Vitamin D and Dental Medicine

*Vitamin D*

reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice. Clinical Cancer activated vitamin D as a means of preventing deep vein thrombosis in renal transplant recipients. Clinical nephrology. 2011 May 1;75(5):440-50.

Apr;7(4):605-10.

2001 Aug;86(S1):S97-103.

endocrinology. 2020 Nov

1;183(5):R133-47.

MedRxiv. 2020 Jan 1.

2020;3(1):106.

Cashman KD, Buttriss JL,

virus/COVID-19 disease. BMJ Nutrition, Prevention & Health.

[146] Lindqvist PG, Epstein E, Olsson H. Does an active sun exposure habit lower the risk of venous thrombotic events? AD-lightful hypothesis. Journal of Thrombosis and Haemostasis. 2009

[147] Brot C, Vestergaard P, Kolthoff N, Gram J, Hermann AP, Sørensen OH. Vitamin D status and its adequacy in healthy Danish perimenopausal women: relationships to dietary intake, sun exposure and serum parathyroid hormone. British Journal of Nutrition.

[148] Bilezikian JP, Bikle D, Hewison M, Lazaretti-Castro M, Formenti AM, Gupta A, Madhavan MV, Nair N, Babalyan V, Hutchings N, Napoli N. Mechanisms in endocrinology: vitamin D and COVID-19. European journal of

[149] Lau FH, Majumder R, Torabi R, Saeg F, Hoffman R, Cirillo JD,

is prevalent in severe COVID-19.

[150] Lanham-New SA, Webb AR,

Fallowfield JL, Masud T, Hewison M, Mathers JC, Kiely M, Welch AA, Ward KA. Vitamin D and SARS-CoV-2

[151] Aslan MT, Aslan İÖ, Özdemir Ö. Letter to the Editor: Is Vitamin D One of the Key Elements in COVID-19 Days? J Nutr Health Aging. 2020;24(9):1038- 1039. doi: 10.1007/s12603-020-1413-5. PMID: 33155635; PMCID: PMC7597430.

Greiffenstein P. Vitamin D insufficiency

Research. 2003 Jun 1;9(6):2350-6.

[139] Holick MF. Vitamin D: its role in cancer prevention and treatment. Progress in biophysics and molecular biology. 2006 Sep 1;92(1):49-59.

[140] Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW, Giovannucci EL. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiology and Prevention Biomarkers. 2004 Sep

[141] John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the NHANES I epidemiologic follow-up study, 1971-1975 to 1992. Cancer Epidemiology and Prevention

Biomarkers. 1999 May 1;8(5):399-406.

[142] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes care.

[143] Martineau AR, Honecker FU, Wilkinson RJ, Griffiths CJ. Vitamin D in

2004 May 1;27(5):1047-53.

the treatment of pulmonary tuberculosis. The Journal of steroid biochemistry and molecular biology.

2007 Mar 1;103(3-5):793-8.

[144] Blondon M, Rodabough RJ, Budrys N, Johnson KC, Berger JS, Shikany JM, Raiesdana A, Heckbert SR, Manson JE, LaCroix AZ, Siscovick D. The Effect of Calcium plus vitamin D supplementation on the risk of venous thromboembolism in the Women's Health Initiative Randomized Controlled Trial. Thrombosis and haemostasis. 2015 May;113(5):999.

[145] Moscarelli L, Zanazzi M, Bertoni E,

Annunziata F, Paudice N, Salvadori M. Renin angiotensin system blockade and

Caroti L, Rosso G, Farsetti S,

1;13(9):1502-8.

**106**

**109**

infants [1].

**Chapter 7**

**Abstract**

**1. Introduction**

for both adults and children [1].

Vitamin D and Dentistry

agent, is said to lessen the incidence of caries and periodontitis.

**Keywords:** Vitamin D, periodontitis, gingivitis, caries

Vitamin D deficiency is a pandemic issue due to decreased vitamin D intake from food and lessened sunlight exposure. Attention is drawn to vitamin D and its role learned in notable clinical disorders such as diabetes, cardiovascular disease and cancers including oral ones. Vitamin D is also very effective along with minerals in the protection of oral health. Vitamin D helps maintain the calcium-phosphate balance and contributes to the shaping of the bone. It is reported that with sufficient vitamin D level, the onset and progression of caries in the tooth structure can be stopped, the formation of caries can be reduced and enamel loss can be prevented. Vitamin D also affects the disease and health conditions of the periodontium. Anti-inflammatory and immunomodulatory functions have a role in the pathogenesis of periodontal disorders. It can reduce bone resorption and suppress the inflammatory outcome related to periodontal diseases by increasing mineral density. Vitamin D has been linked with tooth decay, gingivitis, and tooth loss. Vitamin D, in particular, as a promising oral health-protective

Vitamin D deficiency (**VDD**) owing to significant sunlight decrease in today's conditions and the use of sunscreens that increase in both summer and winter months is considered as a pandemic issue [1–3]. The amount of vitamin D (**vitD**) intake from food is very low. This amount cannot meet the daily vitD requirement

Some of the oldest phytoplankton in the world (species that have existed for more than 750 years) have been reported to produce vitD when exposed to sun exposure. Among the species existing in the world, all species containing vertebrae need the sun for their vitD production [1]. The definition of rickets, which showed devastating bone deformities in children lack of sunlight, was made by Sniadecki in 1822. After approximately 100 years later, The US government had arranged an organization to explain and provide recommendations to parents about the favorable effects of sunlight exposure in order to prevent this disease. In those years, fortification of milk by adding vitD has been found to be quite effective in preventing rickets in the USA. However, they continued to supplement vitD into milk that expired due to the shortage in milk supply after the Second World War in Great Britain. The reason for this, they thought that the vitD added to the milk had extended the shelf life of the milk. Subsequently, vitD supplementation was banned in dairy products in Europe as a result of increasing hypercalcemia cases in

*Elif Gül Aydın and Öner Özdemir*

## **Chapter 7** Vitamin D and Dentistry

*Elif Gül Aydın and Öner Özdemir*

#### **Abstract**

Vitamin D deficiency is a pandemic issue due to decreased vitamin D intake from food and lessened sunlight exposure. Attention is drawn to vitamin D and its role learned in notable clinical disorders such as diabetes, cardiovascular disease and cancers including oral ones. Vitamin D is also very effective along with minerals in the protection of oral health. Vitamin D helps maintain the calcium-phosphate balance and contributes to the shaping of the bone. It is reported that with sufficient vitamin D level, the onset and progression of caries in the tooth structure can be stopped, the formation of caries can be reduced and enamel loss can be prevented. Vitamin D also affects the disease and health conditions of the periodontium. Anti-inflammatory and immunomodulatory functions have a role in the pathogenesis of periodontal disorders. It can reduce bone resorption and suppress the inflammatory outcome related to periodontal diseases by increasing mineral density. Vitamin D has been linked with tooth decay, gingivitis, and tooth loss. Vitamin D, in particular, as a promising oral health-protective agent, is said to lessen the incidence of caries and periodontitis.

**Keywords:** Vitamin D, periodontitis, gingivitis, caries

#### **1. Introduction**

Vitamin D deficiency (**VDD**) owing to significant sunlight decrease in today's conditions and the use of sunscreens that increase in both summer and winter months is considered as a pandemic issue [1–3]. The amount of vitamin D (**vitD**) intake from food is very low. This amount cannot meet the daily vitD requirement for both adults and children [1].

Some of the oldest phytoplankton in the world (species that have existed for more than 750 years) have been reported to produce vitD when exposed to sun exposure. Among the species existing in the world, all species containing vertebrae need the sun for their vitD production [1]. The definition of rickets, which showed devastating bone deformities in children lack of sunlight, was made by Sniadecki in 1822. After approximately 100 years later, The US government had arranged an organization to explain and provide recommendations to parents about the favorable effects of sunlight exposure in order to prevent this disease. In those years, fortification of milk by adding vitD has been found to be quite effective in preventing rickets in the USA. However, they continued to supplement vitD into milk that expired due to the shortage in milk supply after the Second World War in Great Britain. The reason for this, they thought that the vitD added to the milk had extended the shelf life of the milk. Subsequently, vitD supplementation was banned in dairy products in Europe as a result of increasing hypercalcemia cases in infants [1].

It is recognized that vitD levels in serum begin to decrease with age. The reason for this is explained as the decline in endogenous vitD synthesis and the surge in the time spent indoors due to the limitation of physical activity [2, 4].

#### **2. Sources of vitamin D**

The key source of vitD is the sunlight, and the level of 25-hydroxy vitD (25 (OH) D) in serum varies depending on the seasonal change of sunlight. Fatty fish like salmon, mackerel and herring, and fats from fish, containing cod liver oil, are among the rare foods that naturally comprise vitD. Milk, some juice products, some bread, yogurts and cheeses are supplied with vitD in the US. Furthermore, commercially available multivitamin preparations contain varying amounts of vitD and are offered for daily use to individuals [1, 2].

#### **3. Synthesis of vitamin D**

One of the fat-soluble secosteroids recognized as vitD is in control of the increased absorption of phosphate, magnesium and calcium in the gut. In humans, vitD3 (defined as cholecalciferol) and vitD2 (named as ergocalciferol) are identified as the most significant elements in this group. There are two varied ways of obtaining vitD: dietary and non-dietary substance by exposure to sunlight [1, 4].

Ultraviolet (**UV**)- B rays regulate vitD synthesis. Initially, pro- vitD 3 is formed by converting cholesterol to 7- dehydrocholesterol in the intestinal epithelium by oxidation. Then, it is transformed into pro- vitD 3 and transferred to the skin and pre- vitD 3 is produced by UV rays at wavelengths of 270 to 300 nm. The pre- vitD 3 isomerizes to vitD 3 and cholecalciferol in the heat-dependent reaction. Activation of vitD 3 occurs by two hydroxylations and 1α, 25-dihydroxy vitD 3 (calcitriol, the biologically active type of vitD) is formed [5].

#### **4. The effects of VDD on musculoseletal system**

Vitamins are organic compounds that play a role in basic metabolic reactions in our body. Serious problems can occur in the deficiencies of vitamins, since the mechanisms of basic metabolic events will be disrupted.

The serum level required for vitD (25 (OH) D) to be identified as deficient is 50 nmol/L or 20 ng/mL. Concentrations of 25 (OH) D between 51 and 74 nmol/L or 21–29 ng/mL are considered insufficient, while levels of 80 nmol/L or 30 ng/mL are thought to be sufficient [1, 6]. It is presumed that children require the same doses as adults. It is stated that vitD toxicity will not occur until 25 (OH) D levels reach up to 375 nmol/L or 150 ng/mL [1, 4].

The most lately reported recommendations for vitD consumption are 200 IU/ day for children and adults up to the age of 50, 400 IU/day for 50–70 years, and 600 IU/day afterward. The increase in recommendations with age is a clear reflection of the fact that the efficiency of this synthesis decreases with age, although cutaneous synthesis appears to happen in most individuals [4].

Vitamin D has a vital biological role in the human body and helps continue normal growth and mineralization of bone and other calcified tissues, including teeth [2]. Vitamin D deficiency will result in growth delay and the characteristic signs and symptoms of rickets in children. In adults, VDD will accelerate and aggravate both osteopenia and osteoporosis and amplify the risk of fractures of bones. Muscle

**111**

the risk of caries.

*Vitamin D and Dentistry*

recurrence [5].

progression [5].

*DOI: http://dx.doi.org/10.5772/intechopen.98471*

weakness has long been thought to be related with VDD. Vitamin D receptor (VDR) s are available in skeletal muscle, and VDD has been linked with proximal muscle weakness, enhanced body sway, and an augmented risk of falling. Vitamin D

Vitamin D and VDR have increasing importance in recent years as they produce an important role in calcium and phosphorus metabolism as well as homeostasis. Furthermore, attention is drawn to vitD and VDR's role learnt in notable clinical

Oral cancer is defined as malignant neoplasia that occurs in the lips or oral cavity. Oral squamous cell carcinomas (OSCC) are important types consisting of more than 90% of all oral cancers [8]. In recent years, OSCC has generally been observed at increasing rates around the world. Widespread studies on the main risk factors for the development of oral cancers indicate that alcohol consumption and tobacco use increase the risk of oral cancer by 80%. Oral infection due to human papilloma virus (HPV) is defined as another important risk factor for oral infection, pharyngeal and oral cancers [9]. Eliminating significant risk factors, even after diagnosis of oral cancer, can improve prognosis and reduce the risk of

OSCC growth is a multi-step progress that affects vital cellular pathways implicated in tumor development and growth. Various exogenous and endogenous incitements have been shown to lead to multifaceted molecular changes that contribute to cancer development. The anti-neoplastic activity of vitD (calcitriol) has been demonstrated in in vitro and in vivo studies in a wide variety of cancerassociated defects, containing head and neck cancer, and particularly in OSCC [10]. Also, it has the capacity to affect cytostatic chemotherapy and augment apoptosis induction in OSCC cells. Examination of the association between serum vitD level and VDR seems appropriate to guide supportive therapy for patients with precancerous lesions and OSCC [5]. Although the anticancer influences of vitD have been demonstrated by various in vitro and in vivo studies, new data suggests that these influences are controlled by some other elements. Further studies are needed to assess the effects of the vitD system (both ligand and receptor) on the growth of oral cancer and the potential benefits of improving VDD on tumor growth and

A balanced and good diet is necessary and essential for maintaining general body health as well as improving oral health [6]. While the importance of vitamins in general health has been highly researched and developed, their relationship with oral and dental health has not been fully elucidated. Vitamins act as a catalyzer for basic metabolic events in the body that are essential for growth, development,

Minerals such as magnesium, calcium, and phosphorus, the basic structural components of the tooth, should be taken in sufficient levels with the diet. These minerals play a role by interacting with vitamins in strengthening the tooth structure. Especially vitD is related with calcium, magnesium, and zinc [6]. Several possible mechanisms have been suggested to clarify the role of vitD in decreasing

deficiency can also end up with skeletal mineralization disorder [1].

disorders such as diabetes, cardiovascular disease and cancer [5, 7].

**5. The effect of vitamin D and VDR in oral cancer**

**6. Vitamin D relation of oral and dental health**

energy, and cell maintenance [11].

#### *Vitamin D and Dentistry DOI: http://dx.doi.org/10.5772/intechopen.98471*

*Vitamin D*

**2. Sources of vitamin D**

**3. Synthesis of vitamin D**

are offered for daily use to individuals [1, 2].

biologically active type of vitD) is formed [5].

375 nmol/L or 150 ng/mL [1, 4].

**4. The effects of VDD on musculoseletal system**

mechanisms of basic metabolic events will be disrupted.

cutaneous synthesis appears to happen in most individuals [4].

It is recognized that vitD levels in serum begin to decrease with age. The reason for this is explained as the decline in endogenous vitD synthesis and the surge in the

The key source of vitD is the sunlight, and the level of 25-hydroxy vitD (25 (OH) D) in serum varies depending on the seasonal change of sunlight. Fatty fish like salmon, mackerel and herring, and fats from fish, containing cod liver oil, are among the rare foods that naturally comprise vitD. Milk, some juice products, some bread, yogurts and cheeses are supplied with vitD in the US. Furthermore, commercially available multivitamin preparations contain varying amounts of vitD and

One of the fat-soluble secosteroids recognized as vitD is in control of the increased absorption of phosphate, magnesium and calcium in the gut. In humans, vitD3 (defined as cholecalciferol) and vitD2 (named as ergocalciferol) are identified as the most significant elements in this group. There are two varied ways of obtaining vitD: dietary and non-dietary substance by exposure to sunlight [1, 4]. Ultraviolet (**UV**)- B rays regulate vitD synthesis. Initially, pro- vitD 3 is formed by converting cholesterol to 7- dehydrocholesterol in the intestinal epithelium by oxidation. Then, it is transformed into pro- vitD 3 and transferred to the skin and pre- vitD 3 is produced by UV rays at wavelengths of 270 to 300 nm. The pre- vitD 3 isomerizes to vitD 3 and cholecalciferol in the heat-dependent reaction. Activation of vitD 3 occurs by two hydroxylations and 1α, 25-dihydroxy vitD 3 (calcitriol, the

Vitamins are organic compounds that play a role in basic metabolic reactions in our body. Serious problems can occur in the deficiencies of vitamins, since the

The serum level required for vitD (25 (OH) D) to be identified as deficient is 50 nmol/L or 20 ng/mL. Concentrations of 25 (OH) D between 51 and 74 nmol/L or 21–29 ng/mL are considered insufficient, while levels of 80 nmol/L or 30 ng/mL are thought to be sufficient [1, 6]. It is presumed that children require the same doses as adults. It is stated that vitD toxicity will not occur until 25 (OH) D levels reach up to

The most lately reported recommendations for vitD consumption are 200 IU/ day for children and adults up to the age of 50, 400 IU/day for 50–70 years, and 600 IU/day afterward. The increase in recommendations with age is a clear reflection of the fact that the efficiency of this synthesis decreases with age, although

Vitamin D has a vital biological role in the human body and helps continue normal growth and mineralization of bone and other calcified tissues, including teeth [2]. Vitamin D deficiency will result in growth delay and the characteristic signs and symptoms of rickets in children. In adults, VDD will accelerate and aggravate both osteopenia and osteoporosis and amplify the risk of fractures of bones. Muscle

time spent indoors due to the limitation of physical activity [2, 4].

**110**

weakness has long been thought to be related with VDD. Vitamin D receptor (VDR) s are available in skeletal muscle, and VDD has been linked with proximal muscle weakness, enhanced body sway, and an augmented risk of falling. Vitamin D deficiency can also end up with skeletal mineralization disorder [1].

Vitamin D and VDR have increasing importance in recent years as they produce an important role in calcium and phosphorus metabolism as well as homeostasis. Furthermore, attention is drawn to vitD and VDR's role learnt in notable clinical disorders such as diabetes, cardiovascular disease and cancer [5, 7].

#### **5. The effect of vitamin D and VDR in oral cancer**

Oral cancer is defined as malignant neoplasia that occurs in the lips or oral cavity. Oral squamous cell carcinomas (OSCC) are important types consisting of more than 90% of all oral cancers [8]. In recent years, OSCC has generally been observed at increasing rates around the world. Widespread studies on the main risk factors for the development of oral cancers indicate that alcohol consumption and tobacco use increase the risk of oral cancer by 80%. Oral infection due to human papilloma virus (HPV) is defined as another important risk factor for oral infection, pharyngeal and oral cancers [9]. Eliminating significant risk factors, even after diagnosis of oral cancer, can improve prognosis and reduce the risk of recurrence [5].

OSCC growth is a multi-step progress that affects vital cellular pathways implicated in tumor development and growth. Various exogenous and endogenous incitements have been shown to lead to multifaceted molecular changes that contribute to cancer development. The anti-neoplastic activity of vitD (calcitriol) has been demonstrated in in vitro and in vivo studies in a wide variety of cancerassociated defects, containing head and neck cancer, and particularly in OSCC [10]. Also, it has the capacity to affect cytostatic chemotherapy and augment apoptosis induction in OSCC cells. Examination of the association between serum vitD level and VDR seems appropriate to guide supportive therapy for patients with precancerous lesions and OSCC [5]. Although the anticancer influences of vitD have been demonstrated by various in vitro and in vivo studies, new data suggests that these influences are controlled by some other elements. Further studies are needed to assess the effects of the vitD system (both ligand and receptor) on the growth of oral cancer and the potential benefits of improving VDD on tumor growth and progression [5].

#### **6. Vitamin D relation of oral and dental health**

A balanced and good diet is necessary and essential for maintaining general body health as well as improving oral health [6]. While the importance of vitamins in general health has been highly researched and developed, their relationship with oral and dental health has not been fully elucidated. Vitamins act as a catalyzer for basic metabolic events in the body that are essential for growth, development, energy, and cell maintenance [11].

Minerals such as magnesium, calcium, and phosphorus, the basic structural components of the tooth, should be taken in sufficient levels with the diet. These minerals play a role by interacting with vitamins in strengthening the tooth structure. Especially vitD is related with calcium, magnesium, and zinc [6]. Several possible mechanisms have been suggested to clarify the role of vitD in decreasing the risk of caries.

One of these mechanisms is the regulation of serum calcium, phosphate and parathyroid hormone, which are necessary for the formation, calcification, mineralization and protection of teeth. Calcium and phosphate homeostasis is necessary for the formation, calcification, mineralization and maintenance of oral bone and teeth, as well as bone and hard tissue. Enamel and dentin defects- hypoplasia have been linked with hypocalcemia and hypophosphatemia [2, 7].

Dental caries and VDD affect children around the world. In children who had a VDD, changes in both enamel and dentin are observed. Therefore, vitD has a significant role in the formation of oral hard tissue, comprising tooth enamel and dentin, and affects primary teeth development [2].

Vitamin D has a significant role in odontogenesis [2, 12]. The mechanism by which vitD excites the mineralization of tooth enamel involves binding to VDR expressed in both tooth and bone cells. Vitamin D receptors direct the transcription of several target genes, most expressed by ameloblasts and odontoblasts [2, 7, 13]. VDR stimulates the formation of structural gene products in dentin, together with calcium-binding proteins and diverse extracellular matrix proteins. The gene encoding VDR is positioned on chromosome 12q13.11 and comprising several polymorphisms [14]. The VDR gene adjusts the biological role of major vitD metabolites, thus having a key role in the configuration of teeth, particularly in the mineralization of dentin and enamel. Consequently, enamel developmental deficiencies e.g., enamel hypoplasia, can take place in consequence of VDD. It was decided that vitD and VDR at the molecular level influence the tooth germ formation; supplies to the regulation of enamel and dentin structure and maturation; and organizes the phases of dental crown growth [2, 6].

Moreover, vitD adjusts and adapts both the innate and adaptive immune system. The immunological role of vitD is stimulation of the arrangement of some antimicrobial peptides, e.g. defensins and cathelicidin (LL-37), which defend against many pathogens, counting oral bacteria [2, 15]. Cathelicidin (LL-37 or hCAP-18) is controlled by vitD, which has both anti-endotoxin and antimicrobial properties [3].

In mineral deficiencies due to absorption disorders, increased tendency to bleeding, bone resorption, and early tooth loss occur [6]. The chewing process ensures that the person receives the highest possible amount of nutrients, and the number and distribution of teeth affect chewing efficiency. Since diet selection and nutritional status are affected in early tooth loss, deficiency occurs in the intake of vitamins, that is, the two situations create a synergistic effect on each other. During the development of the tooth, the hard tissues of the tooth are strongly affected by nutritional status and thus vitamin deficiency. It is stated that there is a positive correlation between malnutrition and enamel hypoplasia and caries in the primary dentition period in children [11]. In addition, deficiencies of these minerals cause delayed tooth eruption, bleeding gums, destruction patterns in alveolar bone, periodontal disease, enamel or dentin hypoplasia [6, 11].

Vitamin D is also very effective along with minerals in the protection of oral health. Vitamin D helps maintain the calcium-phosphate balance and contributes to the shaping of the bone. It also has important functions by showing anti-inflammatory effects. It is reported that with sufficient vitD level, the onset and progression of caries in the tooth structure can be stopped, the formation of caries can be reduced and enamel loss can be prevented [2, 6, 16].

In the formation of tooth decay, the acid that is produced by bacterial fermentation of the residues on the tooth surface that are not brushed after eating sugary foods lowers the pH below 7 and plays a role in the destruction of the tooth hard tissues. However, it has been recently revealed that dental caries can be reduced with UV- B rays and vitD supplements. Considering the helpful effects of vitD on dental caries, it is thought to be effective in reducing the overall prevalence, especially in

**113**

density [6, 11].

*Vitamin D and Dentistry*

*DOI: http://dx.doi.org/10.5772/intechopen.98471*

effect on individual's overall health [2, 17].

hypoplasia in children [2, 11, 18].

deciduous teeth [2, 11].

and ECC [2, 11, 18].

obtain orthodontic treatment [6].

**7. Vitamin D and periodontal health**

children at risk of early caries [2, 6]. Early childhood caries (**ECC**) were described as the presence of one or more caries, missing (due to caries) or filled (DMFT: decay, missing, filled) tooth surface in any primary teeth in young children under six years old, is one of the most common chronic diseases and can have adverse

Early childhood caries affect the nutritional status and general health of the child. It is stated that children with ECC may have malnutrition, iron deficiency anemia and VDD [2, 16]. When the relationship between vitD intake and caries is evaluated, it is determined that the incidence of tooth decay is higher in children with low vitD or children of mothers with low vitD during pregnancy. There is an association between vitD levels in early childhood (up to 8 years old) and DMFT scores. When serum vitD concentrations are more than 50 nmol in early adolescents (10–11 years) considerably less caries is detected in permanent first molars has been found. Similarly, in children aged 6 to 17 years, they found a 0.66 decrease in DMFT for every 10 ng/ml of serum vitD level increase. In general, malnutrition and shortage in vitamin intake due to malnutrition augments the incidence of enamel

Vitamin D use may have a role in the protection of caries early in life. It is thought to be a promising caries prevention agent, given that vitD supplementation is connected with a 47% reduction in caries in children according to meta-analysis studies [16]. Vitamin D deficiency during pregnancy (a vital period for tooth growth) is related with developmental defects; especially enamel hypoplasia and caries susceptibility. Also, vitD intake during pregnancy diminishes the risk of enamel defects and hypoplasia in babies and is associated with better eruption of

Improving vitD levels in children from an early stage of life appears to be an important task. This requires awareness from pregnancy. Pregnant women should have their vitD levels tested routinely during the first trimester of pregnancy and the risk of VDD, VDD and vitD ingestion should be evaluated. Prenatal vitD levels appear to influence the development of primary dentition

Vitamin D is an essential hormone for the absorption of calcium, magnesium and phosphorus from the intestine, which is necessary for the appropriate mineralization of bones and teeth. In addition, covering the surfaces of the implants with vitD during implant application, which is one of the dental procedures, increases osteointegration. Moreover, applying vitD3 intraperitoneally speeds up orthodontic tooth movement, and even patients receiving vitD and bisphosphonate therapy can

Vitamin D also affects the disease and health conditions of the periodontium. Anti-inflammatory and immunomodulatory functions have a role in the pathogenesis of periodontal disorders [3]. It can reduce bone resorption and suppress the inflammatory outcome related to periodontal diseases by increasing mineral

There is a positive correlation between increased mineral density and decreased bone resorption in the mandibular bone and taking vitD and calcium and magnesium supplements. It is also reported that loss of attachment level is associated with decreased serum vitD levels. It is stated that in individuals with sufficient vitD, periodontal tissues are healthier, and accordingly, gingivitis formation, bleeding

during probing, attachment, bone and tooth loss are reduced [11].

#### *Vitamin D and Dentistry DOI: http://dx.doi.org/10.5772/intechopen.98471*

*Vitamin D*

One of these mechanisms is the regulation of serum calcium, phosphate and parathyroid hormone, which are necessary for the formation, calcification, mineralization and protection of teeth. Calcium and phosphate homeostasis is necessary for the formation, calcification, mineralization and maintenance of oral bone and teeth, as well as bone and hard tissue. Enamel and dentin defects- hypoplasia have

Dental caries and VDD affect children around the world. In children who had a VDD, changes in both enamel and dentin are observed. Therefore, vitD has a significant role in the formation of oral hard tissue, comprising tooth enamel and

Vitamin D has a significant role in odontogenesis [2, 12]. The mechanism by which vitD excites the mineralization of tooth enamel involves binding to VDR expressed in both tooth and bone cells. Vitamin D receptors direct the transcription of several target genes, most expressed by ameloblasts and odontoblasts [2, 7, 13]. VDR stimulates the formation of structural gene products in dentin, together with calcium-binding proteins and diverse extracellular matrix proteins. The gene encoding VDR is positioned on chromosome 12q13.11 and comprising several polymorphisms [14]. The VDR gene adjusts the biological role of major vitD metabolites, thus having a key role in the configuration of teeth, particularly in the mineralization of dentin and enamel. Consequently, enamel developmental deficiencies e.g., enamel hypoplasia, can take place in consequence of VDD. It was decided that vitD and VDR at the molecular level influence the tooth germ formation; supplies to the regulation of enamel and dentin structure and maturation; and

Moreover, vitD adjusts and adapts both the innate and adaptive immune system.

The immunological role of vitD is stimulation of the arrangement of some antimicrobial peptides, e.g. defensins and cathelicidin (LL-37), which defend against many pathogens, counting oral bacteria [2, 15]. Cathelicidin (LL-37 or hCAP-18) is controlled by vitD, which has both anti-endotoxin and antimicrobial properties [3]. In mineral deficiencies due to absorption disorders, increased tendency to bleeding, bone resorption, and early tooth loss occur [6]. The chewing process ensures that the person receives the highest possible amount of nutrients, and the number and distribution of teeth affect chewing efficiency. Since diet selection and nutritional status are affected in early tooth loss, deficiency occurs in the intake of vitamins, that is, the two situations create a synergistic effect on each other. During the development of the tooth, the hard tissues of the tooth are strongly affected by nutritional status and thus vitamin deficiency. It is stated that there is a positive correlation between malnutrition and enamel hypoplasia and caries in the primary dentition period in children [11]. In addition, deficiencies of these minerals cause delayed tooth eruption, bleeding gums, destruction patterns in alveolar bone,

Vitamin D is also very effective along with minerals in the protection of oral health. Vitamin D helps maintain the calcium-phosphate balance and contributes to the shaping of the bone. It also has important functions by showing anti-inflammatory effects. It is reported that with sufficient vitD level, the onset and progression of caries in the tooth structure can be stopped, the formation of caries can be

In the formation of tooth decay, the acid that is produced by bacterial fermentation of the residues on the tooth surface that are not brushed after eating sugary foods lowers the pH below 7 and plays a role in the destruction of the tooth hard tissues. However, it has been recently revealed that dental caries can be reduced with UV- B rays and vitD supplements. Considering the helpful effects of vitD on dental caries, it is thought to be effective in reducing the overall prevalence, especially in

been linked with hypocalcemia and hypophosphatemia [2, 7].

dentin, and affects primary teeth development [2].

organizes the phases of dental crown growth [2, 6].

periodontal disease, enamel or dentin hypoplasia [6, 11].

reduced and enamel loss can be prevented [2, 6, 16].

**112**

children at risk of early caries [2, 6]. Early childhood caries (**ECC**) were described as the presence of one or more caries, missing (due to caries) or filled (DMFT: decay, missing, filled) tooth surface in any primary teeth in young children under six years old, is one of the most common chronic diseases and can have adverse effect on individual's overall health [2, 17].

Early childhood caries affect the nutritional status and general health of the child. It is stated that children with ECC may have malnutrition, iron deficiency anemia and VDD [2, 16]. When the relationship between vitD intake and caries is evaluated, it is determined that the incidence of tooth decay is higher in children with low vitD or children of mothers with low vitD during pregnancy. There is an association between vitD levels in early childhood (up to 8 years old) and DMFT scores. When serum vitD concentrations are more than 50 nmol in early adolescents (10–11 years) considerably less caries is detected in permanent first molars has been found. Similarly, in children aged 6 to 17 years, they found a 0.66 decrease in DMFT for every 10 ng/ml of serum vitD level increase. In general, malnutrition and shortage in vitamin intake due to malnutrition augments the incidence of enamel hypoplasia in children [2, 11, 18].

Vitamin D use may have a role in the protection of caries early in life. It is thought to be a promising caries prevention agent, given that vitD supplementation is connected with a 47% reduction in caries in children according to meta-analysis studies [16]. Vitamin D deficiency during pregnancy (a vital period for tooth growth) is related with developmental defects; especially enamel hypoplasia and caries susceptibility. Also, vitD intake during pregnancy diminishes the risk of enamel defects and hypoplasia in babies and is associated with better eruption of deciduous teeth [2, 11].

Improving vitD levels in children from an early stage of life appears to be an important task. This requires awareness from pregnancy. Pregnant women should have their vitD levels tested routinely during the first trimester of pregnancy and the risk of VDD, VDD and vitD ingestion should be evaluated. Prenatal vitD levels appear to influence the development of primary dentition and ECC [2, 11, 18].

Vitamin D is an essential hormone for the absorption of calcium, magnesium and phosphorus from the intestine, which is necessary for the appropriate mineralization of bones and teeth. In addition, covering the surfaces of the implants with vitD during implant application, which is one of the dental procedures, increases osteointegration. Moreover, applying vitD3 intraperitoneally speeds up orthodontic tooth movement, and even patients receiving vitD and bisphosphonate therapy can obtain orthodontic treatment [6].

#### **7. Vitamin D and periodontal health**

Vitamin D also affects the disease and health conditions of the periodontium. Anti-inflammatory and immunomodulatory functions have a role in the pathogenesis of periodontal disorders [3]. It can reduce bone resorption and suppress the inflammatory outcome related to periodontal diseases by increasing mineral density [6, 11].

There is a positive correlation between increased mineral density and decreased bone resorption in the mandibular bone and taking vitD and calcium and magnesium supplements. It is also reported that loss of attachment level is associated with decreased serum vitD levels. It is stated that in individuals with sufficient vitD, periodontal tissues are healthier, and accordingly, gingivitis formation, bleeding during probing, attachment, bone and tooth loss are reduced [11].

In studies conducted on women's level of vitD in their saliva and serum, a statistically significant relationship was found between gingivitis and periodontitis during their life, pregnancy, menopause and postmenopausal periods [19, 20]. The prevalence of periodontal disease was higher in individuals with low vitD levels [11].

Besides these beneficial effects on bone metabolism, it has been found that periodontitis accelerates the healing with its direct antibiotic effect on periodontal pathogens. Vitamin D reduces inflammatory mediators causing periodontal destruction. Having a diet rich in vitD after periodontal surgical procedures contributes to the faster and easier recovery of periodontal tissues. The quality of the host immune response is highly correlated with healthy and proper nutrition. It plays an important role not only in the prevention of periodontal diseases, but also in facilitating the recovery of tissues in the existing periodontal disease conditions. One of the most important functions of vitD in the immune system is that it has a stimulating effect on human cathelicidin (LL-37). LL-37 has both antimicrobial and anti-endotoxin functions. Vitamin D excites cathelicidin in oral epithelial cells and children with high dental caries activity had low LL-37 levels. Many epithelial antimicrobial peptides, including LL-37, have been termed the guardian of the oral cavity and detected to play important roles in oral health. LL-37 also has significant benefits in decreasing the risk of gingivitis. Maternal VDD also increases the DMFT score in children of 12–35 months old. As a result, vitD may be useful in the treatment of periodontitis due to its direct effects on bone metabolism and potential anti-inflammatory effects on periodonto-pathogens [6, 15].

As diet plays a dominant modifier in the development of periodontal disorders, dentists should inform patients on how good diet influences the supporting the formation of teeth, e.g. the significance of ingesting healthy foods rich in magnesium and vitD in thwarting dental caries [6].

There is common agreement on the effects of vitamin deficiencies or supplementation on oral health, but scientific data is still at a level that needs to be investigated. In particular, multivitamin supplements or the mixture of two or more vitamins lead to more bias as it is not likely to determine the single help of each vitamin.

#### **8. Conclusion**

Vitamin D has been linked with tooth decay, gingivitis, and tooth loss. Vitamin D, in particular, as a promising oral health-protective agent, is said to lessen the incidence of caries and periodontitis, leading to a low-precision result. In order to prevent tooth decay, which is a serious public health problem, existing structural defects in teeth (enamel and dentin hypoplasias) and to maintain oral health, the awareness of health care providers should be increased. It seems to be an issue that should not be overlooked, especially from the early stages of life, to control vitD levels for oral health.

**115**

**Author details**

Elif Gül Aydın1

Sakarya, Turkey

Adapazari/Sakarya, Turkey

\* and Öner Özdemir2

\*Address all correspondence to: elifgul36@hotmail.com

provided the original work is properly cited.

1 Department of Pediatric Dentistry, Faculty of Dentistry, Sakarya University,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Pediatrics, Division of Allergy and Immunology, Sakarya University, Faculty of Medicine, Training and Research Hospital, Adapazari/

*Vitamin D and Dentistry*

*DOI: http://dx.doi.org/10.5772/intechopen.98471*

*Vitamin D and Dentistry DOI: http://dx.doi.org/10.5772/intechopen.98471*

*Vitamin D*

levels [11].

In studies conducted on women's level of vitD in their saliva and serum, a statistically significant relationship was found between gingivitis and periodontitis during their life, pregnancy, menopause and postmenopausal periods [19, 20]. The prevalence of periodontal disease was higher in individuals with low vitD

Besides these beneficial effects on bone metabolism, it has been found that periodontitis accelerates the healing with its direct antibiotic effect on periodontal pathogens. Vitamin D reduces inflammatory mediators causing periodontal destruction. Having a diet rich in vitD after periodontal surgical procedures contributes to the faster and easier recovery of periodontal tissues. The quality of the host immune response is highly correlated with healthy and proper nutrition. It plays an important role not only in the prevention of periodontal diseases, but also in facilitating the recovery of tissues in the existing periodontal disease conditions. One of the most important functions of vitD in the immune system is that it has a stimulating effect on human cathelicidin (LL-37). LL-37 has both antimicrobial and anti-endotoxin functions. Vitamin D excites cathelicidin in oral epithelial cells and children with high dental caries activity had low LL-37 levels. Many epithelial antimicrobial peptides, including LL-37, have been termed the guardian of the oral cavity and detected to play important roles in oral health. LL-37 also has significant benefits in decreasing the risk of gingivitis. Maternal VDD also increases the DMFT score in children of 12–35 months old. As a result, vitD may be useful in the treatment of periodontitis due to its direct effects on bone metabolism and potential

As diet plays a dominant modifier in the development of periodontal disorders, dentists should inform patients on how good diet influences the supporting the formation of teeth, e.g. the significance of ingesting healthy foods rich in magnesium

There is common agreement on the effects of vitamin deficiencies or supplementation on oral health, but scientific data is still at a level that needs to be

investigated. In particular, multivitamin supplements or the mixture of two or more vitamins lead to more bias as it is not likely to determine the single help of each

Vitamin D has been linked with tooth decay, gingivitis, and tooth loss. Vitamin D, in particular, as a promising oral health-protective agent, is said to lessen the incidence of caries and periodontitis, leading to a low-precision result. In order to prevent tooth decay, which is a serious public health problem, existing structural defects in teeth (enamel and dentin hypoplasias) and to maintain oral health, the awareness of health care providers should be increased. It seems to be an issue that should not be overlooked, especially from the early stages of life, to

anti-inflammatory effects on periodonto-pathogens [6, 15].

and vitD in thwarting dental caries [6].

control vitD levels for oral health.

**114**

vitamin.

**8. Conclusion**

### **Author details**

Elif Gül Aydın1 \* and Öner Özdemir2

1 Department of Pediatric Dentistry, Faculty of Dentistry, Sakarya University, Adapazari/Sakarya, Turkey

2 Department of Pediatrics, Division of Allergy and Immunology, Sakarya University, Faculty of Medicine, Training and Research Hospital, Adapazari/ Sakarya, Turkey

\*Address all correspondence to: elifgul36@hotmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] HOLICK, Michael F.; CHEN, Tai C. Vitamin D deficiency: a worldwide problem with health consequences. The American journal of clinical nutrition, 2008, 87 (4):1080-1086

[2] ALMOUDI, Manal Mohamed, et al. Dental caries and vitamin D status in children in Asia. Pediatrics International, 2019, 61 (4): 327-338.

[3] MOLLOY, E. J.; MURPHY, N. Vitamin D, Covid-19 and children. Ir Med J, 2020, 113 (4): 64

[4] HEANEY, Robert P. Vitamin D in health and disease. Clinical Journal of the American Society of Nephrology, 2008, 3 (5): 1535-1541

[5] FATHI, Nazanin, et al. Role of vitamin D and vitamin D receptor (VDR) in oral cancer. Biomedicine & Pharmacotherapy, 2019, 109: 391-401

[6] UWITONZE, Anne Marie, et al. Oral manifestations of magnesium and vitamin D inadequacy. The Journal of steroid biochemistry and molecular biology, 2020, 200: 105636.

[7] FATTURI, Aluhê Lopes, et al. The relationship between molar incisor hypomineralization, dental caries, socioeconomic factors, and polymorphisms in the vitamin D receptor gene: a population-based study. Clinical oral investigations, 2020, 24 (11): 3971-3980

[8] Gandini S, Gnagnarella P, Serrano D, Pasquali E, Raimondi S. Vitamin D receptor polymorphisms and cancer. Adv Exp Med Biol. 2014;810:69-105

[9] CHATURVEDI, Anil K. Epidemiology and clinical aspects of HPV in head and neck cancers. Head and neck pathology, 2012, 6 (1): 16-24.

[10] GRIMM, Martin, et al. Serum vitamin D levels of patients with oral squamous cell carcinoma (OSCC) and expression of vitamin D receptor in oral precancerous lesions and OSCC. *Medicina oral, patologia oral y cirugia bucal*, 2015, 20 (2): 188-195.

[11] CAGETTI, Maria Grazia, et al. The role of vitamins in oral health. A systematic review and meta-analysis. International journal of environmental research and public health, 2020, 17 (3): 938.

[12] ZHANG, Xueming, et al. Regulation of enamel and dentin mineralization by vitamin D receptor. In: *Comparative Dental Morphology*. Karger Publishers, 2009. p. 102-109.

[13] BERDAL, A., et al. Ameloblasts and odontoblasts, target-cells for 1, 25-dihydroxyvitamin D3: a review. International Journal of Developmental Biology, 2003, 39 (1): 257-262.

[14] HOLLA, Lydie Izakovicova, et al. Vitamin D receptor TaqI gene polymorphism and dental caries in Czech children. Caries research, 2017, 51 (1): 7-11.

[15] GYLL, Johanna, et al. Vitamin D status and dental caries in healthy Swedish children. Nutrition journal, 2018, 17 (1): 1-10.

[16] HUJOEL, Philippe P. Vitamin D and dental caries in controlled clinical trials: systematic review and meta-analysis. Nutrition reviews, 2013, 71 (2): 88-97.

[17] Pitts NB, Baez RJ, Diaz-Guillory C, Donly KJ, Alberto Feldens C, McGrath C, Phantumvanit P, Seow WK, Sharkov N, Songpaisan Y, Tinanoff N, Twetman S. Early Childhood Caries: IAPD Bangkok Declaration. J Dent Child (Chic). 2019;86(2):72.

[18] SINGLETON, R., et al. Association of maternal vitamin D deficiency with

**117**

*Vitamin D and Dentistry*

(1): 1-8.

1321-1332.

*DOI: http://dx.doi.org/10.5772/intechopen.98471*

early childhood caries. Journal of dental

[19] WOELBER, Johan Peter, et al. An oral health optimized diet can reduce gingival and periodontal inflammation in humans-a randomized controlled pilot study. BMC oral health, 2017, 17

[20] MILLEN, Amy E., et al. Vitamin D status and 5-year changes in periodontal

postmenopausal women: the Buffalo

disease measures among

OsteoPerio Study. Journal of periodontology, 2014, 85 (10):

research, 2019, 98 (5): 549-555.

*Vitamin D and Dentistry DOI: http://dx.doi.org/10.5772/intechopen.98471*

early childhood caries. Journal of dental research, 2019, 98 (5): 549-555.

[19] WOELBER, Johan Peter, et al. An oral health optimized diet can reduce gingival and periodontal inflammation in humans-a randomized controlled pilot study. BMC oral health, 2017, 17 (1): 1-8.

[20] MILLEN, Amy E., et al. Vitamin D status and 5-year changes in periodontal disease measures among postmenopausal women: the Buffalo OsteoPerio Study. Journal of periodontology, 2014, 85 (10): 1321-1332.

**116**

3971-3980

*Vitamin D*

**References**

[1] HOLICK, Michael F.; CHEN, Tai C. Vitamin D deficiency: a worldwide problem with health consequences. The American journal of clinical nutrition,

squamous cell carcinoma (OSCC) and expression of vitamin D receptor in oral

[11] CAGETTI, Maria Grazia, et al. The role of vitamins in oral health. A systematic review and meta-analysis. International journal of environmental research and public health, 2020, 17

[12] ZHANG, Xueming, et al. Regulation of enamel and dentin mineralization by vitamin D receptor. In: *Comparative Dental Morphology*. Karger Publishers,

[13] BERDAL, A., et al. Ameloblasts and

[14] HOLLA, Lydie Izakovicova, et al.

[15] GYLL, Johanna, et al. Vitamin D status and dental caries in healthy Swedish children. Nutrition journal,

[16] HUJOEL, Philippe P. Vitamin D and dental caries in controlled clinical trials: systematic review and meta-analysis. Nutrition reviews, 2013, 71 (2): 88-97.

[17] Pitts NB, Baez RJ, Diaz-Guillory C,

McGrath C, Phantumvanit P, Seow WK, Sharkov N, Songpaisan Y, Tinanoff N, Twetman S. Early Childhood Caries: IAPD Bangkok Declaration. J Dent Child (Chic). 2019;86(2):72.

[18] SINGLETON, R., et al. Association of maternal vitamin D deficiency with

Donly KJ, Alberto Feldens C,

odontoblasts, target-cells for 1, 25-dihydroxyvitamin D3: a review. International Journal of Developmental

Biology, 2003, 39 (1): 257-262.

Vitamin D receptor TaqI gene polymorphism and dental caries in Czech children. Caries research, 2017, 51

precancerous lesions and OSCC. *Medicina oral, patologia oral y cirugia* 

*bucal*, 2015, 20 (2): 188-195.

(3): 938.

(1): 7-11.

2018, 17 (1): 1-10.

2009. p. 102-109.

[2] ALMOUDI, Manal Mohamed, et al. Dental caries and vitamin D status in

International, 2019, 61 (4): 327-338.

[4] HEANEY, Robert P. Vitamin D in health and disease. Clinical Journal of the American Society of Nephrology,

[5] FATHI, Nazanin, et al. Role of vitamin D and vitamin D receptor (VDR) in oral cancer. Biomedicine & Pharmacotherapy, 2019, 109: 391-401

biology, 2020, 200: 105636.

[9] CHATURVEDI, Anil K.

[7] FATTURI, Aluhê Lopes, et al. The relationship between molar incisor hypomineralization, dental caries, socioeconomic factors, and

polymorphisms in the vitamin D receptor gene: a population-based study. Clinical oral investigations, 2020, 24 (11):

[8] Gandini S, Gnagnarella P, Serrano D, Pasquali E, Raimondi S. Vitamin D receptor polymorphisms and cancer. Adv Exp Med Biol. 2014;810:69-105

Epidemiology and clinical aspects of HPV in head and neck cancers. Head and neck pathology, 2012, 6 (1): 16-24.

[10] GRIMM, Martin, et al. Serum vitamin D levels of patients with oral

[6] UWITONZE, Anne Marie, et al. Oral manifestations of magnesium and vitamin D inadequacy. The Journal of steroid biochemistry and molecular

[3] MOLLOY, E. J.; MURPHY, N. Vitamin D, Covid-19 and children. Ir

2008, 87 (4):1080-1086

children in Asia. Pediatrics

Med J, 2020, 113 (4): 64

2008, 3 (5): 1535-1541

**119**

**Chapter 8**

**Abstract**

*Egle Jagelaviciene*

bone mineral density

**1. Introduction**

The Importance of Vitamin D for

There are many causes of vitamin D deficiency, which determines pathogenesis of many diseases, including periodontal ones. Constant low uptake or deficiency of vitamin D results in progression of periodontal diseases and jaw bone metabolism leads to change of bone mineral density, causes resorption in alveolar bone, tooth loss, changes of masticatory function and osteoporosis. The clinical studies strive to link vitamin D with gingivitis and periodontitis and prove its therapeutic and preventive role, because of vitamin D immunomodulatory, anti-inflammatory and antiproliferative effects for periodontal tissues and best treatment outcome. The purpose of this chapter is to analyze the importance of vitamin D on the pathogenesis of periodontal diseases, its role on regulation of the immune system and defense mechanism, influence on jawbone quality and on the correlation between

Periodontal Tissues

vitamin D concentration in plasma and periodontal diseases.

**Keywords:** vitamin D, vitamin D deficiency, periodontal disease, jawbone,

One billion people on the planet were diagnosed with vitamin D deficiency during the last decade [1]. Opinion, advocating important role of vitamin D and its deficiency in significant number of individuals, prevails within the society, a lot of information is available regarding its use, doses, sources, etc. However, each individual may have different vitamin D needs and the consumption of it should be monitored by testing individual serum levels of D2 (of alimentary origin) and D3 (synthesized in the skin), thus evaluating total level of vitamin D [2]. There are many causes of vitamin D deficiency, which is finally diagnosed if serum level of 25OHD3 is less than 20 ng/mL [3, 4]. This determines pathogenesis of many diseases, including periodontal ones, resulting in loss of masticatory function.

Periodontium (PT) consists of gingiva, periodontal ligament, cementum and alveolar bone. This is functional unit, maintaining homeostasis – the connection between tooth and gingiva makes up a unified whole, preventing penetration of microorganisms, chemical substances, capable to induce inflammation of periodontal tissues (PTs). The periodontal ligament and bone keep tooth inside the alveolar socket, distribute mechanical load of mastication. PT has its own blood supply, neural regulation and defensive mechanisms. Soft and mineralized dental plaque is initiative risk factor of periodontal diseases (PD) – bacterial biofilm and its adhesion to tooth surface induces response of PTs, but in general, diseases are caused by many predisposing factors. PD initially manifest as gingivitis, which, if untreated, spreads

#### **Chapter 8**

## The Importance of Vitamin D for Periodontal Tissues

*Egle Jagelaviciene*

#### **Abstract**

There are many causes of vitamin D deficiency, which determines pathogenesis of many diseases, including periodontal ones. Constant low uptake or deficiency of vitamin D results in progression of periodontal diseases and jaw bone metabolism leads to change of bone mineral density, causes resorption in alveolar bone, tooth loss, changes of masticatory function and osteoporosis. The clinical studies strive to link vitamin D with gingivitis and periodontitis and prove its therapeutic and preventive role, because of vitamin D immunomodulatory, anti-inflammatory and antiproliferative effects for periodontal tissues and best treatment outcome. The purpose of this chapter is to analyze the importance of vitamin D on the pathogenesis of periodontal diseases, its role on regulation of the immune system and defense mechanism, influence on jawbone quality and on the correlation between vitamin D concentration in plasma and periodontal diseases.

**Keywords:** vitamin D, vitamin D deficiency, periodontal disease, jawbone, bone mineral density

#### **1. Introduction**

One billion people on the planet were diagnosed with vitamin D deficiency during the last decade [1]. Opinion, advocating important role of vitamin D and its deficiency in significant number of individuals, prevails within the society, a lot of information is available regarding its use, doses, sources, etc. However, each individual may have different vitamin D needs and the consumption of it should be monitored by testing individual serum levels of D2 (of alimentary origin) and D3 (synthesized in the skin), thus evaluating total level of vitamin D [2]. There are many causes of vitamin D deficiency, which is finally diagnosed if serum level of 25OHD3 is less than 20 ng/mL [3, 4]. This determines pathogenesis of many diseases, including periodontal ones, resulting in loss of masticatory function.

Periodontium (PT) consists of gingiva, periodontal ligament, cementum and alveolar bone. This is functional unit, maintaining homeostasis – the connection between tooth and gingiva makes up a unified whole, preventing penetration of microorganisms, chemical substances, capable to induce inflammation of periodontal tissues (PTs). The periodontal ligament and bone keep tooth inside the alveolar socket, distribute mechanical load of mastication. PT has its own blood supply, neural regulation and defensive mechanisms. Soft and mineralized dental plaque is initiative risk factor of periodontal diseases (PD) – bacterial biofilm and its adhesion to tooth surface induces response of PTs, but in general, diseases are caused by many predisposing factors. PD initially manifest as gingivitis, which, if untreated, spreads

deeper within PT: causing attachment loss, periodontal pocket formation, alveolar bone resorption and tooth loss over time [5, 6]. Increasing number of studies proves importance of vitamin D in prevention and management of oral diseases [7]. Clinical studies strive to link vitamin D with PD and prove its therapeutic and preventive role. Vitamin D is secosteroidal hormone, playing important role in the treatment of gingivitis and periodontitis because of its anti-inflammatory and antibacterial effect on PTs as well as its immunomodulatory, differentiating, anti-proliferative and regulative effect on autoimmune processes, cellular apoptosis and participation in bone metabolism [3, 7–10]. Disintegration and renewal processes of bone depend on metabolism, as constant interchange of mineral substances between bone and blood plasma, where an active form of vitamin D is circulating, takes place [11]. One of the main functions of vitamin D is maintaining of blood levels of calcium and phosphorus by regulating absorption of these substances inside the bowels and reabsorption in kidneys and by enhancing remodeling processes [12, 13]. Bone is like a living and continuously changing organ where resorption and regeneration, i.e. remodelation, take place [14]. For this reason, the old bone is not accumulating and adaptation to changing mechanical forces develops. Jawbone support the teeth in alveolar sockets, skeletal bones protect internal organs and acts as depot of mineral substances especially calcium (also is necessary for normal muscle function) [15]. Osteoporotic (OP) changes of skeletal bones occur because of impaired mineralization due to long term decreased uptake of vitamin D and calcium, increasing risk of fractures, accelerated jawbone resorption causes adentia [16, 17].

#### **2. Vitamin D metabolism**

There are 4 forms of vitamin D (calciferol) – lamisterol (vit. D1), ergocalciferol (vit. D2), cholecalciferol (vit. D3) and dihydrotachysterol (vit. D4), 2 of which being the most important – D2 and D3. Under the influence of UV radiation, ergosterol (plant based) and cholesterol (synthetized from 7-dehydrocholesterol of animal origin) are transformed into vitamin D2 and D3 respectively [1, 18]. Major part of vitamin D, around 90%, is synthesized in epidermis under the effect of the sun, while the rest is absorbed in small intestine together with food, nowadays being enriched with vitamin D with increasing frequency [19, 20]. Hydroxylation of vitamin D is a two-stage process, taking place in liver and kidneys. Thus renal and liver diseases impair metabolism of vitamin D. Enzyme 25-hydroxylase transforms vitamin D3 into 25-hydroxyvitamin D3 25(OH)D3 in liver, which is the main metabolite of vitamin D3, circulating in blood [21]. Recently it was proved that when inflammation occurs gingival fibroblasts and periodontal cells are capable of producing 25-hydroxylase and it appears to be a new extrahepatic site of 25(OH)D3 synthesis [21]. Further, 25-hydroxyvitamin D3 is hydroxylated in kidneys by means of 1 α-hydroxylase into 1,25-dihydroxyvitamin D (1,25(OH)2D3), calcitriol, active form of vitamin D, which is active hormone, participating in calcium absorption in intestines, important for both specific and nonspecific immune response against bacterial infections of oral cavity and other organs [2, 7, 21, 22]. Calcitriol binds to vitamin D-binding protein (DBP) and is transported to the cells of target tissues [23]. Synthesis of 1α-hydroxylase starts after receptors of cellular membranes have been influenced by microorganisms. Calcitriol is activated after binding to vitamin D receptors (VDR) of nuclei of immune and epithelial cells [7, 23–25]. VDR can be found in many human tissues, regulating activity of more than 200 genes in direct or indirect way [26, 27]. Numerous distribution of VDR in tissues determines complex effect of vitamin D, whereas deficiency determines disorders [26–28]. Polymorphism of VDR gene is related to many infectious diseases, including PD

**121**

extended period of time [40, 41].

*The Importance of Vitamin D for Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.96968*

and aggressive form of periodontitis [31, 32].

[28–30]. Polymorphism of VDR gene and exact mechanism of periodontitis remain unclear so far. There is no link established between polymorphism of VDR genes

Marginal gingival epithelium (GE) descends from free inner margin towards root apex and transits to sulcular epithelium – semi permeable membrane. Sulcular epithelium attaches to tooth by means of loose connections, creating favorable conditions for bacterial invasion from dental plaque [33]. Thin and non-keratinized epithelium forms a junctional epithelium (JE), laying at the bottom of gingival sulcus. JE is a narrow structure of 1–2 mm with good regenerative properties, connected to tooth by layer of organic substance. Its cubic and flat cells have gaps and attach to tooth and with each other by means of hemidesmosoms and have 2 basal membranes: internal, near the tooth, and the outer one on the other side, contacting with subepithelial tissue*.* Disruption of the bonds between enamel cuticle and JE leads to inflammatory processes. This anatomical unit plays a barrier function, which is supported by gingival fluid, flushing gingival sulcus – blood filtrate, containing lots of various protective cells (neutrophilic leucocytes, lymphocytes, monocytes, and macrophages), specific antibodies, immunoglobulins, cytokines, proteins, enzymes, epithelial cells and bacteria. The amount of gingival fluid can change due to circadian rhythms and depends on the health of PTs, oral hygiene, mechanic impact while mastication, medications used, etc. [34, 35]. Plasma proteins strengthen junctional epithelium-enamel bonds and namely calcitriol, affecting nonspecific immunity, activates synthesis of proteins, necessary for small adherens, gap and desmosome epithelium intercellular junctions, activates hydrogen peroxide secretion in monocytes, stimulates the synthesis of antimicrobial peptides, chemotaxis, production of cytokines and chemokines, cellular reproduction, vascular permeability, wound healing, and neutralization of bacterial endotoxins [7, 25, 36].

**3. The role of vitamin D in immune response of periodontal tissues**

Hence 1,25(OH)2D3 enhances antibacterial defense of GE [25, 36, 37].

Immune response can be nonspecific and specific. After bacteria have entered

Blood monocytes, after migration into connective tissues, transform into macrophages, which are very important for both, cellular and humoral immunity, as they have surface receptors, reacting with any foreign substance [42]. In the process

the periodontal tissues, defensive mechanism starts – immune response, during which the foreign substance is neutralized and eliminated or memorized. Neutrophilic leucocytes play important role in nonspecific immune response. It is interesting, that these cells are always found in gingival sulcus and this is the only site in organism, where neutrophilic leucocytes can freely migrate from organism outwards. During the bacterial invasion into PTs, chemotactic mechanisms are activated and neutrophilic leucocytes start migrating from blood vessels into inflamed tissues. Right here, together with macrophages, they take part in phagocytosis, thus fighting with different antigens. Neutrophilic leucocytes, monocytes and activated macrophages produce immune mediators (IL-1β, IL-1ra, IL-6, IL-10, IL-12, TNF-α, PGE2, MMP, Interferon γ (IFNγ)) and chemokines [37]. Vitamin D protects the organism from excessive immune response by decreasing the secretion of IL-1, IL-6, IL-8, IL-12, TNF-α cytokines, decreases production of matrix metalloproteinase (MMP) in leucocytes [33, 38]. MMP – enzymes, participating in alterations of intercellular tissues. Blood plasma levels of MMP-3, MMP-8 and MMP-9 increase with PD [39]. Very high level of MMP-9 is detected in cases of rapidly progressing periodontitis, but it can decrease up to 69% taking even little doses of vitamin D for *Vitamin D*

jawbone resorption causes adentia [16, 17].

**2. Vitamin D metabolism**

deeper within PT: causing attachment loss, periodontal pocket formation, alveolar bone resorption and tooth loss over time [5, 6]. Increasing number of studies proves importance of vitamin D in prevention and management of oral diseases [7]. Clinical studies strive to link vitamin D with PD and prove its therapeutic and preventive role. Vitamin D is secosteroidal hormone, playing important role in the treatment of gingivitis and periodontitis because of its anti-inflammatory and antibacterial effect on PTs as well as its immunomodulatory, differentiating, anti-proliferative and regulative effect on autoimmune processes, cellular apoptosis and participation in bone metabolism [3, 7–10]. Disintegration and renewal processes of bone depend on metabolism, as constant interchange of mineral substances between bone and blood plasma, where an active form of vitamin D is circulating, takes place [11]. One of the main functions of vitamin D is maintaining of blood levels of calcium and phosphorus by regulating absorption of these substances inside the bowels and reabsorption in kidneys and by enhancing remodeling processes [12, 13]. Bone is like a living and continuously changing organ where resorption and regeneration, i.e. remodelation, take place [14]. For this reason, the old bone is not accumulating and adaptation to changing mechanical forces develops. Jawbone support the teeth in alveolar sockets, skeletal bones protect internal organs and acts as depot of mineral substances especially calcium (also is necessary for normal muscle function) [15]. Osteoporotic (OP) changes of skeletal bones occur because of impaired mineralization due to long term decreased uptake of vitamin D and calcium, increasing risk of fractures, accelerated

There are 4 forms of vitamin D (calciferol) – lamisterol (vit. D1), ergocalciferol (vit. D2), cholecalciferol (vit. D3) and dihydrotachysterol (vit. D4), 2 of which being the most important – D2 and D3. Under the influence of UV radiation, ergosterol (plant based) and cholesterol (synthetized from 7-dehydrocholesterol of animal origin) are transformed into vitamin D2 and D3 respectively [1, 18]. Major part of vitamin D, around 90%, is synthesized in epidermis under the effect of the sun, while the rest is absorbed in small intestine together with food, nowadays being enriched with vitamin D with increasing frequency [19, 20]. Hydroxylation of vitamin D is a two-stage process, taking place in liver and kidneys. Thus renal and liver diseases impair metabolism of vitamin D. Enzyme 25-hydroxylase transforms vitamin D3 into 25-hydroxyvitamin D3 25(OH)D3 in liver, which is the main metabolite of vitamin D3, circulating in blood [21]. Recently it was proved that when inflammation occurs gingival fibroblasts and periodontal cells are capable of producing 25-hydroxylase and it appears to be a new extrahepatic site of 25(OH)D3 synthesis [21]. Further, 25-hydroxyvitamin D3 is hydroxylated in kidneys by means of 1 α-hydroxylase into 1,25-dihydroxyvitamin D (1,25(OH)2D3), calcitriol, active form of vitamin D, which is active hormone, participating in calcium absorption in intestines, important for both specific and nonspecific immune response against bacterial infections of oral cavity and other organs [2, 7, 21, 22]. Calcitriol binds to vitamin D-binding protein (DBP) and is transported to the cells of target tissues [23]. Synthesis of 1α-hydroxylase starts after receptors of cellular membranes have been influenced by microorganisms. Calcitriol is activated after binding to vitamin D receptors (VDR) of nuclei of immune and epithelial cells [7, 23–25]. VDR can be found in many human tissues, regulating activity of more than 200 genes in direct or indirect way [26, 27]. Numerous distribution of VDR in tissues determines complex effect of vitamin D, whereas deficiency determines disorders [26–28]. Polymorphism of VDR gene is related to many infectious diseases, including PD

**120**

[28–30]. Polymorphism of VDR gene and exact mechanism of periodontitis remain unclear so far. There is no link established between polymorphism of VDR genes and aggressive form of periodontitis [31, 32].

#### **3. The role of vitamin D in immune response of periodontal tissues**

Marginal gingival epithelium (GE) descends from free inner margin towards root apex and transits to sulcular epithelium – semi permeable membrane. Sulcular epithelium attaches to tooth by means of loose connections, creating favorable conditions for bacterial invasion from dental plaque [33]. Thin and non-keratinized epithelium forms a junctional epithelium (JE), laying at the bottom of gingival sulcus. JE is a narrow structure of 1–2 mm with good regenerative properties, connected to tooth by layer of organic substance. Its cubic and flat cells have gaps and attach to tooth and with each other by means of hemidesmosoms and have 2 basal membranes: internal, near the tooth, and the outer one on the other side, contacting with subepithelial tissue*.* Disruption of the bonds between enamel cuticle and JE leads to inflammatory processes. This anatomical unit plays a barrier function, which is supported by gingival fluid, flushing gingival sulcus – blood filtrate, containing lots of various protective cells (neutrophilic leucocytes, lymphocytes, monocytes, and macrophages), specific antibodies, immunoglobulins, cytokines, proteins, enzymes, epithelial cells and bacteria. The amount of gingival fluid can change due to circadian rhythms and depends on the health of PTs, oral hygiene, mechanic impact while mastication, medications used, etc. [34, 35]. Plasma proteins strengthen junctional epithelium-enamel bonds and namely calcitriol, affecting nonspecific immunity, activates synthesis of proteins, necessary for small adherens, gap and desmosome epithelium intercellular junctions, activates hydrogen peroxide secretion in monocytes, stimulates the synthesis of antimicrobial peptides, chemotaxis, production of cytokines and chemokines, cellular reproduction, vascular permeability, wound healing, and neutralization of bacterial endotoxins [7, 25, 36]. Hence 1,25(OH)2D3 enhances antibacterial defense of GE [25, 36, 37].

Immune response can be nonspecific and specific. After bacteria have entered the periodontal tissues, defensive mechanism starts – immune response, during which the foreign substance is neutralized and eliminated or memorized. Neutrophilic leucocytes play important role in nonspecific immune response. It is interesting, that these cells are always found in gingival sulcus and this is the only site in organism, where neutrophilic leucocytes can freely migrate from organism outwards. During the bacterial invasion into PTs, chemotactic mechanisms are activated and neutrophilic leucocytes start migrating from blood vessels into inflamed tissues. Right here, together with macrophages, they take part in phagocytosis, thus fighting with different antigens. Neutrophilic leucocytes, monocytes and activated macrophages produce immune mediators (IL-1β, IL-1ra, IL-6, IL-10, IL-12, TNF-α, PGE2, MMP, Interferon γ (IFNγ)) and chemokines [37]. Vitamin D protects the organism from excessive immune response by decreasing the secretion of IL-1, IL-6, IL-8, IL-12, TNF-α cytokines, decreases production of matrix metalloproteinase (MMP) in leucocytes [33, 38]. MMP – enzymes, participating in alterations of intercellular tissues. Blood plasma levels of MMP-3, MMP-8 and MMP-9 increase with PD [39]. Very high level of MMP-9 is detected in cases of rapidly progressing periodontitis, but it can decrease up to 69% taking even little doses of vitamin D for extended period of time [40, 41].

Blood monocytes, after migration into connective tissues, transform into macrophages, which are very important for both, cellular and humoral immunity, as they have surface receptors, reacting with any foreign substance [42]. In the process of phagocytosis, immunoglobulins and serum complement envelope foreign substance. Such formation enters phagocytic vacuoles and is destroyed by lysosome enzymes. Afterwards these substances are transferred to lymphocytes, determining further immune response [42]. Products of tissue breakdown, histamine and complement system enhances phagocytosis. Specific immune response manifests later. Antibodies circulate in blood, T and B lymphocytes react only to specific antigen. Lymphocytes are often related to Langerhans cells of oral epithelium, producing cytokines, e.g., IL-1, activating T lymphocytes, enhancing proliferation and production of antibodies. Active T lymphocytes have cytotoxic effect. Keratinocytes of oral epithelium produce IL-1 and IL-8, regulating the amount of lymphocytes and polymorphonuclear leucocytes [42]. Impaired specific immunity is responsible for resorption, osteoclast genesis and inflammatory processes of bone, thus causing autoimmune diseases. Calcitriol suppresses progression of OP and PD with signs of autoimmune diseases.

Active hormonal form of vitamin D, 1,25(OH)2D3, directly regulates antimicrobial immune response, modulates cytokine production and stimulates secretion of antimicrobial peptides by monocytes-macrophages and activates release of hydrogen peroxide in monocytes, thus exhibiting anti-inflammatory and antimicrobial properties [7, 43, 44]. Monocytes not only produce cytokines, but TNF-α as well, they release substances, activating lymphocytes and interacting with them as antigen-presenting cell (APC), destroy PTs, accelerate proliferation, differentiation and activation of osteoclasts, move in tissues in chemotactic way and participate in phagocytosis. Antimicrobial peptides play important role in nonspecific immunity against periodontitis causing agents. Antimicrobial peptides, β-defensines and especially cathelicidine LL-37 take part in neutralization of bacterial endotoxins, healing of wounds, regulate cell multiplication, blood vessel permeability, cytokine and chemokine production and chemotaxis, have prolonged antimicrobial activity and neutralize lipopolysaccharides as well [3, 7, 23, 25, 45, 46]. Activity of defensines depends on vitamin D levels [45, 46]. β-defensines show antimicrobial activity on PD bacteria– *Actinobacilus actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum, Candida* and papilloma viruses [47]. APCs, including macrophages and dendritic cells, transform the main 25(OH)D3 form circulating in blood into active 1,25(OH)2D3, and, via VDR, induce cellular response and regulate transcription. Antimicrobial activity via VDR is associated with cathelicidine hCAP-18 gene [48]. Cathelicidine has wide antimicrobial activity against grampositive and gram-negative bacteria, some fungi and viruses [3]. Treatment with vitamin D increases cathelicidine mRNA level in keratinocytes, neutrophils and macrophages [3, 44]. Irritation of macrophage receptors with pathogens increases synthesis of 1,25(OH)2D3, activity in macrophages and production of antibacterial proteins, cathelicidine and β-defensines, increases [43]. Therefore, it is supposed that vitamin D deficiency determines weak antibacterial response and tendency to infections [49].

During specific immune response, 1,25(OH)2D3 affects B and T lymphocytes [7]. The latter release cytokines (interleukine-1, TNF-α, macrophage activating factor, macrophage migration inhibitory factor), stimulating resorption of dental supportive tissues (due to increased number of osteoclasts) and decay of extracellular matrix; release immunoglobulins; destroy pathogens, transferred by macrophages and dendritic cells and participate in production of antibodies. Such immune response mechanism enhances pathogenesis of PTs and aggravates the course of disease [16, 21, 33]. 1,25(OH)2D3 suppresses proliferation, maturation and differentiation of dendritic cells [50]. T lymphocytes are one of the dominating cells in the beginning of PTs pathologic process and its regulator; immature

**123**

*The Importance of Vitamin D for Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.96968*

health of both soft and hard PTs.

**periodontal diseases**

dendritic cells stimulate their tolerance, whereas mature dendritic cells activate them [51]. 1,25(OH)2D3 decreases the number of APCs and ability of T lymphocyte to stimulate monocytes-macrophages [52]. The main target is T helpers. Vitamin D can contribute to formation of acquired immune response by selective stimulation of the specific T helpers [53]. B lymphocytes interact with macrophages and become plasmocytes, releasing Ig, which adhere to antigens. Such antigen–antibody complex activates complement system, initiating production of cytotoxic molecules, increasing blood vessel permeability, acting as chemotactic agents for polymorphonuclear leucocytes and macrophages. Vitamin D inhibits T lymphocyte proliferation, release of immunoglobulins and transformation of B lymphocytes into plasmocytes, hereby suppressing specific immune response, release of IL-1, IL-6, IL-8, IL-12 cytokines and alpha TNF-α [16, 21, 52]. IL-1, IL-6 and TNF-α are potential activators of osteoclasts and supporters of inflammation. IL-1 is released not only by afore mentioned monocyte-macrophages, but by endothelial and epithelial cells, fibroblasts and lymphocytes as well. This substance supports inflamation, stimulates production, differentiation and activation of osteoclasts, leading to resorption of alveolar bone, release of enzymes splitting extracellular matrix and release of E2 prostaglandin, enhancing relaxation of blood vessels and edema in PTs [13]. IL-6 activates synthesis of C reactive protein and glucose metabolism [54]. It is proven, that increase of vitamin D serum levels leads to decrease of IL-6 and leptin (factor indicating inflammation) levels, increase of adiponectin (cytokine inhibitor) and IL-8 levels [54, 55]. IL-8 activates neutrophil chemotaxis and is found in normal PTs. Its levels increase with the progression of inflammatory processes, therefore polymorphonuclear neutrophils are the first to react to inflammation. Its deficiency is related to severe forms of periodontitis. As the amount of pathogens increases, IL-8 levels and number of neutrophils increase as well, causing destruction of PTs [6]. Vitamin D acts on periopathogens, inhibits inflammation of PT and decreases IL-8 expression in periodontal ligament [55]. It can be concluded, that vitamin D plays important role in defensive mechanisms of PT and vital for the

**4. Change in the concentration of 25-hydroxyvitamin D in plasma by** 

There is no unanimous attitude towards the relation between these two factors as there exist differences between populations, test methodology and occurring limitations of the tests. When analyzing the relation between vitamin D, as protective factor, and PD, different criteria of vitamin D and examination of PTs are applied: average plasma level of vitamin D, dosage applied or any other certain diagnostic criteria. Status of PTs is evaluated according to the periodontal pocket depth, clinical attachment level, clinical attachment loss, attachment gain, alveolar bone loss, bone defects in oral cavity or any other selected criteria, such as short/ long term results of periodontal surgery [56]. If only one side of oral cavity is examined, data cannot be accurate and the amount of information is lost. Studies can cover general population or part of it, e.g., smoking individuals, individuals of different age, with different PD, etc. Scientific base of linking these two factors and widening of the knowledge is possible due to widely chosen evaluative protocols and indicators. For example, smoking is risk factor for PD, but with the additional deficiency of vitamin D, destruction of PTs is more severe and more cases are identified [57]. Individuals over 50 year with low vitamin D levels have greater periodontal attachment loss than ones with high levels [58]. PTs in most cases are

#### *The Importance of Vitamin D for Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.96968*

*Vitamin D*

autoimmune diseases.

of phagocytosis, immunoglobulins and serum complement envelope foreign substance. Such formation enters phagocytic vacuoles and is destroyed by lysosome enzymes. Afterwards these substances are transferred to lymphocytes, determining further immune response [42]. Products of tissue breakdown, histamine and complement system enhances phagocytosis. Specific immune response manifests later. Antibodies circulate in blood, T and B lymphocytes react only to specific antigen. Lymphocytes are often related to Langerhans cells of oral epithelium, producing cytokines, e.g., IL-1, activating T lymphocytes, enhancing proliferation and production of antibodies. Active T lymphocytes have cytotoxic effect. Keratinocytes of oral epithelium produce IL-1 and IL-8, regulating the amount of lymphocytes and polymorphonuclear leucocytes [42]. Impaired specific immunity is responsible for resorption, osteoclast genesis and inflammatory processes of bone, thus causing autoimmune diseases. Calcitriol suppresses progression of OP and PD with signs of

Active hormonal form of vitamin D, 1,25(OH)2D3, directly regulates antimicrobial immune response, modulates cytokine production and stimulates secretion of antimicrobial peptides by monocytes-macrophages and activates release of hydrogen peroxide in monocytes, thus exhibiting anti-inflammatory and antimicrobial properties [7, 43, 44]. Monocytes not only produce cytokines, but TNF-α as well, they release substances, activating lymphocytes and interacting with them as antigen-presenting cell (APC), destroy PTs, accelerate proliferation, differentiation and activation of osteoclasts, move in tissues in chemotactic way and participate in phagocytosis. Antimicrobial peptides play important role in nonspecific immunity against periodontitis causing agents. Antimicrobial peptides, β-defensines and especially cathelicidine LL-37 take part in neutralization of bacterial endotoxins, healing of wounds, regulate cell multiplication, blood vessel permeability, cytokine and chemokine production and chemotaxis, have prolonged antimicrobial activity and neutralize lipopolysaccharides as well [3, 7, 23, 25, 45, 46]. Activity of defensines depends on vitamin D levels [45, 46]. β-defensines show antimicrobial activity on PD bacteria– *Actinobacilus actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum, Candida* and papilloma viruses [47]. APCs, including macrophages and dendritic cells, transform the main 25(OH)D3 form circulating in blood into active 1,25(OH)2D3, and, via VDR, induce cellular response and regulate transcription. Antimicrobial activity via VDR is associated with cathelicidine hCAP-18 gene [48]. Cathelicidine has wide antimicrobial activity against grampositive and gram-negative bacteria, some fungi and viruses [3]. Treatment with vitamin D increases cathelicidine mRNA level in keratinocytes, neutrophils and macrophages [3, 44]. Irritation of macrophage receptors with pathogens increases synthesis of 1,25(OH)2D3, activity in macrophages and production of antibacterial proteins, cathelicidine and β-defensines, increases [43]. Therefore, it is supposed that vitamin D deficiency determines weak antibacterial response and tendency to

During specific immune response, 1,25(OH)2D3 affects B and T lymphocytes [7]. The latter release cytokines (interleukine-1, TNF-α, macrophage activating factor, macrophage migration inhibitory factor), stimulating resorption of dental supportive tissues (due to increased number of osteoclasts) and decay of extracellular matrix; release immunoglobulins; destroy pathogens, transferred by macrophages and dendritic cells and participate in production of antibodies. Such immune response mechanism enhances pathogenesis of PTs and aggravates the course of disease [16, 21, 33]. 1,25(OH)2D3 suppresses proliferation, maturation and differentiation of dendritic cells [50]. T lymphocytes are one of the dominating cells in the beginning of PTs pathologic process and its regulator; immature

**122**

infections [49].

dendritic cells stimulate their tolerance, whereas mature dendritic cells activate them [51]. 1,25(OH)2D3 decreases the number of APCs and ability of T lymphocyte to stimulate monocytes-macrophages [52]. The main target is T helpers. Vitamin D can contribute to formation of acquired immune response by selective stimulation of the specific T helpers [53]. B lymphocytes interact with macrophages and become plasmocytes, releasing Ig, which adhere to antigens. Such antigen–antibody complex activates complement system, initiating production of cytotoxic molecules, increasing blood vessel permeability, acting as chemotactic agents for polymorphonuclear leucocytes and macrophages. Vitamin D inhibits T lymphocyte proliferation, release of immunoglobulins and transformation of B lymphocytes into plasmocytes, hereby suppressing specific immune response, release of IL-1, IL-6, IL-8, IL-12 cytokines and alpha TNF-α [16, 21, 52]. IL-1, IL-6 and TNF-α are potential activators of osteoclasts and supporters of inflammation. IL-1 is released not only by afore mentioned monocyte-macrophages, but by endothelial and epithelial cells, fibroblasts and lymphocytes as well. This substance supports inflamation, stimulates production, differentiation and activation of osteoclasts, leading to resorption of alveolar bone, release of enzymes splitting extracellular matrix and release of E2 prostaglandin, enhancing relaxation of blood vessels and edema in PTs [13]. IL-6 activates synthesis of C reactive protein and glucose metabolism [54]. It is proven, that increase of vitamin D serum levels leads to decrease of IL-6 and leptin (factor indicating inflammation) levels, increase of adiponectin (cytokine inhibitor) and IL-8 levels [54, 55]. IL-8 activates neutrophil chemotaxis and is found in normal PTs. Its levels increase with the progression of inflammatory processes, therefore polymorphonuclear neutrophils are the first to react to inflammation. Its deficiency is related to severe forms of periodontitis. As the amount of pathogens increases, IL-8 levels and number of neutrophils increase as well, causing destruction of PTs [6]. Vitamin D acts on periopathogens, inhibits inflammation of PT and decreases IL-8 expression in periodontal ligament [55]. It can be concluded, that vitamin D plays important role in defensive mechanisms of PT and vital for the health of both soft and hard PTs.

#### **4. Change in the concentration of 25-hydroxyvitamin D in plasma by periodontal diseases**

There is no unanimous attitude towards the relation between these two factors as there exist differences between populations, test methodology and occurring limitations of the tests. When analyzing the relation between vitamin D, as protective factor, and PD, different criteria of vitamin D and examination of PTs are applied: average plasma level of vitamin D, dosage applied or any other certain diagnostic criteria. Status of PTs is evaluated according to the periodontal pocket depth, clinical attachment level, clinical attachment loss, attachment gain, alveolar bone loss, bone defects in oral cavity or any other selected criteria, such as short/ long term results of periodontal surgery [56]. If only one side of oral cavity is examined, data cannot be accurate and the amount of information is lost. Studies can cover general population or part of it, e.g., smoking individuals, individuals of different age, with different PD, etc. Scientific base of linking these two factors and widening of the knowledge is possible due to widely chosen evaluative protocols and indicators. For example, smoking is risk factor for PD, but with the additional deficiency of vitamin D, destruction of PTs is more severe and more cases are identified [57]. Individuals over 50 year with low vitamin D levels have greater periodontal attachment loss than ones with high levels [58]. PTs in most cases are

healthier and risk is lower in individuals with sufficient levels of vitamin D, but it is not successfully proved in all the cases, leading to the controversial interpretation of the results obtained [56, 58–61]. It is becoming clear, that performing blood tests and monitoring vitamin D levels it is possible to suspect that individual is suffering from chronic periodontitis and condition of PTs is poor, especially in older population [56, 62, 63]. It can be one of additional diagnostic possibilities.

In case of acute inflammation, serum levels of 25-hydroxyvitamin D are increasing, as periodontal cells are producing it in the site of inflammation as anti-inflammatory agent. Serum levels of 25-hydroxyvitamin D usually are lower in cases of chronic inflammation. Such correlation might be explained that because of low serum levels of vitamin D, ability of epithelium to fight against pathogens is impaired and inflammation develops. Optimal serum level of 25-hydroxyvitamin D for prophylactic and therapeutic purposes should be 90-100 nmol/l, but it is not definitely clear what should be the daily dose of vitamin D in order to achieve these levels [13]. Gingival bleeding are the sign of both, acute and chronic PD. Decreased level of 25-hydroxyvitamin D correlates with worsened health status of PTs; course of chronic gingivitis (with insufficient serum levels) and intensified gingival bleeding [36, 58]. Gingival bleeding during the probing is observed by 20% less in patients with high serum levels of 25(OH)D, those with sufficient (≥ 50 nmol/L) levels of vitamin are less likely to develop PD by 33% and by 42% are less likely to have more than 50% of gingival bleeding [60, 64]. Prolonged combined supplementation of vitamin D and calcium decreases bleeding on probing, changes the clinical attachment level and pockets depth [65]. The tendency to severe periodontitis may decrease up to 33% with daily dose of 800 IU of vitamin D [62]. Exacerbation of gingival bleeding is observed during pregnancy, thus there are data, concerning the influence of vitamin D during this period (if 25(OH) D level < 75 nmol/L) [36]. Without timely evaluation of all these data, periodontitis of more severe form develops, as correlation between increased serum levels of vitamin D3 and severity of PD exists, though it is not always confirmed [36, 66, 67]. There are cases described when serum level of 1,25(OH)D increases significantly following the periodontal treatment [68]. Besides, increased serum level of 25(OH)D is common in patients with aggressive periodontitis (AP)- disease of PTs, affecting young individuals, characterized by rapid destruction of PT and tooth loss. Significantly higher vitamin D binding protein (DBP), IL-6, procalctonine and 25(OH)D3 plasma levels and higher counts of leucocytes and neutrophils are found in patients with this PD [69]. Level of 25(OH)D3 increases due to activation of 25-hydroxylase in periodontal cells in acute inflammation of PTs, and decrease in chronic one [67]. Due to production of this enzyme in cases of AP, levels of 25(OH)D3 in gingival sulcus is up to 300 times higher than in blood plasma [21]. DBP is plasma protein and is synthesized by hepatocytes [70]. It is the main carrier of 25(OH)D3 in the plasma, directly affecting cellular functions, including activity of macrophages [71, 72]. DBP bound to the cell surface, B-lymphocytes, T-lymphocytes, monocytes, neutrophils [70]. The amount of this protein is related to the severity degree of illness with direct relation to neutrophil – increased number of neutrophils and IL-6 can contribute to increased plasma levels of DBP by active periodontitis. DBP is the most important "during inflammation since it induces selective recruitment of neutrophils" [70]. Activated neutrophils can excrete DBP, which expression is regulated by IL-6, participating in immune response [69]. Thus detection of plasma levels of DBP could confirm correlation between it and periodontal inflammation. Anti-inflammatory effect depends on the dose of vitamin supplement. Safe and effective anti-inflammatory dose of 500–2000 IU of vitamin D is recommended. Results are noted earlier when higher dose of 2000 IU is used [73].

**125**

**Author details**

Egle Jagelaviciene

Sciences (LUHS), Kaunas, Lithuania

provided the original work is properly cited.

Department of Dental and Oral Pathology, Lithuanian University of Health

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: egle.jagelaviciene@lsmuni.lt

*The Importance of Vitamin D for Periodontal Tissues DOI: http://dx.doi.org/10.5772/intechopen.96968*

The author declares no conflict of interest.

In conclusion, vitamin D is very unique substance due to its abilities, functions

and participation in various processes. Its optimal serum levels could prevent occurrence of numerous diseases, including such common diseases throughout the world as chronic periodontal diseases, which are social problems, compromising

**5. Conclusion**

individual's quality of life.

**Conflict of interest**

### **5. Conclusion**

*Vitamin D*

healthier and risk is lower in individuals with sufficient levels of vitamin D, but it is not successfully proved in all the cases, leading to the controversial interpretation of the results obtained [56, 58–61]. It is becoming clear, that performing blood tests and monitoring vitamin D levels it is possible to suspect that individual is suffering from chronic periodontitis and condition of PTs is poor, especially in older popula-

In case of acute inflammation, serum levels of 25-hydroxyvitamin D are increasing, as periodontal cells are producing it in the site of inflammation as anti-inflammatory agent. Serum levels of 25-hydroxyvitamin D usually are lower in cases of chronic inflammation. Such correlation might be explained that because of low serum levels of vitamin D, ability of epithelium to fight against pathogens is impaired and inflammation develops. Optimal serum level of 25-hydroxyvitamin D for prophylactic and therapeutic purposes should be 90-100 nmol/l, but it is not definitely clear what should be the daily dose of vitamin D in order to achieve these levels [13]. Gingival bleeding are the sign of both, acute and chronic PD. Decreased level of 25-hydroxyvitamin D correlates with worsened health status of PTs; course of chronic gingivitis (with insufficient serum levels) and intensified gingival bleeding [36, 58]. Gingival bleeding during the probing is observed by 20% less in patients with high serum levels of 25(OH)D, those with sufficient (≥ 50 nmol/L) levels of vitamin are less likely to develop PD by 33% and by 42% are less likely to have more than 50% of gingival bleeding [60, 64]. Prolonged combined supplementation of vitamin D and calcium decreases bleeding on probing, changes the clinical attachment level and pockets depth [65]. The tendency to severe periodontitis may decrease up to 33% with daily dose of 800 IU of vitamin D [62]. Exacerbation of gingival bleeding is observed during pregnancy, thus there are data, concerning the influence of vitamin D during this period (if 25(OH) D level < 75 nmol/L) [36]. Without timely evaluation of all these data, periodontitis of more severe form develops, as correlation between increased serum levels of vitamin D3 and severity of PD exists, though it is not always confirmed [36, 66, 67]. There are cases described when serum level of 1,25(OH)D increases significantly following the periodontal treatment [68]. Besides, increased serum level of 25(OH)D is common in patients with aggressive periodontitis (AP)- disease of PTs, affecting young individuals, characterized by rapid destruction of PT and tooth loss. Significantly higher vitamin D binding protein (DBP), IL-6, procalctonine and 25(OH)D3 plasma levels and higher counts of leucocytes and neutrophils are found in patients with this PD [69]. Level of 25(OH)D3 increases due to activation of 25-hydroxylase in periodontal cells in acute inflammation of PTs, and decrease in chronic one [67]. Due to production of this enzyme in cases of AP, levels of 25(OH)D3 in gingival sulcus is up to 300 times higher than in blood plasma [21]. DBP is plasma protein and is synthesized by hepatocytes [70]. It is the main carrier of 25(OH)D3 in the plasma, directly affecting cellular functions, including activity of macrophages [71, 72]. DBP bound to the cell surface, B-lymphocytes, T-lymphocytes, monocytes, neutrophils [70]. The amount of this protein is related to the severity degree of illness with direct relation to neutrophil – increased number of neutrophils and IL-6 can contribute to increased plasma levels of DBP by active periodontitis. DBP is the most important "during inflammation since it induces selective recruitment of neutrophils" [70]. Activated neutrophils can excrete DBP, which expression is regulated by IL-6, participating in immune response [69]. Thus detection of plasma levels of DBP could confirm correlation between it and periodontal inflammation. Anti-inflammatory effect depends on the dose of vitamin supplement. Safe and effective anti-inflammatory dose of 500–2000 IU of vitamin D is recommended. Results are noted earlier when

tion [56, 62, 63]. It can be one of additional diagnostic possibilities.

**124**

higher dose of 2000 IU is used [73].

In conclusion, vitamin D is very unique substance due to its abilities, functions and participation in various processes. Its optimal serum levels could prevent occurrence of numerous diseases, including such common diseases throughout the world as chronic periodontal diseases, which are social problems, compromising individual's quality of life.

### **Conflict of interest**

The author declares no conflict of interest.

### **Author details**

Egle Jagelaviciene Department of Dental and Oral Pathology, Lithuanian University of Health Sciences (LUHS), Kaunas, Lithuania

\*Address all correspondence to: egle.jagelaviciene@lsmuni.lt

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

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[29] Park K S, Nam J H, Choi J. The short vitamin D receptor is associated with increased risk for generalized aggressive

Caminaga R M, Trevilatto P C, de Souza A P, Barros S P. Polymorphisms in the vitamin D receptor gene are associated with periodontal disease. Journal of Periodontology. 2004; 75, 1090-1095. DOI: 10.1902/jop.2004.75.8.1090

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[30] de Brito Junior R B, Scarel-

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[32] Li-li Chen,\* Hao Li,† Pengpeng Zhang,\* and Shu-mei Wang\* Association Between Vitamin D Receptor Polymorphisms and

DOI: 10.1902/jop.2011.110518

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[22] Bikle DD. Vitamin D Metabolism and Function in the Skin. Molecular and Cellular Endocrinology.2011 Dec 5; 347(1-2): 80-89. DOI: 10.1016/j.

[23] Chun RF, Adams JS, Hewison M. Back to the future: a new look at 'old' vitamin D. Journal of Endocrinology. 2008;198(2):261-9. DOI: 10.1677/

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[20] DeLuca HF. Overview of general physiologic features and functions of vitamin D. American Journal of Clinical Nutrition. 2004;80 (6 Suppl):1689S–96S. DOI: 10.1093/ ajcn/80.6.1689S

[21] Liu K, Meng H, Hou J. Activity of 25-hydroxylase in human gingival fibroblasts and periodontal ligament cells. PLoS One. 2012;7(12):e52053. DOI: 10.1371/journal.pone.0052053

[22] Bikle DD. Vitamin D Metabolism and Function in the Skin. Molecular and Cellular Endocrinology.2011 Dec 5; 347(1-2): 80-89. DOI: 10.1016/j. mce.2011.05.017

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[24] Van der Velden U, Kuzmanova D, Chapple I.L. Micronutritional approaches to periodontal therapy. J. Clin.Periodontol. 2011; 38 (Suppl. 11), 142-158. DOI: 10.1111/j.1600-051X.2010.01663.x

[25] McMahon L, Schwartz K, Yilmaz O, Brown E, Ryan LK, et al. Vitamin D-mediated induction of innate immunity in gingival epithelial cells. *Infection and Immunity*. 2011;79:2250- 2256. DOI: 10.1128/IAI.00099-11

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[28] Bellamy, R, Ruwende, C, Corrah T, McAdam K P, Thursz M, Whittle H C, Hill A V. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. Journal of Infectious Diseases. 1999; 179, 721-724. DOI: 10.1086/314614

[29] Park K S, Nam J H, Choi J. The short vitamin D receptor is associated with increased risk for generalized aggressive periodontitis. Journal of Clinical Periodontology. 2006; 33, 524-528. DOI. org/10.1111/j.1600-051X.2006.00944.x

[30] de Brito Junior R B, Scarel-Caminaga R M, Trevilatto P C, de Souza A P, Barros S P. Polymorphisms in the vitamin D receptor gene are associated with periodontal disease. Journal of Periodontology. 2004; 75, 1090-1095. DOI: 10.1902/jop.2004.75.8.1090

[31] Deng H1, Liu F, Pan Y, Jin X, Wang H, Cao J.BsmI, TaqI, ApaI, and FokI polymorphisms in the vitamin D receptor gene and periodontitis: a meta-analysis of 15 studies including 1338 cases and 1302 controls. Clinical Periodontology. 2011;38(3):199-207. DOI: 10.1111/j.1600-051X.2010.01685.x

[32] Li-li Chen,\* Hao Li,† Pengpeng Zhang,\* and Shu-mei Wang\* Association Between Vitamin D Receptor Polymorphisms and Periodontitis: A Meta-Analysis. Journal of Periodontology 2012;83:1095-1103. DOI: 10.1902/jop.2011.110518

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osteomalacia. Journal of Clinical Investigation 116:1703-1712. DOI: 10.1172/JCI27793

*Vitamin D*

Periodontal Pathology. Medicina 2018; 55(2). DOI: 10.3390/medicina54030045 [41] Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, et al. Circulating MMP9, vitamin D and variation in the

TIMP-1 response with VDR genotype:

[42] Vaitkeviciene I, Jagelaviciene E, Vaitkevicius R. Burnos gleivinė: sandara, funkcijos ir tyrimas (Oral mucosa: structure, functions and examination). LSMU, Leidybos namai,

[43] Liu PT, Stenger S, Li H et al. Tolllike receptor triggering of a vitamin D-mediated human anti-microbial response. Science 2006;311:1770-1773.

DOI: 10.1126/science.1123933

Bourdeau V et al. Cutting edge: 1, 25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. Journal of Immunology. 2004;173:2909-2912. DOI: 10.4049/

[45] Weber G, Heilborn JD, Chamorro Jimenez CI. et al. Vitamin D induces the antimicrobial protein hCAP18 in human skin. Journal of Investigative Dermatology. 2005;124:1080-1082. DOI: 10.1111/j.0022-202X.2005.23687.x

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10.1016/j.jcf.2007.03.003

[47] Zhou C, Assem M, Tay JC,

Watkins PB, Blumberg B, Schuetz EG, Thummel KE 2006 Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced

[44] Wang TT, Nestel FP,

jimmunol.173.5.2909

mechanisms for inflammatory damage in chronic disorders? QJM: An International Journal of Medicine. 2002;95:787-96. DOI.org/10.1093/

qjmed/95.12.787

Kaunas, 2015.

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Leidybos namai, Kaunas, 2019.

periodontologijos kursą (Introduction to the course of periodontology). LSMU,

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[51] Abiko Y, Saitoh M, Nishimura M, Yamazaki M, Sawamura D, Kaku T (2007) Role of β-defensins in oral epithelial health and disease. Medical Molecular Morphology. 40, 179-184.

[52] Almerighi C, Sinistro A, Cavazza A et al. 1a,25-hydroxyvitamin D3 inhibits CD-40L-induced pro-inflammatory and immunomodulatory activity. Cytokine. 2009;45:190-197. DOI: 10.1016/j. cyto.2008.12.009

[53] Nithya Anand, S. C. Chandrasekaran, and Narpat Singh Rajput. Vitamin D and periodontal health: Current concepts. *Journal* of *Indian Society of* Periodontology. 2013 May-Jun; 17(3): 302-308. DOI: 10.4103/0972-124X.115645

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[56] Pinto JPNS, Goergen J, Muniz FWMG, Haas AN. Vitamin D levels and risk for periodontal disease: A systematic review. Journal of Periodontal Research. 2018;1-8. DOI: 10.1111/jre.12531

[57] Lee HJ, Je DI, Won SJ, Paik DI, Bae KH. Association between vitamin D deficiency and periodontal status in current smokers. Community Dentistry and Oral Epidemiology. 2015;43:471- 478. DOI: 10.1111/cdoe.12173

[58] Dietrich T, Joshipura KJ, Dawson-Hughes B, Bischoff-Ferrari HA. Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population. American Journal of Clinical Nutrition. 2004;80:108-113. DOI: 10.1093/ajcn/80.1.108

[59] Millen AE, Andrews CA, LaMonte MJ, et al. Vitamin D status and 5-year changes in periodontal disease measures among postmenopausal women: the Buffalo OsteoPerio Study. Journal of Periodontology. 2014;85:1321- 1332. DOI: 10.1902/jop.2014.130686

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Section 4

Vitamin D and Other

Diseases

Section 4
