Intervention Protocol

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Enamel matrix derivative for periodontal regeneration in teeth with furcation involvement

  1. Brian Stevenson1,*,
  2. David Ricketts1,
  3. Joseph LY Liu2

Editorial Group: Cochrane Oral Health Group

Published Online: 28 MAR 2013

DOI: 10.1002/14651858.CD010361


How to Cite

Stevenson B, Ricketts D, Liu JLY. Enamel matrix derivative for periodontal regeneration in teeth with furcation involvement (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD010361. DOI: 10.1002/14651858.CD010361.

Author Information

  1. 1

    University of Dundee Dental Hospital and School, Department of Restorative Dentistry, Dundee, Tayside, UK

  2. 2

    Scottish Dental Clinical Effectiveness Programme, NHS Education for Scotland, University of Dundee, Dental Health Services Research Unit, Dundee, UK

*Brian Stevenson, Department of Restorative Dentistry, University of Dundee Dental Hospital and School, Park Place, Dundee, Tayside, DD1 4HN, UK. b.stevenson@dundee.ac.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 28 MAR 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Periodontal (gum) disease is the most common cause of loss of tooth support but understanding the processes involved is difficult. This is partly because it is recognised that there are several different types of periodontal disease (Wiebe 2000) and that such disease is multi-factorial in origin, meaning that individuals vary greatly in their susceptibility. This is further complicated by the recognition that periodontal disease progression is often both episodic and site specific (Socransky 1984) meaning that its course in any individual is often highly unpredictable. Around 85% of the population is estimated to have some susceptibility to periodontal disease (Papapanou 1996), with around 5% to 15% of this group being highly susceptible to severe and generalised disease (Oliver 1998).

In health, the periodontal tissues consist of those that invest the tooth root structure and this includes the soft tissues attached to the tooth, namely the gingiva (gum) at the neck of the tooth, the periodontal ligament which is inserted into both the cementum on the root surface and jaw bone in relation to the tooth. The periodontal tissues therefore provide support for the teeth in the jaws. When oral hygiene is suboptimal for each individual patient, bacteria and extracellular substances form a plaque or microbial biofilm at the gum margin which in susceptible patients leads to an inflammatory response which can lead to destruction of the periodontal apparatus. If this periodontal support is reduced, symptoms such as mobility and/or drifting of the teeth may be seen and ultimately, affected teeth may be lost – even though the teeth themselves may be sound.

Mobile/drifting teeth create functional problems for many sufferers as they make chewing hard or fibrous food difficult or even impossible. They can also produce distressing changes in appearance with increases in spacing between the teeth and unattractive tooth alignment. In addition, speaking ability, or even the playing of some musical instruments and singing ability, may also be compromised by changes in tooth position. The overall effect can be detrimental to the overall quality of life of affected patients. Many seek a treatment other than tooth extraction and replacement which will restore some degree of previous function to the remaining dentition.

The most common treatment for periodontal disease, often referred to as non-surgical therapy, is to instruct the patient on improved oral hygiene to prevent the plaque biofilm from building up around the teeth and professional cleaning of the plaque and any calcified plaque (calculus) by a healthcare professional. The aim here is to reduce the inflammatory response to allow repair of the periodontal tissues (Waerhaug 1978).

Some teeth naturally have more than one root and when periodontal disease affects these teeth, the tooth's bone support in the area between the roots (the furcation) can be reduced. This reduction is called ‘furcation involvement’ and is significant, as it results in a reduced prognosis for the affected teeth. There are two reasons for this: firstly it can be extremely difficult for both patient and dentist to gain access to the furcation to clean and treat it and secondly, the pulp (nerve and blood supply) in furcation involved teeth may die. The periodontal treatment of multi-rooted teeth can thus present particular problems and yet preservation of these teeth is often very important if a functional dentition as a whole is to be retained.

The prevalence of furcation lesions is difficult to assess in the general population. However, those who have tried to estimate the level of the problem calculate that up to 14% of people may have at least one tooth with furcation involvement (Albandar 1999). Studies have found that teeth with furcation involvement respond less well to the non-surgical approach to management (Nordland 1987), and are more likely to suffer further bone loss (Claffey 1994). This can also have a detrimental effect on the healing of periodontal lesions around adjacent teeth (Ehnevid 2001) compared with multi-rooted teeth without furcation involvement. Teeth with furcation involvement therefore have a reduced prognosis following non-surgical therapy.

Several adjunctive treatments to non-surgical therapy for teeth with furcation involvement have been described and one of the more recent of these is Emdogain® (Institute Straumann AG, Basel Switzerland). It is not precisely known how the treatment works but it is thought that this therapy mimics tooth development in that a new periodontal support apparatus develops in the treated area. This is possible as the product contains enamel matrix proteins (amelogenins) which occur naturally during tooth development and are part of the process of building the original tooth support of each tooth in the first place (Gestrelius 2000; Hammarstrom 1997). Surgical access is required to place the product and the result achieved is highly technique sensitive.

 

Description of the condition

Furcation involvement occurs when periodontal disease has progressed sufficiently to result in loss of attachment that exposes the bi/tri-furcation of a multi-rooted tooth. Once exposed, attachment loss and bone loss around the furcation occurs in three dimensions. The extent of the horizontal loss is usually described using Hamp's classification (Hamp 1975) (Grade I - < 3 mm horizontal probing depth, Grade II - > 3 mm horizontal probing depth but not through and through, Grade III - through and through lesion) and the vertical component can be assessed with Tarnow's (Tarnow 1984) (Grade A - vertical probing depth of 1 to 3 mm, Grade B - vertical probing depth of 4 to 6 mm, Grade C - vertical probing depth of > 7 mm).

Successful treatment of furcation lesions must result in contours in the furcation areas which the patient can readily keep clean. Several different therapeutic options are available to manage a furcation lesion: root surface debridement (RSD), sometimes with surgical access (open flap debridement (OFD)), surgical access with recontouring of the alveolar bone (OFD with osseous recontouring), removal of hopeless roots or application of specific treatment modalities designed to result in regeneration of lost tissues. Many regenerative procedures have been described to manage teeth with furcation involvement: bone graft (BG) alone (Sanders 1983), barrier membrane (BM) alone (Pontoriero 1987), Emdogain alone (Jepsen 2004) or a combination of these therapies.

 

Description of the intervention

Emdogain is the only commercially available product containing enamel matrix proteins. This proprietary product has been used in all clinical studies to date, it contains lyophilised enamel matrix (both amelogenins and non-amelogenins, though mostly the former) from a porcine source and a propylene glycol alginate (PGL) carrier. Despite its porcine origin, it does not appear to induce an adverse clinical immune response (Froum 2004; Zetterström 1997). Its manufacturer advocates that surgical access to the site(s) is followed by root surface debridement and biomodification prior to application of Emdogain.

 

How the intervention might work

The exact mode of action of Emdogain is not fully understood. However, the rationale for surgical access, root surface preparation and the potential effects of Emdogain will be outlined.

1. Surgical access. It has been demonstrated that root surface debridement following surgical access results in significantly less residual calculus in teeth with furcation involvement when compared to non-surgical treatment (Parashis 1993; Parashis 1993a). A systematic review (Heitz-Mayfield 2002) concluded that surgical treatment is more beneficial in the management of deep (> 6 mm) pockets (around teeth with and without furcation involvement) than non-surgical root surface debridement after a follow-up period of at least 1 year. The solitary trial comparing different surgical and non-surgical approaches for furcation-involved teeth in this systematic review (Kalkwarf 1988) found that there were larger periodontal probing depth (PPD) reductions when either type of surgery (OFD and OFD with osseous recontouring) were compared to coronal scaling after a follow-up period of 2 years. A second systematic review of various types of retrospective and prospective trials (Huynh-Ba 2009) found that teeth with varying severity of furcation involvement had a survival of 43% to 96% following surgical access treatment over a period of 5 to 53 years.

2. Once the furcation is accessed, the roots and bony defect are debrided using hand and/or engine-driven instruments. The manufacturer recommends use of their PrefGel® (a pH neutral 24% Ethylenediaminetetraacetic acid (EDTA) gel) to remove the smear layer and achieve root surface biomodification. EDTA removes the smear layer and exposes both the collagenous matrix of dentine/cementum and their inorganic components on the root surface whilst not inducing necrosis. It is thought to remain in place for at least 2 weeks (Gestrelius 1997).

3. Emdogain is deposited as insoluble spheres onto the root surface. It is restrictive to epithelial downgrowth meaning that epithelial new attachment should not result. When in situ it is thought to allow re-colonisation of the root dentine by periodontal ligament (PDL) cells or induce differentiation of new cells required for the formation of a new periodontal attachment (cementum, PDL fibres and bone). In addition, both the PGL carrier and EDTA are antimicrobial; bacterial colonisation may be reduced or eliminated during the healing phase, increasing the chance of a successful outcome.

 

Why it is important to do this review

There is an increasingly aged population and the percentage of individuals retaining their teeth is also increasing. This will lead to larger numbers of patients with exposed furcations that may require treatment, if further tooth loss is to be avoided.

A systematic review (Venezia 2004) found Emdogain to be of benefit when periodontal regeneration was desired. A further systematic review (Huynh-Ba 2009) that examined the survival of teeth with furcation involvement, could find no evidence to either support or refute the use of Emdogain in the management of furcation lesions when tooth survival 5 years after treatment was the primary outcome measure.

Guided tissue regeneration (GTR) and Emdogain are both used when periodontal regeneration is sought. GTR procedures are potentially expensive, more time consuming to undertake and more likely to result in complications (Esposito 2009) than the equivalent Emdogain procedure. Therefore if Emdogain could be demonstrated to be as effective as GTR in specific clinical situations, its use could result in clinical benefits and cost savings.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

This review aims to examine the effects of Emdogain in the treatment of teeth with furcation involvement and to compare Emdogain's effectiveness with the various guided tissue regeneration procedures used in the treatment of these teeth.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials testing the efficacy of Emdogain with at least 6 months follow-up will be considered for this review. Parallel group trials, cluster trials and split-mouth trials will be included.

 

Types of participants

The human subjects suitable for inclusion will have a clinical diagnosis of localised or generalised, chronic or aggressive periodontitis based on the 1999 International Classification of Periodontal Diseases and Conditions (Armitage 1999) and must have at least one tooth with furcation involvement. The severity of furcation involvement will usually have been assessed in both the horizontal as well as the vertical dimension.

 

Types of interventions

Emdogain following surgical access and debridement for each severity of furcation (using Hamp's grading classification (Hamp 1975)) will be compared to other interventions including.

  1. Emdogain application following non-surgical access.
  2. Placebo or no treatment.
  3. Non-surgical debridement alone.
  4. Open flap debridement (surgical access therapy).
  5. Open flap debridement (surgical access therapy) with placebo.
  6. Open flap debridement with osseous reduction.
  7. Guided tissue regeneration (GTR) with barriers alone.
  8. GTR with bone graft alone.
  9. GTR with combination GTR.

 

Types of outcome measures

 

Primary outcomes

  • Furcation closure (dichotomous measure).
  • Probing attachment level (PAL).
  • Adverse events (pain, swelling, infection and sensitivity).

 

Secondary outcomes

  • Periodontal probing depth (PPD) reduction.
  • Pocket closure (= or < 4 mm) as a proportion of patients treated.
  • Changes in bone level (vertically in relation to the cemento-enamel junction (CEJ) and horizontally in relation to defect wall).
  • Tooth loss.
  • Quality of life (e.g. Oral Heath Impact Profile (OHIP-14)).
  • Cost analysis.
  • Recession.

 

Search methods for identification of studies

For the identification of studies included or considered for this review, we will develop detailed search strategies for each database searched. These will be based on the search strategy developed for MEDLINE but revised appropriately for each database to take account of differences in controlled vocabulary and syntax rules.

The search strategy will not be combined with a search filter for identifying randomised controlled trials (RCTs), as initial scoping searches have indicated that the number of results retrieved from MEDLINE is likely to be small. The subject search will use a combination of controlled vocabulary and free text terms based on the search strategy for searching MEDLINE (Appendix 1).

 

Electronic searches

The following databases will be searched:

  • The Cochrane Oral Health Group's Trials Register (to present)
  • The Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue)
  • MEDLINE via OVID (1948 to present) (Appendix 1)
  • EMBASE via OVID (1980 to present).

 

Searching other resources

The following journals have been identified as important to be handsearched for this review:

  • Journal of Periodontology
  • Journal of Clinical Periodontology
  • Periodontology 2000
  • Clinical Oral Implants Research.

Handsearching of these journals has been undertaken as part of the Cochrane worldwide handsearching programme. See the Cochrane Masterlist of journals handsearched for the dates of search.

Articles in press and those published electronically ahead of the journal issue being released will also be searched in these journals. In addition, manufacturers will be contacted for any unpublished trials.

Other potential trials will be identified by searching the bibliographies of the included trials and by contacting the authors of RCTs investigating enamel matrix derivative.

 

Data collection and analysis

 

Selection of studies

All the identified titles and abstracts will be downloaded to Endnote for subsequent assessment by two review authors (Brian Stevenson (BS) and David Ricketts (DR)) with arbitration by a third author (Joseph LY Liu (JLYL)) if agreement cannot be reached. The above inclusion criteria will be used to assess the eligibility of studies for inclusion. If the article's suitability cannot be assessed from the abstract or if it is not available then the full text will be sought.

The full text of the selected articles will be obtained and re-assessed using the inclusion criteria to establish their suitability for inclusion. This will again be completed in duplicate. Any article that initially appears to meet the inclusion criteria but subsequently is found not to, will be recorded in the table of excluded studies along with the reason for exclusion. In the event of disagreement, resolution will be sought by discussion, however, if no agreement is reached a third author will help to resolve the disagreement.

 

Data extraction and management

Data will be extracted by two review authors independently and recorded on pre-prepared data extraction forms. Authors of the trials will be contacted for clarification of missing data where possible.

In the event of disagreement, resolution will be sought by discussion, however, if no agreement is reached then a third author will help to resolve the disagreement.

For each trial the following data will be recorded.

  • General trial details: year of publication, country of origin, study design (parallel group or split mouth), setting and source of study funding.
  • Specific trial details: participant information including demographic characteristics, tooth type, severity of furcation involvement and periodontal diagnosis.
  • Details on the type of intervention: incision technique, method(s) of instrumentation, surface biomodification, pre- and post-operative anti-infective regimens.
  • Details of the outcomes reported: method of assessment and time intervals for both the primary and secondary outcomes measures.
  • Drop outs and reasons given.

 

Assessment of risk of bias in included studies

An assessment of risk of bias in the included studies will be conducted using the tool in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (Higgins 2011). Two review authors will independently assess the risk of bias in each study, using the descriptors and discussion to reach an agreed level of risk for each study. Again, if no agreement is reached then a third author will mediate. The judgement for each domain and subheading will be recorded in a risk of bias table under the following headings.

  1. Selection bias: (a) random sequence generation, and (b) allocation concealment.
  2. Performance bias: (a) blinding of participants and personnel.
  3. Detection bias: (a) blinding of outcome assessment.
  4. Attrition bias: (a) incomplete outcome data.
  5. Reporting bias: (a) selective reporting.
  6. Other bias: (a) other sources of bias, including observer bias.

These headings and subheadings will be judged as at low, high or unclear risk of bias, and a description of what happened, as reported in the study, will be recorded in a risk of bias table. If insufficient information is present to clearly ascertain the method used within each bias domain then the level of bias will be labelled as unclear.

Studies will be grouped into the following categories.

  • Low risk of bias in all domains (plausible bias unlikely to seriously alter the results).
  • Unclear risk of bias if one or more of the domains are assessed as unclear.
  • High risk of bias (plausible bias that weakens confidence in the results) if one or more domains are assessed at high risk of bias.

A summary risk of bias figure will be presented.

 

Measures of treatment effect

  • Periodontal probing depth (PPD) changes.
  • Probing attachment level (PAL) changes.
  • Furcation closure.
  • Changes in bone level.

Dichotomous outcomes (e.g. furcation closure) will be assessed as risk ratios with 95% confidence intervals.

Continuous outcomes (e.g. changes in bone level) will be presented as mean differences with 95% confidence intervals, providing the same measures are used in each trial.

 

Unit of analysis issues

If we find trials that are randomised by cluster, i.e. groups of individuals randomly allocated to intervention or control, we will check these trials for unit of analysis errors, and if feasible follow the recommendations given in Section 16.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (Higgins 2011).

 

Dealing with missing data

As stated previously, authors of the trials will be contacted if data require clarification or if the data set is incomplete. Data will be excluded until further clarification is available if agreement could not be reached.

 

Assessment of heterogeneity

Statistical variation between studies will be assessed using the I2 statistic following the recommendations of Section 9.5 of the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (Higgins 2011). If this is greater than 40% then potential sources of heterogeneity will be explored through subgroup analysis and, if feasible, meta-regression. Heterogeneity is taken to be statistically significant if the P value is less than 0.10.

 

Assessment of reporting biases

Reporting bias will be assessed using funnel plots and statistical tests where appropriate as described in Section 10.4 of the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (Higgins 2011).

 

Data synthesis

The patient, not the treated site, will be used as the unit of measure. For dichotomous outcomes, the estimates of effects of an intervention will be expressed as risk ratios together with 95% confidence intervals. For continuous outcomes, mean differences and 95% confidence intervals will be used to summarise the data for each group. Numbers needed to treat (NNT) will be calculated for resolution of the furcation lesion.

Forest plots will be produced to summarise the data. A meta-analysis will be conducted to provide a pooled estimate if appropriate. The Cochrane Collaboration guidance will be followed, with effect estimates being combined using a random-effects model where more than three trials are combined.

 

Subgroup analysis and investigation of heterogeneity

We plan to conduct subgroup analysis if the I2 statistic is greater than 40% and statistically significant and a sufficient number of studies is identified. The influence of the following factors on effect estimates will be assessed.

  • Smoking.
  • Incision technique.
  • Level of oral hygiene.
  • Alcohol.

In addition, heterogeneity of effect estimates may be influenced by many factors and these will be recorded.

  • Effect of site of furcation defect.
  • Effect of local anatomical factors (root trunk length, root divergence, distance from cemento-enamel junction (CEJ)).
  • Effect of Emdogain formulation.
  • Effect of root surface modification.
  • Effect of initial inter-proximal bone height.
  • Effect of keratinised tissue thickness.
  • Effect of keratinised tissue width.
  • Effect of tooth mobility.
  • Effect of trial type (split mouth, parallel).
  • Effect of published versus unpublished (manufacturer) trials.
  • Effect of intervention on number of sites with > 2 mm probing attachment level gain.
  • Effect of periodontal diagnosis (generalised chronic periodontitis (GCP), generalised aggressive periodontitis (GAP), localised chronic periodontitis (LCP), localised aggressive periodontitis (LAP)).
  • Effect of operator experience.

If possible, meta-regression will be used to quantify the influence of the potential factors listed above.

 

Sensitivity analysis

If a sufficient number of trials is included, sensitivity analysis will be conducted to assess the impact of the risk of bias on the results. We will do this by excluding trials at high risk of bias and assessing how this exclusion affects the overall estimates of effect of the primary outcomes.

 

Presentation of main results

A summary of findings table will be developed for the primary outcomes of this review using GRADEPro software.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The review authors would like to thank Angela Gilbert for her help with this protocol.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. MEDLINE via OVID search strategy

  1. Emdogain$.mp.
  2. ("enamel matrix derivative$" or "enamel matrix protein$" or "dental enamel protein$").mp.
  3. ((tooth or teeth or molar$) and "enamel protein$").mp.
  4. or/1-3
  5. Furcation defects/
  6. (tooth and (furcation or trifurcation or bifurcation or tri-furcation or bi-furcation)).mp.  
  7. (teeth and (furcation or trifurcation or bifurcation or tri-furcation or bi-furcation)).mp.
  8. (root$ and (furcation or trifurcation or bifurcation or tri-furcation or bi-furcation)).mp.
  9. (defect$ and (furcation or trifurcation or bifurcation or tri-furcation or bi-furcation)).mp.
  10. (periodont$ and (furcation or trifurcation or bifurcation or tri-furcation or bi-furcation)).mp.
  11. (lesion$ and (intra-radicular or intraradicular or "intra radicular")).mp.
  12. (lesion$ and (intra-furcal or intrafurcal or "intra furcal")).mp.
  13. or/5-12
  14. 4 and 13

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Brian Stevenson wrote the protocol with contributions from David Ricketts and Joseph LY Liu.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • SDCEP, UK.
    Joseph LY Liu is supported by the Scottish Dental Clinical Effectiveness Programme.

 

External sources

  • Cochrane Oral Health Group Global Alliance, UK.
    All reviews in the Cochrane Oral Health Group are supported by Global Alliance member organisations (British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; National Center for Dental Hygiene Research & Practice, USA and New York University College of Dentistry, USA) providing funding for the editorial process (http://ohg.cochrane.org).
  • National Institute for Health Research (NIHR), UK.
    All reviews in the Cochrane Oral Health Group are supported by NIHR Systematic Reviews Programme infrastructure funding.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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Venezia 2004
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