This systematic review with meta-analysis aimed to evaluate the effect of antioxidants as an adjuvant in periodontitis treatment. The following databases were consulted: PubMed, Scopus, Web of Science, Cochrane, Lilacs, OpenGrey, and Google Scholar. Based on the PICO strategy, the inclusion criteria comprised interventional studies including periodontitis patients (participants) treated with conventional therapy and antioxidants (intervention) compared to patients treated only with conventional therapy (control) where the periodontal response (outcome) was evaluated. The risk of bias was evaluated using the Cochrane RoB tool (for randomized studies) and ROBINS-I tool (for nonrandomized studies). Quantitative data were analyzed in five random effects meta-analyses considering the following periodontal parameters: clinical attachment loss (CAL), plaque index (PI), gingival index (GI), bleeding on probing (BOP), and probing depth (PD). After all, the level of certainty was measured with the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) tool. Among the 1884 studies identified, only 15 interventional studies were according to the eligibility criteria and they were included in our review. From them, 4 articles presented a high risk of bias. The meta-analysis showed a statistically significant difference for CAL (SMD 0.29 (0.04, 0.55),
Periodontal disease is a chronic inflammatory manifestation in the tissues surrounding the teeth caused by an imbalance between oral biofilms and the host’s response, in which there is a possibility of loss of tooth support tissues [
The excessive presence of free radicals caused by oxidative stress or antioxidant deficiency has been linked to periodontal disease [
The antioxidant defense system can inhibit and/or reduce the damage caused by deleterious action of free radicals or nonradical reactive species [
In the search for adjuvants to conventional periodontal treatments which could present worse than expected results, some literature suggests that supplementation with antioxidant components may help to reduce periodontal damage and its systemic effects when compared to treatment with antibiotics that can cause resistance or onset of secondary infections [
In order to perform this systematic review, the following question was elaborated: “In patients with periodontitis, do antioxidants have an additional clinically meaningful effect when used as adjuvants to conventional therapy?”
This systematic review was registered under the number CRD42017079869 in the PROSPERO database, created by the University of York, responsible for the registration and dissemination of systematic reviews and carried out according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [
The PICO strategy was applied in this systematic review. This acronym stands for an abbreviation of the following components: patient, intervention, comparison, and outcome, which are essential for designing all stages of an interventional systematic review. We included intervention studies in adult humans with periodontitis (P) that compared conventional periodontal treatment with the addition of antioxidants (I) compared to patients who have undergone only conventional periodontal treatment (C) in order to observe periodontal treatment effects (O). Additionally, case reports, descriptive studies, review articles, opinion articles, technical articles, guidelines, animal studies, and
The electronic searches were carried out in the following databases: PubMed, Scopus, Web of Science, Lilacs, Cochrane, Google Scholar, and OpenGrey. There were no restrictions on the date of publication or in the language used in the primary studies. The terms MeSH, keywords, and search strategies were adapted according to each database (Table
Search strategy on each electronic database.
Database | Search format |
---|---|
PubMed | (((((((((((((((((((((((((((Chronic Periodontitis[MeSH Terms]) OR Chronic Periodontitis[Title/Abstract]) OR Chronic Periodontitides[Title/Abstract]) OR Periodontitides, Chronic[Title/Abstract]) OR Periodontitis, Chronic[Title/Abstract]) OR Adult Periodontitis[Title/Abstract]) OR Adult Periodontitides[Title/Abstract]) OR Periodontitides, Adult[Title/Abstract]) OR Periodontitis, Adult[Title/Abstract]) OR Periodontal treatment[Title/Abstract]) OR Periodontal therapy[Title/Abstract]) OR nonsurgical periodontal therapy[Title/Abstract]) OR non-surgical periodontal therapy[Title/Abstract]) OR periodontitis[MeSH Terms]) OR periodontitis[Title/Abstract]) OR Periodontitides[Title/Abstract]) OR Pericementitis[Title/Abstract]) OR Pericementitides[Title/Abstract]) OR Periodontal Diseases[MeSH Terms]) OR Periodontal Diseases[Title/Abstract]) OR Disease, Periodontal[Title/Abstract]) OR Diseases, Periodontal[Title/Abstract]) OR Periodontal Disease[Title/Abstract]) OR Parodontosis[Title/Abstract]) OR Parodontoses[Title/Abstract]) OR Pyorrhea Alveolaris[Title/Abstract])) AND ((((((((((((((((((((((((((((((((((((((((((((((Antioxidants[MeSH Terms]) OR Antioxidants[Title/Abstract]) OR Antioxidant Effect[Title/Abstract]) OR Effect, Antioxidant[Title/Abstract]) OR Anti-Oxidant Effect[Title/Abstract]) OR Anti Oxidant Effect[Title/Abstract]) OR Effect, Anti-Oxidant[Title/Abstract]) OR Anti-Oxidant Effects[Title/Abstract]) OR Anti Oxidant Effects[Title/Abstract]) OR Effects, Anti-Oxidant[Title/Abstract]) OR Antioxidant Effects[Title/Abstract]) OR Effects, Antioxidant[Title/Abstract]) OR Resveratrol[Title/Abstract]) OR Tea[MeSH Terms]) OR Tea[Title/Abstract]) OR Green Tea[Title/Abstract]) OR Green Teas[Title/Abstract]) OR Tea, Green[Title/Abstract]) OR Teas, Green[Title/Abstract]) OR Black Tea[Title/Abstract]) OR Black Teas[Title/Abstract]) OR Tea, Black[Title/Abstract]) OR Teas, Black[Title/Abstract]) OR Ascorbic Acid[MeSH Terms]) OR Ascorbic Acid[Title/Abstract]) OR Acid, Ascorbic[Title/Abstract]) OR L-Ascorbic Acid[Title/Abstract]) OR Acid, L-Ascorbic[Title/Abstract]) OR L Ascorbic Acid[Title/Abstract]) OR Vitamin C[Title/Abstract]) OR Hybrin[Title/Abstract]) OR Magnorbin[Title/Abstract]) OR Sodium Ascorbate[Title/Abstract]) OR Ascorbate, Sodium[Title/Abstract]) OR Ascorbic Acid, Monosodium Salt[Title/Abstract]) OR Ferrous Ascorbate[Title/Abstract]) OR Ascorbate, Ferrous[Title/Abstract]) OR Magnesium Ascorbate[Title/Abstract]) OR Ascorbate, Magnesium[Title/Abstract]) OR Magnesium di-L-Ascorbate[Title/Abstract]) OR Magnesium di L Ascorbate[Title/Abstract]) OR di-L-Ascorbate, Magnesium[Title/Abstract]) OR Magnesium Ascorbicum[Title/Abstract]) OR Vitamin E[MeSH Terms]) OR Vitamin E[Title/Abstract]) |
Scopus | (TITLE-ABS-KEY (“Chronic Periodonti |
Web of Science | TS=(“Chronic Periodonti |
Cochrane | “Chronic Periodontitis” OR “Chronic Periodontitides” OR “Periodontitides, Chronic” OR “Periodontitis, Chronic” OR “Adult Periodontitis” OR “Adult Periodontitides” OR “Periodontitides, Adult” OR “Periodontitis, Adult” OR “Periodontal treatment” OR “Periodontal therapy” OR “nonsurgical periodontal therapy” OR “non-surgical periodontal therapy” OR “periodontitis” OR “Periodontitides” OR “Pericementitis” OR “Pericementitides” OR “Periodontal Diseases” OR “Disease, Periodontal” OR “Diseases, Periodontal” OR “Periodontal Disease” OR “Parodontosis” OR “Parodontoses” OR “Pyorrhea Alveolaris” AND Antioxidants OR “Antioxidant Effect” OR “Effect, Antioxidant” OR “Anti-Oxidant Effect” OR “Anti Oxidant Effect” OR “Effect, Anti-Oxidant” OR “Anti-Oxidant Effects” OR “Anti Oxidant Effects” OR “Effects, Anti-Oxidant” OR “Antioxidant Effects” OR “Effects, Antioxidant” OR Resveratrol OR TeaOR “Green Tea” OR “Green Teas” OR “Tea, Green” OR “Teas, Green” OR “Black Tea” OR “Black Teas” OR “Tea, Black” OR “Teas, Black” OR “Ascorbic Acid” OR “Acid, Ascorbic” OR “L-Ascorbic Acid” OR “Acid, L-Ascorbic” OR “L Ascorbic Acid” OR “Vitamin C” OR HybrinOR MagnorbinOR “Sodium Ascorbate” OR “Ascorbate, Sodium” OR “Ascorbic Acid, Monosodium Salt” OR “Ferrous Ascorbate” OR “Ascorbate, Ferrous” OR “Magnesium Ascorbate” OR “Ascorbate, Magnesium” OR “Magnesium di-L-Ascorbate” OR “Magnesium di L Ascorbate” OR “di-L-Ascorbate, Magnesium” OR “Magnesium Ascorbicum” OR “Vitamin E” |
Lilacs | (tw:((Chronic Periodontitis) OR (Chronic Periodontitides) OR (Periodontitides, Chronic) OR (Periodontitis, Chronic) OR (Adult Periodontitis) OR (Adult Periodontitides) OR (Periodontitides, Adult) OR (Periodontitis, Adult) OR (Periodontal treatment) OR (Periodontal therapy) OR (nonsurgical periodontal therapy) OR (non-surgical periodontal therapy) OR (periodontitis) OR (Periodontitides) OR (Pericementitis) OR (Pericementitides) OR (Periodontal Disease$) OR (Disease, Periodontal) OR (Diseases, Periodontal) OR (Parodontosis) OR (Parodontoses) OR (Pyorrhea Alveolaris))) AND (tw:((Antioxidant$) OR (Antioxidant Effect) OR (Effect, Antioxidant) OR (Anti-Oxidant Effect) OR (Anti Oxidant Effect) OR (Effect, Anti-Oxidant) OR (Effects, Anti-Oxidant) OR (Effects, Antioxidant) OR (Resveratrol) OR (Tea$) OR (Green Tea$) OR (Tea, Green) OR (Teas, Green) OR (Black Tea$) OR (Tea, Black) OR (Teas, Black) OR (Ascorbic Acid) OR (Acid, Ascorbic) OR (L-Ascorbic Acid) OR (Acid, L-Ascorbic) OR (L Ascorbic Acid) OR (Vitamin C) OR (Hybrin) OR (Magnorbin) OR (Sodium Ascorbate) OR (Ascorbate, Sodium) OR (Ascorbic Acid, Monosodium Salt) OR (Ferrous Ascorbate) OR (Ascorbate, Ferrous) OR (Magnesium Ascorbate) OR (Ascorbate, Magnesium) OR (Magnesium di-L-Ascorbate) OR (Magnesium di L Ascorbate) OR (di-L-Ascorbate, Magnesium) OR (Magnesium Ascorbicum) OR (Vitamin E))) |
Google Scholar | Periodontitis+ Antioxidants -review |
OpenGrey | Periodontitis AND Antioxidants |
A search alert was created in each database to notify new studies according to the outlined search strategy. All relevant citations were imported into a bibliographic reference manager (EndNote®, version X7, Thomson Reuters, Philadelphia, USA).
Through the EndNote® manager, the removal of duplicate articles was performed using automatic exclusion added to the manual deletion. After the exclusions, the texts were analyzed for the titles and abstracts and, afterwards, from the reading of the full text when indicated, according to the established eligibility criteria.
The eligible articles resulting from the previous selection were extracted and tabulated including information of the country, year, characteristics of the participants (sample size and age), periodontal parameters measured, the antioxidant used, conventional treatment performed, results, and statistical analysis.
The risk of bias assessment was based on two tools. “The Cochrane Collaboration’s tool for assessing risk of bias” tool [
“The Cochrane Collaboration’s tool for assessing risk of bias” tool [
Criteria for risk assessment of bias according to “the Cochrane Collaboration’s tool for assessing risk of bias (Higgins et al., 2011).
Random sequence generation | |
Criteria for judgment of “low risk” of bias | The articles that appropriately described the method of randomization |
Criteria for judgment of “high risk” of bias | Articles that presented a methodological failure in the randomization criterion or the difficult reproducibility method |
Criteria for judgment of “unclear risk” of bias | When the articles did not describe the method of randomization |
Allocation concealment | |
Criteria for judgment of “low risk” of bias | When the allocation sequences of samples were concealed in the randomization |
Criteria for judgment of “high risk” of bias | When the sequences of allocation of samples were not concealed at randomization |
Criteria for judgment of “unclear risk” of bias | When the allocation sequences were unreported |
Blinding of participants and researchers | |
Criteria for judgment of “low risk” of bias | When the sample was blind |
Criteria for judgment of “high risk” of bias | If the methodology could not be blinded for whatever reason (sample/appraiser) |
Criteria for judgment of “unclear risk” of bias | When the sample was not reported either way |
Blinding of outcome assessment | |
Criteria for judgment of “low risk” of bias | When the evaluators reported that the blinding in the evaluation was effective |
Criteria for judgment of “high risk” of bias | If the study informed the evaluators how the blinding was done |
Criteria for judgment of “unclear risk” of bias | When the blinding was not reported |
Incomplete outcome data | |
Criteria for judgment of “low risk” of bias | When there was an exhaustive description of the main data |
Criteria for judgment of “high risk” of bias | If there was a loss due to an incomplete description of the main results regardless of quantity, nature, and manipulation |
Criteria for judgment of “unclear risk” of bias | When the results were not reported |
Selective reporting | |
Criteria for judgment of “low risk” of bias | When the discussion excluded some of the results |
Criteria for judgment of “high risk” of bias | When the article discussed the data completely |
Criteria for judgment of “unclear risk” of bias | When the organization of the results in the discussion was unclear |
The ROBINS-I (Risk of Bias in Non-randomized Studies of Interventions) tool [
Risk of bias evaluation of nonrandomized clinical trials according to the ROBINS-I tool [
Domain of bias | Description |
---|---|
Preintervention | |
Bias due to confounding | Baseline confounding. When one or more preintervention prognostic factors predict the intervention received at baseline (start of follow-up) |
Time-varying confounding. When the intervention received can change over time and when postintervention prognostic factors affect the intervention received after baseline | |
Bias in selecting participants for study | When selection of participants is related to both intervention and outcome |
Lead time bias. When some follow-up time is excluded from the analysis | |
Immortal time bias. When the interventions are defined in such a way that there is a period of follow-up during which the outcome cannot occur | |
At intervention | |
Bias in classifying interventions | When intervention status is misclassified |
Nondifferential misclassification. Is unrelated to the outcome | |
Differential misclassification. Is related to the outcome or to the risk of the outcome | |
Postintervention | |
Bias due to deviating from intended intervention | When there are systematic differences between intervention and comparator groups in the care provided |
Bias due to missing data | When attrition (loss to follow-up), missed appointments, incomplete data collection, and exclusion of participants from analysis by primary investigators occur |
Bias in measuring outcomes | When outcomes are misclassified or measured with error |
Nondifferential measurement error. Is unrelated to the intervention received; it can be systematic or random | |
Bias in selecting reported result | Selective reporting of results that should be sufficiently reported to allow the estimate to be included in a meta-analysis (or other synthesis) is considered. When selective reporting is based on the direction, magnitude, or statistical significance of intervention effect estimates. Selective outcome reporting. When the effect estimate for an outcome measurement was selected from among analyses of multiple outcome measurements for the outcome domain. Selective analysis reporting. When results are selected from intervention effects estimated in multiple ways |
Judgment for each domain | |
Low RoB | Study is comparable to a well-performed, randomized trial with regard to this domain |
Moderate RoB | Study is sound for a nonrandomized study with regard to this domain but cannot be considered comparable to a well-performed, randomized trial |
Serious RoB | Study has some important problems in this domain |
Critical RoB | Study is too problematic in this domain to provide any useful evidence on the effects of intervention |
No information | No information on which to base a judgment about risk of bias for this domain |
Overall judgment | |
Low RoB | Study is judged to be at low risk of bias for all domains |
Moderate RoB | Study is judged to be at low or moderate risk of bias for all domains |
Serious RoB | Study is judged to be at serious risk of bias in at least one domain, but not at critical risk of bias in any domain |
Critical RoB | Study is judged to be at critical risk of bias in at least one domain |
No information | No clear indication that the study is at serious or critical risk of bias, and there is a lack of information in one or more key domains of bias (a judgment is required for this) |
All evaluations, including searches, study selection, and data extraction, were performed independently by two reviewers (NND and MMLC) and checked by a third-party evaluator (RRL) in case of disagreement.
Data from the included studies were analyzed using Comprehensive Meta-Analysis software (version 3.2; Biostat) to evaluate the efficacy of periodontal therapy (PT) associated with antioxidants in periodontal parameters. This treatment protocol (PT plus antioxidants) was compared to conventional PT only. The main periodontal parameters analyzed by the studies were evaluated in five different random effects meta-analyses: (1st) clinical attachment loss (CAL), (2nd) plaque index (PI), (3rd) gingival index (GI), (4th) bleeding on probing (BOP), and (5th) probing depth (PD). The average and standard deviation of each parameter and the total number of individuals of each group (PT only and PT plus antioxidants) were used. A subgroup analysis was conducted considering the follow-up periods evaluated in studies.
As the studies reported the outcome using similar methods for all parameters, the standard mean difference (SMD) was applied [
Heterogeneity was tested using the
A summary of the overall strength of evidence was presented using the “Grading of Recommendation, Assessment, Development, and Evaluation” (GRADE) tool [
The searches in databases and gray literature articles amounted to 3213, resulting in 1884 after exclusion of duplicates. All 1884 remaining articles were analyzed by titles and abstracts, based on the eligibility criteria, and then 1831 were excluded. Thirty-six studies were analyzed in full text, and 21 of them were excluded, having 15 articles remaining that were included in this review to qualitative synthesis [
Flow diagram of literature search according to the PRISMA statement.
All studies evaluated periodontitis, and in those where there was a group for gingivitis and group for periodontitis presented in the same study [
Summary of the included studies.
Author (year) | Study design | Sample description | Periodontitis diagnostic method | Periodontal treatment | Treatment antioxidant | Statistical analysis | Outcome | |
---|---|---|---|---|---|---|---|---|
Sample size and source, age (years), gender, and groups | Clinical | Laboratory | ||||||
Alkadasi et al. (2017) | RCT | PI |
sRANKL levels in GCF | Scaling and root planning and modified Widman flap procedure | One-way ANOVA with post Dunnett tests | The use of adjunctive NAC resulted in a significant reduction in probing depths in the S-NAC group when compared to the S-nonNAC group at 3 months, but no statistically significant differences in GCF sRANKL levels were observed in the sites that underwent surgical treatment with or without NAC at different time intervals. | ||
Alkadasi et al. (2017) | RCT | PI |
Salivary interleukin 1 beta (IL-1 |
Scaling and root planning | Lycopene (8 mg/day, LycoRed, JAGSONPAL Pharmaceuticals) | Paired |
There was a significant improvement in the parameters of MGI, PI, BOP, IL-1 | |
Arora et al. (2013) | RCT | PPD | Antioxidant capacity (TAC), malondialdehyde (MDA), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) | Scaling and root planning | Chicory leaf extract (2 g/day) | Chicory leaf extract with nonsurgical periodontal therapy may be helpful in controlling the periodontal status. | ||
Babaei et al. (2018) | RCT | PPD |
— | Scaling and root planning | Lycopene (4 mg/day; Lycotas Pharma. Co.) | Paired |
Results show that lycopene is a promising treatment modality as an adjunct to full-mouth SRP of the oral cavity in patients with moderate periodontal disease. | |
Belludi et al. (2013) | RCT | GI |
Total antioxidant capacity in GCF and plasma | Scaling and root planning | Sachets containing green tea (240 ml of water) | Repeated measures ANOVA with post hoc Bonferroni test; independent sample |
Green tea intake as a component of nonsurgical periodontal therapy is promising for superior and rapid resolution of the disease process. Green tea increases the total antioxidant capacity of GCF and plasma along with potent anti-inflammatory, astringent, and antiplaque effects. | |
Chopra et al. (2016) | RCT | PI |
Pentraxin-3 (PXT3) levels in GCF | Scaling and root planning | Gel formulation was prepared from tea tree oil (TTO) (5%, Melaleuca alternifolia, Sigma®, Steinheim, Germany) | Paired |
The local delivery of TTO gel in case of chronic periodontitis may have some beneficial effects to augment the results of the conventional periodontal therapy. | |
Elgendy et al. (2013) | RCT | PPD |
— | Scaling and root planning (SRP) | Green tea (Lahijan green tea) | Wilcoxon test; Mann–Whitney |
The results show that PD and BI reduced significantly in both groups before and after SRP; this reduction in the intervention group was higher than the control group. | |
Ferial et al. (2018) | RCT pilot | GI |
Parameters of total antioxidant capacity (TOAC) and glutathione-S-transferase (GST) in GCF | Scaling and root planning | Green tea dentifrice (1,4%) | Paired |
Green tea dentifrice use showed statistically significant improvements in GI, BOP, CAL, TAOC, and GST levels on intra- and intergroup comparisons at 4 weeks. The results of the present study assert the use of green tea dentifrice as an adjunct to SRP during the active and healing phases following periodontal therapy, thereby enhancing the clinical outcomes. | |
Hrishi et al. (2016) | Open RCT | GI |
Nitrite/nitrate levels, interleukin-1 |
Scaling and root planning. In addition, application of chlorhexidine 0.06% | Standardized fermented papaya gel (SFPG, 7 g) | Mann–Whitney |
All parameters showed a significant improvement in the comparison of the test group with the control group. | |
Kharaeva et al. (2016) | RCT | PI |
— | Scaling and root planning | CoQ10 (Qute 120 mg by Yash Pharma International) | Paired |
The use of coenzyme Q10 oral supplements as an adjunct to scaling and root planning showed significant reduction in gingival inflammation when compared to scaling and root planning alone. | |
Manthena et al. (2015) | RCT | GI |
— | Scaling and root planning | Tablet melatonin 3 mg daily at night | There was significant improvement in all the indices in the group test as compared to the control group. Melatonin is a potential antioxidant, and the clinical improvement it showed was significantly superior to that of the standard control group. | ||
Marawar et al. (2014) | Clinical trial | Community periodontal index of treatment needs | Uric acid determination in saliva sample | Scaling and root planning | Lycopene softgel (6 mg/dose) | One-way ANOVA | There was a reduction in periodontal inflammation with an increase in the salivary uric acid levels seen in subgroups treated by antioxidants in both gingivitis and periodontitis groups. | |
Mathur et al. (2013) | RCT | PPD |
— | Scaling and root planning | Green tea gel (12% |
Regression test; Mann–Whitney |
Green tea gel could provide a superior benefit in reducing BOP and gingival inflammation when used as an adjunct to nonsurgical periodontal treatment. | |
Rattanasu et al. (2016) | RCT | PI |
Levels of superoxide dismutase (SOD) activity (%) | Scaling and root planning | Vitamin E softgel (200 mg/day) | Mann–Whitney |
Systemic and local SOD levels are lowered in periodontitis. Adjunctive vitamin E supplementation improves periodontal healing as well as antioxidant defense. | |
Singh et al. (2014) | RCT | PPD |
Parameters of/total antioxidant capacity (TOAC) in plasma | Scaling and root planning | Vitamin C | Paired |
The nonsurgical periodontal therapy seems to reduce the oxidative stress during the periodontal inflammation. |
RCT: randomized controlled trial; PI: plaque index; GI: gingival index; PD: probing depth; CAL: clinical attachment loss; GCF: gingival crevicular fluid; MGI: modified gingival index; BOP: bleeding on probing; UI: unreported information; BI: percentage of sites with bleeding on probing; PMA: Parma’s papillae-gum margin-alveolar; CPI: community periodontal index.
The PD was the most used evaluation method, present in all studies, followed by gingival and plaque indexes (GI and PI, respectively), CAL, and BOP. One study reports the additional use of the community periodontal index (CPI) as an evaluation method [
Some studies have evaluated laboratory aspects besides clinical aspects such as markers of bone resorption (RANKL) [
A total of 14 randomized clinical trials were assessed for bias risk using the Cochrane tool [
Risk of bias evaluation in randomized trials (Cochrane Collaboration’s tool).
In the risk of bias analysis in the ROBINS-I model, the study by Mathur et al. [
Risk of bias evaluation in nonrandomized trials (ROBINS-I tool).
Domains | ||||||||
---|---|---|---|---|---|---|---|---|
Author | Preintervention | At intervention | Postintervention | Overall risk of bias judgment | ||||
Bias due to confounding | Bias in selecting participants for the study | Bias in classifying interventions | Bias due to deviations from intended intervention | Bias due to missing data | Bias in measuring outcomes | Bias in selecting reported result | ||
Mathur et al. (2013) | Low | Low | Low | Low | NI | Low | Low | Low |
The categories for risk of bias judgements are “low risk,” “moderate risk,” “serious risk,” and “critical risk” of bias. “Low risk” corresponds to the risk of bias in a high-quality randomized trial; NI: no information on which to base a judgement about risk of bias for this domain.
Four studies were excluded from the meta-analyses because they were classified as having “high” risk of bias [
Seven clinical trials evaluating the influence of PT additionally to antioxidant therapy in the mean of CAL were included in this analysis. Including all studies, the heterogeneity was
Forest plot of the first meta-analysis for clinical attachment loss (CAL).
Five clinical trials evaluating the influence of PT additionally to antioxidant therapy in the mean of PI, by analyzed sites, were included in this analysis. Including all studies, the heterogeneity was moderate (
Forest plot of the second meta-analysis for the plaque index (PI).
Six clinical trials evaluating the influence of PT additionally to antioxidant therapy in the mean of GI, per sites, were included in this analysis. Including all studies, the heterogeneity was moderate (
Forest plot of the third meta-analysis for the gingival index (GI).
Three clinical trials evaluating the influence of PT plus antioxidants in the mean of BOP per tooth and two per site were included. With the intention of including as many studies as possible, this analysis was conducted with the three studies that evaluate the BOP per tooth and a substantial heterogeneity was observed (
Forest plot of the fourth meta-analysis for bleeding on probing (BOP).
Six clinical trials evaluating the influence of PT plus antioxidants in the mean of PD, in millimeters per tooth, were included. The pooled heterogeneity was considerable (
Forest plot of the fifth meta-analysis for probing depth (PD).
To assess the quality of evidence across studies, the GRADE approach was applied. Three different evaluations were performed: overall evaluation of the antioxidant effect regarding periodontal indexes (Table
Antioxidant effect regarding periodontal indexes.
Antioxidants compared to placebo for periodontal therapy | |||||
Patient or population: periodontal therapy | |||||
Outcomes | Anticipated absolute effects |
Relative effect (95% CI) | No. of participants (studies) | Certainty of the evidence (grade) | |
Risk with placebo | Risk with antioxidants | ||||
Reduction of bleeding on probing assessed with the bleeding on probing index |
940 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 163 (3 RCTs) | ⨁⨁⨁◯ |
Reduction of the plaque index assessed with the Silness and Loe plaque index |
756 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 243 (5 RCTs) | ⨁⨁⨁⨁ |
Improvement of the gingival index assessed with the Loe and Silness gingival index |
1.000 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 291 (6 RCTs) | ⨁⨁⨁◯ |
Improvement of clinical attachment loss (improvement of CAL) assessed with clinical attachment loss, in mm |
720 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 261 (5 RCTs) | ⨁⨁⨁⨁ |
Improvement of probing depth assessed with probing depth, in mm. |
695 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 253 (6 RCTs) | ⨁⨁⨁◯ |
The role of lycopene.
Summary of findings | |||||
Lycopene compared to placebo for periodontal therapy | |||||
Patient or population: periodontal therapy | |||||
Outcomes | Anticipated absolute effects |
Relative effect (95% CI) | No. of participants (studies) | Certainty of the evidence (grade) | |
Risk with placebo | Risk with lycopene | ||||
Reduction in bleeding on probing assessed with the bleeding on probing index |
808 per 1.000 | 0 per 1.000 (0 to 0) | Cannot estimated | 52 (2 RCTs) | ⨁⨁⨁◯ |
Improvement of clinical attachment loss assessed with clinical attachment loss, in mm. |
192 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 52 (2 RCTs) | ⨁⨁⨁◯ |
Improvement on probing depth assessed with probing depth |
0 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 52 (2 RCTs) | ⨁⨁⨁◯ |
GRADE working group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the real effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.
The role of green tea.
Summary of findings | |||||
Green tea compared to placebo for periodontal therapy | |||||
Patient or population: periodontal therapy | |||||
Outcomes | Anticipated absolute effects |
Relative effect (95% CI) | No. of participants (studies) | Certainty of the evidence (grade) | |
Risk with placebo | Risk with green tea | ||||
Reduction on bleeding on probing assessed with the bleeding on probing index |
203 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 145 (2 RCTs) | ⨁⨁⨁⨁ |
Reduction on the plaque index assessed with the Silness and Loe plaque index |
0 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 145 (2 RCTs) | ⨁⨁⨁⨁ |
Reduction in gingival index assessed with the Loe and Silness gingival index |
1.000 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 145 (2 RCTs) | ⨁⨁⨁⨁ |
Improvement in clinical attachment loss assessed with clinical attachment loss, in mm. |
1.000 per 1.000 | 0 per 1.000 (0 to 0) | Cannot be estimated | 145 (2 RCTs) | ⨁⨁⨁⨁ |
Improvement on probing depth assessed with probing depth, in mm. |
0 per 1.000 | 0 per 1.000 (0 to 0) | Cannot estimated | 145 (2 RCTs) | ⨁⨁⨁⨁ |
GRADE working group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.
Fifteen clinical trials studies were included in this systematic review, and all of them indicated the beneficial effects of antioxidants during periodontitis treatment. Our meta-analyses showed improvement in the parameters of clinical attachment loss, plaque index, gingival index, and bleeding on probing (except in probing depth); thus, the results may lead to a possible reduction of periodontal inflammation—a pattern among patients. Considering the limitations found in periodontal treatment for complete resolution of the inflammatory process, it is interesting to seek additional adjuvants to the only mechanical treatment.
Furthermore, the complexity of interactions between the microbiota, host, and environment must be considered in periodontal therapy. Therefore, additional strategies on treatment and self-care has to be investigated. Clinically, the reduction of the inflammatory pattern to low levels is important to control the periodontal health state. It is important to mention that the inflammation decrease is essential to establish the health of the periodontal tissues [
In this context, etiopathogenic knowledge is fundamental. There are evidences in the literature that point to the role of oxidative stress with a decrease in the antioxidant defenses that stimulate the process of periodontal destruction [
The literature supports the hypotheses about the association pathway between antioxidant defense and improved periodontitis. On the other hand, this association needs support and the establishment of a causal relationship by evidence-based clinical decisions regarding the use of antioxidants [
A systematic review involves the application of methodological strategies that limit bias and evaluate and summarize crucial scientific evidences. These systematic analyzes can help practitioners be aware of the scientific literature [
The search strategy used in this study included the most important databases to health science in addition to the PICO’s strategy, which allows the comparison of the clinical trial results, verifying if there is an additional effect in the use of antioxidants as adjuvants in conventional PT. The search results show that this approach has been slightly studied, especially in considering the antioxidant diversity, as well as the evaluated parameters. Nevertheless, knowing that the antioxidants used have common objectives, the results can be interpreted as a role of antioxidants in general as adjuvants to conventional PT.
A critical point in the context of this review is the type of outcome evaluated, i.e., in which the studies considered periodontal clinical parameters. It can be observed that the PD was the most used parameter. The PD, in the context of the result of periodontal treatment, is one of the most interesting parameters since it is related to the inflammatory status [
However, the literature has pointed out that the absence of clinically detectable inflammation is associated with stability of periodontal destruction [
Regarding the risk of bias evaluation of the included studies, four studies demonstrated a high risk of bias [
The studies of Elgendy et al. [
It is important to emphasize that the quality of the studies presented in this topic is quite impressive, with most studies included presenting a low risk of bias. One of the concerns is the lack of uniformity of the antioxidants used. The number of patients included in the individual studies is quite variable. The use of meta-analyses is aimed at emerging results from different studies, increasing the number of people analyzed, which generates an increase in statistical power.
Considering the problems regarding methodological quality, four studies were excluded from the meta-analysis [
The results of the meta-analyses revealed that using antioxidants as adjuvants to PT improved the following clinical parameters: CAL, BOP, and GI, demonstrating
Generally, the results presented point to more significant reductions in inflammatory parameters when antioxidants are used in comparison to placebo. The GRADE tool showed a moderate to high certainty in the quality of evidence depending not only to the clinical parameter but also to the type of antioxidants used. The clinical significance of the difference between these two therapies should be analyzed warily. However, it is important to note that, regardless of quantity, the reduction of inflammation is significant and deserves attention. Apparently, due to the diversity of the agents used, it is essential that a separate analysis be performed for each of the antioxidants used. The most commonly used antioxidants were lycopene and green tea.
About lycopene, the data showed greater efficacy of this carotenoid in relation to the other antioxidants. The possible explanation for such finding is that this compound has high radical scavenging ability and interferes with other nonoxidizing mechanisms, including anti-inflammatory agents, as reported below [
Lycopene belongs to the family of carotenoids, it is an open-chain isomer of
In other ways, it activates the NF-E2 p45-related factor 2 (Nrf2)/HO-1 pathway, by mechanisms of direct interaction of lycopene or its metabolites with the protein cysteine residue Keap1 that induces the expression and translocation of Nrf2, a regulator of expression of antioxidant genes under both physiological and oxidative stress conditions. In addition, it activates kinases that release and translocate Nrf2 to the nucleus [
In the case of GT, its pharmacological effect is mainly due to polyphenols and flavonoids, notably (-) epicatechin (EC), (-) epigallocatechin (EGC), and the derivatives of gallate, such as (−)-epigallocatechin-3-gallate (EGCG), and (−)-epicatechin-3-gallate (ECG), but it has a low concentration of phenolic acids [
Despite the evidence of the benefits of antioxidants as adjuvants in periodontal therapy, the substantial limitation was the inclusion of a small number of studies in our quantitative synthesis, suggesting more randomized clinical trials which measure periodontal clinical parameters. Another limitation was the use of not only different types of antioxidants between the 15 included studies but also different administrations (capsules, extracts, sachets, dentifrices, gel formulation, etc.), because our review cannot point a specific adjuvant to the clinical treatment.
Moreover, our results corroborate the hypothesis suggested in the scientific literature that oxidative stress is involved in the pathogenesis of periodontal disease. In general, this systematic review indicates that antioxidants are proper adjuvants to periodontal treatment and can improve the oxidative damage promoted to the periodontal tissue during periodontitis.
Based on clinical trials, this systematic review suggested the use of antioxidants, especially lycopene and GT, as good adjuvants in periodontal therapy, modulating oxidative stress on the periodontium during periodontitis. Therefore, antioxidant therapy may lead to the maintenance of periodontal heath and decrease of inflammatory levels, such as improvement of PI, GI, BOP, and CAL. Further longitudinal studies to better understand the mechanisms of inflammation decrease are highly recommended.
The authors declare that there are no conflicts of interest in this paper.
MMLC and NND performed the searches, quality assessment, analysis of results, and manuscript elaboration. MMLC, PCN, and NCFF performed data extraction, analysis of results, and manuscript elaboration. MBM and LCM performed quantitative analysis and manuscript elaboration. NCFF and CFM performed the quality checking of evidence and manuscript elaboration. MCM, CKR, and RRL performed analysis of results and manuscript elaboration. Micaele Maria Lopes Castro and Nathallia Neves Duarte are dividing the first authorship.
The authors would like to thank the Federal University of Pará, Federal University of Rio de Janeiro, Federal University of Rio Grande do Sul, and University of Alberta for the technical and scientific support. This work was supported by Pró-Reitoria de Pesquisa e Pós-Graduação da UFPA (PROPESP, UFPA, Brazil). This research was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES), Finance code 001.