Furcation defects present difficult treatment problems,

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1 Volume 75 Number 9 A Randomized Clinical Trial Comparing Enamel Matrix Derivative and Membrane Treatment of Buccal Class II Furcation Involvement in Mandibular Molars. Part II: Secondary Outcomes Jörg Meyle,* José R. Gonzales,* Rolf H. Bödeker, Thomas Hoffmann, Steffen Richter, Bernd Heinz, Mehrdad Arjomand, Elmar Reich, Anton Sculean, Karin Jepsen, and Søren Jepsen Background: This multicenter, randomized trial compared enamel matrix derivative (EMD) with barrier membranes for the treatment of Class II mandibular furcations with regard to secondary outcomes. The influence of furcation morphology on the effectiveness of either treatment was also evaluated. Methods: Forty-eight patients (age range 28 to 73 years; 22 females, 26 males) with buccal Class II furcation involvements in both contralateral lower first or second molars were included. After initial periodontal treatment, defects were randomized to either EMD or bioabsorbable guided tissue regeneration (GTR) barrier. Study design and the results for the primary parameter were previously described. Results of the following secondary outcome variables are reported here: changes of the hard tissue boundaries describing the anatomical situation of the furcation defect and changes in the following clinical parameters between baseline and 14 months: plaque, level of gingival margin, probing depth, bleeding on probing, attachment level, and bone sounding at five sites/tooth at the buccal side. Descriptive statistics were applied for changes in clinical parameters and measurements of hard tissue boundaries. The differences observed under treatment with EMD or membrane were analyzed by means of the Wilcoxon two-sample test. The difference between the effect of the EMD and membrane treatment was estimated by means of the Hodges-Lehmann estimator. Results: Overall, similar healing results were observed for both treatments. However, there was slightly more recession in the mid-furcation site following membrane treatment (P = 0.04). Additionally, different treatment effects could be detected for the distances from the stent or cemento-enamel junction (CEJ) to the buccal bone crest, mid-distal root (P stent = 0.01; P CEJ = 0.07) and for the distance from the stent or CEJ to the buccal bone crest, mid-mesial root (P stent = 0.01; P CEJ = 0.01). There was no measurable bone resorption in EMD sites, whereas a slight resorption occurred with membrane treatment. Furcation morphology at the time of surgery was not associated with clinical outcome, irrespective of the treatment. Conclusion: With regard to secondary outcome parameters, enamel matrix derivative treatment led to a similar regenerative result as the membrane procedure. J Periodontol 2004;75: KEY WORDS Comparison studies; furcation/surgery; furcation/therapy; guided tissue regeneration; membranes, barrier; proteins, enamel matrix; statistical distribution. * Department of Periodontology, University of Giessen, Giessen, Germany. Department of Statistics, University of Giessen. Department of Periodontology, University of Dresden, Dresden, Germany. Private practice, Hamburg, Germany. Department of Periodontology, University of Homburg, Homburg, Germany. Department of Periodontology, University of Bonn, Bonn, Germany. 1188

2 J Periodontol September 2004 Meyle, Gonzales, Bödeker, et al. Furcation defects present difficult treatment problems, mostly due to the complexity of the furcation morphology. Specifically, in Class II mandibular furcations, several treatment approaches to obtain furcation fill have been used with varying success. They include coronally repositioned flaps, bone replacement grafts, guided tissue regeneration (GTR), or a combination of therapies. 1-7 To date, there is consensus that GTR procedures have resulted in significant gains in clinical attachment levels (AL) both horizontally and vertically in mandibular Class II furcations. 8 Initially, GTR was carried out using a non-resorbable expanded polytetraflouroethylene membrane, alone or in combination with bone grafts In order to remove non-resorbable membranes, though, a second surgery is necessary. Therefore, bioabsorbable barriers have been introduced, either alone or in combination with bone grafts or other graft materials. 13 However, the great variability of clinical outcomes that has been shown for regenerative procedures for furcation defects remains a problem in periodontal therapy. The available scientific information does not clearly indicate the real impact of these therapeutic procedures on the final outcome and prognosis of the affected tooth and patient. 14 The identification of the role of enamel matrix derivatives # (EMD) in the formation of the cementum led to the development of a biological concept for periodontal regeneration. 15 Subsequently, clinical studies in humans and animals, as well as histological research, have shown that the application of EMD leads to the formation of a new connective tissue attachment and new alveolar bone Predominantly, 1- and 2-wall intrabony defects treated with EMD have been reported in the literature. Different mean values for clinical AL gain have been demonstrated, ranging between 1.5 mm and approximately 6 mm, and similar results have been shown for radiographic bone gains. 22,23 Additionally, periodontal regeneration of angular bony defects using EMD has proved to be at least equally effective in terms of probing depth (PD) reduction and AL gain in comparison with different regenerative modalities using barrier membranes. 24 Thus, EMD has been used as an alternative to bone grafts and barrier membranes in the treatment of intrabony defects. 16,25,26 More recently, EMD has been combined with other graft materials, such as bovine-derived bone mineral and bioactive glass. 27,28 There is a lack of data on the effects of EMD in the treatment of periodontal furcation defects. Recently, a multi-center study was conducted to assess the effectiveness of EMD treatment in buccal Class II furcation defects in mandibular molars, and to compare the efficacies of treatment with EMD and a bioabsorbable GTR barrier.** 29 The authors reported a significant clinical improvement obtained with both treatments in the perprotocol (PP) population. The median of the reduction of open horizontal furcation depth was 2.8 mm (interquartile interval: 1.5 mm, 3.5 mm) at sites treated with EMD, compared with 1.8 mm (interquartile interval: 1.0 mm, 2.8 mm) at sites treated with bioabsorbable membrane. Thus, treatment with EMD resulted in more horizontal depth reduction than with the membrane treatment (Hodges-Lehmann estimator: 0.75 mm; 95% confidence interval [CI]: to mm; P = 0.033, Wilcoxon). In addition, secondary outcomes, i.e., hard tissue boundaries and clinical parameters for evaluation of the regeneration of the furcation defects, were studied. Here we report the changes in these parameters. An additional aim was the analysis of the influence of furcation morphology on the effectiveness of either treatment. MATERIALS AND METHODS Study Design The present randomized, examiner-masked, multicenter study had a split-mouth design. Five independent centers participated. The study design included a previous calibration of all investigators and examiners. The examiners, who performed all the clinical assessments at the treated sites, were treatment-masked. Details of the study design have previously been described. 29 Briefly, having met the criteria for inclusion and after giving informed consent, a total of 48 patients (22 females, 26 males) with buccal Class II furcation involvements in both contralateral lower first or second molars were included (horizontal probing depth >3 mm, measured with the Nabers probe). Initial periodontal treatment was performed, to ensure that all patients presented full-mouth plaque and gingival bleeding scores of <25% at the beginning of the active treatment phase. Subsequently, patients were randomized to receive one of two surgical procedures, either EMD or bioabsorbable GTR barrier in the first surgery. Surgeries started with the left side, and continued with the alternative treatment on the right side within 2 to 6 weeks. Assignment of treatment with EMD or membrane was not revealed to the surgeon until the flap was reflected and the root surfaces were debrided. The clinical study was completed after a reentry surgery 14 months later. Clinical Parameters The primary outcome of the study was the change in horizontal furcation depth, determined by measuring the depth of the furcation defect at the deepest point (Fig. 1, parameter h) during the first surgery (baseline) and during the reentry surgery. Additionally, several secondary parameters were recorded. These included # Emdogain, Straumann Biologics Division, Waltham, MA (formerly Biora AB, Malmö, Sweden). ** Resolut, W.L. Gore & Associates, Inc., Flagstaff, AZ. 1189

3 Comparison of Enamel Matrix Derivative and Membranes for Furcation Therapy Volume 75 Number 9 measurements of the hard tissue boundaries describing the anatomical situation of the furcation defect and the following clinical parameters: level of gingival margin (GM), probing depth (PD), attachment level (AL), and bone sounding (BS) at five sites/tooth on the buccal side: mesio-buccal, mid-mesial root, mid-furcation, middistal root and disto-buccal. Bleeding on probing (BOP) observed during PD measurement was also reported. In order to assess oral hygiene status, modified fullmouth plaque and site plaque indices were determined. Both indices were based on determination of the presence or absence of disclosed plaque. The hard tissue boundaries in the furcation defects and the clinical parameters were measured twice, using as reference the cemento-enamel junction (CEJ) and an individually manufactured acrylic stent with grooves at five sites, as previously described. 29 Measurements were recorded using a standard periodontal probe (UNC-15) and rounded to the nearest 0.5 mm. Some of these parameters were measured during follow-up appointments at 1, 3, 6, and 8 to 12 weeks and at 3, 6, and 8 months. Additionally, parameters describing adverse reactions during the study were recorded using special questionnaires (objective and subjective adverse events). Smoking status was also assessed; however, smokers were not excluded from the study. Data Analysis The study was designed both to assess the effectiveness of EMD treatment and to compare the effectiveness of EMD treatment with membrane treatment. As 1190 Figure 1. Intrasurgical measurements of hard tissue boundaries: a = interproximal bone crest, distal; b = buccal bone crest, mid-distal root; c = bone crest of defect, mid-furcation; d = buccal bone crest, mid-mesial root; e = interproximal bone crest, mesial; f = fornix to bone crest of defect; g = width of defect at the bottom of the defect; h = horizontal depth of furcation; i = bottom of the defect. All measurements were made twice, from the cemento-enamel junction and the stent, with the exception of parameters h and i. 29 explained in detail by Jepsen et al., three populations were determined for the analyses: the safety population, the intention-to-treat (ITT) population, and the PP population. 29 The number and characteristics of the patients included in each group, as well as the results of the primary parameter h have been described. 29 In the current paper, the results of the secondary parameters are reported, using the ITT population. Descriptive statistical methods were applied to the parameters of interest and the results were tabulated separately for sequence and/or treatment. First, the homogeneity of the clinical parameters was tested. The Wilcoxon two-sample test was used for the continuous variables and Fisher s exact test was used for the discrete variables. According to the study protocol, the statistical analysis was designed with the objective of demonstrating the effectiveness of each therapy, i.e., the difference or change in the measurements of the clinical parameters (GM, PD, AL, BS) and the measurements of the hard tissue boundaries (shown in Figure 1) between the baseline and the reentry surgeries. For the continuous parameters, the assumption of normal distribution could not be held. The distribution was described by minimum, first quartile, median, third quartile, and maximum and particular sizes were computed for the different locations (mesio-buccal, mid-mesial root, mid-furcation, middistal root and disto-buccal). In accordance with the study design, statistical tests were also performed. Thus, the differences in the distributions of the parameters either under treatment with EMD or membrane were analyzed by means of the Wilcoxon two-sample test. However, the computed P value is only a measure of the distance of the observed value to that expected under the assumption that both samples were drawn from the same population. This means that the greater the P value, the more likely the assumption that both samples were drawn from the same population. Additionally, in order to estimate the difference between the effects of the EMD and membrane treatments, an estimator (Hodges-Lehmann) associated with Wilcoxon s rank sum statistics and the related distribution-free confidence interval, also based on Wilcoxon s rank sum statistics, was computed. The computed P values of the statistical tests, however, have to be interpreted in a descriptive manner. They are a measure of how the observed data differ from that expected under the assumption of no different treatment effect.

4 J Periodontol September 2004 Meyle, Gonzales, Bödeker, et al. Additionally, the influence of furcation morphology on the effectiveness of either treatment was determined. This was performed by analyzing the possible associations between the baseline measurements of the hard tissue boundaries that assessed the alveolar bone levels (Fig. 1, parameters a, c, and e), the morphology of the furcation (parameters f and g) and depth (parameter i) with the parameters describing the effectiveness of treatment based on the changes in clinical outcomes, such as PD reduction and AL gains (in the mid-furcation site), and change in horizontal and vertical furcation depth (parameters h and i). As the assumption of normal distribution could not be made, a non-parametric Spearman s correlation coefficient test was used. Analysis was carried out using a statistical software program. In order to obtain exact estimators for the treatment effects, a second software program was also used. Figure 2. Frequency of BOP in mid-furcation sites. Percentages refer to total number of patients (N = 47). Figure 3. Mean reduction of full-mouth plaque index. Percentages refer to total number of patients (N = 47). RESULTS The results presented here are those relating to the secondary clinical parameters (GM, PD, AL, BS, and BOP) and the hard tissue boundaries (Fig. 1). The ITT population consisted of 48 patients (22 females, 26 males) with a median age of 54 years (range 28 to 73 years). As a result of missing values, the sample size may differ slightly for the various analyses of secondary variables. The patients were randomly assigned to one of two treatment sequences: left EMD right membrane (LE RM; N = 21) and left membrane right EMD (LM RE; N = 27). Ten patients were active smokers: six in the LE RM group and four in the LM RE group. No indication for the rejection of the assumption of homogeneity could be found for the parameters measured before or during surgery. The median reduction of PD in the mid-furcation site changed from 3.5 mm at baseline to 3.0 mm after 14 months in sites treated with EMD, and in membrane treated sites from 3.25 mm to 3.0 mm. The median reduction of AL in the mid-furcation site changed from 7.5 mm at baseline to 7.0 mm after 14 months with EMD treatment, and from 7.38 mm to 7.0 mm with membrane treatment. A reduction in the frequency of BOP in the midfurcation site was determined with both treatments, changing from approximately 40% at the beginning of treatment to 21.3% (EMD) and 23.4% (membrane) after 8 months (Fig. 2). However, after 14 months, a further reduction of BOP was shown only with EMD treatment (10.6%) and not with membrane treatment (25.5%). A reduction in the full-mouth plaque index was also demonstrated with both treatments, changing from approximately 16% after 2 months to 12% after 14 months (Fig. 3). In contrast, a slight increase in the frequency of site plaque in the mid-furcation site was registered for both treatments during the study, from 14.9% (EMD) and 10.4% (membrane) in the second month, to 17% and 25.5%, respectively, after 8 months. However, after 14 months, a slight reduction of site plaque (12.8%) was shown only for the teeth treated with EMD (Fig. 4). The results of the changes in the clinical parameters between treatments are summarized in Table 1. No significant differences after 14 months between treatment with EMD and with membrane at the mesio-buccal, mid-mesial root, mid-distal root, and disto-buccal sites SAS Version 8.01, SAS Institute Inc., Cary, NC. StatXact Version for Windows, CYTEL Software Corporation, Cambridge, MA. 1191

5 Comparison of Enamel Matrix Derivative and Membranes for Furcation Therapy Volume 75 Number 9 Figure 4. Frequency of site plaque in the mid-furcation site. Percentages refer to total number of patients (N = 47). Figure 5. Distribution of the change in the level of gingival margin (GM) measured from the stent to the mid-furcation site, separated by treatment and side.the box contains 50% of the data around the median.the vertical lines extending from the box mark the lowest and the highest value except the outliers. Negative values indicate gingival recession. Table 1. Estimators of the Differences in Changes in Clinical Parameters With EMD or Membrane Hodges-Lehmann Variable Location Estimator* 95% CI P Value Level of gingival margin Mesio-buccal to Mid-mesial root to Mid-furcation to Mid-distal root to Disto-buccal to Probing depth Mesio-buccal to Mid-mesial root to Mid-furcation to Mid-distal root to Disto-buccal to Attachment level Mesio-buccal to Mid-mesial root to Mid-furcation to Mid-distal root to Distobuccal to Bone sounding Mesiobuccal to Mid-mesial root to Mid-furcation to Mid-distal root to Distobuccal to *Estimator of (X EMD,surgery X EMD,reentry ) (X Membrane,surgery X Membrane,reentry ). Wilcoxon two-sample test. Measured from the stent. Clinical and statistically relevant differences. were found. However, an indication of different effects could be detected for the distance from the stent to the GM level in the mid-furcation site (P = 0.04). Figure 5 illustrates the distribution of change in this parameter in the form of box plots. The median change was 0.13 mm and 0 mm (left and right sides, respectively) with EMD treatment, and 0.5 mm with the membrane (both sides). The results of the changes in the hard tissue boundaries between treatments are summarized in Table 2. Different treatment effects were found for the distance from the stent or CEJ to the buccal bone crest, mid-distal root (Figure 1, parameter b) (P stent = 0.01; P CEJ = 0.07). The median change was 0 mm (both sides) with EMD treatment, and 0.5 mm and 0.25 mm (left and right sides, respectively) with the membrane (Fig. 6). Similar results were found for the distance from the stent or CEJ to the buccal bone crest, mid-mesial root (Figure 1, parameter d) (P stent = 0.01; P CEJ = 0.01). In this case, the median change was 0.25 mm and 0 mm (left and right sides, respectively) with EMD, and 0.63 mm and 0.75 mm (left and right sides, respectively) with the membrane (Fig. 7). This demonstrates that the differences between both materials tested were similar, independent from the treatment sequence. Furthermore, the possible influence of furcation morphology on the effectiveness of the treatment was analyzed in this study. No 1192

6 J Periodontol September 2004 Meyle, Gonzales, Bödeker, et al. Table 2. Estimators of the Differences in Changes of Measurements of Hard Tissue Boundaries With EMD or Membrane Hodges-Lehmann Variable* Estimator 95% CI P Value Interproximal bone crest, distal (a) Stent to CEJ to Buccal bone crest, mid-distal root (b) Stent to CEJ to Bone crest of defect, mid-furcation (c) Stent to CEJ to Buccal bone crest, mid-mesial root (d) Stent to CEJ to Interproximal bone crest, mesial (e) Stent to CEJ to Fornix to bone crest of defect (f) to Width of defect at the bottom to of the defect (g) Bottom of the defect (i) Stent to CEJ to * Letters in parentheses refer to parameters in Figure 1. Estimator of (X EMD,surgery X EMD,reentry ) (X Membrane,surgery X Membrane,reentry ). Wilcoxon two-sample test. Clinical and statistically relevant differences. indication of an association between those parameters describing the furcation morphology (Fig. 1, parameters f, g, and i) and the change in the primary parameter h, or parameter f could be demonstrated. Also, no association was found for the parameters a, c, e, f, and g with the change of parameter i, and for the parameters a, c, and e with the changes of PD and AL measured in the mid-furcation site. DISCUSSION In the treatment of mandibular Class II furcations, many comparative studies using diverse materials and therapies have been performed. While some reports demonstrated significant clinical attachment and bone gains, other studies did not show a significant clinical improvement. 14 Similar results have been shown for GTR furcation therapy when bioabsorbable and nonresorbable barriers were compared. 30 Moreover, few studies using bioabsorbable membranes have demonstrated that the furcation defects were filled with bone to more than 50% of the lesion. 31 Thus, the results obtained from most of the GTR procedures, regardless of the barrier membrane used, clearly showed the limitations of this therapy in this type of defect. Figure 6. Distribution of the change in the distance from the stent to the buccal bone crest, mid-distal root (Fig. 1, parameter b), separated by treatment and side. Figure 7. Distribution of the change in the distance from the stent to the buccal bone crest, mid-mesial root (Fig. 1, parameter d), separated by treatment and side. 1193

7 Comparison of Enamel Matrix Derivative and Membranes for Furcation Therapy Volume 75 Number 9 Periodontal regeneration of intrabony defects using EMD is well documented in clinical trials and case reports. 16,32,33 Recently, a multicenter, randomized, controlled clinical study was conducted on 172 patients, evaluating the effect of EMD in deep intrabony defects. The results after 1 year showed greater gains of clinical AL (3.1 ± 1.5 mm) and PD reduction (3.9 ± 1.5 mm) with the use of EMD than with only root debridement and conditioning (clinical AL: 2.5 ± 1.5 mm; PD: 3.3 ± 1.7 mm). 19 Studies comparing EMD and GTR with either bioabsorbable or non-resorbable membranes for the treatments of intrabony defects have been also performed. 24,34,35 These clinical studies indicated that a similar therapeutic effect was achieved by using either EMD or GTR procedures, irrespective of the type of membrane used. In addition, a histological study demonstrated the formation of new connective tissue attachment in human intrabony defects, either with EMD or GTR procedures. 36 There is a lack of data with regard to the effectiveness of EMD for the treatment of Class II furcation defects. Therefore, the present study was designed as a multicenter, randomized clinical study for evaluating and comparing the effects of EMD treatment with GTR using a bioabsorbable membrane in human mandibular buccal Class II furcation defects. In this type of study, the null hypothesis is that there is no different treatment effect between the two treatments. Secondary parameters comprised all the anatomical measurements of hard tissue boundaries in the furcation defect and the clinical parameters assessing the GM level, PD, BOP, AL, and bone level. Under the conditions of this study, treatment with EMD was equally effective with membrane treatment. This result is supported by published data on the clinical gains after treatment of intrabony defects with EMD. 35 However, different effects could be found for the distance from the stent to the GM level at the mid-furcation site (P = 0.04). This indicates that a modest gingival recession occurred in both treatments; however, the level of recession was less in the EMD-treated sites. There is a sparsity of data on gingival recession following regenerative periodontal surgery with EMD. The percentage of BOP was reduced throughout the study, irrespective of the treatment. In addition to clinical outcomes, oral hygiene was monitored throughout the study assessing full-mouth and site plaque indices. Overall, patients showed a good level of compliance. However, whereas full-mouth plaque was reduced, a slight increase in site plaque in the mid-furcation of the tooth after 8 to 14 months was observed. This percentage was higher in membrane-treated teeth than in those treated with EMD. With respect to the hard tissue boundaries, different treatment effects were found for the distance from the stent and the CEJ to the buccal bone crest, in the mid-buccal of the distal root (P stent = 0.01; P CEJ = 0.07), and in the mid-buccal of the mesial root (P stent = 0.01; P CEJ = 0.01). However, the values of these bone level changes were slightly negative in the sites treated with membrane, whereas no changes were found in sites treated with EMD. This means that no measurable bone resorption occurred in the EMD treated sites, whereas a slight resorption resulted in those sites treated with membrane. This is the first time that such an effect of EMD versus membrane treatment on hard tissue margins has been reported. This might be the reason for the minimal recession observed with EMD treatment in the present study. Some variability in outcomes following the GTR technique was expected; however, in the case of EMD it has been reported that clinical improvements were better at sites with deep, rather than shallow, defects. 24 In the present study, no influence of furcation morphology on the effectiveness of the treatment could be demonstrated. In summary, this study demonstrates equivalent clinical results when treatment with EMD was compared with GTR with bioabsorbable membrane in treating mandibular Class II furcations. Evaluation of clinical and osseous changes associated with this study indicated that treatment with EMD led to similar regenerative outcomes as the GTR procedure. ACKNOWLEDGMENT This study was supported by Biora AB, Malmö, Sweden (now Straumann Biologics Division, Waltham, Massachusetts). REFERENCES 1. Lekovic V, Kenney EB, Kovacevic K, Carranza FA Jr. Evaluation of guided tissue regeneration in Class II furcation defects. A clinical re-entry study. 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A prospective controlled clinical study. J Clin Periodontol 2001;28: Sculean A, Donos N, Windisch P, et al. Healing of human intrabony defects following treatment with enamel matrix proteins or guided tissue regeneration. J Periodontal Res 1999;34: Correspondence: Dr. Jörg Meyle and Dr. José R. Gonzales, University of Giessen, Department of Periodontology, Schlangenzahl 14, Giessen, Germany. joerg. meyle@dentist.med.uni-giessen.de; jose.gonzales@dentist. med.uni-giessen.de. Accepted for publication January 5,