UNIVERSIDADE ESTADUAL PAULISTA

“JÚLIO DE MESQUITA FILHO”

Instituto de Ciência e Tecnologia

Campus de São José dos Campos

SYSTEMATIC REVIEW DOI: https://doi.org/10.4322/bds.2025.e4582

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in

any medium, provided the original work is properly cited.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a

systematic review and meta-analysis

Resveratrol como adjuvante no tratamento não cirúrgico da periodontite: revisão sistemática e meta-análise

Nathália Dantas Duarte1 , Cleber Davi Del Rei Daltro Rosa2 , Victor Augusto Alves Bento3 , Gabriel Mulinari-Santos4 ,

Roberta Okamoto4 , Eduardo Piza Pellizzer2 

1 - Departamento de Diagnóstico e Cirurgia, Faculdade de Odontologia de Araçatuba, Universidade Estadual Paulista “Júlio de Mesquita

Filho”, Araçatuba, SP, Brazil.

2 - Departamento de Materiais Odontológicos e Prótese, Faculdade de Odontologia de Araçatuba, Universidade Estadual Paulista “Júlio

de Mesquita Filho”, Araçatuba, SP, Brazil.

3 - Departamento de Prótese, Faculdade de Odontologia de Campo Grande, Universidade Federal do Mato Grosso do Sul, Campo Grande,

MS, Brazil.

4 - Departamento de Ciências Básicas, Faculdade de Odontologia de Araçatuba, Universidade Estadual Paulista “Júlio de Mesquita Filho”,

Araçatuba, SP, Brazil.

How to cite: Duarte ND, Rosa CDDRD, Bento VAA, Mulinari-Santos G, Okamoto R, Pellizzer EP. Resveratrol as adjuvant of non-surgical

periodontitis treatment: a systematic review and meta-analysis. Braz Dent Sci. 2025;28(1):e4582. https://doi.org/10.4322/bds.2025.e4582

ABSTRACT

Objective: This systematic review aims to raise evidence on the effectiveness of the use of resveratrol

supplementation (RV) as an adjuvant therapy for scaling and root planning in the treatment of periodontitis.

Material and Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-

Analysis Guidelines (PRISMA) and was registered in the International Database of Systematic Reviews (PROSPERO

CRD42024507782). PubMed/MEDLINE, Scopus, Embase, and Cochrane Library were searched through October

2024. The PICO question was: “Is the resveratrol supplementation effective as an adjuvant therapy of non-surgical

periodontitis disease treatment?”. The established inclusion criteria were: 1) randomized controlled clinical

trials (RCTs), 2) a minimum of 15 patients with periodontitis disease, and 3) follow-up of at least 4 weeks. The

minimum follow-up duration was 4 weeks. Results: After searching the identied databases, 166 were screened

and 3 were selected for full reading. Therefore, 3 studies were included in the nal analysis. The total number of

participants included in the control group (placebo) was 82, while in the intervention group (RV) was 160, with

a mean age of 38 years. Conclusion: Despite the limitations of the number of studies included in this systematic

review, resveratrol supplementation as an adjuvant to non-surgical periodontal therapy could contribute to

optimizing the treatment of periodontitis.

KEYWORDS

Periodontal diseases; Periodontitis; Phytoestrogens; Resveratrol; Systematic review.

RESUMO

Objetivo: Avaliar as evidências sobre a ecácia do uso da suplementação de resveratrol (RV) como terapia adjuvante

para raspagem e alisamento radicular no tratamento da periodontite. Material e Métodos: Esta revisão seguiu

o Preferred Reporting Items for Systematic Reviews and Meta-Analysis Guidelines (PRISMA) e foi registrada no

International Database of Systematic Reviews (PROSPERO CRD42024507782). As bases de dados utilizadas

PubMed/MEDLINE, Scopus, Embase e Cochrane Library foram pesquisados até outubro de 2024. A pergunta

PICO foi: “A suplementação de resveratrol é ecaz como terapia adjuvante no tratamento não cirúrgico da doença

periodontite?”. Os critérios de inclusão estabelecidos foram: 1) ensaios clínicos randomizados controlados, 2)

mínimo de 15 pacientes com doença periodontal e 3) acompanhamento de pelo menos 4 semanas. A duração

mínima do acompanhamento foi de 4 semanas. Resultados: Após busca nas bases de dados identicadas, 166

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

INTRODUCTION

Periodontitis is a multifactorial chronic

inammatory periodontal disease, the primary

cause is inflammation induced by anaerobic

bacteria [1,2], including

Aggregatibacter

actinomycetemcomitans

Porphyromonas

gingivalis, Tannerella forsythia,

and

Treponema

denticola

which cause dysbiosis of the oral

microbiota [3,4]. After bacterial invasion, the

innate immuno-inflammatory system reacts to

these pathogens by producing pro-inammatory

cytokines, such as TNF-α, IL-6, IL-8, and IL-1β [5].

The initial stage of periodontal disease

involves the action of TNF-α, which increases

the permeability of epithelial cells in the gingival

tissue, optimizing the capacity for invasion of the

main pathogen

gingivalis

, a highly pathogenic

bacterium that causes the development and

progression of periodontal disease [6,7].

Furthermore, TNF-α regulates the production of

innate pro-inammatory cytokines, such as IL-6

and IL-1β [8].

Periodontitis affects supporting tissues,

including the cementum, periodontal ligament,

and alveolar bone and, as such, can be

detrimental [9].The parameter used to evaluate

the extent of support tissue loss, measured as the

distance from the cement-enamel junction to the

base of the pocket, is the clinical attachment level

(CAL), whereas the measured distance from the

free gingival margin to the base of the pocket is

dened as the probing depth (PD) [10].

According to the classication of periodontal

diseases by the American Academy of

Periodontology and the European Federation of

Periodontology in 2017, patients diagnosed with

periodontitis exhibit attachment loss > 3 mm [11].

The primary treatment for periodontitis is

mechanical instrumentation aimed at reducing

the accumulation of subgingival plaque associated

with personal oral hygiene habits [12,13]. In

addition, host defense mechanisms must be

favorable.

However, the presence of furcation or

retention areas can make subgingival mechanical

debridement difficult due to the limited

reach of the instruments. Therefore, systemic

antimicrobials are used as adjuvants for non-

surgical periodontal treatment as therapeutic

strategies for periodontal disease [14]. However,

the frequent use of antibiotics has led to microbial

resistance and systemic side effects [15].

Therefore, researchers are searching for

alternatives to immunomodulatory therapeutic

approaches associated with nonsurgical

periodontal therapy including phytotherapeutics

with effective biological properties [16].

Resveratrol (RV), a phytochemical belonging

to the polyphenol class, was first isolated

in 1939 [17,18]. RV is found in the skin of

grapes, berries, and peanuts. Therefore, red

wine is also a source of RV; the more intense the

grape skin color, the greater the concentration

of polyphenols [19]. Furthermore, RV is found

in small amounts in cocoa beans; therefore, dark

chocolate may also be a source of RV [20].

This biomolecule has garnered signicant

attention due to its diverse biological properties.

Resveratrol (RV) displays antioxidant [19],

anti-inammatory [20,21], and antimicrobial

effects [22]. Additionally, in vitro studies have

suggested that RV may have osteogenic potential

by increasing the expression of RUNX2 genes

through the SIRT1/FOXO3A axis [23]. A clinical

trial also reported RV’s anti-resorptive effect on

bone, which may be mediated by the activation

of endothelial estrogen receptors [24]. Due to

its wide range of effects, RV supplementation

or a diet rich in RV has been investigated as

an adjunctive treatment for several conditions,

including cardiovascular and degenerative

diseases, tumors, diabetes, obesity, metabolic

estudos foram triados e 3 foram selecionados para leitura na íntegra. Portanto, 3 estudos foram incluídos na

análise nal. O número total de participantes incluídos no grupo controle (placebo) foi de 82, enquanto no grupo

intervenção (RV) foi de 160, com média de idade de 38 anos. Conclusão: Apesar das limitações do número de

estudos incluídos nesta revisão sistemática, a suplementação com resveratrol como adjuvante à terapia periodontal

não cirúrgica pode contribuir para otimizar o tratamento da periodontite.

PALAVRAS-CHAVE

Doenças periodontais; Fitoestrógenos; Periodontite; Resveratrol; Revisão sistemática.

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

syndrome, and periodontal disease [25-29]. This

makes RV a promising candidate for adjuvant

therapy in non-surgical periodontitis treatment,

where it could help modulate inammation and

support bone metabolism.

Although two systematic reviews analyzed

RV and evaluated its association with other

phytochemicals (curcumin, quercetin, melatonin,

omega 3, and others) [30,31], evidence supporting

the benets of using RV isolated. As such, the

present systematic review aims to raise evidence

on the effectiveness of RV supplementation as an

adjuvant therapy to scaling and root planning in

the treatment of periodontitis.

MATERIAL AND METHODS

Protocol registration

This systematic review followed the criteria

established by the Preferred Reporting Items

for Systematic Reviews and Meta-Analyses

(PRISMA) and was recorded in the International

Database of Systematic Reviews (PROSPERO

CRD42024507782).

Eligibility criteria

The research question was “Is the resveratrol

supplementation effective as an adjuvant therapy

of non-surgical periodontitis disease treatment?”.

The PICOS question (population, intervention,

comparison, outcome, type of study) was the

“Population” included patients with periodontitis.

The “Intervention” was RV supplementation, while

the “Comparison” was placebo. The “Outcome”

evaluated the clinical attachment loss (CAL) as a

primary outcome, while the secondary outcomes

were probing depth (PD) and inflammatory

markers (IL-6, IL-8, IL-1β; TNF-α). Finally, “Type

of Study” was a randomized controlled clinical

trial, because it is the source of the most reliable

evidence on the effectiveness of interventions [32].

The inclusion criteria involve randomized

controlled clinical trials; a minimum of 15 patients

with periodontitis disease; follow-up of at least 4

weeks; the outcome required in the studies was

clinical attachment level (CAL). The exclusion

criteria were studies with patients underage; articles

involving smokers, and pregnancy; people allergic

to resveratrol; patients taking immunosuppressive

medications or non-steroidal anti-inammatory

drugs; patients using any antioxidant supplement;

people following any specic diets beyond their

usual diets during the last six months; in vitro

studies, animal studies, reviews, case reports,

retrospective studies, non-randomized prospective

interventional studies and studies that did not

include the analyzed outcomes.

Search strategy

Two investigators (N.D.D. and V.A.A.B)

searched independently on the electronic databases

of PubMed/MEDLINE, Scopus, Embase, and

Cochrane Library, studies published until October

of 2024, without language or publication date

restriction, according to eligibility criteria. The

search terms were used for each database. The

selection strategy was based on the following

combination of descriptors in association with

Boolean Operators (Table I). No filters and

database limits were used in the searches. Further,

as a complement, a manual search was carried

out on high-impact periodontics journals such as

the Journal of Periodontology, Journal of Clinical

Periodontology, Periodontology 2000, Journal of

Periodontal Research, and Journal of Periodontal

& Implant Science. Finally, a search was carried

out on the Grey Literature Database [33].

Data extraction (selection and coding)

Once the bibliographic research was

complete, Rayyan® Software [34] was used to

manage the bibliography and remove duplicates.

Two independent researchers (N.D.D. and

V.A.A.B) carried out the initial selection of

studies by reading the title and abstract, then

if the studies agreed with this review they were

consulted in full, after which the inclusion and

Table I - The search terms used for each database

PUBMED SCOPUS EMBASE COCHRANE

(“resveratrol”[MeSH Terms] OR “resveratrol”[All Fields] OR “resveratrol

s”[All Fields] OR “resveratrols”[All Fields]) AND (“periodontal”[All

Fields] OR “periodontally”[All Fields] OR “periodontically”[All

Fields] OR “periodontics”[MeSH Terms] OR “periodontics”[All Fields]

OR “periodontic”[All Fields] OR “periodontitis”[MeSH Terms] OR

“periodontitis”[All Fields] OR “periodontitides”[All Fields])

( TITLE-ABS-KEY

(resveratrol) AND

TITLE-ABS-KEY

(periodontitis) )

‘resveratrol’

resveratrol AND

periodontitis

AND

‘periodontitis’

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

exclusion criteria were applied. A third researcher

(C.D.D.R.D.R.) checked the information. When

there was disagreement, a fourth reviewer (E.P.P.)

was consulted. If the articles’ full texts were

unavailable, the authors were consulted through

the corresponding author in up to 3 attempts. For

data collection and analysis, two authors (N.D.D.

and V.A.A.B.) collected data from the included

studies and a third author (C.D.D.R.D.R.) checked

the information. When there was disagreement,

a fourth reviewer (E.P.P.) was consulted. The

qualitative data collected were the author of

the study and year, number of patients, age,

follow-up in weeks, characterization of control

group, RV supplementation concentration,

placebo and RV administration protocol, clinical

evaluations, biochemical evaluations, outcomes,

conclusion, and effect of RV supplementation as

an adjuvant therapy of non-surgical periodontitis

disease treatment (Table II). The quantitative

data collected was the mean and standard

deviation (Mean ± SD) of the outcomes: CAL,

PD, IL-6, IL-8, IL-1β, and TNF-α (Table III).

Abbreviations: BI: bleeding index; CAL:

clinical attachment level; OHI-S: oral hygiene

index-simplied; PD: probing depth; PI: plaque

index; PPD: probing pocket depth. CRP: C-reactive

protein; GMCSF: granulocyte-macrophage colony

stimulating factor; IL-10: interleukin-10; IL-12p40:

interleukin-12p40; IL-1β: interleukin-1beta;

IL-2: interleukin-2; IL-4: interleukin-4; IL-6:

interleukin-6; IL-8: interleukin-8; INF-γ: interferon-

gamma; MCP-1: monocyte chemoattractant

protein-1; MIP-1α: macrophage inflammatory

protein-1alpha; TAC: total antioxidant capacity;

TNF-α: tumor necrosis factor-alpha.

Abbreviations: CAL: clinical attachment level;

PD: probing depth; IL-1β: interleukin-1beta; IL-6:

interleukin-6; IL-8: interleukin-8; TNF-α: tumor

necrosis factor-alpha; HRV: high dose of RV; LRV:

low dose of RV; MRV: middle dose of RV.

Summary measurements

The meta-analysis was based on an inverse

variance (IV) method. The primary outcome

CAL, in addition to secondary outcomes: PD,

IL-6, IL-8, IL-1β; and TNF-α were considered

continuous outcomes and were evaluated using

the mean difference (MD) evaluated by IV with

a 95% condence interval (CI). The MD values

were signicant when p < 0,05. For statistically

signicant (p < 0,10) heterogeneity, a random-

effect model was used to assess the signicance

of the RV supplementation effect. When no

statistically signicant heterogeneity was found, an

analysis was performed using a xed-effects model.

The software Reviewer Manager 5.4 (Cochrane

Group) was used for the meta-analyses [38].

Bibliometric analysis

The quality of the studies was independently

analyzed by 2 investigators (V.A.A.B., R.O.)

using the ROBINS-I tool that considers the

domain according to pre-intervention (bias

due to confounding, bias in selection of study

participants), intervention (bias in classication

of interventions), and post-intervention (bias due

to deviations from intended interventions, bias

due to missing data, bias in measuring outcomes,

and bias in selection of reported outcomes [39].

Risk of bias

Two authors (V.A.A.B. and C.D.D.R.D.R.)

performed the quality and risk of bias analysis

on the included RCTs using the second version

of the Cochrane risk-of-bias tool for randomized

trials (RoB 2.0). That tool verifies selection,

performance, attrition, reporting, and other

biases. RoB 2.0 addresses ve specic domains: (1)

bias arising from the randomization process; (2)

bias due to deviations from intended interventions;

(3) bias due to missing outcome data; (4) bias in

the measurement of the outcome; and (5) bias in

the selection of the reported results. After dening

the domains, an overall bias will be determined

for each study. Each of these domains will be

categorized as low, high, or some concerns.

RESULTS

Found 332 studies from the previously

selected bases: 104 from PubMed, 109 from

Scopus, 102 from Embase, and 17 from Cochrane.

After removing 166 duplicates, 166 articles were

screened by title and abstract, and 3 were screened

by full text. Therefore, 3 studies were included in

the nal analysis. The details of the search strategy

are illustrated in Figure 1. No studies were found

in the Journal of Periodontology, Journal of

Clinical Periodontology, Periodontology 2000,

Journal of Periodontal Research, Journal of

Periodontal & Implant Science, and the Grey

Literature Database.

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Table II - Detailed data from all studies included. Author and year of the study, number of patients (N), age, follow-up (weeks), control group, RV concentration, placebo and RV administration protocol, clinical

evaluations, biochemical evaluations, conclusion, and eﬀect of RV supplementation

Author Patients (N) Age Follow-up

(weeks) Control Group RV Concentra-

tion

Placebo and

RV Protocol

Clinical Evalu-

ations

Biochemical Evalu-

ations Conclusion RV Eﬀect

Javidetal.

2019 [35] 43 30-60 years 4 Placebo Starch

480 mg (n=22) 240 mg (n=21) 2 pills daily CAL (mm)

IL-6 (pg/ml) TNF-α

(pg/ml) TAC

(mmol/L)

The daily RV

supplementation

in adjunction

with non-surgical

periodontal

treatment may

not change CAL

and TNF-α

Negative

Zhangetal.

2022 [36] 160

Mean 26.52

(control)

27.57 (RV)

8 Placebo (n=40)

High dose

(500 mg)

(n=40) Middle

dose (250 mg)

(n=40) Low

dose (125 mg)

(n=40)

1 capsule daily

CAL (mm) BI

(%) OHI-S PPD

(mm)

TNF-α (pg/ml)

GMCSF (pg/ml)

MIP-1α (pg/ml)

Fibrinogen (pg/ml)

IL-2 (pg/ml) CRP

(pg/ml) INF-γ (pg/

ml) IL-1β (pg/ml) IL-8

(pg/ml) IL-10 (pg/

ml) IL-12p40 (pg/ml)

MCP-1 (pg/ml) IL-4

(pg/ml) IL-6 (pg/ml)

RV treatment has

anti-inﬂammatory

capacity and

decreases

systemic

endotoxin in

patients with

periodontitis.

Positive

Nikniaz etal

2023 [37] 40

Mean 41.7

(control) 44.5

(RV)

4Placebo Starch

480 mg (n=20) 480 mg (n=20) 2 capsules daily

PD (mm) CAL

(mm) PI (%) BI

(%)

IL-8 (pg/ml) IL-1β

(pg/ml)

supplementation

in combination

with non-surgical

periodontal

treatment may

be beneﬁcial in

improvement

the clinical

parameters and

inﬂammatory

condition in

periodontitis

patients.

Positive

Abbreviations: BI: bleeding index; CAL: clinical attachment level; OHI-S: oral hygiene index-simpliﬁed; PD: probing depth; PI: plaque index; PPD: probing pocket depth. CRP: C-reactive protein; GMCSF:

granulocyte-macrophage colony stimulating factor; IL-10: interleukin-10; IL-12p40: interleukin-12p40; IL-1β: interleukin-1beta; IL-2: interleukin-2; IL-4: interleukin-4; IL-6: interleukin-6; IL-8: interleukin-8; INF-γ:

interferon-gamma; MCP-1: monocyte chemoattractant protein-1; MIP-1α: macrophage inﬂammatory protein-1alpha; TAC: total antioxidant capacity; TNF-α: tumor necrosis factor-alpha.

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Characteristics of selected studies

Table III - The quantitative data collected of the outcomes, mean and standard deviation (Mean ± SD)

Parameters Nikniazetal. (2023) [37] Zhangetal. (2022) [36] Javidetal. (2019) [35]

CAL

Case group Placebo group Control group

Before intervention

6.06±0.37

baseline

5.17±0.64

LRV group 2.72 ± 0.5

After intervention

4.18±0.75

4 weeks

3.37±0.56 MRV group 2.2 ± 0.5

3.76±0.88

Control group HRV group Intervention group

Before intervention

3.15±0.96

baseline

4.97±0.58 2.35 ± 0.6

After intervention 4 weeks

3.74±0.6 2 ± 0.4

Case group Placebo group

Before intervention

5.74±0.50

4.44±0.63 LRV group

After intervention

2.82±0.62

2.82±0.58 MRV group

2.15±0.42

Control group HRV group

Before intervention

2.00±0.40

4.27±0.58

After intervention

3.2±0.66

IL-8

Case group Placebo group

Before intervention

756±210 -

systemic

18.67±3.65 356±116 –

local

After intervention

LRV group

17.36±3.03 354±142 –

systemic

142±70 –

local

Control group MRV group

Before intervention

350±152 –

systemic

16.83±2.63 128±67 –

local

After intervention

HRV group

16.97±1.97 326±137 –

systemic

114±43 -

local

IL-1β

Case group Placebo group

Before intervention

543±150 -

systemic

7.54±3.74 408±144 –

local

After intervention

LRV group

4.34±2.27 220±105 –

systemic

175±80 –

local

MRV group

Control group 210±90 –

systemic

Before intervention

172±76 –

local

6.24±3.16 HRV group

After intervention

196±68 –

systemic

4.96±2.67 163±55 –

local

Abbreviations: CAL: clinical attachment level; PD: probing depth; IL-1β: interleukin-1beta; IL-6: interleukin-6; IL-8: interleukin-8; TNF-α: tumor

necrosis factor-alpha; HRV: high dose of RV; LRV: low dose of RV; MRV: middle dose of RV.

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Parameters Nikniazetal. (2023) [37] Zhangetal. (2022) [36] Javidetal. (2019) [35]

TNF-α

Placebo group Control group

625±210 -

systemic baseline

415±101 –

local

10.56 ± 0.61

LRV group

4 weeks

112±102 –

systemic

10.57 ± 0.68

174±96 –

local

MRV group Intervention group

108±118 –

systemic baseline

124±118 –

local

10.49 ± 0.47

HRV group

4 weeks

104±98–

systemic

10.33 ± 0.66

104±98 –

local

IL-6

Placebo group Control group

285±100 -

systemic baseline

342±105 –

local

2.08 ± 0.82

LRV group

4 weeks

456±142 –

systemic

1.85 ± 0.59

610±179 –

local

MRV group Intervention group

486±162 –

systemic baseline

635±198 –

local

2.19 ± 1.09

HRV group

4 weeks

493±172 –

systemic

1.58 ± 1.06

550±202 –

local

Abbreviations: CAL: clinical attachment level; PD: probing depth; IL-1β: interleukin-1beta; IL-6: interleukin-6; IL-8: interleukin-8; TNF-α: tumor

necrosis factor-alpha; HRV: high dose of RV; LRV: low dose of RV; MRV: middle dose of RV.

Table III - Continued...

Figure 1 - Search strategy.

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Detailed data from all studies included are

listed in Table II and Table III. The total number

of participants included in the control group

(placebo) was 82, while in the intervention group

(RV) was 160, with a mean age of 38 years.

The important difference to consider between

the patients included in the papers is that in

the study by Javid et al. [35], the patients have

type 2 diabetes, while in the other two studies

Zhang et al. [36] and Nikniaz et al. [37] the

patients were not diabetic. The follow-up period

it was ranged from 4 to 8 weeks. In the study

by Zhang et al. [36] three concentrations of RV

were tested, high-dose (500 mg/d), middle-dose

(250 mg/d), and low-dose (125 mg/d), while in

the other studies only one dose of RV was tested,

240 mg - 2 pills/d Javid et al. [35] and 480 mg -

2 pills/d Nikniaz et al. [37].

The scaling and root planning protocol was

performed for all participants using ultrasonic

Gracey curettes and scalers during the study by

Javid et al. [35] and a piezoelectric ultrasonic by

Nikniaz et al. [37]. The non-surgical periodontal

therapy protocol was not specied in the study

by Zhang et al. [36]. To measure the pocket

depth (CAL and PD), Nikniaz et al. [37] used

a Williams probe, and Javid et al. [35] used a

University of North Carolina no 15 probe. In the

Zhang et al. [36], it was not specified which

instrument was used to measure the pocket depth.

The inammatory markers were analyzed

using a salivary sample collected between 9

AM and 12 PM and were measured by ELISA

method using a laboratory kit [37]. In the

other two studies, was collected 5 ml of blood

in the morning hours [35,36]. The levels of

inammatory markers were determined using

fluorescence detection kits [36], while in the

study carried out by Javid et al. [35] was

performed ELISA method. All patients received

non-surgical periodontal treatment and oral

hygiene instructions during the studies.

Meta-analysis

The meta-analysis included three studies

that contained quantitative data related to the

outcomes. The three studies were included for the

rst outcome on clinical attachment loss [35-37].

The Zhang et al. [36] study was divided into HRV

(high-dose), MRV (middle-dose), and LRV (low-

dose). The results showed that associating RV

supplementation with non-surgical periodontal

therapy gains the clinical attachment level (CAL):

(P<0.00001; MD 1.53 [CI 0.51 to 2.56]; I2=98%;

P=0.003) (Figure 2). About the secondary

outcomes, Zhang et al. [36] and Nikniaz et al.

[37] reduced periodontal pocket depths (PD):

(P<0.00001; MD 2.68 [CI 1.55 to 3.80]; I2=99%;

P<0.0001) (Figure 2). Inammatory markers

analysis in Zhang et al. [36] investigation

showed IL-8: (P<0.00001); MD 313.24 [CI

243.27 to 383.21]; I2=90%; P<0.00001). IL1-β:

(P<0.00001); MD 285.35 [CI 242.40 to 328.30];

I2=76%; P=0.0009). TNF-α: (P<0.00001);

MD 395.61 [CI 297.62 to 493.60]; I2=95%;

P<0.00001). IL-6: (P<0.00001); MD -222.22

[CI -258.82 to -185.62]; I2=51%; P=0.07)

(Figure 3). Therefore, the study showed the anti-

inammatory effect of RV, through the reduction

of inammatory markers, except for IL-6.

Figure 2 - Forest plot evaluating clinical attachment level (CAL) and probing pocket depth (PD) - a statistically signiﬁcant diﬀerence (p < 0.05)

favorable to RV supplementation.

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Risk of bias

The evaluation of results for the quality

of the methodology using the RoB 2.0 tool for

randomized interventional studies indicated a

moderate risk of bias in studies Zhang et al. [36]

and Nikniaz et al. [37], identifying deciencies,

mainly in the domain D4 and D5, while the study

of Javid et al. [35] indicated a serious risk of bias,

identifying deciencies in domain D3, D4, and

D5 (Figure 4).

DISCUSSION

In this study, the hypothesis that

supplementation with RV, as an adjuvant to

nonsurgical periodontal therapy, could improve

the treatment of periodontitis was conrmed, and

a signicant difference between groups treated

with RV versus placebo was observed.

Although non-surgical periodontal treatment

(scaling and root planning) is considered to be

the “gold standard” method for treating patients

diagnosed with periodontitis, the search for

adjuvant alternatives to enhance periodontal

tissue repair is ongoing.

Recently, phytotherapy has become a hot

topic in Dentistry due to its accessibility, cost-

effectiveness, and absence of side effects compared

with synthetic drugs [40]. Systemic treatment

with RV is currently used in Periodontology.

However, clinical studies are limited, which

explains the existence of only four published

randomized clinical trials (RCTs). Currently, most

studies available in the literature investigating

RV treatment associated with nonsurgical

periodontal therapy are in vitro and in vivo.

Results of the present systematic review

are consistent with many preclinical studies in

Figure 3 - Forest plot evaluating inﬂammatory markers - a statistically signiﬁcant diﬀerence (p < 0.05) favorable to RV supplementation.

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

rats demonstrating that nonsurgical periodontal

treatment associated with RV supplementation

has benecial effects against the progression of

experimental periodontitis [16,41]. In addition,

the anti-inammatory properties of RV protect

against further damage to the periodontal

tissues [42,43]. A previous systematic review

evaluated the effect of RV on the progression

of periodontitis in rats and reported positive

results [44]. The studies by Zhang et al. [36]

and Nikniaz et al. [37] consider that RV

supplementation associated with non-surgical

periodontal treatment has anti-inflammatory

capacity and can be beneficial in improving

clinical parameters in patients with periodontitis.

In contrast, the study by Javid et al. [35]

included diabetic patients with periodontitis,

in which there was no benefit from RV

supplementation in the adjuvant treatment of non-

surgical periodontal therapy. Considering systemic

factors that can modify the host’s susceptibility

to periodontal disease progression and response

to non-surgical periodontal therapy [45,46].

The mechanism involved in the pathogenesis of

diabetes mellitus-associated periodontitis is by

AGE-RAGE axis, which intensies inammation

and compromises periodontal tissue repair

after scaling and root planning [45]. Therefore,

clinicians must consider this issue to ensure

appropriate patient management and successful

treatment of periodontitis.

One aspect in common between the three

included studies [35-37] is that patients taking

immunosuppressants, anti-inammatory drugs,

or antioxidant supplements were excluded to

avoid interference with the results and to ensure

the validity of the data. Immunosuppressive

and anti-inflammatory can affect the host’s

inammatory and immune responses, potentially

interfering with the effects of resveratrol, which

has anti-inflammatory properties [20,21].

Additionally, these medications could compromise

the reliability of immunological markers analysis.

Similarly, antioxidant supplementation, like

vitamin C [47], selenium [48], and others, may

affect RV effects, making it difcult to evaluate

the isolated action of RV.

As a limitation, this systematic review and

meta-analysis considered only one RCT involving

patients with type 2 diabetes, as this topic is

still scarce in the literature. Therefore, in this

study, two investigations involving patients

with periodontitis without systemic diseases

and one involving patients with diabetes were

included. Furthermore, other limitations included

variations in the RV dose, different frequencies

of RV consumption across the studies, and the

number of available RCTs.

Therefore, new RCTs with dose

standardization and different evaluation methods

should be conducted to conrm the results of this

review. Regarding the heterogeneity in the meta-

analysis of outcomes, the I2 value demonstrated

that study variability was high.

The development of new RCTs to test RV

supplementation associated with nonsurgical

periodontal therapy in patients with periodontitis

without systemic diseases and those with diabetes

is fundamental to lling current knowledge gaps

in the literature and contributing to the evidence

supporting the benets of RV for the treatment

of periodontitis and improving the success of the

therapy.

CONCLUSION

Despite the limitations of the number

of studies included in this systematic review,

resveratrol supplementation as an adjuvant to

non-surgical periodontal therapy could contribute

to optimizing the treatment of periodontitis.

Figure 4 - Results of risk of bias in studies based on RoB 2.0 tool.

Low risk

Some concerns

High risk

D1 D2 D3 D4 D5 Overall

Javid et al. 2019 [35]

Zhang et al. 2022 [36]

Nikniaz et al. 2023 [37]

D1 Randomization process

D2 Deviations from the intended Interventions

D3 Missing outcome data

D4 Measurement of the outcome

D5 Selection of the reported result

Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Acknowledgements

The authors would like to thank The São

Paulo Research Foundation (FAPESP) for the

Master’s scholarship [Process: 2022/07158-8].

Author’s Contributions

NDD: Conceptualization, Methodology,

Formal Analysis, Investigation, Data Curation,

Writing – Original Draft Preparation, Writing

– Review & Editing, Visualization, Funding

Acquisition. CDDRDR: Methodology, Software,

Data Curation, Writing – Review & Editing.

VAAB: Methodology, Software, Formal

Analysis, Investigation, Writing – Original Draft

Preparation. GMS: Resources, Supervision. RO:

Validation, Supervision. EPP: Conceptualization,

Validation, Visualization, Supervision, Project

Administration.

Conict of Interest

The authors have no conicts of interest to

declare.

Funding

This research did not receive any specic

grant from funding agencies in the public,

commercial, or not-for-prot sectors.

Regulatory Statement

This systematic review was conducted

through a search strategy in electronic databases.

The approval for ethics committee for the reviewed

studies were obtained in their original work.

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Braz Dent Sci 2025 Jan/Mar;28 (1): e4582

Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Duarte ND et al.

Resveratrol as adjuvant of non-surgical periodontitis treatment: a systematic review and meta-analysis

Duarte ND et al. Resveratrol as adjuvant of non-surgical periodontitis

treatment: a systematic review and meta-analysis

Date submitted: 2024 Nov 19

Accept submission: 2025 Mar 13

Nathália Dantas Duarte

(Corresponding address)

Departamento de Diagnóstico e Cirurgia, Faculdade de Odontologia de Araçatuba,

Universidade Estadual Paulista “Júlio de Mesquita Filho”, Araçatuba, SP, Brazil.

Email: nd.duarte@unesp.br