Published online 2020 May 19. doi: 10.3390/nu12051471
Authors: João Botelho,1,2,*† Vanessa Machado,1,2,3,† Luís Proença,4 Ana Sintra Delgado,2,3 and José João Mendes2Abstract
Vitamin D (VD) levels have been gaining growing attention in Oral Health. During growth and adulthood, VD deficiency (VDD) is associated with a wide variety of oral health disorders, and impaired VD synthesis may expedite some of these conditions. In children, severe VDD can induce defective tooth mineralization, resulting in dentin and enamel defects. As a consequence, these defects may increase the risk of the onset and progression of dental caries. Further, VDD has been associated with higher prevalence of periodontitis and gingival inflammation, and several recent preclinical and clinical studies have unveiled potential pathways through which Vitamin D may interact with the periodontium. VDD correction through supplementation may contribute to a successful treatment of periodontitis; however, alveolar bone regeneration procedures performed in baseline VDD patients seem more prone to failure. Vitamin D may also be linked with some oral pathology entities such as certain oral cancers and events of osteonecrosis of the jaw. This review aims to provide comprehensive evidence of how VD levels should be considered to promote good oral health, and to summarize how VDD may hamper oral development and its role in certain oral conditions.1. Introduction
Vitamin D is a steroid hormone obtained mainly from exposure to sunlight, but also from diet and dietary supplements 1,2,3,4,5>. Foods naturally containing vitamin D are rare, and it can be found in oily fish (such as salmon, mackerel, and herring) and oils from fish (e.g., cod liver oil) 2>. Vitamin D is a generic name comprising Vitamin D2 and D3. While Vitamin D2 is manufactured through ultraviolet irradiation of ergosterol from yeast, Vitamin D3 results from ultraviolet irradiation of 7-dehydrocholesterol from lanolin 4,6,7> (Figure 1) exhibiting the biological activity of cholecalciferol (vitamin D3), and it is synthesized in the human skin. Measurement of serum 25-hydroxyvitamin D (25
Vitamin D is a steroid hormone obtained mainly from exposure to sunlight, but also from diet and dietary supplements 1,2,3,4,5>. Foods naturally containing vitamin D are rare, and it can be found in oily fish (such as salmon, mackerel, and herring) and oils from fish (e.g., cod liver oil) 2>. Vitamin D is a generic name comprising Vitamin D2 and D3. While Vitamin D2 is manufactured through ultraviolet irradiation of ergosterol from yeast, Vitamin D3 results from ultraviolet irradiation of 7-dehydrocholesterol from lanolin 4,6,7> (Figure 1) exhibiting the biological activity of cholecalciferol (vitamin D3), and it is synthesized in the human skin. Measurement of serum 25-hydroxyvitamin D (25
Public awareness of vitamin D has increased exponentially due to a worldwide prevalence of vitamin D deficiency (VDD) 2,3,7,15,16,17,18>. This prevalence is worrisome and is of the utmost importance for general health, with special focus on children, pregnancy, some forms of cancer and infection prevention 19,20,21,22>.
In general, the major cause of VDD is the lack of exposure to sunlight with adequate ultraviolet B rays (exogenous factor) 6,17>. VDD can also arise from a nutritional deficit due to inadequate intakes of vitamin D, or hereditary disorders from absorption and metabolic conversion 6>. Additionally, drug related VDD is also possible due to iatrogenic increased clearance (for instance, with phenytoin, carbamazepine and oxcarbazepine regimens) 23>.
The role of nutrition in oral diseases has gained popularity and recent investigations have uncovered increasingly relevant relationships between nutritional deficits and oral pathologies 24,25>. Concerning oral diseases, caries and periodontal diseases are complex multifactorial diseases and remain the two most prevalent diseases worldwide 26,27>. Both caries and periodontal disease are associated with VDD and its pathophysiologic processes 28,29,30,31>. The mechanisms by which vitamin D impacts oral health are not just based on bone metabolism. Nowadays, research has unveiled that VDD compromises odontogenesis, resulting in a hypomineralized dentition susceptible to fracture and caries lesions 29>. VDD was also linked to worse periodontal health and might be involved in the immune mechanism towards periodontal infection 32>. Furthermore, VDD in association with periodontitis has been recently linked to potential systemic repercussions during pregnancy, throughout orthodontic treatment, in post-menopausal women or in some oral pathologies 22,33,34>.
The latest breakthroughs led us to elaborate a review aiming to comprehensively summarize the available evidence of the effect of vitamin D on oral health and its major complications. Furthermore, we discuss the impact of recent studies where VDD correction was implemented through supplementation which might underpin future clinical guidelines.
2. Vitamin D Deficiency Impact on Oral Health
2.1. Vitamin D Deficiency in Tooth Mineralization and CariesTeeth are mineralized organs, surrounded by alveolar bone, and formed by three distinctive hard tissues: enamel, dentin, and cementum. The tooth mineralization process occurs parallel to skeletal mineralization, yet if mineral metabolism is disturbed then failures will occur similarly to those that occur in bone tissue. Vitamin D plays a key role in bone and tooth mineralization, and when levels are unregulated it can lead to the “rachitic tooth”, which is a defective and hypomineralized organ highly susceptible to fracture and decay 35,36>.
The mechanisms by which VDD affects tooth mineralization are well debated elsewhere 35,36>. The main biological basis relies on the fact that severe VDD (<10 ng/mL) causes hypocalcemia and hypophosphatemia with secondary hyperparathyroidism (driven by hypocalcemia) 37,38>. This hyperparathyroidism promotes intestinal absorption of calcium (Ca2+), and renal production of 1 α,25-dihydroxyvitamin D (1,25
Apart from its mineralization homeostasis role, circulating vitamin D can initiate a signaling pathway through vitamin D receptors (VDR). VDR is a ligand-activated transcription factor that controls gene expression through vitamin D elements (VDRE) 39>. For instance, some of these responsive genes affect bone, mineral metabolism, immune response, cell life cycle and migration, skeletal muscle, detoxification, and energy metabolism 8,39,40,41,42,43>. Vitamin D upregulates VDR which, in turn, can induce structural gene products, including calcium-binding proteins and various extracellular matrix proteins (e.g., enamels, amelogenins, dentin sialoglycoproteins, and dentin phosphoproteins), resulting in the formation of dentin and enamel 35,44>.
Beyond the typical VDD causes, nutritional deficiency or reduction of sunlight exposure, there are genetic deficiencies originating from mutations encoding elements of the vitamin D metabolic machinery. The main causes of VDD, second to genetic mutations, are abnormal enzyme secretion (i.e., vitamin D-dependent rickets type 1, VDDR-I) and anomalous VDR function or signaling (vitamin D-dependent rickets type 2, VDDR-IIa; hereditary defects in the vitamin D receptor-effector system, HDVDR) 35>. These genetic conditions cause defective mineralized tissues, despite normal vitamin D consumption or sunlight exposure and, ultimately, will increase the risk of mineralized tooth tissue hypoplasia (i.e., amelogenesis imperfecta, dentinogenesis imperfecta, enamel hypoplasia) or higher risk of caries 35>.
Remarkably, deciduous dentition can be influenced by maternal 25(OH)D levels, despite the influence of inherited defects of the fetus 45,46>. Fetal serum-circulating levels of vitamin D follow the maternal concentration and can be used as a standard surrogate marker to the fetus 47>. Therefore, if maternal 25(OH)D levels turn unbalanced, this may have direct repercussions on the baby’s health 48> and, in particular, on tooth development 45,46,49,50,51>. The pattern of mineralization defect depends on the specific week of gestation when maternal VDD occurred. For example, approximately at the 13th week from conception, the human primary maxillary central incisor begins its calcification, and if there is a VDD status, there could be a hypoplasia/mineralization defect on the incisal third of the crown. Nowadays, it is known that maternal VDD at 12–16, 20–32 and 36–40 weeks results in defects at the incisal third, middle third and cervical third, respectively 51>. In a randomized clinical trial (RCT), vitamin D supplementation during pregnancy revealed that pregnant women with < 15 ng/mL of vitamin D had a 14% higher risk of deciduous dentition 51>. In contrast, high-dose vitamin D supplementation during pregnancy was associated with an approximately 50% reduced odds of enamel defects 49,52>. In another RCT, high-dose Vitamin D supplementation during pregnancy was linked to 50% lower risk of enamel defects in the newborn, underlying once more the likely preventive role of Vitamin D for enamel defects 49>.
Furthermore, untreated caries in deciduous and permanent teeth were the most prevalent condition, affecting 9% and 35% of global population, respectively 53>. Moreover, according to WHO, caries is the fourth-most expensive chronic disease to treat 54>. This infectious disease has a complex and multifactorial etiology. Environmental factors, such as cariogenic diet with a high carbohydrate content, cariogenic bacteria, and poor oral hygiene were the most widely studied risk factors 55,56,57>. Nevertheless, when exposed to the same environmental risk factors, some patients are more susceptible or resistant to caries than others, so that environmental factors alone are insufficient to explain the prevalence and incidence of caries 58,59,60>. Currently the evidence highlights the association of low levels of vitamin D and the high prevalence of caries in both children and adults, although the mechanism remains unclear 61,62,63,64,65,66,67,68>.
Additionally, vitamin D exerts several roles in the control of the human immune system, and an optimal vitamin D concentration (≥75 nmol/L) is associated with lower odds for dental caries in children 29,69,70>. However, the studies’ results are contradictory 45,62,71,72>. A recent systematic review of controlled clinical trials, with data from 2827 children, investigated the impact of vitamin D supplementation on dental caries prevention 28,73>. The results of this study show that vitamin D supplementation reduced the risk of caries in about 47%, but with low certainty 28>. Another research supports that caries-free children were twice as likely to have optimal vitamin D concentrations (≥75 nmol/L) and those with severe early childhood caries were at nearly three times the odds of having deficient levels (<35 nmol/L) 29>. On the one hand, it is important to clarify that serum vitamin D does not change the major structure of teeth since this structure remains constant until some extrinsic factor causes its wear. Notwithstanding, apparently vitamin D prevents caries lesions through immune regulation, promoting microbial eradication with peptide activity as discussed above.
The roles of both UVB and antimicrobial peptides (AMPs) in cariogenic bacteria reduction have been studied 74,75,76,77,78,79,80,81>. The mechanism through which UVB reduces the risk of dental caries is likely to be through the production of vitamin D and followed by the induction of AMPs, which have antimicrobial properties 74,76,77,78,79,80,81>. AMPs are host defense peptides, mostly cationic and amphiphilic molecules, that are essential elements of the innate immunity against several bacteria, fungi and viruses 75,78>. Investigations seem to point to a combination of AMPs rather than a specific role of a single AMP 79>, and they have been proposed as potential application for the prevention and treatment of dental caries 80,81>. Remarkably, Streptococcus mutans, a primary etiological agent of dental caries, may resist host salivary AMPs explaining its virulence in dental caries pathophysiology 74,77,80>.
Hence, we can conclude that vitamin D control levels prior to conception may be important to reduce the risk of enamel defects in deciduous teeth and should be controlled throughout pregnancy and after delivery.
2.2. Vitamin D Deficiency and PeriodontitisPeriodontitis is a complex polymicrobial disease induced by plaque and with persistent chronic inflammation 82>. Periodontitis is one of the two most prevalent diseases worldwide and its severe stage is the sixth most prevalent, with strong socioeconomic and systemic repercussions 26,27,83,84,85>. It has great impact on quality of life and is recovered after periodontal therapy 86,87>. The systemic link between periodontitis and other diseases and conditions has escalated, such as diabetes 88>, ischemic stroke 89>, cardiovascular disease (CVD) 90>, rheumatoid arthritis 91>, inflammatory bowel disease 92>, stress 93>, solid-organ transplanted individuals 94>, or preterm birth 95>. Furthermore, the impact of nutrition on periodontal health, and in particular VDD, has been intensively investigated 96,97,98,99,100> and a recent European consensus stated that an inadequate vitamin D status impacts periodontal health and oral functions 24>.
Several cross-sectional studies have compared the levels of Vitamin D between individuals with periodontitis and without periodontitis; however, the results remain diverse. While most reports show that periodontitis was associated with lower levels of Vitamin D compared to non-periodontitis 101,102,103,104,105>, another has reported no differences 106>. Further, vitamin D concentrations were associated with higher periodontal destruction, severe periodontitis stages and higher tooth loss 30,107,108,109>. In otherwise healthy patients (CVD and diabetes mellitus), lower levels of Vitamin D were also associated when periodontitis was diagnosed 102,104>.
Data from the NHANES III study, performed in the USA, showed that individuals with the highest levels of vitamin D experienced 20% less bleeding on probing than those with the lowest levels 30>. Other investigations also demonstrated that lower levels of gingival inflammation are associated with people without periodontitis 101,104>.
Comprehensively, the inflammatory and immune actions against periodontal pathogens are triggered by the host immune system. As previously mentioned, salivary low levels of vitamin D were associated with higher levels of inflammation biomarkers in periodontitis patients when compared to periodontally healthy patients (namely IL-35, IL-17A and transforming growth factor), supporting the presence of an inflammatory microenvironment 106>. Remarkably, vitamin D supplementation was linked to a decrease of salivary cytokines before nonsurgical periodontal treatment 110>. In addition, a cross-sectional study showed through gingival samples that periodontitis patients exhibited lower levels of VDR and fewer fibroblast cells with higher inflammatory cell infiltration compared with healthy periodontal individuals 111>.
Although not fully understood, Vitamin D has apparent fine-tuning, anti-inflammatory and mineralization effects on the periodontium according to the latest in vitro evidence. A study showed that vitamin D may decrease the number of live porphyromonas gingivalis through active autophagy 112> and might alleviate the inflammatory burden of periodontitis in rodent models: decreasing inflammatory levels (RANKL, TNF-α, IL-1, MMP-9) 113,114,115,116>; inhibiting IL-6 overexpression 117>; and suppressing alveolar damage via inhibition of bone loss, apparently through systemic T-helper cells 118>. In cultured human periodontal cells, Vitamin D induced a comparable mineralization effect to vitamin C 119>.
Thus both preclinical and clinical studies support the idea that vitamin D, through its metabolic pathway, might be involved in the pathogenesis of periodontitis, by impacting tooth mineral density and being reversely correlated with disease severity of periodontitis 25,97,120> (Figure 3).
From a genetic perspective, the role of VDR variants in periodontitis has been the subject of great consideration. In two recent evidence-based studies, a number of VDR polymorphisms were correlated with higher risk of developing periodontitis 121,122>. Notwithstanding, the VDR variants’ impact on periodontitis still remains to be consolidated since it depends on the number of studies, and is expected to increase considerably in the future.
On the other hand, the influence of vitamin D supplementation was studied in both nonsurgical and surgical periodontal treatments. Vitamin D and calcium supplementation showed moderate positive effects on periodontal health after nonsurgical periodontal treatment 98,110,111,123,124>. Further, baseline VDD negatively influenced periodontal surgery outcomes, even when supplementation was used to compensate for low levels 125> (Figure 3). Despite that these studies show vitamin D as a hypothetical hallmark for the success of patients’ treatment, more studies are warranted to infer scientific fallouts and permit definite conclusions.
In addition, a number of reports have explored the association between periodontitis and maternal VDD and found that pregnant women with moderate to severe periodontitis were linked to lower serum levels of vitamin D, compared to women with periodontal health 99,126,127,128,129>. Importantly, non-surgical periodontal treatment during pregnancy was proved to be successful in reducing adverse pregnancy outcomes; however, concomitant vitamin D supplementation showed mild clinical improvements in birthweight 128,130,131,132,133>. As such, future studies should assess this relationship in greater detail considering the amount of evidence that Vitamin D impacts periodontal health and maternal health.
With the increase in importance of aesthetic requirements, facial micro- and macro-aesthetics and smile have become a priority for adolescents and adults 134,135>. Consequently, orthodontic treatments have become increasingly prevalent.
Tooth movement relies on the application of predetermined forces that cause mechanical stimuli with two simultaneous processes: (1) bone resorption on the pressure site, through osteoclastic activity; and (2) bone formation on the tension site, by osteoblastic action 136,137,138>. These two processes in combination with mechanical, chemical or electrical stimuli, might result in faster teeth movement 139,140,141,142>. Regarding the chemical factors, vitamin D might play a key role in tooth movement during orthodontic treatment and has shown promising results 33>. Albeit animal observational in nature, there is an increasing body of evidence showing that local application of vitamin D results in a faster tooth movement 136,143,144,145>. Notwithstanding, VDD in animal models causes a slower rate of tooth movement, and consequent treatment delay or complications 136,143,144>. In this sense, future studies in humans are needed to determine if VDD has a clinically significant effect on tooth movement and if vitamin D supplementation during orthodontic treatment, for instance in hypovitaminosis cases, improves the coupling of formation and resorption in alveolar bone remodeling during orthodontic tooth movement.
2.4. Vitamin D Deficiency and Oral PathologyVitamin D might play an important function in the onset and progression of certain oral cancers, though there is still much to research. Remarkably, VDD is more common in patients with oral neoplastic lesions 22>. In a case-control study, VDD was associated with increased risk of squamous cell carcinoma of the esophagus, oral, and pharyngeal cancers, which were more prevalent in heavy smokers and severe alcoholism 146>. Another study has revealed that VDR expression was increased in premalignant lesions and oral cancer, and vitamin D supplementation significantly diminished therapy-related toxicities in late-stage oral cancers, with less morbidity and better quality of life 120>. Therefore, future studies should make efforts to clarify how VDD relates to oral cancer development and its therapeutic efficacy towards anticancer toxicity medications.
The role of VDD in osteonecrosis of the jaw (ONJ) is an increasingly discussed topic; however, Vitamin D status in ONJ individuals remains unestablished 147,148,149>. ONJ is characterized by a progressive death of the exposed jawbone in a patient chronically exposed to anti-absorption or anti-angiogenic medications, and no history of mandibular radiotherapy or metastatic disease of the jaw (Patel et al., 2018). Due to its role in bone mineralization, several studies have investigated the levels of Vitamin D in ONJ cases, mainly derived from osteoporosis and cancer patients 148,149,150,151,152,153,154>. The most recent evidence suggests that VDD is not a risk factor for the onset of ONJ events 148,154>, while other studies underline a potential role 149,153>. Nonetheless, future studies should focus on the influence of baseline VDD and of Vitamin D supplementation towards ONJ, as well as the establishment of 25(OH)D level standards for patients at high risk of ONJ events.
3. Conclusions
VDD is highly implicated with oral diseases and has been linked with a higher risk of tooth defects, caries, periodontitis and oral treatments failure. The maintenance of appropriate 25(OH)D levels has shown to be associated with better oral development and health throughout life, though the impact of VDD correction through supplementation demands more evidence to allow definitive conclusions and potential clinical guidelines. Nevertheless, 25(OH)D levels should be considered to ensure a balanced oral health, and these levels need to be verified before the treatment of any oral conditions to warrant fruitful treatment outcomes.References
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