INTRODUCTION:

Vitamin D is the fat soluble vitamin. It is obtained by endogenously through in skin induced by ultra violet radiation from sun light and exogenously through dietary sources which includes of milk products, oily fishes, cod liver oil and egg yolk are considered as rich sources for vitamin D.¹ Vitamin D generally plays important physiological role in mediating calcium absorption and regulating muco-skeletal functions. Important functions of vitamin D are it maintains the serum calcium and phosphorus level, immune function, cellular growth and differentiation, in regulation of cardiovascular health, prevention of periodontal disease, cancer prevention, wound healing and skeletal integrity.^2-6

Definition

Vitamin D deficiency is defined by the experts, as 25 hydroxy vitamin D level less than 20ng / milli-liter. (50 nl mol/liter). Vitamin D intoxication is seen when the serum levels of 25-hydroxyvitamin D are greater than 150ng per milli liter (374 nmol per liter).^7-10

Current recommendations and intake

Recommended daily intake is 400-600IU and 1000-2000mgs for the people who are above fifty years of age and it’s estimated that there are about 1 billion people who are under risk of vitamin D deficiency.¹

The values consists of four types of daily intake which can be used for assessing diets of individual and groups.,

1. Estimated average requirement (EAR).

2. Recommended dietary allowance (RDA) it meets up to 97 -98% of an individual’s needs.

3. Adequate intake (AI). Seen in the sustained healthy individual.

4. Upper level (UL). Individual has high level but posses no adverse effect.

The adequate level for adults was set about 1000mg/ mg of calcium and 5.0 µg (200 IU) of vitamin D is required. For people like teens 15 - 19 years of age and 1200mg/day and 10.0 µg and 400(IU)/day of vitamin D for ages of 60 – 70 years.¹¹ The adverse effects are seen when the intake exceeds above 250 -1250µg per day.¹¹ The symptoms includes hypercalcemia, constipation, increased thirst, malaise and hyperthyroidism ¹²etc.

Risk factor

Vitamin D deficiency shows risk in infectious and chronic inflammatory diseases, osteoporosis, osteopenia and osteomalacia, the bone mass, low alveolar bone density and associated with tooth loss and leads to high risk for periodontitis.¹³

Formation and synthesis

Vitamin D is a secosteroid, in which the B ring of the conical steroid structure is ruptured and the synthesized form of 7- hydrocholesterol, an intermediate metabolite in cholesterol synthesis or derived from dietary sources. Vitamin D is obtained from sunlight and other dietary supplements.

Vitamin D which is obtained through solar u-v radiation penetrates through skin and gets converts to 7-dihydrocholesterol and forms pre vitamin D and again converts to vitamin D₃¹⁴. Vitamin D formed from skin and diet is absorbed and accumulates in the liver undergoes hydroxylation and metabolized to form 25 hydroxy vitamin D called as calcidol. This is used to determine an individual’s vitamin D status And this 25 hydroxy vitamin D is again metabolized in the kidney by an enzyme 25-hydroxy vitamin D 1alpha hydroxylase to active form called 1,25 hydroxy vitamin D which is called as cacitrol. The renal production of 1,25(OH) vitamin D is highly regulated by plasma parathyroid hormone levels and serum calcium and phosphorous levels. The efficiency of absorption of renal calcium and intestinal calcium and phosphorous level is increased in the presence of 1,25 dihydroxy vitamin D¹⁵.

Vitamin D in bone metabolism

Without Vitamin D only 10-15% of dietary calcium and 60% of phosphorus is absorbed. The interaction of 1,25 –dihydroxy vitamin D with the vitamin D receptor increases the efficiency of intestinal absorption of calcium for about 30-40% and approximately 80% of phosphorus absorption.^7,14,15 1,25,(OH)D₃ plays important role in maintaining oral health through its action on bone and mineral metabolism and innate immunity through vitamin D gene receptor polymorphism. Through the combined actions of liver, kidney, bone, parathyroid hormone and intestine vitamin D helps in mineral haemostasis. Vitamin D helps in maintaining the extracellular calcium levels.

Vitamin D which is obtained through diet and sun light undergoes metabolic modification in specific organs like kidney and liver, then metabolized form is released into circulation. This binds to carrier proteins in the plasma and reaches to different organs. Then mediates its action through VDR which is the transcription factor for the target genes.

VDR stimulates the calcium uptake in the intestine and transports by up regulating expression of epithelial calcium, a cytosolic calcium binding protein and plasma membrane proteins, with this action both calcium and phosphorous enhances the vitamin D to help to create optimum conditions for bone mineralization.1,25 (OH)₂Dis recognized by its receptors in the osteoblast formation which causes increase in the expression of the receptor activator of nuclear factor ƙb ligand (RANKL) .This receptor for RANKL on proteoclasts, binds with RANKL, which induces pre-osteoclasts to become mature osteoclacts cells. This mature clasts cells remove the calcium and phosphorous from the bone, maintaining the calcium and phosphorous levels in the blood, this optimum levels are used to maintain and promote mineralization of bone.

Vitamin D and periodontal health

Vitamin D deficiency is considered as one of the primarily reason for periodontitis which shows symptoms of decreased alveolar bone and tooth loss. Vitamin D is extremely important in the process of keeping the teeth anchored into the socket, research have shown that people with vitamin D deficiency are much more likely to have periodontal disease.

Periodontitis is considered as infectious disease resulting in inflammation within the supporting tissues of the teeth, progressive attachment loss and tooth loss. Vitamin D has shown significant improvement in the periodontal health. Dietary supplements of vitamin D and calcium may improve periodontal health, increases the bone mineral density in mandible and inhibit the alveolar bone resorption^16,17.

Garcia.et.al¹⁸ reported that vitamin D supplements reduces the severity of periodontal health in dose higher than 800-1000IU. It also plays important role in bone calcium hemostasis and acts as anti inflammatory agent because it inhibits immune cell cytokine expression and causes monocytes and macrophages to secrete molecules that have strong antibiotic effect on periodontal pathogen and inhibit inflammatory mediatory action that contribute to periodontal destruction. Periodontitis affects both hard and soft tissues. Auto degenerative mechanisms in which monocytes respond to bacteria invasion and secrete cytokines, which in turn causes lymphatic infiltration, bone resorption, dissolution of extracellular matrix.

Cytokine regulates the body inflammatory response by transmitting signals between cells such as IL-1, IL-6 etc., increases the TNF alpha which is potent signaling osteoclastogenic agents. IL-6 also stimulates the release of MMP which degrade the extracellular matrix and PGE₂ and causes bone resorption. Vitamin D also plays important role in discovery of VDR in the immune cells including activated CD+4 ,CD+8, TandB cells, neutrophils, antigen presenting cells like macrophages and dentric cells. ^19,20

Vitamin D also exhibits antimicrobial activity against oral microbes including periodontitis related bacteria like Actinobacillus actinomycetemscomitans, Porphyromonas gingivalis, Fusobacterium nucleatum, Candida and Papilloma virus²¹. Vitamin D also exhibits pro-differentiation effects on associated monocytes, stimulating phenotypic features associated phagocytic activity. Vitamin D also increases the phagocytic activity against the oral pathogens.²²

Vitamin D on alveolar bone

The individual with low vitamin D intake and calcium are prone to severe gingival inflammation, increased probing depth, increased alveolar bone resorption which sequentially leads to tooth loss and causes periodontitis. In examination of data on 12000, individuals who were tested in Third National Health and Nutrition Examination Survey (NHANES), in the study it was found that individual with low dietary intake of vitamin D has shown increased ill effects in the oral health²³. The association between serum level of vitamin D and tooth attachment loss was found inversely proportion to each other, inspite of being independent of other factors like smoking and diabetes. It was suggested that this inverse relationship might be attributable to anti-inflammatory effects of vitamin D. But this study had limitations because it was cross sectional and serum level of vitamin D was focused at one point.

In another study of dietary survey was conducted and alveolar crest height measurements was made on 550 male persons, the subject who has low alveolar bone density, if the distance from CEJ to alveolar crest on periapical radiographs was equal or greater than 20%, of the distance from CEJ to the root tip and high bone loss was mentioned having value lesser 20%²⁴. The number of individuals who progressed from low to high alveolar bone loss was 30% higher in subjects who consumed less than 1000mg/day of calcium over 7 years period than in those who consumed more than 1000mg/day.

And in low calcium intake and particularly low vitamin D intake results in low serum level of calcium that stimulates the parathyroid gland to produce PTH which results in osteoclastogenesis. Number infectious disease have been linked the low levels of vitamin D and this can also suppress cytokine production. Periodontal pathogen are unique in periodontal disease and it may effect in vitamin D and calcium on alveolar bone is more pronounced than in other parts²⁵.

Vitamin D receptor (VDR) gene receptor and polymorphism

Periodontitis is characterized by enhanced resorption of alveolar bone which supports the teeth and is highly associated with intra oral inflammation after infection with associated bacteria to it. The VDR gene polymorphism was deeply related to the occurrence of tuberculosis and hepatitis B infection. This may be indicated that is there is close relationship between VDR gene polymorphism and other immunological function. Vitamin D activates the monocots which suppresses the lymphocytic proliferation and stimulates cell mediated immunity²⁶.

Chronic periodontitis is one the most common disease prevalent and main cause for tooth loss. The individual who are susceptible to periodontitis, searches for susceptibility gene for periodontitis in adult has been made and genes encoding proteins responsible for immunity such as interleukin – 1, immunoglobulin G, Fc receptor are suspectable genes. Initially vitamin D receptor gene, which was considered to regulate bone metabolism aroused considerable interest as a risk factor for osteoporosis and periodontitis^27,28,29 (Ferrari et al. 1995, Matsuyama et al. 1995 Tokita et al.,1996). This may be interrupted to indicate close relationship between VDR gene polymorphism and immunological action. This is because the active hormonal form of 25-hydroxy cholecalciferol , 1 25-hydroxyvitamin D activates, monocytes, stimulates cell mediated and suppresses lymphocyte proliferation. In connection with the VDR gene, the onset of which is triggered by reduced immunity against bacteria and enhanced bone resorption.

VDR gene is which is located in chromosome 12 and that its polymorphism is detected by the presence or absence of a restriction site for fok 1 in the translation initiation ATG site of exon 2 (Ames et al.,1999)³⁰as well as Bms 1 and Apa 1 in inttron (Morrison et al.,1992)³¹ and by that Taq 1 exon 1.(Gerrio et al.1997, Ongphiphadhanakul et al.1997)^32,33.

Vitamin D plays role in VDR gene receptor and polymorphism. This VDR polymorphisms are associated with several disease like periodontitis, osteoporosis, diabetes etc^34-36. The Restriction fragment length polymorphism (RFL’S), BsmI, Tru9l, Taql, EcoRV and Apal., may influence the mRNA stability ³⁷.Taql RFLP is associated with periodontitis has been reported ^38-40.

Association between less frequent t allele is associated with early onset periodontitis (aggressive periodontitis) in Caucasians was reported⁴¹. The TT genotype and T allele is associated with chronic periodontitis, in Japanese and Caucasians subjects^39,40. While tt genotype tt allele is associated with early onset of periodontitis in Chinese subjects³⁸. A strong association between Chinese female patients with aggressive periodontitis and Tt genotype was associated³⁶. The tt genotype t allele are associated with decrease bone mineral density and indication of osteoporosis^42,43. The Bsml RFPL in combination with RFPLs are associated with aggressive periodontitis and chronic periodontitis^44,45. An inverse relationship is found between serum 25-hydroxy vitamin D₃ and periodontal disease has been reported⁴⁶. These findings indicate that 1,25,(OH)₂D₃, plays important role in prevention of periodontal disease and hypo-morphic VDR alleles and its reduced levels of 1,25(OH)₂D₃.,associated with periodontitis.

VDR ligands applications

VDR ligands also has therapeutic applications like in treating bone and mineral disorder, periodontitis, cancer, leukemia, infectious disease etc.

In periodontitis when there is insufficient clearance of periodondopathic bacteria and subsequent bone destruction are suggests to cause aggressive periodontitis³⁵. VDR ligands stimulate the innate immunity by inducing anti- microbial peptides and have bone anabolic effects suggesting that VDR ligands can be used in prevention of aggressive periodontitis⁴⁷. A deregulated release of pro-inflammatory cytokines by monocytes/macrophages and lymphocytes is considered to induce chronic periodontitis, since 1,25 (OH)2D3 got immunomodulatory effects, including inhibition of pro-inflammatory cytokine release³⁵.

VDR ligands which are activated, suppress the renin expression and VDR null mice develop cardiovascular diseases such as cardiac hypertrophy and hypertension due to dysregulation of rennin-angiotensin system^48,49. VDR acts as metabolic sensor for secondary bile acids like lithocholic acid and induces the expression of genes involved in the metabolism and excretion of toxic acids hence VDR targeted therapies can be applied to cardio vascular diseases⁵⁰. These findings suggests VDR – therapies can be applied for cardiovascular diseases.

VDR ligands may be used in treatment of chronic periodontitis. It is also found that VDR ligands also used in treating oropharyngeal cancer currently⁴⁷. The adverse effects especially hypercalcemia, limit the clinical application of 1,25(OH)₂D₃ and its derivatives to bone and mineral disorder and psoriasis, combined dosing of 1,25,(OH)D₃ with other drugs is one approach to overcome the adverse effects ,with development of tissues selective or function selective VDR modulator with low calcemic activity provides different approach⁵¹.

CONCLUSION:

Vitamin D has been shown to regulate musculoskeletal health by mediating calcium absorption. There are studies which proves that vitamin D deficiency may place subjects at risk for low mineral bone density or osteoporosis and osteopenia as well as chronic inflammatory diseases. Vitamin D is used to treat rickets and osteomalacia. But in addition it is also used as anti cancer, immune modulator and innate immunity functions .1,25(OH)₂D₃ - VDR plays vital role in oral haemostasis and its dysfunction may cause periodontal disease^52,53. The deficiency also causes bone loss and inflammation which are known symptoms of periodontal disease therefore Vitamin D deficiency is considered as risk factor for periodontitis.

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Received on 02.12.2013 Modified on 09.12.2013

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