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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 4  |  Page : 227-232

Vitamin D: A “Sun Shine” on the periodontium


1 Department of Periodontics, Pushpagiri College of Dental Sciences, Thiruvalla, Kerala, India
2 Consultant Periodontist, Sanjeevani Hospital, Chengannur, Kerala, India
3 Consultant Periodontist, Jayvees Dental Clinic, Maramon, Kerala, India

Date of Submission15-Oct-2019
Date of Acceptance01-Nov-2019
Date of Web Publication22-Jan-2020

Correspondence Address:
Dr. Annie Kitty George
Department of Periodontics, Pushpagiri college of Dental Sciences Medicity, Perumthuruty, Thiruvalla, Kerala
India
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DOI: 10.4103/srmjrds.srmjrds_70_19

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  Abstract 

Vitamin D is a fat-soluble vitamin with pleiotropic effects on different organ systems of the body. Major portion of the vitamin is synthesized in the epidermis under the influence of sunlight. Conventionally, Vitamin D had been solely associated with the metabolism and health of skeletal tissues. Osteomalacia/osteoporosis in adults and rickets in children were the only symptoms previously attributed to Vitamin D deficiency. The potential role of adequate Vitamin D for the proper functioning of diverse tissues throughout the body is now well recognized. The prevalence of Vitamin D deficiency or insufficiency is rampant and affects people of all ages. Vitamin D is essential for the maintenance of periodontal health. Adequate levels of the vitamin have a “perio-protective” effect and can decrease susceptibility to periodontal diseases. This “sunshine effect” of the vitamin on the periodontium can be mainly attributed to its immune-modulatory action. This review addresses the basics of Vitamin D metabolism and underlines the role of Vitamin D on periodontal health, disease, and therapy.

Keywords: Periodontal therapy, periodontitis, Vitamin D


How to cite this article:
George AK, Balram B, Joseph AE. Vitamin D: A “Sun Shine” on the periodontium. SRM J Res Dent Sci 2019;10:227-32

How to cite this URL:
George AK, Balram B, Joseph AE. Vitamin D: A “Sun Shine” on the periodontium. SRM J Res Dent Sci [serial online] 2019 [cited 2020 Jul 13];10:227-32. Available from: http://www.srmjrds.in/text.asp?2019/10/4/227/276375


  Introduction Top


”Vitamin D” is a conglomeration of fat-soluble molecules.[1] A large fraction of the body's Vitamin D is obtained by the exposure of the skin to sunlight. Ultraviolet B penetrates the epidermis and converts 7-dehydrocholesterol in the skin to Vitamin D3 (cholecalciferol). The remaining fraction of the vitamin is absorbed from the gut in the form of Vitamin D3 or as Vitamin D2 (ergocalciferol). Foods of animal origin such as fish, meat, and dairy products are rich sources of Vitamin D. In circulation, Vitamin D binds to the Vitamin D-binding protein. Vitamin D2 and D3 are not biologically active. They are first hydroxylated into 25(OH)D in the liver, then 25(OH)D undergoes hydroxylation again in the kidney into the biologically active 1, 25(OH)2D. The conversion of Vitamin D2 and D3 to its biologically active form can to a lesser extent, occur in other tissues of the body.[2],[3] The plasma half-life of 1,25(OH)2D is only about 4 h, but 25(OH)D has a longer half-life of about 3 weeks. Therefore, the level of 25(OH)D is usually estimated as a reliable measure of plasma Vitamin D. 1, 25(OH)2D is considered a hormone as it circulates throughout the body to optimize functions in diverse tissues. 1, 25(OH)2D binds to Vitamin D nuclear receptor (VDR) to exert its actions. VDRs are distributed widely, and its content is highest in the tissues involved in calcium homeostasis, such as the bone, intestine, kidney, and parathyroid gland[4] VDRs are also present on many cells of the immune system. VDR joins the retinoid X receptor (RXR) to form a heterodimer-VDR/RXR. The VDR/RXR subsequently binds to Vitamin D response elements (VDRE) in target genes to regulate gene expression.[5] This review underlines the role of Vitamin D on periodontal health, disease, and/or therapy.


  Vitamin d-Insufficiency and Deficiency Top


Plasma concentration of 25(OH)D is usually 25–138 nanomoles per liter (nmol/L). However, there is no clear agreement on the ideal levels of serum 25(OH)D. The Endocrine Society Clinical Practice Guideline[3] defines Vitamin D deficiency as plasma 25(OH)D level <20 ng/mL (50 nmol/L). A plasma level of 21–29 ng/mL (52–72 nmol/L) is considered insufficient. A Vitamin D deficient individual has to be treated daily with 6000 International Units of Vitamin D2 or Vitamin D3, followed by a maintenance dose of 1500–2000 IU/day to achieve and maintain plasma levels of 75 nmol/L.[3] It is understood that a plasma level of 70 nmol/L of Vitamin D augments intestinal uptake of calcium and phosphorus and optimizes health and function of skeletal and muscle tissues. Plasma concentration of the vitamin necessary for health and the maintenance of nonskeletal tissue are, however, not yet still precisely defined.[3]


  Role of Vitamin d on Periodontal Health, Disease, and Therapy Top


Evidence gathered from prevalence studies indicates that a deficiency of Vitamin D can predispose individuals to an increased risk of periodontal diseases.[6],[7],[8],[9],[10] It is also reported that Vitamin D supplementation (Vitamin D alone or Vitamin D plus calcium) may improve periodontal stability, may increase bone density of maxilla and mandible and may decrease resorption of alveolar bone.[9],[11],[12],[13],[14] Based on the US National Health and Nutrition Examination Survey,[15],[16] Dietrich et al. reported that Vitamin D concentrations were inversely and significantly associated with clinical attachment loss in participants ≥50 years. The study participants in the lowest 25(OH)D (3) quintile, had more periodontal attachment loss than those in the highest quintile. They also reported a higher protective effect of Vitamin D in men. In their study, the observed association between low 25(OH)D (3) and attachment loss was independent of bone mineral density. This observation highlighted the anti-inflammatory role of Vitamin D.[15] To study the anti-inflammatory effects of serum Vitamin D on the gingiva, Dietrich et al. compared the level of gingival inflammation in relation to plasma concentration of 25(OH)D. They reported that participants with higher 25(OH)D levels were 20% less likely to have bleeding on probing than participants who had lower levels of 25(OH)D.[16] (P for trend <0.001). The anti-inflammatory role of Vitamin D was further underlined by Jönsson et al.[17] They used data from the Third US National Health and Nutrition Examination Survey to study the synergistic effect of hormone replacement therapy (HRT) and serum Vitamin D on clinical attachment loss and tooth loss in postmenopausal women. Women on HRT and high plasma 25-hydroxy Vitamin D levels had lesser clinical attachment loss than women with low 25-hydroxy Vitamin D levels. The synergistic effect of HRT and high Vitamin D levels also had an inverse relation to the number of missing teeth in postmenopausal women. In order to provide mechanistic explanations to their population-based findings, the authors conducted in vitro experiments. Their study results showed that Vitamin D and estrogen plus progesterone decreased the production of pro-inflammatory cytokines and chemokines in human monocytes treated with lipopolysaccharide (LPS).

Jabbar et al.[18] reported that a higher proportion of osteoporotic postmenopausal women had periodontal diseases when compared to age- and gender-matched controls without osteoporosis. Women with osteoporosis and periodontal disease had lower serum levels of 25-hydroxy Vitamin D and higher levels of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG).

Severe periodontitis patients who underwent flap surgery, and were Vitamin D deficient had less of probing pocket depth reduction and gain of attachment than participants who had sufficient levels of Vitamin D.[19] Studies indicate that adequate levels of Vitamin D are also essential in the postsurgical phase to achieve perfect wound healing after periodontal surgery.[19]

Schulze-Späte et al.[20] reported from their longitudinal study that even though at baseline, men with severe periodontitis had lower levels of Vitamin D, the measure of serum Vitamin D was not a good predictor of disease progression in participants with chronic periodontitis. Yet another large 5 years prospective study in postmenopausal women found no association between Vitamin D level at baseline and measures of periodontal disease. The authors also reported that adequate Vitamin D levels have no protective effect against periodontal disease progression.[21] The results from these studies, however, cannot be considered representative of the serum Vitamin D and periodontitis association in the general population. While the former investigation by Schulze-Späte et al. dealt only with a selected cohort of men ≥65 years enrolled in the study of “Osteoporotic Fractures in Men,”[20] the latter study sample was a group of women in the postmenopausal age, recruited in the “Buffalo OsteoPerio Study.”[21],[22]

Krall et al.[23], in a randomized placebo-controlled longitudinal study, evaluated the effect of calcium and Vitamin D supplementation in healthy controls. 700 IU of 25-hydroxy Vitamin D3 was administered for the treatment group. The primary outcome of the study was measured in terms of the number of teeth lost over a time period of 42 months. Beneficial effects for Vitamin D supplementation were not reported. Their results ought to be interpreted in the light of the small sample size and the crude measurement of tooth loss over a period of 42 months. A number of recent studies also observed poor Vitamin D status in the study groups with periodontitis than among healthy controls.[24],[25],[26] From the results of a longitudinal study on 1904 participants and a mean follow-up period of 5.9 years, the authors reported that tooth mortality decreased by 13% for every 10 μg/L increase in serum 25-hydroxy Vitamin D.[26]

Patients who underwent surgery for maxillary sinus floor augmentation were randomly allocated into a treatment group receiving 5000 IU of Vitamin D3 and a placebo group by Schulze-Späte et al.[27] The two groups did not differ in terms of graft resorption or osteoid formation. Interestingly, in the Vitamin D group, there was an increased presence of osteoclasts surrounding the graft material. This observation may be reflective of pronounced metabolic activity in augmented sites in the treatment group receiving Vitamin D3.

The statistical association seen between Vitamin D and periodontal health/disease/treatment can be explained by the effects of Vitamin D on alveolar bone metabolism, its pleiotropic effects on innate and acquired immune responses, and several Vitamin D receptor gene polymorphisms [Figure 1].
Figure 1: Role of Vitamin D on periodontal health

Click here to view



  Vitamin d and Alveolar Bone Metabolism Top


The primary role of 1, 25(OH)2D is in maintaining calcium and bone homeostasis. By virtue of its osteoprotective effects, optimal levels of 1,25(OH)2D reduces alveolar bone resorption.[28],[29] RANK is expressed on the surface of osteoclast progenitor cells. RANKL, and OPG are produced by osteoblasts. The CD4 + T lymphocytes play an active role in bone remodeling.[30] RANKL to RANK binding leads to the differentiation of osteoclast precursor cells into the functional mature osteoclasts. OPG functions as a soluble decoy receptor for RANKL and can antagonize RANK-RANKL interaction. RANKL gene promoter structure contains VDRE. Interaction of Vitamin D with the VDR upregulates RANKL expression in bone marrow-derived stromal cells and osteoblasts.[31] 1, 25(OH)2D also downregulates OPG. The combined action of Vitamin D in the upregulation of RANKL and reduced expression of OPG favors osteoclastic activation and bone resorption.[32] Kitazawa et al. reported that though Vitamin D decreased the expression of OPG initially, the OPG levels increased on continued exposure to the vitamin.[32] Their study underlined the transient nature of osteoclastic activity of Vitamin D. Furthermore, Vitamin D stimulates osteopontin and alkaline phosphatase activity in osteoblasts. Vitamin D has a significant effect on bone resorption and remodeling. Vitamin D may also promote osteoblastic proliferation and differentiation on prolonged exposure to the vitamin.


  Immunomodulatory Role of Vitamin d in Periodontal Health, Disease, and Therapy Top


Vitamin D was ascribed a definite immunomodulatory effect with the discovery of VDR on the cells of the immune system.[5] Furthermore, antigen-presenting cells such as macrophages and dendritic cells express the 1α-hydroxylase enzyme, which transforms biologically inactive 25(OH)D3 to the bioactive 1,25-(OH) 2D3.[28] Vitamin D can modulate the innate immune response by its effect on innate antibacterial activity and antigen presentation. In the innate immune response, pathogen-associated molecular patterns are sensed by toll-like receptors. This is followed by increased synthesis and activity of 1,25-(OH) 2D3 in macrophages[33] ultimately leading to the generation of antibacterial substances such as cathelicidin and beta-defensins. According to Wang et al.,[34] the expression of cathelicidins and defensins is dependent on optimal plasma concentration of Vitamin D. 1,25-(OH) 2D3 can promote expression of cathelicidins in diverse cell types such as macrophages, keratinocytes,[35] neutrophils, and T lymphocytes.[36] Vitamin D also affects adaptive immune response. It was seen in in vitro studies that 1,25-(OH) 2D3 inhibited the proliferation, differentiation, and maturation of dendritic cells[37],[38] and reduced expression of major histocompatibility complex class 2, CD40, CD80, and CD86 molecules.[37],[38],[39] Vitamin D affects the macrophages and dendritic cells by dampening their ability for antigen presentation and T-cell activation.[39],[40]In vitro studies wherein the Vitamin D receptors were “silenced” reported macrophage hyperresponsiveness on LPS stimulation. This exaggerated macrophage response to Gram-negative bacterial challenge was also observed in studies conducted in Vitamin D receptor knockout mice. It is plausible that Vitamin D supplementation may augment/modulate antibacterial response against putative periodontal pathogens.[41]

Macrophages can be divided into the pro-inflammatory M1 and the anti-inflammatory M2 phenotypes. Macrophages of the M1 phenotype generate pro-inflammatory molecules such as nitric oxide, tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1 beta. M2 phenotype produces the anti-inflammatory cytokine-IL-10. Vitamin D can enable macrophage phenotype switch from M1 to M2.[42]

1,25-(OH) 2D3 also decreases the expression of pro-inflammatory cytokines IL-1, IL-6, TNF-α, IL-8, and IL-12 in monocytes.[39],[43] IL-2 is a key pro-inflammatory cytokine implicated in T- and B-lymphocyte proliferation and activation. The promoter region of IL-2 has VDRE. By decreasing the expression of IL-2, Vitamin D causes the inhibition of both T- and B-lymphocytes.[44],[45] 1,25-(OH) 2D3 also affects B-cell differentiation, isotype switching, and immunoglobulin production.[46] However, the most important role of Vitamin D is on the T-lymphocytes affecting their proliferation, differentiation, and function. The effect of Vitamin D is mainly focused on the T-helper cells.[47] Vitamin D modulates the specific immune response by selective stimulation and inhibition of specific T-helper cell subpopulations. Experimental evidence points out that Vitamin D augments Th2 cell development (IL-4, IL-5, and IL-10 production) and inhibits Th-1 cells (interferon-gamma production).[48] Vitamin D inhibits cytokine production by Th-17 cells.[49] Further, Vitamin D also stimulates T-regulatory cell activity.[50] Furthermore, reports from in vivo and in vitro studies point out that therapy with Vitamin D promotes the function of natural killer T-cells.[51]

Vitamin D exerts its anti-inflammatory actions on prostaglandin synthesis and cyclooxygenase pathways. Production of matrix metalloproteinases (MMPs) is also inhibited. Inhibition of MMPs will help reduce the LPS induced tissue destruction seen in periodontitis.[52]

The deficiency of Vitamin D has a detrimental effect on wound healing. 1, 25(OH)2D/VDR signaling promotes proliferation and differentiation of keratinocytes and mobilization of monocytes/macrophages in the early phase of tissue healing.In vivo experiments conducted in VDR-deficient laboratory animals show impaired granulation tissue formation, characterized by decreased vascularization, and poor extracellular matrix composition.[53]

The pleiotropic immunomodulatory effects of Vitamin D can be described as a combination of its increased antimicrobial effect and its ability to induce an anti-inflammatory macrophage and T-cell differentiation.[54]


  Vitamin d Receptor Polymorphisms and Periodontal Diseases Top


Vitamin D receptor gene polymorphisms may affect alveolar bone remodeling and host response to periodontopathic bacteria. Polymorphisms in the VDR genes are usually studied by restriction enzyme digestion and polymerase chain reaction. A number of VDR restriction fragment length polymorphism (RFLPs) have been recognized to be associated with periodontal disease. In terms of their capacity to increase periodontal disease susceptibility, the most studied are the Taq I-Bsm I-, Apa I-, and Fok I- VDR polymorphisms.[55],[56],[57],[58] Results of these studies are often mixed and inconclusive. Future studies in this regard are required to better understand the functional relevance of VDR RFLPs and periodontal disease pathogenesis.[59]


  Conclusion Top


In addition to the effect of Vitamin D on calcium homeostasis, it also has potent immunomodulatory action. The significant association seen between Vitamin D and periodontal health, disease, and/or therapy can be explained by its actions on alveolar bone metabolism, host response to microbial challenge and polymorphisms in the Vitamin D receptor.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Abstract
Introduction
Vitamin d-Insuff...
Role of Vitamin ...
Vitamin d and Al...
Immunomodulatory...
Vitamin d Recept...
Conclusion
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