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Curr Oral Health Rep (2016) 3:337–346

DOI 10.1007/s40496-016-0116-9

EPIDEMIOLOGY (M LAINE, SECTION EDITOR)

The Potential Impact of Essential Nutrients Vitamins C and D


upon Periodontal Disease Pathogenesis and Therapeutic
Outcomes
Gareth R Brock 1 & Iain L C Chapple 2

Published online: 7 October 2016


# Springer International Publishing AG 2016

Abstract Diet has powerful effects upon inflammatory status, chronic diseases, largely because it is driven by different ex-
arguably as strong or stronger than microbial plaque. Despite a posures that individually impact to differing degrees of mag-
relationship between diet and periodontal inflammatory markers nitude in different patients and which also interact with each
being established over 30 years ago, it is only recently that the other in a variable manner (the biological phenotype). These
mechanisms underpinning these effects have begun to be exam- exposure categories include genetic (gene polymorphisms),
ined in detail. Following an analysis of the evidence base in environmental (stress, bacteria), lifestyle/behavioural (exer-
2011, this review focuses upon the most contemporaneous ev- cise, nutrition) and pharmacological (different drugs) expo-
idence relating specifically to the micronutrient vitamins C and sures. Individual constituents of these broad categories are
D and their potential impact upon periodontal disease pathogen- component causes of periodontitis, since they contribute to a
esis and/or therapeutic outcomes. The authors bring together series of biological events that drive exaggerated inflamma-
both epidemiological and laboratory data and aim to outline tion [1] and/or inflammation that fails to resolve [2]. Nutrients
avenues for potential studies given the limited number of larger are broadly categorised into six classes:
well-conducted clinical interventional trials completed to date.
& Vitamins (A, B, C, D, E, K)
Keywords Periodontitis . Micronutrients . Dietary & Minerals/trace elements (selenium, zinc, copper, iron)
supplements . Vitamin C . Ascorbic acid . Vitamin D & Proteins
& Carbohydrates
& Fats (including essential fatty acids, ω3 and ω6)
Introduction & Water

The ‘signature’ host response of periodontitis exhibits wide Broadly, they may be categorised as or ‘micronutrients’
phenotypic heterogeneity as is the case with many complex (minerals, vitamins) required by the body in relatively small
amounts and ‘macronutrients’ (proteins, fats, carbohydrates,
polyunsaturated fatty acids/PUFAs) required by the body in
This article is part of the Topical Collection on Epidemiology
relatively large quantities from the diet [3]. It has long been
recognised that diet adversely influences inflammatory peri-
* Gareth R Brock
gareth.brock@manchester.ac.uk odontal status. A classical study in 1984 [4] observed that
irrespective of levels of plaque, more gingival bleeding was
experienced in young adults who undertook 21 days of exper-
1
Division of Dentistry, School of Medical Sciences, Faculty of imental gingivitis whilst fed on multiple daily snacks of re-
Biology, Medicine and Health, The University of Manchester, J R
Moore Building, Oxford Road, Manchester M13 9PL, UK
fined carbohydrates, than when the same volunteers crossed
2
over within the same study to a low-sugar diet. More recently,
School of Dentistry, Institute of Clinical Sciences, College of
Medical & Dental Sciences, The University of irmingham,
a Swiss study found that when 10 adults were placed in a
Birmingham Dental School and Hospital, 5 Mill Pool Way, ‘stone-age’ environment for 4 weeks, with no oral hygiene
Birmingham B5 7EG, UK and diets were ‘stone-age’ in nature (id est. low in simple
338 Curr Oral Health Rep (2016) 3:337–346

sugars and high in antioxidant micronutrients, fish oils and resulting vitamin C radical is ultimately restored to its non-
fibre), they remarkably demonstrated significant decreases in radical state by the chain breaking antioxidant glutathione
gingival bleeding and probing depths, despite significant in- (GSH) (Fig. 1).
creases in plaque accumulation [5]. Diet therefore has power- Statistics from the Health and Social Care Information
ful effects upon inflammatory status, arguably as strong or Centre that compiles data sent by more than 300 National
stronger than microbial plaque, and until recently, the mecha- Health Service (NHS) Trusts in England and approximately
nisms underpinning those effects were poorly understood. 200 independent sector organisations for activity commis-
The evidence base for nutrition as a factor influencing peri- sioned by NHS England show a rise in the diagnoses of scur-
odontal health and disease was recently reviewed by Van der vy—Summer 2013–2014 showed 15 cases where this was the
Velden et al. [3] and this chapter therefore focuses upon the primary cause for admission, and 94 cases where this was the
most contemporaneous evidence relating specifically to vita- primary or secondary diagnosis [7]. Despite these relatively
min C and vitamin D (and calcium) as essential nutrients that low numbers, subclinical vitamin C (ascorbate) deficiency
may impact upon periodontal disease pathogenesis and/or seems to be more commonplace. Assuming a normal ascor-
therapeutic outcomes. bate serum concentration range of 5–15 mg/L, the risk of
developing scurvy becomes significant at <2 mg/L. Fain
(2003) defined <5 mg/L as ascorbate insufficiency and
Vitamin C <2 mg/L as deficiency; in hospitalised individuals, 16 % had
levels <2 mg/L and 56 % had less than 5 mg/L [8].
History, Nutritional Value and Deficiency
The Relevance of Vitamin C in Tissue Biochemistry
‘They all in general had putrid gums, the spots and lassitude,
with weakness of the knees’—James Lind’s observations of The reduced form of vitamin C (ascorbic acid, ascorbate) can
12 sailors on board the Salisbury at the start of his experiment be synthesised from glucuronate by vertebrates that retain this
on 20 May 1747, some 8 weeks after leaving port. By the end capacity; however, the last enzymatic step in its synthesis
of May, the two men assigned to the citrus fruit (vitamin C) cannot be achieved in man due to a mutation in the gene that
arm of his study were almost fully recovered—although the encodes this enzyme. Therefore, ascorbic acid and its oxidised
Royal Navy did not adopt citrus rations and eliminate scurvy form dehydroascorbic acid (DHAA) must be obtained through
until 1795 [6]. Vitamin C is an essential micronutrient and an dietary intake. Furthermore, as this is a water-soluble vitamin,
enzyme co-factor that acts as an electron donor that maintains there is a limited storage pool and the threshold for renal
metal ions in a reduced state for optimum enzyme activity. It is excretion is low; the mechanistic case for ascorbate insuffi-
also a powerful water-soluble antioxidant capable of ciency and deficiency is therefore clear.
regenerating vitamin E from its radical, which forms during The relationship between chronic inflammatory diseases
oxygen radical attack on the lipid membranes of cells. The and redox imbalance has been established both in general

Fig. 1 Intracellular reducing power linked to the antioxidant status of subsequently be regenerated intracellularly by glutathione (GSH)-depen-
both the lipid- and water-soluble environment. Following vitamin E dent dehydroascorbate reductase to yield oxidised glutathione (GSSG) or
(tocopherol) oxidation to the tocopheryl radical by an attacking radical by nicotinamide adenine dinucleotide phosphate (NADPH)-dependent
(R·), alpha tocopherol can be regenerated by a redox reaction with ascor- dehydroascorbate reductase to yield oxidised NADP+
bic acid at the lipid-water interface. The oxidised form of ascorbate can
Curr Oral Health Rep (2016) 3:337–346 339

terms and also in relation to periodontal disease. The antiox- females also maintain higher plasma ascorbate levels than
idant capacity of ascorbate as a powerful scavenger of reactive men at a given vitamin C intake. Extracellular oxidised vita-
oxygen and nitrogen species is therefore central to its protec- min C (dehydroascorbate) is partly transported intracellularly
tive role. Post-translational modifications of polypeptide pro- via facilitative glucose transporters; an excess of glucose may
collagen require iron-dependent enzymes, which are protected therefore competitively block DHA uptake and impair
by vitamin C from reactive oxygen species (ROS) attack. recycling/extracellular clearance of DHA as well as inhibit
These modifications help to promote the synthesis of a mature neutrophil functions as described above. In a concept that
collagen network and allow secretion into the extracellular was developed nearly 30 years ago [13], recent research has
milieu within the periodontal tissues. Ascorbate also influ- begun to shed light on the importance that excess glucose has
ences the biosynthesis of other connective tissue components on ascorbate concentrations in red blood cells with subsequent
including elastin, fibronectin, proteoglycans, bone matrix and microvascular angiopathy [14]. The significance that this may
elastin-associated fibrillin. Both ascorbate and DHAA are have on compromised host defences in the periodontal com-
concentrated intracellularly, whereas ascorbate that has under- plex of poorly controlled diabetes patients remains to be
gone radical scavenging can be recycled intracellularly via determined.
another potent antioxidant reduced glutathione (GSH) Rich sources of vitamin C include kiwi fruit, yellow pep-
(Fig. 1). GSH levels in extracellular fluids can be rapidly pers and broccoli; the sensitivity of ascorbate to light, heat and
depleted in conditions of oxidative stress unless there is suffi- air would indicate that fresh products need to be consumed in
cient chain-breaking activity provided by further GSH synthe- a raw state or only lightly cooked. Pharmacokinetic models
sis. With these systems in mind, it is hardly surprising that have shown that maximum bioavailability is usually attained
high concentrations (10–40 times higher than plasma) of at lower doses when supplements are used and declines with
ascorbate are present within cells that are key to the periodon- elevation in supplement dose (70–90 % for usual dietary in-
tal inflammatory environment—namely endothelial cells, takes of 30–180 mg/day, <50 % for doses 1250 mg) [15, 16].
neutrophilic polymorphonuclear leukocytes (neutrophils) One must also consider the attendant risk of tooth wear that
and macrophages. Furthermore, ascorbate has been shown regular use of non-buffered chewable vitamin C preparations
not only to enhance chemotaxis of normal neutrophils but also may pose [17]. Furthermore, supplementation with high doses
to improve microtubule assembly and their subsequent bacte- of vitamin C in isolation also acts as a clear risk factor for renal
ricidal activity with impaired lysosome degranulation, as is stone formation [18]. The relative importance or significance
seen in the improved clinical course of patients with of a given antioxidant may therefore rely not only on its reac-
Chediak-Higashi syndrome, following ascorbate supplemen- tion and concentration in a given compartment but also on its
tation. Moreover, typical plasma ascorbate concentrations ability to interact with antioxidant regeneration systems of
have been shown to scavenge hypochlorous acid (HOCl), varying types, such as intracellular dehydroascorbate
one of many powerful oxidants generated by myeloperoxidase recycling via GSH-dependent mechanisms, and the synergis-
in activated neutrophils and monocytes [9]; it is in turn tic relationship between vitamin C and vitamin E whereby
hypothesised that this protects against further tissue damage water-soluble ascorbate can interrupt free radical chain prop-
that alpha-1-antiprotease inactivation and low-density lipo- agation in the lipid phase.
protein (LDL) oxidation would contribute indirectly to as the
result of uninhibited phagocyte-derived oxidants in the locally Vitamin C and Periodontal Diseases
inflamed periodontal tissues.
The recommended dietary allowance (RDA) of 90 mg/day for
A Mechanistic Link Between Vitamin C, Excess Glucose adult men and 75 mg/day for adult women is based on vitamin
and Periodontal Tissue Pathology? C intake to maintain near-maximum neutrophil concentrations
with minimal urinary excretion of ascorbate, with an increase
The efficiency of vitamin C active transport in the small intes- of 35 mg/day in smokers given the increased oxidative stress
tine appears to decrease with increasing doses and impaired that smoking poses. Scorbutic gingivitis (Fig. 2) is reported at
intestinal absorption in the elderly has been suggested as one levels <10 mg/day [19]. Nevertheless, data on which these
mechanism, although the majority of evidence indicates that recommendations were made is limited and therefore on the
there is no greater incidence of vitamin C deficiency with basis of more recent evidence, some authorities have recom-
advancing age [10]. Plasma ascorbate concentration has a sig- mended that the ideal daily intake of vitamin C should be up to
moidal relationship with increased daily intake, the plateau of 200 mg from a variety of fresh fruit and vegetables [20–22].
which is lower in women than males [11]. Furthermore, The vast majority of studies from the early 1980s onwards
smokers typically exhibit a lower plasma ascorbate concentra- report an inverse association between serum/plasma vitamin C
tion compared with non-smokers or former smokers, even concentrations and periodontal status, although the measures
when adjusted for differences in vitamin C intake [12]; and populations within which each study has been conducted
340 Curr Oral Health Rep (2016) 3:337–346

found between plasma vitamin C levels and the severity of


attachment loss in a relatively large population deprived of
regular dental care [27], as well as in an elderly Japanese
population [28].
A recent longitudinal retrospective cohort study with a 2-
year follow-up aimed to explore the relationship between in-
take of dietary antioxidants and periodontal disease in
community-dwelling older Japanese [29]. The results suggest
that antioxidant micronutrient levels (including vitamin C)
which can be obtained through diet rather than supplements
have a positive protective impact on the periodontal tissues.
Interestingly, the mean levels of vitamin C intake were ap-
Fig. 2 Scorbutic gingivitis is reported at levels <10 mg/day vitamin C
proximately 200 mg/day, matching the suggested intake of
intake Levine [30] but exceeding the 70 mg/day found in the
British National Diet and Nutrition Survey of over 65 s [31],
although estimates were made using a food frequency ques-
vary widely [3]. Furthermore, most research to date is of tionnaire which has a tendency to overestimate levels of in-
cross-sectional design. Although smoking clearly reduces take. Nevertheless, these data concur with the former Japanese
mean serum/plasma vitamin C concentration, NHANES III studies reported in 2007 and 2009 and imply that dietary
data analysis has shown this inverse relationship in current, modification to increase the consumption of fruits and other
former and never smokers, although the inverse association vegetables (containing not only vitamin C) may be beneficial
appears to be stronger in never smokers [23]. to oral health and have a therapeutic and preventative role in
A recent study comparing systemically healthy subjects periodontal disease [32, 33]. This cohort was observed over a
(n = 150) and type 2 diabetes patients with (n = 150) and with- short time period, did not report any additional supplement
out (n = 150) periodontitis showed the same trend, with de- use, had a limited number of teeth and did not report any
creased serum vitamin C concentrations in volunteers with related diseases; therefore, the authors report that overestima-
diabetes regardless of periodontal status, although mean con- tion due to residual confounding of the observed association
centrations in those subjects who also had periodontitis as a remained a risk in their analysis.
co-morbidity were even lower [24].
So does hampered neutrophil function due to reduced plas- The Impact of Vitamin C on Therapeutic Outcomes
ma vitamin C concentration explain this relationship? A recent
study with a relatively small group of periodontitis (n = 21) There are very few intervention studies examining whether
and control (n = 21) subjects did show a negative correlation greater intake of fruits and vegetables or specific
between neutrophil vitamin C concentrations in patients’ and micronutrients with antioxidant/anti-inflammatory activity
probing pocket depth, although there were no significant dif- are associated with improved clinical and dietary measures
ferences in peripheral neutrophil and peripheral blood mono- after routine non-surgical periodontal therapy. Javid et al. ex-
nuclear cell vitamin C concentrations between these two vol- amined the impact of personalised dietary intervention de-
unteer groups [25]. Whilst the relationship between low plas- signed to increase consumption of fruits, vegetables and
ma vitamin C concentration and periodontitis could not there- whole grains on these measures [34]. At 3 and 6 months’
fore be explained by a hampered peripheral leucocyte function post-intervention (including routine non-surgical therapy),
due to a lack of intracellular vitamin C, it may be that neutro- those subjects given tailored advice (n = 18) showed a signif-
phils with lower vitamin C concentrations may exit periodon- icantly higher intake of fruits and vegetables in addition to a
tal tissues via gingival crevicular fluid rather than returning to significantly increased plasma total antioxidant capacity com-
systemic circulation. An alternative explanation is that leuko- pared with unadvised controls (n = 19). As part of this, vita-
cyte vitamin C concentrations are protected by GSH oxida- min C intake was approximately 50 mg/day higher following
tion, as recent data has demonstrated GSH deficiency and a advice delivery, a difference that was maintained throughout
lowered ratio of GSH to its oxidised counterpart in neutrophils the study period. The findings provide support for delivering
from periodontitis patients relative to controls [26•]. personalised dietary interventions to patients with chronic
Furthermore, those patients with vitamin C insufficiency (i.e. periodontitis to improve their fruit and vegetable intake and
not sufficiently deficient to develop signs of scurvy) presented showed that baseline intake was consistently lower than UK
with greater bone loss compared with patients whose plasma [35] and World Health Organisation recommendations [36].
vitamin C was within normal limits. The data corroborates a The authors suggested that the lack of any significant changes
previous study where a significant inverse association was in periodontal indices may have resulted from the magnitude
Curr Oral Health Rep (2016) 3:337–346 341

of the dietary change being insufficient to alter these indices or The Role of Dietary Intervention to Increase Intake
that the period allocated after the dietary intervention or the of Foods Rich in Antioxidants (Rather Than
power of study were not sufficient to determine any significant by Synthetic Supplementation) in Patients
differences in these measures between the two groups. with Periodontal Disease
A North American cohort study of 63 non-smokers and 23
smokers showed that non-smokers with greater intakes of Larger, well-controlled clinical studies are required to build
fruits and vegetables (analysed by a validated food question- upon the currently limited evidence regarding improved tissue
naire) had a lower percentage of sites with probing depths resistance to periodontitis as a preventive or therapeutic strat-
>3 mm after debridement compared with patients with lower egy, or before it develops, during treatment and with the aim
intakes, having adjusted for BMI and bleeding on probing. of preventing disease recurrence.
Vitamin C was the nutrient most strongly correlated with peri- Studies investigating correlations between vegetarianism
odontal healing, although higher dietary intakes of the antiox- and oral health are rare. The first such cross-sectional study
idants vitamin C, β-carotene and α-tocopherol were all asso- with 200 age, smoking and gender-matched participants split
ciated with greater probing depth reductions. However, asso- equally between vegetarians (with at least a 2-year dietary
ciations were consistently attenuated when contributions from history) and non-vegetarians, reported significantly lower
dietary supplements were included in the authors’ analyses, probing pocket depths and % bleeding on probing in vegetar-
suggesting again that the synergistic effect of whole foods ian participants [41]. The reported association may relate to a
rather than purified compounds in supplements offers a more healthier lifestyle in general, and therefore, factors such as
robust approach, in addition to the potential benefit of more obesity/BMI may play a role, as well as frequency of dental
than 5000 plant-based phytochemicals that have not been ex- visits and better dental home care. However, the reported find-
amined here [37•]. This may also explain the findings of a ings may also have a nutritional basis with greater quantities
small intervention study where two groups (n = 15 per group) of antioxidant micronutrient consumption. Jenzsch et al. [42]
of chronic periodontitis patients were treated with a standard have previously reported that a planned dietary intervention
non-surgical protocol; however, one group was supplemented without changes to oral hygiene regimen or professional den-
with 2 g/day vitamin C for 4 weeks post-therapy [38]. Despite tal input can influence probing pocket depths and inflamma-
both groups’ total plasma antioxidant capacity significantly tory markers and therefore these cross-sectional findings may
increasing following therapy, vitamin C supplementation genuinely represent positive effects of a vegetarian diet upon
showed no additional clinical or plasma antioxidant benefit. periodontal tissues.
Whilst this may also be explained by low subject numbers and
clinical therapeutic outcomes, one may speculate that supple-
mentation with single vitamin has limitations given that anti- Vitamin D and Calcium
oxidants in vivo act in concert. Willershausen et al. examined
a small cohort of dental students before and after their final Supplementation Is Not Universally Agreed Upon
examinations, having divided the cohort into a non-
supplemented group and a test group provided with a daily There has been a significant volume of scientific literature
micronutrient combination for 3 months. Measurements for published on vitamin D compared with other vitamins, al-
vitamins C and E increased after 3 months supplementation; though some authorities are advising caution in ‘the recent
despite poorer plaque control in both test and control groups rush to elevate serum 25(OH)D concentrations universally’
thought to be related to exams, a smaller increase (albeit non- [43]. The classical expression of vitamin D deficiency is poor
significant) in sulcular bleeding was reported in those subjects skeletal development and bone and joint deterioration, how-
taking the micronutrient combination compared with the con- ever, as well as promoting calcium absorption in the gut and
trol group [39]. maintaining adequate serum calcium and phosphate concen-
A similar two-arm 8-week study with non-smoking trations for bone growth and remodelling, vitamin D plays
volunteers screened for mild to severe periodontitis in- significant roles in the modulation of cell growth and neuro-
cluded a group who were supplemented with a complex muscular, immune and inflammatory functions [44].
multivitamin and phytonutrient formulation group (n = 40) Vitamin D is a fat-soluble vitamin that is naturally present
and a placebo formulation (n = 45). The nutritional sup- in very few foods. Endogenous production can also be trig-
plement modestly decreased periodontal inflammation; for gered in the skin under the influence of ultraviolet light. Both
probing depths of ≥4 mm, the nutritional supplement was dietary and endogenous forms are biologically inert and un-
associated with a significant decrease in the gingival in- dergo two hydroxylation reactions for activation: the first in
dex score and although not statistically significant, the the liver (vitamin D to 25-hydroxyvitamin D: 25(OH)D,
test supplement group demonstrated a decrease in bleed- calcidiol) and the second primarily in the kidney to form phys-
ing scores [40]. iologically active 1,25-dihydroxyvitamin D (1,25(OH)2D,
342 Curr Oral Health Rep (2016) 3:337–346

calcitriol). Serum 25(OH)D concentrations are regarded as a the higher levels recommended by the International
reliable indicator of vitamin status and function as a biomarker Osteoporosis Foundation [52], some authorities suggest that
of exposure (given a circulating half-life of 15 days) [45], even these would only normalise serum calcidiol concentra-
although it is not clear to what extent this serves as a biomark- tions in not more than half the US population (reviewed in
er of health status/outcomes [46]. In contrast, calcitriol has a [53]).
short half-life and is therefore an unreliable indicator of vita- It is therefore not surprising that optimal serum vitamin D
min D status. Furthermore, considerable variability has concentrations for bone health are the subject of continuing
existed in serum calcidiol measurements until 2009 when a debate, although the Endocrine Society has issued clinical
standard reference material that permits cross-laboratory and practice guidelines of >30 ng/mL to maximise the effect of
cross-assay standardisation was made available; indeed the vitamin D on calcium, bone and muscle metabolism [47].
relationship between increased vitamin D intake and serum Nationally representative data estimated that 9.9 % of the
calcidiol levels is reported to be non-linear. US population is vitamin D deficient (25[OH]D <20 ng/mL)
The major source of vitamin D is exposure to natural sun- and 32 % is insufficient (25[OH]D 21–29 ng/mL), using cut
light; furthermore, vitamin D produced in the skin may last at points to maintain healthy bones defined by the Institute of
least twice as long in the blood compared with ingested vita- Medicine (IOM).
min D. Whilst topical sunscreen application, increased skin Review of the contemporaneous scientific literature recent-
pigmentation and obesity can dramatically reduce vitamin D ly led the US Agency for Healthcare Research and Quality to
synthesis, alteration in the zenith angle of the sun due to a conclude that it is still not possible to specify a relationship
change in latitude and season or even time of day also have between vitamin D and health outcomes other than bone
a profound influence on the skin’s vitamin D synthesis [47]. health [54]. Furthermore, a meta-review of systematic reviews
Seasonal variation, location and body fat therefore significant- and meta-analyses suggests that there is no highly convincing
ly affect the diagnosis of vitamin D sufficiency and should be evidence for a clear role for vitamin D supplementation in a
carefully considered when conducting investigations [48]. wide range of health outcomes (skeletal, malignant, cardiovas-
Vitamin D exerts its biological effects by binding to the cular, autoimmune, infectious metabolic and other diseases),
vitamin D receptor (VDR); a potential role for vitamin D in although ‘associations with a selection of outcomes are prob-
periodontal health is supported by polymorphisms in the VDR able’ [55]. To illustrate this, a recent publication found that
gene which have been reported in many studies to be associ- patients given high doses of vitamin D or those on lower doses
ated with periodontitis [49, 50]. The vitamin D–VDR com- that increased vitamin D blood levels within the optimal range
plex stimulates RANKL (receptor activator of nuclear factor had a 20–30 % increased rate of fractures and falls compared
kappa-B ligand) expression in cells such as osteoblasts and with those on low doses or who failed to reach ‘optimal blood
downregulates OPG (osteoprotegerin), thus favouring differ- levels’ [56]. The strategy of supplementation to achieve plas-
entiation and activation of osteoclasts and increased bone re- ma concentrations of 30 ng/mL has not been established by
sorption. Low vitamin D levels may stimulate an increase in randomised, controlled trials to reduce the risks of fractures or
circulating levels of parathyroid hormone which indirectly falls, but on the basis of observations showing healthy sub-
stimulate bone resorption in order to liberate vitamin D. jects have higher plasma vitamin concentrations.
Although vitamin D therefore appears to stimulate bone re-
sorption, the catabolic effects can be transient and after longer The Relationship Between Vitamin D and Periodontal
periods of exposure may facilitate osteoblast proliferation, the Disease Prevalence
relevance being the length of time for which future interven-
tion trials are conducted for (for review, see [51]). Epidemiological (cross-sectional) data regarding the preva-
lence of periodontitis and serum vitamin D levels initially
The Debate over Optimal Vitamin D Intake appears somewhat conflicting, although trends do seem to
exist. Authors who examined the US NHANES dataset have
There is ongoing debate regarding what constitutes adequate previously reported serum calcidiol levels to be significantly
vitamin D intake. In 2010, the US Institute of Medicine re- and inversely associated with attachment loss in men and
leased new recommendations for dietary intake of vitamin D: women ≥50 years independently of bone mineral density
400 IU/day (0–12 months of age), 600 IU/day (1–70 years of [57]; subsequent analysis of the same dataset also found that
age) and 800 IU/day for older adults (>70 years of age) (IU = low calcidiol levels were associated with greater amounts of
25 ng). Several experts feel that although these Institute of bleeding on probing. The most recent analysis of a Korean
Medicine recommendations may prevent clinical vitamin D dataset demonstrated that periodontal status (examined by
insufficiency (typically reported as <30 ng/mL) and deficien- CPITN measures) was inversely correlated in current smokers
cy (<20 ng/mL), they may be suboptimal with regard to auto- alone; the authors suggesting that this may be due to the clin-
crine mechanisms of vitamin D action [51]. Indeed, even at ical measures employed to assess attachment loss or that
Curr Oral Health Rep (2016) 3:337–346 343

smoking influences the effect of vitamin D on periodontal clinical parameters regardless of such supplements. The au-
tissues [58]. Alshouibi et al. also reported that total vitamin thors pointed out that between-group differences of serum
D intake was inversely associated with the odds of having vitamin D concentrations were limited, and therefore, not all
severe periodontitis where total intake was ≥800 IU/day in subjects who used supplements may have had sufficient sup-
an older all-male North American patient sample (mean age plementation to ensure obtaining serum concentrations within
∼63 years) [59]. normal limits, thus potentially limiting clinical improvement
One study reported a positive association between plasma [67].
calcidiol and periodontal inflammation in young Chinese pa- Only one study to date has investigated the association
tients with aggressive periodontitis (n = 66; median age 27), between the vitamin D metabolite calcitriol and severity of
whereas those patients with chronic periodontitis (n = 52) did chronic periodontitis, possibly because this vitamin D marker
not present with significantly different plasma calcidiol con- is more labile than calcidiol. All volunteers were type 1 dia-
centrations relative to healthy control subjects [60]. However, betes patients (mean HbA1c 8.5 % over 1 and 3 years). The
there was no statistically significant correlation between plas- serum level of calcitriol was associated with periodontal dis-
ma calcidiol levels and attachment loss or probing depth, and ease severity in all subjects and non-smokers; subjects with
all subjects had sub-optimal serum vitamin D levels and were greater calcitriol concentrations were significantly more likely
therefore vitamin D insufficient or deficient. to belong to the group of subjects with no or mild periodontitis
than the group with moderate or severe disease. Moreover,
The Association Between Vitamin D and the Progression 8 weeks following non-surgical therapy, a significant increase
of Periodontitis in calcitriol concentrations was reported, despite virtually no
effect on calcidiol concentrations [68]. The authors concluded
Prospective studies examining associations between disease that this metabolite may vary in concentration between sys-
progression and calcidiol concentrations that reflect intake temic and local pools, although both smoking and diabetes
from all sources (diet, supplements and sun exposure) are may influence these data.
limited. Zhan et al. concluded that increasing concentrations
of calcidiol were associated with a reduced risk for tooth loss Vitamin D, Vitamin D Receptor Polymorphisms
but not progression of clinical attachment loss over the follow- and the Innate Immune Response
up period (mean 5.9 years) [61]. This was equivalent to a 13 %
decreased risk of tooth loss with each 10 ng/mL increase in Vitamin D can also affect bone metabolism via anti-
25(OH)D concentration. There may be a small favourable inflammatory mechanisms. For example, calcitriol interferes
effect on reduced CAL loss; however, measurement error with nuclear factor-kappa B activation and significantly
and adjustment for vitamin D supplement use may have atten- downregulates Porphyromonas gingivalis-induced expression
uated findings [62]. Two other prospective studies also ob- of IL-8, an important pro-inflammatory cytokine, in cultured
served no association between calcidiol and progression of human periodontal ligament cells, although the various path-
periodontitis, although one did observe a protective effect of ways through which this may occur are yet to be fully eluci-
‘optimal’ vitamin D concentration and tooth loss [63, 64]. dated [69].
However, at baseline, Millen et al. found a 33 % lower odds Assuming that reduced vitamin D can lead to increased
of prevalent periodontal disease (defined using the AAP def- clinical signs of periodontal inflammation, this hypothesis al-
inition), among women with adequate compared with inade- so fits with vitamin D receptor gene polymorphisms’ associ-
quate vitamin D status, and an inverse association between ation with periodontitis. Whilst this has been traditionally as-
serum vitamin D concentration and percentage of sites that cribed to the role of vitamin D in bone loss, vitamin D-
bled on probing [65]. mediated gene regulation (via VDR) of the innate immune
A further prospective study in a cohort of older American response, i.e. the first line of defence against colonisation by
men followed this trend with more severe periodontitis signif- periodontal pathogens may also play at least as important a
icantly associated with lower levels of calcidiol, but not with role. The enhancing of innate antimicrobial defence by host
disease progression. Furthermore, bleeding on probing was peptides such as LL-37 by active vitamin D (calcitriol) in
greater in those subjects with the lowest serum vitamin D gingival epithelial cells certainly points to the potential impor-
concentrations [66]. tance of vitamin D in the primary prevention of the inflamma-
A cross-sectional and subsequent prospective cohort study tory periodontal diseases [70].
in post-menopausal females also showed that calcium and In summary, these data suggest that adequate vitamin D
vitamin D supplementation had a modest positive effect (less levels may exert a protective influence in periodontal health,
BOP) on periodontal health over 12 months in subjects en- both in a primary prevention and a maintenance phase of care.
rolled on a periodontal maintenance programme. This appears likely to relate to reducing acute measures of
Nevertheless, consistent dental care improved periodontal periodontal inflammation rather than measures that reflect
344 Curr Oral Health Rep (2016) 3:337–346

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