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

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1 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 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 Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials. Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

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 RCTs 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< ). 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 of periodontal intrabony defects compared to OFD alone. Of the 17 included RCTs with at least 1 year, 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. Periodontal Regenerative Procedures 2

3 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, 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- 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- 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 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 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 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 Periodontal Regenerative Procedures 3

4 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 effect (-0.369, P<0.0001), indicating that BGS was associated with less crestal resorption than OFD. Heterogeneity was significant (P 0.05). The 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< ) 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 of intrabony defects. Trombelli et al. (2002) 9 reviewed the adjunctive effect of graft materials and biological agents compared with OFD in the of deep intrabony defects. Twenty-six trials (6-12 months ) 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 polymethylmethacrylate, polylactic acid granules, and emanel matrix proteins. Meta-analysis results evaluating the differences in CAL gain and PPD reduction following 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 groups. Periodontal Regenerative Procedures 4

5 Randomized controlled trials Of the 35 RCTs, 10 studies compared EMD versus OFD, 3 studies compared EMD versus scaling and root planning, 6 studies compared GTR versus OFD, 7 studies compared BGS versus OFD, and 9 studies 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 of periodontal intrabony defects. Four trials 10,13,16,17 used a parallel design and 6 trials 11,12,14,15,18,19 used split-mouth design. One trial 16 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 was 6 months, 11 8 months, months, 10,12,14,16-19 and 24 months. 13 The commercially available EMD used was Emdogain. Six trials 10,11,13,14,16,17 provided clinical data and 4 trials 12,15,18,19 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 compared to baseline. For CAL gain and PPD reduction, 8 studies 10,13-19 showed that combination of EMD and OFD provided additional benefit while 2 studies 11,12 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 of periodontal intrabony defects. All 3 trials were of split-mouth design, having 16, 22, and 16 patients, respectively. Most patients completed the study. The study was 3 months, 21 6 months, 22 and 12 months. 20 One trial 22 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 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 of periodontal intrabony defects (4 RCTs ) and Class II furcation defects (2 RCTs 27,28 ). Five RCTs 23,24,26-28 were of split-mouth design with patient populations ranging from 9 to 16 individuals, and one RCT 25 was of parallel design having 51 patients. Treatment was 6 months, 27,28 8 months, 26 9 Periodontal Regenerative Procedures 5

6 months, 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 of intrabony defects, two RCTs 23,26 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 of furcation defects, both RCTs 27,28 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 of periodontal intrabony defects. There were 3 trials 31,32,35 using parallel design, and 4 trials 29,30,33,34 using split-mouth design. The study population ranged from 12 to 45 patients. The study was 6 months 29,33-35 and 12 months 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 glass 34,35 ) 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 matrix 30 or calcium phosphate bone cement 32 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 of periodontal intrabony defects (8 RCTs 36,37,39-44,46 ) and Class II furcation defects (1 RCT 38 ). OFD was present in all test groups. One study with two reports 36,45 compared EMD plus GRT versus OFD, 6 studies 37-42,46 compared GTR plus BSG versus OFD (two reports 39,41 were from the same trial), one study 43 compared EMD plus GTR and BGS versus OFD, and one study 44 compared EMD plus BGS versus OFD. Four studies 36,37,39,41,42 used parallel design and 5 studies 38,40,43,44,46 used split-mouth design. EMD + GRT versus OFD Both reports 36,45 were from the same trial, reporting the results over a 12 month and 10 year period, respectively. Fifty-six patients with intrabony Periodontal Regenerative Procedures 6

7 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 modalities had higher clinical effects than OFD alone. The combined 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 trial 38 assessed the efficacy of GTR (bioabsorbable membrane or connective tissue graft) with or without BGS (resorbable hydroxyapatite) for the 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 trials 37,39-42,46 assessed the efficacy of GTR (bioresorbable collagen membrane 37,39-42,46, polylactic acid barrier 42 ) plus BGS (bovine bone mineral) for the of intrabony defects. The patient population ranged from 22 to 124 patients. Treatment s 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 RCT 25 assessed the efficacy of EMD (Emdogain) plus GTR (bioabsorbable collage membrane) plus BGS (bovine bone mineral) for the of intrabony defects in 18 patients. The was 6 months and all patients completed the study. The study found that the combined regenerative therapy results in better clinical outcomes than 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 RCT 44 assessed the efficacy of EMD (Emdogain) plus BGS (bovine bone mineral) for the of intrabony defects in 24 patients. The 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. Periodontal Regenerative Procedures 7

8 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 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 of intrabony defects. GTR was also found to result in greater improvement in attachment levels for 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 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 decisionmaking about the various methods of periodontal regeneration. Periodontal Regenerative Procedures 8

9 PREPARED BY: Health Technology Inquiry Service Tel: Periodontal Regenerative Procedures 9

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11 longitudinal placebo-controlled clinical trial in adult periodontitis patients. J Periodontol Jan;76(1): Francetti L, Del FM, Basso M, Testori T, Weinstein R. Enamel matrix proteins in the of intra-bony defects. A prospective 24-month clinical trial. J Clin Periodontol Jan;31(1): Wachtel H, Schenk G, Bohm S, Weng D, Zuhr O, Hurzeler MB. Microsurgical access flap and enamel matrix derivative for the of periodontal intrabony defects: a controlled clinical study. J Clin Periodontol Jun;30(6): Yilmaz S, Kuru B, tuna-kirac E. Enamel matrix proteins in the of periodontal sites with horizontal type of bone loss. J Clin Periodontol Mar;30(3): Tonetti MS, Lang NP, Cortellini P, Suvan JE, Adriaens P, Dubravec D, et al. Enamel matrix proteins in the regenerative therapy of deep intrabony defects. J Clin Periodontol Apr;29(4): Zucchelli G, Bernardi F, Montebugnoli L, De SM. Enamel matrix proteins and guided tissue regeneration with titanium-reinforced expanded polytetrafluoroethylene membranes in the of infrabony defects: a comparative controlled clinical trial. J Periodontol Jan;73(1): Froum SJ, Weinberg MA, Rosenberg E, Tarnow D. A comparative study utilizing open flap debridement with and without enamel matrix derivative in the of periodontal intrabony defects: a 12-month re-entry study. J Periodontol Jan;72(1): Okuda K, Momose M, Miyazaki A, Murata M, Yokoyama S, Yonezawa Y, et al. Enamel matrix derivative in the of human intrabony osseous defects. J Periodontol Dec;71(12): Mombelli A, Brochut P, Plagnat D, Casagni F, Giannopoulou C. Enamel matrix proteins and systemic antibiotics as adjuncts to non-surgical periodontal : clinical effects. J Clin Periodontol Mar;32(3): Gutierrez MA, Mellonig JT, Cochran DL. Evaluation of enamel matrix derivative as an adjunct to non-surgical periodontal therapy. J Clin Periodontol Aug;30(8): Sculean A, Windisch P, Keglevich T, Gera I. Histologic evaluation of human intrabony defects following non-surgical periodontal therapy with and without application of an enamel matrix protein derivative. J Periodontol Feb;74(2): Nickles K, Ratka-Kruger P, Neukranz E, Raetzke P, Eickholz P. Open flap debridement and guided tissue regeneration after 10 years in infrabony defects. J Clin Periodontol Nov;36(11): Gamal AY, Mailhot JM. A novel marginal periosteal pedicle graft as an autogenous guided tissue membrane for the of intrabony periodontal defects. J Int Acad Periodontol Oct;10(4): Periodontal Regenerative Procedures 11

12 25. Paolantonio M, Perinetti G, Dolci M, Perfetti G, Tete S, Sammartino G, et al. Surgical of periodontal intrabony defects with calcium sulfate implant and barrier versus collagen barrier or open flap debridement alone: a 12-month randomized controlled clinical trial. J Periodontol Oct;79(10): Joly JC, Palioto DB, de Lima AF, Mota LF, Caffesse R. Clinical and radiographic evaluation of periodontal intrabony defects treated with guided tissue regeneration. A pilot study. J Periodontol Apr;73(4): Cury PR, Jeffcoat MK, Sallum AW, Cafesse R, Nociti Junior FH, Sallum EA. Clinical and radiographic evaluation of guided tissue regeneration in the of class II furcation defects. A randomized clinical trial. Am J Dent Sep;16 Spec No:13A-6A. 28. Prathibha PK, Faizuddin M, Pradeep AR. Clinical evaluation of guided tissue regeneration procedure in the of grade II mandibular molar furcations. Indian J Dent Res Jan;13(1): Heinz B, Kasaj A, Teich M, Jepsen S. Clinical effects of nanocrystalline hydroxyapatite paste in the of intrabony periodontal defects: a randomized controlled clinical study. Clin Oral Investig. Epub 2009 Aug Kaya Y, Yalim M, Bahcecitapar M, Balos K. Comparison of applying particulate demineralized bone matrix (DBM), putty DBM and open flap debridement in periodontal horizontal bone defects. A 12-month longitudinal, multi-centre, triple-blind, split-mouth, randomized, controlled clinical study. Part 2 - evaluation of the interdental soft tissue. J Oral Rehabil Jul;36(7): Stein JM, Fickl S, Yekta SS, Hoischen U, Ocklenburg C, Smeets R. Clinical evaluation of a biphasic calcium composite grafting material in the of human periodontal intrabony defects: a 12-month randomized controlled clinical trial. J Periodontol Nov;80(11): Shirakata Y, Setoguchi T, Machigashira M, Matsuyama T, Furuichi Y, Hasegawa K, et al. Comparison of injectable calcium phosphate bone cement grafting and open flap debridement in periodontal intrabony defects: a randomized clinical trial. J Periodontol Jan;79(1): Bhongade ML, Tiwari IR. A comparative evaluation of the effectiveness of an anorganic bone matrix/cell binding peptide with an open flap debridement in human infrabony defects: a clinical and radiographic study. J Contemp Dent Pract. 2007;8(6): Park JS, Suh JJ, Choi SH, Moon IS, Cho KS, Kim CK, et al. Effects of pre clinical parameters on bioactive glass implantation in intrabony periodontal defects. J Periodontol Jun;72(6): Rosenberg ES, Fox GK, Cohen C. Bioactive glass granules for regeneration of human periodontal defects. J Esthet Dent. 2000;12(5): Periodontal Regenerative Procedures 12

13 36. Sculean A, Kiss A, Miliauskaite A, Schwarz F, Arweiler NB, Hannig M. Ten-year results following of intra-bony defects with enamel matrix proteins and guided tissue regeneration. J Clin Periodontol Sep;35(9): Sculean A, Schwarz F, Chiantella GC, Donos N, Arweiler NB, Brecx M, et al. Five-year results of a prospective, randomized, controlled study evaluating of intra-bony defects with a natural bone mineral and GTR. J Clin Periodontol Jan;34(1): 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 Oct;7(4): 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 of intrabony defects. II: radiographic predictors and outcomes. J Clin Periodontol May;33(5): 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 of intrabony defects in humans. Int J Periodontics Restorative Dent Feb;25(1): Tonetti MS, Cortellini P, Lang NP, Suvan JE, Adriaens P, Dubravec D, et al. Clinical outcomes following of human intrabony defects with GTR/bone replacement material or access flap alone. A multicenter randomized controlled clinical trial. J Clin Periodontol Sep;31(9): Vouros I, Aristodimou E, Konstantinidis A. Guided tissue regeneration in intrabony periodontal defects following with two bioabsorbable membranes in combination with bovine bone mineral graft. A clinical and radiographic study. J Clin Periodontol Oct;31(10): 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 May;72(5): 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 of intrabony defects in humans. J Clin Periodontol Nov;28(11): 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 May;28(5): 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 Periodontal Regenerative Procedures 13

14 combination with a collagen membrane of porcine origin in the of intrabony defects in humans. J Clin Periodontol Dec;27(12): Periodontal Regenerative Procedures 14

15 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]; < Changes in PPD (9; 371) 0.88 [0.44, 1.31]; 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) Interventions Weighted mean difference (mm) [95% CI] CAL gain Heterogeneity P-value Gingival recession Probing depth reduction Bone gain. Surgical re-entry GTR only GTR; parallel group studies GTR; split-mouth studies GTR + bone substitutes (16; 750) 1.22 [0.80, 1.64]; <0.001 (8; 472) 1.71 [1.02, 2.40]; <0.001 (8; 278) 0.79 [0.37, 1.21]; 0.01 (2, 50) 1.25 [0.89, 1.61]; 0.91 (11; 473) 1.21 [0.53, 1.88]; <0.001 (5, 255) 1.59 [0.21, 2.97]; <0.001 (6, 218) 0.87 [0.38, 1.36]; 0.11 (2, 50) 1.24 [0.89, 1.59]; 0.85 (8; 387) 0.26 [0.08, 0.44]; 0.92 (4; 235) 0.15 [-0.12, 0.42]; 0.81 (4; 152) 0.35 [0.11, 0.60]; 0.94 (1, 20) [-0.43, -0.23]; NA CAL: clinical attachment level; CI: confident interval; GTR: guided tissue regeneration; NA: not applicable (3, 60) 1.39 [1.08, 1.71]; 0.65 NA NA (1, 20) 3.37 [3.14, 3.61]; NA Periodontal Regenerative Procedures 15

16 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) Outcomes Weighted Mean Difference between GTR and ODF (mm), significant p- value Periodontal intra-bony defects Furcation defects CAL gain (24; 867) NA 0.811, P< Probing depth (PD) reduction (23; 835) NA 0.775, P< Gingival recession (GR) (19; 719) NA Vertical probing attachment level (VPAL) gain Vertical probing depth (VPD) reduction Horizontal open probing attachment level (HOPA) gain 0.775, NS NA (15; 376) 0.860, P< NA (13; 314) 0.803, P< 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) Reduction in horizontal furcation depth (at surgical re-entry) 1.51 [0.39, 2.62]; 0.00 Maxillary class II (4; 66) 1.05 [0.46, 1.64]; 0.00 Mandibular and maxillary class II (4; 61) 0.87 [-0.08, 1.82]; 0.99 Gain in vertical probing attachment level Reduction in vertical probing depth 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 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 Maxillary class II (mesial) (2; 19) 1.42 [0.28, 2.55]; 0.39 Periodontal Regenerative Procedures 16

17 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 ± ± ± 1.65, NS ± ± 1.97 Autograft 0.72 ± ± ± 1.38, NS 1.62 ± 1.53 Calcium phosphate ceramic 1.20 ± ± ± 1.34, NS ± 0.98, NS 1.58 ± 1.77 Coralline calcium 0.91 ± ± 2.16, NS ± 1.34, NS ± ± 1.82 carbonate Bioactive glass 1.05 ± ± ± 1.81, NS ± 0.94, NS 1.61 ± 1.47, NS Total 0.553, P< , P= , NS , P< , P< 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 Outcomes Interventions (Number of studies; Number of patients) Weighted mean difference (mm) [95% CI]; Heterogeneity P-value CAL change PPD change Autogenous bone graft (1, 22) NA 1.20 ± 0.39, NS Bone allograft (6; 89) 0.36 [-0.16, 0.87]; (6; 89) 0.41 [0.16, 0.66]; Coralline calcium carbonate (4; 97) 0.90 [0.53, 1.27]; (4; 97) 0.04 [-1.78, 1.87]; <0.001 Bioactive glass (4; 90) 1.04 [0.31, 1.76]; (4; 90) 0.60 [0.20, 1.00]; Hydroxyapatite implant (4; 76) 1.40 [0.64, 2.16]; (5; 88) 0.91 [0.32, 1.50]; 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 Periodontal Regenerative Procedures 17

18 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 Adverse events Jentsch et al., Test (T): OFD + EMD Clinical NR Δ CAL (T: 0.97±0.92; C: RCT, parallel groups, ±0.55; p<0.001) groups, 12 months 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 supraalveolar-type defects, 39 completed the study SPT intervals: every 3 months [EMD: Emdogain ] [OFD: papilla preservation technique] 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 Combination of EMD and OFD showed significant clinical benefit during surgical of supraalveolar pockets Chambrone et al., groups, 6 months Compare the clinical effect of of 2- or 3-wall intrabony defects with OFD combined or not with EMP 13 patients (10 females, 3 males, range interproximal intrabony defects, 2,3 walls, 13 completed the study Test (T): OFD + EMD SPT intervals: every 2 months [EMD: Emdogain ] [OFD: papilla preservation technique] 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) NR OFD combined with EMD did not improve of intrabony defects compared to OFD alone GI (T: 0.33±0.77; C: 0.50±0.90, NS) DM (T: 0.25±0.62; C: 0.08±0.28; NS) Rosing et al., groups, 6 & 12 months 16 patients (gender: NR, range years), chronic interproximal intrabony defects (PPD 6 mm), Test (T): OFD + EMD 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 Periodontal Regenerative Procedures 18

19 Study / Objectives Participants Treatment Effects at end of 14 completed the study due to two test teeth lost To evaluate the effects of EMD on clinical and radiographic parameters of periodontal intrabony defects [OFD: papilla preservation technique] 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) Adverse events to placebo Francetti et al., RCT, parallel groups, 2 groups, 12 & 24 months To evaluate the efficacy of EMD combined with surgical of periodontal intra-bony defects, as compared with surgery alone 24 patients (13 females, 11 males, range: 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 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) The use of EDM as an adjunct to periodontal surgery in the of angular defects possibly enhances periodontal regeneration rate 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) Watchtel et al., groups, 6 & 12 months To assess the clinical effect of the microsurgical access flap and EMD with an emphasis on the 11 patients (8 females, 3 males, range: intrabony defects, 1, 2 or 3 walls, 11 completed the study Test (T): OFD + EMD SPT intervals: NA [EMD: Emdogain ] [OFD: modified papilla preservation technique] Clinical (6 months) Δ CAL (T: 2.8±1.3; C: 2.0±1.3; <0.05) 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 Periodontal Regenerative Procedures 19

20 Study / Objectives Participants Treatment Effects at end of evaluation of early 1.7±1.4; <0.05) wound healing 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) Adverse events Yilmaz et al., groups, 8 months 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: interproximal intrabony defects (PPD 4 mm), 20 completed the study Test (T): OFD + EMD SPT intervals: NA [EMD: Emdogain ] 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 showed better clinical improvements as compared to the conventional flap debridement Tonetti et al., RCT, multicenter, parallel groups, 2 groups, 12 months 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 interproximal intrabony defects (PPD 3 mm), 166 completed the study Test (T): OFD + EMD SPT intervals: every 3 months [EMD: Emdogain ] [OFD: papilla preservation technique] 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 of intrabony defects Zucchelli et al., RCT, parallel groups, 3 groups, 12 months To compare the clinical 90 patients (49 females, 41 males, range interproximal intrabony defects (PPD 3 mm), Test 1 (T1): OFD + EMD Test 2 (T2): OFD + GTR 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; The use of EMD or GTR resulted in significant improvements in clinical parameters compared to the Periodontal Regenerative Procedures 20