Holick's July 2007 NEJM Paper on Vitamin D

[updated July 28, 2010]

Since the material below was written a good overview of the area was written up in the [July 26, 2010] which discusses benefits and toxicity. Also Holick has since written a book, The Vitamin D Solution.

Michael Holick of the Boston University has just published a review paper on Vitamin D deficiency in the July 2007 New England Journal of Medicine (NEJM). [PMID: 17634462]. The paper discusses the role of Vitamin D in many diseases but here we review the portion of the paper most associated with prostate cancer. Prior to reading the material here the reader may wish to review our post on Vitamin D and Prostate Cancer.

Before reading further Dr. Richard Lehman had these thoughts on the paper: "You are vitamin D deficient, very probably, and this is making your muscles ache, slowing you brain, thinning your bones and making you more likely to get cancer and heart disease. The secret of the Mediterranean is not its food but its sunshine. Or both. Go on, take your clothes off, get outside, and eat lots of oily fish, cheese, wild fungi and eggs. Abandon your miserable existence in the dark North and start living before it is too late. Alternatively, get a sunbed and take large daily supplements of vitamin D. It’s the elixir of life, according to this very thorough and plausible review."

• most tissues and cells in the body have a vitamin D receptor
• several can convert circulating vitamin D to active vitamin D
• vitamin D has a role in decreasing risk of cancer, autoimmune diseases and cardiovascular disease
• excess previtamin D3 is destroyed by sunlight so excessive sunlight exposure will not result in toxic levels
• D2 supplements are made from UV irradiation of ergosterol from yeast
• D3 supplements are made from UV irradiation of 7-dehydrocholesterol from lanolin. (My comment: perhaps one might be able to increase the Vitamin D they get from the sun by applying lanolin to the skin prior to exposure?)
• the active form of vitamin is regulated by parathyroid, calcium and phosphorus levels in the blood
• fibroblast growth factor 23 secreted from bone suppresses the synthesis of active Vitamin D
• the active form of Vitamin D:
  • increases calcium and phosphorus absorption in the kidneys and intestines
  • increases CYP24 which in turn inactivates both the circulating and active forms of vitamin D by turning it into the inactive water-soluble calcitroic acid
• deficiency is regaded by most experts as having a circulating vitamin D level of less than 20 ng/ml (i.e. less than 50 nmol/liter)
• as circulating vitamin D increases parathyroid hormone levels decrease until circulating vitamin D reaches 30 to 40 ng/ml (75-100 nmol/liter) at which point parathyroid levels level off (at their lowest point)
• intenstinal transport of calcium increases by 45% to 65% when vitamin D levels increases from 20 ng/ml to 32 ng/ml (50-80 nmol/l)
• 30 ng/ml can be considered an sufficient level for vitamin D and 150 ng/ml (375 nmol/l) can be regarded as a toxic level

Cancer

• people living at high latitudes are at increased risk for Hodgkin's lymphoma, colon cancer, pancreatic cancer, prostate cancer, ovarian cancer, breast cancer and other cancers
• people living at high latitudes are more likely to die from these same cancers if they get it
• epidemiologic studies indicate that circulating vitamin D levels below 20 ng/ml are associated with 30% to 50% increased risk of colon cancer, prostate cancer and breast cancer as well as a higher likelihood of dying of those cancers if they get it.
• Levels of the active form of vitamin D are not associated with risk in colorectal cancer.
• one study showed a relative risk of 0.53 of colorectal cancer when 244 to 652 IU/day were taken
• it has been hypothesized that the active form of vitamin D can induce cell death in malgnant cells and can prevent angiogenesis

Requirements

• Institute of Medicine (see chapter on Vitamin D in their book) says daily intake should be 200 IU/day for children and adults up to 50 and 600 for adults over 50
• many experts believe that 800 - 1000 IU/day should be recommended for those without adequate sun exposure
• vitamin D2 is 30% as effective as D3 so three times as much is needed (Update: Although earlier work published in 1998 [PMID: 9771862] and 2004 [PMID: 15531486] seemed to support the lesser effectiveness of D2, since the NEJM paper came out Holick has specifically investigated this further and concluded that D2 is, in fact, equal to D3 in maintaining blood serum levels [PMID: 18089691] [Full text])
• one inexpensive method is to give patients 50K IU capsule of D2 once a week for 8 weeks followed by every other week after that.
• another method is 1000 IU per day of D3 or 3000 IU/day of D2
• another method is to give 100K IU of D3 once every 3 months. It was shown to maintain circulating D levels at 20 ng/ml or higher.
• additional considerations may be appropriate for those with kidney disease, malabsorption problems or those on anticonvulsants, glucocorticoids or other drugs involving the steriod and xenobiotic receptor
• exposure of the arms and legs for 5 to 30 minutes depending on time of day, latitude, season and skin pigmentation between the hours of 10am and 3pm twice a week is often sufficient
• most tanning beds emit 2% to 6% UV and can be effective in moderation
• exposure in tanning beds for 30% to 50% of the time recommended for tanning can prevent vitamin D deficiency and will have lower risk of skin cancer than a full exposure

Toxicity

• levels of vitamin D which are too high are associated with hypercalcemia (excess calcium) and hyperphosphatemia (excess phosphorus). 50K IU/day would raise circulating D levels to 150 mg/ml (374 nmol/l) and would be associated with such problems.
• doses of 10K IU/day for up to 5 months have not been seen to cause problems. See [PMID: 15225842] [full text] which in turn references [PMID: 12499343] [full text].
• certain disorders may predispose patients to be more susceptible to calcium levels which are too low or too high

Methods of Measurement

• assays for circulating D3 can be used to assess deficiency
• radioimmunoassays measure D2+D3
• liquid chromatography and mass spectroscopy can report D2 and D3 separately
• a combined total of D2+D3 of 30 ng/ml is generally sufficient