Vitamin D Research

Listed below are copies of some important Vitamin D research with a few clarification comments. Copying these here is an attempt to prevent lost links in finding these studies in the future.

The following article is copied from Oncology Times with experts reporting from a Government (National Institutes of Health) sponsored Vitamin D workshop:

"In October 2003, the NIH cosponsored the Vitamin D and Health in the 21st Century: Bone and Beyond conference, which explored the role of vitamin D in osteoporosis and other diseases. Participants concluded that overall, Americans' current intakes of vitamin D may be too low for optimal health.

Concerns were also raised about Americans' use of sun screens, which help to prevent skin cancer but block the sunlight from which the skin synthesizes vitamin D. The current daily vitamin D recommendations of the Food and Nutrition Board (FNB) of the National Academy of Sciences' Institute of Medicine were set in 1997: 200 IU up to age 50; 400 IU for people aged 51 to 70; and 600 IU for people over age 70.

Most multivitamin supplements contain 400 IU; the FNB (Food and Nutrition Board) is now considering whether recommended intakes of vitamin D need to be reviewed.

Undergirding recent studies on vitamin D's potential role in cancer is knowledge that the vitamin D receptor is found in many body tissues other than bone, including the prostate gland-site of a number of current vitamin D-related studies.

Also bolstering the new research is an increased understanding that active forms of vitamin D, including analogs, can:

* Boost immunity.

* Reduce cellular proliferation.

* Enhance cellular differentiation.

* Foster cellular apoptosis (natural cell death at end of life span process).

It may be, several speakers suggested, that vitamin D and its analogs act to maintain a normal cellular phenotype. Conversely, low circulating levels of vitamin D may promote abnormal cellular growth.

Epidemiologic and observational studies have also laid a foundation for research linking vitamin D and cancer. Clinical data link low circulating levels of the biologically active, hormonal metabolite of vitamin D-1,25-dihydroxyvitamin D3-with a higher risk of cancer incidence, especially of prostate cancer.

 

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Prospective Study of About 50,000 Men

In a prospective study of vitamin D intake and cancer in American men, Edward Giovannucci, MD, Professor of Nutrition and Epidemiology at Harvard School of Public Health, and his colleagues found support for a protective effect of vitamin D against cancer incidence, and even more so against cancer mortality.

The researchers examined vitamin D intake in relation to the risk of total cancer incidence and mortality from 1986 to 2000 in nearly 50,000 men (initially cancer-free) participating in the Health Professionals Follow-Up Study.

In this study a higher recent intake of vitamin D-600 IU daily or greater vs less than 150 IU daily-was associated with a lower risk of cancer incidence and cancer mortality.

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Dr. Giovannucci said this inverse association was apparent for both dietary vitamin D and vitamin D from supplements, and held for lung, prostate, colorectal, pancreatic, and other cancers combined.

African American race, obesity, and Northeast residence (where long winters reduce skin exposure to sunlight) were independent risk factors for cancer mortality, especially if vitamin D intake was low.

Our findings support a benefit of vitamin D intake against cancer incidence and particularly mortality, especially in groups susceptible to vitamin D deficiency, he concluded, adding, High intake of retinol [a form of vitamin A found in multivitamins], which antagonizes vitamin D actions, partially offsets this benefit.

Our findings suggest that hypovitaminosis D, which is more common in African Americans, obese individuals and those living in the Northeast of the United States, may partially explain high cancer mortality in these groups.

Asked in an interview about potential vitamin D toxicity, Dr. Giovannucci said that virtually no evidence of vitamin D toxicity has been found at daily levels of 800 IU-well above current recommendations.

He also noted that even very high exposure to sunlight-which would increase the amount of vitamin D synthesized by the skin-has never produced a known case of hypercalcemia.

At the 2003 NIH conference, Robert P. Heaney, MD, Professor of Medicine at Creighton University and an attendee at the most recent meeting, presented data showing that the daily tolerable upper limit for vitamin D is about 2,000 IU.

 

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Health Danger of Low Circulating Levels of Vitamin D in African Americans

Additional research at the NIH meeting pinpointed the health danger of low circulating levels of vitamin D in African American men and women (whose dark skin reduces their ability to synthesize vitamin D).

African Americans have higher incidence and mortality rates from certain cancers, especially prostate, breast, and colon, which are often attributed strictly to racial disparities in health care.

In a study of dietary intake and circulating vitamin D levels from the third National Health and Nutrition Examination Survey (NHANES III), researchers from the Center for Food Safety and Applied Nutrition of the Food and Drug Administration, analyzed vitamin D intake from milk, food, and supplements and circulating vitamin D levels.

The researchers found that on average the vitamin D serum level (nmol/L) was 79 for white adults and 48.20 for black adults.

Compared with whites, blacks have higher incidence and mortality of certain aggressive cancers that are not attributed to disparities in health care, the researchers concluded.

The significant racial differences in vitamin D intake from all sources and poorer nutritional status…should raise strong concern given the strong association between poor vitamin D status and increased risk of cancer.

Gary G. Schwartz, PhD, Associate Professor of Cancer Biology and Public Health Sciences at Wake Forest University School of Medicine, also provided support for the vitamin D hypothesis.

Noting that at every age the mortality rate from prostate cancer is about 50% higher in black men than in white men, he suggested that prostate cancer may be at least in part a vitamin D deficiency disease in certain populations.

Scandinavian men (whose exposure to sunlight is low due to their northern latitude) share a risk of prostate cancer similar to that of blacks, noted Dr. Schwartz, who is also Scientific Director of the Prostate Cancer Center of Excellence at Wake Forest's Comprehensive Cancer Center.

 

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Prostate Gland Expresses Vitamin D Receptor & Synthesizes Active Vitamin D

It has been known since 1992 that the prostate gland expresses the vitamin D receptor, but recent research by Dr. Schwartz's group shows that the prostate also synthesizes active vitamin D-1,25(OH)_-2D.

Since the prostate makes its own active vitamin D essentially from sunlight, and active vitamin D inhibits growth and metastasis of prostate cells, lack of sunlight or vitamin D is a biochemically credible explanation for much of prostate cancer, Dr. Schwartz explained.

In addition to the effects of reduced skin synthesis of vitamin D, it is possible that certain population groups could have vitamin D polymorphisms which place them at greater risk of prostate cancer, he continued.

Intrinsically I think that if we can prevent rickets, we can prevent prostate cancer. The prostate does not live by androgens alone. Personally I've been trying to sensitize urologists to this for quite some time.

But the challenge, said Dr. Schwartz, is trying to apply emerging knowledge about vitamin D and cancer to clinical practice.

For example, should physicians routinely measure circulating vitamin D levels, especially in African Americans and nursing home residents (whose skin is rarely exposed to sunlight)? Should oncologists recommend vitamin D supplements in addition to standard cancer treatments? If so, at what IU level?

Answers to these questions will hopefully evolve from current research.

The evolution of our understanding of the role of vitamin D in cancer parallels our understanding of the role of vitamin D in rickets, Dr. Schwartz said. In both diseases, ecologic observations about solar radiation preceded experimental observations and were subsequently validated by them.

 

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Seasonal Variations in PSA

Seasonal variations in the rate of rise of prostate-specific antigen in 192 patients with untreated, clinically localized, low-to-intermediate grade prostate cancer provide further support for the vitamin D hypothesis.

A study presented by researchers from Mount Sinai Hospital, Toronto-Sunnybrook Regional Cancer Center, and Sunnybrook & Women's College Health Sciences Centre at the University of Toronto showed that the men's higher vitamin D levels in the spring quarter (April, May, June) when sunlight exposure is higher, were associated with a slower rise in PSA than was observed in the other quarters of the year, when exposure to sunlight was lower.

These results are consistent with the vitamin D hypothesis, that the higher vitamin D nutrition associated with spring and summer can slow progression of certain forms of cancer, the researchers concluded.

A study from the same research group showed that vitamin D in the form of cholecalciferol slowed the rate of rise in PSA levels in 15 men with relapsed prostate cancer.

 

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Analog of Calcitriol Inhibits Prostate Cancer Cell Growth with Less Hypercalcemia Than Calcitriol in Early Studies

A number of studies presented at the meeting indicated that an analog of calcitriol, QW1624F2-2, inhibits prostate cancer cell growth both in the test tube and in laboratory animals (primarily mice) with less hypercalcemia than calcitriol.

In an Italian multicenter, randomized, placebo-controlled Phase II study of the vitamin D analog BXL-628 in men with benign prostatic hypertrophy, this analog arrested prostate cell growth, with what the researchers termed excellent safety. BXL-628 had already shown inhibition of prostate cell growth in rat and dog models before it was given to the human study participants.

A potential role for vitamin D analogs in colon, breast, bladder, pancreatic, and skin cancer is also being studied, according to data presented at the meeting.

Some-but not all-studies of vitamin D metabolites in serum have shown a higher risk of colon cancer in people whose oral intake of vitamin D was below the median."  END OF ARTICLE

Analysis:  This last section sums up the problem, giving higher natural hormonal D dosages, linked to cancer prevention, has a serious drawback in that it stimulates increased calcium uptake or absorption. High calcium levels must be counterproductive to protecting cells against cancer. How could this be? Or is it due to high calcium reducing activation of and conversion to the hormonal active form of vitamin D.

The types of cancer known to be associated with high blood calcium are:

	Multiple Myeloma
	Lung Cancer (squamous cell cancer of the lung, not all lung cancers)
	Breast Cancer (advanced disease)
	Kidney Cancer
	Head and neck cancers  Prostate cancers  **Institute of Medicine issued an amended vitamin D RDA report Nov 2010. The new recommended vitamin D levels are 600 iu for ages 1-70 and 800 iu for 71+.  This is up by 200 iu for each age group from the past. The new upper limit increased from 2000 iu to 4000 iu. BUT, the report did acknowledge that some studies have found adverse effects or increased risks could begin when blood levels of the inert form (25OHD) of vitamin D increased over 30 ng/mL (75 nmol/L) up to 48 ng /mL (150nmol/L). The adverse effects included increased mortality, cardiovascular diseases, cancers, to even falls and bone fractures. Yes, some positive effects were also found. linkwww.iom.edu/reports/20120/dietary-reference-intakes-for-calcium-and-vitamin-d.aspx It is important to remember that while vitamin D exhibits classic toxicity effects at only very high intake levels, 40,000 iu over time, this report mentions that taking calcium and vitamin D at the recommended levels for bone health may have some influence in the health of other body areas, such as those mentioned above as well as for infectious diseases (flu), autoimmune conditions, dementia, and diabetes. Mostly positive results with a few negatives. The positive are sometimes from the influence of vitamin D expression on certain genes and the negative ones can occur due to over expression of some of the positive effects of vitamin D on increasing calcium levels and the subsequent activities.The research reviewed by the committee setting these RDA reported that the current information available from research did not give them enough facts to make any judgements about calcium and vitamin D's influence in these other areas. The median level of vitamin D as 25(OH)D measured in the population of the U.S. was just 16 ng/mL. A level of 20 ng/ml (50nmol/L) was considered desirable by this committee to satisfy basic bone health conditions. NOTE: In a study by Anthony W. Norman published in American Journal of Clinical Nutrition, vol 88 no.2 page 4915, the following conclusions were reached for D actions.:  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.  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.  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.  Check out these results from the prestigious NHANES STUDY: Abstract Vitamin D has been hypothesized to protect against cancer. We followed 16,819 participants in NHANES III (Third National Health and Nutritional Examination Survey) from 1988 to 2006, expanding on an earlier NHANES III study (1988-2000). Using Cox proportional hazards regression models, we examined risk related to baseline serum 25-hydroxyvitamin D [25(OH)D] for total cancer mortality, in both sexes, and by racial/ethnic groups, as well as for site-specific cancers. Because serum was collected in the south in cooler months and in the north in warmer months, we examined associations by collection season ("summer/higher latitude" and "winter/lower latitude"). We identified 884 cancer deaths during 225,212 person-years. Overall cancer mortality risks were unrelated to baseline 25(OH)D status in both season/latitude groups, and in non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans. In men, risks were elevated at higher levels {e.g., for ≥100 nmol/L, relative risk (RR) = 1.85 [95% confidence interval (CI), 1.02-3.35] compared with <37.5 nmol/L}. Although risks were unrelated to 25(OH)D in all women combined, risks significantly decreased with increasing 25(OH)D in the summer/higher latitude group [for ≥100 nmol/L, RR = 0.52 (95% CI, 0.25-1.15) compared with <37.5 nmol/L; P(trend) = 0.03, based on continuous values]. We also observed a suggestion of an inverse association with colorectal cancer mortality (P(trend) = 0.09) and a positive association with lung cancer mortality among males (P(trend) = 0.03). Our results do not support the hypothesis that 25(OH)D is associated with reduced cancer mortality. Although cancer mortality in females was inversely associated with 25(OH)D in the summer/higher latitude group, cancer mortality at some sites was increased among men with higher 25(OH)D. These findings argue for caution before increasing 25(OH)D levels to prevent cancer.-- ©2010 AACR. Did you see the "In men, risks were elevated at higher levels" of vitamin D on cancer. The types of cancer that most likely influenced this are Prostate, and the also mentioned lung cancers. Please re-read the highlighted type above and read what is coming out of the Institute of Medicine concerning the new recommendations for vitamin D.  From a Wall Street Journal Blog: Can Too Much Vitamin D Be Hazardous to Your Health? By Katherine Hobson   in WSJ blog  The Institute of Medicine has finally weighed in on the issue of how much vitamin D we should be getting. As the WSJ’s Melinda Beck reports today, the 600 international units now recommended for most of us is three times the old recommendation of 200 IUs, but it’s a lot less than what some advocates say we need. Low levels of the vitamin have been associated with a host of ills, including heart disease and some cancers, but that’s a far cry from showing that increasing intake will protect against those problems.  Patsy Brannon, a professor of nutritional sciences at Cornell University and member of the IOM panel that produced the report, tells the WSJ that the group paid attention to possible risks of taking too much of the vitamin. The group raised the upper limit of safe consumption for vitamin D to 4,000 IUs, saying that “the risk for harm begins to increase” after that. (It also found a 2,000 IU safe intake ceiling for calcium, the other nutrient covered by the report.) So what happens when people take too much vitamin D? At very high levels — above 10,000 IUs a day — there’s a risk of kidney and tissue damage, the report says. (Here’s a list of case reports of vitamin D toxicity included in the report.) In addition, “the lack of data on the safety of higher intakes of vitamin D when used chronically is very concerning,” the report says. A recent editorial in the American Journal of Epidemiology discussing the issue of anti-cancer claims for various vitamins over the years notes that an analysis of existing research found no association between levels of vitamin D in the blood and several cancers. But it did find that “the risk of pancreatic cancer was doubled for those in the highest quintile of circulating vitamin D levels.” The editorialist, Tim Byers of the  University of Colorado Comprehensive Cancer Center and the Colorado School of Public Health, continues: This observation is disconcerting both because pancreatic cancer is now the fourth leading cause of cancer death in the United States and because the proponents of the vitamin D hypothesis are now arguing that substantially elevating circulating blood concentrations into that range should be a nutritional policy objective for the general population. Brannon tells the WSJ that the panel also saw a tentative association between death from prostate cancer and other causes in men with high blood levels of the vitamin, though it may not ever be possible to test the validity of those connections. ** VDBP: There is one mechanism under review concerning pancreatic cancer risk that has to do with the levels of a vitamin D BINDING PROTEIN (VDBP and sometimes just DBP). This protein attaches to the 25(OH)D or low active circulating D form so that it might no longer be available in a free form to enter into functions. This could be a monitor or feedback factor for controlling body vitamin D levels.   ref   Here is the finding from this study: "Men with higher 25(OH)D concentrations and serum DBP below the median (lower than normal) showed greatly elevated risk of pancreatic cancer..."  It sure looks like the level of DBP is an important factor in regulating vitamin D actions. This means that just measuring 25(OH)D levels might NOT give enough facts to adequately predict D level effects. BOTH 25(OH)D and vitamin D Binding Protein levels must be known. CAN YOU NOW SEE WHY JUST INCREASING VITAMIN D BLOOD LEVELS MAY BE HAZARDOUS TO YOUR HEALTH? Article SIDEBAR: Chemotherapeutic drugs are not very effective against pancreatic cancers. Researchers have discovered that vitamin D is responsible for blocking drug actions. Blocking vitamin D receptors on cancer cells allows the cancer cells to die. They like vitamin D and use it to their advantage, quite different than other types of cancers where the cancer cells destroy vitamin D and increase the speed of hormone D breakdown because D is destructive to the cancer cells. ref Closing Comment: the PRECAUTIONARY PRINCIPLE is at work here. Many "so-called" vitamin D experts are ignoring some of these vitamin D concepts, especially possible negative adverse effects and associations at below toxic levels. Wisdom is looking like moderation again. You need to stay within certain parameters or dosage windows which are NOT exactly scientifically known yet. The higher dosages now available on vitamin shelves should not be taken as a signal that they completely safe, especially for longer term usage, even if just measuring D blood levels. Increase sunshine exposure to sensible amounts.