use by the body, it is storage for a future time. About 85% of plasma vitamin D is bound to VDBP. ref
• Many conversions of vitamin D take place before the final active hormone form is produced. These conversions require magnesium, listed as Mg in circle on this chart  
• If magnesium levels are low, (65% are deficient) this would inhibit vitamin D conversion and storage in the blood and give low D readings. ref ref
• Vitamin D genes help direct the building a non-active protein called osteocalcin which has as one of it's primary functions once activated to bind calcium into bone. ref
• Osteocalcin is activated by vitamin K2 to not only perform this building bone function, but osteocalcin also helps regulate blood sugar levels. Maintaining the correct dosage ranges for vitamins D & vitamin K is vital to this blood sugar control mechanism. Still more to discover. ref
• Vitamin D and vitamin K are team members that work together to not only control bone building, but also to regulate blood sugar as well as to limit artery, vein, and soft tissue calcification, plus new information shows it also helps control prostate cell growth. Dr report ***
• Vitamin D by itself might increase artery calcification while together ref, vitamins D & K limit this process and keep calcium going into bones and not into arteries.
• Higher is not always better in older people. ref This reference mentions lower D levels associated with longevity if certain gene mutations are not present. This gene mutation increases D levels and is associated with shorter lifespan. Very interesting! (Since this study is opposite of many others, it has to have other research to support these findings. The gene changes could be responsible and need to be compared to genes in other studies where the opposite results were obtained.)
• NOTE: You will find in studies there are 2 different ways to measure and report vitamin D levels. One ng/ml is equal to about 2.49 nmol/L. This means 20 ng/ml is equal to about 50 nmol/L.
• Vitamin D participates in innate immune system by producing LL-37, a peptide with antimicrobial actions, especially against TB.
• Vitamin D receptor also works with Bile Acids to detox and protect intestinal gut barrier and gut bacterial health, reducing potential for bacterial overgrowth and barrier compromise. IBS?
• Vitamin D is under investigation for LL-37 effects on AIDS progression.
• Vitamin D also decreases beta amyloid production in the brain and speeds breakdown. ref 
• It has to be determined if disease lowers vitamin D levels or low vitamin D levels cause disease.
• The active form of D combines with Vitamin D receptors, VDR, and not only regulates PTH levels, but also it's own levels. New research is showing how vitamin D/VDR actions help destroy cancer cells. ref
• Vitamin D has to combine with a from of vitamin A, 9-cis retinoic acid as RXRa or RXRb, before any of the VDR functions happen. ref
• Hormone D actions on tissues chart

TWO IMPORTANT POINTS OF VITAMIN D FUNCTIONS NEED MENTIONING 

• Vitamin D as the Hormone form is generated to maintain calcium and phosphate levels in the blood. When blood levels of calcium get too low, Hormone D is generated to increase calcium absorption from food in the digestive system and stop elimination of calcium out of the body. If that is not enough, the hormone D also can pull calcium out of bones.  Calcium is needed in the blood at 1% to help muscles contract, nerves fire, and enzymes react.
  • FYI: Nature builds in checks and balances for processes. While vitamin D is pulling out calcium by dissolving bone, it is also telling bone building cells to get ready to re-build more bone to replace what the current necessary activity is breaking down. 
• Over the last ten years, another vital function for vitamin D was discovered. This time the vitamin D storage form plays more of a role which surprised Scientists since mostly this form was thought of as being inert without any function. It is needed at levels sufficient to allow it to go into at least 36 different cell types and at least 10 different organs and tissues. INSIDE THESE CELLS AND TISSUES, THE LOW ACTIVE STORAGE FORM IS CONVERTED INTO THE ACTIVE HORMONE Vitamin D FORM WITH THE HELP OF AN ENZYME PRODUCED IN THE KIDNEYS AND LIVER. The Hormone form of vitamin D is 1000 times stronger acting than the storage form. The storage form lasts in the blood for many weeks while the hormone form lasts for only hours.
• This process protects the cells and tissues to prevent DNA damage which could lead to tumor cell promotion as well as insure immune functions to prevent and fight off infections.

1. 1. Discussions on Vitamin D dosage need to address both of these functions to arrive at the maximum/minimum and most beneficial vitamin D storage form level.
   2. As research results are reported, there appears to be certain levels of the storage form for vitamin D that give the optimal action across all activity areas. Not too low, BUT NOT TOO HIGH EITHER. ref
   3. The mega-dosages available now in stores such as 5,000 and 10,000 should NOT be used for long periods of time, over 2 months, unless under Doctor's care and monitored for blood levels.
   4. Health articles are full of mis-information, a time for precautionary principles. 
   5. A concept getting reported as if it was fact has a serious flaw. 10,000 IUs is not necessarily safe because that is how much sunlight appears to generate in a short period of time, 20 minutes using a tanning bed. article 

DBP - The Vitamin D Binding Protein that is changing the D story

While the function of vitamin D binding protein, DBP, has been observed for a long time, it is only quite recently that a new twist has emerged. It concerns the nature of the strength of these bonds. About 85-90% of 25-OHD3 is strongly bound to DBP while 10-14% is weakly bound to the protein albumin with just 1% of 25-OHD3 as free unbound. This now has new significance as 25OHD-DBP is so tightly bound that it is for all intensive purposes, not bio-available for body functions. It just serves as storage form that can later be unbound from DBP so the Kidneys can convert into the hormone form as needed. ref

FYI: Check out these vital functions attributed to vitamin D binding protein (DBP) ref

Thus, it is only the 10-15% of 25-OHD3 bound to albumin or free form that is bio-active. It is this amount that shows an association with higher bone mineral density while the DBP bound 25OHD3 does not. This bio-active amount can be further modified by genetics about 35%. ref 

Of Interest: Mono- and Polyunsaturated fatty acids lower DBP affinity for binding with the 2 vitamin D forms. Saturated fats do not influence. This may have advantages or disadvantages depending upon current body conditions. ref

PLEASE READ THE NEXT 3 ARTICLES ON VITAMIN D FOR SOME INSIGHT AND CLARIFICATION. Article 1.  ALL THE ANSWERS ARE NOT YET KNOWN.  ref  includes questions the US institute of Medicine still needs to clarify for RDI amounts. Here is an interesting work on Vitamin D myths.

FYI: Animal studies show that higher amounts of hormone vitamin D (1,25(OH2)D3) are associated with lower calcification in arteries. ref This is a good thing as artery calcification means artery disease is occurring. Thus, the opposite, lower hormone vitamin D levels, would mean arteries are healthier. This seems to be a paradox since Nutritionists always say to take more vitamin D for strong bones. Remember, supplemental vitamin D is in the storage form and not active. This storage form does not relate directly to the levels of the hormone active form. But, an explanation is needed. Stay tuned!

**This new reference needs to be enhanced. Higher dosages of vitamin D supplements REDUCED bone density over 3 years. At 3 years, the reductions in bone density for the different groups: the 400 IU group down -1.2%, the 4000 IU group was down -2.4%, and the 10,000 IU group was down -3.5%. This is a real eye popper. You do not need high dosages of vitamin D. BUT, there are some potential defects in study methods. The test subjects were mostly at normal levels of vitamin D storage form. This may not repesent the larger population where deficiency levels are more pronounced.

***This Doctor report is included for the information on actions of Vitamins D and K2, NOT for the recommendations of amounts. Since this Doctor was using his patients, the patients were being tested and medically monitored. Thus, he could adjust dosages based upon test results. There could be other associations that might influence different conditions under D and K2 control such as blood sugar maintenance that were missed by this Doctor looking only at the one condition in question, or the conditions that may only reveal over time, plus the aspect of individual variations. 

Many different disease conditons have vitamin D associations, such as artery and heart health, bone strength, blood sugar regulation, and also a number of cancers. It looks like there many also be different dosages of vitamin D optimal for each conditon. This appears to present a problem for determing the ideal vitamin D supplement dose. Going overboard is not the asnwer, especially for bones. article What is the ideal amount? article

VITAMIN D and NATURE

IT IS ONLY NATURAL

Often natural functions are not as selective as we might want them to be. They just function the same in all situations, counter to those with triage actions. 

One of the main functions of VITAMIN D is to increase calcium and phosphorus absorption when needed. But it also increases the absorption of other minerals too. Some of these minerals may not be desirable for body functions, like heavy metals such as Lead, Cadmium, and radioactive isotopes of strontium and cesium. ref

 This is another reason science should be researching to find the most optimal vitamin D levels with the least adverse effects. And why reaching for the new higher Vitamin D dosages might not always be the prudent choice. Why do you think this aspect is seldom mentioned by "vitamin experts"? Do they consider it of little significance? Or are they simply not aware of this aspect?

Interestingly, the healthier the diet and greater quantities of organic foods, the greater the chance for heavy metal contamination.  Whole and organic foods with natural fertilizers have a higher possibility of contamination. And if they are concentrated, this contamination percentage is often increased.

While this in probably not the intention of Nature's design for vitamin D, it is an unfortunate consequence.

Remember this! Mother Nature seldom if ever lets sunshine generate a toxic vitamin D level, while supplements bypass this protective mechanism and can reach toxic levels. While Vitamin D toxicity needs very large amounts, it is often missed by many Scientists that it is the over activity influence of high but still lower than toxic levels that are responsible for some of the adverse effects of vitamin D. It is just the way it functions that gets it into trouble at higher levels. This reference from Colorado State University College of Veterinary Medicine and Biomedical Sciences gives a great simple overview. ref

VITAMIN D2 VERSUS VITAMIN D3

Vitamin D is available in 2 forms. Vitamin D2 and Vitamin D3. The D2 is a vegetarian source and vitamin D3 sources include Fish oil, Lanolin, and Lichen, an algae and fungal combination. Vitamin D2 is not as effective as vitamin D3. PLus, higher D2 intake may. lower both D3 and the hormone form of D3. ref ref

A new "plant" source of vitamin D3, generally thought of as an animal source vitamin, is now available from lichen. The lichen plants do not produce the vitamin D, but associated fungi and algae really do the work as they are attached to the lichen. Lichen contain both vitamin D2 and vitamin D3. Some species have more D2 while the one used for supplements has more D3. The analysis is about 65% D3 and 35% D2.The extraction method uses ethanol (molecular disstillation planned in future to eliminate ethanol alcohol) and involves other unknown steps to purify and concentrate. The finished produce probably still contains some vitamin D2. UV-B light is needed for this vitamin D building process in the lichen. ref and vitamin D2 from mushrooms ref

SKIN CANCER AND SUN INDUCED VITAMIN D

CRITICAL IMPORTANCE: The medical recommendation is to have people use vitamin D fortified foods or take Vitamin D supplements and avoid sunlight due to future skin cancer considerations. BUT, It was discovered that UVB sunlight on skin stimulates the innate immune system of LL-37 possibly through a vitamin D pathway. Would increasing vitamin D blood levels using supplements bypass this immune system set up without some UVB exposure? Since the innate immune system protects the skin against bacterial infections as well as many other adverse skin conditions, possibly even cancer, is it wise to completely avoid sunlight? ref ref Shouldn't Scientists be finding out how much sunlight each skin type needs to provide this innate skin protection without future skin damage?  ref   

Yes, you can get skin cancers in areas never exposed to sunlight. There are other causes for cancer. What the reference above reports is that some UVB sunlight exposure might help protect against the development of skin cancer. This discovery is apparently in direct contrast to the views expressed by the Skin Cancer Foundation. ref

BUT, maybe this is just another case of some is beneficial but too much is detrimental. The sun must be able to both stimulate the innate immune system in small doses plus it can also damage skin at higher doses and become immunosuppressive. There are some researchers that even say this damage is caused by the sun producing higher amounts of vitamin D.

You can see why this is such a complex issue that needs some common sense scientific study to arrive at the safest and most effective use of nature's healing tool, sunshine. It is obvious that some skin types were designed for more sun exposure while others for less due to the differing amount of pigmentation. The adaptive skin process of tanning is a response to protect skin cells against excess sun exposure. BUT, you never want to damage skin cells by overexposure. Where that point occurs varies for the different skin types.  What is the right amount of vitamin D?

Also continue down to the next sections below. This next linked article has copied reference studies that explain some of the issues involved. article

Here is another view. According to information summerized on Consumerlab.com, the amount with the lowest mortality associated with it is just under 39 ng/ml. Scroll down to "How much is too much?">   ref

While there are some professionals who recommend higher vitamin D amounts, over 5,000 IUs, this may not be optimal.  It may very well be that there are different levels for certain subsets of the population, especially those with gene mutations. Remember, only about 10% of Hawaiian surfers were able to get their vitamin D levels over 50 ng/mL from many hours of sunlight a day. 

DBP on Solid Bone

DBP stands for Vitamin D Binding Protein. For the better part of it's known life, DBP was just thought of as a vehicle to move all vitamin D forms in the body to target tissues for use. Now, that picture is changing. 

DBP is rapidly changing The Vitamin D story

While the function of vitamin D binding protein, DBP, has been observed for a long time, it is only quite recently that a few twists have emerged. One concerns the nature of the strength of these bounds and the real bio-active status of vitamin D. In the blood stream, about 85-90% of 25-OHD3 is strongly bound to DBP while 10-14% is weakly bound to the protein albumin and 1% of 25-OHD3 is free unbound. This now has new significance as vitamin D combined with DBP is so tightly bound that it is for all intensive purposes, not bio-available for body functions in that form. It just serves as a storage and delayed form for the Kidneys to convert into the hormone form when needed. Thus, it is only the 10-15% of 25-OHD3 bound to albumin or free form that is bio-active at any one time. It is this amount that shows an association with higher bone mineral density while the DBP bound 25OHD3 rarely reflects this influence. ref ref

Now, as if this is not enough to ponder, along comes another twist. The protein DBP also has other vital functions to perform either bound or not bound to vitamin D. ref  Following is a sentence copied from this reference: "Many studies have discussed the link between DBP-phenotypes and susceptibility or resistance to osteoporosis, Graves' disease, Hashimoto's thyroiditis, diabetes, COPD, AIDS, multiple sclerosis, sarcoidosis and rheumatic fever..."

Researchers now have to figure out how to best maximize all these different functions such as the vitally important one of preventing Actin polymerization. Actin forms necessary vital filaments to give cells their unique shape. But as cells naturally die, this released actin material needs to be quickly broken down and eliminated because it's rigid structure can damage surrounding tissues and cells. While there has never been found a deficiency of DBP, it's levels appear to be related somehow with the 25-OHD3 form of vitamin D. 

Over the years, DBP has readily changed into slightly different forms of Gc protein. While there are now over 120 forms, Gc1 and Gc2 dominate most as these these configurations: Gc1:1, Gc1:2, and Gc2:2. These different forms or SNPs modify the action level of DBP. People with more of Gc2:2 grow better bones than Gc1:1. Gc2 forms a weaker bond with DBP. The three are also listed as Gc1F, Gc1S, and Gc2 in some studies. Better bone growth exists without Gc1F. These types were discovered about 55 years ago.

DBP explains apparent controversial observations 

Dark skin people, who generally have lower levels of vitamin D as 25-OHD3, might also have lower DBP levels which means that the amount of bio-available free vitamin D might be the same as a light skin person with higher vitamin D. This would give them a higher bone mineral density than expected. This shouldn't happen given the current mainstream medicine bone building theories of higher calcium and vitamin D needed for stronger bones since they don't recognize the DBP bound part as mostly inert.

So, maybe it's time for another theory that better explains this situation. Along comes the DBP hormone theory. Below is the rest of the theory that helps explain the above given situation plus many other mysterious observational realities. Example: South Africans on their native diet consume daily about 300 mg of calcium while their relatives who move to the United States consume 750 mg or more but have a 9 times greater hip fracture rate.

DBP and 25-OHD3 are somehow linked. One may control the other and determine say how much 25-OHD3 the body should build and store given the amount of DBP present, or vice versa. But, the levles of DBP and vitamin D do vary in relationship to each other. And this changes health parameters. Thus, just increasing the intake of vitamin D (or calcium) supplements might not be enough to get to the proper bone health picture. Or it might negatively impact bone health by inadvertently hindering a natural balalnce. Some Nutritionists and other professionals who do not understand how this new theory works may be looking for and measuring the wrong parameters and thus giving faulty advice.

It is not necessarily how much vitamin D is present, but how much of it is bio-available to the body that is important as a percentage of the total vitamin D. Someone with lower vitamin D storage levels than another person could actually have more bio-active D form present. The DBP could be a rate limiting factor for how much vitamin D the body wants to optimally store. With sunlight production, the amount of vitamin D that is turned into storage form is limited, but with supplementation, this limiting pathway does not factor. The possibility to upset this body balance process is thus mostly from supplementation and the reason could be DBP.

The body adapting DBP levels could be the reason people survive the long winters with little sun to manufacture vitamin D. As vitamin D storage levels fall in the winter, the body may also reduce DBP to maintain a steady vitamin D action potential. Plus, vitamin D is also stored in fat which can be released. 

The DBP binding hormone theory explains more observed bone facts than any other theory, such as why studies of calcium with or without vitamin D are not always successful in building bone density or preventing fractures. Plus partly explain why lifetime milk drinkers can have more fractures, not less. The DBP research is still in early stages of discovery. Perhaps this is the reason that so many Doctors and Nutritionists are not yet aware of it and the Public is clearly in the dark.

SIDEBAR: Vitamin D exists in 2 main forms, and a number of secondary but still important ones too. One as 25-OHD3 is the storage form and the other as 1,25 OH2D3, the hormone form. The storage form is stable and lasts for 2-4 weeks while the hormone form is not stable and is destroyed in hours. These forms are mostly transported in the body attached to DBP. Once at their target tissues, they attach to VDR, vitamin D Receptor sites on cell membranes. At these receptors, the vitamin D directs the body to build certain structures needed to signal bone building and also to prevent the calcification of soft tissues and artery walls. Plus, these elements, one called osteocalcin, also participate in controlling blood sugar regulation. When vitamin D first produces osteocalcin, it is not active to work these functions. Vitamin K and a few minerals are needed to activate osteocalcin. The balance between the non-active and the active, or carboxylated osteocalcin, is what controls blood sugar.

New research now believes that the 85% of storage form vitamin D attached to DBP is non active and only the free or loosely bound to albumin vitamin D is the active part.  It is of interest to understand that the storage form vitamin D has a 1000 times stronger affinity to attach to DBP than the hormone form of D while the hormone form has a 1000 times stronger attachment to vitamin D receptors on cell membranes. It can be deducted as to why these different attractions exist when one understands the new DBP theory. With the knowledge from the DBP hormone theory, a greater measure of vitamin D sufficiency can be determined using "bioavailable 25-OHD levels" for better treatment protocols to target "the relationship between vitamin D and a wide range of outcomes including fracture, infections, cancer, and cardiovascular disease." 

The Free-Hormone Hypothesis

The DBP hormone theory fails under the scientific term for Free-Hormone Hypothesis. ref This hypothesis says that free unbound hormone is highly active and readily passes into cells. And it is responsible for most of the nutrient or vitamin-like action. For vitamin D, this also includes the loosely bound vitamin D with the abundant albumin protein. BUT, also with vitamin D, this free hormone theory may not be entirely universal to all body tissues or cells. There are about 11 tissue types, such as breast, prostate, and colon to name a few, where storage vitamin D is converted in the celll to the hormone form which then acts to protect that cell and tissue. What is not completely known yet is if the vitamin D bound to DBP also be used for this purpose or just the "free" bio-available D. The cells in these tissues contain an enzyme that performs this conversion process. It is the same one the Kidneys use when the hormone form of D is needed directed by PTH from the parathyroid gland to correct a low blood calcium level.

This new free-hormone hypothesis for vitamin D research is still in a very early stage according to scientific years, maybe only 6. It takes about 10 years before there is general acceptance by the scientific community and the Public finally finds this out. The internet should shorten this somewhat.

This type of research is very lab technique intensive, expensive, and easily subject to errors. That is one reason a longer time frame is needed to verify.

Wrap Up

This information is presented mainly to let the reader become aware that all the facts for bone health are not completely known yet. And also that numerous elements are involved in bone health with some of the obvious observations and resulting assumptions are not always correct. One could measure lower vitamin D levels but still have strong bones. DBP is very likely one of the failsafe systems the body incorporates to control rates for vitamin D functions and to extend vitamin D life in the body. Look at this study on Breast Cancer prevention and 25-OHD levels. ref A U-shaped curve indicates more cancers at both lower and higher vitamin D levels.** The middle levels are the healthiest, yet some Doctors and Nutritionists are promoting higher and higher levels. Can you guess why mother nature uses DBP to control 24-OHD levels and extend their availablity?

How and if there are any other lifestyle patterns or supplemental nutrients that can impact DBP functions, it is too early to tell. Obviously, there probably is an optimal level for 25-OHD and DBP, plus vital information concerning who is at greater risk from certain DBP gene patterns and needs appropriate treatment protocols.

**The safest level exhibiting the lowest breast cancer rate was for vitamin D between 76-99 nmol/L (or 30-40 ng/ml) (Strange, this is really close to the level recommended by the new vitamin criteria.) Below 75 the cancer rate was 1.88-2.46 (double the rate of women between 76-99) and if over 100 it was again about 1.75 - 2 times greater. To arrive at the safe vitamin D levels, one may need to be in the sun for 2 hours a day*** (as the Hawaiian surfer study showed very moderate D levels from many sun hours) or take supplemental vitamin D3 at 1500 -2000 IUs. Once one starts on a higher vitamin D amount, it takes 3 months to reach a plateau. After that, the supplemented vitamin D amount can be reduced by about half to maintain. This level assumes that most people are low as research has discovered. CAUTION: Sun exposure needs to be gradually increased. The amount of skin showing determines the length of sun exposure needed. Only 20 minutes with a bathing suit while 2 hours wearing a short sleeve shirt and pants.

To get to a detrimental reading for vitamin D over a 100 nmol/L, if starting at 50 nmol/L, slightly higher than average for women in the US, would require 4000 IUs or more for 3 months. DBP levels and gene types might knock this down a little and require slightly higher dosages to get over the 100 reading. The ideal level appears to be closer to the middle, say 85 nmol/L or 33 ng/ml.

This correlates almost exactly with a study showing the lowest mortality from cardiovascular disease is exhibited with vitamin D levels of 28 ng/ml, (70 nmol/L) ref

***A study showed 20 minutes in a tanning booth was equal to taking 10,000 units of vitamin D2. But, the Hawaiian surfer study did not show levels anywhere near this high from surfers in the sun daily for 3 hours. Did the study not factor in the sun feedback process that limits how high vitamin D blood levels rise? Another study Hollis co-authored acknowledged that many people do not produce high enough vitamin D levels just from sun exposure. Check it out here. 51% under 31ng/mL from lots of sun time.

WHAT TO DO

To test or not to test for vitamin D levels and just increase with sun exposure and/ or vitamin D pills. ref This reference says not to test since testing is expensive and it is not known what levels are healthiest. PLUS, unless one also knows their DBP gene types, the tested level has less meaning. The safest approach is to get some sun exposure without burning plus take a moderate dosage supplement of vitamin D3, 600-1000.

With the results from a yearly physical examination, your Doctor can better analyze  information your status and health condition for proper amounts to supplement or get sun exposure. Sun exposure has a built in failsafe process while supplements do not. Best to not rely on supplements only.

Optimal Vitamin D Level

Is there an ideal vitamin D blood level?

CAUTION: The following information needs to have this precaution added. One of the functions of active, short-lived, hormone form of vitamin D is to increase absorption of calcium from food in the intestinal tract. But, it turns out this process may not just pinpoint calcium, it also increases a few other minerals, also including toxic metals like lead. ref Studies show that children exhibiting higher vitamin D levels sometimes also have higher blood levels of lead. This could either be due to increased lead absorption or from lead released out of bones, another side effect function of vitamin D. To prevent the absorption of toxic metals, the essential minerals like magnesium, phosphorus, zinc, and copper must be at adequate amounts. Since a number of populations have wide degrees of deficiency for some of these minerals, it is prudent to avoid known toxic metal containing foods such as sprouted grass grains, certain vegetables, plus rice protein powders. Children are more susceptible to lead uptake than adults. This is one reason it may be prudent to monitor vitamin D dosages until science settles this issue. ref ref< vitamin C too.

Vitamin D supplements are available in 2 forms, vitamin D2 and D3. While some research says both are equal, over the long haul, they are not equal with D3 showing higher blood levels than from D2. ref  

Here is a review that studied research to arrive at the "Ideal" blood vitamin D level for 25-OHD3. The blood level this review decided upon as ideal was between 35-40 ng/mL, or 90-100 nmol/L. This information was put together almost 9 years ago. There have been some modifiers since then as noted below. One exception might include males with a family history of prostate cancer. In this case, the safe vitamin D level might be 20-25. At higher levels, the enzyme needed to activate the hormone form of vitamin D is down regulated.

From the last article on VDBP, standing for Vitamin D Binding Protein, the ratio of VDBP to 25-OHD3 must now be a factor that could modify this amount either way. Then there is the fact that while most cancers exhibit less risk at increasing D levels, there are some like pancreatic and prostate that show more risk as vitamin D levels increase above natural, or at least as these higher levels may influence calcium behavior.

Of Interest: There is also the possibility this goes deeper into the relationship of calcium to magnesium that is really involved. If magnesium levels are adequate, which they are not in 64% of population,  ref, then vitamin D actions and calcium levels have less impact and it is the magnesium level that is critical factor. ref ref ref

Here are the health factors from the above review that played a role in this determination: "...maintain muscle strength, prevent falls, improve dental health, and prevent cancer (especially colorectal cancer). Weaker evidence for vitamin D includes preventing multiple sclerosis, other cancers, arthritis, hypertension, and tuberculosis, as well as solving insulin problems (diabetes mellitus)."

Here are the ways 2 items from this list are aided by vitamin D. Vitamin D induces the production of LL-37, an infection fighter. This natural antibody shows action for the health of the mouth and gums and also lungs. ref  

Diabetes, multiple sclerosis, and rheumatoid arthritis are all types of autoimmune diseases. ref

Optimal Blood Levels May Vary

It is entirely possible that there could be an optimal vitamin D level that is slightly different for each health condition or that varies by individuals as well due to genetics. Here is a report showing that the level of vitamin D exhibiting the lowest CRP blood level is 21ng/ml. This Johns Hopkins study shows that at both lower and higher vitamin D levels the amount of CRP goes up. CRP stands for C-Reactive Protein, an indicator of inflammation in the body that is linked with cardiovascular disease. ref  But, not all people with elevated CRP will develop cardiovascular disease. 

The Ideal Optimal Vitamin D level has to factor in all these differences. These differences may be reported as if they represent the optimal D level. For some cancers, the optimal D level might be over 50 ng/ml while at this level, other adverse conditions might surface in other diseases or issues, like for prostate or pancreatic cancers. Since the ideal vitamin D blood level may vary, an could vary, an optimal range for the ideal vitamin D level would be necessary.

SIDEBAR: New research shows that a certain level of the storage form of vitamin D is needed to participate in ideal bone remodeling between bone building cells and bone tearing down cells. That amount from animal studies is 32 ng/mL. Some tests of Americans puts vitamin D levels low at 15 ng/mL. To get that up to 32 ng/mL, a supplement dosage of 1700IUs would be needed for 3 months. But if at 25 ng/mL, only 700 IU would be needed for a few months.

Wrap Up

Copied here is a wise summation from the review referenced at the beginning of this article. "Why not surpass the number of 35-40 ng/ml as some experts have suggested? Unfortunately, higher does not mean better. Medical research is replete with examples of where a little higher helped, but more was not necessarily better. Supraphysiologic levels beyond what is now recommended in this manuscript is not yet supported in medical literature. It is interesting that some studies (for example, in the area of prostate cancer) have not yet found considerable benefits to achieving such higher vitamin D levels (Mucci & Spiegelman, 2008). In fact, it has been suggested that long-term significant increases in vitamin D could be detrimental. Thus, some experts suggest that there is no harm of carrying high vitamin D levels (70 ng/ml or more for example), but this recommendation is based on acute and not chronic observations." 

Acute means short term while chronic involves over a longer length of time. Just because vitamin D3 is available with 5,000 -10,000 units does not mean it is safe for everyone. ref  One Brand of vitamin D3 with 5,000 IUs says to take 1 or 2 daily, while another says to take one every other day. The latter one would average 2500 per day, a much safer "higher" amount to take for the general public.

Taking 5,000 per day would over 3 months increase the ng/ml number by anywhere from 30-50. The lower number in people who weigh more and the higher for people who weigh less since fat absorbs vitamin D.  If one was at 15 ng/ml to start, a typical average in USA, that would mean a new total of 45-60, possibly slightly increasing adverse risk for some people. Taking 2500 would increase starting number by 15-25, arriving at a total between 30-40. ref  After 3 months, no further increases occur unless the dosage gets larger. If more than 2500 is taken, it might be wise to do so with medical supervision knowing the starting number. 

The issue here is not that 5,000 to 10,000 of vitamin D is toxic. It is that these amounts could increase the blood calcium level too high with resulting detrimental consequences, or it could interfere with the hormone form of vitamin D when it is needed to stimulate vitamin D receptors. This issue is still in question, as is what the next reference found.

VITAL CAUTION: (This is for CKD, chronic Kidney disease, who might have conversion problems and may not be the same for normal healthy individuals) Here is a reference that reveals it is better to slowly build up vitamin D levels if they are low. A rapid increase of blood vitamin D levels may have undesirerable consequences. It increases the mechanism to speed the destruction of vitamin D into a non active form and eliminate it our of the body. This rapid D increase accomplishes this destructive action by activating certain enzymes. Plus, the rapid increase also has little effect to lower PTH levels to protect calcium in bones. (The higher doses were from IV) What if any effects oral higher dosages of vitamin D over 2500 IU might have for this occurrence is still unknown. Research with higher dosages is not looking at this aspect. Slowly increasing vitamin D blood levels with conservative D amounts does not activate these enzymes but does significantly lower PTH levels. ref  ref

Bottom Line: It appears that lower PTH levels are more important than higher vitamin D levels to safe against bone loss in the elderly. ref

Not all research agrees with what the last reference found. But, if this is proven to be valid, better to opt now to follow since no harm. Quite a bit of research looks at the relationship between PTH and vitamin D blood levels. BUT, it is the hormone form of vitamin D (1,25(OH)2D3) that interacts with PTH and not so much the measured storage form of D (25OHD3) in blood. Also, (24,25(OH)2D3 is rarely measured which is the form of D that controls and destroys the hormone D form.

MEN, PROSTATE, & VITAMIN D 

Here is one report revealing that men with higher vitamin D levels as well as higher DBP levels increase their risk for prostate cancer. Also mentioned in this report is that pancreatic cancers are higher in people with high vitamin D and low DBP levels.

SIDEBAR: Vitamin D Binding Protein (VDBP) levels influence the effects of vitamin D. A higher VDBP to vitamin D molar ratio appears to reduce the benefits of vitamin D. More of the vitamin D is VDBP bound so less is available as "free" vitamin D, the bio-active form. How this molar ratio can be impacted is still under research. DBP has a few different forms that further modify how DBP influences vitamin D actions. There are 3 major DBP forms that significantly impact vitamin D. 

Copied here is the conclusion from a VDBP study on Diabetes: "Conclusions: Low 25(OH)D levels were associated with risk for diabetes among whites, but not blacks, with the strongest associations observed among those genetically predisposed to high DBP levels. The effects of vitamin D supplementation for the prevention of diabetes may differ by race and bio available vitamin D levels."  ref

Note: 25-OHD3 has a 1000 times greater affinity for D Binding Protein than the hormone form of D, 1,25(OH)2D3. While the Hormone form has a 1000 times greater attraction to vitamin D receptor sites on cells. Can you see a possibility that too high a pool of vitamin D as 25-OHD3 might interfere with the action of the hormone form at cellular receptor sites? They are a synergistic team and function together. ref

SIDBAR - Another Vital Function for Vitamin D

Copied here to prevent it getting lost, a study showing that Vitamin D slows down the speed of telomere shortening prolonging the life of leukocyte cells. This should reduce the development of some age-related diseases.

"Am J Clin Nutr. 2007 Nov;86(5):1420-5.

Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women.(not in Men)

Richards JB, Valdes AM, Gardner JP, Paximadas D, Kimura M, Nessa A, Lu X, Surdulescu GL, Swaminathan R, Spector TD, Aviv A.

Twin Research and Genetic Epidemiology, St Thomas' Hospital, King's College, London School of Medicine, London, United Kingdom. brent.richards@kcl.ac.uk

Abstract

BACKGROUND: Vitamin D is a potent inhibitor of the proinflammatory response and thereby diminishes turnover of leukocytes. Leukocyte telomere length (LTL) is a predictor of aging-related disease and decreases with each cell cycle and increased inflammation.

OBJECTIVE: The objective of the study was to examine whether vitamin D concentrations would attenuate the rate of telomere attrition in leukocytes, such that higher vitamin D concentrations would be associated with longer LTL.

DESIGN: Serum vitamin D concentrations were measured in 2160 women aged 18-79 y (mean age: 49.4) from a large population-based cohort of twins. LTL was measured by using the Southern blot method.

RESULTS: Age was negatively correlated with LTL (r = -0.40, P < 0.0001). Serum vitamin D concentrations were positively associated with LTL (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging. This difference was further accentuated by increased concentrations of C-reactive protein, which is a measure of systemic inflammation.

CONCLUSION: Our findings suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases."

This study did not measure people taking extra Vitamin D, it just found that people with higher levels of vitamin D from sun and food had longer telomere length, which is a good thing, compared to people with the lowest blood levels of vitamin D. (The 3 levels used for vitamin D measured in at 16 ng/mL, 29 ng/mL, and 50ng/mL)

REMEMBER: Cancer and maybe other diseases have the ability to lower the conversion of vitamin D and also speed the elimination out of the body of the hormone form of vitamin D. Thus, a low vitamin D reading needs a complete body examination to eliminate the possibility of a non-observable cancer. Most studies fail to show benefits from improved vitamin D levels AFTER a disease is present.

Bottom Line: It appears that lower PTH levels are more important than higher vitamin D levels to safeguard against bone loss in the elderly. ref ref