Donald L. Trump, MD, FACP
Candace S. Johnson, PhD
Roswell Park Cancer Institute Buffalo, NY
We all “know” about vitamin D – it’s the vitamin that prevents rickets (a childhood bone disease) and preserves bone density among postmenopausal women – and likely men on androgen deprivation for prostate cancer. But this article will briefly review the increasing recognition that vitamin D effects are multifaceted and involve many aspects of health.
Vitamin D is a term used to describe a class of molecules – and it is misleading in several ways:
1. Vitamin D is really a hormone; a vitamin is a substance you must get in your diet – e.g. vitamin A, C, E, K, B…. But vitamin D is manufactured in the body – and that’s the definition of a hormone.
Vitamin D is manufactured in a series of steps: first, light strikes the skin and induces the chemical change of a cholesterol molecule into a vitamin D molecule (vitamin D3); in the liver and then in the kidney this molecule is further modified resulting in the most active vitamin D molecule, 1,25(OH)2D3 (calcitriol). Calcitriol is a prescription drug.
2. There are really more than 5 different vitamin D molecules: pre D3, D3, 25(OH) D3 are each intermediate steps in the production of 1,25(OH)2D3 (calcitriol). 1,24,25(OH)3D3 is the major breakdown product of calcitriol and is largely inactive – but it is a “vitamin D.” To make matters more confusing there is a plant derived form of vitamin D – vitamin D2. D2 is a “vitamin D” but probably not quite as active as D3 – and not very important in human health and nutrition.
There are (3) important molecules to which you should pay attention:
a. D3 (also called cholecalciferol): This is the form of vitamin D in nutritional and vitamin supplements. The government-defined recommended daily allowance (RDA) is 400 international units (400 IU). Vitamin supplements are available which contain 200 IU, 400 IU, 800 IU, 1000 IU, and 2000 IU.
b. 25(OH) D3 (25 hydroxycholecalciferol): This is the form of vitamin D that is readily measurable in the blood and is the best measure of whether an individual has “enough” vitamin D in their body. The “normal” level of 25(OH) D3 is 32 ng/mL – 100 ng/mL.
c. 1,25(OH)2D3 (calcitriol): This is the prescription drug form of vitamin D – the most potent D vitamin. Its main use is in individuals with either kidney failure or osteoporosis; the usual dose is 1-1.5 micrograms per day.
The “stores” of vitamin D in the body are reflected by the blood level of 25(OH) D3. In the past 2 years the “normal” range has been broadened from 15-50 ng/mL to 32-100 ng/mL. Perhaps the best measure of what is optimal is that level which suppresses or reduces the normal biochemical reactions which are “upregulated” when vitamin D deficiency exits. Among the body’s responses to low vitamin D levels are an increase in the production of parathyroid hormone (PTH) and loss of bone density.
If blood 25(OH) D3 levels are raised into the 32-100 ng/mL level, PTH levels decrease and loss of bone density improves in most individuals. Whether this level (32-100) reflects the optimal or ideal for any individual is not clear. It is clear that these levels of 25(OH) D3 are completely safe.
It is interesting to consider that humans evolved in sub-Sahara Africa – a part of the world with a great deal of sunlight. Humans likely evolved with deeply pigmented skin – and pigment protects the skin from sun damage and minimizes the production of D3 in the skin. As populations migrated out of sub-Sahara Africa lighter skin color evolved – in part, it could be argued, to increase the body’s ability to make vitamin D. In less equatorial latitudes, those who made more vitamin D in their skin (i.e. had lighter skin) perhaps had an evolutionary advantage.
There are many studies which indicate that there may be an inverse relationship between environmental light exposure (i.e. latitude), estimated blood vitamin D level as well as measured blood vitamin D level and the frequency of and death rate from many cancers. Prostate, breast, lung, colorectal and pancreatic cancer are all cancers that may have a causative and prognostic link to vitamin D – the lower the vitamin D level, the higher the risk of cancer and cancer death.
There has been considerable research which has greatly expanded our knowledge of how 1,25D3 is produced, transported to cells all over the body, enters cells and induces changes in cellular activity and function. Among the things 1,25D3 induces in cells are reduced cell movement, reduced cell division, increased cellular maturation and differentiation. The multitude of 1,25D3 effects all seem to happen through the binding of 1,25D3 (vitamin D) to the vitamin D receptor (VDR).
When 1,25D3 and VDR associate, this complex binds to another protein (RXR) and this complex sits on special locations on DNA in the cells chromosomes and causes the activity or blocks the activity of many genes. These and these changes in gene activity result in a huge number of vitamin D associated biologic activities. Without VDR, none of these 1,25D3 effects occur.
As a way to understand what 1,25D3 does, scientists have been able to develop a so-called vitamin D receptor knock out mouse (VDR KO mouse). Using molecular techniques it has been possible to “make a mouse” that has no VDR and therefore, 1,25D3 has no way of influencing cell growth and integrity. Studying what happens to such mice provides important information about what 1,25D3 does. The following table lists the abnormalities that afflict the VDR KO mouse:
1. low blood calcium
2. weak bones (“rickets”)
3. hairless skin
4. abnormal muscle development
5. high blood pressure
6. abnormal heart muscle development
7. increased susceptibility to infection
8. increased susceptibility to blood clot formation
It is likely that this is an incomplete list of “diseases” the VDR KO mouse has; studies of this mouse are just beginning. This list and further studies on this mouse emphasize the wide range of vitamin D effects and suggests that there may be many human disorders that could be influenced by vitamin D.
1. Vitamin D Deficiency: There are several studies which indicate that many people have lower than ideal vitamin D levels. Thomas and colleagues described > 250 patients admitted to the Massachusetts General Hospital. 57% of those patients had abnormally low levels of 25(OH) D3 – and in 1998 abnormally low was defined as < 15 ng/mL! We have recently looked at 25(OH) D3 levels in more than 200 prostate and colorectal cancer patients; 70% of patients had 25(OH) D3 levels < 32 ng/mL. As expected African Americans had lower levels than Caucasians, levels were lower in the late winter and early spring and patients with more advanced disease had lower levels. There is very limited information on the frequency of Vitamin D deficiency among men with prostate cancer – or individuals with any form of cancer; however, the information available suggests vitamin D deficiency or insufficiency (lower levels than are ideal) is common. There is little information about the impact of cholecalciferol (D3) replacement on cancer. We have begun careful studies of replacement which we hope will clarify how often replacement is needed and what is the optimal replacement dose.
2. Role of vitamin D administration:
a) Osteoporosis – There are data that vitamin D replacement (~400-800 IU D3) + calcium supplementation (1200-1500 ng) reduces the rate of development of osteoporosis in post menopausal women.
b) Cancer Prevention – Calcium + vitamin D supplementation have been studied as a preventive for colon polyps and colon cancer. While the largest study completed failed to show benefit of this treatment it seems likely that this result was confounded by the inordinately low dose used (400 IU/d).
[excerpt on Calcitriol + Chemotherapy removed/outdated]
Punch Line: Vitamin D is very likely to have much broader health effects than bone and calcium changes. Vitamin D deficiency is common – due to life style and environmental light exposure considerations; we recommend that all prostate cancer patients ask their doctors to measure their 25(OH) D3 levels and oversee supplementation to assure blood levels are at least in the normal range. Vitamin D supplementation merits continued study as a potential cancer preventive and treatment approach. High dose vitamin D (calcitriol) is a very effective agent in the laboratory and clinical results are encouraging. We suspect that high dose vitamin D will find a role in prostate cancer treatment. Vitamin D is not a vitamin, it’s a hormone and we believe it is a hormone important in cancer treatment.