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Association to mechanism to causality: vitamin D’s effect on inflammation of the gums

Posted on: August 23, 2013   by  tom.weishaar@gmail.com

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A typical path in science may look a little something like this:

  • Starts with an observation of an association between a characteristic and a health condition…
  • Then to an explanation of the mechanism by which the characteristic could cause the health condition…
  • Then to a randomized controlled trial that shows the direction of the causal relationship between the characteristic and the health condition.

Sometimes the mechanism is discovered last, but not in the studies we’re looking at today. And in this set of studies, both the mechanism study and causality study cite the initial study that observed the association.

For those of you whose eyes have glazed over from how abstract I’m being, let’s get specific with the link between vitamin D and gingivitis. We’re talking about vitamin D levels as the characteristic and inflammation as the health condition. In these studies, the specific kind of inflammation we’re looking at is gingivitis – inflamed gums.

First came the 2005 study noting an association between serum 25-hydroxyvitamin D (25(OH)D) levels and gum inflammation:

Dietrich T, Nunn M, Dawson-Hughes B, Bischoff-Ferrari HA. Association between serum concentrations of 25-hydroxyvitamin D and gingival inflammation. American Journal of Clinical Nutrition. Sep 2005;82(3):575-580.

This study analyzed data collected between 1988 and 1994 by NHANES III, a large survey done by the federal government on the health of a representative sample of the U.S. population. Among hundreds of other things, this survey included both a vitamin D test and a dental exam that reported gum bleeding on probing for each tooth in each individual. Bleeding on probing is a specific method used by dentists to identify gingivitis – gum inflammation. The study sample was 77,503 probes in 6,700 individuals.

The study found a clear linear trend – the higher the vitamin D level, the lower the prevalence of gingivitis. There was no vitamin D level at which the relationship leveled off; the 10% of individuals with the highest levels of vitamin D (the group median was 45 ng/mL) had the lowest levels of gingivitis.

Next came the 2012 study examining the mechanism by which vitamin D levels impact inflammation of the gums:

Liu KN, Meng HX, Hou JX. Characterization of the Autocrine/Paracrine Function of Vitamin D in Human Gingival Fibroblasts and Periodontal Ligament Cells. Plos One. Jun 2012;7(6).

This study was essentially addressed to those in the medical, public health, and nutrition communities who are stuck on the classic understanding of vitamin D. The classic understanding is that vitamin D is activated in the kidney and passes in the blood stream as a hormone to control blood calcium levels. In this understanding vitamin D has an endocrine function – it is created at one place in the body and is used to send signals to cells in other parts of the body. In the classic understanding, vitamin D has do with bone health and nothing more.

The modern understanding of vitamin D includes this endocrine signaling, but also understands that vitamin D is also activated inside many other cells, where it is used to signal the DNA machinery inside that cell (autocrine signaling) or inside adjacent cells (paracrine signaling) to up- or down-regulate genes that code for specific proteins.

In the classic understanding of vitamin D, 25(OH)D is turned into the active form of vitamin D by an enzyme made from a gene called CYP27B1. In the kidney, this gene is up- and down-regulated by parathyroid hormone, calcium, and activated vitamin D itself. When the gene is up-regulated, more of a certain protein is made which results in more 25(OH)D being converted to activated vitamin D.

What this study shows is that this specific gene is also strongly up-regulated inside a certain type of cell in the gums by IL-1 beta, a protein that mediates inflammatory response, and by sodium butyrate, a metabolite of a type of bacteria associated with gum inflammation. After the CYP27B1 gene is up-regulated inside a cell, more of the cell’s 25(OH)D is converted into activated vitamin D, which in turn signals the DNA machinery of that cell and nearby cells to produce other proteins that reduce inflammation.

Interesting, but does it really work? To demonstrate that effectively, we need a randomized control trial, and this year we got one:

Hiremath VP, Rao CB, Naik V, Prasad KVV. Anti-inflammatory Effect of Vitamin D on Gingivitis: A Dose-Response Randomised Control Trial. Oral Health Prev. Dent. 2013;11(1):61-69.

This study was done by researchers at the Maratha Mandal Dental College in Belgaum, India. The study used the Löe and Silness gingival index to measure inflammation, which resulted in a score of 0 to 3 for each subject in the study. This measurement was taken four times: at the beginning of the study, after 30 days, after 60 days, and after 90 days. Serum 25(OH)D was measured in each subject at the beginning of the study and again at the end of the study 90 days later.

The study’s 96 subjects were split into four groups randomly assigned to different levels of vitamin D supplementation. Personnel involved in measuring gingival scores were blind to which group the subjects were in. The supplements were in coded kits of 30 tablets. Neither the subjects nor the investigators knew how much vitamin D each group was getting until the codes were broken at the end of the study:  0 (placebo), 500, 1000, or 2000 IUs.

As shown in Figure 1, the placebo group started out with a mean serum 25(OH)D of 28 ng/mL and ended the study at 29. The 500 IU group started at 24 and ended at 37; the 1000 IU group went from 27 to 44; and the 2000 IU group from 22 to 52. In the placebo group, mean gingival index scores went from 2.24 at the beginning of the study to 1.90 at the end. In the 500 IU group, the scores went from 2.24 to 0.88; in the 1000 IU group from 2.40 to 0.55 and in the 2000 IU group from 2.41 to 0.34. Compared to baseline gingival scores, the 2000 IU group showed statistically significant improvement after one month, the 1000 IU group after two months, and the 500 IU group after three months. The change in the placebo group was not statistically significant.

gingivitis-graph

I should note that subjects were excluded from this study if their serum 25(OH)D was less than 20 ng/mL or more than 65. They had to have a gingivitis score of at least 1, but were excluded if their teeth or gums were in bad shape (periodontal pockets > 3 mm). They were in good general health, aged 18 to 64, including both men and premenopausal, not pregnant women. The study excluded individuals who were currently smokers or who had been so in the last five years, as well as individuals taking medications to control inflammation.

There are several interesting things we can say as a result of this set of studies:

  • Vitamin D levels have an impact on inflammation.
  • Gingivitis can be used as model of inflammation in humans.
  • Even at mean serum 25(OH)D levels over 50 ng/mL, mean gingival inflammation scores neither leveled off nor reached zero.
  • Dental professionals may be a good target group for vitamin D messaging – they’ve done a wonderful job with fluoride to prevent cavities through the years – would they do the same with vitamin D to prevent gum inflammation and its sequelae?

4 Responses to Association to mechanism to causality: vitamin D’s effect on inflammation of the gums

  1. IAW

    To: Tom Weishaar
    Part of your story above was the inspiration for me to post a comment to the CDC on Dr. Cannell’s story “CDC opens a docket for reduction of UV exposure”. Thanks to you and all the VDC for your great stories and inspiration.
    Ivy

  2. Rita and Misty

    It concerns me that as of August 26, 2013 at 10:00 a.m. ET there are only 29 comments on the CDC site. VDC members–please consider posting a comment on the CDC site. There is strength in numbers. It is one of the very few things I do believe.

  3. Rebecca Oshiro

    Thank you for such an interesting and comprehensive article. Will be sharing this with my dentist!

  4. Tom Weishaar
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