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.2024.e4350

Braz Dent Sci 2024 July/Sept;27 (3): e4350

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.

Skeletal bone density is associated with periodontitis: systematic

review and metanalysis

Densidade mineral esquelética está associada com periodontite: revisão sistemática e meta-análise

Fernando Lopes KLOECKNER1 , Otto Ferraz Fernandes BARROS2 , Jaíne Cocco ULIANA1 , Karla Zanini KANTORSKI1 

1 - Universidade Federal de Santa Maria, Curso de Odontologia, Programa de Pós-graduação em Ciências Odontológicas. Santa Maria,

RS, Brazil.

2 - Universidade Federal de Santa Maria, Curso de Odontologia. Santa Maria, RS, Brazil.

How to cite: Kloeckner FL, Barros OFF, Uliana JC, Kantorski KZ. Skeletal bone density is associated with periodontitis: systematic review

and metanalysis. Braz Dent Sci. 2024;27(3):e4350. https://doi.org/10.4322/bds.2024.e4350

ABSTRACT

Objective: This study aimed to evaluate whether low skeletal bone density conditions, such as osteoporosis

(OPR), osteopenia (OPN) and low bone mineral density (low BMD) are associated with periodontitis.

Material and Methods: Embase, Lilacs, PubMed, Scopus, Web of Science, Livivo and Google Scholar were

searched up to July 2023. Observational studies comparing different BMD levels, showing clinical data of

periodontitis and with adjusted analysis for confounding factors were included. Reviewers independently

conducted study selection, data extraction, methodological quality and certainty of evidence assessments.

Results: 32 studies were included, 20 eligible for the metanalysis. Subjects with OPR/OPN/lowBMD show

signicantly more odds of having periodontitis (OR=1.40, 95%CI=1.26-1.53, I

=82.9%). Association

between skeletal bone density and periodontitis showed dose-response gradient, with higher effect size

in osteoporotic when compared to the osteopenic subjects. Statistical association with low heterogeneity

was observed in female (OR=1.42, 95%CI=1.13-1.71, I2=20.4%), in post-menopausal women (OR=1.47,

95%CI=1.15-1.78, I2=18.7%) and periodontitis case-denition based in clinical attachment level/alveolar

bone loss (OR=1.39, 95%CI 1.16-1.62, I2=26.5%). Conclusion: Routine periodontal supportive care and

screening for skeletal bone diseases risk groups, may be an important tool to fully assess and care for patients

with osteoporosis and osteopenia.

KEYWORDS

Metanalysis; Osteopenia; Osteoporosis; Periodontal attachment loss; Periodontitis.

RESUMO

Objetivo: Este estudo teve como objetivo avaliar se condições de baixa densidade óssea esquelética, como osteoporose

(OPR), osteopenia (OPN) e baixa densidade mineral óssea (low BMD) estão associadas à periodontite. Material

e métodos: Foram pesquisados Embase, Lilacs, PubMed, Scopus, Web of Science, Livivo e Google Scholar até

julho de 2023. Estudos observacionais que comparavam diferentes níveis de BMD, apresentavam dados clínicos

de periodontite e análises ajustadas para fatores de confusão foram incluídos. Revisores conduziram de forma

independente a seleção de estudos, extração de dados, avaliação da qualidade metodológica e da certeza das

evidências. Resultados: Foram incluídos 32 estudos, sendo 20 elegíveis para metanálise. Indivíduos com OPR/

OPN/low BMD apresentaram signicativamente mais chances de ter periodontite (OR=1.40, IC95%=1.26-1.53,

I2=82.9%). A associação entre densidade óssea esquelética e periodontite mostrou um gradiente de resposta

à dose, com maior tamanho de efeito em indivíduos osteoporóticos em comparação com os osteopênicos.

Foi observada associação estatística com baixa heterogeneidade em mulheres (OR=1.42, IC95%=1.13-1,71,

I2=20.4%), em mulheres pós-menopáusicas (OR=1.47, IC95%=1.15-1.78, I2=18.7%) e na denição de casos

de periodontite com base no nível clínico de inserção (OR=1.39, IC95%=1.16-1.62, I2=26.5%). Conclusão:

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

INTRODUCTION

Osteoporosis (OPR), osteopenia (OPN)

and low bone mineral density (BMD) are

metabolic conditions that affect bone density and

structure, producing an unbalanced absorption/

apposition ratio [1]. In these conditions, bone

mass decreased and generates a greater risk

of fracture [2]. OPR affects over 200 million

people worldwide [3] and causes more than

8.9 million fractures annually [4]. In the United

States more than 10.2 million Americans have

OPR and an additional 43.4 million have low

bone density [5]. One in three women and one

in ve men of age over 50 years will experience

osteoporotic fractures [6].

Periodontitis is an immune-inammatory

disorder initiated by dysbiosis that compromises

the integrity and function of tooth-supporting

structures and if not correctly treated, tooth loss

may follow [7]. Notably, severe periodontitis has

been ranked as the sixth most prevalent condition

globally, affecting 10.8% of adult populations [8].

Periodontitis and OPR have a relatively

“silent” nature leading many patients to seek

“symptom-oriented” care for advanced-stage

periodontitis [9] or in cases of OPR when bone

fractures have already occurred [10]. Periodontitis

and OPR are bone disorders associated with

inammation [11], aging [12] and share risk

modiers factors such as calcium and vitamin

D deficiency [13,14] and smoking [11,15].

Considering the similarities, it raises the question

whether a systemic skeletal disease like OPR

could be associated to localized periodontal bone

destruction.

Recently, studies using a Mendelian

randomization showed no association between

BMD and periodontitis [16,17]. The authors

suggest caution before generalization of the

findings and appoint some limitations such

as: exposure and outcome summary obtained

from individuals with European ancestry, case-

definition of periodontitis based on different

criteria including self-reported periodontitis, and

because in the Mendelian randomization analysis

age- and gender-data were unavailable.

In previous systematic reviews, some

methodological characteristics harmed the

interpretation and restricting the external validity

of the ndings. Among these characteristics are no

information about age range or sex of the included

subjects [18], inclusion of only postmenopausal

women [19,20], absence assessment of risk of

bias [18,20] and of certainty of evidence [18-21],

and no careful about adjust to confounding variables

in primary studies [18-21]. As consequence, the

existing systematic evidences on the association

between low BMD and periodontitis are practically

restricted to the postmenopausal women [19,20]

with no consideration about produced certainty

of evidence.

This is the first systematic review to our

knowledge to investigate the association between

low skeletal bone density and periodontitis (i)

including only primary studies with adjustment

for covariates strengthening the effect estimate,

(ii) including individuals of both sexes and

without age restrictions expanding the external

validity of the results, (iii) and carrying out risk of

bias, publication bias and certainty of the evidence

assessment. Moreover, we explored the effect of

different case-denition of periodontitis and OPR

on the association strength. We hypothesized that

(i) Low skeletal bone density would be associated

with periodontitis with dose-response gradient;

and (ii) the highest effect size would be observed

when periodontitis case-denition was based on

destructive parameters compared to the case

denition based inammatory parameters.

MATERIAL AND METHODS

Review question

“Do subjects with low skeletal bone density

have higher odds for loss of tooth-supporting

structures and of teeth when compared to those

with normal bone conditions?”

O cuidado periodontal de rotina e a triagem para grupos de risco de doenças ósseas esqueléticas podem ser

ferramentas importantes para avaliar e cuidar de pacientes com osteoporose e osteopenia.

PALAVRAS-CHAVE

Meta-análise; Osteopenia; Osteoporose; Perda de inserção periodontal; Periodontite.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Protocol and registration

Our protocol was registered in the Prospective

The study followed the guideline of the Preferred

Reporting Items for Systematic Review and Meta-

analysis checklist [22].

Inclusion criteria

The PECO(S) strategy consisted of the

following acronym: Patients with any age and sex;

Exposure to low BMD, OPR or OPN; Comparison

with subjects showing normal BMD; Outcome

representing periodontitis, clinical attachment

level, alveolar bone loss, tooth loss; and Study

design considering observational studies.

Eligible studies presented the following

criteria: (a) observational design; (b) comparison

between normal BMD and osteoporotic, osteopenic

or low BMD groups; (c) clinical measure of

clinical attachment level (CAL), radiographic

alveolar bone loss, tooth loss, and/or periodontitis

diagnosis; and (d) statistical analysis considering

adjust for confounders factors.

Studies with self-report measures, reviews,

case reports and clinical trials; reports without

adjustment for confounding factors; and papers not

written in Latin-Roman alphabet were excluded.

Search strategy

Our database search was up to July 2023.

Search strategies were customized for each

database considering controlled and free terms

(Appendix 1). Medline/PubMed, Embase, Lilacs,

Web of Science, Livivo and Scopus were searched.

Grey literature was searched on Google Scholar.

Reference lists of included studies and other

systematic reviews were checked for additional

reports. EndNote (Thomson Reuters, New York,

USA) and Rayyan software [23] were used to

manage references and to identify and remove

duplicate hits.

Study selection and data extraction

Three independent reviewers performed the

selection of studies and data extraction. In the rst

phase, titles and abstracts were evaluated. In the

second phase, eligibility criteria were applied to the

full texts. Disagreements were solved by a fourth

reviewer. A standardized data extraction form was

used to obtain relevant data from methodological

characteristics and principal ndings. If data were

missing or unclear, three attempts to contact the

corresponding authors were performed at an

interval of 7 to 10 days via email or ResearchGate.

Methodological quality assessment

Three reviewers independently assessed

the methodological quality using the NewCastle

Ottawa Scale (NOS) for cohort, cross-sectional

and case-control studies [24]. Conflicts were

solved by consensus. Studies were categorized as

high (≥7), moderate (4-6) or low (0-3) quality

according to total score [25].

Outcomes

The main outcome was periodontitis

prevalence. Additional outcomes were CAL and

tooth loss.

Data synthesis and analysis

The effect measure adopted was the adjusted

odds ratio (OR) and respective 95% CI. The Der-

Simonian and Laird’s random effects model was

used. Heterogeneity assessment was performed

considering the direction and size of the effect esti-

mates in the forest plot, I2 scores and Q-statistic.

Heterogeneity causes were explored with subgroup

analysis. A dose response gradient was assessed

by subgroups analysis considering reported data

from osteoporosis and osteopenia, separately,

and data from studies reporting low BMD only.

Case-definition of OPR and periodontitis, sex,

menopause, BMD assessment tool and risk of

bias [26] were analyzed. All analyses were con-

ducted using the Stata software, version 14.0 (Stata

Corporation; College Station, TX, USA). Results

were reported using the informative statements to

communicate the ndings of systematic reviews of

interventions [27] considering the magnitude of

the effect and the certainty of the evidence. Effect

size was reported considering outcomes with preva-

lence of 10% or greater, the cutoff was: trivial effect

1.1 to 1.54, small 1.53 to 2.71, moderate 2.74 to

4.01 and large >4.01) [28].

Assessment of publication bias

Publication bias was analyzed using funnel

plots (visually) and Egger’s statistical test was

performed [29].

Assessment of quality of evidence

The GRADE (Grading of Recommendations

Assessment, Development and Evaluation)

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

system was used to determine the certainty of

the evidence gathered [30].

RESULTS

Study selection

The systematic search yielded 6,293 records;

4,312 titles/abstracts were evaluated after

duplicate removal. Of this total, 212 reports were

included for full text reading. Thirty-two studies

were retained for qualitative analysis, 20 of which

were included in the meta-analysis. The owchart

of the study selection process is presented in

Figure 1. Authorship and exclusion reasons of the

180 reports are presented in Appendix 2.

Study characteristics

The characteristics of the 32 included studies

are presented in the Table I. The reports included

7 cohort [38,40-42,45,46,60], 21 cross-sectional

[31-37,39,43,44,47-49,51-53,56,58,59,61,62]

and 4 case-control studies [50,54,55,57]. Of the

32 included studies, eighteen [31,32,35,36,38-

42,44-47,50,57,58,60,61] and fourteen

[33,34,37,43,48,49,51-57,59,62] were classied

as low and moderate risk of bias, respectively

(Appendix 3).

A total of 3.032.309 subjects aged

18 to 100 years were evaluated. Thirteen studies

included males [31,35,36,38-42,44,45,47,52,55].

However, only one presented separately data

from males and females [40] reporting that

women with periodontitis were more likely to

develop OPR [HR: 1.22, 95% CI 1.01-1.48], while

no signicant statistically risk was veried in men

(HR 1.39, 95% CI 0.85-2.29) [40].

BMD was assessed by DXA tool in 25 studies

[31-34,36,37,39,40,42,44,47-57,59-62]. Case-de-

nition criteria of OPN and OPR according to the WHO

was reported in 20 studies [31-35,37,39,42,43,49-

53,55-57,59,61,62]. Fifteen studies defined a

periodontitis case using CAL or radiographic bone

loss [31,33,34,36,37,39,41,49,50,52-54,56,57,59].

Figure 1 - Flowchart of the process of identiﬁcation, screening and inclusion of studies.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Table I - The characteristic of the included studies considering the association between OPR/OPN/low BMD and periodontitis

Authorship, Country,

design study Sample, Sex, Age Groups OPR/OPN case

deﬁnition, BMD tool Periodontitis Results

Pengetal. [31], USA, cross-

sectional 6,377 Male/female, 45-60y Normal BMD,

OPN, OPR WHO, DXA CAL, PD

OR for periodontitis in

whole sample: OPN: OR 1.08

(0.86-1.36), OPR: OR 1.66

(1.00-2.77)

Lee [32], South Korea,

cross-sectional 2,573 Female, 45-60y Normal BMD,

OPR WHO, DXA CPITN OR for periodontitis: OPR:

OR 1.25 (1.00-1.6)

Zamanietal. [33], Iran,

cross-sectional 94 Female, 50-75y Normal BMD,

OPN, OPR WHO, DXA CAL, Bone loss

β for alveolar bone loss:

BMD: β - 1.122

(SE 0.35; p=0.002)

Baldodiaetal. [34], India,

cross-sectional 112 Female, 52-59y Normal BMD,

OPN WHO, DXA CAL, PD, BOP β for CAL: OPN ß 0.206;

SE 0.045

Chouetal. [35], Taiwan,

cross-sectional 7,298 Male/female, 40-44y Normal BMD,

OPN, OPR WHO, Ultrasound CPI>3 OR for periodontitis: OPN/

OPR: OR 1.13 (1.02-1.26)

Costaetal. [36], Brazil,

cross-sectional 2,032 Male/female, 18-19y Normal BMD,

low BMD BMD Z score, DXA CAL, PD

OR for severe periodontitis:

Low BMD: OR 2.08

(1.12-3.85)

Gil-Montoyaetal. [37],

Spain, cross-sectional 173 Female, 45-72y Normal BMD,

OPN, OPR WHO, DXA CAL

β for percentage of sites

with CAL≥6mm:

Women≤58y: OPR: β 0.37

(-9.6 to10.4), OPN: β 3.63,

(-10.7 to 17.9)

Women>58 y: OPR: β 27.06

(11.31 to 42.81), OPN: β

30.12 (-2.14 to 62.4)

Leeetal. [38], South Korea,

cohort 558,147 Male/female, ≥ 60y Healthy oral,

Period ICD-11 Periodontal

therapy type

OR for periodontitis: OPR:

OR 1.37 (1.35-1.40)

Mongkornkarnetal. [39],

Taiwan, cross-sectional 3,282 Male/female, 30‐82y Normal BMD,

OPN, OPR WHO, DXA CAL, PD

OR for periodontitis: OPR:

OR 0.98 (0.67-1.44), OPN:

OR 0.99 (0.82-1.21)

Choietal. [40], South

Korea, cohort

13,464 Male/female,

30-60+y

No Period,

Period ICD-10, DXA Periodontal

therapy type

HR for OPR: Males with

periodontitis: HR 1.39

(0.85-2.29), Female with

periodontitis: HR 1.22

(1.01-1.48)

Leeetal. [41], South Korea,

retrospective

354,850 Male/female,

40-79y

Healthy oral,

Period

ICD-10 (codes M08-

M82) CAL OR for periodontitis: OPR:

OR 1.22 (1.18-1.27)

Mauetal. [42], Taiwan,

cohort

88,389 Male/female,

40-65+y Period, Control WHO, DXA Periodontal

therapy type

HR for the development of

OPR: Mild periodontitis HR

1.56 (1.30-1.76), Moderate:

HR 2.09 (1.60-2.72)

Richaetal. [43], India,

cross-sectional

600 menopausal women,

45-65y

Non-Period,

Period WHO, QUS CPI≥3

OR for osteoporosis:

Periodontitis OR 0.92

(0.53-1.60)

Huangetal. [44], Taiwan,

cross-sectional

85,583 Male/female, <50-

80+y

No- Period,

Period ICD-9-CM 733.0, DXA Periodontal

therapy type

OR for osteoporosis: Good

OH/periodontitis: OR

1.29 (1.12-1.49); Poor OH/

periodontitis: OR 6.02

(4.65-7.81)

Linetal. [45], Taiwan,

cohort 1,878,401 Male/female No- Period,

Period ICD-9-CM code 733.0 Periodontal

therapy type

OR for osteoporosis: OR

2.03 (1.29-3.20)

Male OR 2.37 (0.88-6.39),

Female OR 1.96 (1.17-3.26)

Changetal. [46], Taiwan,

cohort

10,102 Male/female,

50-100y OPR, Non OPR ICD-9-CM code 733.0

to 733.90 ICD-9-CM.

Stratiﬁed Cox proportional-

hazards regression.

Periodontitis incidence:

OPR: HR 1.14 (1.05-1.24)

Kimetal. [47], South Korea,

cross-sectional 9,977 Male/female, 40+y No- Period,

Period DXA CPI≥ 3

OR for periodontitis: OPN:

OR 1.30 (1.15-1.47), OPR: OR

2.26 (1.83-2.78)

Iwasakietal. [48], Japan,

cross-sectional 397 women, 60-80y Normal BMD,

OPN, OPR

OPN: 70%-80% yan,

OPR ≤70% yan. DXA NA

β for CAL mean: OPN: ß

0.18, SD 0.08, p=0.022

OPR: ß 0.26, SD 0.09,

p=0.003.

Abbreviations: BMD: bone mineral density; OPR: osteoporosis; OPN: osteopenia; Period: periodontitis; WHO: world health organization; DXA:

dual-energy x-ray absorptiometry; QUS: quantitative ultrasound technique; PD: probing depth; CAL: clinical attachment level; BOP: bleeding on

probing; CPI: community periodontal index; CPITN: community periodontal index of treatment needs. NA: Not applicable.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Five studies that used multivariate linear

regression [33,34,37,48,51], and three popula-

tion-based cohort studies from South Korea [40]

and Taiwan [42,46] that reported hazard

ratio as an effect measure, were not included

in our metanalysis. All them demonstrated a

statistical association between OPR and loss

of periodontal support tissue (CAL or bone

loss) [33,34,37,48,51], and between OPR and

periodontitis [40,42,46]. Four studies reported

the association between low BMD and tooth

loss [58,60-62], with two of them observing no

signicant association between OPR and tooth

loss [58,61]. Twenty studies reporting OR as effect

measures for the association between OPR/OPN/

low BMD and periodontitis were included in the

present metanalysis [31,32,35,36,38,39,41,43-

45,47,49,50,52-54,56-59].

Metanalysis

Among the 20 metanalysis studies, 15 reported

data from OPR or OPN cases [31,32,38,39,41,43-

45,49,52-54,56,57,59], while 5 studies reported a

general low BMD status, without a clearly dened

category such as OPR or OPN [35,36,47,54,58].

Subjects with OPR/OPN/low BMD show

significantly more odds of periodontitis (OR

1.40, 95% CI 1.26-1.53, I2=82.9%, p=0.000,

prediction interval 1.03 to 1.77) with low certainty

of evidence (Figure 2).

In summary, the results from subgroup

analysis (Table II) showed that patients with

OPR/OPN/low BMD have statistically higher

odds for periodontitis when compared to the

patients with normal BMD, independently of

the periodontitis case-definition, OPR case-

Authorship, Country,

design study Sample, Sex, Age Groups OPR/OPN case

deﬁnition, BMD tool Periodontitis Results

Marjanovicetal. [49], UK,

cross-sectional 380 female, 45-65y Non-OPR, OPR WHO, DXA CAL, PD OR for periodontitis: OPR:

OR 1.17 (0.67-2.05).

Passosetal. [50], Brazil,

case-control

521 postmenopausal

women, 50-87y

No- Period,

Period DXA, WHO CAL, PD OR for periodontitis: OPN/

OPR: OR 2.24 (1.24-4.06)

Pepelassietal. [51], Greece,

cross-sectional

90 women with

periodontitis, 45-70y

Normal BMD,

OPN, OPR WHO, DXA NA

β for CAL mean adjusted

for menopause: OPR: β

0.69 p=0.03, OPN: B β 0.12

p=0.55

Adjusted for smoking: OPR:

β 0.63 p=0.05, OPN: β 0.12

p=0.54

Moedanoetal. [52],

Mexico, cross-sectional 166 Male/female, 60- 85y Normal BMD,

OPN, OPR WHO, DXA CAL

OR for periodontitis

severity: OPR: OR 1.36

(0.80-2.31)

Al Habashnehetal. [53],

Jordan, cross-sectional

400 postmenopausal

women, 50-75y

Normal BMD,

OPN, OPR WHO, DXA CAL, PD

OR for periodontitis: OPR:

OR 2.45 (1.38-4.34), OPN:

OR 1.35 (0.78-2.35)

Passosetal. [54], Brazil,

case-control

139 postmenopausal

women, >50y

No- Period,

Period DXA CAL, PD, BOP OR for periodontitis: OR

2.02 (0.79-5.19)

Shumetal. [55], China,

case-control 200 male, 69-78y Control, OPN,

OPR WHO, DXA NA

Percentage of sites CAL≥6

mm: OPR: coef 5.3 (0.1-10)

p=0.045, OPN: coef -0.8

(-6.0 to 4.4) p=0.757.

Brennanetal. [56], USA,

cross-sectional

1,256 post-menopausal

women

Normal BMD,

OPN, OPR WHO, DXA Alveolar crestal

height

OR for clinical oral bone loss:

OPR: OR 1.75 (1.09-2.82),

OPN: OR 1.09 (0.78-1.52)

Gomes-Filhoetal. [57],

Brazil, case-control

139 postmenopausal

women, 50-80y

No periodontal

disease, Period WHO, DXA

CAL, PD, BOP,

radiographic bone

loss

OR for periodontitis: OPR:

OR 2.71 (1.12-6.55)

Inagakietal. [58], Japan,

cross-sectional

356 Female, Pre- and post-

menopausal

No/mild

Period,

moderate/

severe Period

OPN: 70%-80% yan,

OPR ≤70% yan, CXD CPITN

OR for OPR/OPN

Moderate/severe

periodontitis: OR 2.0 (1.1-

3.7)

Wactawski-Wendeetal.

[59], USA, cross-sectional

1,341 postmenopausal

women, 53.2-85.1y

Normal, Low,

Moderate, and

Osteoporotic

T-score

WHO, DXA Alveolar crestal

height

OR for alveolar crestal

height: OPR: OR 1.90 (1.19-

3.05)

Abbreviations: BMD: bone mineral density; OPR: osteoporosis; OPN: osteopenia; Period: periodontitis; WHO: world health organization; DXA:

dual-energy x-ray absorptiometry; QUS: quantitative ultrasound technique; PD: probing depth; CAL: clinical attachment level; BOP: bleeding on

probing; CPI: community periodontal index; CPITN: community periodontal index of treatment needs. NA: Not applicable.

Table I - Continued...

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

denition, sex, tool type used to evaluate BMD,

study design and risk of bias of the included

studies and if the diagnosis was osteoporosis

or osteopenia. The association observed in the

pre-menopause women subgroup was non-

signicant, but only 2 studies were available

for metanalysis. We observed a heterogeneity

reduction between females (OR 1.42, 95% CI

1.13-1.71, I2=20.4%, p=0.255) when compared

overall estimate. Grouped data from female/

male showed high heterogeneity. Unfortunately,

data from males only was not available. Lower

heterogeneity was also observed in post-

menopausal women (OR 1.47, 95% CI 1.15-

1.78, I2 18.7%, p=0.271) when compared to

the overall estimates. A dose response gradient

of the association between skeletal bone density

and periodontitis was observed in subgroups

analysis. OPR maintained the effect estimate

(OR 1.43, 95% CI 1.27-1.58, I2=84.4%,

p=0.000) when compared to the overall

estimate, while OPN reduced the estimate (OR

1.14 95% CI 1.02-1.27, I2=24.4%, p=0.251),

and low BMD without dened diagnosis lost

statistical signicance (OR 1.61 95% CI 0.94-

2.28, I2=48.5%, p=0.120.

Criteria to dene OPN/OPR diagnosis (WHO

or others) did not change the effect size and

maintained the heterogeneity. Tool type to evaluate

BMD did not explain the heterogeneity. However,

BMD evaluation using DXA tool increased the

effect size (OR 1.94, 95% CI 1.50-2.37) when

compared to the overall estimate, while other

tools, such as ultrasound, QUS or not reported (OR

1.25, 95% CI 1.11-1.38) reduced the size effect.

Studies that classied periodontitis using CAL/

Bone Loss (CAL/PD and CDC/AAP) maintained the

effect size in comparison to the general aggregated

analysis and reduced heterogeneity (OR 1.39, 95%

CI 1.16 to 1.62, I2=26.5%,).

Regarding the study design, low heterogeneity

was veried only in case-control studies (I2 0.0%,

p=0.927), despite of the imprecision highlighted

by the amplitude of the condence intervals when

compared to the other study design. In studies

with moderate and low risk of bias, OPR/OPN/

low BMD remained statistically associated with

periodontitis.

Sensitivity analysis omitting one by one

of the studies demonstrated no change in the

statistical significance and estimate direction

(Appendix 4).

Figure 2 - Forest plot of OPR/OPN/low BMD and periodontitis in a random eﬀects model meta-analysis.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Assessment of publication bias

Although Egger’s test has indicated no

significant publication bias (p=0.228), we

observed, in the visual analysis of the funnel

plot, asymmetric distribution of the effect

estimates (Appendix 5). Trim and ll sensibility

analysis was performed to measure the impact of

publication bias on the metanalysis (Appendix 6).

Eight studies were lled, although a reduction of

effect size was observed, statistical signicance

remained in the lled meta-analysis (OR 1.28,

95% CI 1.13-1.42).

Assessment of certainty of evidence

No major problems were observed regard-

ing risk of bias, inconsistency, indirectness and

imprecision. Studies showed an inversely pro-

portional relationship between BMD categories

and periodontitis in the dose-response gradient

domain. Although publication bias was detected,

trim and fill sensibility analysis revealed a

slight reduction of effect size and no signicant

changes to statistical signicance. Thus, cer-

tainty of evidence was graded low (Table III).

DISCUSSION

The present study shows statistical

association between low skeletal bone density and

periodontitis with dose-response gradient, OPR

is associated with periodontitis, while a weaker

association between OPN and periodontitis

was found. The heterogeneity was explained

by subgroups analyses, particularly by women,

presence of menopause and by periodontitis case-

denition from destructive parameters (CAL and

alveolar bone loss). BMD assessment using DXA

increased the effect size. These ndings partially

confirmed our initial hypothesis, since that

Table II - Subgroups analysis

Subgroups Number of studies Pooled OR (95% CI) I2p (heterogeneity)

All studies 20 1.40 (1.26-1.53) 82.9% 0.000

BMD category

Osteoporosis 16 1.43 (1.27-1.58) 84.4% 0.000

Osteopenia 6 1.14 (1.02-1.27) 24.4% 0.251

Low BMD 4 1.61 (0.94-2.28) 48.5% 0.120

Periodontitis deﬁnition

CAL/Bone loss 12 1.39 (1.16-1.62) 26.5% 0.184

Others 8 1.55 (1.27-1.83 89.7% 0.000

OPR deﬁnition

WHO 14 1.46 (1.20-1.72) 63.2% 0.001

Others 6 1.43 (1.23-1.63) 92.9% 0.000

Sex subgroups

Female/male 10 1.40 (1.24-1.56) 91% 0.000

Female 10 1.42 (1.13-1.71) 20.4% 0.255

Menopause

Post-menopause 10 1.47 (1.15-1.78) 18.7% 0.271

Pre-menopause 2 1.46 (0.72-2.21) 34.6% 0.216

Tool type to evaluate BMD

DXA 15 1.94 (1.50-2.37) 76.1% 0.000

Others 5 1.25 (1.11-1.38) 91.6% 0.000

Study design

Cross-sectional 14 1.67 (1.33-2.01) 81.4% 0.000

Cohort 3 1.31 (1.17-1.46) 94.2% 0.000

Case-control 3 2.26 (1.17-3.35) 0.0% 0.927

Risk of bias

Moderate 7 1.47 (1.07-1.87) 25.8% 0.232

Low 13 1.39 (1.24-1.54) 88.3% 0.000

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

periodontitis case-denition based on destructive

parameters did not increase the effect estimate

size, although it reduced the heterogeneity in

comparison to the overall estimate.

Independently of the case-denition of OPR

and of periodontitis, the association between

OPR and periodontitis remained statistically

signicant. OPR case-denitions following WHO

criteria compared to others, as well as periodontitis

case-denition from destructive parameters (CAL,

alveolar bone loss) rather than by inammatory

parameters (CPITN) reduced heterogeneity.

Periodontal parameters that indicate destructive

process of support tissue reflects the lifetime

experience of periodontitis and is a critical

outcome measure for diagnosing and staging

periodontitis [7]. Although subgroups analysis

according the equipment type used to evaluate

the BMD did not explain the heterogeneity,

DXA strengthened the effect estimate. DXA is

considered the gold-standard to evaluate BMD

and to establish OPR and OPN diagnosis [63].

Comparison of female with female/male

data indicated that female have higher odds

of periodontitis particularly after menopause.

Unfortunately, only one study reported separately

data according to sex showing no association

between OPR and periodontitis in males [40].

Men lose 15-45% of cancellous bone and 5-15% of

cortical bone with advancing age, whereas women

lose 35-50% of cancellous bone and 25-30% of

cortical bone. Besides, men have shorter life

expectancy means being exposed for a shorter

period to the low BMD and its consequences [64].

In previous systematic reviews [21], OPR was

associated with periodontitis in women and men,

with a larger effect size in women. Male data were

obtained from only 3 studies, more substantial

evidence for the association of osteoporosis in

men and periodontitis is still needed.

No previous systematic review explored the

association between OPR and periodontitis in pre-

and post-menopausal women. Here, we observed

association in post-menopausal, but no statistical

association in pre-menopause women. Several

mechanistic links can take part in this phenomenon,

such as ageing process, oxidative stress, hormonal

changes and cellular senescence [11,65]. During

menopause, women estrogen levels are reduced,

this hormonal imbalance is associated with a gap

between bone resorption and formation, as well

as lower calcium absorption [66], these metabolic

changes in menopause, together with ageing and

exposure to risk factors such as smoking and

vitamin deciencies can upregulate the production

of inflammatory mediators, impairing bone

remodeling and promoting osteoclast activity,

weakening skeletal bone structure, leading to the

risk of fractures [67]. These systemic changes

in homeostasis, bone density and structure are

hypothesized to take part in the association between

osteoporosis and periodontitis, exacerbating the

local progression of active periodontal tissue

destruction [68]. In this context, antiresorptive

medication may be an important modulating

factor to the association between OPR and

periodontitis in postmenopausal women. In a

case-control study including 521 postmenopausal

women, the odds having of periodontitis were

of 2.51 (95%CI 1.33-4.72) and of 1.17 (95%CI

0.19-7.36) in osteopenic/osteoporotic women

non-users and users of antiresorptive medication,

respectively [54]. Further studies have reported

that treatment for osteoporosis may lead to

improvements in periodontal attachment loss

parameters in post-menopausal women [69,70].

Additionally, addressing shared risk factors such

as smoking cessation and nutritional deciencies

may also be strategic as part of a common risk

factor approach for both diseases [11,68].

Previous metanalysis found higher

effect measure to association between OPR

and periodontitis than those reported here.

Xu et al. [21] reported an OR of 1.96 (95%CI

1.50-2.54), while we found an OR of 1.40 (95%CI

1.26-1.53) resulting in a trivial effect size [28].

This discordance can be explained because

Table III - GRADE certainty of evidence assessment

Certainty assessment

Periodontitis (Assessed with: Clinical or Radiographic measurement based on attachment level or bone level)

N studies Study Design Risk of

Bias Inconsistency Indirectness Imprecision Other domains Eﬀect size

(95% CI) Certainty Importance

20 observational

studies not serious not serious not serious not serious

publication

bias, gradient

dose-response

OR 1.40

(1.26 to 1.53) Low Important

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

we included only studies with adjusted effect

measured, due the difference in other inclusion

criteria and an update of studies from 2021.

As a strength, our systematic review used a

sensitive search strategy across six databases and

gray literature, which allowed us to reach a large

number of results. We examined 4,312 reports,

while previous systematic reviews examined

145 to 1,206 records [18-21]. In addition,

we included only studies with adjusted effect

measures, minimizing the interference of potential

confounders on the effect estimate. With broad

inclusion criteria, we could explore the role of the

case-denition of OPR and periodontitis, of the

menopause presence and of the equipment type

used to evaluate BMD on the effect estimates.

Finally, in the quantitative analysis, we found

significant values for the prediction interval,

which indicates that in new studies similar to

those included in our review, the possible effect

will be the same as reported here.

Notably, this is the rst systematic review

to investigate the association between skeletal

bone density conditions such as OPR, OPN and

low BMD and periodontitis including studies with

adjustment for covariates and presenting both,

risk of bias and certainty of evidence assessment.

Besides, this is the rst systematic review to our

knowledge, to investigate the impact of case-

denition of osteoporosis and periodontitis, even

as to directly compare pre- and post-menopausal

women on the association estimate. However,

some limitations must be considered when

interpreting our ndings. First, although there

were no restrictions regarding sex, only one study

reported adjusted estimates in males only [55]

impairing the external validity of our ndings.

Second, although we included only studies

with adjusted analysis, we realized that some

important confounders were explored in few

studies. For example, of the 20 studies included

in the metanalysis, hormone replacement therapy

[49,56,59], vitamin D [31,53,56,59], obesity/

weight/BMI [31,32,35,36,38,39,44,47,56,59]

were variables included in the regression model

in, 3, 4 and 10 studies, respectively. Smoking, a

recognized factor of risk at OPR and periodontitis,

was included in 13 studies [31,32,35,36,39,41,4

7,49,50,54,56,57,59]. Therefore, future studies

should explore more complex analysis models to

determine the true size effect of the association

between OPR and periodontitis. Finally, a risk

for publication bias was detected in a funnel

plot analysis, this bias occurs when there is an

over representation of published studies with

statistically signicant results, while studies with

non-signicant or negative ndings are less likely

to be published. When trim and ll sensibility

analysis was performed, only a small reduction

of effect size was observed, with no important

changes related to statistical signicance.

CONCLUSION

The main finding of our study is that

osteoporotic and osteopenic individuals have

higher odds of periodontitis when compared to

individuals with normal BMD. Then, dentists

must be attentive to patients with risk to develop

skeletal bone diseases to promote preventive

care for periodontitis. Routine oral supportive

care and screening for risk groups, may be an

important tool to fully assess and care for patients

with osteoporosis and osteopenia.

As implications to future research, we

highlight that the evidences of association between

low BMD and periodontitis are scarce in male, and

studies should explore more complex analysis

models considering important confounding

factors, for example smoke, hormone replacement

therapy, vitamin D, obesity/weight/BMI.

Acknowledgements

We thank the Brazilian fostering agency

Coordenação de Aperfeiçoamento de Pessoal de

Nível Superior (CAPES) for the nancial support.

Author’s Contributions

FLK: Investigation, Data Curation, Formal

Analysis, Writing – Original Draft Preparation.

OFFB: Investigation, Data Curation, Formal

Analysis, Writing – Original Draft Preparation.

JCU: Methodology, Investigation, Data Curation,

Formal Analysis, Visualization, Writing – Original

Draft Preparation. KZK: Conceptualization,

Methodology, Investigation, Data Curation,

Formal Analysis, Writing – Review & Editing,

Supervision, Project Administration. All authors

approved of the final version and agreed to

be accountable for all aspects of the work in

ensuring that questions related to the accuracy or

integrity of any part of the work are appropriately

investigated and resolved.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Conict of Interest

The authors have no conicts of interest to

declare.

Funding

This study was partially financed by the

Coordenação de Aperfeiçoamento de Pessoal de

Nível Superior – Brasil (CAPES) - Finance Code

001. We emphasize that the aforementioned

institution did not have any role in the study

design, data collection or analysis, the decision

to publish, or in preparing the manuscript.

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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Karla Zanini Kantorski

(Corresponding address)

Universidade Federal de Santa Maria, Curso de Odontologia, Santa Maria, RS, Brazil.

Email: kzkantorski@gmail.com

Date submitted: 2024 Apr 24

Accept submission: 2024 Aug 24

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Appendix 1. Search strategy according to database

Database Search strategy

Pubmed

#1”bone diseases, metabolic”[MeSH Terms] OR “osteoporosis, postmenopausal”[MeSH Terms] OR (“osteoporosis, postmenopausal”[MeSH

Terms] OR “osteoporosis”[MeSH Terms]) OR “bone density”[MeSH Terms] OR “fractures, bone”[MeSH Terms] OR “Low Bone Mineral Density”[All

Fields] OR “Low Bone Densities”[All Fields] OR “Low Bone Density”[All Fields] OR “Bone Mineral Density”[All Fields] OR (“bone diseases,

metabolic”[MeSH Terms] OR (“bone”[All Fields] AND “diseases”[All Fields] AND “metabolic”[All Fields]) OR “Metabolic Bone Diseases”[All Fields]

OR “osteopenia”[All Fields] OR “osteopenias”[All Fields]) OR (“bone diseases, metabolic”[MeSH Terms] OR (“bone”[All Fields] AND “diseases”[All

Fields] AND “metabolic”[All Fields]) OR “Metabolic Bone Diseases”[All Fields] OR “osteopenia”[All Fields] OR “osteopenias”[All Fields]) OR

“Metabolic Bone Diseases”[All Fields] OR “Metabolic Bone Disease”[All Fields] OR “Perimenopausal Bone Loss”[All Fields] OR “Post-Menopausal

Osteoporosis”[All Fields] OR “Postmenopausal Osteoporosis”[All Fields] OR “Postmenopausal Osteoporoses”[All Fields] OR “Postmenopausal

Bone Loss”[All Fields] OR (“osteoporosis”[MeSH Terms] OR “osteoporosis”[All Fields] OR “osteoporoses”[All Fields] OR “osteoporosis,

postmenopausal”[MeSH Terms] OR (“osteoporosis”[All Fields] AND “postmenopausal”[All Fields]) OR “Postmenopausal Osteoporosis”[All Fields])

OR “Post-Traumatic Osteoporosis”[All Fields] OR “Senile Osteoporosis”[All Fields] OR “Age-Related Bone Loss”[All Fields] OR “Age-Related Bone

Losses”[All Fields] OR “age related osteoporosis”[All Fields] OR “age related osteoporosis”[All Fields] OR “Age-Related Osteoporoses”[All Fields]

OR “Bone Densities”[All Fields] OR “Bone Mineral Density”[All Fields] OR “Bone Mineral Densities”[All Fields] OR “Bone Mineral Content”[All

Fields] OR “Bone Mineral Contents”[All Fields] OR “Bone Fracture”[All Fields]

#2”Periodontal Diseases”[MeSH Terms] OR “periodontal attachment loss”[MeSH Terms] OR “alveolar bone loss”[MeSH Terms] OR

“periodontitis”[MeSH Terms] OR “Chronic Periodontitis”[MeSH Terms] OR “Aggressive Periodontitis”[MeSH Terms] OR “Tooth Loss”[MeSH

Terms] OR “Tooth Mobility”[MeSH Terms] OR “Clinical Attachment Loss”[All Fields] OR “Clinical Attachment Level”[All Fields] OR “Alveolar

Bone Losses”[All Fields] OR “Alveolar Resorption”[All Fields] OR “Periodontal Bone Losses”[All Fields] OR “Periodontal Bone Loss”[All

Fields] OR “Periodontal Resorption”[All Fields] OR “Adult Periodontitis”[All Fields] OR “Prepubertal Periodontitis”[All Fields] OR “early onset

periodontitis”[All Fields] OR “early onset periodontitis”[All Fields] OR “Juvenile Periodontitis”[All Fields] OR “Tooth Mobilities”[All Fields] OR

“Probing Depth”[All Fields] OR “Periodontal Pocket”[All Fields]

#3 “absorptiometry, photon”[MeSH Terms] OR “Densitometry”[All Fields] OR “Bone densitometry”[All Fields] OR “Dual-Energy X-Ray

Absorptiometry”[All Fields] OR “DXA”[All Fields] OR “DEXA”[All Fields] OR “DXA Scan”[All Fields] OR “DEXA Scan”[All Fields] OR “t score”[All

Fields] OR “t score”[All Fields] OR “Frax”[All Fields] OR “Frax Tool”[All Fields] OR “BMD”[All Fields] OR “BMD Test”[All Fields] OR “Dual

Photon Absorptiometry”[All Fields] OR “x ray densitometry”[All Fields] OR “x ray densitometry”[All Fields] OR “x ray photodensitometry”[All

Fields] OR “x ray photodensitometry”[All Fields] OR “Dual Photon Absorptiometry”[All Fields] OR “Dual Energy”[All Fields] OR “Bone Mineral

Density”[All Fields] OR “fractures, bone”[MeSH Terms]

#4: #1 AND #2 AND #3

EMBASE *

#1 “bone density” OR “bone disease” OR “bone densitometry” OR “metabolic bone disease” OR “osteopenia” OR “involutional osteoporosis”

OR “low bone mineral density” OR osteoporosis OR “postmenopause osteoporosis” OR “fragility fracture” OR “senile osteoporosis” OR

“posttraumatic osteoporosis” OR “bone demineralization”

#2 Periodontitis OR “periodontal disease” OR “periodontal disease assessment” OR “Alveolar Bone Loss” OR “Chronic Periodontitis” OR

“aggressive periodontitis” OR “Clinical attachment loss” OR “Clinical attachment level” OR “probing depth” OR “tooth loss” OR “Tooth

Mobility”

#3 “bone densitometry” OR “dual energy X ray absorptiometry” OR “frax tool” OR “bone density” OR “DXA” OR “T score”

#4: #1 AND #2 AND #3

Web of

Science

#1 “osteoporosis postmenopausal” OR “osteoporosis” OR “senile osteoporosis” OR “age related bone loss” OR “age related osteoporosis” OR

“bone density” OR “bone densities” OR “bone mineral density” OR “osteopenia” OR “age related osteoporosis” OR “bone mineral densities”

OR “bone mineral content” OR “low bone density”

#2 “periodontal attachment loss” OR “clinical attachment level” OR “periodontal diseases” OR “periodontal disease” OR “periodontitis” OR

“periodontal bone loss” OR “probing depth” OR “alveolar bone loss” OR “tooth loss”

#3 “densitometries” OR “Dual-Energy X-Ray Absorptiometry” OR “dual energy” OR “DXA scans” OR “DEXA scans” OR “absorptiometry” OR

“bone mineral density” OR “fracture” OR “DXA” OR “DEXA” OR “T score”

#4: #1 AND #2 AND #3

Scopus

#1 TITLE-ABS-KEY

“osteoporosis postmenopausal” OR “osteoporosis” OR “senile osteoporosis” OR “age related bone loss” OR “age related osteoporosis” OR

“bone density” OR “bone densities” OR “bone mineral density” OR “osteopenia” OR “age related osteoporosis” OR “bone mineral densities”

OR “bone mineral content”

#2 TITLE-ABS-KEY

“periodontal attachment loss” OR “clinical attachment level” OR “periodontal diseases” OR “periodontal disease” OR “periodontitis” OR

“clinical attachment level” OR “periodontal bone loss” OR “probing depth” OR “tooth loss”

#3 TITLE-ABS-KEY

“densitometries” OR “Dual-Energy X-Ray Absorptiometry” OR “dual energy” OR “DXA scans” OR “DEXA scans” OR “absorptiometry” OR “bone

mineral density” OR “fracture” OR “DXA” OR “DEXA” OR “T score”

#4: #1 AND #2 AND #3

LILACS ** (osteoporosis OR “bone mineral density” OR “bone density” OR “osteoporose”) AND (Periodontitis OR “periodontal diseases” OR “alveolar

bone loss” OR “periodontite” OR “doença periodontal” OR “tooth loss” OR “perda dentária”)

LIVIVO *** (“osteoporosis” OR “age related bone loss” OR “bone density” OR “bone mineral density” OR “osteopenia” OR “low bone density”) AND

(“clinical attachment level” OR “periodontal diseases” OR “periodontal disease” OR “periodontitis” OR “probing depth” OR “alveolar bone loss”

OR “tooth loss”)

Google

Scholar allintitle: osteoporosis OR osteopenia OR “bone mineral density” OR “bone density” AND Periodontitis OR “periodontal diseases” OR

“alveolar bone loss” OR “tooth loss”

*Embase, we used Emtree terms with explode function and added all synonymous. **Lilacs, we applied ﬁlters to remove: systematic review,

overview, case report, qualitative research and clinical practice guidelines. ***Livivo, we removed the books and included only articles.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Appendix 2. Records and exclusion reason after the full-text reading

Authors and year Reason for exclusion

1. Agrawal, Richaetal. 2021 1

2. Aguilera-Barreiroetal. 2014 2

3. Akrametal. 2018 2

4. Al-Rawi 2007 2

5. Allietal. 2013 3

6. Allietal. 2015 2

7. Al-Sosowaetal. 2022 1

8. Antonenkoetal. 2011 4

9. Aspallietal. 2014 2

10. Ateeqetal. 2021 5

11. Atrushkevichetal. 2014 4

12. Ayedetal. 2018 2

13. Ayedetal. 2019 2

14. Barrosetal. 2012 2

15. Bertuluccietal. 2012 2

16. Brennanetal. 2007 5

17. Bullonetal. 2005 2

18. Calciorietal. 2022 6

19. Darceyetal. 2013 2

20. Darceyetal. 2013 b 6

21. Dargahietal. 2018 2

22. Dhandapanietal. 2023 2

23. Dietrichetal. 2004 5

24. Drozdzowskaetal. 2006 7

25. Dunceaetal. 2022 8

26. Earnshawetal. 1998 7

27. Ehsanpour & Etemadi 2018 2

28. Eldersetal. 1992 7

29. Erdoganetal. 2009 2

30. Familietal. 2005 5

31. Farcasetal. 2019 7

32. Ferreiraetal. 2008 7

33. Garnier Rodriguezetal. 2017 3

34. Gearyetal. 2013 4

35. Gearyetal. 2015 4

36. Gondinetal. 2013 5

37. Grgićetal. 2017 2

38. Grocholewiczetal. 2012 7

39. Guretal. 2003 5.

40. Haerianetal. 2019 2

41. Haerian-Ardakanietal. 2014 9

42. Haghighatietal. 2007 9

43. Hanaietal. 2015 3

44. Hassanvadetal. 2016 2

45. Hattatoğlu-Sönmezetal. 2008 2

46. Henriques & Neto 2011 5

47. Hérnandez-Viguerasetal. 2016 2

48. Hildeboltetal. 1997 5

49. Hildeboltetal. 2000 5

50. Hongetal. 2021 10

51. Ignasiaketal. 2016 7

52. Inagakietal. 2001 11 (Sample overlap from Inagakietal. 2005, which was included).

53. Iwasakietal. 2021 4

54. Jangetal. 2015 5

55. Jinetal. 2022 5

56. Julurietal. 2015 2

57. Kapooretal. 2017 10

58. Kayeetal. 2017 5

1: Without BMD data; 2: Without adjust to covariates; 3: Wrong exposition; 4: Wrong background; 5: Without comparison groups according

to diﬀerent BMD levels; 6: Wrong study design; 7: Wrong eﬀect measure; 8: Wrong outcome measures; 9: Studies not written in Latin-Roman

alphabet; 10: Self-reported data; 11: Overlap samples.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Authors and year Reason for exclusion

59. Khorsandetal. 2006 9

60. Kimetal. 2016 8

61. Klemettietal. 1994 7

62. Kodugantietal. 2009 6

63. Kralletal. 1994 5

64. Kralletal. 1996 5

65. Kralletal. 2005 6

66. Kralletal. 2006 6

67. Kulesetal. 2021 6

68. Kribbsetal. 1990 7

69. Kulikowska-Bielaczycetal. 2006 7

70. Lafzietal. 2012 2

71. LaMonteetal. 2013 2

72. LaMonteetal. 2021 5

73. Lee 2015 11[Korea NHANES 2010-2011, sample overlap from Jietal. 2016 (NHANES 2011-2012), which was included].

74. Lee & Myong 2022 8

75. Lekamwasam & Lenora 2006 5

76. Lenora & Lekamwasam 2003 5

77. Lohanaetal. 2015 7

78. Lopesetal. 2006 2

79. Lopesetal. 2008a 2

80. Lopesetal. 2008b 2

81. Mafetanoetal. 2007 2

82. Manjunathetal. 2019 7

83. Martinez-Maestreetal. 2013 3

84. Mashalkaretal. 2018 2

85. Masulilietal. 2016 2

86. Mazur & Bilozetskyi 2016 3

87. Mochizuki, Takeshietal. 2023 9

88. Moeintaghavietal. 2013 2

89. Moghadametal. 2016 4

90. Mohammadetal. 1996 7

91. Mohammadetal. 1997 7

92. Mohammadetal. 2003 2

93. Mohammad Gorji-nejadetal. 2023 9

94. Mohiuddinetal. 2023 2

95. Moulietal. 2021 8

96. Munhozetal. 2019 8

97. Murrietaetal. 2016 8

98. Nayaketal. 2020 7

99. Nicopoulou-Karayiannietal. 2009 5

100. Niramitchainonetal. 2020 11 (Overlap sample from Mongkornkarnetal. 2019, which was included).

101. Öçakaetal. 2015 3

102. Oztürk Tonguçetal. 2012 2

103. Ozetal. 2010 2

104. Panetal. 2019 2

105. Pallosetal. 2006 2

106. Pavičinetal. 2013 8

107. Pavičinetal. 2017 7

108. Payneetal. 1999 2

109. Pejčićetal. 2005 2

110 Penonietal. 2016 7

111. Penonietal. 2018 5

112. Penonietal. 2019 2

113. Pereiraetal. 2014 2

114. Perssonetal. 2011 8

115. Phippsetal. 2007 7

1: Without BMD data; 2: Without adjust to covariates; 3: Wrong exposition; 4: Wrong background; 5: Without comparison groups according

to diﬀerent BMD levels; 6: Wrong study design; 7: Wrong eﬀect measure; 8: Wrong outcome measures; 9: Studies not written in Latin-Roman

alphabet; 10: Self-reported data; 11: Overlap samples.

Appendix 2. Continued...

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Authors and year Reason for exclusion

116. Piateketal. 2013 2

117. Pilgrametal. 2002 5

118. Pourjavadetal. 2012 2

119. Priebeetal. 2017 3

120. Predaetal. 2022 2

121. Predaetal. 2022b 6

122. Reinhardtetal. 1999 2

123. Renvertetal. 2011 2

124. Rieuwpassaetal. 2019 4

125. Ronderosetal. 2000 7

126. Sawyetal. 2010 8

127. Shenetal. 2004 2

128. Shroutetal. 2000 8

129. Shu-Nyu Tangetal. 2022 9

130. Silveiraetal. 2016 3

131. Singhetal. 2011 5

132. Singhetal. 2012 8

133. Singhetal. 2014 7

134. Sireetal. 2021 8

135. Slaidinaetal. 2011 8

136. Sperretal. 2018 10

137. Stagraczynskietal. 2015 7

138. Streckfusetal. 1997 7

139. Sultan & Rao 2011 5

140. Sureshetal. 2010 2

141. Svedhaetal. 2017 2

142. Taguchietal. 1995 5

143. Taguchietal. 1995b 4

144. Taguchietal. 1999 7

145. Taguchietal. 2004 5

146. Taguchietal. 2007 3

147. Taguchietal. 2022 6

148. Taketal. 2014 5

149. Takahashietal. 2012 5

150. Takaishietal. 2005 7

151. Takaishietal. 2012 2

152. Tanakaetal. 2020 7

153. Tanrioveretal. 2014 8

154. Tezaletal. 2000 5

155. Tougeretal. 2005 6

156. Ursărescuetal. 2012 7

157. Ursărescuetal. 2016 8

158. Vescinietal. 2005 3

159. Vishwanathetal. 2011 3

160. Vlasiadisetal. 2008 8

161. Vlasiadisetal. 2007 5

162. von Wovernetal. 1977 3

163. von Wovernetal. 1992 3

164. von Wovernetal. 1994 3

165. von Wovernetal. 1996 3

166. von Wovernetal. 2001 4

167. Wakaietal. 2013 8

168. Wang et la. 2013 3

169. Weyantetal. 1999 5

170. Yakaretal. 2021 1

171. Yasaretal. 2006 8

172. Yeetal. 2020 4

1: Without BMD data; 2: Without adjust to covariates; 3: Wrong exposition; 4: Wrong background; 5: Without comparison groups according

to diﬀerent BMD levels; 6: Wrong study design; 7: Wrong eﬀect measure; 8: Wrong outcome measures; 9: Studies not written in Latin-Roman

alphabet; 10: Self-reported data; 11: Overlap samples.

Appendix 2. Continued...

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Authors and year Reason for exclusion

173. Yoshiharaetal. 2003 5

174. Yoshiharaetal. 2004 3

175. Yoshiharaetal. 2005 5

176. Yuetal. 2021a 10

177. Yuetal. 2021b 10

178. Zhangetal. 2010 5

179. Zhuetal. 2019 9

180. Zhuetal. 2020 9

1: Without BMD data; 2: Without adjust to covariates; 3: Wrong exposition; 4: Wrong background; 5: Without comparison groups according

to diﬀerent BMD levels; 6: Wrong study design; 7: Wrong eﬀect measure; 8: Wrong outcome measures; 9: Studies not written in Latin-Roman

alphabet; 10: Self-reported data; 11: Overlap samples.

Appendix 2. Continued...

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Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Appendix 3. Newcastle-Ottawa scale quality assessment of included studies

Cross-sectional Studies Selection Comparabil-

ity Outcome Max 9* Max 100% Risk of bias

Pengetal. 2023 *** ** ** 7/9 77.77% Low

Leeetal. 2022 *** ** ** 7/9 77.77% Low

Zamanietal. 2022 * * ** 4/9 44.44% Moderate

Baldodiaetal. 2021 ** * *** 6/9 66.66% Moderate

Chouetal. 2021 *** ** ** 7/9 77.77% Low

Costaetal. 2021 *** ** *** 8/9 88.88% Low

Gil-Montoyaetal. 2021 * ** *** 6/9 66.66% Moderate

Leeetal. 2020 *** ** ** 7/9 77.77% Low

Mongkornkarnetal. 2019 **** ** *** 9/9 100% Low

Richaetal. 2017 ** * ** 5/9 55.55% Moderate

Huangetal. 2016 *** ** ** 7/9 77.77% Low

Jietal. 2016 *** ** ** 7/9 77.77% Low

Kimetal. 2015 ** * ** 5/9 55.55% Moderate

Kimetal. 2014 *** ** ** 7/9 77.77% Low

Iwasakietal. 2013 ** ** ** 6/9 66.66% Moderate

Marjanovic E. J. 2013 ** ** ** 6/9 66.66% Moderate

Papelassietal. 2012 ** * *** 6/9 66.66% Moderate

Moedanoetal. 2011. ** ** ** 6/9 66.66% Moderate

Al Habashnehetal. 2010 * ** ** 5/9 55.55% Moderate

Shumetal. 2010 * ** ** 5/9 55.55% Moderate

Brennanetal. 2008 ** ** ** 6/9 66.66% Moderate

Inagakietal. 2005 ** ** *** 7/9 77.77% Low

Wactawski-Wendeetal. 2005 ** ** ** 6/9 66.66% Moderate

Case-control Studies Selection Comparability Outcome Max 9* Max 100% Risk of bias

Passosetal. 2013 *** ** ** 7/9 77.77% Low

Passosetal. 2010 ** ** ** 6/9 66.66% Moderate

Gomes-Filhoetal. 2007 *** ** ** 7/9 77.77% Low

Cohort Studies Selection Comparability Outcome Max 9 * Max 100% Risk of bias

Leeetal. 2020 *** ** ** 7/9 33.33% Low

Choietal. 2017 **** ** *** 9/9 100% Low

Leeetal. 2017 *** ** *** 8/9 88.88% Low

Mauetal. 2017 *** ** *** 8/9 88.88% Low

Changetal. 2014 **** ** *** 9/9 100% Low

Iwasakietal. 2012 *** ** ** 7/9 33.33% Low

Classiﬁed according to the risk of bias: (a) high (0-3 stars); (b) medium (4-6 stars); or (c) low (≥7 stars). Asterisks represent the number of stars,

* (1 star), ** (2 stars), *** (3 stars), **** (4 stars).

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Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Appendix 4. Forest plot of OPR/OPN/low BMD and periodontitis in a random ef-

fects model meta-analysis.

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Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Appendix 5. Funnel Plot with pseudo 95% condence limits for exploring publica-

tion bias. Each point represents a separate study effect size and standard of error

plotted.

Braz Dent Sci 2024 July/Sept;27 (3): e4350

Kloeckner FL et al. Skeletal bone density is associ ated with periodontitis: systematic revie w and metanalysis

Kloeckner FL et al. Skeletal bone density is associated with periodontitis:

systematic review and metanalysis

Appendix 6. Trim and Fill Funnel Plot with pseudo 95% condence limits for

exploring publication bias. Each point represents a separate study effect size and

standard of error plotted.