l0157 periodontal regenerative procedures final · periodontal regenerative procedures 2 summary of...

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TITLE: Periodontal Regenerative Procedures for Patients with Periodontal Disease: A Review of Clinical Effectiveness

DATE: 05 March 2010 CONTEXT AND POLICY ISSUES: The primary goal of periodontal therapy is to regenerate the tooth supporting apparatus, which has been damaged by periodontal disease.1 Several surgical techniques have been developed in an attempt to regenerate the periodontal tissues including open flap debridement (OFD), and the use of adjunctive therapy to OFD such as guided tissue regeneration (GTR), bone graft substitutes (BGS), and enamel matrix derivatives (EMD).2 Different techniques of OFD include the modified Whitman flap, the simplified or the modified papilla preservation techniques, and the coronally advanced flap.2 GTR barriers are either resorbable or non-resorbable membranes, which have been found to enhance periodontal regeneration.3 EMD are composed primarily of amelogenin and related proteins that are derived from porcine tooth buds.4 BGS include a wide range of graft materials including autografts, allografts, xenografts, and synthetic/semi-synthetic materials.5 These treatment modalities have been evaluated clinically by many clinical trials.5-7

This report reviews the evidence for clinical effectiveness of periodontal regenerative procedures compared to standard procedures including surgical (OFD) or non-surgical (scaling and root planning, SRP). RESEARCH QUESTION: What is the clinical effectiveness of periodontal regenerative procedures compared to standard procedures for patients with periodontal disease? METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, The Cochrane Library (Issue 1, 2010), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between 2000 and Feb 2010. Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials.

Periodontal Regenerative Procedures 2

SUMMARY OF FINDINGS: Only studies comparing a regenerative procedure to OFD or to scaling and root planing were included. Six systematic reviews and meta-analyses,3,5-9 and 37 articles of 35 RCTs10-46 were identified. The intrabony defects and furcation defects are two typical periodontal diseases covered in those studies. Systematic reviews and meta-analyses EMD versus OFD Esposito et al. (2010)6 reviewed the clinical effects of EMD for periodontal tissue regeneration in intrabony defects, compared to OFD, GTR, and various BGS. Only the effects of EMD versus OFD are shown in Appendix 1. Nine trials (371 patients) of EMD compared to OFD of 1-year follow-up were included for meta-analysis. The surgical techniques for OFD included the modified Whitman flap in four trials and the simplified or modified papilla preservation techniques in five trials. Meta-analysis of the nine trials showed a significant gain in clinical attachment level (CAL) for EMD compared to OFD alone (1.08 [0.61, 1.55]); heterogeneity was significant (P<0.00001). There was also a significant reduction in pocket probing depth (PPD) for EMD versus OFD (0.88 [0.44, 1.31]); heterogeneity was also significant (P=0.001). There was however no differences between EMD and OFD for changes in gingival recession (GR) and radiographic bone level (RBL). The authors warn that the results should be interpreted with great caution due to high degree of heterogeneity, although 1-year application of EMD showed significant improvement in CAL gain and PPD reduction when compared to placebo or control. GTR versus OFD Needleman et al. (2008)7 conducted a systematic review to assess the efficacy of GTR in the treatment of periodontal intrabony defects compared to OFD alone. Of the 17 included RCTs with at least 1 year duration, 16 tested GTR versus OFD and two tested GTR plus bone substitutes versus OFD (one RCT tested GTR, and GTR plus bone substitutes versus OFD). Of the 16 trials that tested GTR only, 8 trials had parallel design and 8 trials had split-mouth design. The numbers of studies and number of patients used for meta-analyses of the outcomes are shown in Appendix 2. For GTR only, there was a significant improvement in CAL gain (1.22 [0.80, 1.64]) and PPD reduction (1.21 [0.53, 1.88]) in the GTR groups compared with the groups of OFD only. There was however significant heterogeneity in the studies (P<0.001). The bone gain measured at surgical re-entry by hard tissue probing was also significantly greater for GTR compared with OFD (1.39 [1.08, 1.71]); no statistically significant heterogeneity (P=0.65) was reported. For GR, there was a significant difference between GTR and OFD (0.26 [0.08, 0.44]), with GTR group having less recession than the control group. Similar results in CAL gain, PPD reduction, and bone gain were found for trials comparing GTR plus bone substitutes against OFD. The authors concluded that the use of GTR significantly improved attachment gain, reduced pocket depth, resulted in less of an increase in GR, and a greater increase in hard tissue compared with OFD alone. However, it is difficult to generalize the conclusions owing to marked heterogeneity. Bias in study design including randomization, concealment of allocation, and blinding might be factors contributing to heterogeneity.


Murphy & Gunsolley (2003)3 reviewed the efficacy of GTR procedures in patients with periodontal intrabony defects and furcation defects compared with surgical controls (OFD) on clinical outcomes. The number of studies with at least 6 month duration, number of patients, and meta-analytic results of the outcomes were shown in Appendix 3. Collagen, polymer, and expanded polytetrafluoroethylene are three predominant types of GTR barriers used in the studies. For intrabony defects, meta-analysis of studies using GTR resulted in significantly greater gain in CAL (0.811, P<0.0001) and PPD reduction (0.775, P<0.0001) when compared to OFD controls, but heterogeneity was significant (P<0.05). Differences between test and control groups for post-treatment recession were not significant. For furcation defects, meta-analysis of included studies demonstrated that GTR procedures resulted in significantly greater gain in vertical probing attachment level (VPAL) (0.860, P<0.0001) and horizontal open probing attachment level (HOPA) (1.063, P=0.001), and greater reduction in vertical probing depth (VPD) (0.803, P<0.0001) when compared to OFD controls, but heterogeneity was significant (P<0.05). The amount of post-treatment recession was also not significant between test and control groups. The authors concluded that GTR procedures compared to OFD controls resulted in significantly more favorable outcomes for intrabony defects (CAL gain, PPD reduction) and for furcation defects (VPAL, VPD, HOPA). There were insufficient data for the enhancement of tooth survival facilitated by GTR procedures. The authors also stated that the variability in outcome measures that are clinically relevant continues to be a problem with GTR procedures. Jepsen et al. (2002)8 reviewed the evidence of effectiveness of GTR for furcation defects compared to OFD. Fourteen trials with outcome data useful in meta-analysis were included. Summary of meta-analyses for different outcomes is reported in Appendix 4. The primary outcome measure was reduction in open horizontal furcation depth (HFD), while the secondary outcome measures were frequency of furcation closure, gain in horizontal and vertical probing attachment, and reduction in vertical probing depth. Meta-analytic results of the limited number of studies showed that GTR resulted in significant improvement for both primary and secondary outcome measures when compared with OFD alone. However, heterogeneity was substantial and significant in many cases. The authors concluded that GTR was generally more effective than OFD in reducing open horizontal furcation depths, horizontal and vertical attachment levels, and pocket depths for mandibular or maxillary class II furcation defects. The authors warned that the general conclusions about the clinical benefit of GTR should be interpreted with caution due to the fact that the improvements were modest and variable and the number of studies was limited. BGS versus OFD Reynolds et al. (2003)5 reviewed the efficacy of BGS in the treatment of periodontal intrabony and furcation defects. Forty-nine RCTs for intrabony defects and 17 RCTs for furcation defects met the inclusion criteria. Meta-analyses were not performed for treatment effects of furcation defects due to insufficient studies with a comparable design. The results of meta-analysis comparing BGS versus OFD with respect to the treatment of intrabony defects are shown in Appendix 5. The BGS materials examined in those studies were autogenous bone, allogenic bone, calcium phosphate ceramic (porous/nonporous hydroxyapatite), bioactive glass, coralline


calcium carbonate, polylactic acid, polymethylmethacrylate, polyhydroxylethyl-methacrylate / calcium hydroxide polymer, hydroxyapatite cement, and hydroxyapatite-glycosaminoglycan.

For CAL gain, a significant effect was found in the overall analysis (0.553, P<0.0001) and in each BGS category, with non-significant tests for heterogeneity in all cases (P≥0.05).

For PPD reduction, a significant effect was found in the overall analysis (0.308, P=0.002) and in each BGS category, except the coralline calcium carbonate group. Heterogeneity was not significant (P≥0.05).

For GR, comparison of BGS and OFD in the overall analysis yielded no significant effect (-0.121). Heterogeneity across studies was not significant (P≥0.05).

For crestal bone loss, overall analysis showed a significant treatment effect (-0.369, P<0.0001), indicating that BGS was associated with less crestal resorption than OFD. Heterogeneity was significant (P≤0.05). The treatment effect was significant for the bone allograft and coralline calcium carbonate groups, and non-significant effects were observed in the bioactive glass and autogenous bone groups.

For bone level, the meta-analysis revealed significant effects for changes in bone level in all BGS, except bioactive glass. The combined analysis was significantly in favor of BGS (1.039, P<0.00001) with significant heterogeneity (P≤0.001).

The authors concluded that BGS generally improved clinical outcomes (CAL gain, PPD reduction, crestal bone loss, bone fill) compared to OFD alone in the treatment of intrabony defects. Trombelli et al. (2002)9 reviewed the adjunctive effect of graft materials and biological agents compared with OFD in the treatment of deep intrabony defects. Twenty-six trials (6-12 months duration) with a total of 605 patients (1306 defects) were included for systematic review. The BGS included autogenous bone grafts, bone allograft, dentin allograft, coralline calcium carbonate, bioactive glass, hydroxyapatite, calcium-layered composite of polymethyl-methacrylate, polylactic acid granules, and emanel matrix proteins. Meta-analysis results evaluating the differences in CAL gain and PPD reduction following treatment with graft materials and biological agents when compared with OFD procedures are shown in Appendix 6. For CAL gain, the use of coralline calcium carbonate, bioactive glass, and hydroxyapatite resulted in statistically significant improvement when compared with OFD alone. Autogenous bone graft and bone allograft did not show any significant difference for CAL gain compared with OFD. Heterogeneity was significant within studies of bone allograft, bioactive glass, hydroxyapatite and emanel matrix proteins (P≤0.05). For PPD reduction, bone allograft, bioactive glass, hydroxyapatite, and emanel matrix proteins showed significant improvement when compared with OFD alone. Coralline calcium carbonate did not show any significant difference for PPD reduction compared with OFD. Heterogeneity was significant within studies of coralline calcium carbonate, hydroxyapatite, and emanel matrix proteins (P≤0.05). The authors concluded that the use of specific biomaterials and biological agents was more effective than OFD alone in improving attachment levels in intrabony defects. However, general conclusions about expected clinical benefits should be interpreted with caution due to significant heterogeneity in results between studies in most treatment groups.


Randomized controlled trials Of the 35 RCTs, 10 studies10-19 compared EMD versus OFD, 3 studies20-22 compared EMD versus scaling and root planning, 6 studies23-28 compared GTR versus OFD, 7 studies29-35 compared BGS versus OFD, and 9 studies36-46 compared combined periodontal regenerative therapy versus OFD. EMD versus OFD Appendix 7 presents the characteristics and outcomes of the 10 RCTs comparing the efficacy of EMD plus OFD (test) versus OFD alone (control) for the treatment of periodontal intrabony defects. Four trials10,13,16,17 used a parallel design and 6 trials11,12,14,15,18,19 used split-mouth design. One trial16 was multicenter having 169 patients, while the patient populations of the rest of the trials ranged from 11 to 90. Most patients completed the studies. Maximum treatment duration was 6 months,11 8 months,15 12 months,10,12,14,16-19 and 24 months.13 The commercially available EMD used was Emdogain®. Six trials10,11,13,14,16,17 provided clinical data and 4 trials12,15,18,19 provided both clinical and radiographic data. The common clinical data was CAL gain, PPD reduction, and GR.

In all studies, both test and control groups showed significant improvement in clinical outcomes at end of treatment compared to baseline. For CAL gain and PPD reduction, 8 studies10,13-19 showed that combination of EMD and OFD provided additional benefit while 2 studies11,12 found no further improvement compared to OFD alone. There were no significant differences between groups in terms of gingival, plaque, and bleeding on probing scores. Adverse events were either not reported or not found. EMD versus SRP Appendix 8 presents the characteristics and outcomes of the 3 RCTs comparing the efficacy of EMD plus SRP (test) versus SRP alone or with placebo (control) for the treatment of periodontal intrabony defects. All 3 trials20-22 were of split-mouth design, having 16, 22, and 16 patients, respectively. Most patients completed the study. The study duration was 3 months,21 6 months,22 and 12 months.20 One trial22 had three arms: SRP (using hand instrument) plus EMD, SRP (using ultrasonic instrument) plus EMD, and SRP (using ultrasonic instrument). The commercially available product Emdogain® was used for EMD. All 3 studies reported only clinical data; most commonly CAL gain and PPD reduction.

Compared to baseline, both treatment groups showed statistically significant changes in CAL and PPD in all three studies. However, there were no significant differences between groups for any clinical parameters. Thus, the authors of all three studies suggested that there was no significant benefit of EMD adjunctive to non-surgical debridement therapy. GTR versus OFD Appendix 9 presents the characteristics and outcomes of the 6 RCTs comparing the efficacy of GTR plus OFD (test) versus OFD alone (control) for the treatment of periodontal intrabony defects (4 RCTs23-26) and Class II furcation defects (2 RCTs27,28). Five RCTs23,24,26-28 were of split-mouth design with patient populations ranging from 9 to 16 individuals, and one RCT25 was of parallel design having 51 patients. Treatment duration was 6 months,27,28 8 months,26 9


months,24 12 months,25 and 10 years.23 Different GTR barriers were used for the test groups, including bioabsorbable collagen,25,26 bioabsorbable polylactide acetyltributyl citrate,23 marginal periosteal pedicle graft,24 calcium sulfate,25 bioabsorbable polylactic acid,27 and non-resorbable polytetrafluoroethylene.28

In all studies, both test and control groups showed a significant improvement for either clinical or radiographic parameters when compared with baseline. Of the 4 RCTs that assessed the efficacy of GTR in the treatment of intrabony defects, two RCTs23,26 did not find any significant differences in clinical outcomes (CAL gain and PPD reduction) between both groups, while the other two RCTs showed that the application of GTR in combination of OFD significantly improved clinical and radiographic parameters of intrabony defects. For treatment of furcation defects, both RCTs27,28 showed that combination of GTR and OFD provided a significantly greater improvement in vertical and horizontal clinical attachment levels. There were no significant differences between the test and control groups in terms of gingival recession, plaque index, and bleeding on probing scores in all studies. No adverse events were reported at end of the studies. BGS versus OFD Appendix 10 presents the characteristics and outcomes of the 7 RCTs comparing the efficacy of BGS plus OFD (test) versus OFD alone (test) for the treatment of periodontal intrabony defects. There were 3 trials31,32,35 using parallel design, and 4 trials29,30,33,34 using split-mouth design. The study population ranged from 12 to 45 patients. The study duration was 6 months29,33-35 and 12 months.30-32 Most patients completed the study. Different BGS were used in the test groups, including nanocrystaline hydroxyapatite,29 particulate or putty demineralized bone matrix,30 biphasic calcium composite,31 autogenous bone spongiosa,31 calcium phosphate,32 anorganic bone matrix/cell binding peptide,33 and bioactive glass.34,35

The clinical outcomes of both test and control groups in all studies were significantly improved compared to baseline. Five studies showed that the use of BGS (nanocrystaline hydroxyapatite,29 biphasic calcium composite,31 autogenous bone spongiosa,31 anorganic bone matrix/cell binding peptide,33 and bioactive glass34,35) yielded better clinical or radiographic results in conjunction with OFD than with OFD alone. Two studies did not find any superior clinical outcomes for demineralized bone matrix30 or calcium phosphate bone cement32 groups compared to OFD groups. Major adverse events were not found in any study. GR was also not significantly different between the test and control groups. Combined periodontal regenerative therapy versus OFD Appendix 11 presents the characteristics and outcomes of the 9 RCTs comparing the efficacy of different combined regenerative therapies (test) versus OFD alone (control) for the treatment of periodontal intrabony defects (8 RCTs36,37,39-44,46) and Class II furcation defects (1 RCT38). OFD was present in all test groups. One study with two reports36,45 compared EMD plus GRT versus OFD, 6 studies37-42,46 compared GTR plus BSG versus OFD (two reports39,41 were from the same trial), one study43 compared EMD plus GTR and BGS versus OFD, and one study44 compared EMD plus BGS versus OFD. Four studies36,37,39,41,42 used parallel design and 5 studies38,40,43,44,46 used split-mouth design.

EMD + GRT versus OFD – Both reports36,45 were from the same trial, reporting the results over a 12 month and 10 year period, respectively. Fifty-six patients with intrabony


defects entered the study and 38 completed the 10 year evaluation. There were four group comparisons: EMD (Emdogain), GTR (bioabsorbable membrane), EMD + GTR, and OFD alone. The clinical outcomes (CAL gain, PPD reduction) obtained with all four approaches were maintained over a period of 10 years. All three regenerative treatment modalities had higher clinical effects than OFD alone. The combined treatment of EMD plus GTR did not provide additional improvement compared to EMD or GTR alone. There was no difference between groups for plaque, gingival, or bleeding on probing indices.

GTR + BSG versus OFD – One trial38 assessed the efficacy of GTR (bioabsorbable membrane or connective tissue graft) with or without BGS (resorbable hydroxyapatite) for the treatment of mandibular Class II furcation defects in 20 patients. It was found that, at 12 months, both GTR therapies with or without BGS resulted in significantly favorable clinical and radiographic outcomes compared to OFD alone.

Five trials37,39-42,46 assessed the efficacy of GTR (bioresorbable collagen membrane37,39-

42,46, polylactic acid barrier42) plus BGS (bovine bone mineral) for the treatment of intrabony defects. The patient population ranged from 22 to 124 patients. Treatment durations were 6 months,40,46 1 year,37,39,41,42 and 5 years.37 All studies showed that combined therapy of GTR plus BGS resulted in significantly better clinical or radiographic outcomes compared to OFD alone. However, none of the studies had control arms of GTR or BGS alone. It is therefore uncertain that whether the combined GTR and BGS could provide additional benefit.

EMD + GTR + BGS versus OFD – One RCT25 assessed the efficacy of EMD (Emdogain) plus GTR (bioabsorbable collage membrane) plus BGS (bovine bone mineral) for the treatment of intrabony defects in 18 patients. The treatment duration was 6 months and all patients completed the study. The study found that the combined regenerative therapy results in better clinical outcomes than treatment with OFD alone. However, it is uncertain whether the combined therapy had any additional effect compared to EDM, GTR, or BGS alone.

EMD + BGS versus OFD - One RCT44 assessed the efficacy of EMD (Emdogain) plus BGS (bovine bone mineral) for the treatment of intrabony defects in 24 patients. The treatment duration was 6 months and all patients completed the study. The study found that combining EMD and BGS as regenerative technique for intrabony defects resulted in statistically significantly more favorable clinical outcomes than OFD alone. The lack of control arms of EDM or BGS alone questions the efficacy of the combined therapy.

Overall summary from all studies Table 1 lists the number of systematic reviews/meta-analyses and RCTs whose primary clinical outcomes of the test groups were either better or not different when compared with the control groups. No studies found that regenerative procedures were worse than controls.


Table 1: Summary of the Evidence from Systematic Reviews and RCTs Interventions Better than control Same as control

EMD +OFD vs. OFD 1 SR/MA; 8 RCTs 2 RCTs GTR + OFD vs. OFD 3 SR/MA; 4 RCTs 2 RCTs BGS + OFD vs. OFD 2 SR/MA; 5 RCTs 2 RCTs EMD + SRP vs. SRP — 3 RCTs EMD + GTR + OFD vs. OFD 1 RCT — GTR + BGS + OFD vs. OFD 6 RCTs — EMD + GTR + BGS + OFD vs. OFD 1 RCT — EMD + BGS + OFD vs. OFD 1 RCT —

BGS: bone graft substitutes; EMD: enamel matrix derivatives; GTR: guided tissue regeneration; OFD: open flap debridement; SRP: scaling and root planing; RCT: randomized controlled trial; SR/MA: systematic review / meta-analysis; vs.: versus

Limitations Meta-analytic results from all included systematic reviews demonstrated significant heterogeneity for most outcome parameters across studies. Most studies had small patient populations (less than 50). Not every study conducted re-entry examination or radiographic assessment for bone level gained at the end of study. The differences in clinical outcomes such as CAL gain and PDD reduction between the test and control groups were often modest. Also, as previously mentioned, both test and control groups in all included RCTs showed significant improvement in clinical or radiographic outcomes compared with baseline. Therefore, it is debatable whether the clinical gain of periodontal attachment provided by the interventions has any clinical relevance. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: For the treatment of intrabony defects, the majority of evidence showed that the use EMD, GTR, and BGS as adjunctive to periodontal surgery (OFD) yields significant benefit in clinical outcomes measured by CAL gain and PPD reduction. For EMD, the recent systematic review did not find any significant changes in radiographic bone levels compared to OFD despite significant differences in clinical parameters. The findings of three RCTs do not support the use of EMD during routine non-surgical scaling and root planning. For GTR, there was evidence for a significant improvement in bone gain compared to OFD for treatment of intrabony defects. GTR was also found to result in greater improvement in attachment levels for treatment of furcation defects. For BGS, meta-analytic results of a systematic review showed that the application of all bone substitutes, except bioactive glass, in conjunction to OFD, resulted in significant gain in bone fill for the treatment of intrabony defects. The benefit of the combined periodontal regenerative therapy in term of cost and effectiveness remains to be determined. Overall, despite ample evidence showing significant clinical benefit of different periodontal regenerative modalities compared to the conventional OFD, heterogeneity across studies was substantial, the differences between tests and controls were often modest, and both test and control groups showed significant improvement in either clinical or radiographic outcomes at the end of study compared to baseline. These limitations may be a consideration for decision-making about the various methods of periodontal regeneration.


PREPARED BY: Health Technology Inquiry Service Email: [email protected] Tel: 1-866-898-8439


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34. Park JS, Suh JJ, Choi SH, Moon IS, Cho KS, Kim CK, et al. Effects of pretreatment clinical parameters on bioactive glass implantation in intrabony periodontal defects. J Periodontol. 2001 Jun;72(6):730-40.

35. Rosenberg ES, Fox GK, Cohen C. Bioactive glass granules for regeneration of human periodontal defects. J Esthet Dent. 2000;12(5):248-57.


36. Sculean A, Kiss A, Miliauskaite A, Schwarz F, Arweiler NB, Hannig M. Ten-year results following treatment of intra-bony defects with enamel matrix proteins and guided tissue regeneration. J Clin Periodontol. 2008 Sep;35(9):817-24.

37. Sculean A, Schwarz F, Chiantella GC, Donos N, Arweiler NB, Brecx M, et al. Five-year results of a prospective, randomized, controlled study evaluating treatment of intra-bony defects with a natural bone mineral and GTR. J Clin Periodontol. 2007 Jan;34(1):72-7.

38. Belal MH, Al-Noamany FA, El-Tonsy MM, El-Guindy HM, Ishikawa I. Treatment of human class II furcation defects using connective tissue grafts, bioabsorbable membrane, and resorbable hydroxylapatite: a comparative study. J Int Acad Periodontol. 2005 Oct;7(4):114-28.

39. Linares A, Cortellini P, Lang NP, Suvan J, Tonetti MS, European Research Group on Periodontology (ErgoPerio). Guided tissue regeneration/deproteinized bovine bone mineral or papilla preservation flaps alone for treatment of intrabony defects. II: radiographic predictors and outcomes. J Clin Periodontol. 2006 May;33(5):351-8.

40. Camargo PM, Lekovic V, Weinlaender M, Vasilic N, Madzarevic M, Kenney EB. A reentry study on the use of bovine porous bone mineral, GTR, and platelet-rich plasma in the regenerative treatment of intrabony defects in humans. Int J Periodontics Restorative Dent. 2005 Feb;25(1):49-59.

41. Tonetti MS, Cortellini P, Lang NP, Suvan JE, Adriaens P, Dubravec D, et al. Clinical outcomes following treatment of human intrabony defects with GTR/bone replacement material or access flap alone. A multicenter randomized controlled clinical trial. J Clin Periodontol. 2004 Sep;31(9):770-6.

42. Vouros I, Aristodimou E, Konstantinidis A. Guided tissue regeneration in intrabony periodontal defects following treatment with two bioabsorbable membranes in combination with bovine bone mineral graft. A clinical and radiographic study. J Clin Periodontol. 2004 Oct;31(10):908-17.

43. Lekovic V, Camargo PM, Weinlaender M, Kenney EB, Vasilic N. Combination use of bovine porous bone mineral, enamel matrix proteins, and a bioabsorbable membrane in intrabony periodontal defects in humans. J Periodontol. 2001 May;72(5):583-9.

44. Camargo PM, Lekovic V, Weinlaender M, Vasilic N, Kenney EB, Madzarevic M. The effectiveness of enamel matrix proteins used in combination with bovine porous bone mineral in the treatment of intrabony defects in humans. J Clin Periodontol. 2001 Nov;28(11):1016-22.

45. 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. J Clin Periodontol. 2001 May;28(5):397-403.

46. Camargo PM, Lekovic V, Weinlaender M, Nedic M, Vasilic N, Wolinsky LE, et al. A controlled re-entry study on the effectiveness of bovine porous bone mineral used in


combination with a collagen membrane of porcine origin in the treatment of intrabony defects in humans. J Clin Periodontol. 2000 Dec;27(12):889-96.


APPENDIX 1: Meta-Analyses Results from the Systematic Review of Esposito et al. (2010)6 Comparing Enamel Matrix Derivative (Emdogain) Versus Open Flap Debridement or Placebo in Patients with Periodontal Intra-Bony Defects

Outcomes Number of studies; Number of Patients)

Weighted mean difference (mm) [95% CI]; Het. P-value)

Changes in CAL (9; 371) 1.08 [0.61, 1.55]; <0.00001 Changes in PPD (9; 371) 0.88 [0.44, 1.31]; 0.001 Changes in GR (6, 302) 0.09 [-0.20, 0.37]; 0.13 Changes in RBL (3, 75) 0.69 [-0.53, 1.92]; 0.01 CAL: clinical attachment level; CI: confident interval; GR: gingival recession; Het.: heterogeneity; PPD: probing pocket depth; RBL: radiographic bone level APPENDIX 2: Meta-Analyses Results from the Systematic Review of Needleman et al. (2008)7 Comparing Guided Tissue Regeneration Versus Open Flap Debridement in Patients with Periodontal Intra-Bony Defects

Outcomes (Number of studies; Number of patients) Weighted mean difference (mm) [95% CI]

Heterogeneity P-value

Interventions

CAL gain Probing depth reduction

Gingival recession Bone gain. Surgical re-entry

GTR only (16; 750)

1.22 [0.80, 1.64]; <0.001

(11; 473) 1.21 [0.53, 1.88];

<0.001

(8; 387) 0.26 [0.08, 0.44];

0.92

(3, 60) 1.39 [1.08, 1.71];

0.65 GTR; parallel group studies

(8; 472) 1.71 [1.02, 2.40];

<0.001

(5, 255) 1.59 [0.21, 2.97];

<0.001

(4; 235) 0.15 [-0.12, 0.42];

0.81

NA

GTR; split-mouth studies

(8; 278) 0.79 [0.37, 1.21];

0.01

(6, 218) 0.87 [0.38, 1.36];

0.11

(4; 152) 0.35 [0.11, 0.60];

0.94

NA

GTR + bone substitutes

(2, 50) 1.25 [0.89, 1.61];

0.91

(2, 50) 1.24 [0.89, 1.59];

0.85

(1, 20) -0.33 [-0.43, -0.23];

NA

(1, 20) 3.37 [3.14, 3.61]; NA

CAL: clinical attachment level; CI: confident interval; GTR: guided tissue regeneration; NA: not applicable


APPENDIX 3: Meta-Analyses Results from the Systematic Review Of Murphy & Gunsolley (2003)3 Comparing Guided Tissue Regeneration Versus Open Flap Debridement in Patients with Periodontal Intra-Bony Defects and Furcation Defects

(Number of studies; Number of patients) Weighted Mean Difference between GTR and ODF (mm), significant p-

value

Outcomes

Periodontal intra-bony defects Furcation defects CAL gain (24; 867)

0.811, P<0.0001

NA

Probing depth (PD) reduction (23; 835)

0.775, P<0.0001

NA

Gingival recession (GR) (19; 719)

0.775, NS

NA

Vertical probing attachment level (VPAL) gain

NA (15; 376)

0.860, P<0.0001 Vertical probing depth (VPD) reduction

NA (13; 314)

0.803, P<0.0001 Horizontal open probing attachment level (HOPA) gain

NA (10; 264)

1.063, P=0.001 CAL: clinical attachment level; GTR: guided tissue regeneration; NA: not applicable; NS: not significant; OFD: open flap debridement APPENDIX 4: Meta-Analyses Results from the Systematic Review of Jepsen et al. (2002)8 Comparing Guided Tissue Regeneration Versus Open Flap Debridement in Patients with Periodontal Furcation Defects

Outcomes Defect type (N of studies; N of patients) (Weighted mean difference (mm)

[95% CI]; Het. P-value) Mandibular class II (4; 52)

1.51 [0.39, 2.62]; 0.00 Maxillary class II (4; 66)

1.05 [0.46, 1.64]; 0.00

Reduction in horizontal furcation depth (at surgical re-entry)

Mandibular and maxillary class II (4; 61)

0.87 [-0.08, 1.82]; 0.99

Mandibular class II (6; 83)

1.77 [0.63, 2.91]; 0.00 Maxillary class II (mesial) (2; 19)

0.76 [0.29, 1.22]; 0.19 Maxillary class II (2; 30)

0.82 [0.47, 1.18]; 0.72

Gain in vertical probing attachment level

Mandibular and maxillary class II (5; 101)

0.62 [0.30, 0.94]; 0.92

Mandibular class II (4; 50)

1.16 [-0.20, 2.52]; 0.00

Reduction in vertical probing depth Maxillary class II (mesial) (2; 19)

1.42 [0.28, 2.55]; 0.39


Outcomes Defect type (N of studies; N of patients) (Weighted mean difference (mm)

[95% CI]; Het. P-value) Maxillary class II (2; 30)

0.79 [0.44; 1.15]; 0.93 Mandibular and maxillary class II (5; 101)

0.92 [0.45, 1.38]; 0.03 CI: confident interval; GTR: guided tissue regeneration; Het.: heterogeneity; N: number; OFD: open flap debridement APPENDIX 5: Meta-analyses Results from the Systematic Review of Reynolds et al. (2003)5 Comparing Bone Graft Substitutes versus Open Flap Debridement in Patients with Periodontal Intra-Bony Defects

BGS Weighted Mean Difference between GTR and ODF (mm) ± SD CAL gain PPD reduction GR Crestal

resorption Bone fill

Allograft 0.44 ±2.25 0.43 ± 2.25 -0.01 ± 1.65, NS -0.43 ± 1.38 1.06 ± 1.97 Autograft 0.72 ± 1.82 0.60 ± 1.35 -0.32 ± 1.38, NS 1.62 ± 1.53 Calcium phosphate ceramic

1.20 ± 2.22 0.74 ± 2.12 -0.16 ± 1.34, NS -0.19 ± 0.98, NS 1.58 ± 1.77

Coralline calcium carbonate

0.91 ± 1.94 0.09 ± 2.16, NS -0.25 ± 1.34, NS -0.30 ± 0.62 2.21 ± 1.82

Bioactive glass 1.05 ± 1.89 0.71 ± 2.22 -0.28 ± 1.81, NS -0.13 ± 0.94, NS 1.61 ± 1.47, NS Total 0.553, P<0.0001 0.308, P=0.002 -0.121, NS -0.369,

P<0.0001 1.039, P<0.0001

BGS: bone graft substitutes; CAL: clinical attachment level;; GR:: gingival recession; GTR: bone graft substitute; N: number; NA: not applicable; NS: not significant; PPD:; probing pocket depth; OFD: open flap debridement; SD: standard deviation

APPENDIX 6: Meta-Analyses Results from the Systematic Review of Trombelli et al. (2002)9 Comparing Graft Materials and Biological Agents Versus Open Flap Debridement in Patients with Periodontal Intra-Bony Defects

Interventions

Outcomes (Number of studies; Number of patients)

Weighted mean difference (mm) [95% CI]; Heterogeneity P-value CAL change PPD change

Autogenous bone graft (1, 22) 1.20 ± 0.39, NS

NA

Bone allograft (6; 89)

0.36 [-0.16, 0.87]; 0.013

(6; 89)

0.41 [0.16, 0.66]; 0.067 Coralline calcium carbonate (4; 97)

0.90 [0.53, 1.27]; 0.104

(4; 97)

0.04 [-1.78, 1.87]; <0.001 Bioactive glass (4; 90)

1.04 [0.31, 1.76]; 0.024

(4; 90)

0.60 [0.20, 1.00]; 0.684 Hydroxyapatite implant (4; 76)

1.40 [0.64, 2.16]; 0.013

(5; 88)

0.91 [0.32, 1.50]; 0.006 Enamel matrix proteins (5; 251)

1.33 [0.78, 1.88]; <0.001

(5; 251)

1.60 [0.59, 2.62]; <0.001 CAL: clinical attachment level; CI: confident interval; OFD: open flap debridement; PPD: probing pocket depth


APPENDIX 7: Characteristics and Outcome Parameters of the Included RCTs Comparing Enamel Matrix Derivatives Versus Open Flap Debridement

Study / Objectives Participants Treatment Effects at end of treatment

Adverse events Conclusion

Jentsch et al., 200810

RCT, parallel groups, 2 groups, 12 months duration

To check if the results of access flap surgery in suprabony defects are improved by additional application of EMD

39 patients (29 females, 10 males, range 25-63 years), chronic periodontitis with supra-alveolar-type defects, 39 completed the study

Test (T): OFD + EMD

Control (C): OFD

SPT intervals: every 3 months

[EMD: Emdogain®]

[OFD: papilla preservation technique]

Clinical Δ CAL (T: 0.97±0.92; C: 0.07±0.55; p<0.001)

Δ PPD (T : 1.55±0.90; C: 0.41±0.66; p<0.001)

NS difference between groups for bleeding index at end of study

NR Combination of EMD and OFD showed significant clinical benefit during surgical treatment of supra-alveolar pockets

Chambrone et al., 200711

RCT, split-mouth, 2 groups, 6 months duration Compare the clinical effect of treatment of 2- or 3-wall intrabony defects with OFD combined or not with EMP

13 patients (10 females, 3 males, range 32-43 years), chronic periodontitis with interproximal intrabony defects, 2,3 walls, 13 completed the study

Test (T): OFD + EMD

Control (C): OFD


[EMD: Emdogain®]


Clinical CAL (T: 10.75±2.26; C: 10.58±2.23; NS)

PPD (T: 2.67± 1.15; C: 2.00± 0.95; NS)

GR (T: 2.33±1.43; C: 1.16±1.33; NS)

KT (T: 3.50±1.38; C: 4.20±1.20; NS)

PI (T: 0.66±0.65; C: 0.58±0.65; NS)

GI (T: 0.33±0.77; C: 0.50±0.90, NS)

DM (T: 0.25±0.62; C: 0.08±0.28; NS)

NR OFD combined with EMD did not improve treatment of intrabony defects compared to OFD alone

Rosing et al., 200512

RCT, split-mouth, 2 groups, 6 & 12 months duration

16 patients (gender: NR, range 29-54 years), chronic periodontitis with interproximal intrabony defects (PPD ≥6 mm),

Test (T): OFD + EMD

Control (C): OFD

SPT intervals: NA

Clinical (12 months) CAL (T: 10.92±1.92; C: 11.31±1.86; NS)

PPD (T: 3.40± 1.82; C: 2.99± 1.07; NS)

NR Use of EDM did not result in more improvement in clinical and radiographic parameters compared




To evaluate the effects of EMD on clinical and radiographic parameters of periodontal intrabony defects

14 completed the study due to two test teeth lost


Radiographic (12 months) CEJ-bone crest (T: 2.76± 1.38; C: 2.41± 0.77; NS)

CEJ-bottom of defect (T: 5.39± 2.23; C: 5.17± 1.47; NS)

to placebo

Francetti et al., 200413

RCT, parallel groups, 2 groups, 12 & 24 months duration

To evaluate the efficacy of EMD combined with surgical treatment of periodontal intra-bony defects, as compared with surgery alone

24 patients (13 females, 11 males, range: 30-66 years), chronic periodontitis with intrabony defects, 1, 2 or 3 walls, 24 completed the study at 12 months, 22 completed the study at 24 months

Test (T): OFD + EMD

Control (C): OFD

SPT intervals: monthly during the first year

[EMD: Emdogain®]

[OFD: simplified papilla preservation flap technique]

Clinical (12 months) Δ CAL (T: 4.14±1.35; C: 2.29±0.95; <0.05)

Δ PPD (T: 4.71± 1.60; C: 2.57± 1.27; <0.05)

Δ IBD (T: 2.96± 1.13; C: 1.44± 0.74; <0.05) Clinical (24 months) Δ CAL (T: 4.29±1.38; C: 2.71±0.76; <0.05)

Δ PPD (T: 4.86± 1.95; C: 3.00± 1.15; NS)

Δ IBD (T: 3.44± 1.18; C: 1.84± 0.53; <0.05)

None found The use of EDM as an adjunct to periodontal surgery in the treatment of angular defects possibly enhances periodontal regeneration rate

Watchtel et al., 200314

RCT, split-mouth, 2 groups, 6 & 12 months duration

To assess the clinical effect of the microsurgical access flap and EMD treatment with an emphasis on the

11 patients (8 females, 3 males, range: 28-64 years), chronic periodontitis with intrabony defects, 1, 2 or 3 walls, 11 completed the study

Test (T): OFD + EMD

Control (C): OFD

SPT intervals: NA

[EMD: Emdogain®]

[OFD: modified papilla preservation technique]


Δ PPD (T: 3.3± 1.2; C: 2.2± 0.8; <0.05)

Δ GR (T: 0.5± 0.8; C: 0.2± 0.8; <0.05) Clinical (12 months) Δ CAL (T: 3.6±1.6; C:

NR For PPD reduction and CAL gain, the combination with EMD application appeared to be superior to the microsurgical access flap alone




evaluation of early wound healing

1.7±1.4; <0.05)

Δ PPD (T: 3.9± 1.4; C: 2.1± 1.1; <0.05)

Δ GR (T: 0.3± 0.8; C: 0.4± 0.9; NS)

Yilmaz et al., 200315

RCT, split-mouth, 2 groups, 8 months duration

To assess the clinical and radiographic outcome of horizontal type of bone loss over a period of 8 months following periodontal surgery with adjunctive use of EMD

20 patients (14 females, 6 males, range: 35-56 years), chronic periodontitis with interproximal intrabony defects (PPD ≥4 mm), 20 completed the study

Test (T): OFD + EMD

Control (C): OFD

SPT intervals: NA

[EMD: Emdogain®]

[OFD: conventional flap debridement]

Clinical Δ CAL (T vs. C, p<0.001)

Δ PPD (T vs. C, p<0.001)

Δ GR (T vs. C, p<0.05)

Radiographic Δ RBL (T vs. C, NS)

NR EMD treatment showed better clinical improvements as compared to the conventional flap debridement

Tonetti et al., 200216

RCT, multicenter, parallel groups, 2 groups, 12 months duration

To compare the clinical outcomes of papilla preservation flap surgery with or without the application of EMD

169 patients (97 females, 72 males, age 48±9 years), chronic periodontitis with interproximal intrabony defects (PPD ≥3 mm), 166 completed the study

Test (T): OFD + EMD

Control (C): OFD


[EMD: Emdogain®]


Clinical Δ CAL (T: 3.1±1.5; C: 2.5±1.5; 0.01)

Δ PPD (T: 3.9± 1.7; C: 3.3± 1.7; 0.02)

Δ GR (T: 0.8± 1.2; C: 0.8± 1.2; NS)

NR The use of EMD combined with papilla preservation flaps provide significant additional benefit in the regenerative treatment of intrabony defects

Zucchelli et al., 200217


To compare the clinical

90 patients (49 females, 41 males, range 30-61 years), chronic periodontitis with interproximal intrabony defects (PPD ≥3 mm),

Test 1 (T1): OFD + EMD

Test 2 (T2): OFD + GTR

Control (C): OFD

SPT intervals: every

Clinical Δ CAL (T1: 4.2±0.9; T2 : 4.9±1.6; C: 2.6±0.8; <0.05 for T1 or T2 vs. C)

Δ PPD (T1: 5.1±0.7;

None found The use of EMD or GTR resulted in significant improvements in clinical parameters compared to the




outcomes of 3 surgical modalities in the treatment of deep interproximal intrabony defects

90 completed the study month

[EMD: Emdogain®]

[GTR: titanium reinforced non-resorbable ePTFE membrane]

[OFD: simplified papilla preservation flap technique]

T2 : 6.5±1.6; C: 4.5±1.0; <0.05 for T1 or T2 vs. C)

Δ GR (T1: 1.0±0.5; T2 : 1.6±1.0; C: 1.9±0.8; <0.05 for T1 vs. C; NS for T2 vs. C)

NS difference between groups for plaque scores or bleeding scores

access flap procedure alone

Froum et al., 200118

RCT, split-mouth, 2 groups, 12 months duration, re-entry

To compare at 12 months postsurgery sites treated with OFD alone to those treated with OFD and EMD

23 patients (gender: NR, range: 19-71 years), chronic periodontitis with interproximal intrabony defects, NR completed the study

Test (T): OFD + EMD

Control (C): OFD

SPT intervals: every 2 weeks for the first 6 weeks and every month for the next 10 months

[EMD: Emdogain®]

Clinical (6 months) Δ CAL (T: 4.26; C: 2.75; <0.0001)

Δ PPD (T: 4.94; C: 2.24; <0.0001)

Δ GR (T: 0.61; C: 1.29; 0.0001)

Δ DF (T: 3.83; C: 1.47; <0.0001)

Δ CBR (T: 0.46; C: 1.29; <0.0001)

NS difference between groups for plaque indices or gingival indices

Radiographic The average percent of defect fill was more than 3 times greater for T vs. C (74% vs. 23%)

NR The use of EMD in combination with OFD is clinically superior to OFD alone in all parameters evaluated

Okuda et al., 200019

RCT, split-mouth, 2

16 patients (8 females, 8 males, age: 56±11 years), chronic

Test (T): OFD + EMD

Control (C): OFD +


NR Treatment with flap surgery and EMD, compared to flap




groups, 12 months duration

To compare the clinical and radiographic effects of EMD treatment to that of placebo-controlled treatment for intrabony defects

periodontitis with interproximal intrabony defects (PPD ≥4 mm), 16 completed the study

placebo

SPT intervals: weekly for the first 6 weeks and every month thereafter

[EMD: Emdogain®]

[OFD: conventional access flap surgery]

Δ PPD (T: 3.0± 0.97; C: 2.22± 0.81; 0.0002)

Δ GR (T: 1.22± 0.16; C: 1.22± 0.88; NS)

NS difference between groups for plaque, gingival and bleeding indices

Radiographic Δ RBL (T: 20.2± 16.6; C: -3.94± 23.3; 0.0005)

surgery with placebo, produced improvement in intrabony periodontal defects

CAL: clinical attachment level; CBR: crestal bone resorption; CEJ: cemento-enamel junction; DF: defect fill; DM: dental mobility; EMD: enamel matrix derivatives; GI: gingival index; GR: gingival recession; IBD: infra-bony defect depth; KT: keratinized tissue width; Δ: mean differences of baseline and end of study; NR: not reported; NS: not significant; OFD: open flap debridement; PI: plaque index; PPD: probing pocket depth; RBL: radiographic bone level; SPT: supportive periodontal therapy; vs. versus


APPENDIX 8: Characteristics and Outcome Parameters of the Included RCTs Comparing Enamel Matrix Derivatives Versus Scaling and Root Planing



Mombelli et al., 200520


To evaluate the clinical effects of non-surgical periodontal treatment, supplemented with EDM

16 patients (gender: NR, range: 25-65 years), chronic periodontitis with interproximal intrabony defects (PPD ≥5 mm), 14 completed the study

Test (T): SRP + EMD

Control (C): SRP + placebo

SPT intervals: NA

[EMD: Emdogain®]

Clinical (12 months) CAL (T: 6.4±2.4; C: 7.1±1.6; NS)

PPD (T: 4.8±1.5; C: 5.5± 1.7; NS)

NR There was no significant benefit of EMD adjunctive to SRP

Gutierrez et al., 200321


To evaluate the adjunctive use of EMD on periodontal healing following SRP

22 patients (11 females, 11 males, age >18 years), chronic periodontitis with interproximal intrabony defects (PPD ≥5 mm), 20 completed the study

Test (T): SRP + EMD

Control (C): SRP

SPT intervals: every month

[EMD: Emdogain®]

Clinical Δ CAL (T: 1.4±0.3; C: 1.8±0.4; NS)

Δ PPD (T: 2.0±0.3; C: 2.3± 0.4; NS)

NS difference between groups in plaque scores and bleeding scores

NR The findings do not support the use of EMD during routine, nonsurgical debridement of periodontal pockets

Sculean et al., 200322


To clinically and histologically evaluate healing of human intrabony defects following non-surgical periodontal treatment with and without application of EMD

16 patients (gender: NR, age: NR), advanced intrabony defects, completed study: NR

Test 1(T1): SRP (hand instrument) + EMD

Test 1(T1): SRP (ultrasonic instrument) + EMD

Control (C): SRP (ultrasonic instrument)


[EMD: Emdogain®]

Clinical Δ CAL (T1: 2.0±0.7; T2: 1.5±1.3; C: 1.5±1.0; NS)

Δ PPD (T1: 3.0±1.0; T2: 2.2±1.7; C: 2.2± 1.0; NS)

Healing occurred consistently through formation of a long junctional epithelium along the instrumented root surface in all groups

None found The study failed to show periodontal regeneration in advanced human intrabony defects following non-surgical treatment with subgingival application of EMD

CAL: clinical attachment level; EMD: enamel matrix derivatives; GI: gingival index; GR: gingival recession; Δ: mean differences of baseline and end of study; NR: not reported; NS: not significant; PPD: probing pocket depth; SPT: supportive periodontal therapy; SRP: scaling and root planing


APPENDIX 9: Characteristics and Outcome Parameters of the Included RCTs Comparing Guided Tissue Regeneration Versus Open Flap Debridement



Nickles et al., 200923

RCT, split-mouth, 2 groups, 10 years duration

To evaluate the 10-year results after OFD and GTR therapy of intrabony defects

16 patients (8 females, 8 males, range: 29-61 years), chronic periodontitis with intrabony defects, 2 or 3 walls (PPD ≥5 mm), 15 completed the study

Test (T): OFD + GTR

Control (C): OFD

SPT intervals: every year

[GTR: bioabsorbable polylactide acetyltributyl citrate barrier ]


Clinical (12 months) Δ CAL (T: 3.50±1.90; C: 3.60±2.67; NS)

Δ PPD (T: 3.95±2.19; C: 3.60± 2.59; NS)

Clinical (10 years) Δ CAL (T: 2.85±2.24; C: 3.65±3.36; NS)

Δ PPD (T: 4.15±2.47; C: 4.40± 2.84; NS)

NS difference between groups in plaque scores, bleeding scores, or radiographic bone level a either 1 year or 10 years’ follow-up

Six teeth (2 OFD, 4 GTR) in four patients had been extracted

The vertical attachment gains achieved either by OFD and GTR therapy using bioabsorbable barriers could be maintained up to 10 years after surgery.

The study failed to show statistically significant differences in clinical outcomes between both groups after 12 and 120 months

Gamal et al., 200824


To examine the effects of a novel periosteal pedicle graft as a guided tissue membrane for treating proximal intrabony defects in comparison to an open flap debridement

15 patients (5 females, 10 males, range: 27-45 years), chronic periodontitis with intrabony defects, 2 or 3 walls (PPD >5 mm), 15 completed the study

Test (T): OFD + GTR

Control (C): OFD

SPT intervals: every 2weeks for the first two months and then every month

[GTR: marginal periosteal pedicle graft]


Clinical (9 months) Δ CAL (T: 3.4; C: 2.0; <0.01)

Δ PPD (T: 3.8; C: 2.5; <0.01)

Radiographic (9 months) Δ IBD (T: 2.2; C: 0.6; <0.01)

NS difference between groups in plaque scores, bleeding scores, or gingival indices

None found The placement of a marginal periosteal pedicle graft as a barrier membrane significantly improved clinical and radiographic parameters of deep intrabony defects and proved superior to OFD alone




Paolantonio et al., 200825

RCT, parallel groups, 3 groups, 12 months duration, re-entry

To compare the clinical outcomes of guided tissue regeneration with calcium sulfate graft and membrane or OFD only

51 patients (29 females, 22 males, range: 41-62 years), chronic periodontitis with intrabony defects, 2 or 3 walls (PPD ≥6 mm), 38 completed the study

Test 1(T1): OFD+ GTR1

Test 2(T2): OFD + GTR2 (collagen barrier)

Control (C): OFD

SPT intervals: biweekly for the first 2months and every 3 months thereafter

[GTR1: calcium sulfate barrier]

[GTR2: bioabsorbable collagen barrier]


Clinical CAL (T1: 5.8±1.0; T2: 5.5±1.0; C: 6.9±0.9; <0.001 for T1 or T2 vs. C)

PPD (T1: 3.4±0.7; T2: 2.8±0.7; C: 4.4±0.8; <0.001 for T1 or T2 vs. C)

GR (T1: 2.4±0.8; T2 : 2.7±1.0; C: 2.5±0.8; NS)

DBL (T1: 5.1±1.3; T2: 4.4±0.8; C: 5.4±1.4; <0.05 for T1 or T2 vs. C)

None found Both GTR produced additional clinical benefit over OFD alone

Joly et al., 200226


To clinically and radiographically evaluate the effect of guided tissue regeneration using a bioabsorbable barrier in the treatment of intrabony defects in humans


Test (T): OFD + GTR

Control (C): OFD

SPT intervals: NA

[GTR: bioabsorbable membrane]

[OFD: conventional flap surgery]

Clinical Δ CAL (T : 2.37±0.37; C : 1.65±0.35; NS)

Δ PPD (T : 2.64±0.42; C : 1.84±0.36; NS)

Δ GR (T : 0.27± 0.07; C : 0.20± 0.05; NS)

Radiographic Δ OD (T : 6.2± 0.81; C : 0.34± 0.67; <0.01)

Δ RBL (T : 41.8± 5.09; C : 22.34± 2.5; <0.01)

NR The use of GTR in combination with OFD was as effective as OFD alone for clinical outcomes, but more effective than OFD alone in regard to the amount of bone regeneration.

Cury et al., 200327

RCT, split-mouth, 2 groups, 6 months

9 patients (7 females, 2 males, mean age: 45 years), Class II furcation

Test (T): OFD + GTR

Control (C): OFD

Clinical Δ CAL-v (T : 0.62±1.43; C : 1.16±0.98; 0.02)

NR GTR provided greater improvement in horizontal clinical




duration

To evaluate the treatment outcomes of GTR with a bioabsorbable membrane in Class II furcation defects in mandibular molars

defects, 9 completed the study SPT intervals: NA

[GTR: bioabsorbable polylactic acid membrane]

[OFD: conventional periodontal surgery]

Δ CAL-h (T : 2.27±2.21; C : 1.01±1.21; 0.01)

Δ PPD (T : 1.67±1.38; C : 2.51±1.69; 0.01)

Δ GR (T : 1.04± 1.40; C : 1.24± 0.96; NS)

Radiographic Δ RBL (T : -0.14± 0.41; C : 0.86± 0.41; 0.028)

attachment level and the possibility of complete closure of defects compared with OFD alone

Prathibha et al., 200228


To clinically evaluate the potential of GTR in the treatment of mandibular molar grade II furcations using a nonresorbable barrier, and compare it with OFD alone

10 patients (gender: NR, range: 20-50 years), mandibular molar grade II furcation defects, 10 completed the study

Test (T): OFD + GTR

Control (C): OFD

SPT intervals: NA

[GTR: nonresorbable polytetrafluoroethylene]


Clinical Δ VOPA (T: 1.08; C: 0.16; <0.05)

Δ HOPA (T: 2.4; C: 0.64; <0.05)

Δ PALG (T: 1.66; C: 0.61; <0.05)

Δ ACR (T: 0.16; C: 0.63; <0.05)

Δ GR (T: 0.29; C: 0.32; NS)

NR Both groups showed gain in vertical and horizontal open probing attachment and defect depth reduction when compared to baseline values, with the experimental sites showing statistically significant improvement over the controls

ACR: alveolar crestal resorption; CAL: clinical attachment level; DBL: defect bone levels; IBD: intra-bony defects; GI: gingival index; GR: gingival recession; GTR: guided tissue regeneration; h: horizontal; HOPA: horizontal open probing attachment; Δ: mean differences of baseline and end of study; NA: not applicable; NR: not reported; NS: not significant; OFD: open flap debridement; PALG: probing attachment level gain; PPD: probing pocket depth; RBL: radiographic bone level; SPT: supportive periodontal therapy; v: vertical; VOPA: vertical open probing attachment


APPENDIX 10: Characteristics and Outcome Parameters of the Included RCTs Comparing Bone Graft Substitutes Versus Open Flap Debridement



Heinz et al., 200929


To compare the clinical outcomes of papilla flap surgery with or without the application of a novel nanocrystalline hydroxyapatite bone graft substitute

15 patients (8 females, 7 males, range: 38-50 years), periodontal intrabony defects (PPD≥5 mm), 14 completed the study

Test (T): OFD + BGS

Control (C): OFD

SPT intervals: 6 weeks, 12 weeks and 6 months

[BGS: nanocrystalline hydroxyapatite] [OFD: papilla preservation flap technique]

Clinical Δ PBL (T: 4.3±1.4; C: 2.6±1.4; <0.05)

Δ PPD (T: 4.3±1.6; C: 2.9±1.1; <0.05)

None found Treatment of intrabony periodontal defects with a nanocrystalline hydroxyapatite bone graft substitute results in significantly improved clinical outcomes compared with OFD alone

Kaya et al., 200930


To assess interproximal soft tissue changes following application of particulate form demineralized bone matrix (DBM), putty form DBM, and OFD

25 patients (12 females, 13 males, range: 32-65 years), range: 38-50 years), periodontal intrabony defects (PPD≥5 mm), completed the study: NR

Test 1 (T1): OFD+ BGS1

Test 2 (T2): OFD + BGS2

Control (C): OFD


[BGS1: particulate DBM]

[BGS2: putty DBM]

[OFD: modified curtain technique]

Clinical (12 months) i) plaque index ii) gingival index iii) presence of

interdermal soft tissues clefts or craters

iv) loss of interdermal papilla height by using papilla presence index

NS difference among groups for all parameters (p>0.05)

None found Treatment of periodontal intrabony defects using either particulate form or putty form of DBM did not significantly improve clinical outcomes compared to OFD alone

Stein et al., 200931

RCT, parallel groups, 3 groups, 12 months

45 patients (31 females, 14 males, range: 33-69 years), chronic periodontitis with

Test 1(T1): OFD+ BGS1

Test 2(T2): OFD +


Not found The clinical benefit of biphasic calcium composite was equivalent to




duration

To compare the clinical outcome of a novel biphasic calcium composite biomaterial versus autogenous bone spongiosa or OFD for the treatment of intrabony periodontal defects

intrabony defects, (PPD >7 mm), 10 completed the study

BGS2

Control (C): OFD


[BGS1: novel biphasic calcium composite]

[BGS2: autogenous bone spongiosa]

[OFD: simplified papilla preservation technique]

Δ PPD (T1: 3.6±0.7; T2 : 3.4±0.8; C: 2.8±0.8; <0.05 for T1 vs. C; NS for T2 vs. C)

Δ GR (T1: 0.5±0.6; T2 : 0.6±0.6; C: 1.2±0.6; <0.05 for T1 or T2 vs. C)

NS difference among groups for plaque and gingival indices

autogenous bone spongiosa and superior to OFD alone

Shirakata et al., 200832


To evaluate the clinical efficacy of a new injectable calcium phosphate bone cement in human periodontal intrabony defects

30 patients (18 females; 12 males, age: 53.4±9.1 years), chronic periodontitis with intrabony defects, 2 or 3 walls (PPD ≥4 mm), 10 completed the study

Test (T): OFD + BGS

Control (C): OFD


[BGS: calcium phosphate]


Clinical (9 months) Δ CAL (T: 2.3±1.0; C: 1.4±0.8; NS)

Δ PPD (T: 3.4±1.2; C: 3.3±1.2; NS)

Δ GR (T: 1.1±1.1; C: 1.9±0.9; NS)

Radiographic (9 months) Δ RBL (T: 1.2±0.8; C: 0.3±0.7; <0.01)

None found The study failed to demonstrate any superior clinical outcomes for calcium phosphate bone cement group compared to OFD group; however, radiographs revealed more favorable results in the calcium phosphate group

Bhongade et al., 200733


To clinically and radiographically evaluate the effectiveness of the combination of anorganic bone matrix

16 patients (8 females, 8 males, range: 22-48 years), chronic periodontitis with intrabony defects, (PPD ≥5 mm), 16 completed the study

Test (T): OFD + BGS

Control (C): OFD

SPT intervals: 1, 3 and 6 months

[BGS: anorganic bone matrix/cell binding peptide]


Clinical Δ CAL (T: 2.86±0.37; C: 1.42±0.48; <0.05)

Δ PPD (T: 2.98±0.35; C: 1.68±0.56; <0.05)

Δ GR (T: 0.12±0.13; C: 0.26±0.29; NS)

Radiographic Δ RBL (T: 3.4±0.7; C: 0.9±0.6; <0.05)

None found The use of synthetic cell binding peptide combined with anorganic bone matrix yields better clinical and radiographic results in conjunction with OFD than with OFD alone




and cell binding peptide during regenerative periodontal procedures

Park et al., 200134


To examine the effectiveness of a bioactive glass as bone substitute on periodontal intrabony defects


Test (T): OFD + BGS

Control (C): OFD

SPT intervals: 3 weeks, 3 months and 6 months

[BGS: bioactive glass]


Clinical Δ CAL (T: 3.0±1.4; C: 1.8±1.2; <0.05)

Δ PPD (T: 4.1±1.8; C: 3.4±1.2; NS)

Δ GR (T: 1.1±1.0; C: 1.5±2.0; NS)

Δ BPD (T: 2.8±1.3; C: 1.3±1.2; NS)

None found Use of bioactive glass as bone substitute with OFD resulted in significantly greater improvements in CAL and BPD over OFD alone

Rosenberg et al., 200035


To evaluate the effectiveness of bioactive glass for the generative treatment of interproximal intrabony periodontal defects

12 patients (6 females, 6 males, mean age:41 years), chronic periodontitis with intrabony defects, 2 or 3 walls (PPD ≥6 mm), 38 completed the study

Test (T): OFD + BGS

Control (C): OFD SPT intervals: NA

[BGS: bioactive glass]


Clinical Δ CAL (T: 2.21±0.81; C: 1.00±0.78; <0.01)

Δ PPD (T: 1.43±0.67; C: -0.05±0.52, <0.001)

Δ GR (T: 0.25±0.75; C: 0.25±0.72; NS)

None found The use of bioactive glass in human interproximal intrabony periodontal defects resulted in significantly better hard tissue fill and clinical attachment gain than OFD alone

BGS: bone graft substitutes; BPD: bone probing depth; CAL: clinical attachment level; DBM: demineralized bone matrix; Δ: mean differences of baseline and end of study; GR: gingival recession; NA: not applicable; NR: not reported; NS: not significant; OFD: open flap debridement; PBL: probing bone level; PPD: probing pocket depth; RBL: radiographic bone level; SPT: supportive periodontal therapy


APPENDIX 11: Characteristics and Outcome Parameters of the Included RCTs Comparing Combined Regenerative Therapy Versus Open Flap Debridement




RCT, parallel groups, 4 groups, 10 years duration

To evaluate the 10-year results following treatment with EDM, GTR, EBM+GTR, and OFD alone

56 patients, 38 completed 10-year evaluation (gender: NR, mean age: 52±12.6 years), chronic periodontitis with intrabony defects, 1, 2 or 3 walls (PPD ≥6 mm)

Test 1 (T1): OFD + EDM


Test 3 (T3): OFD + EDM + GTR

Control (C): OFD

SPT intervals: every second week during the first 2 months, every month during the first year and every 3 months thereafter

[EMD: Emdogain®]

[GTR: bioabsorbable membrane]


Clinical (1 year) Δ CAL (T1: 3.4±1.0; T2: 3.2±1.4, T3: 3.3±1.1 C: 2.0±1.2; <0.05 for T1, T2 or T3 vs. C)

Clinical (10 year) Δ CAL (T1: 2.9±1.4; T2: 2.8±1.2, T3: 2.9±1.2 C: 1.8±1.1; <0.05 for T1, T2 or T3 vs. C)

NS difference between groups for PPD, GR, plaque and gingival indices, and bleeding on probing

None found The clinical outcomes obtained with all four approaches can be maintained over a period of 10 years

CAL gain in EDM, GTR, or EBM+GTR was significantly better than that in OFD alone


RCT, parallel groups, 2 groups, 1 and 5 years duration

To evaluate the treatment of deep intrabony defects either with OFD and a combination of GTR and BGS (test) or OFD alone (control)

28 patients (15 females, 13 males), chronic periodontitis with intrabony defects, 19 patients (10 females, 9 males, mean age 45±8.5 years) completed 5 years

Test (T): OFD + GTR + BGS

Control (C): OFD

SPT intervals: every second week during the first 2 months, every month during the first year and every 3 months thereafter

[GTR: bioresorbable collagen membrane]

[BGS: bovine bone mineral]

Clinical (1 year) Δ CAL (T: 4.0±1.0; C: 1.8±0.8; <0.01)

Δ PPD (T: 5.4±1.5; C: 4.0±0.9; ≤0.05)

Δ GR (T: 1.3±1.3; C: 2.2±0.8; NS)

Clinical (5 years) Δ CAL (T: 3.7±1.1; C: 1.4±0.7; <0.01)

Δ PPD (T: 4.8±1.6; C: 3.3±1.4; ≤0.05)

Δ GR (T: 1.1±1.2; C:

None found Treatment of intrabony defects with OFD+GTR+BGS may result in significantly higher CAL gains than treatment with OFD, and the clinical results obtained after both treatments can be maintained over a period of 5 years





2.0±0.8; NS)

NS difference between groups for plaque index, gingival index, and bleeding on probing

Belal et al., 200538

RCT, split-mouth, 5 groups, 12 months’ duration, re-entry

To evaluate clinical outcomes and assess digital subtraction radiographic changes after using bioabsorbable membrane or a connective tissue graft as a barrier, with or without resorbable hydroxyapatite in the treatment of mandibular class II furcations

20 patients (7 females, 13 males, range: 35-55 years), mandibular class II furcation defects, number completed the study: NR

Test 1 (T1) : OFD + GTR1

Test 2 (T2) : OFD + GTR1 + BGS

Test 3 (T3) : OFD + GTR2

Test 4 (T4) : OFD + GTR2 + BGS

Control (C) : ODF


[GTR1: bioabsorbable membrane]

[GTR2 : connective tissue graft]

[BGS : hydroxyapatite]


All experimental groups showed statistically significant improvement in the clinical parameters and bone density as compared to the control group

None found GTR therapy with or without resorbable hydroxyapatite showed significantly favorable results clinically and radiographically compared to OFD alone

Cortellini et al., 200639

RCT, parallel groups, 2 groups, multicenter, 1 year duration

To compare the

124 patients (76 females, 48 males, mean age: 50.3 years), advanced chronic periodontitis with at least one intrabony defect of ≥3 mm, 1, 2, or 3 walls,


Control (C): OFD SPT intervals: every 3 months

Radiographic (1 year) RBL (T : 3.3±2.0; C: 1.8±1.9; 0.002)

% of radiographic resolution (T : 59±24; C: 30±32; <0.0001)

NR Regenerative periodontal surgery with GTR/bone replacement materials offers an additional benefit in terms of radiographic resolution




radiographic outcomes of OFD with or without the application of combination of GTR and BGS

Secondary analysis of Tonetti et al., 200341

120 completed the study [GTR: bioresorbable collagen membrane]



of the intrabony defect and predictability of outcomes with respect to OFD alone

Camargo et al., 200540


To compare the effectiveness of a combination therapy consisting of bone mineral, GTR and platelet rich plasma in the regeneration of periodontal defects in humans

28 patients (12 females, 16 males, mean age: 41±13 years), chronic periodontitis with intrabony defects (PPD ≥6 mm), 28 completed the study

Test (T): OFD + GTR + BGS + PRP

Control (C): OFD

SPT intervals: weekly during the first month, and then 3 and 6 months




[PRP: platelet rich plasma]

Clinical (buccal) Δ CAL (T: 4.52±1.24; C: 1.47±1.95; <0.001)

Δ PPD (T: 5.06±1.51; C: 2.99±1.42; <0.001)

Δ GR (T: 1.66±0.46; C: 1.61±0.41; NS)

Δ DBF (T: 5.12±1.34; C: 1.66±0.96; <0.001)

Clinical (lingual) Δ CAL (T: 4.27±1.31; C: 1.39±0.92; <0.01)

Δ PPD (T: 4.90±1.49; C: 2.78±0.82; <0.01)

Δ GR (T: 1.69±0.42; C: 1.65±0.43; NS)

Δ DBF (T: 5.04±1.31; C: 1.62±1.31; <0.001)

NS difference between groups for plaque and bleeding index

None found The combined therapy was clinically more effective than OFD alone for treatment of intrabony defects in patients with advanced periodontitis

Tonetti et al., 200441

RCT, parallel groups, 2 groups, multicenter, 1

124 patients (76 females, 48 males, mean age: 50.3 years), advanced chronic


Control (C): OFD

Clinical (1 year) Δ CAL (T: 3.3±1.7; C: 2.5±1.5; 0.004)

NR Regenerative periodontal surgery with GTR/bone replacement materials




year duration

To compare the clinical outcomes of OFD with or without the application of combination of GTR and BGS

periodontitis with at least one intrabony defect of ≥3 mm, 1, 2, or 3 walls, 120 completed the study





Δ PPD (T: 3.7±1.8; C: 3.2±1.5; 0.02)

Δ GR (T: 0.3±1.2; C: 0.7±0.9; 0.04)

offers an additional benefit in terms of CAL gain, PPD reductions, and predictability of outcomes with respect to OFD alone

Vouros et al., 200442


To compare the clinical and radiographic outcomes of two bioabsorbable barriers combined with bone mineral graft, with OFD alone for treating intrabony defects

34 patients (23 females, 11 males, range: 32-61 years), chronic periodontitis with at least one intrabony defect of ≥7 mm, 1, 2, or 3 walls, 34 completed the study

Test 1 (T1): OFD + GTR1 + BGS

Test 2 (T2): OFD + GTR2 + BGS

Control (C): OFD


[GTR1: bioresorbable collagen membrane]

[GTR2: polylactic acid barrier]

[BGS: bovine bone mineral] [OFD: conventional periodontal surgery]


Δ PPD (T1: 5.08±1.81; T2 : 4.72±1.35; C: 2.50±0.59; <0.05 for T1 or T2 vs. C)

Radiographic %Δ RBL (T1: 23.68±11.93; T2 : 20.01±13.32; C: 6.36±9.24; <0.05 for T1 or T2 vs. C)

NR The use of two barrier membranes in combination with bone mineral graft significantly improved clinical and radiographic parameters of deep intrabony pockets and proved superior to OFD alone

Lekovic et al., 200143


To evaluate the effectiveness of a

18 patients (8 females, 10 males, mean age: 42 years), chronic periodontitis with intrabony defects (PPD >6 mm), 18 completed the study

Test (T): OFD + EMD + GTR + BGS

Control (C): OFD

SPT intervals: weekly up to 1 month, and then at 3 and 6 months


Δ PPD (T: 4.95±1.52; C: 2.83±0.83; <0.001)

Δ GR (T: 1.48±0.28; C:

None found A combination of OFD + EMD + GTR + BGS results in better clinical resolution of intrabony defects than treatment with OFD alone




combination of EMD, BGS (bone mineral) and GTR as regeneration therapy for intrabony defects and compare it to OFD alone

[EMD: Emdogain®]




1.54±0.33; NS)

Δ DBF (T: 4.76±1.36; C: 1.78±0.92; <0.001)


Δ PPD (T: 4.90±1.49; C: 2.78±0.82; <0.01)

Δ GR (T: 1.42±0.31; C: 1.57±0.34; NS)

Δ DBF (T: 4.81±1.37; C: 1.67±0.90; <0.001)



RCT, split-mouth, 2 groups, 6 months’ duration

To evaluate the effectiveness of EMD used in combination with bone mineral (BGS), compared with OFD in the treatment of intrabony defects

24 patients (gender: NR, mean age: 42 years), chronic periodontitis with intrabony defects (PPD >6 mm), 24 completed the study

Test (T): OFD + EMD + BGS

Control (C): OFD


[EMD: Emdogain®]




Δ PPD (T: 3.99±1.40; C: 1.64±1.38; <0.001)

Δ GR (T: 1.16±1.22; C: 1.19±1.26; NS)

Δ DBF (T: 3.93±1.52; C: 1.08±0.98; <0.001)


Δ PPD (T: 3.82±1.38; C: 1.54±1.34; <0.01)

Δ GR (T: 1.28±1.24; C: 1.21±1.28; NS)

None found Combining EMD and BGS as a regenerative technique for intrabony defects results in statistically and clinically significant more favorable results than OFD alone




Δ DBF (T: 3.71±1.51; C: 1.04±1.06; <0.001)




To evaluate clinically the treatment effect of EMD, GTR, EMD + GTR, and OFD alone on intrabony defects

56 patients (32 females, 24 males, range: 29-68 years), chronic periodontitis with intrabony defects (PPD ≥6 mm), completed the study: NR

Test 1 (T1): OFD + EMD


Test 3 (T3): OFD + EMD + GTR

Control (C): OFD

SPT intervals: every second week during the first 2 months, then every month

[EMD: Emdogain®]

[GTR: bioresorbable collagen membrane] [OFD: conventional periodontal surgery

Clinical Δ CAL (T1: 3.4±1.5; T2: 3.1±1.5, T3: 3.4±1.1 C: 1.7±1.5; <0.05 for T1, T2 or T3 vs. C)

Δ PPD (T1: 4.1±1.7; T2: 4.2±1.9, T3: 4.3±1.4 C: 3.7±1.4; <0.05 for T1, T2 or T3 vs. C)

Δ GR (T1: 0.7±0.8; T2: 1.1±1.4, T3: 1.1±0.9, C: 1.7±1.1; NS)

NS difference between groups for plaque, gingival, and bleeding index

None found All three regenerative treatment modalities may lead to higher clinical effects than OFD alone. The combined treatment of EMD+GTR does not seem to improve the outcome



To evaluate the clinical effectiveness of GTR + bone mineral in the treatment of intrabony defects

22 patients (gender: NR, mean age: 43 years), chronic periodontitis with intrabony defects (PPD >6 mm), 22 completed the study


Control (C): OFD





Δ PPD (T: 4.03±0.94; C: 2.14±0.88; <0.001)

Δ GR (T: 1.13±0.32; C: 1.38±0.28; NS)

Δ DBF (T: 3.81±0.82; C: 1.14±0.86; <0.001)

None found Combining GTR and BGS as a regenerative technique for intrabony defects results in statistically and clinically significantly more favorable results than OFD alone






Δ PPD (T: 3.14±0.90; C: 2.26±0.81; <0.01)

Δ GR (T: 1.10±0.30; C: 1.34±0.36; NS)

Δ DBF (T: 3.66±0.81; C: 1.12±0.88; <0.001)


BGS: bone graft substitutes; BPD: bone probing depth; CAL: clinical attachment level; DBF: defect bone fill; DBM: demineralized bone matrix; EMD: enamel matrix derivatives; Δ: mean differences of baseline and end of study; GTR: guided tissue regeneration; GR: gingival recession; NA: not applicable; NR: not reported; NS: not significant; OFD: open flap debridement; PBL: probing bone level; PPD: probing pocket depth; PRP: platelet rich plasma; RBL: radiographic bone level; SPT: supportive periodontal therapy

l0157 periodontal regenerative procedures final · periodontal regenerative procedures 2 summary of...

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