guided infrabony review willey blackwell

Guided tissue regeneration for periodontal infra-bony defects

(Review)

Needleman I, Worthington HV, Giedrys-Leeper E, Tucker R

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2008, Issue 4

http://www.thecochranelibrary.com

Guided tissue regeneration for periodontal infra-bony defects (Review)

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 GTR versus control, Outcome 1 Attachment gain (change). . . . . . . . . . . 29

Analysis 1.2. Comparison 1 GTR versus control, Outcome 2 Sites gaining less than 2 mm attachment. . . . . . 31

Analysis 1.3. Comparison 1 GTR versus control, Outcome 3 Probing pocket depth (change). . . . . . . . . 32

Analysis 1.4. Comparison 1 GTR versus control, Outcome 4 Recession (change from baseline). . . . . . . . . 33

33WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iGuided tissue regeneration for periodontal infra-bony defects (Review)


[Intervention Review]


Ian Needleman1, Helen V Worthington2 , Elaine Giedrys-Leeper1, Richard Tucker1

1Unit of Periodontology, Division of Restorative Dental Sciences, UCL Eastman Dental Institute, London, UK. 2Cochrane Oral

Health Group, MANDEC, School of Dentistry, The University of Manchester, Manchester, UK

Contact address: Ian Needleman, Unit of Periodontology, Division of Restorative Dental Sciences, UCL Eastman Den-

tal Institute, University College London (UCL), University of London, 256 Gray’s Inn Road, London, WC1X 8LD, UK.

[email protected].

Editorial group: Cochrane Oral Health Group.

Publication status and date: Edited (no change to conclusions), published in Issue 4, 2008.

Review content assessed as up-to-date: 12 January 2006.

Citation: Needleman I, Worthington HV, Giedrys-Leeper E, Tucker R. Guided tissue regeneration for periodontal infra-bony defects.

Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD001724. DOI: 10.1002/14651858.CD001724.pub2.


A B S T R A C T

Background

Conventional treatment of destructive periodontal (gum) disease arrests the disease but does not usually regain the bone support or

connective tissue lost in the disease process. Guided tissue regeneration (GTR) is a surgical procedure that specifically aims to regenerate

the periodontal tissues when the disease is advanced and could overcome some of the limitations of conventional therapy.

Objectives

To assess the efficacy of GTR in the treatment of periodontal infra-bony defects measured against conventional surgery (open flap

debridement (OFD)) and factors affecting outcomes.

Search strategy

We conducted an electronic search of the Cochrane Oral Health Group Trials Register, MEDLINE and EMBASE up to April 2004.

Handsearching included Journal of Periodontology, Journal of Clinical Periodontology, Journal of Periodontal Research and bibliographies

of all relevant papers and review articles up to April 2004. In addition, we contacted experts/groups/companies involved in surgical

research to find other trials or unpublished material or to clarify ambiguous or missing data and posted requests for data on two

periodontal electronic discussion groups.

Selection criteria

Randomised, controlled trials (RCTs) of at least 12 months duration comparing guided tissue regeneration (with or without graft

materials) with open flap debridement for the treatment of periodontal infra-bony defects. Furcation involvements and studies specifically

treating aggressive periodontitis were excluded.

Data collection and analysis

Screening of possible studies and data extraction was conducted independently. The methodological quality of studies was assessed

in duplicate using individual components and agreement determined by Kappa scores. Methodological quality was used in sensitivity

analyses to test the robustness of the conclusions. The Cochrane Collaboration statistical guidelines were followed and the results

expressed as mean differences (MD and 95% CI) for continuous outcomes and risk ratios (RR and 95% CI) for dichotomous outcomes

calculated using random-effects models. Any heterogeneity was investigated. The primary outcome measure was change in clinical

attachment.

1Guided tissue regeneration for periodontal infra-bony defects (Review)


mailto:[email protected]

Main results

The search produced 626 titles, of these 596 were clearly not relevant to the review. The full text of 32 studies of possible relevance was

obtained and 15 studies were excluded. Therefore 17 RCTs were included in this review, 16 studies testing GTR alone and two testing

GTR + bone substitutes (one study had both test treatment arms).

No tooth loss was reported in any study although these data are incomplete where patient follow up was not complete. For attachment

level change, the mean difference between GTR and OFD was 1.22 mm (95% CI Random Effects: 0.80 to 1.64, Chi2 for heterogeneity

69.1 (df = 15), P < 0.001, I2 = 78%) and for GTR + bone substitutes was 1.25 mm (95% CI 0.89 to 1.61, Chi2 for heterogeneity 0.01

(df = 1), P = 0.91). GTR showed a significant benefit when comparing the numbers of sites failing to gain 2 mm attachment with risk

ratio 0.54 (95% CI Random Effects: 0.31 to 0.96, Chi2 for heterogeneity 8.9 (df = 5), P = 0.11). The number needed to treat (NNT)

for GTR to achieve one extra site gaining 2 mm or more attachment over open flap debridement was therefore 8 (95% CI 5 to 33),

based on an incidence of 28% of sites in the control group failing to gain 2 mm or more of attachment. For baseline incidences in the

range of the control groups of 3% and 55% the NNTs are 71 and 4.

Probing depth reduction was greater for GTR than OFD: 1.21 mm (95% CI 0.53 to 1.88, Chi2 for heterogeneity 62.9 (df = 10), P <

0.001, I2 = 84%) or GTR + bone substitutes, weighted mean difference 1.24 mm (95% CI 0.89 to 1.59, Chi2 for heterogeneity 0.03

(df = 1), P = 0.85).

For gingival recession, a statistically significant difference between GTR and open flap debridement controls was evident (mean

difference 0.26 mm (95% CI Random Effects: 0.08, 0.43, Chi2 for heterogeneity 2.7 (df = 8), P = 0.95), with a greater change in

recession from baseline for the control group.

Regarding hard tissue probing at surgical re-entry, a statistically significant greater gain was found for GTR compared with open flap

debridement. This amounted to a weighted mean difference of 1.39 mm (95% CI 1.08 to 1.71, Chi2 for heterogeneity 0.85 (df = 2),

P = 0.65). For GTR + bone substitutes the difference was greater, with mean difference 3.37 mm (95% CI 3.14 to 3.61).

Adverse effects were generally minor although with an increased treatment time for GTR. Exposure of the barrier membrane was

frequently reported with a lack of evidence of an effect on healing.

Authors’ conclusions

GTR has a greater effect on probing measures of periodontal treatment than open flap debridement, including improved attachment

gain, reduced pocket depth, less increase in gingival recession and more gain in hard tissue probing at re-entry surgery. However there

is marked variability between studies and the clinical relevance of these changes is unknown. As a result, it is difficult to draw general

conclusions about the clinical benefit of GTR. Whilst there is evidence that GTR can demonstrate a significant improvement over

conventional open flap surgery, the factors affecting outcomes are unclear from the literature and these might include study conduct

issues such as bias. Therefore, patients and health professionals need to consider the predictability of the technique compared with

other methods of treatment before making final decisions on use. Since trial reports were often incomplete, we recommend that future

trials should follow the CONSORT statement both in their conduct and reporting.

There is therefore little value in future research repeating simple, small efficacy studies. The priority should be to identify factors

associated with improved outcomes as well as investigating outcomes relevant to patients. Types of research might include large

observational studies to generate hypotheses for testing in clinical trials, qualitative studies on patient-centred outcomes and trials

exploring innovative analytic methods such as multilevel modelling. Open flap surgery should remain the control comparison in these

studies.

P L A I N L A N G U A G E S U M M A R Y


Current treatments for destructive periodontal (gum) disease are not able to restore damaged bone and connective tissue support for

teeth. There are therefore limitations in treating patients with advanced disease. The surgical technique, guided tissue regeneration

(GTR) may be able to achieve regeneration and therefore improve upon conventional surgical results. The results of this review

have shown some advantage to using GTR in infra-bony defects but with wide variations in the benefits achievable compared with

conventional surgery. We were unable to identify conclusively factors responsible for this variability. Therefore, patients and health

professionals need to consider the predictability of the technique compared with other methods of treatment before making final



decisions on use. Adverse effects of treatment were generally minor and similar between groups although with an increased treatment

time for GTR. We recommend further research to address the issue of variability and to identify which characteristics of the disease or

the patient are more clearly associated with a beneficial outcome.

B A C K G R O U N D

Chronic periodontitis

Chronic periodontitis (CP) is a destructive gum condition, which

is estimated to affect 10 to 30% of the world-wide population (

Baelum 1986; Löe 1986; Oliver 1991). CP is caused by the bacte-

ria within dental plaque, stimulating inflammation within the pe-

riodontal tissues. In the susceptible individual, the result will be a

breakdown of both the connective tissues which attach to the tooth

and the supporting bone around the root. This usually results in

the formation of a periodontal pocket around the root which acts

as a reservoir for bacteria. The morbidity of this condition can be

underestimated and may include an uncomfortable loosening of

the teeth (which may impair eating), cosmetic problems (as teeth

drift or gums recede), a tendency to abscess formation within the

pocket and eventual tooth loss.

Treatment of periodontitis

The objectives for treating periodontitis are mainly concerned with

stabilising or arresting the condition and the crucial role of the pa-

tient’s home care plaque control is well recognised (Lindhe 1975).

The debridement of bacterial deposits coating the surface of the

root, deep within the periodontal pocket is also essential and is

achieved in the first instance, by scaling techniques. In addition,

periodontal surgery is used where the depth of the deposits within

the pocket, prevents adequate access for debridement.

The infra-bony defect and its treatment

Often, the bony destruction in periodontitis forms a crater-like

defect around the root and this is called an infra-bony defect when

the base of the periodontal pocket projects into and is surrounded

by the jaw bone. Infra-bony defects present major challenges to

periodontal treatment. Following treatment, healing occurs by re-

pair but without the formation of new supporting tissue (Caton

1976). In addition, residual periodontal pockets may remain after

treatment of deep defects and are a risk factor for further deteri-

oration (Claffey 1990). A particular concern for many patients is

that conventional surgery tends to increase gum recession, which

can cause cosmetic problems.

In an attempt to overcome some of these limitations, surgical tech-

niques have been developed to regenerate the tissues lost in the

disease process. The most documented of these is guided tissue

regeneration (GTR) and case reports have shown healing with the

formation of new attachment (Garrett 1996). In this procedure,

a biocompatible barrier membrane (either resorbable or non-re-

sorbable) is surgically implanted to cover and protect the bone

defect. If non-resorbable, the barrier is surgically removed 4 to 6

weeks after implantation. Connective tissue and bone regeneration

may then occur within the bone defect protected by the barrier.

The biological explanation for this procedure is the prevention

of migration of the epithelial periodontal tissues into the crater,

allowing time for bone and other attachment tissues to heal. Dur-

ing normal healing, it appears that the epithelial tissues migrate

rapidly into the wound, preventing regeneration (Karring 1993).

However understanding of this process is incomplete.

Although GTR is accepted into clinical practice, a systematic re-

view of its effectiveness is important since the procedure is techni-

cally demanding and financially costly, in view of the expense of

the barrier membranes (approximately US$100 to $300).

O B J E C T I V E S

The objective of this review is to assess the effect of GTR in the

treatment of periodontal infra-bony defects measured against con-

ventional access flap surgery (open flap debridement), with respect

to clinical, radiographic and patient-centred outcomes.

M E T H O D S

Criteria for considering studies for this review



Types of studies

Randomised, controlled trials (RCTs) of at least 12 months du-

ration. Quality assessment issues are addressed in the methods of

review.

Types of participants

Patients with a clinical diagnosis of chronic periodontitis (CP) or

periodontitis in subjects aged 21 years or older. Studies that address

GTR exclusively around furcation involved teeth were excluded.

The lower age limit was selected in order to be as inclusive of studies

as possible but studies specifically treating aggressive periodontitis

were excluded as this is currently classified as a different form of

periodontitis (much less common and of more rapid progression)

and might respond differently to treatment (Tonetti 1999).

Types of interventions

(1) Guided tissue regeneration (GTR) versus open flap debride-

ment.

(2) GTR and bone substitutes combined versus open flap debride-

ment.

Types of outcome measures

Primary outcomes

• Tooth loss

• Change in attachment levels

• Patient well-being or quality of life.

Secondary outcomes

• Change in probing depths

• Change in gingival recession

• Changes in bone/hard tissue (a) Radiographic, (b) Hard

tissue probing at surgical re-entry

• Disease recurrence (% sites with ≥ 2 mm loss of probing

attachment measured from 12 months after treatment)

• Percentage of sites with ≤ 4 mm probing depth at

completion of study

• Aesthetics (change: better or worse in patient’s opinion)

• Post-operative complications (including pain, infection)

• Economic outcomes.

Search methods for identification of studies

A search of the Cochrane Oral Health Group Trials Register,

EMBASE and MEDLINE was conducted up to and including

April 2004. We used the strategy: “guided tissue regeneration”

OR “guided-tissue-regeneration” OR “GTR” OR “periodontal re-

generation” OR “periodontal-regeneration” OR “intra bony de-

fect*” OR “intrabony defect*” OR “intra-bony defect*” OR “infra

bony defect*” OR “infrabony defect*” OR “infra-bony defect*”

OR “intra osseous” OR “intraosseous” OR “intra-osseous”. For

MEDLINE this also included the first two phases of the sensitive

search strategy for randomised controlled trials of the Cochrane

Oral Health group and was adapted for other databases. Hand-

searching included a complete search of Journal of Periodontology,

Journal of Clinical Periodontology and Journal of Periodontal Re-

search up to April 2004 and bibliographies of all relevant papers

and review articles. In addition, for the original review we con-

tacted experts/groups/companies involved in surgical research to

find other trials or unpublished material or to clarify ambiguous

or missing data and posted requests for data on two periodontal

electronic discussion groups: International Association for Dental

Research - Dental Faculty, Periodontal Research Group website

(www.iadr-dentalfaculty.org/sigs/index.html) and the Periodont

electronic newsletter ([email protected]) up to September

2000.

Data collection and analysis

Titles and abstracts of the search results, were screened by two

independent review authors (Richard Tucker (RT), Ian Needle-

man (IN)). The full text of all studies of possible relevance were

obtained for independent assessment by three review authors (RT,

IN and Elaine Giedrys-Leeper ( EGL)) against the stated inclusion

criteria. Any disagreement was resolved by discussion amongst the

review authors and authors of the trials were contacted to provide

missing data where possible. Data entry on to a computer was

performed by two review authors (RT and Helen Worthington

(HW)).

Methodological quality (protection from bias)

The methodological quality of included studies was assessed using

components shown to affect study outcomes (typically by exagger-

ation of treatment effect) including, allocation concealment (con-

cealment of the randomisation code from those recruiting patients

to avoid selection bias) and blinding of examiners and therapists

(Juni 2001; Moher 1998; Schulz 1995). Methodological quality

was used in sensitivity analyses to test the robustness of the con-

clusions but was not used to exclude studies qualifying for the

review on the basis of their inclusion criteria. Agreement between

investigators in the review for these components was checked us-

ing Kappa statistics.



http://www.iadr-dentalfaculty.org/sigs/index.html




Concealment of allocation criteria

• Adequate allocation concealment would include either

central randomisation or sequentially numbered sealed opaque

envelopes.

• Inadequate allocation concealment if there is an open

allocation sequence and the participants and trialists can foresee

the upcoming assignment.

• Unclear allocation concealment where the method cannot

be determined.

Blinding of examiner criteria

This assessed whether persons measuring the outcome of care were

aware of which treatment the participant received, and was graded

as yes, no or unclear.

Blinding of surgeon criteria

This could only be achieved if defect preparation was complete

prior to informing the operator of treatment allocation. For split-

mouth studies, this would demand preparation of both test and

control sites simultaneously and was graded as yes, no or unclear.

Data synthesis

A weighted treatment effect was calculated and the results were

expressed as mean differences (MD) and 95% confidence interval

(CI) for continuous outcomes and risk ratio (RR) and 95% CI for

dichotomous outcomes. The analysis for the continuous outcome

variables was conducted using the generic inverse variance statis-

tical method where the mean differences and standard errors are

entered for all studies so that the parallel group studies and intra-

individual (split-mouth) studies could be combined (see Results).

Variance imputation methods were used to estimate appropriate

variance estimates in some split-mouth studies, where the appro-

priate standard deviation of the differences was not included in

study reports (Follmann 1992). The primary outcome measure

was gain in attachment. Random-effects models were used for

analyses and the significance of discrepancies in the estimates of the

treatment effects from the different trials were assessed by means of

Cochran’s test for heterogeneity. If any significant heterogeneity (P

< 0.1) was detected it was planned to investigate this. Publication

bias was examined using both the Begg and Mazumdar rank cor-

relation test and the Egger regression asymmetry test (Begg 1994;

Egger 1997).

A subgroup analysis was conducted for the eight parallel group and

eight split-mouth studies for attachment change to see whether it

is appropriate to combine these study designs in the meta-analysis.

Only one of the five split-mouth studies (Cortellini 1998) stated

the standard deviation of the mean difference for two of the out-

comes (change in attachment and change in probing depth). It was

possible to calculate this for these two outcomes from the raw data

in another split-mouth study (Chung 1990) and to estimate this

from P-values in a further study (Mora 1996). The intra-patient

correlations from these studies ranged from 0.14 to 0.43. An in-

tra-patient correlation of 0.25 was used throughout this review to

estimate the standard errors for the other five split-mouth studies

(Blumenthal 1990; Loos 2002; Pontoriero 1999; Pritlove-Carson

1995; Ratka-Kruger 2000). Sensitivity analyses were conducted

imputing standard errors for the intra-patient correlation of zero,

which would provide a very conservative estimate of the standard

error.

Subgroup analyses were planned to investigate the effects of fac-

tors thought to be most influential on periodontal outcomes in-

cluding smoking status, barrier membrane type (resorbable versus

non-resorbable) and surgical technique (conventional flap versus

papilla preservation flap). A further sensitivity analysis examined

periodontal outcomes with exclusion of studies providing more

frequent post-operative maintenance than is practicable in clinical

practice (defined as maintenance visits more frequent than every

3 months, commencing 3 months post-surgery).

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

See Characteristics of included studies table.

Of the 17 included trials (Table 1), three were multicentre stud-

ies with the following numbers of individuals completing each

study; 136 patients in a parallel group design (Tonetti 1998),

23 patients in an intra-individual design (Cortellini 1998) and

109 patients employing a parallel group design (Cortellini 2001).

Of the single-centre trials, there were five intra-individual (split-

mouth) trials ranging from 10 to 40 participants (Blumenthal

1990; Chung 1990; Mora 1996; Pontoriero 1999; Pritlove-Carson

1995), seven parallel group trials ranging from 36 to 90 partic-

ipants (Cortellini 1995; Cortellini 1996; Kim 1998; Mayfield

1998; Sculean 2001; Silvestri 2000; Zucchelli 2002) and two

studies containing both split-mouth and parallel group elements

(Loos 2002; Ratka-Kruger 2000) contributing 16 and 25 in-

dividuals respectively. Six trials were based in private practice

(Cortellini 1995; Cortellini 1996; Cortellini 1998; Cortellini

2001; Sculean 2001; Tonetti 1998), nine trials were University-

based (Blumenthal 1990; Chung 1990; Kim 1998; Loos 2002;

Mayfield 1998; Mora 1996; Pontoriero 1999; Pritlove-Carson

1995; Ratka-Kruger 2000) and for two trials, the setting was not

clear (Silvestri 2000; Zucchelli 2002). Three studies (Chung 1990;

Mayfield 1998; Tonetti 1998) were supported, in part, by compa-

nies whose products were being used as interventions in the trials.



Table 1. Summary of meta-analyses for different outcomes and sensitivity analyses

Outcome Study type N of studies Het. Chi2 Het. P-value Mean difference 95% CI (RE)

Attachment gain GTR only 16 69.1 <0.001 1.22 0.80, 1.64

Attachment gain GTR parallel

group studies

8 34.4 <0.001 1.71 1.02, 2.40

Attachment gain GTR split-

mouth studies

8 18.5 0.01 0.79 0.37, 1.21

Attachment gain GTR + bone

substitutes

2 0.01 0.91 1.25 0.89, 1.61

Attachment gain Sensitivity analy-

sis: GTR only as-

suming intra-pa-

tient correlation

= 0

16 63.3 <0.001 1.24 0.82, 1.66

Attachment gain Sensitivity analy-

sis: GTR

only adequate al-

location conceal-

ment

7 30.4 <0.001 1.63 0.85, 2.42

Attachment gain Sensitivity anal-

ysis: GTR only,

examiner blind

8 44.8 <0.001 1.27 0.50, 2.04


ysis: GTR only,

therapist blind

8 32.4 <0.001 1.19 0.57, 1.81


ysis: GTR only,

examiner and

therapist blind

3 4.4 0.11 0.41 -0.33, 1.08

Probing depth

reduction

GTR only 11 62.9 <0.001 1.21 0.53, 1.88

Probing depth

reduction

GTR parallel

group studies

5 43.6 <0.001 1.59 0.21, 2.97

Probing depth

reduction

GTR split-

mouth studies

6 9.1 0.11 0.87 0.38, 1.36

Probing depth

reduction

GTR + bone

substitutes

2 0.03 0.85 1.24 0.89, 1.59



Table 1. Summary of meta-analyses for different outcomes and sensitivity analyses (Continued)

Gingival

recession

GTR only 8 2.6 0.92 0.26 0.08, 0.44

Gingival

recession

GTR parallel

group studies

4 0.97 0.81 0.15 -0.12, 0.42

Gingival

recession

GTR split-

mouth studies

4 0.41 0.94 0.35 0.11, 0.60

Gingival

recession

GTR + bone

substitutes

1 N/A N/A -0.33 -0.43, -0.23

Bone gain. Sur-

gical re-entry

GTR only 3 0.85 0.65 1.39 1.08, 1.71

Bone gain. Sur-

gical re-entry

GTR + bone

substitutes

1 N/A N/A 3.37 3.14, 3.61

The age range of all the included studies was from 21 to 81.

However, two studies presented mean ages of 48.7 to 50.8 years (

Mayfield 1998) and 36 to 39 years (Loos 2002) . All studies had

both male and female participants, but with differing proportions.

One study had more participants who were smokers than non-

smokers, with 21 out of 38 smokers (Mayfield 1998).

See Characteristics of excluded studies table.

There were 15 excluded studies seven of which reported 6 months

data only (Chaves 1996; Eickholz 1996; Kilic 1997; Kim 1996;

Kwan 1998; Nygaard-Ostby 1996; Quteish 1992). Of the other

eight studies, six were written in English, one in German and the

other in Japanese. The latter two were translated revealing that

one (Eger 1998) did not have access flap control and the other (

Yoshinari 1996) was not an RCT. Of the remaining studies, three

were either not fully randomised controlled trials (Becker 1996;

Eickholz 1998; Zybutz 2000) one was quasi-randomised (Bratthall

1998) and a further study did not employ GTR (Shamiri 1992).

One used a unique radiographic assessment for which the out-

comes could not be compared with other radiographic techniques

(Iversen 1996).

Risk of bias in included studies

Randomisation was reported in all studies included in this review.

An adequate method of randomisation, was present in the follow-

ing studies (Blumenthal 1990; Cortellini 1995; Cortellini 1996;

Cortellini 1998; Cortellini 2001; Loos 2002; Mora 1996; Pritlove-

Carson 1995; Sculean 2001; Tonetti 1998; Zucchelli 2002). It

was unclear as to how the following studies randomised their treat-

ment groups (Chung 1990; Kim 1998; Mayfield 1998; Pontoriero

1999; Ratka-Kruger 2000; Silvestri 2000)

Concealment of the randomisation code during patient selec-

tion, was adequate in nine studies (Cortellini 1995; Cortellini

1996; Cortellini 1998; Cortellini 2001; Mora 1996; Pritlove-

Carson 1995; Sculean 2001;Tonetti 1998; Zucchelli 2002) and

this was not clear in seven studies (Blumenthal 1990; Chung 1990;

Kim 1998; Loos 2002; Mayfield 1998; Pontoriero 1999; Silvestri

2000). Examiner blinding was described in eight of the studies (

Cortellini 1995; Cortellini 1996; Kim 1998; Loos 2002; Mayfield

1998; Pontoriero 1999; Sculean 2001; Zucchelli 2002). Operator

blinding (such as by revealing the treatment code only after defect

preparation was complete) was present in the following eight stud-

ies (Cortellini 1995; Cortellini 1996; Cortellini 1998; Loos 2002;

Pontoriero 1999; Pritlove-Carson 1995; Sculean 2001; Tonetti

1998).

In all studies, participants entering a study could be accounted for

at study completion. However, a high number of withdrawals or

drop outs were reported for two studies; 33% drop outs (Chung

1990) 35% losses (Kim 1998) and much smaller numbers for

the multicentre studies (Cortellini 1998; Cortellini 2001; Tonetti

1998).

Effects of interventions



Inter-investigator agreement

The Kappa scores (standard error (SE)) for key elements of inter-

investigator agreement were the following: allocation concealment

0.64 (0.26), therapist blinding 0.64 (0.26) and examiner blinding

0.88 (0.24). These scores indicate a good level of agreement.

Tooth loss

No teeth were reported lost in either experimental group in any

study. However, in studies where patient follow up was incomplete,

it was unclear whether tooth loss might have contributed to this

deficit.

Comparisons

Change in attachment level (Comparison 1, Outcomes 1.1,

1.2)

A subgroup analysis was conducted for the eight parallel group and

eight split-mouth studies for attachment change to see whether

it is appropriate to combine these study designs in the meta-

analysis (Subgroups 1.1.1 and 1.1.2). Only one of the five split-

mouth studies (Cortellini 1998) stated the standard deviation of

the mean difference for two of the outcomes (change in attach-

ment and change in probing depth). It was possible to calculate

this for these two outcomes from the raw data in another split-

mouth study (Chung 1990) and to estimate this from P-values in

a further study (Mora 1996). The intra-patient correlations from

these studies ranged from 0.14 to 0.43. An intra-patient corre-

lation of 0.25 was used throughout this review to estimate the

standard errors for the other five split-mouth studies (Blumenthal

1990; Loos 2002; Pontoriero 1999; Pritlove-Carson 1995; Ratka-

Kruger 2000). Sensitivity analyses were conducted imputing stan-

dard errors for the intra-patient correlation of zero, which would

provide a very conservative estimate of the standard error.

Sixteen studies presented attachment level data for GTR alone,

eight parallel group trials (Cortellini 1995; Cortellini 1996;

Cortellini 2001; Mayfield 1998; Sculean 2001; Silvestri 2000;

Tonetti 1998; Zucchelli 2002) and eight split-mouth studies (

Blumenthal 1990; Chung 1990; Cortellini 1998; Loos 2002;

Mora 1996; Pontoriero 1999; Pritlove-Carson 1995; Ratka-

Kruger 2000) The results for this analysis show a statistically sig-

nificantly greater attachment gain for test groups compared with

open flap debridement. For GTR the weighted mean difference

between test and control was 1.22 mm (95% CI Random Effects

0.80 to 1.64, Chi2 for heterogeneity 69.1 (df = 15), P < 0.001,

I2 = 78%) There appeared to be a difference between the two

subgroups based on the study design with the subgroup of split-

mouth studies having a lower treatment effect 0.79 mm (95% CI

Random Effects 0.37 to 1.21, compared to that for the parallel

group studies 1.71 mm (95% CI Random Effects 1.02 to 2.40).

This difference was statistically significant (metaregression slope

coefficient -0.91, 95% CI -1.71 to -0.11, P = 0.026). The sensi-

tivity analysis imputing an intra-patient correlation of zero only

made a small difference to the estimate for the split-mouth stud-

ies, with weighted mean difference 0.82 mm (95% CI Random

Effects 0.40 to 1.24).

There were two studies for GTR + bone substitutes (Blumenthal

1990; Kim 1998) and the weighted mean difference for these two

studies was 1.25 mm (95% CI 0.89 to 1.61, Chi2 for heterogeneity

0.01 (df = 1), P = 0.91), similar to the overall result for GTR alone.

From an additional (post-hoc) analysis for GTR, in six parallel

group studies (Cortellini 1995; Cortellini 1996; Cortellini 2001;

Mayfield 1998; Tonetti 1998; Zucchelli 2002) it was possible to

extract data for number of sites gaining less than 2 mm of attach-

ment. This again showed a significant benefit for GTR, risk ratio

0.54 (95% CI Random Effects 0.31 to 0.96, Chi2 for heterogene-

ity 8.91 (df = 5), P = 0.11) (Comparison 1, Outcome 1.2). The

number needed to treat (NNT) for GTR to achieve one extra site

gaining 2 mm or more attachment over open flap debridement

was therefore 8 (95% CI 5 to 33), based on an incidence of 28% of

sites in the control group failing to gain 2 mm or more of attach-

ment. For baseline incidences in the range of the control groups

of 3% and 55% the NNTs are 71 and 4. It should be noted that

the calculation of NNT values based on arbitrary cut-thresholds

derived from continuous data may not be appropriate. We are cur-

rently examining this phenomenon.

Sensitivity analysis

In order to investigate the robustness of the results with respect

to very frequent maintenance that may be impractical to pro-

vide in many clinics (< 3 monthly after the first 3 months post-

surgery), we conducted a sensitivity analysis excluding seven stud-

ies with very frequent follow up (included studies: Blumenthal

1990; Cortellini 2001, Chung 1990; Loos 2002, Mora 1996;

Pritlove-Carson 1995, Silvestri 2000, Ratka-Kruger 2000; Tonetti

1998. This showed a small reduction of the weighted mean dif-

ference to 0.95 mm (95% CI Random Effects 0.4960 to 1.40)

which was not significant (metaregression slope coefficient -0.62

(se = 0.43), P = 0.15) (Table 2).



Table 2. Random-effects metaregression analysis of attachment change

Characteristic Number of studies Slope estimate 95% CI Slope interpretation P-value

Frequency of main-

tenance

16 -0.62 -1.46 to 0.22 Higher attach-

ment change for visits < 3

months

0.15

Type of GTR barrier 18 comparisons -0.70 -1.55 to 0.15 Higher attach-

ment change for non-ab-

sorbable membrane

0.11

Surgical technique 16 0.75 -0.10 to 1.59 Higher attachment

change for papilla preser-

vation

0.09

A subgroup analysis was also conducted comparing the six

studies with papilla preservation with the 10 studies where the

papilla was not fully preserved. Although a higher attachment

change was found for papilla preservation this subgroup analysis

was not statistically significant (P = 0.09, Table 2). Comparison of

studies using an absorbable versus non-absorbable membrane type

also gave rise to a non-significant difference between the subgroups

(P = 0.11; Table 2).

Sensitivity analyses for attachment level change which excluded

poorer quality studies resulted in reduced numbers of incorporated

studies although heterogeneity remained statistically significant (

Table 1). When studies without surgeon blinding were excluded,

the summary estimate was similar and heterogeneity was still sig-

nificant. When studies without both surgeon blinding and ex-

aminer blinding were excluded, the difference between GTR and

OFD became non-statistically significant and with no significant

heterogeneity (three studies: mean difference 0.41mm 95% CI -

0.33 to 1.08, heterogeneity P = 0.11). Caution should be exer-

cised here as the number of studies in these comparisons was also

much lower which in itself could reduce heterogeneity. Subgroup

analysis of parallel group and split-mouth studies reduced the het-

erogeneity, although there was still a great deal of unexplained

heterogeneity. However as all the findings for each outcomes were

in the same direction we felt it was appropriate to undertake the

meta-analyses as shown.

Change in probing depth (Comparison 1, Outcome 1.3)

There were 11 studies for GTR alone including change in probing

depth as an outcome, five parallel group studies (Cortellini 2001;

Mayfield 1998; Sculean 2001; Silvestri 2000; Zucchelli 2002) and

six split-mouth studies (Blumenthal 1990; Cortellini 1998; Loos

2002; Mora 1996; Pontoriero 1999; Ratka-Kruger 2000). The

standard errors for one split-mouth study was given in the report

(Cortellini 1998) and could be estimated for a further study (

Mora 1996). The intra-patient correlations were 0.11 and 0.1224

and so a value of 0.1 was used to calculate the standard errors for

the other split-mouth studies. A sensitivity analysis was conducted

imputing standard errors for the intra-patient correlation of zero,

which would provide a very conservative estimate of the standard

error.

The results demonstrated a significantly greater probing depth

reduction for GTR, mean difference of 1.21 mm (95% CI 0.53

to 1.88, Chi2 for heterogeneity 62.9 (df = 10), P < 0.001, I2 =

84%). Although the treatment effect for split mouth studies was

lower, this was not statistically significant (metaregression slope

coefficient -0.72, 95% CI -2.21 to 0.78, P = 0.35).

There were also two studies for GTR + bone substitutes (

Blumenthal 1990; Kim 1998) with weighted mean difference 1.24

mm (95% CI 0.89 to 1.59, Chi2 for heterogeneity 0.03 (df = 1),

P = 0.85) similar to that for the GTR alone.

Gingival recession (Comparison 1, Outcome 1.4)

Nine studies for GTR had gingival recession as an outcome, four

with a parallel group design (Cortellini 2001; Mayfield 1998;

Sculean 2001; Zucchelli 2002) and five with a split-mouth de-

sign (Blumenthal 1990; Loos 2002; Mora 1996; Pontoriero 1999;

Ratka-Kruger 2000) and for GTR + bone substitutes one study

(Blumenthal 1990). We were unable to estimate any of the in-

tra-patient correlations and we decided to use a value of 0.25 for

the split-mouth studies for this outcome. A statistically significant

difference between GTR and open flap debridement controls was



evident (weighted mean difference 0.26 mm (95% CI Random

Effects 0.08 to 0.43, Chi2 for heterogeneity 2.7 (df = 8), P = 0.95),

with a greater change in recession from baseline for the control

group.

The single study of GTR + bone substitutes showed slightly greater

recession for test than controls, with mean difference -0.33 mm

(95% CI -0.43 to -0.23).

Bone change

Radiographic data was contained in two studies. One used in-

tra-oral radiographs and customised stents to aid reproducibility

of radiographic geometry (Mayfield 1998). This showed 0.6 mm

gain in bone from the base of the defect in both test and control

groups. The other study reported using ’standardised radiographs’

(Ratka-Kruger 2000). Descriptive data only were reported indicat-

ing ’only minute changes in bone structure were noticeable’. Re-

garding surgical re-entry, three studies (Blumenthal 1990; Chung

1990; Mora 1996) reported data for GTR alone and one study for

the combination of GTR + bone substitute (Blumenthal 1990).

For GTR, a statistically significant greater gain in hard tissue prob-

ing was found for GTR compared with open flap debridement.

This amounted to a weighted mean difference of 1.39 mm (95%

CI 1.08 to 1.71, Chi2 for heterogeneity 0.85 (df = 2), P = 0.65).

For GTR + bone substitutes the difference was greater, with a

mean difference 3.37 mm (95% CI 3.14 to 3.61).

Adverse effects and patient-reported outcomes

There were only limited data on these outcomes (Table 3). Heal-

ing was generally reported to be uneventful for both test and con-

trol groups. Exposure of the GTR barrier membrane was widely

reported and ranged from 20% of sites treated with the non-re-

sorbable titanium-reinforced material (Cortellini 1995) to 68%

for non-resorbable ePTFE barriers (Mayfield 1998). There seemed

little difference on membrane exposure between the different ma-

terials, particularly comparing resorbable versus non-resorbable.

The effect of membrane exposure was generally reported to be

modest although such an event could result in the need for more

rigorous maintenance (and therefore appointments) or the use of

systemic antibiotics.

Table 3. Adverse events and patient reported outcomes

Study Outcome

Blumenthal 1990 ’Throughout the study, ’No infection, untoward reactions, infection or delayed healing occured’.

Chung 1990 ’During the post-surgical healing phase of this study, no adverse tissue reactions were noted in any test sites’.

Cortellini 1995 ’Healing in all cases was uneventful. Membrane exposure occurred in 20% of cases in the test group [GTR

titanium] and in 60% of cases in the GTR control group [GTR ePTFE]; in all these instances the extent of

exposure was minimal and always limited to a small portion of the interdental tissue’.

Cortellini 1996 ’All sites healed uneventfully. No clinically detectable or subjectively reported side effects were reported in

any treated patient’.

Cortellini 1998 No reported

Cortellini 2001 Pain: No significant difference for postoperative pain between groups (VAS scale). Morbidity: 36% test

patients reported that the procedure interfered with daily activity for an average of 2.7 days, 32% controls

reported that procedure interfered with daily activity for an average of 2.4 days. Post-operative oedema

was most frequent complication: GTR 62% patients, acces flap 40% (estimated from figure 3) statistically

greater for GTR P = 0.01. GTR barrier membrane exposure was greatest at 3 weeks after surgery at 54% of

membranes.

Kim 1998 ’Clinical healing was uneventful in both groups. Limited signs of inflammation, swelling, or redness were

observed’.



Table 3. Adverse events and patient reported outcomes (Continued)

Mayfield 1998 ’All sites healed uneventfully, and no clinical signs of infection or flap instability were observed. There were

no side effects reported in any treated patient’. Membrane exposure: by 3 weeks after surgery 15/22 (68%)

had shown some exposure.

Mora 1996 Membrane exposure: 40% by 3 weeks after surgery. For these sites, maintenance was intensified (mouthwash

and topical antiseptic). No suppuration observed.

Pontoriero 1999 Not reported.

Pritlove-Carson 1995 ’All surgical sites healed with minimum patient discomfort and no signs of infection, with the exception

of one case where a purulent discharge was observed on the outer aspect of one membrane around a lower

molar at the fourth week. Antibiotics were prescribed and the membrane removed at 6 weeks’.

Ratka-Kruger 2000 ’No serious wound healing problems or inflammatory reactions were seen at the sites that had received

membranes’. Membrane exposure: 49% of sites by week 4.

Sculean 2001 ’The postoperative healing was generally uneventful and consisted mainly of postoperative swelling and/or

diarrhoea due to the antibiotic regimen. Neither allergic reactions nor suppuration were observed after any

of the treatments. Membrane exposure: 6/14 (43%) sites

Silvestri 2000 No reported.

Tonetti 1998 Not reported.

Zucchelli 2002 ’All sites healed uneventfully’. Membrane exposure: 10/33 sites (33%).

Time for procedure

One study (Cortellini 2001) measured time taken for the proce-

dures. The average surgical time for GTR procedures was 98.8

minutes (SD 45.7) and for access flap surgery 74.9 minutes (SD

33.6) and this was highly statistically significant (P = 0.001).

Impact of study quality

Heterogeneity

Sensitivity analyses for attachment level change which excluded

poorer quality studies resulted in reduced numbers of incorporated

studies although heterogeneity remained statistically significant

(see Table 1). Although subgroup analysis of parallel group and

split-mouth studies reduced the heterogeneity there was still a great

deal of unexplained heterogeneity, however as all the findings for

each outcomes were going in the same direction we felt it was

appropriate to undertake the meta-analyses as shown.

Prognostic factors

The variability in reporting data on prognostic factors such as ini-

tial defect depth, plaque levels and smoking prevented a meaning-

ful comparison. One study (Mayfield 1998) presented a subgroup

analysis comparing clinical changes in smokers and non-smok-

ers. This showed reduced benefits in smokers for attachment gain

(GTR group: non-smokers 1.9 mm SD 1.5, smokers 0.8 mm SD

0.8) although with little effect on probing depth change. However,

this result should be viewed with some caution as the groups were

not intentionally balanced with respect to disease levels.

Publication bias



We tested publication bias using the Begg and Mazumdar rank

correlation test, which found no evidence of a correlation between

the effect estimates and their variances, indicating no evidence of

publication bias (P = 0.53). The results of the Egger regression

asymmetry test also suggested no evidence of publication bias (P

= 0.43). There is no strong evidence of publication bias and 16

studies were included in this analysis.

Other outcomes

No data were found for the following outcomes:

• Disease recurrence (% sites with ≥ 2 mm loss of probing

attachment measured from 12 months after treatment)

• Ease of maintenance (% of sites with < 4 mm probing

depth)

• Aesthetics (change: better or worse in patient’s opinion)

• Cost/benefit (treatment time plus estimated material costs).

D I S C U S S I O N

Guided tissue regeneration alone

This systematic review has shown an overall mean increase in at-

tachment gain for GTR over open flap debridement (mean differ-

ence 1.22 mm, 95% CI 0.8 to 1.64). However, this value may not

be a valid estimate of effect since the difference between study out-

comes (heterogeneity) is substantial and statistically significant.

Therefore, the value should not be quoted to demonstrate the

magnitude of difference between the two therapies. It should be

noted that 11/16 trials produced a statistically significant greater

gain in attachment with GTR than OFD and with no statistically

significant publication bias (see below). Therefore, we suggest that

the data indicate that GTR can produce a statistically significant

greater gain in attachment however, the magnitude of this superi-

ority is not clear.

Tooth loss values did not give evidence of a difference between

studies. Since the studies were of no more than 12 months du-

ration, such a finding is not surprising and may not be helpful

in distinguishing between treatments. Progression of attachment

loss may proceed at rates from 0.1 to 3mm per year (Cobb 1996;

Lindhe 1989). Therefore, multi-year studies are likely to be needed

to evaluate tooth loss adequately.

The results of the 16 randomised controlled trials included in this

review show a substantial variation in their results. The mean addi-

tional attachment gain from GTR over that achieved by open flap

debridement surgery ranged between studies from 0.02 to 3.60

mm. This range is large and the differences are difficult to rec-

oncile. We have attempted to explore some of the possible causes

of this heterogeneity and these analyses should be viewed as ex-

ploratory observations. These investigations included analyses of

protection from bias as well as factors affecting clinical hetero-

geneity.

Protection from bias

Since study quality has been shown to have a direct impact on the

size of the effect of treatment we explored this effect with sensitiv-

ity analyses including allocation concealment, examiner and ther-

apist blinding. The results of these analyses were not consistent.

For attachment gain, excluding studies without adequate conceal-

ment of the randomisation code or examiner blinding did not

substantially affect the estimate or reduce heterogeneity.

However, when studies without both surgeon blinding and ex-

aminer blinding were excluded, the difference between GTR and

OFD became non-statistically significant and with no significant

heterogeneity (three studies: mean difference 0.41 mm 95% CI

-0.33 to 1.08, heterogeneity P = 0.41). Caution should be exer-

cised here as the number of studies in these comparisons was also

much lower which in itself could reduce heterogeneity. However,

the trend to a reduction of the magnitude of effect with greater

protection from bias is in line with previous studies of the impact

of bias (Juni 2001; Moher 1998; Schulz 1995). If further studies

are to be conducted on GTR, it is critical that they employ greater

methodological rigour and in particular in their protection against

these biases.

Publication bias was investigated and found not to be statistically

significant. Whilst these tests are conservative in their ability to

demonstrate such bias, the number of studies included (16) should

be adequate to identify publication bias if it was present. Therefore,

we can conclude that there is no evidence of an effect of publication

bias on the summary values.

Clinical heterogeneity

Available data allowed the investigation of several clinical aspects

that we hypothesised, a priori, could affect heterogeneity. These in-

cluded, frequency of supportive maintenance care (more than ev-

ery 3 months versus 3-monthly after the first 3 months of healing),

type of GTR barrier membrane (resorbable versus non-resorbable)

and surgical technique (papilla preservation technique versus con-

ventional approach). Random-effects metaregression analyses were

conducted to compare each of these subgroups.

The hypothesis for excluding studies with frequent maintenance

was based on the finding that frequency of maintenance care can

affect periodontal surgical results (Westfelt 1983). However, the

analysis for this review showed neither a statistically significant ef-

fect on the summary estimate nor an elimination of heterogeneity

(P = 0.15). Membrane type might be important. The difference

between GTR and OFD for attachment gain was greater for non-

absorbable barriers than absorbable barriers. However this differ-

ence was not statistically significant by metaregression (P = 0.11).



Surgical techniques aiming to retain the interdental soft tissue have

been proposed with the potential to achieve and maintain primary

closure during wound healing. It has been suggested that such

methods could therefore produce greater clinical improvements (

Cortellini 1999). The meta-analysis for the six studies with papilla

preservation did not show a statistically significant difference com-

pared with the overall estimate despite the apparent greater at-

tachment gain (0.75 mm, 95% CI -0.10 to 1.59, P = 0.09) and

therefore the heterogeneity remained highly statistically signifi-

cant. However, the 95% confidence interval only just includes a

value of no difference suggesting that papilla preservation might

be important and should be examined in future studies.

Another explanation for the heterogeneity might be variability be-

tween studies in prognostic factors that have been documented to

affect the outcome of regenerative surgery. These include; plaque

levels, cigarette smoking and defect severity as expressed by base-

line probing depth, attachment level and bone defect depth at

baseline. Regarding plaque and smoking, it is apparent that dif-

ferences in the way that both factors are reported between studies

prevent sensible comparison. For instance, some studies present

full mouth plaque scores, others measure plaque at the experimen-

tal sites only and other studies present plaque index values or no

plaque data. The effect of smoking on reducing the gain in attach-

ment following surgery is reported in only one subgroup analysis

of an RCT (Mayfield 1998). This result highlights the need for

more research into prognostic factors to help explain heterogene-

ity.

Therefore, the extent to which we have been successful in explain-

ing the troubling extent of the heterogeneity has been limited. It

should be noted however, that heterogeneity existed not only be-

tween studies but also within them. In two large multicentre trials

(Cortellini 2001; Tonetti 1998) the results between centres within

each study showed a substantial variability (from best to worst) in

attachment gain of between 1.73 mm and 2.1 mm respectively.

Therefore, although efficacy of GTR has been demonstrated in

some studies, the effectiveness and generalisability of such a tech-

nique has not been demonstrated.

Variability of results is clearly an important issue when consider-

ing the relevance of a treatment to clinical practice. Although we

have explored some of the possible causes of heterogeneity in this

systematic review, we have been unable to determine definitively

what factors account for this. The number and characteristics of

studies currently available is insufficient to answer this clinically

relevant problem.

In terms of clinical significance, mean difference values are difficult

to interpret. However, the risk ratio for sites gaining less than 2

mm attachment demonstrated that sites treated with GTR were

38% less likely to fail to attain a gain of 2 mm of attachment or

more than those treated by open flap debridement (risk ratio 0.54

(95% CI 0.31 to 0.96). There was no significant heterogeneity

between the studies. The number needed to treat (NNT) for GTR

to achieve one extra site gaining 2 mm or more attachment over

open flap debridement was 8 (95% CI 5 to 33) i.e. 8 patients need

to be treated for one to achieve this benefit over OFD. This is

unchanged from the original review despite the inclusion of data

from two further studies (Cortellini 2001; Zucchelli 2002).

Other clinical outcomes indicate statistically greater improvements

with GTR compared with OFD. As with attachment level gain,

heterogeneity with probing depth hampers a conclusion of the

size of this improvement. The analysis of recession indicated more

recession following the use of OFD compared with GTR and with

no heterogeneity (0.26 mm, 95% CI 0.08 to 0.43, heterogeneity

P = 0.96, n = 9). The result for gingival recession is interesting

since although 7 of the 9 studies produced more recession with

OFD, this difference was statistically significant in only one study (

Pontoriero 1999). However, the greater precision that is achievable

when multiple studies are combined with meta-analysis means

that overall, statistically significantly more recession can be shown

to occur following OFD.

Adverse effects and patient-reported outcomes

Adverse effects were generally minor and similar between GTR

and access flap surgery. Membrane exposure was a common find-

ing and represents the main difference in postoperative healing

between groups. Whilst membrane exposure has been associated

with poorer clinical outcomes (Selvig 1992) one study in this series

of trials did not find a negative effect on clinical attachment level

(Cortellini 2001). A further possible implication with membrane

exposure is an increase in need for professional plaque removal

visits or the provision of systemic antibiotics as reported in these

studies, either for prevention or treatment of infection around the

membrane. However, there is no clear evidence of how such a sit-

uation is best managed.

Effect of study design

This analysis has demonstrated a statistically significant difference

between parallel group and split-mouth studies with respect to at-

tachment level change. Split-mouth studies produced a more con-

servative estimate of attachment level gain. Whilst there remained

statistically significant heterogeneity in both subgroups, the dif-

ference between split-mouth and parallel group was statistically

significant by metaregression. To our knowledge, this is the first

time that such a difference has been demonstrated and underlines

the importance of analysing by study design. The reasons leading

to smaller differences between two interventions can only be spec-

ulated upon. This might be a chance finding as a result of produc-

ing two subgroups of studies. Possibly, protection from bias could

be more straightforward in split-mouth studies. For instance, se-

lection bias might be at less risk as the patient provides both exper-

imental groups. Furthermore, split-mouth studies might facilitate



the maintenance of masking for patient, examiner and therapist

if the patient provides both groups. Alternatively it may be pos-

sible that there is some cross-over benefit, either local or systemic

as has been previously suggested, and this effect could reduce the

difference in outcome between interventions (Hujoel 1992).

GTR plus bone grafts

Only two studies could be located examining the combination

of GTR and bone grafts versus open flap debridement in a ran-

domised, 12 month design (Blumenthal 1990; Kim 1998). The

effects of the combination treatment were similar to GTR alone for

attachment gain, but with slightly more probing depth reduction

(1.2 mm), greater gain in hard tissue probing at re-entry surgery

(3.4 mm) in one study and a gain in gingival recession in a further

study.

Reporting quality

We found that many study reports were incomplete in their pre-

sentation of methods or results. We contacted 19 authors to clarify

missing or ambiguous data. However, we would recommend that

authors of RCTs follow the CONSORT statement (www.consort-

statement.org) which provide clear guidance on presentation of

trial reports and would help systematic reviewing of the literature.

Statistical methods

This review considered parallel group and split-mouth studies. In

theory the combining of the treatment effects from these studies

should be straightforward, however, due to the poor reporting of

the data from the split-mouth studies, the standard deviation of

the difference had to be estimated. This was achieved by using the

results of the split-mouth studies that presented the necessary data

to calculate the intra-patient correlation for the other split-mouth

studies. Sensitivity analyses were carried out imputing different

values for the intra-patient correlation and the results of these were

very similar to the results presented in this review.

Comparison with previous thorough reviews andmeta-analyses

Two recent meta-analyses have reported greater benefits to GTR

than found in the present systematic review. One review indicated

a difference in attachment gain between GTR and open flap de-

bridement of 2.7 mm (Laurell 1998) and a second review reported

1.6 mm difference (Cortellini 2000). Differences in the meth-

ods of these reviews that may help to explain the results include

the incorporation of uncontrolled and unblinded studies in one (

Laurell 1998) and unclear selection criteria for randomised con-

trolled trials in the second, including the inclusion of studies of

shorter duration (16). A recent systematic review (Murphy 2003)

on GTR produced broadly similar findings to our present review.

In terms of gain in clinical attachment, GTR produced 0.81 mm

greater gain than OFD (P < 0.001) (no confidence interval pre-

sented for the difference). The result contained highly statistically

significant heterogeneity. This group did not find a statistically

significant difference between different types of barrier material.

Differences in search strategy, inclusion of both randomised and

non-randomised studies and of studies of shorter duration of fol-

low up, may have accounted for these differences.

The results of this update are similar to those of the original review,

even though six more trials have been included. The major dif-

ference was found for gingival recession which is now significant.

This shows a greater increase in gingival recession from baseline

with the control group of access flap. In addition, further explo-

ration of heterogeneity has now been possible.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Eleven out of 16 studies showed greater attachment gain for guided

tissue regeneration (GTR) over open flap debridement. However,

this systematic review has shown that the outcomes following GTR

are highly variable, both between and within studies. Therefore,

patients and health professionals need to consider the predictabil-

ity of the technique compared with other methods of treatment

before making final decisions on use.

A meta-analysis comparing GTR with open flap debridement in-

dicates greater clinical attachment gain of 1.22 mm (95% CI 0.80

to 1.64) and probing depth reduction of 1.21 mm (95% CI 0.53 to

1.88) for GTR over open flap debridement. However, the highly

statistically significant heterogeneity between studies indicates that

these summary values may be not reliable summary values for the

magnitude of probing changes.

Statistically significantly greater gingival recession occurs follow-

ing access flap surgery than following the use of guided tissue re-

generation (mean difference 0.26 mm 95% CI 0.08 to 0.43) and

with no statistically significant heterogeneity.

There are few data from controlled studies of 12 months duration

on the combination of bone substitutes with guided tissue regen-

eration but the results suggest little added benefit beyond a gain

in hard tissue probing at surgical re-entry.

Few data exist to answer important questions such as patient eval-

uation of outcomes.

The use of papilla preservation flaps versus conventional flap de-

signs should be further evaluated in randomised controlled trials.



http://www.consort-statement.org

http://www.consort-statement.org

Implications for research

There is little value in future research repeating, small efficacy stud-

ies. Studies of sufficient size to examine the effect of possible prog-

nostic or technical factors on outcomes are needed. These might

include, type of infra-bony defect, type of barrier membrane and

type of surgical flap design. Types of research might include large

observational studies to generate hypotheses for testing in clinical

trials, qualitative studies on patient-centred outcomes and trials

exploring innovative analytic methods such as multilevel mod-

elling. Open flap surgery should remain the control comparison

in these studies.

Control of bias (especially randomisation, concealment of alloca-

tion and blinding of examiner and operator where possible) needs

to be more rigorously employed in study designs and this might

be an important factor in explaining heterogeneity.

Greater attention in designing and reporting studies should be

given to study quality issues as set out in the CONSORT state-

ment. This will help to facilitate the evaluation of these studies.

Greater consideration in study design should be given to outcomes

that capture the boarder patient experience including patient cen-

tred and economic outcomes and evaluation of adverse effects.

Two treatments that produce similar clinical changes may be quite

different from the patient or economic perspective.

A C K N O W L E D G E M E N T S

We would like to thank Sylvia Bickley at the Cochrane Oral Health

Group (OHG) in Manchester UK, for her tremendous help in

searching the literature and Emma Tavender, also at the Cochrane

OHG for her administrative support. We are deeply grateful to the

many researchers and clinicians who have provided clarification of

data and comments on this review.

R E F E R E N C E S

References to studies included in this review

Blumenthal 1990 {published data only}

Blumenthal N, Steinberg J. The use of collagen membrane barriers

in conjunction with combined demineralized bone-collagen gel

implants in human infrabony defects. Journal of Periodontology

1990;61(6):319–27.

Chung 1990 {published data only}

Chung KM, Salkin LM, Stein MD, Freedman AL. Clinical

evaluation of a biodegradable collagen membrane in guided tissue

regeneration. Journal of Periodontology 1990;61(12):732–6.

Cortellini 1995 {published and unpublished data}

Cortellini P, Pini Prato G, Tonetti M. Periodontal regeneration of

human intrabony defects with titanium reinforced membranes. A

controlled clinical trial. Journal of Periodontology 1995;66(9):

797–803.


Cortellini P, Pini Prato G, Tonetti M. Periodontal regeneration of

human intrabony defects with bioresorbable membranes. A

controlled clinical trial. Journal of Periodontology 1996;67(3):

217–23.


Cortellini P, Carnevale G, Sanz M, Tonetti M. Treatment of deep

and shallow intrabony defects. A multicenter randomized

controlled clinical trial. Journal of Clinical Periodontology 1998;25

(12):981–7.



Cortellini 2001 {published data only}

Cortellini P, Tonetti MS, Lang NP, Suvan JE, Zuchelli G, Vangsted

T, et al.The simplified papilla preservation flap in the regenerative

treatment of deep intrabony defects: clinical outcomes and

postoperative morbidity. Journal of Periodontology 2001;72(12):

1702–12.

Kim 1998 {published data only}

Kim CK, Chai JK, Cho KS, Moon IS, Choi SH, Sottosanti JS, et

al.Periodontal repair in intrabony defects treated with a calcium

sulfate implant and calcium sufate barrier. Journal of Periodontology

1998;69(12):1317–24.

Loos 2002 {published data only}

Loos BG, Louwerse PH, van Winkelhoff AJ, Burger W, Gilijamse

M, Hart AA, et al.Use of barrier membranes and systemic

antibiotics in the treatment of intraosseous defects. Journal of

Clinical Periodontology 2002;29(10):910–21.

Mayfield 1998 {published data only}

Mayfield L, Soderholm G, Hallstrom H, Kullendorff B,

Edwardsson S, Bratthal G, et al.Guided tissue regeneration for the

treatment of intraosseous defects using a bioabsorbable membrane.

A controlled clinical study. Journal of Clinical Periodontology 1998;

25(7):585–95.

Mora 1996 {published and unpublished data}

Mora F, Etienne D, Ouhayoun J. Treatment of interproximal

angular defects by GTR: 1 year follow-up. Journal of Oral

Rehabilitation 1996;23(9):599–606.

Pontoriero 1999 {published data only}

Pontoriero R, Wennstrom J, Lindhe J. The use of barrier

membranes and enamel matrix proteins in the treatment of angular

bone defects. Journal of Clinical Periodontology 1999;26(12):

833–40.

Pritlove-Carson 1995 {published and unpublished data}

Pritlove-Carson S, Palmer R, Floyd P. Evaluation of GTR in the

treatment of paired periodontal defects. British Dental Journal

1995;179(10):388–94.

Ratka-Kruger 2000 {published data only}

Ratka-Kruger P, Neukranz E, Raetzke P. Guided tissue regeneration

procedure with bioresorbable membranes versus conventional flap

surgery in the treatment of infrabony periodontal defects. Journal of


Sculean 2001 {published data only}

Sculean A, Windisch P, Chiantella GC, Donos N, Brecx M, Reich

E. Treatment of intrabony defects with enamel matrix proteins and

guided tissue regeneration. A prospective controlled clinical study.

Journal of Clinical Periodontology 2001;28(5):397–403.

Silvestri 2000 {published data only}

Silvestri M, Ricci G, Rasperini G, Sartori S, Cattaneo V.

Comparison of treatment of intrabony defects with enamel matrix

derivative, guided tisue regeneration with a nonresorbable

membrane and modified Widman flap. A pilot study. Journal of


Tonetti 1998 {published and unpublished data}

Tonetti MS, Cortellini P, Suvan JE, Adriaens P, Baldi C, Dubravec

D, et al.Generalizability of the added benefits of guided tissue

regeneration in the treatment of deep intrabony defects. Evaluation

in a multi-center randomized controlled clinical trial. Journal of

Periodontology 1998;69(11):1183–92.

Zucchelli 2002 {published data only}

Zucchelli G, Bernardi F, De Motebugnoli L. Enamel matrix

proteins and guided tissue regeneration with titanium-reinforced

expanded polytetrafluoroethylene membranes in the treatment of

infrabony defects: a comparative controlled clinical trial. Journal of


References to studies excluded from this review

Becker 1996 {published data only}

Becker W, Becker BE, Mellonig J, Caffesse RG, Warrer K, Caton

JG, et al.A prospective multi-center study evaluating periodontal

regeneration for Class II furcation invasions and intrabony defects

after treatment with a bioresorbable membrane: 1-year results.

Journal of Periodontology 1996;67(7):641–9.

Bratthall 1998 {published data only}

Bratthall G, Soderholm G, Neiderud AM, Kullendorff B,

Edwardsson S, Attstrom R. Guided tissue regeneration in the

treatment of human infrabony defects. Clinical, radiographical and

microbiological results: a pilot study. Journal of Clinical


Chaves 1996 {published data only}

Chaves ES, Geurs NC, Reddy MS, Jeffcoat MK. Clinical and

radiographic digital imaging evaluation of a bioresorbable

membrane in the treatment of periodontal bone defects.

International Journal of Periodontics and Restorative Dentistry 1996;

16(5):443–53.

Eger 1998 {published data only}

Eger T, Muller H-P. [Parodontale Regeneration in vertikalen

Konochendeften mit resorbierbaren Membranen und Schumel-

Matrix-Protein]. Deutsche Zahnarztliche Zeitschrift 1998;53:590–4.

Eickholz 1996 {published data only}

Eickholz P, Benn DK, Staehle HJ. Radiographic evaluation of bone

regeneration following periodontal surgery with or without

expanded polytetrafluoroethylene barriers. Journal of Periodontology

1996;67(4):379–85.

Eickholz 1998 {published data only}

Eickholz P, Lenhard M, Benn DK, Staehle HJ. Periodontal surgery

of vertical bony defects with or without synthetic bioabsorbable

barriers. 12-month results. Journal of Periodontology 1998;69(11):

1210–17.

Iversen 1996 {published data only}

Iversen B, Albandar J, Oydna J, Gjermo P. Bone density after 1 year

in periodontal lesions treated surgically with or without ePTFE

membrane placement. Journal of Clinical Periodontology 1996;23

(6):512–6.

Kilic 1997 {published data only}

Kilic AR, Efeoglu E, Yilmaz S. Guided tissue regeneration in

conjunction with hydroxyapatite-collagen grafts for intrabony

defects. A clinical and radiological evaluation. Journal of Clinical


Kim 1996 {published data only}

Kim CK, Choi EJ, Cho KS, Chai JK, Wikesjo UM. Periodontal

repair in intrabony defects treated with a calcium carbonate implant



and guided tissue regeneration. Journal of Periodontology 1996;67

(12):1301–6.

Kwan 1998 {published data only}

Kwan SK, Lekovic V, Camargo PM, Klokkevold PR, Kenney EB,

Nedic M, et al.The use of autogenous periosteal grafts as barriers

for the treatment of intrabony defects in humans. Journal of


Nygaard-Ostby 1996 {published data only}

Nygaard-Ostby P, Tellefsen G, Sigurdsson TJ, Zimmerman GJ,

Wikesjo UM. Periodontal healing following reconstructive surgery:

effect of guided tissue regeneration. Journal of Clinical


Quteish 1992 {published data only}

Quteish D, Dolby AE. The use of irradiated-crosslinked human

collagen membrane in guided tissue regeneration. Journal of


Shamiri 1992 {published data only}

Shahmiri S, Singh I, Stahl S. Clinical response to the use of the

HTR Polymer Implant in human intrabony lesions. International

Journal of Periodontics and Restorative Dentistry 1992;12(4):294–9.

Yoshinari 1996 {published data only}

Yoshinari N, Tohya T, Inagaki K, Mori A, Nishiyama S, Koide M,

et al.5 years of clinical evaluation of nonresorbable membranes in

the treatment of intrabony defects following guided tissue

regeneration. Nagoya, Japan: Department of Periodontology,

School of Dentistry, Aichigakuin University 1996; Vol. 494:211–9.

Zybutz 2000 {published data only}

Zybutz MD, Laurell L, Rapoport DA, Persson GR. Treatment of

intrabony defects with resorbable materials, non-resorbable

materials and flap debridement. Journal of Clinical Periodontology

2000;27(3):169–78.

Additional references

Baelum 1986

Baelum V, Fejerskov O, Karring T. Oral hygiene, gingivitis and

periodontal breakdown in adult Tanzanians. Journal of Periodontal

Research 1986;21(3):221–32.

Begg 1994

Begg CB, Mazumdar M. Operating charateristics of a rank

correlation test for publication bias. Biometrics 1994;50(4):

1088–101.

Caton 1976

Caton J, Zander HA. Osseous repair of an infrabony pocket

without new attachment of connective tissue. Journal of Clinical


Claffey 1990

Claffey N, Nylund K, Kinger T, Garret S, Egelberg J. Diagnostic

predictability of scores of plaque, bleeding, suppuration and

probing depth for probing attachment loss. Journal of Clinical


Cobb 1996

Cobb CM. Non-surgical pocket therapy: mechanical. Annals of


Cortellini 1999

Cortellini P, Prato GP, Tonetti MS. The simplified papilla

preservation flap. A novel surgical approach for the management of

soft tissues in regenerative procedures. International Journal of

Periodontics and Restorative Dentistry 1999;19(6):589–99.

Cortellini 2000

Cortellini P, Tonetti M. Focus on intrabony defects: guided tissue

regeneration. Periodontology 2000 2000;22:104–32.

Egger 1997

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-

analysis detected by a simple, graphical test. BMJ 1997;315(7109):

629–34.

Follmann 1992

Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for

overviews of clinical trials with continuous response. Journal of

Clinical Epidemiology 1992;45(7):769–73.

Garrett 1996

Garrett S. Periodontal regeneration around natural teeth. Annals of


Hujoel 1992

Hujoel PP, DeRouen TA. Validity issues in split-mouth trials.

Journal of Clinical Periodontology 1992;19(9):625–7.

Juni 2001

Juni P, Altman DG, Egger M. Systematic reviews in health care:

Assessing the quality of controlled clinical trials. BMJ 2001;323

(7303):42–6.

Karring 1993

Karring S, Nyman T, Gottlow J, Laurell L. Development of the

biological concept of guided tissue regeneration - animal and

human studies. Periodontology 2000 1993;1:26–35.

Laurell 1998

Laurell L, Gottlow J, Zybutz M, Persson R. Treatment of intrabony

defects by different surgical procedures. A literature review. Journal

of Periodontology 1998;69(3):303–13.

Lindhe 1975

Lindhe J, Nyman S. The effect of plaque control and surgical

pocket elimination on the establishment and maintenance of

periodontal health. A longitudinal study of periodontal therapy in

cases of advanced disease. Journal of Clinical Periodontology 1975;2

(2):67–79.

Lindhe 1989

Lindhe J, Okamoto H, Yoneyama T, Haffajee A, Socransky SS.

Periodontal loser sites in untreated adult subjects. Journal of


Löe 1986

Löe H, Anerud A, Boysen H, Morrison E. The natural history of

periodontal disease in man. Rapid, moderate and no loss of

attachment in Sri Lankan labourers 14 to 46 years of age. Journal of


Moher 1998

Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et

al.Does quality of reports of randomised trials affect estimates of

intervention efficacy reported in meta-analyses?. Lancet 1998;352

(9128):609–13.



Murphy 2003

Murphy KG, Gunsolley JC. Guided tissue regeneration for the

treatment of periodontal intrabony and furcation defects. A

systematic review. Annals of Periodontology 2003;8(1):266–302.

Oliver 1991

Oliver R, Brown L, Loe H. Variations in the prevalence and extent

of periodontitis. Journal of the American Dental Association 1991;

122(6):43–8.

Schulz 1995

Schulz K, Chalmers I, Hayes RJ, Altman DG. Empirical evidence

of bias: dimensions of methodological quality associated with

estimates of treatment effects in controlled trials. JAMA 1995;273

(5):408–12.

Selvig 1992

Selvig K, Kersten B, Chamberlain A, Wikesjo U, Nilveus R.

Regenerative surgery of intrabony periodontal defects using e-

PTFE barrier membranes. Scanning electron microscopic

evaluation of retrieved membranes vs. clinical healing. Journal of


Tonetti 1998

Tonetti M, Cortellini P, Suvan JE, Adriaens P, Baldi C, Dubravec

D, et al.Generalizability of the added benefits of guided tissue

regeneration in the treatment of deep intrabony defects. Evaluation

in a multi-center randomized controlled clinical trial. Journal of


Tonetti 1999

Tonetti M, Mombelli A. Early-onset periodontitis. Annals of


Westfelt 1983

Westfelt E, Nyman S, Socransky SS, Lindhe J. Significance of

frequency of professional tooth cleaning for healing following

periodontal surgery. Journal of Clinical Periodontology 1983;10(2):

148–56.

References to other published versions of this review

Needleman 2001

Needleman IG, Giedrys-Leeper E, Tucker RJ, Worthington HV.

Guided tissue regeneration for periodontal infra-bony defects.

Cochrane Database of Systematic Reviews 2001, Issue 2. [Art. No.:

CD001724. DOI: 10.1002/14651858.CD001724]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Blumenthal 1990

Methods RCT, split mouth,

5 treatment groups, 12 months duration.

Participants 10 individuals, 4 female, aged 34-57, with moderate to advanced periodontal disease.

Interventions Control: OFD

Test 1: Resorbable collagen membrane.

Test 2: Collagen membrane over combined AAA bone-collagen implant.

Antigen-extracted allogenic bone implant (not included in this analysis).

Combined AAA bone-collagen implant (not included in analysis).

Maintenance intervals: 3 monthly after first 2 months post-surgery.

Outcomes Hard tissue measurements at re-entry surgery; soft tissues measurements:

PAL

PD

Recession

(non-standardised probing).

Notes University based.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Chung 1990

Methods RCT, split mouth, 2 treatment groups, 12 months duration.

Participants 15 individuals (8 females) commenced study and 10 completed it, aged 21-39.

Interventions Test: Resorbable collagen (Perio-Barrier).

Control: Modified Widman surgery.

Outcomes Hard tissue measurements at re-entry surgery and soft tissue measurements:

PAL

PD

Manual probe with acrylic stent.

Notes University based and supported by Colla-Tec Corporation.



Chung 1990 (Continued)

Risk of bias



Cortellini 1995

Methods RCT, parallel design, 3 treatment groups, 12 months duration.

Participants 45 individuals, 24 females 25-61 years of age. 1 defect per individual, 15 indivduals per group. 17 incisors,

13 canines, 7 premolars & 8 molars.

Interventions Test 1: Titanium reinforced non-resorbable Gore-Tex membranes removed after 6/52.

Test 2: Non-absorbable, standard Gore-Tex membranes removed after 4/52.

Controls: Modified Widman surgery.

Maintenance intervals after initial 2 months: every month.

Outcomes PAL

PD

Recession

Controlled force probing

Notes Practice based study.

Risk of bias


Allocation concealment? Yes A - Adequate

Cortellini 1996


Participants 36 individuals, 23 females: 30-58 years of age. 1 infra-bony defect per individual; 12 individuals per

group. Tooth population: 8 incisors, 5 canines, 8 premolars & 15 molars.

Interventions Test 1: Resorbable, Resolut membrane.

Test 2: Non-resobable standard Gore-Tex membrane removed after 6/52.


Maintenance intervals after initial 2 months performed every month.

Outcomes PAL

PD

Recession



Cortellini 1996 (Continued)


Notes Practice based study.

Risk of bias



Cortellini 1998

Methods Multicentre (3 centres) RCT, split-mouth design, 2 treatment groups, 12 months duration.

Participants 23 individuals,13 females, aged 25-70. 2 defects per individual.

Interventions Test: Resorbable Guidor membrane.

Control: Open flap debridement.

Maintenance intervals after initial 2 months performed every month.

Outcomes PAL

PD

Recession


Notes Practice-based study.

Risk of bias



Cortellini 2001

Methods Multicentre (8 centres) RCT, parallel design, 2 treatment groups, 12 months duration.

Participants 109 individuals, age > 21 years. One defect per individual.

Interventions Test: Resorbable Guideor membrane with simplified papilla preservation flap.

Control: Simplified papilla preservation flap.

Maintenance intervals after 3 months were every 3 months

Outcomes PAL

PD

Recession

Controlled force probe



Cortellini 2001 (Continued)

Notes Practice-based study.

Risk of bias



Kim 1998


Participants 40 individuals aged 27-56 commenced the study and 26 (13 females) completed it.

Interventions Test: Demin. bone matrix + resorbable calcium sulphate barrier.

Control: Modified Widman flap.

Maintenance: 3 monthly

Outcomes PAL

PD

Manual probe


Risk of bias



Loos 2002

Methods RCT, parallel and split mouth, 4 treatment groups, 12 months duration. All surgery performed by one

operator.

Participants 25 individuals, 12 without antibiotics (mean age 26 years, 6 females), 7 smokers, 13 with antibiotics

(mean age 39 years, 7 females), 5 smokers.

Interventions Test: Resorbable Guidor membrane with antibiotics.

Test: Guidor membrane without antibiotics.

Control: Open flap debridement with antibiotics.

Control: Open flap debridement without antibiotics.

Maintenance intervals after 3 months, 3 monthly.



Loos 2002 (Continued)

Outcomes PAL

PD

Recession

Controlled force probe (Florida probe)

Notes University-based.

Risk of bias



Mayfield 1998


Surgery performed by 3 different therapists.

Participants 40 individuals commenced study and 38 (22 females) completed it. Mean ages: Test, 50.8 yr, Control,

48.7 yr.



Maintenance after initial 3 month period performed every month up to 6 months, then every 4-6 weeks.

Outcomes PAL

PD

Manual probe with acrylic stent.

Notes University based. Supported in part by Guidor AB, Huddinge, Sweden.

Risk of bias



Mora 1996

Methods RCT, split-mouth design, 2 treatment groups, 12 months duration.

Participants 10 individuals, 6 females, 23-61 years of age, 2 defects per individual .

Interventions Test: Non-resorbable ePTFE membranes removed after 4/52 (test).

Control: Open flap debridement . Maintenance intervals after initial 3 months: every 3-4 weeks up to 6

months, then every 2-3 months.



Mora 1996 (Continued)

Outcomes Hard tissue measurements at re-entry surgery.

Soft tissue measurements:

PAL

PD

Recession

Manual probe, acrylic stent.


Risk of bias



Pontoriero 1999

Methods RCT, split-mouth design, 4 treatment groups, 12 months duration.

Participants 40 individuals, 25 females, 32-61 years of age.

Interventions Test: Absorbable Guidor.

Test: Absorbable Resolut.

Test: Non-absorbable Gore-Tex.

Emdogain.

All groups with own control (Split mouth). Maintenance at 2 weekly intervals.

Outcomes PAL

PD

Recession

Controlled force probe.

Notes Practice based.

Risk of bias


Allocation concealment? Unclear D - Not used

Pritlove-Carson 1995

Methods RCT, split-mouth study, 2 treatment groups, 12 months duration.

Participants 9 individuals, 7 females, 23-47 years of age contributing 20 pairs of proximal defects.



Pritlove-Carson 1995 (Continued)

Interventions Test: Non-resorbable Gore-Tex membranes removed after 5-6/52.


Maintenance intervals after initial 3 months: 3-4 weeks up to 6 months, then 2-3 months up to 12 months.

Outcomes PAL

PD

Recession

Both manual and controlled force probing.

Notes University based. Supported by Medical Charity.

Risk of bias



Ratka-Kruger 2000

Methods RCT with both split-mouth and parallel group elements, 12 months.




Maintenance visits at 3, 6 and 12 months.

Outcomes PAL

PD

Recession

Manual probe


Risk of bias



Sculean 2001

Methods RCT parallel design, 4 treatment groups, 12 months duration.

Participants 56 individuals, 32 females, 29-68 years of age



Sculean 2001 (Continued)

Interventions Test: Resorbable Resolut membrane.

Test: Emdogain only.

Test: Emdogain in combination with absorbable membrane Resolut.


Maintenance every month after first 3 months.

Outcomes PAL

PD

Recession

Manual probe


Risk of bias



Silvestri 2000

Methods RCT parallel design, 3 treatment groups, 12 months duration.

Participants 30 individuals, 19 females, age >/= 21 years of age.

Interventions Test: Emdogain.

Control: Non-resorbable Titanium reinforced ePTFE membrane.

Control: Open flap debridement. Maintenance at 3 month intervals.

Outcomes PAL

PD

Recession

Pressure sensitive probe

Notes Uncertain whether practice or University based.

Risk of bias





Tonetti 1998

Methods RCT multicentre (11 centres), parallel group, 2 treatment groups, 12 months duration.

Participants 143 individuals, 81 females, 26-81 years of age commenced study aged 26-81. 136 individuals completed

study.

Interventions Test: Resorbable Resolut membrane.


Maintenance every 3 months after initial 3 months.

Outcomes PAL

PD

Recession


Notes Practice based. Supported in part by industry.

Risk of bias



Zucchelli 2002



Interventions Test: Emdogain, simplified papilla preservation flap (SPPF)

Control: Non-resorbable Titanium reinforced ePTFE membrane with SPPF.

Control: Open flap debridement SPPF .Maintenance at 1 month recall intervals.

Outcomes PAL

PD

Recession

Controlled force probe

Notes Practice and University based.

Risk of bias





Characteristics of excluded studies [ordered by study ID]

Becker 1996 No control group

Bratthall 1998 Quasi-randomised

Chaves 1996 6 month data only

Eger 1998 No open flap debridement control

Eickholz 1996 6 month data only

Eickholz 1998 Allocation to test and control groups was not randomised

Iversen 1996 Bone density measurement technique does not correlate with radiographic assessments in other studies

Kilic 1997 6 month data only

Kim 1996 6 month data only

Kwan 1998 6 month data only

Nygaard-Ostby 1996 6 month data only

Quteish 1992 6 month data only

Shamiri 1992 Did not employ GTR

Yoshinari 1996 Not a randomised controlled trial

Zybutz 2000 Control group not randomly selected



D A T A A N D A N A L Y S E S

Comparison 1. GTR versus control

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Attachment gain (change) 16 750 mean difference (Random, 95% CI) 1.22 [0.80, 1.64]

1.1 Parallel group studies 8 472 mean difference (Random, 95% CI) 1.71 [1.02, 2.40]

1.2 Split-mouth studies 8 278 mean difference (Random, 95% CI) 0.79 [0.37, 1.21]

2 Sites gaining less than 2 mm

attachment

6 424 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.31, 0.96]

3 Probing pocket depth (change) 11 473 mean difference (Random, 95% CI) 1.21 [0.53, 1.88]

3.1 Parallel group studies 5 255 mean difference (Random, 95% CI) 1.59 [0.21, 2.97]


4 Recession (change from baseline) 9 407 mean difference (Random, 95% CI) 0.26 [0.08, 0.43]

4.1 Parallel group studies 4 235 mean difference (Random, 95% CI) 0.15 [-0.12, 0.42]


Analysis 1.1. Comparison 1 GTR versus control, Outcome 1 Attachment gain (change).

Review: Guided tissue regeneration for periodontal infra-bony defects

Comparison: 1 GTR versus control

Outcome: 1 Attachment gain (change)

Study or subgroup Treatment Control mean difference (SE) mean difference Weight mean difference

N N IV,Random,95% CI IV,Random,95% CI

1 Parallel group studies

Cortellini 1995 30 15 2.2 (0.648) 4.9 % 2.20 [ 0.93, 3.47 ]

Cortellini 1996 24 12 2.6 (0.411) 6.6 % 2.60 [ 1.79, 3.41 ]

Cortellini 2001 55 54 0.9 (0.38) 6.8 % 0.90 [ 0.16, 1.64 ]

Mayfield 1998 20 18 0.2 (0.638) 4.9 % 0.20 [ -1.05, 1.45 ]

Sculean 2001 14 14 1.4 (0.57) 5.4 % 1.40 [ 0.28, 2.52 ]

Silvestri 2000 10 10 3.6 (0.74) 4.3 % 3.60 [ 2.15, 5.05 ]

Tonetti 1998 69 67 0.86 (0.27) 7.6 % 0.86 [ 0.33, 1.39 ]

Zucchelli 2002 30 30 2.3 (0.33) 7.2 % 2.30 [ 1.65, 2.95 ]

Subtotal (95% CI) 47.8 % 1.71 [ 1.02, 2.40 ]

-4 -2 0 2 4

Favours control Favours GTR

(Continued . . . )



(. . . Continued)Study or subgroup Treatment Control mean difference (SE) mean difference Weight mean difference


Heterogeneity: Tau2 = 0.74; Chi2 = 34.37, df = 7 (P = 0.00001); I2 =80%

Test for overall effect: Z = 4.87 (P < 0.00001)

2 Split-mouth studies

Blumenthal 1990 10 10 0.42 (0.24) 7.8 % 0.42 [ -0.05, 0.89 ]

Chung 1990 10 10 1.27 (0.27) 7.6 % 1.27 [ 0.74, 1.80 ]

Cortellini 1998 23 23 1.4 (0.48) 6.1 % 1.40 [ 0.46, 2.34 ]

Loos 2002 25 25 0.11 (0.34) 7.1 % 0.11 [ -0.56, 0.78 ]

Mora 1996 10 10 1.3 (0.36) 7.0 % 1.30 [ 0.59, 2.01 ]

Pontoriero 1999 30 30 1.3 (0.38) 6.8 % 1.30 [ 0.56, 2.04 ]

Pritlove-Carson 1995 20 20 0.02 (0.44) 6.4 % 0.02 [ -0.84, 0.88 ]

Ratka-Kruger 2000 11 11 0.18 (0.92) 3.4 % 0.18 [ -1.62, 1.98 ]

Subtotal (95% CI) 52.2 % 0.79 [ 0.37, 1.21 ]


Test for overall effect: Z = 3.69 (P = 0.00022)

Total (95% CI) 100.0 % 1.22 [ 0.80, 1.64 ]

Heterogeneity: Tau2 = 0.54; Chi2 = 69.07, df = 15 (P<0.00001); I2 =78%

Test for overall effect: Z = 5.66 (P < 0.00001)

-4 -2 0 2 4




Analysis 1.2. Comparison 1 GTR versus control, Outcome 2 Sites gaining less than 2 mm attachment.



Outcome: 2 Sites gaining less than 2 mm attachment

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

Cortellini 1995 1/30 2/15 5.3 % 0.25 [ 0.02, 2.54 ]

Cortellini 1996 0/24 2/12 3.4 % 0.10 [ 0.01, 2.01 ]

Cortellini 2001 10/55 17/54 27.5 % 0.58 [ 0.29, 1.15 ]

Mayfield 1998 10/18 11/20 31.2 % 1.01 [ 0.57, 1.79 ]

Tonetti 1998 11/69 22/67 28.9 % 0.49 [ 0.26, 0.92 ]

Zucchelli 2002 0/30 7/30 3.7 % 0.07 [ 0.00, 1.12 ]

Total (95% CI) 226 198 100.0 % 0.54 [ 0.31, 0.96 ]

Total events: 32 (Treatment), 61 (Control)



0.1 0.2 0.5 1 2 5 10

Favours GTR Favours control



Analysis 1.3. Comparison 1 GTR versus control, Outcome 3 Probing pocket depth (change).



Outcome: 3 Probing pocket depth (change)




Cortellini 2001 55 54 0.8 (0.44) 9.6 % 0.80 [ -0.06, 1.66 ]

Mayfield 1998 20 18 0.1 (0.62) 8.3 % 0.10 [ -1.12, 1.32 ]

Sculean 2001 14 14 0.5 (0.53) 9.0 % 0.50 [ -0.54, 1.54 ]

Silvestri 2000 10 10 4.5 (0.54) 8.9 % 4.50 [ 3.44, 5.56 ]

Zucchelli 2002 30 30 2 (0.34) 10.3 % 2.00 [ 1.33, 2.67 ]

Subtotal (95% CI) 46.2 % 1.59 [ 0.21, 2.97 ]




Blumenthal 1990 10 10 0.48 (0.26) 10.7 % 0.48 [ -0.03, 0.99 ]

Cortellini 1998 23 23 1.3 (0.54) 8.9 % 1.30 [ 0.24, 2.36 ]

Loos 2002 25 25 0.14 (0.5) 9.2 % 0.14 [ -0.84, 1.12 ]

Mora 1996 10 10 1.8 (0.52) 9.1 % 1.80 [ 0.78, 2.82 ]

Pontoriero 1999 30 30 1.13 (0.34) 10.3 % 1.13 [ 0.46, 1.80 ]

Ratka-Kruger 2000 11 11 0.23 (1.03) 5.6 % 0.23 [ -1.79, 2.25 ]

Subtotal (95% CI) 53.8 % 0.87 [ 0.38, 1.36 ]



Total (95% CI) 100.0 % 1.21 [ 0.53, 1.88 ]



-4 -2 0 2 4




Analysis 1.4. Comparison 1 GTR versus control, Outcome 4 Recession (change from baseline).



Outcome: 4 Recession (change from baseline)




Cortellini 2001 55 54 0 (0.23) 15.3 % 0.0 [ -0.45, 0.45 ]

Mayfield 1998 20 18 0.2 (0.292) 9.5 % 0.20 [ -0.37, 0.77 ]

Sculean 2001 14 14 0 (0.491) 3.4 % 0.0 [ -0.96, 0.96 ]

Zucchelli 2002 30 30 0.3 (0.232) 15.1 % 0.30 [ -0.15, 0.75 ]

Subtotal (95% CI) 43.3 % 0.15 [ -0.12, 0.42 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.97, df = 3 (P = 0.81); I2 =0.0%



Blumenthal 1990 10 10 0.28 (0.2) 20.3 % 0.28 [ -0.11, 0.67 ]

Loos 2002 25 25 0.27 (0.56) 2.6 % 0.27 [ -0.83, 1.37 ]

Mora 1996 10 10 0.35 (0.24) 14.1 % 0.35 [ -0.12, 0.82 ]

Pontoriero 1999 30 30 0.47 (0.23) 15.3 % 0.47 [ 0.02, 0.92 ]

Ratka-Kruger 2000 11 11 0.14 (0.43) 4.4 % 0.14 [ -0.70, 0.98 ]

Subtotal (95% CI) 56.7 % 0.34 [ 0.10, 0.57 ]



Total (95% CI) 100.0 % 0.26 [ 0.08, 0.43 ]



-1 -0.5 0 0.5 1

Favours GTR Favours control

W H A T ’ S N E W

Last assessed as up-to-date: 12 January 2006.

13 August 2008 Amended Converted to new review format.



H I S T O R Y

Protocol first published: Issue 1, 1999

Review first published: Issue 2, 2001

13 January 2006 New search has been performed Searches updated.

13 January 2006 New citation required but conclusions have not changed Six new studies have been added to the previous version

of this review. The overall results however are similar

and the conclusions remain unchanged. A new table

of tooth loss, adverse effects and patient experience has

been added.

C O N T R I B U T I O N S O F A U T H O R S

Ian Needleman (IN), Elaine Giedrys-Leeper (EG) and Richard Tucker (RT) wrote the protocol. They independently and in duplicate

assessed the eligibility of studies, extracted data and assessed the quality of the studies. Helen Worthington (HW) conducted the

statistical analysis. All four review authors wrote the review.

D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

• University of Manchester, UK.

• University College London, UK.

External sources

• No sources of support supplied



I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Guided Tissue Regeneration, Periodontal; Alveolar Bone Loss [etiology; ∗surgery]; Bone Transplantation; Chronic Disease; Debride-

ment [methods]; Periodontitis [∗complications]; Randomized Controlled Trials as Topic

MeSH check words

Humans



guided infrabony review willey blackwell

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