Received: 16 January 2023 Revised: 5 March 2023 Accepted: 27 March 2023

DOI: 10.1111/jcpe.13814

ORIGINAL ARTICLE

Long-term stability of infrabony defects treated with

enamel matrix derivative alone: A retrospective two-centre
cohort study

Ilona Koronna 1,2 | Beate Schacher 1 | Iulia Dahmer 3,4 | Katrin Nickles 1,5 |
6 6 1 1,7
Sarah K. Sonnenschein | Ti-Sun Kim | Peter Eickholz | Hari Petsos

1
Department of Periodontology, Center for
Dentistry and Oral Medicine (Carolinum), Abstract
Goethe University Frankfurt, Frankfurt,
Aim: To assess the long-term stability of attachment gain in infrabony defects
Germany
2
Private Practice, Hanau, Germany
(IBDs) 10 years after regenerative treatment with an enamel matrix derivative
3
Institute of Biostatistics and Mathematical (EMD) alone.
Modeling, Goethe University Frankfurt,
Materials and Methods: Two centres (Frankfurt [F] and Heidelberg [HD]) invited
Frankfurt, Germany
4
Center of Dentistry and Oral Medicine
patients for re-examination 120 ± 12 months after regenerative therapy. Re-
(Carolinum), Goethe University Frankfurt, examination included clinical examination (periodontal probing depths (PPD), vertical
Frankfurt, Germany
5
clinical attachment level (CAL), plaque index (PlI), gingival index (GI), plaque control
Private Practice, Mannheim, Germany
6
record, gingival bleeding index and periodontal risk assessment) and review of patient
Section of Periodontology, Department of
Conservative Dentistry, Clinic for Oral, Dental charts (number of supportive periodontal care [SPC] visits).
and Maxillofacial Diseases, University Hospital
Results: Both centres included 52 patients (29 female; median baseline age:
Heidelberg, Frankfurt, Germany
7
Private Practice, Butzbach, Germany
52.0 years; lower/upper quartile: 45.0/58.8 years; eight smokers), each contributing
one IBD. Nine teeth were lost. For the remaining 43 teeth, regenerative therapy
Correspondence
Hari Petsos, Poliklinik für Parodontologie,
showed significant CAL gain after 1 year (3.0; 2.0/4.4 mm; p < .001) and 10 years
ZZMK (Carolinum), Johann Wolfgang Goethe- (3.0; 1.5/4.1 mm; p < .001) during which CAL remained stable ( 0.5; 1.0/1.0 mm;
Universität Frankfurt Theodor-Stern-Kai
7 (Haus 29), 60596 Frankfurt am Main, p = 1.000) after an average SPC of 9 years. Mixed-model regression analyses
Germany. revealed a positive association of CAL gain from 1 to 10 years with CAL 12 months
Email: petsos@med.uni-frankfurt.de
post operation (logistic: p = .01) as well as a higher probability for CAL loss with an
Funding information increasing vertical extent of a three-walled defect component (linear: p = .008). Cox
Moessner Stiftung (Frankfurt am Main,
Germany)
proportional hazard analysis showed a positive association between PlI after
12 months and tooth loss (p = .046).
Conclusion: Regenerative therapy of IBDs showed stable results over 9 years. CAL
gain is associated with CAL after 12 months and decreasing initial defect depth in a
three-walled defect morphology. Tooth loss is associated with PlI 12 months post
operation.
Clinical trial number: DRKS00021148 (URL: https://drks.de).

KEYWORDS
enamel matrix derivates, guided tissue regeneration, longitudinal studies, periodontal, tooth loss

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© 2023 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.

996 wileyonlinelibrary.com/journal/jcpe J Clin Periodontol. 2023;50:996–1009.

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KORONNA ET AL. 997

Clinical relevance
Scientific rationale for study: To evaluate clinically the long-term stability of regenerative therapy
of infrabony defects.
Principal findings: Although there was a significant gain in the mean clinical attachment level
(CAL) and reduction in periodontal probing depths 1 and 10 years after regenerative treatment
compared to baseline, both parameters could be kept stable during the observation period. Nev-
ertheless, nine teeth were lost between 1 and 10 years. CAL values 1 year after regenerative
therapy and a decreasing vertical extent of three-walled defect component were significantly
associated with CAL gain from 1 to 10 years. Tooth loss was associated with the plaque index
12 months after surgery.
Practical implications: It seems important to critically survey the CAL and plaque index
12 months after regenerative therapy in order to assess the long-term stability of periodontal
attachment. However, after 12 months, initially deeper three-walled defect components are
likely to lose some of their gained attachment in the long run.

1 | I N T RO DU CT I O N However, because of the technical sensitivity of membranes and

Long-term tooth retention in the presence of deep infra-alveolar bony
defects (IBDs) and increased periodontal probing depths (PPDs) is a
clinical challenge in everyday practice. Therefore, different therapeu-
tic approaches have been proposed to deal with these defects
(e.g., guided tissue regeneration [GTR] and enamel matrix derivative
[EMD]) (Cortellini & Tonetti, 2015; Pagliaro et al., 2008). The clinical
practice guidelines of the European Federation of Periodontology rec-
ommend regenerative therapy for residual pockets after active peri-
odontal therapy (APT) with infra-alveolar defects ≥3 mm (Sanz
et al., 2020).
It has been shown that, up to 10 years post operation, periodon-
tal regeneration is beneficial in the treatment of one-, two- and three-
walled infra-alveolar defects or a combination thereof in terms of
changes in clinical attachment gain and radiological bone fill (Cortellini
et al., 2017; Cortellini & Tonetti, 2015; Nibali et al., 2020; Petsos
et al., 2019; Sculean et al., 2008; Stavropoulos et al., 2021). A predict-
able achievement of vertical clinical attachment level (CAL) gain and
PPD reduction is a key element for clinical decision making for regen-
erative therapy (Esposito et al., 2009; Murphy & Gunsolley, 2003;
Needleman et al., 2006). Numerous studies have indicated that the
results achieved with regenerative therapy can be maintained in the
long term, thus allowing successful treatment (Cieplik et al., 2020;
Cortellini et al., 2017; Dori et al., 2013; Nygaard-Ostby et al., 2010;
Petsos et al., 2019; Pretzl et al., 2009; Sculean et al., 2008). This is
confirmed by a recent systematic review based on 30 studies over a
medium- (3–5 years) to long-term (>5–20 years) follow-up period. A
mean PPD reduction of 0.60–2.37 mm, an average CAL gain of 1.26–
2.66 mm and a low tooth loss (TL) rate of 0.4% were observed
(Stavropoulos et al., 2021). Only 8 of these 30 studies covered a
follow-up period of 10 or more years (Cortellini et al., 2017; Dori
et al., 2013; Nickles et al., 2009; Nygaard-Ostby et al., 2010;
Petsos et al., 2019; Pretzl et al., 2009; Pretzl, Kim, et al., 2008;
Sculean et al., 2008), one of which considered the use of EMD alone
(Sculean et al., 2008).
the associated high demands on surgical skills, they are increasingly
being replaced by EMD in everyday clinical practice. From a clinical
point of view, additional long-term evidence on clinical outcomes and
TL data after treatment of IBDs with EMD alone is needed. From the
patient's point of view, regenerative treatment of IBDs is an increas-
ingly minimally invasive, complex and cost-intensive procedure to
retain teeth. The average cost of such regenerative procedures is
lower compared to that of fixed replacement of the affected teeth
(Cortellini et al., 2017, 2020) but still high for patients to expect long-
term success. Not least for these reasons, it is important to generate
additional long-term data to identify the risk factors that help to real-
istically inform affected patients in advance about the expectations
and prognoses.
This two-centre, retrospective cohort study was initiated to ana-
lyse the long-term CAL stability of IBDs treated regeneratively with
EMD alone, and thus to contribute to existing long-term data.
2 | M A T E R I A L S A N D M ET H O D S
This analysis is part of an ongoing follow-up of regeneratively treated
IBDs. Five-year results have been reported earlier (Nickles
et al., 2017). The Frankfurt Department of Periodontology and the
Heidelberg Section of Periodontology have collaborated on regenera-
tive treatment previously (Eickholz et al., 2014). Thus, to collect data
of a larger number of patients, those from Frankfurt and Heidelberg
Universities were analysed.
2.1 | Patients
All patients who received regenerative therapy for IBDs with EMD
alone between May 2005 and May 2009 at the Department of Peri-
odontology of the Johann Wolfgang Goethe-University Frankfurt/
Main (F) or the Section of Periodontology of the Department of

998
Conservative Dentistry of the University Hospital Heidelberg
(HD) were consecutively screened and invited for study participation
between May 2015 and November 2019. Patients had to fulfil the fol-
lowing inclusion criteria:
1. Age ≥18 years at baseline;
2. Initial diagnosis of moderate or severe periodontitis (Armitage, 1999);
3. Panoramic radiograph or complete set of periapical radiographs
from baseline;
4. Completion of initial APT (modified full-mouth disinfection;
Eickholz et al., 2013 [steps I and II] and re-evaluation of non-surgi-
cal therapy 3 months later [baseline] Sanz et al., 2020);
5. Full-mouth plaque score ≤30% (O'Leary et al., 1972) at baseline;
6. Regenerative therapy to re-examination: 120 ± 12 months;
7. Regenerative treatment of one IBD (interproximal angular defect,
radiographic infrabony component (INFRA) ≥ 3 mm (Sanz et al.,
2020), CAL > 6 mm and PPD ≥ 6 mm before regenerative treat-
ment) solely with EMD;
8. Presence of comprehensive baseline and 12-month data (PPD,
CAL, plaque index [PlI] and gingival index [GI]) (Loe, 1967) at six
sites/tooth.
The following were the exclusion criteria:
1. Systemic disease or condition (e.g., heart valve replacement)
requiring antibiotic prophylaxis for clinical measurements that trig-
ger transitory bacteraemia (e.g., PPD and CAL);
2. Intake of cyclosporin;
3. Report of chronic alcohol abuse.
All eligible study participants were contacted consecutively and, if
possible, recruited. The study was approved by the Institutional
Review Boards for Human Studies of both centres (F: approval num-
ber 251/10 incl. amendment of April 14, 2020; HD: approval number
S-332/2014) and registered with the German Clinical Trials Register
(ID: DRKS00021148; URL: https://drks.de). All participants were
informed of the risks, benefits and procedures of the study and pro-
vided written informed consent.
2.2 | Clinical measurements
The clinical parameters, namely PPD, CAL, modified PlI and GI, were
recorded at six sites per tooth (mesio-buccal, mid-buccal, disto-buccal,
disto-lingual, mid-lingual, mesio-lingual) at baseline and after 12 and
120 ± 12 months. For some patients, data from a 5-year evaluation
were available (Nickles et al., 2017), which were taken into account in
the present study. PPD was measured from the gingival margin to the
base of the pocket. Pocket closure was defined as PPD ≤ 4 mm. CAL
was assessed as the distance from the cemento-enamel junction (CEJ)
to the base of the pocket. If the CEJ had been replaced by a restora-
tion, the restoration margin (RM) served as reference. All measure-
ments were made to the nearest 0.5 mm using a rigid, millimetre-
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KORONNA ET AL.
scaled manual periodontal probe (PCPUNC 15; Hu Friedy, IL, USA). All
clinical measurements were performed by five trained and experi-
enced periodontists (Ti-Sun Kim, Beate Schacher, Sarah
K. Sonnenschein, Peter Eickholz, Hari Petsos). All participating exam-
iners from F had been calibrated for PPD and CAL in earlier studies
through repeated measurements within one quadrant of patients to
ensure a deviation of <1 mm (Harks et al., 2015; Petsos et al., 2020;
Rollke et al., 2012). Examiners from HD were calibrated through mea-
surements against a reference model; the relative agreement (mea-
surement accuracy within ±1.0 mm) was >90% for PPD and CAL. No
cross-centre calibration was performed.
2.3 | Periodontal surgery
Surgical procedures have been described in detail previously (Nickles
et al., 2017; Rollke et al., 2012). All defects were treated solely with
EMD (Emdogain, Institut Straumann, Basel, Switzerland) (Figure 1a,b).
For illustration, the clinical documentation of a treated patient (ID #02,
tooth 13) at baseline and at 12 and 120 months is shown in Figure 1.
Flap preparation followed the modified or simplified papilla pres-
ervation flap until 5 mm of the bony margin was exposed, allowing a
complete visualization of the IBD (Cortellini et al., 1999; Cortellini,
Prato, & Tonetti, 1995; Figure 1c). Afterwards, the inflammatory gran-
ulation tissue was completely removed, root surfaces were scaled and
the root was planned. Before the application of EMD, the following
intra-surgical parameters were documented to the nearest 0.5 mm
using the above-mentioned probe: (i) distance from the CEJ/RM to
the most coronal point of the alveolar crest; (ii) distance from the
CEJ/RM to the most apical extension of the bony defect at six sites
per tooth; and (iii) INFRA as well as the three-, two- and one-walled
components of the defect (Cortellini et al., 1993; Cortellini, Pini
Prato, & Tonetti, 1995; Nickles et al., 2017).
Then, EMD was applied according to the manufacturer's instruc-
tions (Nickles et al., 2017). Wounds were closed primarily and
tension-free using synthetic, non-resorbable sutures (Figure 1d). Sur-
gery as well as baseline and 12-month assessments (Figure 1e) of clin-
ical data were performed by 10 periodontal specialists or
postgraduate periodontics students in their final year (Susanne Scharf,
Lasse Röllke, Rita Arndt†, Martin Wohlfeil, Jens Kaltschmitt, Diana
Kriegar, Ti-Sun Kim, Beate Schacher, Katrin Nickles, Peter Eickholz).
As some patients were participants in a placebo-controlled random-
ized clinical trial (RCT), 20 of them received 200 mg of doxycycline once
daily for 7 days (Eickholz et al., 2014; Rollke et al., 2012). Eighteen other
participants also took part in the RCT but were assigned to the placebo
group. Post-operatively, all participants were advised to rinse with
0.12% chlorhexidine digluconate solution (ParoEx, Sunstar, Etoy,
Switzerland) twice daily for 2 min for 5–7 weeks and to refrain from
individual mechanical plaque control. Thus, during this period, patients
were seen every week for control and gentle cleaning of teeth. If neces-
sary, 400 mg of ibuprofen to be taken daily was prescribed for the
†
Dr. Rita Arndt has passed away.
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KORONNA ET AL. 999

F I G U R E 1 Exemple of a regeneratively treated (enamel matrix derivate) tooth 13 (tooth 15 has been removed): (a) clinical view at baseline,
(b) baseline non-standardized radiograph showing an infrabony defect mesio-lateral to tooth 13 in the coronal third of the root, (c) intra-surgical
defect morphology (buccal view: infrabony circumferential vertical bone defect component), (d) post-surgical wound closure, (e) clinical view after
12 months, (f) clinical view after 120 months, (g) non-standardized radiograph after 120 months showing that a small component remains from
the original infrabony defect. Nickles, K., Eickholz, P.: Langzeitergebnisse regenerativer Therapieverfahren. Parodontologie 2013; 24 (4): 441-452.

patient's comfort. Sutures were removed after 1–2 weeks (Nickles
et al., 2017; Rollke et al., 2012). In the first post-operative year, a quar-
terly supportive periodontal care (SPC) interval was agreed upon with
the patients. From the second year onwards, the patient-specific risk
of disease progression was determined using the periodontal risk
assessment (PRA) (Lang & Tonetti, 2003) and allocated to the SPC
interval as follows: low risk, one SPC/year; moderate risk, two
SPCs/year; and high risk, three SPCs/year (Eickholz et al., 2008;
Ramseier & Lang, 1999). To assign compliance, SPC interval recom-
mendations were compared with the intervals actually documented
in the patient file. Once a patient exceeded the interval determined
during SPC by more than 100%, she/he was considered to be non-
compliant (Eickholz et al., 2008). In case of continuation of the SPC
with the referrer, these patients were considered non-compliant,
as the perception of appointments and content of the SPC were
beyond our knowledge.
2.4 | 10-year re-examination
In addition to the clinical measurements, the following parameters
were recorded or checked by patients' charts after 10 years
(Figure 1f,g):
1. Gingival bleeding index (Ainamo & Bay, 1975) and plaque control
record (O'Leary et al., 1972);
2. Self-reported smoking status (non-smokers [never smoked], former
smokers [stopped smoking ≥5 years ago], active smokers [stopped
smoking <5 years ago or currently smoking]) (Lang & Tonetti, 2003);
3. If patients lost a tooth outside the respective centre, she/he was
asked for the reason; otherwise, the reason was obtained from the
patients' file (periodontal diseases [combination of progressive
CAL loss, furcation involvement II/III; Hamp et al., 1975 and/or
tooth mobility II/III; Nyman et al., 1975]), caries (carious lesions

1000
that could not be restored), endodontic complications that could
not be managed by a revision, orthodontics (lack of space, balan-
cing extractions), prosthetic considerations (unusable as abutment
tooth) or trauma (untreatable fractures) (Petsos et al., 2020);
4. Original baseline diagnoses (Armitage, 1999) were reclassified into
stages using baseline periodontal charts based on interproximal
CAL and missing teeth as well as complexity and into grades
according to the bone loss age index as well as smoking and diabe-
tes status (Tonetti et al., 2018).
2.5 | Statistical analysis
The patient was considered the statistical unit. Changes in CAL and
PPD between 12 and 120 ± 12 months were defined as the primary
and secondary target variables. All other parameters were considered
control variables. Since data for CAL and PPD changes were not nor-
mally distributed (Kolmogorov–Smirnov test; PPD: p = 0.022, CAL:
p = 0.025), patient characteristics were calculated as medians (lower
[Q1]/upper [Q3] quartile) and/or frequencies, while clinical parame-
ters were described as medians (Q1/Q3). Existing 5-year data were
analysed descriptively since they were available only for the Frankfurt
cohort.
Intra-group comparisons (baseline/12/60/120 ± 12 months) for
CAL gain and PPD reduction were made using the Friedman test.
Mixed-model linear and logistic regression analyses were performed
for the dependent variable (CAL change) from 12 to 120 months
(linear/dichotomous), and Cox proportional hazard regression analysis
was performed for TL between surgery and 120 months. The centre
(F, HD) was used as a random factor and the respective stratifying
variable. Independent variables for multivariate regression analyses
were determined on the basis of significance in the univariate regres-
sions relating the dependent variables with gender, age, smoking, dia-
betes, surgeon, examiner, post-operative antibiotic intake, GI, PlI,
PPD, CAL, bleeding on probing (BOP), tooth type, jaw, staging, grad-
ing, number of SPCs, compliance, INFRA, number of defect walls and
root canal treatment to avoid confounding and reduce bias (Table S1).
The teeth extracted for periodontal reasons were considered in the
analyses up to the 10-year re-examination via the last observation
carried forward method.
A significance level of 0.05 was chosen. Data were processed
using the IBM SPSS Statistics 28 software package (SPSS, Chicago,
IL, USA).
3 | RESULTS
3.1 | Patients
Of the 73 records originally identified, those of 66 patients were re-
examined 120 ± 12 months post operation (F: 54, HD: 12), 26 of
whom (F: 26, HD: 0) were already part of a 5-year evaluation (Nickles
et al., 2017). Fourteen patients had to be excluded (missing data:
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KORONNA ET AL.
intrasurgical parameters [5x]; 12-month data [2x]; baseline radio-
graphs [1x]; additional application of membrane or filler [5x]; bias
reduction since the examiner performed fewer than four follow-up
examinations [1x]). Therefore, 52 patients (F: 43, HD: 9), each contrib-
uting one IBD, were considered for data analysis. The follow-up
period was 9.0 years, over which a median of 19.0 SPC appointments
per patient took place. Overall, half of all patients were compliant with
their SPC. In F 48.8% (n = 21) and in HD 55.6% (n = 5) of the patients
were compliant (p = .714). Patients who were compliant attended, on
average, 12 more SPCs (n = 26.2) than those who were not compliant
(n = 14.5; p = .092). The overall distribution of actually perceived
SPCs/year was <1 in 36.5%, 1 in 38.5%, 2 in 13.5% and 3 in 11.5% of
patient cases. The distribution by centre was as follows: F: <1
SPC/year: 34.9%, 1 SPC/year: 34.9%, 2 SPCs/year: 16.3%, 3 SPCs/
year: 14.0%; HD: <1 SPC/year: 44.4%, 1 SPC/year: 55.6%, 2 SPCs/
year: 0%, 3 SPCs/year: 0% ( p = .292). One patient had diabetes (base-
line HbA1c: 6.8%). Table 1 provides further patient characteristics. A
total of nine teeth (five multi-rooted and four single-rooted) were lost
in F (seven for periodontal reasons, one due to non-restorable caries,
one due to endodontic complications). Five of the seven teeth lost
for periodontal reasons were extracted from non-compliant patients.
One of the nine teeth was lost after 2 years, two were lost between
3 and 5 years and six between 6 and 9 years post operation. Twice
as many teeth were lost in non-compliant patients (66.7%, n = 6)
compared to patients who regularly participated in SPC (33.3%,
n = 3). However, this observation was not significant ( p = .271).
Three teeth (5.8%) were surgically re-treated during the follow-up,
and in two cases the tooth was later lost for periodontal reasons.
Four teeth (7.7%) had already received root canal treatment before
surgey, and a further seven (13.5%) received root canal treatment
within the follow-up. In total, five of the nine extracted teeth had a
root canal treatment. Table 2 shows the distribution of IBDs in the
different teeth. Table 3 provides data on intra-surgical defect char-
acteristics, reporting a median baseline infrabony component
of 5.0 mm.
3.2 | Clinical parameters
While PlI did not show significant changes across all follow-up times,
after 12 and 120 months GI decreased significantly compared to
baseline (p < .001) but remained stable ( p = .370) between 12 and
120 months (Table 4).
Regenerative therapy revealed a significant CAL gain and PPD
reduction after 12 (CAL: 3.0; 2.0/4.4 mm; p < .001; PPD: 4.0; 4.4/
2.5 mm; p < .001), 60 (CAL: 3.5; 2.0/4.8 mm; p < .001; PPD: 3.5;
5.0/ 2.3 mm; p < .001) and 120 months (CAL: 3.0; 1.5/4.1 mm;
p < .001; PPD: 3.8; 5.0/ 2.4 mm; p < .001). The analysis failed to
detect any significant changes for both parameters between 12 and
120 months (CAL: 0.5; 1.0/1.0 mm; p = 1.000; PPD: 0.0;
1.0/1.0 mm; p = 1.000). The change in the number of residual PPD
4–5 mm and ≥6 mm over the follow-up period was similar to the
mean PPD change (Table 4). Between 12 and 120 months, a total of
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KORONNA ET AL. 1001

TABLE 1 Patient characteristics.

Baseline 12 months 60 months 120 months

a
Total number, n (%) 52 (100) 52 (100) 29 52 (100)
Frankfurt 43 (82.7) 43 (82.7) 29 (100)a 43 (82.7)
a
Heidelberg 9 (17.3) 9 (17.3) 0 (0) 9 (17.3)
Female, n (%) 29 (55.8) 29 (55.8) 13 (44.8)a 29 (55.8)
a
Age (years), median, lower/upper quartile 52.0; 45.0/58.8 53.0; 46.0/59.0 62.0; 48.5/67.0 62.5; 55.0/68.8
Initial diagnosis, n (%)
Stage III/Stage IV 46 (88.5)/6 (11.5) — — —
Grade A/B/C 1 (1.9)/19 (36.5)/32 (61.5) — — —
Smoking status/characteristics at baseline, n (%)
Non-smokers 22 (42.3) 22 (42.3) 6 (20.7)a 21 (40.4)
a
Former smokers 22 (42.3) 22 (42.3) 19 (65.5) 26 (50.0)
a
Active smokers 8 (15.4) 8 (15.4) 4 (13.8) 5 (9.6)
GBI (%), median, lower/upper quartile 4.0; 2.0/8.0a 4.0; 2.0/8.0a 3.0; 2.0/8.0a 2.0; 1.0/4.0
a a
PCR (%), median, lower/upper quartile 20.5; 13.3/29.0 23.0; 15.0/39.0 17.0; 13.0/30.0 24.0; 15.0/41.5
BOP (%), median, lower/upper quartile 15.0; 11.0/22.0a 13.0; 8.0/17.0a 11.0; 7.0/16.0a 10.5; 5.5/15.7
Root canal treatment 4 4 9 11
Periods, (years), median, lower/upper quartile
Baseline—12/60/120 months — 1.4; 1.2/1.6 5.1; 5.0/5.5a 10.1; 9.9/10.4
12–60/120 months — — 4.0; 3.9/4.4a 9.0; 8.9/9.4
Number of teeth, median, lower/upper quartile 25.0; 23.0/28.0 25.0; 22.3/28.0 25.0; 22.5/28.0a 24.0; 21.0/27.0
Pocket closure (PPD ≤ 4 mm), n (%) — 31 (59.6) 17 (32.7) a
28 (53.8)
Residual PPD, n (%)
4–5 mm — 23 (44.2) 19 (36.5) 15 (28.8)
≥6 mm 9 (17.3) 3 (5.8) 11 (21.2)
Number of SPC visits, median, lower/upper quartile — 3.0; 3.0/4.0 12.0; 10.5/15.5 a
19.0; 14.0/24.0
Number of compliant patients, n (%) — — — 26 (50.0)
SPC(s) per year, n (%)
<1 SPC — 2 (3.8) 6 (20.7)a 19 (36.5)
At least 1 SPC — 1 (1.9) 4 (13.8) a
20 (38.5)
At least 2 SPCs — 7 (13.5) 12 (41.4) a
7 (13.5)
At least 3 SPCs — 42 (80.8) 7 (24.1)a 6 (11.5)
Periodontal risk assessment, n (%)
Low risk — 0 (0.0)a 3 (10.4)a 6 (11.5)
Moderate risk — 30 (69.8) a
17 (58.6) a
35 (67.3)
High risk — 13 (30.2)a 9 (31.0)a 11 (21.2)

Abbreviations: BOP, bleeding on probing; GBI, gingival bleeding index; PCR, plaque control record; PPD, periodontal probing depth; SPC, supportive
periodontal care.
a
Missing information for Heidelberg cohort.

18 IBDs (36.0%) showed a CAL gain, with 8 (16.0%) of them showing
a CAL gain of ≥2 mm. In 26 IBDs (52.0%), a CAL loss (12 to
120 months) was observed, with 7 (14.0%) of those IBDs showing
a CAL loss ≥2 mm. When comparing the group with long-term
(12–120 months) stable CAL or CAL gain (≥0 mm) to that with CAL
loss (<0 mm), CAL at 12 months after surgery was significantly
higher in the group with stable CAL ( p = .001; CAL loss: 4.5;
3.5/6.3 mm; stable CAL: 7.5; 6.1/9.0 mm).
Regarding differences between CAL stability/gain (≥0 mm) and
CAL loss (<0 mm) for individual factors, significantly more teeth in the
CAL stable/gain group underwent root canal treatment between the
regenerative approach and the 10-year follow-up than in the CAL loss
group (CAL stable/gain: n = 6, CAL loss: n = 0; p = .007). Further-
more, CAL at 12 months ( p < .001) and the associated change in CAL
between baseline and 12 months ( p = .001) were significantly lower
in the CAL loss group than in the CAL stable/gain group. Looking at
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1002 KORONNA ET AL.

TABLE 2 Distribution of defects according to tooth type and jaw. and CAL gain were observed 12 months after surgery and remained

Tooth type Maxilla Mandible Total stable for 9.0 years. Present data revealed a median CAL gain of
3.0 mm after 12 months, with an initial INFRA of 5.0 mm, which was
Anterior 8 (1) 9 (0) 17 (1)
stable after 120 months (mean PPD: 0.15 mm; p = 1.000; CAL:
Premolar 8 (2) 7 (2) 15 (4)
0.06 mm; p = 1.000). These findings confirm those of previous stud-
Molar 6 (0) 14 (4) 20 (4)
ies, which considered at least the same follow-up period and failed to
Total 22 (3) 30 (6) 52 (9)
show significant CAL changes between short- and long-term results
Note: In parentheses: number of extracted teeth after 120 months. (Cortellini et al., 2017; Dori et al., 2013; Nygaard-Ostby et al., 2010;
Petsos et al., 2019; Pretzl et al., 2009; Pretzl, Kim, et al., 2008; Sculean

T A B L E 3 Intrasurgical characteristics of infrabony defects
(median; lower/upper quartile).
Total number 52
CEJ to bottom of defect (mm) 10.0; 9.0/11.9
Alveolar crest to bottom of defect (mm) 5.5; 4.0/8.0
INFRA (mm) 5.0; 4.0/7.0
Three-wall component (mm) 3.0; 1.6/4.0
Two-wall component (mm) 1.5; 0.5/2.5
One-wall component (mm) 0.0; 0.0/1.0
Abbreviations: CEJ, cemento-enamel junction; INFRA, infrabony defect
component.
the groups with and without TL, after 12 months both PCR ( p = .001)
and CAL ( p = .046) were significantly higher in the group with TL than
in the group without TL.
Looking at the number of closed pockets over time, there was a
20% increase in the group with stable/increasing CAL over the first
4 years, which could be kept stable for another 5 years (12 months:
54.2%, 60 months: 73.3%, 120 months: 66.7%), whereas there was
15% initial decrease in the number of closed PPDs in the group with
CAL loss, which also remained stable afterwards (12 months: 65.4%,
60 months: 50.0%, 120 months: 53.8%). Descriptive data on all
groups are presented in Table 5.
The independent variables for the mixed models were selected
according to significance based on univariate regressions (Table S1).
Mixed-model linear regression analyses (Table 6) revealed a signifi-
cantly negative association of an increasing defect depth of three-
walled IBDs and CAL gain between 12 and 120 months ( p = .008;
Table 6). A 1-mm increase in CAL 12 months after surgery increased
the likelihood of CAL gain by a factor of 2.0 (Table 7). Cox propor-
tional hazard regression analysis revealed a significant association
between TL and PlI 12 months after surgery with a five-fold increase
in risk (hazard ratio [HR] = 4.965) of TL if PlI increased at 12 months
(Table 8).
4 | DISCUSSION
A recently published systematic review concluded that regenerative
therapy of IBDs results in shallower residual PPDs and a larger CAL
gain in the long term (Stavropoulos et al., 2021). The results of the
present study confirm this conclusion. A significant PPD reduction
et al., 2008). The reported CAL stability varied between 1.62 mm
CAL loss and 1.2 mm CAL gain. In detail, the reported CAL gains were
0.2 mm (resorbable polyglactin barriers; Pretzl, Kim, et al., 2008),
0.4 mm (bioabsorbable poly-D,L-lactid-co-glycolid barriers; Sculean
et al., 2008, bioabsorbable poly-D,L-lactid-co-glycolid barriers + EMD;
Sculean et al., 2008 and autogenous bone graft; Nygaard-Ostby
et al., 2010), 0.5 mm (EMD; Sculean et al., 2008 and EMD + natural
bone mineral; Dori et al., 2013), 0.7 mm (EMD + β-tricalcium phos-
phate; Dori et al., 2013) and 1.2 mm (autogenous bone graft + biore-
sorbable polylactic acid barriers; Nygaard-Ostby et al., 2010). The
corresponding CAL losses were 0.1 mm (non-resorbable titanium-
reinforced expanded polytetrafluoroethylene barriers; Cortellini
et al., 2017), 0.9 mm (bioabsorbable polylactide acetyl tributyl citrate
barriers; Petsos et al., 2019) and 1.6 mm (bioabsorbable polylactide
acetyl tributyl citrate barriers; Pretzl et al., 2009). However, two of
the studies mentioned (Cortellini et al., 2017; Petsos et al., 2019) re-
examined a 20-year follow-up, a period that was twice as long as in
the present study. In addition, baseline defect-associated characteris-
tics such as INFRA (between 3.9 mm; Sculean et al., 2008 and
5.8 mm; Cortellini et al., 2017), PPD (between 7.3 mm; Nygaard-
Ostby et al., 2010 and 8.7 mm; Petsos et al., 2019) and CAL (between
7.9 mm; Pretzl, Kim, et al., 2008 and 10.3 mm; Cortellini et al., 2017)
differ and may have influenced the results significantly (Cortellini &
Tonetti, 2015).
Patient compliance is an important factor regarding the long-term
stability of regenerated IBDs (Dori et al., 2013; Nygaard-Ostby
et al., 2010; Pretzl, Kim, et al., 2008; Sculean et al., 2008). The present
study failed to show any association in this matter, but there was a
redistribution in the frequency of the actually perceived SPCs per year
12, 60 and 120 months post operation. Although 81% of the patients
came at least three times a year in the first year, the proportion
reduced to only 24% after 60 months and only 12% after 120 months.
The patients participated on average in 20.4 SPCs over 9 years of
follow-up (2.2 SPCs/patient/year), which may be a reason for the sta-
bility achieved. However, the number of SPCs was not associated
with long-term CAL gain in the present study, which may be due to an
average of about two SPCs/patient/year. The actual distribution of
SPCs turned out to be significantly more inhomogeneous over the
follow-up period. The assignment of SPC frequency using PRA results
in different intervals. However, information from the study by Matu-
liene et al. (2010) seems to demonstrate the current inability to effec-
tively match the secondary preventive protocol with the individual
risk level calculated according to PRA (Matuliene et al., 2010). Five of
the 9 patients who lost teeth and 6 of 26 the patients who showed
 KORONNA ET AL.

TABLE 4 Clinical parameters of treated teeth.

Residual Residual
PPD (mm) CAL (mm)
PlI GI PPD 4–5 mm PPD ≥6 mm
Median; lower/upper Median; lower/ Median; lower/ Median; lower/upper
n quartile upper quartile upper quartile Mean ± SD n (%) n (%) quartile Mean ± SD
Baseline 52 0.0; (0.0/1.0) 2.0; (0.0/2.0) 7.8; (7.0/8.9) 7.88 ± 1.44 0 (0) 52 (100) 9.3; (8.0/10.9) 9.15 ± 1.88
1 year after therapy 52 0.5; (0.0/1.0) 0.0; (0.0/2.0) 4.0; (3.0/5.0) 4.35 ± 1.70 23 (44.2) 9 (17.3) 6.0; (4.0/8.0) 6.16 ± 2.31
Change 1 year after therapy 52 0.0; (0.0/0.0) 0.0; ( 1.8/0.0) 4.0; ( 4.4/ 2.5) 3.61 ± 1.49 23 (44.2) 43 (82.7) 3.0; ( 4.4/ 2.0) 3.18 ± 1.59
p-Value .604 <.001 <.001 .002 <.001 <.001
5 years after therapy a 26 0.0; ( 1.0/0.5) 0.0; (0.0/1.5) 4.0; (3.8/5.0) 4.33 ± 1.08 19 (73.0) 3 (5.8) 6.0; (4.8/7.8) 6.12 ± 1.99
Change 5 years after therapya 26 0.0; ( 1.0/0.5) 1.0; ( 2.0/0.0) 3.5; ( 5.0/ 2.3) 3.55 ± 1.65 19 (73.0) 23 (88.4) 3.5; ( 4.8/ 2.0) 3.52 ± 1.90
p-Value .430 .001 <.001 <.001 <.001 <.001
Change from 1 to 5 years after therapya 26 0.0; 1.0/1.0 0.0; 0.0/0.0 0.0; ( 1.0/1.0) 0.14 ± 1.21 4 (15.4) 6 (23.1) 0.5; ( 1.0/1.3) 0.31 ± 2.07
p-Value .544 .625 1.000 1.000 1.000 1.000
10 years after therapy 50 0.0; (0.0/1.0) 0.0; (0.0/0.0) 4.0; (3.0/6.0) 4.51 ± 2.15 17 (32.7) 14 (28.0) 6.0; (5.0/8.0) 6.39 ± 1.99
Change 10 years after therapy 50 0.0; (0.0/0.0) 1.0; ( 2.0/0.0) 3.8; ( 5.0/ 2.4) 3.50 ± 1.91 17 (34.0) 38 (76.0) 3.0; ( 4.1/ 1.5) 2.79 ± 2.01
p-Value .197 <.001 <.001 .031 <.001 <.001
Change from 1 to 10 years after therapy 50 0.0; (0.0/1.0) 0.0; ( 1.0/0.0) 0.0; ( 1.0/1.0) 0.15 ± 1.77 6 (12.0) 5 (10.0) 0.5; ( 1.0/1.0) 0.06 ± 1.98
p-Value .515 .370 1.000 1.000 1.000 1.000
Change from 5 to 10 years after therapya 26 0.0; (0.0/1.0) 0.0; (0.0/0.0) 0.3; ( 1.0/1.0) 0.06 ± 1.77 2 (7.7) 11 (42.3) 0.5; ( 1.0/1.5) 0.54 ± 2.26
p-Value .072 .708 1.000 .564 1.000 1.000

Abbreviations: CAL, vertical clinical attachment level; GI, gingival index; n, number of treated teeth; PlI, plaque index; PPD, periodontal probing depth; SD, standard deviation.
a
Missing information for Heidelberg cohort.
1003

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1004 KORONNA ET AL.

T A B L E 5 Patient- and defect-specific characteristics according to tooth loss (TL) and clinical attachment level (CAL) change between 12 and
120 months.

CAL change between 12 and 120 months

Without TL With TL <0 mm (loss) ≥0 mm (stable/gain)

Total number 43 9 26 24
Females, n (%) 23 (53.5) 6 (66.7) 16 (61.5) 12 (50.0)
Age (years), median, lower/upper 51.0; 44.0/58.0 58.0; 46.0/65.5 52.5; 46.8/59.0 57.0; 45.8/64.8
quartile
Initial diagnosis, n (%)
Stage III/Stage IV 37 (86.0)/6 (14.0) 9 (100)/0 (0) 22 (84.6)/4 (15.4) 22 (91.7)/2 (8.3)
Grade A/B/C 0 (0)/17 (39.5)/26 (60.5) 1 (11.1)/2 (22.2), 6 (66.7) 0 (0)/13 (50.0)/13 (50.0) 0 (0)/6 (25.0)/18 (75.0)
Smoking status/characteristics after 12 months, n (%)
Non-smokers 17 (39.5) 5 (55.6) 12 (46.82) 8 (33.3)
Former smokers 21 (48.8) 1 (11.1) 8 (30.8) 14 (58.3)
Active smokers 5 (11.6) 3 (33.3) 6 (23.1) 2 (8.3)
GBI (%), median, lower/upper quartile 3.0; 2.0/8.0 7.0; 0.5/10.5 4.0; 2.0/7.8 3.0; 1.0/10.0
after 12 monthsa
PCR (%), median, lower/upper quartile 20.0; 12.8/28.5 43.0; 28.5/51.0 19.0; 12.3/35.8 27.0; 19.5/37.5
after 12 monthsa
BOP (%), median, lower/upper 13.0; 7.8/15.5 17.0; 9.0/20.5 13.5; 9.0/18.8 13.0; 6.5/16.0
quartile after 12 monthsa
Root canal treatment
Baseline 2 (4.7) 2 (22.2) 2 (7.7) 2 (8.3)
Post-operative 4 (9.3) 3 (33.3) 0 (0.0) 6 (25.0)
Number of teeth, (n) median, lower/ 25.0; 22.0/28.0 25.0; 23.5/26.0 25.5; 22.0/28.0 23.5; 22.3/26.0
upper quartile after 12 months
Number of SPC visits, (n) median, 19.0; 14.0/24.0 19.0; 11.5/30.0 19.0; 12.8/24.3 19.5; 14.5/24.8
lower/upper quartile
Number of compliant patients, n (%) 23 (53.5) 3 (33.3) 12 (46.2) 13 (54.2)
Pocket closure, n (%)
12 months 27 (62.8) 4 (44.4) 17 (65.4) 13 (54.2)
60 monthsa 15 (60.0) 2 (50.0) 6 (50.0) 11 (73.3)
Residual PPD 4–5 mm, n (%)
12 months 20 (46.5) 3 (33.3) 11 (42.3) 11 (45.8)
a
60 months 16 (64.0) 3 (75.0) 10 (83.3) 8 (53.3)
Residual PPD ≥ 6 mm, n (%)
12 months 6 (14.0) 3 (33.3) 3 (11.5) 6 (25.0)
a
60 months 2 (8.0) 1 (25.0) 1 (8.3) 1 (6.7)
PPD (mm), median, lower/upper quartile
Baseline 7.0; 7.0/8.5 8.0; 7.0/9.5 8.0; 6.9/8.5 7.3; 7.0/9.0
12 months 4.0; 3.0/5.0 5.0; 3.0/6.5 4.0; 3.0/5.0 4.0; 3.1/5.8
a
60 months 4.0; 3.3/5.0 4.3; 4.0/6.4 4.3; 4.0/5.0 4.0; 3.0/5.0
Change from baseline to 12 months 4.0; 4.5/ 2.5 4.0; 4.3/ 2.5 4.0; 4.6/ 3.4 3.0; 4.0/ 2.1
CAL (mm), median, lower/upper quartile
Baseline 9.0; 7.5/10.5 9.5; 8.0/11.5 8.3; 7.0/10.5 9.5; 8.0/11.0
12 months 6.0; 4.0/7.5 8.0; 5.5/9.0 4.5; 3.5/6.3 7.5; 6.1/9.0
a
60 months 6.0; 4.8/7.3 7.5; 4.1/9.4 5.0; 5.0/6.4 6.5; 3.5/8.0
Change from baseline to 12 months 3.0; 4.0/ 2.0 4.0; 4.8/ 2.3 3.5; 5.0/ 3.0 2.0; 4.0/ 1.1
INFRA (mm), median, lower/upper 5.0; 4.0/7.0 5.5; 4.8/6.8 5.3; 4.0/7.1 5.0; 4.0/6.8
quartile
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KORONNA ET AL. 1005

TABLE 5 (Continued)

CAL change between 12 and 120 months

Without TL With TL <0 mm (loss) ≥0 mm (stable/gain)

a
PRA after 12 months, n (%)
Low risk 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Moderate risk 26 (76.5) 4 (44.4) 14 (70.0) 15 (71.4)
High risk 8 (23.5) 5 (55.6) 6 (30.3) 6 (28.6)

Abbreviations: BOP, bleeding on probing; GBI, gingival bleeding index; PCR, plaque control record; PPD, periodontal probing depth; PRA, periodontal risk
assessment; SPC, supportive periodontal care.
a
Missing information for Heidelberg cohort.

T A B L E 6 Mixed linear regression

95% CI for b
analysis: Attachment gain from 1 to b SE (b) p-Value
10 years after therapy. Lower Upper
Constant –2.780 1.388 5.577 0.016 .051
CAL after 1 year at test teeth 0.224 0.114 0.006 0.453 .056
Grade 0.810 0.508 0.213 1.833 .118
Three-wall component (vertical extent) 0.290 0.105 0.501 0.78 .008
Root canal treatment (baseline –120 months) 0.807 0.794 0.792 2.407 .315

Note: n = 50. For this analyses, the centre (F, HD) was chosen as the random factor.
Abbreviations: b, regression coefficient; CAL, vertical clinical attachment level; CI, confidence interval;
OR, odds ratio; SE, standard error.

T A B L E 7 Mixed logistic regression

95% CI for OR
analysis: Attachment gain/loss from 1 to b OR p-Value
10 years after therapy. Lower Upper
Constant 4.423 0.012 0.001 0.164 .01
CAL after 1 year at test teeth 0.703 2.019 1.347 3.027 .01

Note: n = 50. For this analyses, the centre (F, HD) was chosen as the random factor.
Abbreviations: b, regression coefficient; CAL, vertical clinical attachment level; CI, confidence interval;
OR, odds ratio; SE, standard error.

T A B L E 8 Cox proportional hazard

95% CI for HR
regression analysis: Tooth loss. b SE (b) Wald df HR p-Value
Lower Upper
Constant
PlI 1 year after therapy 1.602 0.805 3.967 1 4.965 1.026 24.026 .046

Note: n = 43.
Abbreviations: b, regression coefficient; CI, confidence interval; df, degree of freedom; HR, hazard ratio;
PlI, plaque index; SE, standard error.

CAL loss between 12 and 120 months were at high risk of PRA for
which the assigned SPC interval may not have adequately adapted.
This could be the reason why no association was found between
either the number of SPCs or the compliance based on the PRA and
the long-term CAL gain was found.
Furthermore, when combining patients/IBDs from different cen-
tres, a ‘centre effect’ may play an important role. However, this effect
is a variable influcenced by multiple factors, which is why mixed
models with centre stratification were chosen to account for the
effect. The centre effect sums up all geographically different prefer-
ences of patients (e.g., nutrition, socio-economic status) and surgeons
(e.g., experience), as well as surgical skills of the practitioners, which
are not controlled for (Cortellini & Tonetti, 2015). Thus, it is not
appropriate to interpret the centre effect exclusively as a result of dif-
ferent surgical skills. In the present cohort, it is noteworthy that all
teeth were lost in F. Baseline PPD (F: 7.5; 7.0/9.0 mm, 7.9 ± 1.5 mm;
HD: 8.0; 7.0/8.3 mm, 7.9 ± 1.3 mm), CAL (F: 9.5; 8.0/11.0 mm, 9.3
± 1.9 mm; HD: 8.0; 6.8/10.3 mm, 8.4 ± 2.0 mm) and INFRA (F: 5.5;

1006
4.0/7.0 mm, 5.7 ± 3.0 mm; HD: 5.0; 4.5/6.0 mm, 5.6 ± 1.9 mm) were
similar. In addition, in F an average of seven more SPCs per patient
were observed compared to HD. The decisive factor that differenti-
ates both centres from each other may be that more than twice as
many surgeons were involved in F (seven) than in HD (three). Further-
more, the more the number of patients included per centre, the more
likely that teeth will be lost. Frankfurt contributed 4 times more
patients (43) than HD (9) to this study.
The percentage of lost teeth found (17.3%) is above the range of
0% (Pretzl et al., 2009; Sculean et al., 2008) to 14.6% (Nickles
et al., 2009) reported for 10-year data and within the range of 4.9%
(Cortellini et al., 2017) to 47.1% (Cieplik et al., 2020) of existing
20-year data. This is probably due to the severity of baseline defect
characteristics, which were in the upper range for both CAL (9.3 mm;
8.0/10.9 mm, 9.15 ± 1.88 mm) and INFRA (5.0 mm; 4.0/7.0 mm,
5.68 ± 2.78 mm) compared with studies reporting long-term (10-year)
results (Dori et al., 2013; Nickles et al., 2009; Nygaard-Ostby
et al., 2010; Pretzl et al., 2009; Pretzl, Kim, et al., 2008; Sculean
et al., 2008). Moreover, half of the extracted teeth were molars, which
show less long-term stability anyway (Pretzl, Kaltschmitt, et al., 2008).
Mixed logistic regression analysis revealed a significant positive
association between CAL gain from 12 to 120 months and CAL after
12 months in the treated teeth. When comparing the subgroups of
the treated teeth that lost CAL and those that gained CAL between
12 and 120 months, on average, approximately 1.5 mm more CAL
was found in the group that gained attachment from baseline to
12 months compared to the group that lost attachment. At first
glance, this appears paradoxical. However, an IBD that gained consid-
erable attachment 12 months after treatment may have reached its
maximum regenerative capacity rapidly, whereas other defects heal
more slowly and may experience additional CAL gain later than
12 months after surgery. Whereas the latter may gain further, an IBD
that is ‘maximally’ regenerated may only lose. Interestingly, an
increase in the number of pocket closures within the first 60 months
was observed in the CAL stable/gain group, but the number
decreased in the CAL loss group. In both groups, the result achieved
after 60 months remained stable over 120 months. This is in contra-
diction with the conclusion of a recent systematic review, which
described a PPD ≤ 4 mm as a viable approach to regenerative therapy,
albeit only for short-term outcomes (Aimetti et al., 2021). In the long
term, the present results show that stable CAL tends to lead to pocket
closure, but this is not always the case, which in turn illustrates that
long-term stable results are influenced by multiple factors. The
repeatedly proven influence of the baseline PPD on the long-term sta-
bility of the CAL could not be confirmed in this study, even though
the initial PPD in the CAL stable group tended to be somewhat lower
than in the CAL loss group (Cortellini et al., 2017; Petsos et al., 2019).
In addition, linear regression analysis revealed a negative associa-
tion between the extent of a three-walled defect component and CAL
gain between 12 and 120 months. This in no way means that deeper
defects cannot regenerate with long-term stability. Similar to the
above-mentioned association of a decreasing CAL after 12 months
with long-term CAL loss, an initially deeper defect probably also has a
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KORONNA ET AL.
higher risk of losing partial CAL in the long term compared to an ini-
tially shallower defect component. For the most part, deep and nar-
row three-walled defects are described as clinically more favourable.
In the short term, deeper defects seem to respond clinically and radio-
graphically very well to regenerative approaches (Cortellini &
Tonetti, 2015; Eickholz et al., 1996, 2004), but in the long term they
remain stable but seem to have an increased risk of partially losing
CAL compared to shallower defects in the present cohort. Deeper
defects are more likely to adopt narrower defect angles; however, in
the present study no information could be gained on the correspond-
ing defect angles. Furthermore, only 2 of the 52 defects examined
were exclusively three-walled defects, and all other defects were
combination defects with other one- or two-walled parts.
Another important factor that has been shown to strongly influ-
ence the long-term stability of regenerative treatment outcomes is
smoking (Cortellini & Tonetti, 2015; Sculean et al., 2008; Tonetti
et al., 1995). In the present study, 17.4% of the patients who lost CAL
between 12 and 120 months were active smokers compared to only
5% in the stable CAL group. Even though there was no significant
influence of post-operative root canal treatments (RCTs) on CAL gain,
it was shown that RCTs were significantly more frequent, at least in
the case of CAL stability/gain. This confirms the observation of Cor-
tellini and Tonetti (2001), who could not show a negative effect of
RCTs on the regenerative treatment outcome.
Cox proportional hazard regression analysis showed that an increase
in PlI by one code 12 months after surgery increases the risk for TL by a
factor of five. It seems plausible that increasing PlI as a local descriptor of
plaque control in the treated teeth may be associated with TL. Looking at
generalized plaque control, it is noteworthy that patients with TL over
10 years showed 23% higher plaque control record (PCR) at the
12-month re-examination than those who did not lose any teeth. This is
expressed in parallel in a twice-as-high gingival bleeding index (GBI). How-
ever, eight of the nine lost teeth were lost 3–9 years post operation and
thus ≥2 years after the 12-month period; therefore, it is difficult to relate
these findings to TL. Looking at the actual frequency of SPCs, it is note-
worthy that 56% of patients who lost teeth underwent ≤1 SPC/year,
while this value was 33% in the group without TL. It may be concluded
that less frequent SPC may lead to an increase in PlI after 12 months.
The frequency of maintenance visits as a risk factor for TL was recently
confirmed in a study on prognostic factors of clinical outcomes after
guided tissue regeneration (GTR). Moreover, a tooth survival rate of
72.7% was found, which is comparable to the present rate of 82.7%.
However, the study only looked at GTR combined with bone allografts,
which is why the comparison is limited (Majzoub et al., 2020).
At the patient level, there were about 20% more active smokers in
the TL group than in the non-TL group. In addition, it should be empha-
sized that 55.6% of patients with TL were at high risk for PRA 12 months
post operation compared to 23.5% of those who did not lose their teeth.
However, no significant associations between smoking and PRA could be
found in the present study. This is probably due to the overall small num-
ber of patients, which is one of the limitations of this study.
At the tooth level, the fact that the proportion of teeth with
pocket closure halved in patients with and without TL from 12 to

KORONNA ET AL.
60 months is striking and probably clinically relevant and was always
lower in the TL group than in the non-TL group. Even though no sta-
tistical association was found here, pocket closure after 12 months
seems to be able to provide a general indication of the further clinical
course. Concomitantly, patients with later TL showed 2 mm higher
CAL after 12 months than patients without TL. CAL ≥ 7 mm
12 months after surgery as a TL predictor has already been described
(Cieplik et al., 2020) and is confirmed by the present findings.
However, generalizing these findings for future therapy decisions
could be wrong, as many other risk factors play a decisive role at this
point (Cortellini & Tonetti, 2015). Overall, there is little evidence for
predictors of TL or CAL stability after regenerative therapy of IBDs
for periods ≥10 years (Cieplik et al., 2020; Cortellini et al., 2017;
Petsos et al., 2019), which is why this study, despite its limitations,
provides further insights.
Every retrospective study is subject to a certain selection bias
(here, e.g., 10 different surgeons, 5 follow-up examiners, use of antibi-
otics). Nevertheless, in the present study, both the bias and possible
confounding within the mixed-model regression analyses were coun-
teracted by means of numerous univariate regressions related to the
primary target parameter, namely the CAL change from 12 to
120 months. Further limitations of this study are as follows: (i) The
long follow-up period is both a strength in terms of generating long-
term results and a limitation since the retrospective analysis led to the
involvement of many operators and examiners without calibration
across centers; (ii) The present cohort study does not make any com-
parison with a control group, which is also due to the retrospective
nature of the study; (iii) The inclusion of cohorts of similar size from
both centres would presumably have contributed to further insights
into the centre effect.
5 | C O N CL U S I O N S
• 82.7% of the regeneratively treated teeth could be retained over
9 years. PlI after 12 months was an indicator for TL.
• 86.0% of the retained teeth with predominantly treated three-
walled IBD components showed a stable CAL (no CAL loss
≥2 mm) over 9 years. In 60.0% of the cases, pocket closure was
achieved, while 28.0% showed residual PPD ≥ 6 mm after
10 years.
• Low CAL values 12 months post operation are associated with a
long-term stable CAL result. Thus, CAL should be viewed critically
during the re-evaluation.
• Initially deeper three-walled IBD components are more likely to
lose some of their gained attachment in the long term.
• Further prolonged, clinically controlled trials should be initiated to
demonstrate the achievable long-term stability of regenerative
treatment.
AUTHOR CONTRIBUTIONS
All authors contributed substantially to the interpretation of the data
for the work and to drafting and critically revising the manuscript.
1600051x, 2023, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpe.13814 by National Cheng Kung University, Wiley Online Library on [01/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1007
They gave their final approval of the version to be published and
agreed to be accountable for all aspects of the work. Additionally,
Peter Eickholz and Hari Petsos conceived and designed the study.
Ilona Koronna, Beate Schacher, Katrin Nickles, Peter Eickholz and Hari
Petsos collected the data for Frankfurt; Ti-Sun Kim and Sarah
K. Sonnenschein collected the data for Heidelberg. Ilona Koronna and
Hari Petsos supervised methodical approaches. Iulia Dahmer analysed
data. Ilona Koronna and Hari Petsos led the writing and managed the
group.
AC KNOW LEDG EME NT S
We would like to thank all colleagues who are not listed as authors
but were involved in this project and thus made it possible. Many
thanks to Rita Arndt†, Tatjana Ramich, Susanne Scharf, Diana Kriegar,
Lasse Röllke, Martin Wohlfeil and Jens Kaltschmitt. Open Access
funding enabled and organized by Projekt DEAL.
FUNDING INF ORMATI ON
The study was in part self-funded by the authors and their institutions
and by a Moessner Stiftung research grant (Frankfurt am Main,
Germany) to the Department of Periodontology, Center for Dentistry
and Oral Medicine, Johann Wolfgang Goethe University, Frankfurt/
Main, Germany.
CONFLIC T OF INTER E ST STATEMENT
The authors declare that they have no conflict of interests related to
this study.
DATA AVAILABILITY STAT EMEN T
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ET HICS S TAT E MENT
The trial was approved by the Institutional Review Boards for Human
Studies of the Medical Faculty of the Johann Wolfgang Goethe Uni-
versity (approval number 251/10, amendment from 2020) and the
Medical Faculty of Heidelberg University (approval number S-
332/2014).
OR CID
Katrin Nickles https://orcid.org/0000-0002-3785-8364
Sarah K. Sonnenschein https://orcid.org/0000-0001-6062-1069
Peter Eickholz https://orcid.org/0000-0002-1655-8055
Hari Petsos https://orcid.org/0000-0002-8901-8017
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How to cite this article: Koronna, I., Schacher, B., Dahmer, I.,
Nickles, K., Sonnenschein, S. K., Kim, T.-S., Eickholz, P., &
Petsos, H. (2023). Long-term stability of infrabony defects
treated with enamel matrix derivative alone: A retrospective
two-centre cohort study. Journal of Clinical Periodontology,
50(7), 996–1009. https://doi.org/10.1111/jcpe.13814