Vitamin D and Mortality

Thousands of research studies have cropped up on Vitamin D over the last 10 years. Many looked to see if vitamin D levels impact mortality rates. Here is one meta-analysis, analyzes many already existing studies, that found some vital trends that are quite revealing. Here is the study.

What they found in a nutshell is this: "In conclusion, our results implicated that long-term supplementation of vitamin D may have a beneficial effect on overall mortality, especially in patients with vitamin D insufficiency and younger than 80 years. Vitamin D in a dose of 800 IU daily or less was found to be more favorable than a dose greater than 800 IU and treatment with cholecalciferol (D3) was more favorable than ergocalciferol (D2)."

"Dose of 800 IU daily or less...most favorable"

Here is the conclusion mentioned in the abstract:  "The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration."

Question: Now, what do you think the upper recommended amount of vitamin D is in the new vitamin criteria presented on this website?

If vitamin D levels were low at the beginning of the studies, less than 20 ng/mL, there was greater benefit from vitamin D supplements than if beginning levels were over 20ng/mL. Calcium with vitamin D was better than vitamin D alone. For bone health, from other studies, a vitamin D reading of over 18 ng/mL appears to be significant enough to protect bones and any increase over this amount had little extra value. But this meta-analysis was looking at overall mortality. Remember this is just looking at associations, and not causes. There are many diseases that have been found to have mechanisms that lower vitamin D levels, like cancer, and this possibly influences studies like this one.

But, there are possible explanations for these results. And this chart seems to uphold this study too. Taking 800IU would likely increase an 18 ng/mL reading up to 26ng/mL after 3 months and with a little sun, a reading of 30-33 would be likely. This appears to be about the same results as shown in the above linked chart. The lowest mortality level appears to be between 25-40 ng/mL. Over 50ng/mL there is a rapid increase in mortality the same as under 20 ng/mL.

QUESTION: Why is the Vitamin D Council recommending very high levels such as 50ng/mL and higher? article This appears to be too high according to the above chart. Still controversy for correct levels to maintain all the different applications of vitamin D involvement. Remember, while low dosages of vitamin D supplements( 800IU) tended to prevent falls in Seniors, higher vitamin D intakes increased probability of falls and thus fractures. ref Fractures of hips in Seniors tend to increase mortality. Is the Vitamin D Council working one factor against another, benefits in one area against detriments in another?

Here is one rational for apparent opposite effects, beneficial if levels low and detrimental if already high. Vitamin D hormone actions include increasing the absorption of calcium from food to maintain blood calcium levels at a vital percent. A problem occurs with higher vitamin D intake, along with the calcium comes many other essential minerals as well (magnesium, phosphorus, selenium, zinc) plus a few undesirable ones too, like lead.

The amount of lead absorbed would depend upon two things, the amount of lead in the foods, plus the amount of the other essential minerals. The proper amount of essential minerals act to block out the heavy toxic minerals like lead. Children are more susceptible to lead absorption. Be careful picking concentrated health foods like vegetable juices, green powders, or rice proteins. All have found lead amounts, as has some plant source calcum from algae. 

Unfortunately, the level of deficiencies for many essential minerals is far to high for magnesium (64%) and calcium (49%). These are presenting an open door for lead and other toxic minerals to enter. The detrimental findings for higher vitmain D levels might be due to these toxic minerals and not just to vitmain D by itself. Although there are many ways for the vitamin D system to fail. The number of players involved is far more than almost any other vitamin function. 

The players; Sunshine, UV radiation, Cholesterol, 7-Dehyrocholesterol, CYP2R1, calcidiol, cholecalciferol, ergocalciferol, 25(OH)D3, Magnesium, PTH, calcitriol, 1,25(OH)2D3, VDBP, albumin bound D, , unbound D, VDR, VDR/RXR, vitamin K2, ostocalcin, LL-37, vitamin D 25-hydorxylase, CYP2R1, vitamin D metabolites, sterol 27-hydroxylase (CYP27A1), calcifediol, 24,25-Dihydroxycholeciferol, P450cc24, etc. Check out chart for yourself. 

Vitamin D Dosage Questions for the Experts

With the development of greater understanding for the many vitamin D areas of influence, is there a level of the passive D form 25OHD3 that is best, including cancer protection?   The vitamin D experts of today seem to be of the mindset that much greater levels than the currently recommended 600 IUs intake (and 20 -30 ng/ml) are needed to build up the blood levels to the 40+ ng/ml levels which some nutritionists are recommending is needed for cancer reduction.  

Since toxic reactions do not show up until 20,000-40,000 IUs taken over time, some experts are recommending 5000, even 10,000 IUs as safe and necessary. This could generate ng/nl levels well over 50 and even up to 90 or 100 ng/mL (nanograms per millilter). 100 ng/ml would be 250 nmol/L (nanomoles per liter). Some people exhibit a resisitance to storage form vitamin D build up, possibly a gene change.

NOTE: Additional research results insight is pointing to vitamin D supplements as helpful if you are low, BUT at higher beginning levels, taking extra can turn from beneficial to harmful and increase certain cancer risks or cardiovascular links to artery calcification, plus prostate risks need to be evaluated. These points are being missed by some nutritionists. GET tested before you supplement dosages higher than 2500 IUs, especially for extended periods of time. ref <in kidney disease  ---  

The concern is not over vitamin D toxicity, but about the possibility of influencing Calcium activities in a negative way. Or possibly it could be due to an interference of the passive D form blocking out the attachment of the active hormone form to vitamin D receptor sites (VDR). Not all research at this time is on the side of these vitamin D experts. Below are some of the associations from research that need to be answered before larger D dosages should be routinely consumed plus that question going over 40ng/ml, which might be nature's average limit for 25 OHD, the storage form of passive D. ref

• Dr Martha Booth, a neurologist at Duke University, found than higher blood levels of calcium and vitamin D were the only two variables after various adjustments that were positively associated with greater size and numbers of brain lesions verified by MRI pictures. Vascular lesions such can be associated with calcification of brain blood vessels or due to mini-strokes causing brain cell damage. A weakened vessel wall from faulty nutrition to maintain collagen and ellastin integrity could also be a factor.
• The NHANES study did not find that 25OHD status was related to overall mortality risks except in men, were an elevated risk at higher levels was found. (Could mostly be from prostate and lung cancers)
• For women, while non significant overall, risks were decreased for women in summer living at higher latitudes. 
• In a subset of people who exhibit a B allele modification, a gene controlling artery calcification, higher vitamin D might put them in greater jeopardy by increasing calcium blood levels. 
• One of the methods used to verify that 10,000 IU is safe and equal to full sun production of about 20 minutes is flawed. The research used vitamin D2 which is only at best 50% of the activity level of vitamin D3. It probably is only 30% over time. This would mean the safe level for vitamin D3 is only 3000 IUs and not 10,000, at least using this method. (This could mainly be due to longer lasting effects of vitamin D3 and not from the quick results of equal doses.) Look at Conclusion in this ref  ref  ref
• Sun produced vitamin D has a failsafe mechanism also induced by sunshine that acts as a feedback loop to control how much of the sun produced non-active vitamin D3 actually gets added to the circulating D pool. Some is destroyed. This mechanism does NOT let passive D levels get too high. Supplemental vitamin D does not exhibit this feedback loop and can get higher than the body would naturally produce.
• A new Fragility study to determine the vitamin D levels associated with the least fragility symptoms in Seniors found that the best levels were between 20-26 ng/ml, with both under 15 and over 30 having greater adverse effect symptoms.
• While Dr Giovannucci found a protective effect from higher vitamin D levels against cancer in the large Health Professionals Follow-Up Study, these intake levels were only 600 IUs or greater versus 150 or less, not the mega dosage D supplements of 2500 - 10,000 that have recently become available.
• One potential risk of increasing vitamin D intake; if conditions already exist for placing calcium in artery lesions, more vitamin D might accelerate this effect by increasing calcium blood levels, although this has not always been observed.
• Here is a Middle Eastern study that compares different load level vitamin D supplement protocols on blood storage D build up. since D is often low without sun exposure, most effective and safe protocol is to take 2000 IUs for 3 months and then maintain at 1000 IUs. 225% increase. ref 

ARE THE (VITAMIN D) EXPERTS wrong again?

vitamin D on Cancer and vice versa

Why proper levels of the storage vitamin D form as 25(OH)D3 are vitally important in cancer prevention.

The amount of research ongoing for vitamin D is mind-boggling. The fact that there exist synergistic actions between the 2 forms of vitamin D (passive D as 25-OHD3, and hormone D as 1,25(OH)2D3) opens up new avenues to determine the proper level for the passive storage form 25OHD3. It is known that the passive storage form 25OHD3 can turn into the active form right in some tissues with the help of a certain enzyme. The correct levels of 25OHD3 circulating in the body provides feedback mechanisms to produce the needed amount of this enzyme. And also provide enough for the Kidneys to produce the hormone form of D when reduced blood levels of calcium dictate. Since breast tissues are one place 25OHD3 is converted to the hormone D form to protect cells against becoming cancerous, let's start there to analyze what is happening.  

BREAST CANCER

Abstract - from PMID # 18767073

Mammary epithelial cell transformation is associated with deregulation of the vitamin D pathway.

Kemmis CM, Welsh J.

Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA.

"The vitamin D endocrine system mediates anti-proliferative and pro-differentiating signaling in multiple epithelial tissues, including mammary gland and breast tumors. The vitamin D metabolite 1alpha,25(OH)2D3 mediates growth inhibitory signaling via activation of the vitamin D receptor (VDR), a ligand dependent transcription factor. 1alpha,25(OH)2 D3 is synthesized from 25(OH)D3 (the major circulating form of the vitamin) by the mitochondrial enzyme CYP27b1 in renal and other tissues. Human mammary epithelial (HME) cells express VDR and CYP27b1 and undergo growth inhibition when exposed to physiological concentrations of 25(OH)D3, suggesting that autocrine or paracrine vitamin D signaling contributes to maintenance of differentiation and quiescence in the mammary epithelium. In the current studies we tested the hypothesis that cancer cells would exhibit reduced sensitivity to vitamin D mediated negative growth regulation. We used a series of progressively transformed HME cell lines expressing known oncogenic manipulations to study the effects of transformation per se on the vitamin D pathway. We report that mRNA and protein levels of VDR and CYP27b1 were reduced greater than 70% upon stable introduction of known oncogenes (SV40 T antigens and H-rasV12) into HME cells. Oncogenic transformation was also associated with reduced 1alpha,25(OH)2D3 synthesis, and cellular sensitivity to growth inhibition by 1alpha,25(OH)2D3 and 25(OH)D3 was decreased approximately 100-fold in transformed cells. These studies provide evidence that disruption of the vitamin D signaling pathway occurs early in the cancer development process."

   

Simple ANALYSIS

This discussion reveals that before cancer cells appear and grow into a tumor, vitamin D, as the passive D storage form 25(OH)D3, protects mammary cells by forming the hormone D form right in the cells and thus directs normal cell functions and cell division processes. But once cancer occurs or gets large enough to create problems, possibly due to low vitamin D levels, the damaged cells become transformed and start to de-activate these protective vitamin D actions. Here is how the cancer cells begin to upset the vitamin D protective mechanisms. First, the cancer cells actually increase the production of the hormone from of vitamin D. This devious move by cancer cells decreases the passive vitamin D levels which jeopardies future hormone D production abilities. At the same time, cancer cells also increase the speed that the hormone vitamin D form is de-activated and broken down into it's non-active metabolite form. Plus, cancer interferes with Vitamin D receptor (VDR) docking sites. These actions lower the protective abilities of the active vitamin D by 100 times compared to the levels observed in normal healthy breast tissue cells. 

This information gives scientists a couple of new enzyme avenues to attack in attempting to influence and control cancer cell growth rate, either by slowing the breakdown enzyme action, and/or increasing the enzyme necessary for the conversion into the hormone D form. 

Maintaining the proper level of the passive D form for long term prevention aspects sounds like the smartest option at this time, especially since the cancer cell essentially eliminates the vitamin D protective pathway as it grows larger.

Finding the proper 25OHD3 level is PRIORITY ONE.

The following research also supports this model:

Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

Kelly Townsend1, Claire M. Banwell1, Michelle Guy2, Kay W. Colston2, Janine L. Mansi2, Paul M. Stewart1, Moray J. Campbell1 and Martin Hewison1

 Authors' Affiliations:¹Division of Medical Sciences, Institute of Biomedical Research, Endocrinology and Metabolism, University of Birmingham, Birmingham, United Kingdom and ²Department of Cellular and Molecular Medicine, St. George's Hospital Medical School, London, United Kingdom

Abstract

Purpose: Vitamin D seems to exert a protective effect against common cancers, although this does not correlate with circulating levels of active 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], indicating a more localized activation of vitamin D. The aim of this study was to investigate the significance of this in breast cancer. (It is the passive D levels and the amount of enzyme necessary to convert the passive D into the hormone D right in the cell that is of vital value)

Experimental Design: Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D–activating enzyme 1α-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41 tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1α-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.

Results: Expression of mRNA for 1α-hydroxylase (27-fold; P < 5 × 10⁻¹¹), vitamin D receptor (7-fold; P < 1.5 × 10⁻⁸), and 24-hydroxylase (4-fold; P < 0.02) was higher in breast tumors. 1α-Hydroxylase enzyme activity was also higher in tumors (44.3 ± 11.4 versus 12.4 ± 4.8 fmol/h/mg protein in nonneoplastic tissue; P < 0.05). However, production of inactive 1,24,25-trihydroxyvitamin D₃ was also significantly higher in tumors (84.8 ± 11.7 versus 33.6 ± 8.5 fmol/h/mg protein; P < 0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH)₂D₃. (this is the hormone D form)

Conclusion: These data indicate that the vitamin D–activating enzyme 1α-hydroxylase is up-regulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH)₂D₃ production in tumors by catalyzing catabolism to less active vitamin D metabolites. The enzymes involved in autocrine metabolism of vitamin D in breast tissue may therefore provide important targets for both the prevention and treatment of breast cancer."

WRAP UP

When Vitamin D levels as 25-OHD3 are within a proper range, they are able to enter into certain tissue cells such as breast, prostate, colon, pancreas, and with the help of an enzyme, produce the hormone D form with all it's cell protective activities.

Once cancer cells grow to a sufficient number, they develop mechanisms to defeat this vitamin D protective pathway by increasing the breakdown speed of the hormone D into a non-active form. This negates the protective affects of vitamin D by as much as 100 times.

NOTE: Looking at pancreatic cancer, a protective role of 30% reduction was found for individuals consuming about 600 IUs of vitamin D total compared to those consuming under 150 IUs. This might represent body levels of vitamin D at above 20 ng/ml as beneficial compared to less than 15 ng/ml. Plus, over 40 ng/ml offered no extra increased protection. Consuming the new mega dosages of 2500 IUs and up for over 3 months may not be wise as these amounts could build levels over 40. According to the NHANES chart and some research reports as mentioned in the Vitamin D facts article, this might not be wise for some conditions.