The relationship between tooth loss and hypertension: a systematic review and meta-analysis

As tooth loss is the high end of periodontal problems and edentulous individuals are at higher risk of nutritional problems like obesity, understanding the association between tooth loss and hypertension is important for improving cardiovascular health. We searched for publications from the last two decades using three electronic databases (PubMed, Web of Science and Scopus) and conducted a systematic review and meta-analysis on the association between tooth loss and hypertension according to PRISMA-P guidelines. Quality assessments were performed using the Newcastle–Ottawa Scale and the GRADE approach. Twenty-four studies (20 cross-sectional, and 4 cohort) met the inclusion criteria for this review. Most cross-sectional studies showed that subjects with more tooth loss exhibited a greater proportion of hypertension and higher systolic blood pressure than those with less tooth loss. Meta-analyses revealed a statistically significant association between tooth loss and hypertension. The pooled odds ratios of hypertension for having tooth loss with no tooth loss and for edentulous with dentate were 2.22 (95% CI 2.00–2.45) and 4.94 (95% CI 4.04–6.05), respectively. In cohort studies, subjects with more tooth loss had a greater incidence of hypertension than those with less tooth loss during the follow-up period. The present systematic review and meta-analysis suggests that tooth loss is associated with an increased risk of hypertension and higher systolic blood pressure.

The overall quality of evidence was evaluated using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) framework 33 . In this review, a narrative GRADE was chosen according to the types of studies included. Certainty of the evidence was evaluated in terms of study design, risk of bias, inconsistency, indirectness, and imprecision parameters, with categorization into one of four ratings: high, moderate, low, and very low 34 . Evidence issued in this review includes observational data, it started at low quality and then other issues within the magnitude of the effect, inconsistency, indirectness, imprecision, and counteracting plausible residual bias or confounding could be used to downgrade the evidence 35 . However, the quality of evidence can increase if studies strictly meet one of the following criteria: the magnitude of the treatment effect is very large. There is evidence of a dose-response relationship, or all plausible biases would decrease the magnitude of the treatment effect 36 . Data extraction. Data were extracted from each eligible study by three independent authors (Akio Tada, Rumi Tano, and Hiroko Miura) using a specifically developed data extraction sheet. Disagreements were resolved by consensus. The following data were extracted from each eligible study: first author, publication year, setting, type of study, number of subjects, confounding factors (demographic factors, socio-economic factors, health habits including smoking and alcohol consumption, and systemic disease such as diabetes, hypercholesterolemia, and obesity), and outcome measures including both adjusted odds ratios and 95% confidence intervals (CIs).
Statistical analysis. Meta-analyses were conducted using a random-effects model. Studies were excluded if they did not report an outcome in each group or did not have enough information available to calculate the OR. The numbers of subjects according to the status of the remaining teeth and the presence of hypertension were extracted from each study. A separate meta-analysis was performed for each outcome variable. Effect sizes were reported as pooled ORs with 95% CIs for categorical outcomes. The heterogeneity of the effect size estimates across these studies was quantified using the I 2 statistic. The I 2 statistic ranges from 0 to 100% (I 2 < 25%, low heterogeneity; I 2 = 25-50%, moderate heterogeneity; and I 2 ≥ 50%, substantial heterogeneity) 37 . All data analyses were performed using STATA version 16. Quality evaluation for each article. The quality of the studies was evaluated using NOS scores (Table 2).
Association between number of remaining/missing teeth and hypertension. The prevalence of hypertension was compared between/among groups with different number of remaining teeth in six crosssectional studies 46,48,49,52,54,56 (Table 1). Four of the six studies showed negatively significant associations between the number of remaining teeth and hypertension after controlling for confounders 46,49,52,56 . Another study found that the association was slightly below the threshold of statistical significance 54 . On the other hand, a different study failed to find an association between the number of remaining teeth and hypertension 48 .
Six cross-sectional studies analyzed the association between number of missing teeth and hypertension 38,[41][42][43][44]50 (Table 1). Two studies showed that groups with hypertension had higher mean 43 or median 44 of number of missing teeth than normal blood pressure group. Four of the six studies displayed that positively significant   38,41,45,50 . One study showed that menopausal women with hypertension had a higher number of remaining teeth than those without hypertension 43 . In Dar-Odeh's study, the association was marginally significant 42 .

Association between number of remaining/missing teeth and SBP/DBP. Four studies analyzed
the associations between number of remaining teeth and SBP/DBP 40,52,53,56 (Table 1). Two studies demonstrated that the number of remaining teeth was inversely associated with SBP and DBP even after adjusting for covariates 52,53 . In Holzke's study, men with fewer teeth had significantly higher SBP than those with higher teeth was significantly higher, but this association was not observed in women 56 . Another study showed that the population with a higher number of remaining teeth exhibited a significantly higher SBP than the population with a lower number of remaining teeth, but this association was not observed with DBP 40 . However, the significance disappeared after adjusting for covariates. A further six studies analyzed the associations between number of missing teeth and SBP/DBP 39,45,47,51,55,57 (Table 1). Two studies reported that populations with a greater number of missing teeth exhibited significantly higher SBP or DBP than those with a smaller number of missing teeth 39,51 but this significance disappeared after adjustment for potential confounding factors. On the other hand, two studies found that a population with more missing teeth had significantly higher SBP and DBP than the population with fewer missing teeth after adjusting the confounding factors 47,55 . In Darnard's study 51 , a sub-population with missing teeth > 10 was 1.17 times more likely to have SBP > 140 mmHg than the sub-population with missing teeth ≤10 among adults aged < 65 years. However, this association was not observed among adults aged ≥ 65 years.
Cohort study. Four studies performed cohort study [58][59][60] (Table 1). Three studies have compared incidence of hypertension in regard to different number of teeth [58][59][60] . One study made a comparison between subjects who are edentulous and those who are dentate 61 . Edentulous participants had a significantly higher risk of incidence of hypertension after adjusting for confounders. Two study analyzed the association between the number of teeth at baseline and the incidence of hypertension during follow-up. A significant higher incidence of hypertension was observed in population with lower number of teeth in one study 58 but not in another 60 after adjusting for confounders. Kim et al. compared missing teeth between subjects who had hypertension and those who did not at baseline 59 . In univariate analysis, the hypertension group had a higher risk of tooth loss than the normal group. However, in the multivariable analysis, the opposite result was observed.

Meta-analysis.
Separate meta-analyses regarding the risk of hypertension were carried out for "no tooth loss" versus "tooth loss" and for "dentate" versus "edentulous". Three studies entered in the meta-analysis and found that those with tooth loss have a significantly higher prevalence of hypertension than those with no tooth loss 42,46,50 . Based on the data of the studies for "no tooth loss" versus "tooth loss", the pooled summary odds ratio was 2.22 (95% CI 2.00-2.45) in the random-effect model for the group with tooth loss compared to the nontooth loss group (Fig. 2). In other words, the tooth loss group was 2.22-fold more likely to be diagnosed with hypertension. As for "dentate" versus "edentulous", two studies found that edentulous subjects had a significantly higher prevalence of hypertension than dentate subjects 46,50 and the pooled summary OR was 4.94 (95% CI 4.04-6.05) in the random-effect model for the edentulous group compared to the dentate group (Fig. 3). These findings were statistically significant (p < 0.001). However, the statistical heterogeneity was high across all studies (I 2 = 94.8% and 99.1%, respectively). between tooth loss and hypertension with individuals having greater tooth loss exhibiting a higher prevalence of hypertension and higher blood pressure. Only two studies reported no association between tooth loss and hypertension without adjusting for possible confounding factors. Evidence from our literature review suggested that tooth loss is thought to have a significant association with hypertension. However, a few studies reported that this significant association disappeared after adjusting with possible confounding factors and the odds ratios for this association in most studies, which ranges between 1 and 2, are not very large. Therefore, the extent of the association between tooth loss and hypertension may be varied. There are two possible cascades related to the association between tooth loss and hypertension. It is speculated that progression of periodontitis, a major cause of tooth loss, consequently results in hypertension. The mechanisms by which periodontitis elicits hypertension are complex and not fully elucidated. The major mechanism by which increased blood pressure occurs in patients with periodontitis is likely to be the spread of inflammation and secondary damage to the vascular endothelium [63][64][65][66] . Periodontal tissue covers a wide area of the oral cavity. The influence of local inflammation of periodontitis occurring in a large proportion of the oral cavity may significantly contribute to systemic inflammation mediated by C-reactive protein and main inflammatory cytokines such as tumor necrosis factor alpha, interleukin 1b and interleukin 6 67,68 . Increases in nitrate-reducing bacteria, which are observed in patients with periodontitis may induce a reduction of nitric oxide, which may consequently lead to an increase in blood pressure [69][70][71] . It was also reported that an intervention of non-surgical periodontal treatment leads to an improvement of both periodontal status and hypertension 72 . Another reason is that tooth loss causes a decrease in masticatory function, thereby inducing obesity. There are two possible explanations for the association between mastication and obesity. One is that the eating habits of people with poor masticatory function, and decreased consumption of vegetables and fruits, and higher consumption of high energy food, tend to cause obesity compared to those with adequate mastication [73][74][75][76] . Another is that a reduction in chewing leads to a decrease in diet-induced thermogenesis and inactivation of neuronal histamine, which may consequently lead to obesity [77][78][79] .
In patients with metabolic syndrome, other factors, such as diabetes and hyperlipidemia, add to this complex relationship. Obesity is one of the causes of diabetes 80 and diabetes and periodontitis have a bidirectional relationship 81 . In some of the studies reviewed in this article, the association between tooth loss and hypertension disappeared after adjustment for confounders (demographic factors, socio-economic factors, health behavior and general health). This suggests that other factors have a considerable influence on this association. It is thought that various factors interact with each other in a complicated cascade from tooth loss to hypertension.
This systematic review aimed to analyze the association between tooth loss and hypertension by systematically summarizing the scientific evidence from clinical studies during the last two decades. Twenty-four studies were included, with a total of 772,683 adults. To the best of our knowledge, this is the first systematic literature review to examine this association. The results of this review may help elucidate the influence of oral health on blood pressure.

Comparison of the association between tooth loss and hypertension. The association between
tooth loss and hypertension was compared for each geographical location. Studies conducted in Central-South America showed a trend for weaker association compared to other areas; one with no association 48 , one with approaching significance level (p = 0.067) 54 , and one with disappearance of significance after adjustment with confounders 40 in 5 studies. The reason for the difference is unclear. In Central-South America studies, studies from this region showed higher tooth loss than those from other areas' studies, particularly developed countries. Tooth loss in younger people may not cause hypertension easily. More detailed analysis is needed.
There was a difference in the association between tooth loss and hypertension between men and women. For women, the association between tooth loss and hypertension was marginally or not observed in studies including younger subjects (19-39 years) 42,56 . On the other hand, significant associations were found in studies with www.nature.com/scientificreports/ subjects aged 40 or older years after adjusting confounders 44,47,49,59 . It is thought that younger subjects with tooth loss may have smaller prevalence of hypertension than older subjects with tooth loss. However, in the Völzke's study including individuals aged 20-79 years, the significant association was found among men unlike among women 56 . In a Korean study, men aged 40 and older did not show the significant association unlike women 49 . Various factors may influence this association.

Difference in the association with hypertension between SBP and DBP. Although a significant
association between SBP and tooth loss was observed, the association between DBP and tooth loss was not significant. The reasons why SBP exhibits a stronger association with tooth loss than DBP is unclear. The proportion of individuals with diastolic hypertension (systolic-diastolic hypertension [SDH] or isolated diastolic hypertension [IDH]) decreased, while that of those with systolic hypertension increased with age. Accumulation of advanced glycation end products (AGE) with aging leads to increased arterial stiffness and contributes to the development of isolated systolic hypertension 82,83 . Excessive intake of animal-derived foods which are rich in fat and AGE may increase the risk of hypertension and other chronic disease [84][85][86][87] . In general, since individuals who suffer from decreased masticatory function due to tooth loss tend to eat foods that are high in fat [88][89][90][91] , this may induce AGE accumulation, consequently contribution to increased SBP.
Cohort studies. Two prospective cohort studies demonstrated an increased incidence of hypertension in individuals with more tooth loss during the observation period 58,61 . On the contrary, one study reported that subjects with hypertension experienced lower tooth loss than those without hypertension 59 . Therefore, the association between tooth loss and hypertension may not be bidirectional. In other words, hypertension may not cause tooth loss.

Quality of studies.
Of the 24 included studies, 16 (66.7%) adjusted the association between blood pressure and tooth loss with all possible confounding factors [39][40][41][45][46][47][48][49][50]53,55,56,[58][59][60] . Of the remaining eight studies, 4 studies lacked adjustment for only one confounding facto 38,42,51,52 . The most important confounding factor was obesity, and almost all studies adjusted for this. These adjustments strengthen the reliability of the evidence obtained in this review. However, three studies that investigated patients from university hospitals failed to adjust for socio-economic factors 38,42,51 . The characteristics of these studies' settings might make it difficult to obtain data of socio-economic factors.
Eight studies employed self-reported data on the number of teeth and/or hypertension. Some studies have shown strong validity of self-reported number of tooth loss in high-income countries 88,89 . One study examined in health professionals in the US, expecting high validity against clinically measured results 60 . However, the validity of the self-reported number of lost teeth has not been evaluated in lower and middle-income countries. Moreover, the validity of self-reported hypertension in developing countries is not high 90,91 . Since most of the studies that employed self-reported data on the number of teeth and/or hypertension in this review were performed in developing countries, self-reported data may deviate from true values. Since subjective measurements have the possibility to give considerable optimistic results compared with practitioners' measurements 92 , self-reported data may often be underestimated.

Strengths and limitations.
There are several limitations in this study. First, all studies included in this review were observational studies. Intervention studies are necessary to analyze the causal relationships.
Second, the grouping of participants according to the number of teeth differed among the studies. Due to this problem, only small-scale meta-analyses were performed. Moreover, the only meta-analyses that were carried out were to compare the hypertension rate for tooth loss vs. no tooth loss and for dentate vs. edentulous. Pooled odds ratio data based on a cut-off value for the number of teeth is valuable for estimating the association between the number of remaining teeth and hypertension. Moreover, it may be a rough indication for maintaining oral health to prevent hypertension.
Third, some studies could not be included in meta-analysis because of lack of data for real number of subjects by tooth loss and hypertension. This lack lowers the value of results of meta-analysis. Nonetheless, odds ratios for the association between tooth loss and hypertension of these studies are similar to those of studies included meta-analysis. It is thought that missing of these data would give little influence on pooled ORs.
Forth, several studies have investigated many specialized subjects, including patients from clinics or hospitals 38,39,42,44,54 , menopausal women 43,45,57,61 , and male health care specialists 60 . Although it is problematic to apply the results of these studies to the general population, the large number of subjects in their studies increases the reliability of the study results.
The strength of our study is that it included many studies with a large number of subjects. Eleven of the 24 included studies have investigated large-scale community dwellings of > 1000 individuals 40,41,46,49,50,52,53,55,56,58,59 , which enhances the credibility of the results of the studies. The greater the sample size, the smaller the error, which makes the results more reliable.
Future direction. Although lost teeth cannot be regenerated, they can be restored by prosthetics. Provision of prosthetics can improve both masticatory function and diet. When decreased mastication elicits obesity and subsequently hypertension, the provision of prosthetics may improve increased blood hypertension. The number of teeth acts only as an anatomical indicator. There is an indicator, functional teeth that is the sum of the number of natural teeth and the number of lost teeth that are restored by prosthetics. It is of interest to investigate the association between the number of functional teeth and hypertension. www.nature.com/scientificreports/ The lack of standardized division criteria for tooth loss makes it impossible to compare the strength of associations between tooth loss and hypertension observed in reviewed studies. The unification of division standards for tooth loss should be proposed.

Conclusion
In the present review, we provided an overview and appraisal of studies regarding the relationship between the number of teeth/tooth loss and hypertension. People with fewer remaining teeth or more tooth loss exhibited a higher prevalence of hypertension. Those with more tooth loss had significantly higher SBP but not DBP than those with less tooth loss. Those with more tooth loss showed a higher incidence of hypertension than those with less tooth loss during the observation period (Supplementary Information).

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.