Vitamin D and periodontitis: shedding the light

Vitamin D overview

Vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol) are the two major forms of vitamin D – a secosteroid.⁹ In this article, the term vitamin D will refer to both forms.

Biochemistry

Vitamin D is the product of photochemical reactions using sunlight containing UVB radiation. It can be obtained from two main sources: endogenous production via cutaneous synthesis (vitamin D₃); and diet (vitamin D₂ and D₃). Factors affecting the rate of vitamin D₃ formation include UVB radiation and melanin. The former is affected by the zenith angle of the sun, altitude, cloud cover and air pollution.⁹ Quantitatively, cutaneous synthesis is the most important source and dietary derived sources, listed in Table 1, tend to play supporting roles where inadequate cutaneous production is apparent.^9,10 Rich dietary sources of vitamin D₂ are limited, resulting in fortified foods. Natural food sources rich in vitamin D₃ include egg, oily fish and animal products.⁹

Table 1. Mean vitamin D content in different foods.9

Food	Mean vitamin D content per 100 g
	μg	IU
Fish Herring (grilled) Salmon (farmed, grilled) Mackerel (grilled) Sardines (grilled) Tuna (baked)	16.17.88.55.13.1	644312340204124
Eggs Egg (whole, boiled) Egg (yolk, boiled)	0.2/12812.6	128504
Meat Liver (lamb, fried) Liver (calf, fried) Beef (rump steak, fried)	0.90.30.7	361228
Fortified foods Bran flakes Cornflakes Rice cereal Fat spreads	4.24.24.27.5	168168168300

A double bond between carbon atoms 22 and 23 and a methyl (-CH₃) side chain at carbon atom 24 gives vitamin D₂ a molecular mass 3.1% greater than that of its analogue (Figure 1). This distinguishing factor results in its reduced affinity for vitamin D binding protein (VDP), an important molecule in the transport of vitamin D. Consequently, vitamin D₂ has a faster clearance from the circulation, which limits its conversion to the active form.^9,10 Therefore, vitamin D₂ will not result in as high a serum level of the subsequent substrate forms of vitamin D as will comparable amounts of vitamin D₃.¹⁰

The biologically inert dietary and endogenous forms of vitamin D, bound to VDP, are transported to the liver to undergo two hydroxylation reactions for activation:^9,10

25-hydroxylation: vitamin D → 25-hydroxyvitamin D (25(OH)D);

– 25(OH)D binds to VDP and is transported to the kidney;

1α-hydroxylation: 25(OH)D → 1,25-dihydroxyvitamin D (1,25(OH)₂D)

Despite 25(OH)D being biologically inactive, it is a recognized biomarker owing to its long half-life and ability to reflect the cumulative cutaneous and dietary supply of the micronutrient.⁹

Mechanisms of action linking vitamin D and periodontitis

Genomic effects of vitamin D are exerted via the VDR. This receptor is responsible for the transcribing of over 1400 genes – the equivalent of 4% of all human genes.¹² Genomic activity of vitamin D demonstrates antimicrobial and immunomodulatory, more specifically anti-inflammatory, mechanisms of action.¹³ Thus, theoretically VDR gene polymorphisms could have an impact on disease susceptibility and progression through altered gene expression and subsequent mechanisms of action.

Association between vitamin D and periodontitis

An array of studies (Table 2), discuss the association between vitamin D and periodontitis. Supporting the notion of vitamin D's anti-inflammatory role, a longitudinal study found an inverse association between 25(OH)D and salivary cytokine production.²⁹ Lower quintiles of 25(OH)D levels have revealed greater clinical attachment loss (AL) of 0.39 mm or 0.26 mm in men and women, respectively,³⁰ while higher quintiles of serum 25(OH)D demonstrate a reduced incidence of periodontitis, reduced prevalence of teeth associated with deeper periodontal pockets and tooth loss.^31,32 In addition, an increase in vitamin D increments reduced the odds of developing moderate and severe periodontitis and alveolar bone loss.^33,34

The interpretation of the research is complicated by varied definitions of vitamin D deficiency, biomarker and periodontal measurements, and methodological designs. Taken together, such variations in study designs contribute to the difficulty in performing a meta-analysis of studies. Nonetheless, numerous studies explored in Table 2 identified statistically significant associations between reduced vitamin D levels and poor periodontal parameters and increased vitamin D levels with favourable periodontal health. Such results are appealing for the management of periodontitis.

Association between VDR polymorphisms and periodontitis

Among putative genetic risk factors, the VDR gene is one of three genes that have emerged as having a strong level of evidence with periodontitis.⁸ Restriction fragment length polymorphisms (RFLPs) have been identified in TaqI (rs731236), ApaI (rs7975232), BsmI (rs1544410) and FokI (rs2228570).^35,36

Table 3 presents some of the studies that have examined VDR polymorphisms and periodontitis. While some meta-analyses demonstrate ApaI may be associated with a reduced risk of periodontitis in a Chinese population, another found it could not be generalized to Caucasians.^36,37,38 Protective associations to periodontitis with a TaqI variant is evident in some case-control studies.^38,39 Yet, meta-analyses have shown that the TaqI polymorphism has no association to periodontitis.^36,40 While two meta-analyses demonstrated FokI variants to be implicated in ‘aggressive’ periodontitis in subjects of Asian origin, another found no significant association in any genotype of FokI.^35,36,38 Furthermore, conflicting findings between BsmI and periodontitis are evident.^36,38

The lack of concrete associations between VDR polymorphisms and periodontitis may be reflective of the different exposures among populations as phenotypic heterogeneity is the combined result of genetic, environmental and biological interactions. Such conflicting results have led to limited success in deciphering significant and reproducible VDR gene polymorphisms for susceptibility to periodontitis.

Effects of vitamin D supplementation on periodontitis and periodontal therapy

There are few interventional studies assessing VDS solely as an adjuvant to periodontal therapy, which makes it difficult to draw definitive conclusions. Nevertheless, those that are available show promising results. A double-blind randomized controlled trial (RCT) allocated adult patients with moderate to severe periodontitis to experimental groups that received daily 4000 IU oral VDS for 16 weeks, or a placebo. At week 8, both groups, underwent non-surgical periodontal therapy (NSPT) with the aim of eliciting a systemic inflammatory response. Although no significant effects on periodontal parameters were observed after 16 weeks, this RCT highlighted two pivotal outcomes of VDS in the experimental group: reduced cytotoxic T cells routinely involved in tissue damage; and increased induction of autophagy-related proteins. Therefore, it can be hypothesized that VDS can mediate and counteract the cytotoxic T cell response during periodontal therapy, which could otherwise increase periodontal tissue damage.⁴¹

Consistent with the studies listed in Table 4, Gao et al found improvements in periodontal health parameters in their double-blind RCT. The RCT involved moderate to severe periodontitis subjects who underwent 3 months of NSPT prior to assignment to one of two intervention groups (daily 1000 IU or 2000 IU vitamin D) or a placebo group. Dose-dependent and statistically significant increased reductions in AL and periodontal pocket depths (PPD) for moderate and deep periodontal pockets were evident among intervention groups.⁴² Although, differences between the intervention and placebo groups were statistically significant, they may not be clinically remarkable.

Individuals who required periodontal surgery received daily calcium and vitamin D and either self-administered teriparatide (synthetic parathyroid hormone) or a placebo. Greater clinical attachment level (CAL) gain and PPD reduction were evident in the vitamin D sufficient subjects compared to deficient subjects. Teriparatide-treated vitamin D sufficient subjects showed greater infrabony defect resolution.⁷

Considering all three studies, it can be speculated that vitamin D can positively affect treatment outcomes of periodontal therapy – whether surgical or not. Enhancing vitamin D levels via supplementation or diet can demonstrate improved periodontal health outcomes. Although the sole effect of vitamin D in a deficient population cannot be explained in such studies, it can be hypothesized that synergistic mechanisms between vitamin D and other supplements and nutrients could have resulted in the host immunomodulatory changes evident to prevent onset or progression of periodontitis. Yet, studies examining serum 25(OH)D levels, a biologically inactive marker, allow for potential confounding because it is an indicator of supply rather than function. The same oral dose of vitamin D supplementation results in wide interindividual variability of 25(OH)D, some of which may be accounted for by polymorphisms of specific genes in the vitamin D metabolic pathway.⁴³ Therefore, studies investigating a biologically active marker may be more apt.

Clinical guidelines

The European Federation of Periodontology (EFP) workshop from 2011 confirmed the inverse correlation between vitamin D and periodontitis, and discussed the potential for micronutritional approaches as novel periodontal therapies.⁴⁴ Proceedings of the workshop recommended adequate daily intake of vitamin D, via changes in diet, lifestyle or supplements, for the prevention and treatment of periodontitis.¹⁶ Recent EFP treatment guidelines have analysed the research on the use of adjunctive agents, such as antioxidant micronutrients, in supportive periodontal care and were unable to comment on their effectiveness. Although, omega-3 polyunsaturated fatty acids were not currently recommended for use as an adjunct to subgingival instrumentation, there was no specific mention for the use of vitamin D.⁴⁵

Conclusion

This article has explored the mechanisms and evidence underpinning vitamin D as a potential modifiable risk factor and host modulator for periodontitis. Further research may help to define, not only a causal relationship, but which periodontitis patients would benefit from a vitamin D screen, adding a further layer to the concept of ‘personalized medicine’.

Moreover, VDR gene polymorphisms appear to affect an individual's biological response, highlighting the potential importance of nutrigenetics. Thus, genomic approaches, more specifically genetic testing, may soon become a pragmatic approach to identify and manage at-risk individuals.

Periodontitis is a complex disease with many implications. Therefore, it is critical for dental professionals to continue to increase their understanding and awareness of nutritional deficiencies and periodontitis management. The dental team will continue to play an important role in identifying systemic issues in their patients, as well as working with appropriate medical professionals to correct them. Subsequently correcting the nutritional deficiency, although not a panacea, may be a safe, effective and inexpensive adjuvant therapy.