Occasionally, I miss very important vitamin D papers. Professors Bruce Hollis and Carol Wagner published such a paper in late 2013.
Hollis BW, Wagner CL. Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: Why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013 Dec;98(12):4619-28. doi: 10.1210/jc.2013-2653. Epub 2013 Oct 8. Review.
In this paper, they provide reasons why daily dosing of vitamin D is much better than stoss or bolus dosing (such as weekly, monthly, etc.). As many as 60% of the vitamin D clinical trials published to date used bolus dosing, not daily dosing. Many of those trials resulted in negative findings. Why?
The reason may be that the current vitamin D canon (accepted belief) is incorrect. Current canon is the autocrine theory, which states that all of the relevant parent compound (vitamin D) is transported to the liver where it is metabolized to 25(OH)D, and this 25(OH)D is then transported by vitamin D binding protein (VDBP) to the 33 tissues that utilize vitamin D. The cells in these tissues then absorb 25(OH)D through the cell membranes where it is again metabolized to form the steroid hormone calcitriol, which regulates genes.
However, this may be not be accurate, as 25(OH)D is strongly bound to vitamin D binding protein (VDBP), and not much of it is free to passively diffuse across cell membranes. The 25(OH)D/VDBP complex can be transported across cell membranes by specialized transporter proteins, but to date, these transporter proteins have not been found in very many tissues.
Hollis and Wagner theory states that it’s the parent compound (vitamin D) that diffuses across cell membranes. Very little vitamin D is bound to VDBP, so it is free to cross the cell membranes in large amounts by passive diffusion where it is metabolized into calcitriol. This would explain why the parent compound, vitamin D, disappears from the blood so quickly (12-24 hours); it is absorbed into cells.
I asked the famous vitamin D expert, Professor Hector DeLuca, about the canonical autocrine theory.
“The jury is still out on the so-called autocrine production of calcitriol. I do know that serum calcitriol is undetectable (below our limits of detection (<5 ng/ml) in animals without kidneys). Certainly in diseases like sarcoidosis, there is extra-renal production of calcitriol. However, no convincing in vivo (animal) experiment that demonstrates extra-renal production of calcitriol has appeared. There are lots of reports that say extra-renal cells in vitro (test tube) can produce calcitriol. It is not clear if this in vitro demonstration represents in vivo reality.”
He went on the say, “We already know that VDBP knockout experiments (experimental animals bred to have no VDBP) carried out by Nancy Cook did not reveal any abnormalities in vitamin D function (Safadi et al., J. Clin. Invest. 103:239-251, 1999), so there must be another mechanism whereby calcitriol ends up in tissues.”
If Hollis and Wagner are correct, it explains why so many bolus dosing studies using weekly, monthly or longer doses are negative. When using those doses, even large amounts of vitamin D would be cleared from the systemic circulation in several days and thus not be available to diffuse into cells and work vitamin D’s magic.