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Effect of Alveolar Ridge Preservation Interventions Following Tooth

Extraction: A Systematic Review and Meta-Analysis

Article  in  Journal Of Clinical Periodontology · January 2019

DOI: 10.1111/jcpe.13057

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Received: 1 August 2018    Revised: 22 October 2018    Accepted: 8 November 2018

DOI: 10.1111/jcpe.13057

SUPPLEMENT ARTICLE

Effect of alveolar ridge preservation interventions following

tooth extraction: A systematic review and meta-­analysis

Gustavo Avila-Ortiz1  | Leandro Chambrone1,2  | Fabio Vignoletti3

1
Department of Periodontics, University of
Iowa, Iowa City, Iowa
2
School of Dentistry, Ibirapuera University,
São Paulo, Brazil
3
Department of Periodontology, Universidad
Complutense de Madrid, Madrid, Spain
Correspondence
Gustavo Avila-Ortiz, Department of
Periodontics, The University of Iowa, Iowa
City, IA.
Email: gustavo-avila@uiowa.edu
Abstract
Aim: The aim of this systematic review was to critically analyse the available evidence
on the effect of different modalities of alveolar ridge preservation (ARP) as compared
to tooth extraction alone in function of relevant clinical, radiographic and patient-­
centred outcomes.
Material and Methods: A comprehensive search aimed at identifying pertinent litera-
ture for the purpose of this review was conducted by two independent examiners.
Only randomized clinical trials (RCTs) that met the eligibility criteria were selected.
Relevant data from these RCTs were collated into evidence tables. Endpoints of in-
terest included clinical, radiographic and patient-­
reported outcome measures
(PROMs). Interventions reported in the selected studies were clustered into ARP
treatment modalities. All these different ARP modalities were compared to the con-
trol therapy (i.e. spontaneous socket healing) in each individual study after a 3-­ to
6-­month healing period. Random-­effects meta-­analyses were conducted if at least
two studies within the same ARP treatment modality reported on the same outcome
of interest.
Results: A combined database, grey literature and hand search identified 3,003
records, of which 1,789 were screened after removal of duplicates. Following the
application of the eligibility criteria, 25 articles for a total of 22 RCTs were in-
cluded in the final selection, from which nine different ARP treatment modalities
were identified: (a) bovine bone particles (BBP) + socket sealing (SS), (b) construct
made of 90% bovine bone granules and 10% porcine collagen (BBG/PC) + SS, (c)
cortico-­c ancellous porcine bone particles (CPBP) + SS, (d) allograft particles
(AG) + SS, (e) alloplastic material (AP) with or without SS, (f) autologous blood-­
derived products (ABDP), (g) cell therapy (CTh), (h) recombinant morphogenic
protein-­2 (rhBMP-2) and (i) SS alone. Quantitative analyses for different ARP mo-
dalities, all of which involved socket grafting with a bone substitute, were feasible
for a subset of clinical and radiographic outcomes. The results of a pooled quanti-
tative analysis revealed that ARP via socket grafting (ARP-­SG), as compared to
tooth extraction alone, prevents horizontal (M = 1.99 mm; 95% CI 1.54–2.44;
p < 0.00001), vertical mid-­buccal (M = 1.72 mm; 95% CI 0.96–2.48; p < 0.00001)
and vertical mid-­lingual (M = 1.16 mm; 95% CI 0.81–1.52; p < 0.00001) bone re-
sorption. Whether there is a superior ARP or SS approach could not be determined
on the basis of the selected evidence. However, the application of particulate

J Clin Periodontol. 2019;1–29. wileyonlinelibrary.com/journal/jcpe   © 2019 John Wiley & Sons A/S. |  1
Published by John Wiley & Sons Ltd
 |
2       AVILA-­ORTIZ et al.

xenogenic or allogenic materials covered with an absorbable collagen membrane or

a rapidly absorbable collagen sponge was associated with the most favourable out-
comes in terms of horizontal ridge preservation. A specific quantitative analysis
showed that sites presenting a buccal bone thickness >1.0 mm exhibited more fa-
vourable ridge preservation outcomes (difference between ARP [AG + SS] and
control = 3.2 mm), as compared to sites with a thinner buccal wall (difference be-
tween ARP [AG + SS] and control = 1.29 mm). The effect of other local and sys-
temic factors could not be assessed as part of the quantitative analyses. PROMs
were comparable between the experimental and the control group in two studies
involving the use of ABDP. The effect of other ARP modalities on PROMs could not
be investigated, as these outcomes were not reported in any other clinical trial in-
cluded in this study.
Conclusion: Alveolar ridge preservation is an effective therapy to attenuate the di-
mensional reduction of the alveolar ridge that normally takes place after tooth
extraction.

KEYWORDS
alveolar bone atrophy, alveolar bone grafting, alveolar ridge, bone graft(s), bone remodelling,
evidence-based dentistry

1 |  I NTRO D U C TI O N
Clinical Relevance
Maintenance of the natural dentition in optimal conditions of
health, function and aesthetics, with the ultimate goal of enhancing Scientific rationale for the study: There is limited information

the well-­b eing of patients, remains as the main objective of peri- available regarding the effect of specific alveolar ridge

odontal therapy (AAP, 2011, Chapple & Wilson, 2014). However, preservation (ARP) treatment modalities on the basis of

dental extraction is inevitable under certain circumstances that relevant endpoints that could be used to make decisions in

subsequently require the consideration of tooth replacement daily clinical practice. Principal findings: ARP is an effective

options. Among them, fixed dental prostheses (FDPs) are re- approach to attenuate the dimensional reduction of the

garded as a highly predictable and therapeutically versatile alter- alveolar ridge that normally takes place after tooth

native, also associated with long-­term patient quality of life (Ali, extraction. The beneficial effects of ARP seem to be more

Baker, Shahrbaf, Martin, & Vettore, 2018; Wolleb, Sailer, Thoma, pronounced in preventing horizontal bone resorption,

Menghini, & Hammerle, 2012). Nonetheless, FDPs, whether they followed by vertical mid-­buccal and vertical mid-­lingual

are tooth-­or implant-­supported, cannot fully replace all the in- bone changes. The magnitude of this effect was larger in

herent functions and properties of natural teeth (Giannobile & patients receiving xenogenic and allogenic bone substi-

Lang, 2016; Levin & Halperin-­Sternfeld, 2013) and are not exempt tutes covered by an absorbable collagen barrier. Practical

of complications and diseases (Berglundh et al., 2018; Pjetursson, implications: ARP should be considered in conjunction with

Sailer, Makarov, Zwahlen, & Thoma, 2015; Sailer, Makarov, Thoma, minimally traumatic tooth extraction in order to minimize

Zwahlen, & Pjetursson, 2015), some of which represent a major alveolar ridge reduction.

challenge, such as recurrent caries and periodontitis of abutment

teeth (Tan et al., 2006; Tan, Pjetursson, Lang, & Chan, 2004), and
peri-­implantitis (Schwarz, Derks, Monje, & Wang, 2018). To min-
imize the occurrence of biological and mechanical implant com-
plications, proper treatment planning and technical execution are
fundamental. In clinical scenarios involving a hopeless tooth indi-
cated for extraction, and considering future replacement with an
FDP, adequate management of the extraction site may contribute
to achieve predictable and satisfactory outcomes, particularly in
the anterior aesthetic zone.
Tooth extraction triggers a cascade of biological events, medi-
ated by both the local inflammatory response that follows the sur-
gical intervention and the deprivation of masticatory stimulation of
the periodontium, which elicit an alteration of the homoeostasis and
structural integrity of the periodontal tissues. As a consequence, a
physiologic process of disuse atrophy, characterized by an intense
resorption of the alveolar bone and a partial invagination of the
mucosa, takes place over the first weeks after tooth extraction, as
AVILA-­ORTIZ et al.       3 |
shown in multiple preclinical and clinical studies (Araujo & Lindhe,
2.1 | Clinical scenarios
2005; Chappuis et al., 2013, 2015; Discepoli et al., 2013; Trombelli
et al., 2008). The extent and magnitude of the bone remodelling pro- In this review, the clinical scenarios of interest were (a) intact or
cess may vary depending on individual local and systemic factors, well-­preserved extraction sites (Figure 1) and (b) damaged extrac-
but it typically results into certain degree of horizontal and vertical tion sites presenting extensive alveolar bone fenestrations and/or
alveolar ridge reduction, mainly affecting the bucco-­coronal aspect dehiscences, which were defined as defects involving a minimum of
(Tan, Wong, Wong, & Lang, 2012; Van der Weijden, Dell'Acqua, & 50% of alveolar bone height loss on any wall (Figure 2).
Slot, 2009). Bone and/or soft tissue augmentation procedures are
often indicated for the management of deficient edentulous ridges
2.2 | PICO question (Population, Intervention,
prior to or at the time of implant placement, which may increase the
Comparison and Outcomes)
risk of morbidity, treatment expenses and, possibly, total treatment
time (Lim, Lin, Monje, Chan, & Wang, 2018). What is the effect of different modalities of ARP performed im-
In an attempt to attenuate the resorptive events that follow mediately after tooth extraction in adult human subjects compared
tooth loss and to minimize the need for ancillary ridge augmenta- to tooth extraction alone in function of clinical, radiographic and
tion procedures prior to delivery of implant-­and/or tooth-­supported patient-­reported outcome measures?
restorations, different interceptive therapies have been proposed,
including partial extraction protocols (Baumer, Zuhr, Rebele, &
2.2.1 | Population
Hurzeler, 2017; Hurzeler et al., 2010; Salama, Ishikawa, Salama,
Funato, & Garber, 2007), forced orthodontic extrusion (Amato, Adult human subjects requiring tooth extraction in any sector of the
Mirabella, Macca, & Tarnow, 2012; Joo, Son, & Lee, 2016; Salama mouth.
& Salama, 1993) and alveolar ridge preservation (ARP) performed
immediately after complete tooth extraction. A wide variety of ARP
2.2.2 | Intervention
treatment modalities have been described in the past 20 years, in-
cluding socket grafting with a biomaterial alone (Artzi, Tal, & Dayan, Tooth extraction and ARP, which was defined as “any local thera-
2000), overbuilding of the facial bony wall (Brugnami & Caiazzo, peutic intervention in addition to standard of care tooth extraction
2011), occluding the access to the socket by interposing a barrier ele- carried out immediately after complete tooth extraction and primar-
ment (Lekovic et al., 1998), or a combination of some of them (Iasella ily aimed at preserving alveolar ridge contours to provide maximum
et al., 2003), with or without primary intention healing. ARP thera- bone and/or soft tissue availability for future implant placement or
pies are widely indicated in contemporary dental practice and there delivery of a tooth-­supported FDP.”
is solid evidence supporting their effectiveness, as shown in previ- Alveolar ridge preservation interventions may include filling
ous systematic reviews (Avila-­Ortiz, Elangovan, Kramer, Blanchette, the socket with a biomaterial (e.g. bone particles, collagen sponge
& Dawson, 2014; Iocca, Farcomeni, Pardinas Lopez, & Talib, 2017; or autologous blood-­derived products), which is generally known
MacBeth, Trullenque-­Eriksson, Donos, & Mardas, 2017; Vignoletti as alveolar ridge preservation via socket grafting (ARP-­SG), the sole
et al., 2012; Vittorini Orgeas, Clementini, De Risi, & de Sanctis,
2013). However, there is limited information available in previously
conducted systematic reviews based on clinical trials regarding
the performance of specific ARP treatment modalities compared
to tooth extraction alone on the basis of significant endpoints that
could be of use to make clinical decisions (Willenbacher, Al-­Nawas,
Berres, Kammerer, & Schiegnitz, 2016).
Hence, in alignment with the goal of the XV European Workshop
in Periodontology, the aim of this systematic review was to com-
prehensively and critically analyse the current evidence regarding
the effect of different modalities of ARP as compared to tooth
extraction alone in function of relevant clinical, radiographic and
patient-­centred outcomes.

2 | M ATE R I A L A N D M E TH O DS

This systematic review fully adhered to the guidelines of the

F I G U R E   1   Drawing illustrating a post-­extraction socket that
Preferred Reporting of Systematic Reviews and Meta-­analyses exhibits complete integrity of the alveolar bone
(PRISMA) statement (Moher, Liberati, Tetzlaff, & Altman, 2009).
 |
4       AVILA-­ORTIZ et al.
F I G U R E   2   Drawing illustrating a post-­extraction socket that
exhibits an extensive buccal bone dehiscence
application of a barrier material (autogenous or exogenous) to pro-
tect the underlying bone compartment, which is commonly termed
as socket sealing (SS), or a combination of both, either by primary
intention healing following flap advancement (covered) or by sec-
ondary intention healing (exposed).
2.2.3 | Comparison
Standard of care tooth extraction only (i.e. tooth extraction, with or
without socket curettage and irrigation, and suturing as required).
2.2.4 | Outcomes of interest
1. Clinical: Dimensional (linear [horizontal, mid-buccal, mid-lingual,
mesial and distal] and volumetric) changes of the alveolar ridge
(including soft tissue and bone measurements), rate of com-
plications, feasibility of implant placement, need for additional
grafting at the time of implant placement, and implant survival
and success rate.
2. Radiographic: Dimensional (linear [horizontal, mid-buccal, mid-
lingual, mesial and distal] and volumetric) radiographic changes of
the alveolar bone and marginal bone loss around implants.
3. Patient-reported outcome measures (PROMs): Reported
discomfort, perceived benefit and quality of life.
With the purpose of comprehensively addressing other clinically
relevant facets related to the focused PICO question, the effect of sev-
eral local and systemic factors on relevant outcomes of interest was
explored.
These factors were divided into three major categories: (a)
surgical-­related (i.e. flap elevation, bone grafting material, use of SS
material, primary or secondary intention healing), (b) local anatom-
ical (i.e. single-­vs. multi-­rooted, bone and soft tissue thickness and
socket integrity) and (c) patient-­related (i.e. age, smoking habits and
history of periodontitis).
2.3 | Article eligibility criteria
Only articles reporting RCTs with a proper parallel arms or split-­
mouth design (i.e. all subjects enrolled in the study received the
same therapies) were included. Non-­randomized clinical trials, case
series, cohort and cross-­sectional studies, and descriptive reviews
and editorials were not eligible. Studies must have recruited human
adult patients (>18 years of age) in need of at least one single-­/
multi-­rooted tooth extraction, with the exception of third molars. A
minimum post-­operative follow-­up period of 3 months (≥12 weeks)
and a maximum of 6 months (≤24 weeks) were required for inclusion.
Studies must have compared ARP (test) with untreated extraction
sites left to heal spontaneously (control) to be eligible. Studies that
involved any interim intervention that may have affected any of the
outcomes of interest (e.g. delivery of mucosa-­supported temporary
prosthesis) were excluded. Additionally, included studies must
have reported at least one of the aforementioned outcomes of
interest (i.e. clinical, radiographic or patient-­centred outcomes). For
inclusion of studies reporting dimensional changes of the alveolar
bone measured clinical or radiographically, these measurements
must have been made within the most coronal 3 mm. For inclusion
of studies reporting implant-­related outcomes, implants must have
been in functional loading for a minimum of 12 months. No minimum
number of patients per group for inclusion was set. For study series
that used the same population, only the study with the longest
follow-­up was included.
2.4 | Information sources and literature
search protocol
Four electronic databases were searched for articles relevant in
the context of this systematic review: National Library of Medicine
(MEDLINE—PubMed), Scopus, Cochrane Library and Web of
Science. Only articles published in English were eligible. No limits re-
garding publication date or status were set. The terms and strategy
used to search each individual database are available in Appendix 1.
The last search was conducted on 16 April 2018. To complement the
database search, cross-­searching of cited references in 24 system-
atic reviews on the topic of ARP published until 1 May 2018 (Atieh
et al., 2015; Avila-­Ortiz et al., 2014; Barallat et al., 2014; Castro et al.,
2017; Chan, Lin, Fu, & Wang, 2013; Corbella, Taschieri, Francetti,
Weinstein, & Del Fabbro, 2017; De Risi, Clementini, Vittorini,
Mannocci, & De Sanctis, 2015; Del Fabbro et al., 2017; Horvath,
Mardas, Mezzomo, Needleman, & Donos, 2012; Iocca et al., 2017;
Jambhekar, Kernen, & Bidra, 2015; Lee, Lee, Koo, Seol, & Lee, 2018;
MacBeth et al., 2017; Mardas, Trullenque-­Eriksson, MacBeth, Petrie,
& Donos, 2015; Moraschini & Barboza, 2015; Morjaria, Wilson, &
Palmer, 2014; Moslemi, Khoshkam, Rafiei, Bahrami, & Aslroosta,
2018; Natto, Yaghmoor, Bannuru, & Nevins, 2017; Ten Heggeler,
Slot, & Van der Weijden, 2011; Troiano et al., 2017; Vignoletti et al.,
AVILA-­ORTIZ et al.
2012; Vittorini Orgeas et al., 2013; Weng, Stock, & Schliephake,
2011; Willenbacher et al., 2016) was also performed. Additionally, in
an attempt to identify relevant information in the grey literature, two
open databases, OpenGrey (www.opengrey.eu) and Grey Literature
Report (www.greylit.org), were searched on 15 September 2018
using the term “alveolar ridge preservation.”
2.5 | Article selection
Two reviewers (G.A. and F.V.) independently read the title and
abstract of the entries yielded from the initial electronic database
search. After this initial assessment, both reviewers read separately
the full-­text versions of the studies that could be potentially included
in this systematic review. The final selection of articles was made on
the basis of the eligibility criteria described above. Any disagreement
in the final selection was resolved by open discussion between both
reviewers. In the case that no agreement could be reached, the other
co-­author (L.C.) acted as arbiter.
2.6 | Data extraction
Data from the studies included in the final selection were extracted
by one of the authors (G.A). The accuracy of the data was verified
independently by the other two co-­authors (F.V. and L.C.). Aside
from the aforementioned clinical, radiographic and patient-­
reported outcome measures, additional extracted data included
year of publication and first author, study design (i.e. parallel arms
or split-­mouth), initial number of participants, distribution of sites
by treatment groups, number of dropouts, details of the ARP
intervention(s), age and gender of participants, smoking habits,
reason for extraction, socket anatomy (single-­or multi-­
rooted),
integrity of extraction site, buccal bone thickness, SS and modality,
flap elevation, primary closure, healing period, whether implant
placement was performed and follow-­
up time after functional
loading.
If data were missing, the authors of the original articles were
contacted and asked to provide further details.
2.7 | Assessment of risk of bias in selected studies
Two authors (G.A. and L.C.) independently determined the risk of
bias of each study included in the final selection using the Cochrane
Collaboration's tool for assessing risk of bias in randomized clinical
trials (Higgins et al., 2011). Disagreement between the reviewers
was resolved by open discussion and consensus.
The following domains were assessed:
• Random sequence generation (selection bias);
• Allocation concealment (selection bias);
• Blinding of participants and personnel (performance bias);
• Blinding of outcome assessment (detection bias);
• Incomplete outcome data (attrition bias);
• Selective outcome reporting (reporting bias);
|
      5
• Other bias.
Based on the overall risk of bias, individual studies were catego-
rized as being at low, high or unclear risk of bias according to the fol-
lowing criteria:
• Low risk of bias (plausible bias unlikely to seriously alter the re-
sults) if all domains were at low risk of bias;
• High risk of bias (plausible bias that seriously weakens confidence
in the results) if one or more domains were at high risk of bias; or
• Unclear risk of bias (plausible bias that raises some doubt about
the results) if one or more domains were at unclear risk of bias.
2.8 | Data synthesis
Data were collated into evidence tables and clustered according
to the treatment modality and outcome parameters. Descriptive
summary was performed to determine the quantity of data, checking
further for study variations in terms of study characteristics, study
quality and results. Random-­effects meta-­analyses of continuous
data were pooled outcomes and expressed as weighted mean
differences (MD) with their associated 95% confidence intervals
(CI). The analyses were conducted using the generic inverse variance
statistical method where the MD and standard error (SE) are entered
for all studies in order to accommodate data pooling from split-­mouth
and parallel-­group studies in a single meta-­analysis and facilitate
data synthesis (Stedman, Curtin, Elbourne, Kesselheim, & Brookhart,
2011). For split-­mouth trials, an intra-­cluster correlation coefficient
of 0.05 was assumed, while for parallel trials, a coefficient of zero
for the calculation of SE. Statistical heterogeneity was assessed by
calculation of the Q statistic. The significance of discrepancies in
the estimates of the treatment effects from the different trials was
assessed by means of Cochrane's test for heterogeneity and the I2
statistic. Analyses were performed using RevMan software (Review
Manager, version 5.3; Nordic Cochrane Centre, Copenhagen,
Denmark).
3 | R E S U LT S
3.1 | Literature selection process
The initial database search yielded a total of 2,998 entries, of
which 1,346 were found in PubMed, 25 in Scopus, 171 in Cochrane
Library and 1,456 in Web of Science. A total of two additional ar-
ticles were identified through cross reference checking and hand
searching. The grey literature search rendered only three relevant
entries, all of which were doctoral theses written in French that
were not eligible for inclusion in this systematic review. After
excluding all duplicates, the total number of entries was 1,789.
A total of 1,714 articles were excluded after review of title and
abstract. Hence, full-­text review was conducted for 75 articles.
Kappa score for inter-­examiner agreement for title and abstract
 |
6       AVILA-­ORTIZ et al.
review was 0.82 (95% CI: 0.75–0.89). A total of 50 additional ar-
ticles were excluded after full-­text review and application of the
eligibility criteria. The list of excluded articles and the reasons for
exclusion are available in Appendix 2. The final selection consisted
of 25 articles, for a total of 22 studies (Aimetti, Romano, Griga, &
Godio, 2009; Alissa, Esposito, Horner, & Oliver, 2010; Araujo, da
Silva, de Mendonca, & Lindhe, 2015; Barone, Ricci, Tonelli, Santini,
& Covani, 2013; Barone, Toti, Menchini-­Fabris, et al., 2017; Barone,
Toti, Quaranta, et al., 2017; Cardaropoli, Tamagnone, Roffredo,
& Gaveglio, 2014, 2015; Cardaropoli, Tamagnone, Roffredo,
Gaveglio, & Cardaropoli, 2012; Festa, Addabbo, Laino, Femiano,
& Rullo, 2013; Fiorellini et al., 2005; Guarnieri et al., 2017; Iasella
et al., 2003; Iorio-­Siciliano et al., 2017; Jung et al., 2013; Karaca,
Er, Gulsahi, & Koseoglu, 2015; Kotsakis, Salama, Chrepa, Hinrichs,
& Gaillard, 2014; Madan et al., 2014; Pang et al., 2014; Pelegrine,
da Costa, Correa, & Marques, 2010; Rasperini, Canullo, Dellavia,
Pellegrini, & Simion, 2010; Schneider et al., 2014; Spinato, Galindo-­
Moreno, Zaffe, Bernardello, & Soardi, 2014; Temmerman et al.,
2016; Thalmair, Fickl, Schneider, Hinze, & Wachtel, 2013). A flow
chart that depicts this selection process is displayed in Figure 3.
3.2 | Characteristics of included studies
The general characteristics of the 22 studies included in the final
selection are displayed in Table 1.
F I G U R E   3   Flow chart displaying the search process and article
selection
3.2.1 | Study design
Eighteen of the selected RCTs had a parallel arms design, while four
were conducted following a split-­mouth design (Festa et al., 2013;
Karaca et al., 2015; Madan et al., 2014; Temmerman et al., 2016).
Of the 18 trials with a parallel arms design, seven had more than
one experimental group (Barone, Toti, Menchini-­Fabris, et al., 2017;
Barone, Toti, Quaranta, et al., 2017; Fiorellini et al., 2005; Guarnieri
et al., 2017; Jung et al., 2013; Kotsakis et al., 2014; Schneider et al.,
2014; Thalmair et al., 2013). Patient withdrawal rate was reported
in all articles, and only in four studies, a subset of subjects did not
complete the clinical trial (Alissa et al., 2010; Barone, Toti, Menchini-­
Fabris, et al., 2017; Guarnieri et al., 2017; Rasperini et al., 2010);
however, the attrition rate was minimal and it did not seem to affect
the reliability of the data in any of these studies.
3.2.2 | Population and setting
Eight studies did not recruit smokers (Aimetti et al., 2009; Festa
et al., 2013; Iorio-­Siciliano et al., 2017; Pang et al., 2014; Pelegrine
et al., 2010; Rasperini et al., 2010; Spinato et al., 2014; Temmerman
et al., 2016), while 10 studies allowed for the inclusion of current
smokers (Alissa et al., 2010; Barone et al., 2013; Barone, Toti,
Menchini-­Fabris, et al., 2017; Barone, Toti, Quaranta, et al., 2017;
Cardaropoli et al., 2012, 2014, 2015; Guarnieri et al., 2017; Iasella
et al., 2003; Jung et al., 2013; Kotsakis et al., 2014; Schneider et al.,
2014; Thalmair et al., 2013), of which four did not report specific
data on the distribution of smokers per group (Barone et al., 2013;
Cardaropoli et al., 2012, 2014, 2015; Iasella et al., 2003; Kotsakis
et al., 2014). In four studies, whether smokers were recruited was
not reported (Araujo et al., 2015; Fiorellini et al., 2005; Karaca et al.,
2015; Madan et al., 2014). History of periodontitis was not reported
in any of the selected studies.
Out of the 22 included studies, the vast majority (n = 19) were
conducted in a university setting, two were carried out in a private
practice setting (Cardaropoli et al., 2012, 2014, 2015; Spinato et al.,
2014), and in one study, the setting was unclear (Guarnieri et al.,
2017).
3.2.3 | Treatment site features
Reasons for extraction were reported in 10 trials (Aimetti et al.,
2009; Alissa et al., 2010; Araujo et al., 2015; Barone et al., 2013;
Barone, Toti, Quaranta, et al., 2017; Cardaropoli et al., 2012, 2014,
2015; Jung et al., 2013; Karaca et al., 2015; Schneider et al., 2014;
Spinato et al., 2014; Thalmair et al., 2013) and included a wide
variety of indications, mainly crown or root fractures, extensive
caries, endodontic failure, orthodontic and periodontal. Regarding
socket anatomy, 12 studies included single-­rooted teeth exclu-
sively (Aimetti et al., 2009; Araujo et al., 2015; Festa et al., 2013;
Fiorellini et al., 2005; Iasella et al., 2003; Jung et al., 2013; Karaca
et al., 2015; Madan et al., 2014; Pelegrine et al., 2010; Schneider
et al., 2014; Spinato et al., 2014; Temmerman et al., 2016; Thalmair
AVILA-­ORTIZ et al.
et al., 2013), only one study included only multi-­rooted teeth
(Rasperini et al., 2010), eight studies included a mix of single-­
and multi-­rooted sites in all treatment groups (Alissa et al., 2010;
Barone et al., 2013; Barone, Toti, Menchini-­Fabris, et al., 2017;
Barone, Toti, Quaranta, et al., 2017; Cardaropoli et al., 2012, 2014,
2015; Guarnieri et al., 2017; Iorio-­Siciliano et al., 2017; Kotsakis
et al., 2014), and one study did not report specific details on this
parameter (Pang et al., 2014). Thirteen studies included extrac-
tion sites that did not present significant bone damage (Aimetti
et al., 2009; Araujo et al., 2015; Barone et al., 2013; Barone, Toti,
Menchini-­Fabris, et al., 2017; Cardaropoli et al., 2012, 2014, 2015;
Festa et al., 2013; Iasella et al., 2003; Kotsakis et al., 2014; Madan
et al., 2014; Pelegrine et al., 2010; Rasperini et al., 2010; Spinato
et al., 2014; Thalmair et al., 2013), while only three studies re-
ported the inclusion of sites presenting extensive alveolar bone
defects (Barone, Toti, Quaranta, et al., 2017; Fiorellini et al., 2005;
Temmerman et al., 2016). In two studies, the severity of socket
damaged varied from site to site, as one of the inclusion criteria
was that at least 50% of the buccal bone wall must have been
present (Guarnieri et al., 2017; Jung et al., 2013; Schneider et al.,
2014), and in four studies, this factor was not reported or was un-
clear (Alissa et al., 2010; Iorio-­Siciliano et al., 2017; Karaca et al.,
2015; Pang et al., 2014).
Data on buccal bone thickness at baseline were reported in
eight studies (Barone, Toti, Quaranta, et al., 2017; Cardaropoli
et al., 2012, 2014, 2015; Guarnieri et al., 2017; Iorio-­S iciliano
et al., 2017; Jung et al., 2013; Pelegrine et al., 2010; Schneider
et al., 2014; Spinato et al., 2014; Temmerman et al., 2016), but it
was not recorded consistently across studies, as some investiga-
tors measured this parameter at variable heights respective to the
crestal bone and using different measurement methods (e.g. di-
rect clinical measurement using callipers or radiographic assess-
ment). Five of these RCTs explored the influence of buccal bone
thickness on the outcomes of therapy (Barone, Toti, Quaranta,
et al., 2017; Cardaropoli et al., 2014; Guarnieri et al., 2017; Iorio-­
Siciliano et al., 2017; Spinato et al., 2014). In four of these studies,
it was observed that sites presenting a thick buccal bone pheno-
type (i.e. >1.0 to 1.5 mm) exhibited more favourable outcomes
in all groups. Conversely, Cardaropoli and collaborators observed
no correlation between the initial thickness of the buccal bone
and the final alveolar bone dimension in the experimental group,
indicating that ARP-­S G may negate the potential negative influ-
ence of thin buccal bone (Cardaropoli et al., 2014). Soft tissue
thickness (gingival/mucosal phenotype) was not reported in any
of the selected articles. Whether a flap was elevated at baseline
was reported in all 22 studies. In eight studies, the authors re-
ported having performed flap elevation at the time of tooth ex-
traction (Alissa et al., 2010; Festa et al., 2013; Fiorellini et al.,
2005; Iasella et al., 2003; Iorio-­S iciliano et al., 2017; Kotsakis
et al., 2014; Pang et al., 2014; Pelegrine et al., 2010), and in five
of these trials, primary closure was intentionally achieved (Alissa
et al., 2010; Festa et al., 2013; Fiorellini et al., 2005; Pang et al.,
2014; Pelegrine et al., 2010).
|
      7
3.2.4 | Follow-­up time
The healing time or period prior to implant placement reported in
the selected studies varied widely. The healing time was 3 months
in five studies (Aimetti et al., 2009; Alissa et al., 2010; Barone, Toti,
Quaranta, et al., 2017; Karaca et al., 2015; Temmerman et al., 2016),
4 months in seven studies (Araujo et al., 2015; Barone et al., 2013
Barone, Toti, Menchini-­Fabris, et al., 2017; Cardaropoli et al., 2012,
2014, 2015; Fiorellini et al., 2005; Spinato et al., 2014; Thalmair et al.,
2013), 5 months in one study (Kotsakis et al., 2014) and 6 months
in seven studies (Festa et al., 2013; Iorio-­Siciliano et al., 2017; Jung
et al., 2013; Madan et al., 2014; Pang et al., 2014; Pelegrine et al.,
2010; Rasperini et al., 2010; Schneider et al., 2014). Only two stud-
ies reported healing periods of 4–6 months (Iasella et al., 2003) and
5–6 months (Guarnieri et al., 2017), respectively. Only three studies
reported an implant follow-­up, which was of 12 months, in two tri-
als (Cardaropoli et al., 2012, 2014, 2015; Pang et al., 2014) and of a
period of 12–20 months in one of the included RCTs (Kotsakis et al.,
2014).
3.3 | Risk of bias in selected studies
According to the Cochrane Collaboration's tool for assessing risk
of bias, 10 of the selected studies exhibited an unclear risk of
bias (Aimetti et al., 2009; Alissa et al., 2010; Araujo et al., 2015;
Cardaropoli et al., 2012, 2014, 2015; Festa et al., 2013; Fiorellini
et al., 2005; Guarnieri et al., 2017; Pelegrine et al., 2010; Rasperini
et al., 2010; Thalmair et al., 2013), whereas twelve were associated
with a high risk of bias (Barone et al., 2013; Barone, Toti, Menchini-­
Fabris, et al., 2017; Barone, Toti, Quaranta, et al., 2017; Iasella et al.,
2003; Iorio-­Siciliano et al., 2017; Jung et al., 2013; Karaca et al.,
2015; Kotsakis et al., 2014; Madan et al., 2014; Pang et al., 2014;
Schneider et al., 2014; Spinato et al., 2014; Temmerman et al., 2016).
None of the selected studies presented a low risk of bias. The most
common reason for assignment of a high risk of bias was the absence
of blinding for outcome assessment, as displayed in Figure 4.
Additionally, in most of the studies it was unclear whether alloca-
tion concealment was implemented or whether participants and per-
sonnel were blinded when pertinent. On the contrary, most studies
reported adequate random sequence generation and no risk of at-
trition or reporting bias was identified for any of the selected RCTs.
Other sources of bias were identified in four studies. Specifically, in
one study there was a significantly higher number of smokers in one
of the experimental groups (Jung et al., 2013; Schneider et al., 2014),
and in three trials, all of them with a parallel arms design, the dis-
tribution of subjects per group was markedly uneven (Barone, Toti,
Menchini-­Fabris, et al., 2017; Kotsakis et al., 2014; Spinato et al.,
2014).
3.4 | Treatment modalities
Alveolar ridge preservation interventions reported in any of
the experimental groups of the selected studies were clustered
 |
8       AVILA-­ORTIZ et al.

TA B L E   1   General characteristics of included studies

Alveolar ridge
preservation
intervention(s) (We can
subclassify the
Study design Initial number of interventions after the Age
Publication(s) Parallel arms participants and data extraction is Socket sealed in distribution
Author(s) and year or split-­mouth distribution by groups Dropouts completed) ARP group(s) (years) Gender distribution

Iasella et al. (2003) RCT 24 subjects for a total of 24 No Allograft (particulate Yes Range: 28–76 14 females
Parallel arms sockets FDBA) Bovine collagen Mean: 10 males
Divided into two groups: Socket sealed with membrane 51.5 ± 13.6 (Details on group
Control (n = 12) and absorbable collagen (Details on distribution not
Experimental (n = 12) membrane group reported)
distribution
not reported)

Fiorellini et al. RCT 80 subjects for a total of 95 No Experimental 1: ACS No Mean: 47.4 37 females
(2005) Parallel arms sockets But 4 subjects alone (Details on 43 males
Divided into four groups:* had to be Experimental 2: group (Details on group
Control (n = 20), excluded due 0.75 mg/mL of rhBMP-­2 distribution distribution not
Experimental 1 (n = 17), to inherent in ACS not reported) reported)
Experimental 2 (n = 22) study errors Experimental 3:
and Experimental 3 1.50 mg/mL of rhBMP-­2
(n = 21) in ACS
*Specific number of sites
per group not reported

Aimetti et al. (2009) RCT 40 subjects for a total of 40 No Alloplast No Range: 36–68 18 females
Parallel arms sockets (medical-­grade calcium Mean: 22 males
Divided into two groups: sulphate hemihydrate 51.2 ± 8.4 (Control group: 8
Control (n = 18) and [MGCSH]) (Control females and 10 males/
Experimental (n = 22) group: Experimental group: 10
51.8 ± 8.6/ females and 10 males)
Experimental
group:
50.8 ± 8.4)

Alissa et al. (2010) RCT 23 subjects for a total of 29 Yes Autologous blood-­derived No Control group 15 females
Parallel arms sockets Control group product (Platelet-­rich Range: 20–52 8 males
Divided into two groups: n = 3 plasma gel) Mean: 30.4 (Control group: 8
Control (n = 12 subjects Experimental Experimental females and 3 males/
and 15 sockets) and group n = 4 group Experimental group: 7
Experimental (n = 11 Range: 21–40 females and 5 males)
subjects and 14 sockets) Mean: 30.6

Pelegrine et al. RCT 13 subjects for a total of 30 No Cell therapy No Control group 6 females
(2010) Parallel arms sockets (Autologous bone Range: 36–54 7 males
Divided into two groups: marrow graft) Mean: 43.5 (Control group: 2
Control (n = 6 subjects and Experimental females and 4 males/
15 sockets) and group Experimental group: 4
Experimental (n = 7 Range: 28–70 females and 3 males)
subjects and 15 sockets) Mean: 51

Rasperini et al. RCT 11 subjects for a total of 11 Yes Xenograft (Construct with Yes Mean: 54 N/R
(2010) Parallel arms sockets Control group 90% bovine bone Porcine collagen (Details on
Divided into two groups: n = 1 granules and 10% membrane group
Control (n = 4)* and Experimental porcine collagen) distribution
Experimental (n = 7) group n = 1 Socket sealed with not reported)
*Only data from control absorbable porcine
sites presenting no collagen membrane
significant bone defects
are included in this
systematic review, since
no sites with dehiscence
defects were allocated in
the Experimental group

Cardaropoli et al. RCT 41 subjects for a total of 48 No Xenograft (Bovine bone Yes Range: 24–71 17 females
(2012, 2014, Parallel arms sockets particles) Porcine collagen Mean: 24 males
2015) Divided into two groups: Socket sealed with membrane 47.2 ± 12.9 (Details on group
Control (n = 24 sockets) absorbable porcine (Details on distribution not
and Experimental (n = 24 collagen membrane group reported)
sockets) distribution
not reported)
Specific number of
patients per group is
unclear
AVILA-­ORTIZ et al. |
      9

Flap Primary Ridge Maximum implant

Inclusion of History of Reason(s) for Socket anatomy Socket Buccal bone elevation in closure in healing follow-­up time
smokers periodontitis extraction Single-­/multi-­rooted integrity thickness ARP group(s) ARP group(s) Time/Period after loading

Yes N/R N/R Single-­rooted No significant N/R Yes No 4–6 months N/A

But defects
insufficient
data provided

N/R N/R N/R Single-­rooted Buccal N/A Yes Yes 4 months N/A
dehiscence (Only sites
defects presenting
(At least 50% buccal
of buccal wall dehiscences
missing) were included)

N/A N/R Root or crown Single-­rooted No significant N/R No N/A 3 months N/A
(Smoking was fractures, defects
an exclusion non-­restorable
criterion) caries, and
residual roots

(Details on group
distribution not
reported)

Control group: N/R Caries (60.9%) Control: 7 N/R N/R Yes Yes 3 months N/A
3 smokers Endodontic single-­rooted and 7
Experimental failure (21.7%) multi-­rooted
group: 7 Others (17.4%) Experimental: 5
smokers (Details on group single-­rooted and
distribution not 10 multi-­rooted
reported)

N/A N/R N/R Single-­rooted No significant Control: 1.83 ± Yes Yes 6 months N/A
(Smoking was defects 0.77
an exclusion Experimental:
criterion) 0.9 ±  0.81

N/A N/R N/R Multi-­rooted Most sites N/R No No 6 months N/A

(Smoking was presented no
an exclusion significant
criterion) defects, but
four sites in
the Control
group did not
exhibit an
intact buccal
bone wall

Yes N/R Root fracture, Control: No significant Measured at No No 4 months 12 months

But periodontal 6 single-­rooted and defects baseline
insufficient involvement, 18 multi-­rooted (3 mm apical to
data provided endodontic Experimental: the crest)
failure and 10 single-­rooted
advanced caries and 14 Control:
multi-­rooted 1.19 ± 0.59
(Details on group
distribution not Experimental:
reported) 1.23 ± 0.57

(Continues)
 |
10       AVILA-­ORTIZ et al.

TA B L E   1   (Continued)

Alveolar ridge
preservation
intervention(s) (We can
subclassify the
Study design Initial number of interventions after the Age
Publication(s) Parallel arms participants and data extraction is Socket sealed in distribution
Author(s) and year or split-­mouth distribution by groups Dropouts completed) ARP group(s) (years) Gender distribution

Barone et al. (2013) RCT 58 subjects for a total of 58 No Xenograft Yes Control group 38 females
Parallel arms sockets (Cortico-cancellous Porcine collagen Range: 29–57 20 males
Divided into two groups: porcine bone particles) membrane Mean: (Control group: 18
Control (n = 29) and Socket sealed with 39.3 ± 15.5 females and 11 males/
Experimental (n = 29) absorbable porcine Experimental Experimental group: 20*
collagen membrane group females and 9 males)
Range: 32–62
Mean: *There is likely a typo in
41.8 ± 14.0 Table 1 of the article

Festa et al. (2013) RCT 15 subjects for a total of 30 No Xenograft Yes Range: 28–58 9 females
Split-­mouth sockets (Cortico-cancellous Porcine collagen 6 males
Divided into two groups: porcine bone particles) membrane
Control (n = 15) and Socket sealed with
Experimental (n = 15) absorbable porcine
collagen membrane

Jung et al. (2013), RCT 40 subjects for a total of 40 No Experimental 1: alloplast Yes Control: Control: 4 females/6 males
Schneider et al. Parallel arms sockets Although data (bTCP with a Experimental 48 ± 15 Experimental 1: 4 females
(2014) Divided into four groups: of four polylactide–co-­ Group 2: Experimental /6 males
Control (n = 10), patients (two glycolide coating) collagen matrix 1: 59 ± 11 Experimental 2: 6 females
Experimental 1 (n = 10), from the Experimental 2: Experimental Experimental /4 males
Experimental 2 (n = 10) Control group, xenograft (construct Group 3: 2: 65 ± 13 Experimental 3: 8 females
and Experimental 3 one from with 90% bovine bone autologous soft Experimental /2 males
(n = 10) Experimental granules and 10% tissue punch 3: 49 ± 14
Group 1 and porcine collagen) and
one from socket sealed with a
Experimental porcine collagen matrix
Group 2) could Experimental 3:
not be xenograft (construct
obtained for with 90% bovine bone
the cast granules and 10%
analyses-­soft porcine collagen) and
tissue socket sealed with
measurements autologous soft tissue
punch

Thalmair et al. RCT 30 subjects for a total of 30 No Experimental 1: xenograft Yes Control: Control: 5 females/3 males
(2013) Parallel arms sockets (cortico-cancellous Experimental 46.4 ± 8.9 Experimental 1: 4 females
Divided into four groups: porcine bone particles) Groups 2 and 3: Experimental /6 males
Control (n = 7), and socket sealed with autologous soft 1: 50.5 ± 13.5 Experimental 2: 1 female
Experimental 1 (n = 8), autologous soft tissue tissue punch Experimental /7 males
Experimental 2 (n = 8) and punch 2: 41.7 ± 6.5 Experimental 3: 2 females
Experimental 3 (n = 7) Experimental 2: socket Experimental / 5 males
sealed with autologous 3: 52.0 ± 14.6
soft tissue punch
Experimental 3:
xenograft (cortico-
cancellous porcine bone
particles alone)
AVILA-­ORTIZ et al. |
      11

Flap Primary Ridge Maximum implant

Inclusion of History of Reason(s) for Socket anatomy Socket Buccal bone elevation in closure in healing follow-­up time
smokers periodontitis extraction Single-­/multi-­rooted integrity thickness ARP group(s) ARP group(s) Time/Period after loading

Yes N/R Control: Caries 8 single-­rooted and No significant Measured at No N/A 4 months N/A
Insufficient (45%), Fracture 21 multi-­rooted in defects baseline, but
data provided (41%), each group specific data
Endodontic not reported
(14%),
Periodontal (1%)

Experimental:
Caries (47%),
Fracture
(38%),Endodontic
(10%),
Periodontal (4%)

*There is a
discrepancy
between the data
reported in the
text and in the
graphs

N/A N/R N/R Single-­rooted No significant N/R Yes Yes 6 months N/A
(Smoking was defects
an exclusion
criterion)

Control: 1 N/R Control: Single-­rooted Variable 1 mm apical to No N/A 6 months N/A

smoker Orthodontic (At least 50% the crest
Experimental (n = 1), of the buccal Control:
1: 1 smoker endodontic bone wall 1.1 ± 0.7
Experimental (n = 5), fracture must have Experimental 1:
2: 2 smokers or limited tooth been present 0.8 ± 0.3
Experimental structure (n = 4) for inclusion) Experimental 2:
3: 7 smokers Experimental 1: 0.6 ± 0.2
Endodontic Experimental 3:
(n = 4), fracture 1.3 ± 0.7
or limited tooth
structure (n = 6)
Experimental 2:
Endodontic
(n = 2), fracture
or limited tooth
structure (n = 8)
Experimental 3:
Endodontic
(n = 4), fracture
or limited tooth
structure (n = 6)

Control: 2 N/R Control: Single-­rooted No significant N/R No N/A 4 months N/A

smokers Endodontic defects
Experimental (n = 3), fractures
1: 2 smokers (n = 2), caries
Experimental (n = 2)
2: 1 smoker Experimental 1:
Experimental Endodontic
3: 2 smokers (n = 5), fracture
(n = 3)
Experimental 2:
Endodontic
(n = 4), fracture
(n = 2), caries
(n = 2)
Experimental 3:
Endodontic
(n = 3), fracture
(n = 2), caries
(n = 2)

(Continues)
 |
12       AVILA-­ORTIZ et al.

TA B L E   1   (Continued)

Alveolar ridge
preservation
intervention(s) (We can
subclassify the
Study design Initial number of interventions after the Age
Publication(s) Parallel arms participants and data extraction is Socket sealed in distribution
Author(s) and year or split-­mouth distribution by groups Dropouts completed) ARP group(s) (years) Gender distribution

Kotsakis et al. RCT 24 subjects for a total of 30 No Experimental 1: alloplast YES Control: 43.8 Control: 1 female/5 males
(2014) Parallel arms sockets (calcium phosphosilicate Experimental Experimental Experimental 1: 4
Divided into three groups: putty) and socket sealed Groups 1 and 2: 1: 43.3 females/6 males
Control (n = 6 for 6 with a bovine collagen Bovine collagen Experimental Experimental 2: 2
sockets), Experimental 1 sponge sponge 2: 39.8 females/6 males
(n = 10 for 12 sockets) and Experimental 2:
Experimental 2 (n = 8 for xenograft (bovine bone
12 sockets) particles) and socket
sealed with a bovine
collagen sponge

Madan et al. (2014) RCT 15 subjects for a total of 60 No Alloplast (polylactide– No Range: 20–45 8 females
Split-­mouth sockets polyglycolide [PLA-­P GA] 7 males
Divided into two groups: sponge)
Control (n = 30 sockets)
and Experimental (n = 30
sockets)

Pang et al. (2014) RCT 30 subjects for a total of 30 No Xenograft (bovine bone Yes Range: 22–47 16 females
Parallel arms sockets particles) Porcine collagen Mean: 37 14 males
Divided into two groups: Socket sealed with membrane (Details on (Details on group
Control (n = 15) and absorbable porcine group distribution not reported)
Experimental (n = 15) collagen membrane distribution
not reported)

Spinato et al. (2014) RCT 31 subjects for a total of 31 No Allograft (particulate Yes Range: 27–74 21 females
Parallel arms sockets FDBA) Bovine collagen Mean: 48.5 10 males
Divided into two groups: Socket sealed with sponge (Details on (Details on group
Control (n = 12) and bovine collagen sponge group distribution not reported)
Experimental (n = 19) distribution
not reported)

Araujo et al. (2015) RCT 28 subjects for a total of 28 No Xenograft (construct with Yes Range: 21–50 N/R
Parallel arms sockets 90% bovine bone Autologous soft (Details on
Divided into two groups: granules and 10% tissue punch group
Control (n = 14) and porcine collagen) distribution
Experimental (n = 14) Socket sealed with not reported)
autologous soft tissue
punch

Karaca et al. (2015) RCT 10 subjects for a total of 20 No Socket sealed with Yes Range: 36–60 5 females
Split-­mouth sockets* autologous soft tissue Autologous soft Mean: 46.7 5 males
Divided into two groups: punch tissue punch
Control (n = 10) and
Experimental (n = 10)

Temmerman et al. RCT 22 subjects for a total of 44 No Autologous blood-­derived No Mean: 54 ± 11 7 females
(2016) Split-­mouth sockets* product (L-­PRF clot) 15 males
Divided into two groups:
Control (n = 22) and
Experimental (n = 22)
AVILA-­ORTIZ et al.       13|

Flap Primary Ridge Maximum implant

Inclusion of History of Reason(s) for Socket anatomy Socket Buccal bone elevation in closure in healing follow-­up time
smokers periodontitis extraction Single-­/multi-­rooted integrity thickness ARP group(s) ARP group(s) Time/Period after loading

YES N/R N/R Control: 3 No significant N/R Yes No 5 months 12–20 months

But single-­rooted and 3 defects
insufficient multi-­rooted
data provided Experimental 1: 6
single-­rooted and 6
multi-­rooted
Experimental 2: 7
single-­rooted and 5
multi-­rooted

N/R N/R N/R Single-­rooted No significant N/R No N/A 6 months N/A

defects

N/A N/R N/R Unclear N/R N/R Yes Yes 6 months 12 months
(Smoking was
an exclusion
criterion)

N/A N/R Root fracture Single-­rooted No significant Categorized in No N/A 4 months N/A
(Smoking was (n = 8), defects thick (>1 mm) or
an exclusion periodontal thin (≤1 mm)
criterion) involvement Control: 6 thick
(n = 9), and 6 thin
endodontic Experimental: 8
failure (n = 2) and thick and 11
untreatable thin
caries (n = 12)

(Details on group
distribution not
reported)

N/R N/R Caries and root Single-­rooted No significant N/R No N/A 4 months N/A
fracture defects
(Details on group
distribution not
reported)

N/R N/R Severe Single-­rooted N/R N/R No N/A 3 months N/A

periodontal
disease and
prosthetic
reasons
(Details on group
distribution not
reported)

N/A N/R N/R Single-­rooted Most sites 1 mm apical to No N/A 3 months N/A
(Smoking was presented no the crest
an exclusion significant Control:
criterion) defects, but 1.58 ± 1.4
one control Experimental:
and three 1.15 ± 0.7
experimental
sockets
presented a
buccal
dehiscence
ranging from
3 to 6 mm

(Continues)
 |
14       AVILA-­ORTIZ et al.

TA B L E   1   (Continued)

Alveolar ridge
preservation
intervention(s) (We can
subclassify the
Study design Initial number of interventions after the Age
Publication(s) Parallel arms participants and data extraction is Socket sealed in distribution
Author(s) and year or split-­mouth distribution by groups Dropouts completed) ARP group(s) (years) Gender distribution

Barone, Toti, RCT 55 subjects for a total of 55 Yes Experimental 1: xenograft Yes Control: Control: 15 females/
Menchini-­Fabris, Parallel arms sockets A total of 12 (cortico-cancellous Porcine collagen 46.3 ± 11.1 7 males
et al. (2017) Divided into three groups: patients did porcine bone particles) membrane Experimental Experimental 1: 7
Control (n = 25), not complete and socket sealed with 1: 47.2 ± 10.2 females/4 males
Experimental 1 (n = 15) the study, absorbable collagen Experimental Experimental 2: 7
and Experimental 2 which resulted membrane 2: 50.7 ± 8.7 females/3 males
(n = 15) in a final Experimental 2:
sample of 22 xenograft (pre-­hydrated
sites in the collagenated
Control group, cortico-cancellous
11 sites in porcine bone particles)
Experimental and socket sealed with
Group 1 and absorbable collagen
10 sites in membrane
Experimental
Group 2

Barone, Toti, RCT 90 subjects for a total of 90 No Experimental 1: xenograft Yes Control: Control: 18 females/
Quaranta, et al. Parallel arms sockets (cortico-cancellous Porcine collagen 46.3 ± 11.1 2 males
(2017) Divided into three groups: porcine bone particles) membrane (range 28–70) Experimental 1: 20
Control (n = 30), and socket sealed with Experimental females/10 males
Experimental 1 (n = 30) porcine collagen 1: 47.2 ± 10.2 Experimental 2: 16
and Experimental 2 membrane (range 25–63) females/14 males
(n = 30) Experimental 2: Experimental
xenograft (pre-­hydrated 2: 50.7 ± 8.7
collagenated (range 31–64)
cortico-cancellous
porcine bone particles)
and socket sealed with
porcine collagen
membrane

Guarnieri et al. RCT 30 subjects for a total of 30 Yes Experimental 1: socket Yes Control: range Control: 4 females/5 males
(2017) Parallel arms sockets A total of 4 sealed with porcine Porcine collagen 21–56 Experimental 1: 6
Divided into three groups: patients did collagen membrane membrane Experimental females/3 males
Control (n = 10), not complete Experimental 2: 1: range Experimental 2: 2
Experimental 1 (n = 10) the study, xenograft (porcine bone 19–60 females/6 males
and Experimental 2 which resulted particles) and socket Experimental
(n = 10) in a final sealed with porcine 2: range
sample of 9 collagen membrane 20–63
sites in the
Control group,
9 sites in
Experimental
Group 1 and 8
sites in
Experimental
Group 2

Iorio-­Siciliano et al. RCT 20 subjects for a total of 20 No Xenograft (construct with Yes Control: Control: 4 females/6
(2017) Parallel arms sockets 90% bovine bone Porcine collagen 40.2 ± 12.1 males
Divided into two groups: granules and 10% membrane Experimental: Experimental: 5 females/
Control (n = 10) and porcine collagen) 38.2 ± 9.4 5 males
Experimental (n = 10) Socket sealed with
porcine collagen
membrane
AVILA-­ORTIZ et al. |
      15

Flap Primary Ridge Maximum implant

Inclusion of History of Reason(s) for Socket anatomy Socket Buccal bone elevation in closure in healing follow-­up time
smokers periodontitis extraction Single-­/multi-­rooted integrity thickness ARP group(s) ARP group(s) Time/Period after loading

Control: 2 N/R N/R Control: 8 No significant N/R No N/A 4 months N/A

smokers single-­rooted and defects
Experimental 14 multi-­rooted
1: 3 smokers Experimental 1: 4
Experimental single-­rooted and 7
2: No multi-­rooted
smokers Experimental 2: 6
single-­rooted and 4
multi-­rooted

Control: 5 N/R Control: Caries Control: 8 Sites Buccal bone No N/A 3 months N/A
smokers (n = 14), single-­rooted and presenting thickness
Experimental endodontic 22 multi-­rooted buccal bone <1.5 mm
1: 6 smokers (n = 3), fracture Experimental 1: 14 damage Control: 7/30
Experimental (n = 13) single-­rooted and Control: 13 Experimental 1:
2: 4 smokers Experimental 1: 16 multi-­rooted out of 30 20/30
Caries (n = 10), Experimental 2: Experimental Experimental 2:
endodontic 10 single-­rooted 1: 18 out of 14/30
(n = 16), fracture and 20 30
(n = 14) multi-­rooted Experimental
Experimental 2: 2: 10 out of
Caries (n = 14), 30
endodontic
(n = 6), fracture
(n = 10)

Control: 2 N/R N/R Control: 4 Variable Measured at No N/A 5–6 months N/A

smokers single-­rooted and 5 (At least 50% baseline and
Experimental multi-­rooted of the buccal categorized in a
1: 3 smokers Experimental 1: 6 bone wall dichotomous
Experimental single-­rooted and 3 must have way (<1.5 mm
2: 3 smokers multi-­rooted been present or ≥1.5 mm),
Experimental 2: 4 for inclusion) but specific
single-­rooted and 4 data per group
multi-­rooted not reported

N/A N/R N/R Combination of Unclear Buccal bone Yes No 6 months N/A
(Smoking was single-­ and thickness
an exclusion multi-­rooted teeth, <1.0 mm
criterion) but distribution per Control: 3/10
group is unclear Experimental:
6/10
 |
16       AVILA-­ORTIZ et al.
F I G U R E   4   Diagram illustrating risk of bias for all selected randomized clinical trials
into nine treatment modalities, namely (a) bovine bone particles
(BBP) + SS, (b) construct made of 90% bovine bone granules and
10% porcine collagen (BBG/PC) + SS, (c) cortico-­c ancellous por-
cine bone particles (CPBP) + SS, (d) allograft particles (AG) + SS, (e)
alloplastic material (AP) with or without SS, (f) autologous blood-­
derived products (ABDP), (g) cell therapy (CTh), (h) recombinant
morphogenic protein-­2 (rhBMP-2) and (i) SS alone. All these dif-
ferent ARP modalities were compared to the control therapy (i.e.
spontaneous socket healing) in each individual study. The specific
distribution of the nine treatment modalities by study, subcatego-
rized by primary or secondary intention healing, is displayed in
Table 2.
3.5 | Qualitative assessment of outcomes in
selected studies
3.5.1 | Clinical outcomes
The collected data pertaining to clinical outcomes of interest are dis-
played in Table S1.
Horizontal bone changes
Differences in horizontal bone changes between control and ex-
perimental groups assessed by direct clinical measurement were
reported in eleven studies (Aimetti et al., 2009; Barone et al., 2013;
Barone, Toti, Quaranta, et al., 2017; Cardaropoli et al., 2012, 2014,
2015; Festa et al., 2013; Guarnieri et al., 2017; Iasella et al., 2003;
Iorio-­Siciliano et al., 2017; Kotsakis et al., 2014; Pelegrine et al.,
2010; Spinato et al., 2014). In these studies, all ARP therapies ren-
dered more favourable results than the control.
Vertical bone changes
Differences in vertical bone changes between control and experi-
mental groups at the mid-­buccal were reported in 12 studies (Aimetti
et al., 2009; Barone et al., 2013; Barone, Toti, Quaranta, et al., 2017;
Cardaropoli et al., 2012, 2014, 2015; Festa et al., 2013; Guarnieri
et al., 2017; Iasella et al., 2003; Iorio-­Siciliano et al., 2017; Madan
et al., 2014; Pelegrine et al., 2010; Rasperini et al., 2010; Spinato
et al., 2014), while mid-­lingual changes were reported in nine stud-
ies (Aimetti et al., 2009; Barone et al., 2013; Barone, Toti, Quaranta,
et al., 2017; Festa et al., 2013; Guarnieri et al., 2017; Iasella et al.,
2003; Iorio-­Siciliano et al., 2017; Madan et al., 2014; Spinato et al.,
2014) and mesial and distal changes in five studies (Aimetti et al.,
2009; Barone et al., 2013; Iasella et al., 2003; Iorio-­Siciliano et al.,
2017; Madan et al., 2014). ARP therapies rendered more favourable
results than the control for all these vertical parameters, except in one
study in which there were no differences between groups in terms of
mesial and distal height changes (Iorio-­Siciliano et al., 2017). In one
study, it was observed that sites exhibiting a buccal bone thickness
of more than 1 mm at baseline were associated with more favour-
able horizontal, vertical mid-­buccal and vertical mid-­lingual linear
outcomes, regardless of the treatment group (Spinato et al., 2014).
Linear and volumetric soft tissue changes
Differences between groups in terms of horizontal soft tissue
changes were reported in four studies (Cardaropoli et al., 2012,
2014, 2015; Iasella et al., 2003; Jung et al., 2013; Schneider et al.,
2014; Thalmair et al., 2013), while mid-­buccal vertical soft tissue
changes were only reported in one study (Cardaropoli et al., 2012,
2014, 2015). None of the selected studies reported on mid-­lingual
vertical soft tissue changes between groups. Two studies reported
soft tissue volumetric (contour) differences between control and
different experimental groups (Barone, Toti, Menchini-­Fabris, et al.,
2017; Thalmair et al., 2013). For all soft tissue parameters analysed,
the results observed in association with the control group were con-
sistently inferior to the corresponding ARP treatment.
Implant-­related outcomes
Five studies reported on the feasibility of implant placement with
no additional bone grafting (Barone et al., 2013; Cardaropoli et al.,
TA B L E   2   Distribution of treatment modalities by study, subcategorized by primary (orange shading) or secondary intention healing (green shading)
AVILA-­ORTIZ et al.
|
      17
 |
18       AVILA-­ORTIZ et al.
2012, 2014, 2015; Fiorellini et al., 2005; Kotsakis et al., 2014;
Rasperini et al., 2010). ARP was strongly associated with a higher
chance of reducing the need for ancillary bone grafting prior to or
at the time of implant placement (range: 55–100%) as compared to
the control (range: 33.3–66%). Implant survival rate after a minimum
of 12 months post-­functional loading was reported in three stud-
ies (Cardaropoli et al., 2012, 2014, 2015; Kotsakis et al., 2014; Pang
et al., 2014), while implant success rate was presented in two studies
(Cardaropoli et al., 2012, 2014, 2015; Kotsakis et al., 2014), but no
differences between groups were observed for either outcome.
Complications
Only four studies reported the occurrence of complications (Alissa
et al., 2010; Araujo et al., 2015; Fiorellini et al., 2005; Temmerman
et al., 2016), but there did not seem to be a pattern of association
with any particular therapy.
3.5.2 | Radiographic outcomes
All radiographic outcomes of interest are shown in Table S1.
Differences between control and experimental groups in
terms of radiographic horizontal bone linear changes measured in
CBCT scan images were reported in four studies (Fiorellini et al.,
2005; Jung et al., 2013; Pang et al., 2014; Schneider et al., 2014;
Temmerman et al., 2016), while data on mid-­buccal and mid-­lingual
lingual radiographic changes were available in five (Araujo et al.,
2015; Fiorellini et al., 2005; Jung et al., 2013; Karaca et al., 2015;
Schneider et al., 2014; Temmerman et al., 2016) and four studies
(Araujo et al., 2015; Jung et al., 2013; Karaca et al., 2015; Schneider
et al., 2014; Temmerman et al., 2016), respectively. None of the se-
lected studies reported on radiographic linear changes at mesial and
distal sites. For all linear radiographic parameters, ARP therapies
consistently rendered more favourable results than the control, with
the exception of two studies (Araujo et al., 2015; Jung et al., 2013).
In the trial by Araujo et al., the control group exhibited slightly better
results in terms of radiographic mid-­buccal and mid-­lingual vertical
reduction as compared to the experimental therapy (BBG/PC + SS);
however, these differences were not clinically or statistically signifi-
cant. In the study by Jung et al., one of the three experimental ther-
apies, which consisted of the application of an alloplast (βTCP with a
polylactide–co-­glycolide coating) without any additional membrane,
rendered significantly inferior results as compared to the control in
terms of horizontal (−6.1 ± 2.5 mm vs. 3.3 ± 2.0 mm), mid-­buccal
(−2.0 ± 2.4 mm vs. −0.5 ± 0.9 mm) and mid-­lingual linear changes
(−1.7 ± 0.6 mm vs. −0.6 ± 0.6 mm).
Only one study reported on bone volumetric outcomes (Pang
et al., 2014), revealing less contour reduction in the experimen-
tal group compared to the control (−262.06 ± 33.08 mm3 vs.
−342.32 ± 36.41 mm3). Similarly, data on peri-­implant marginal bone
level changes were available only in one study (Cardaropoli et al.,
2012, 2014, 2015). In this study, mesial and distal pooled marginal
bone changes were virtually the same between the experimental
and the control group (0.33 ± 0.28 vs. 0.35 ± 0.28).
3.5.3 | Patient-­reported outcome measures
As shown in Table S1, only two studies reported PROMs (Alissa
et al., 2010; Temmerman et al., 2016). The results were compara-
ble between the experimental and the control group for all param-
eters of interest (i.e. reported discomfort, perceived benefit and
quality-­of-­life scores). Interestingly, these two are the only stud-
ies in the final selection that involved the application of ABDP,
particularly platelet-­rich plasma gel and leucocyte–platelet-­rich
fibrin clot.
3.6 | Pooled estimates (Quantitative Analyses)
Meta-­a nalyses were only performed if at least two studies within
the same ARP treatment modality reported on the same outcome
of interest. As depicted in Figure 3, of the 22 RCTs included in
this systematic review, 16 studies (Aimetti et al., 2009; Araujo
et al., 2015; Barone et al., 2013; Barone, Toti, Menchini-­Fabris,
et al., 2017; Barone, Toti, Quaranta, et al., 2017; Cardaropoli et al.,
2012, 2014, 2015; Festa et al., 2013; Guarnieri et al., 2017; Iasella
et al., 2003; Iorio-­S iciliano et al., 2017; Jung et al., 2013; Kotsakis
et al., 2014; Madan et al., 2014; Rasperini et al., 2010; Schneider
et al., 2014; Spinato et al., 2014; Thalmair et al., 2013) could be
employed to conduct meta-­a nalyses for a total of six comparisons.
Studies were subdivided in function of the anatomy of the
treated extraction sites (single-­or multi-­rooted) when feasible.
3.6.1 | Comparison 1—All bone substitutes
versus Control
Three outcomes of interest could be analysed.
Outcome 1.1. Clinical horizontal bone change (mm):
There was strong evidence of a reduced amount of alveolar bone
resorption for ARP-­SG using a bone substitute compared to control
therapy (p < 0.00001, MD = 1.99 mm, 95% CI 1.54–2.44, χ2 = 96.82,
df = 11, p < 0.00001, I2 
= 89.0%). Particulate bovine xenografts
(MD = 2.24 mm, CI 0.10–4.39), porcine xenografts (MD = 2.25 mm,
CI 1.86–2.64) and particulate allografts (MD = 2.01 mm, CI 0.54–
3.48), in combination with an absorbable collagen membrane or a
rapidly absorbable sponge, rendered more favourable results than
collagenated bovine xenografts covered with a collagen membrane
(MD = 1.20 mm, CI 0.14–2.26) or alloplastic materials left exposed or
covered with a rapidly absorbable collagen sponge (MD = 1.25 mm,
CI 0.79–1.71), as displayed in Figure 5.
Outcome 1.2. Clinical vertical mid-­buccal bone change (mm):
There was strong evidence of a reduced amount of alveolar
bone resorption for ARP-­S G using a bone substitute (i.e. xeno-
graft with SS, allograft with SS or alloplastic material without
SS) compared to control therapy (p < 0.00001, MD = 1.72 mm,
95% CI 0.96–2.48, χ 2 = 479.96, df = 10, p < 0.00001, I 2 = 98.0%).
Collagenated bovine xenografts covered with a collagen
AVILA-­ORTIZ et al.
F I G U R E   5   Forest Plot for Outcome 1.1
membrane (MD = 2.62 mm, CI −2.52 to 7.76) and alloplastic ma-
terials left exposed (MD = 2.21 mm, CI −0.73 to 5.15) rendered
more favourable results than porcine xenografts covered with
a collagen membrane (MD = 1.76 mm, CI 1.29–2.23) or particu-
late allograft covered with a rapidly absorbable collagen sponge
(MD = 1.33 mm, CI 0.81–1.86), as displayed in Figure 6.
Outcome 1.3. Clinical vertical mid-­lingual bone change (mm):
There was strong evidence of a reduced amount of alveolar
bone resorption for ARP-­S G using a bone substitute (i.e. xeno-
graft with SS, allograft with SS or alloplastic material without SS)
compared to control therapy (p < 0.00001, MD = 1.16 mm, 95%
2 2
CI 0.81–1.52, χ  = 38.72, df = 8, p < 0.00001, I  = 79.0%). Porcine
xenografts covered with a collagen membrane (MD = 1.82 mm,
CI 0.99–2.65) or particulate allograft covered with a rapidly
absorbable collagen sponge (MD = 1.17 mm, CI 0.57–1.78) ren-
dered more favourable results than collagenated bovine xeno-
grafts covered with a collagen membrane (MD = 0.60 mm, CI
0.13–1.07) or alloplastic materials left exposed (MD = 0.69 mm,
CI −0.17 to 1.54), as displayed in Figure 7.
|
      19
3.6.2 | Comparison 2—BBP with SS versus Control
Only one outcome of interest could be analysed.
Outcome 2.1. Clinical horizontal bone change (mm):
There was evidence of a reduced amount of alveolar bone re-
sorption for BBP + SS (with a porcine collagen membrane or sponge)
compared to control therapy (p = 0.04, MD = 2.24 mm, 95% CI 0.10–
4.39, χ2 = 35.01, df = 1, p < 0.00001, I2 = 97.0%).
3.6.3 | Comparison 3—BBG/PC with SS
versus Control
Three outcomes of interest could be analysed.
Outcome 3.1. Clinical vertical mid-­buccal bone change (mm):
Although the weighed MD showed a positive effect in favour of
the ARP-­SG therapy, there was insufficient evidence of a difference
between BBG/PC + SS (with a porcine collagen membrane) and con-
trol (p = 0.32, MD = 2.62 mm, 95% CI −2.52 to 7.76, χ2 = 2.80, df = 1,
p = 0.09, I2 = 64.0%).
 |
20       AVILA-­ORTIZ et al.
F I G U R E   6   Forest Plot for Outcome 1.2
Outcome 3.2. Radiographic vertical mid-­buccal bone change (mm):
There was insufficient evidence of a difference between BBG/
PC + SS (with autologous soft tissue punch) and control (p = 0.75,
MD = 0.37 mm, 95% CI −1.86 to 2.59, χ2 = 5.28, df = 1, p = 0.02,
I2 = 81.0%).
Outcome 3.3. Radiographic vertical mid-­lingual bone change (mm):
There was insufficient evidence of a difference between BBG/
PC + SS (with autologous soft tissue punch) and control (p = 0.76,
MD = 0.13 mm, 95% CI −0.70 to 0.96, χ2 = 4.00, df = 1, p = 0.05,
I2 = 75.0%).
3.6.4 | Comparison 4—CPBP with SS versus Control
Five outcomes of interest could be analysed.
Outcome 4.1. Clinical horizontal bone change (mm):
There was evidence of a reduced amount of alveolar bone resorp-
tion for CPBP + SS (with a porcine collagen membrane or autologous
tissue punch) compared to control therapy (p < 0.0001, MD = 2.25 mm,
95% CI 1.86–2.64, χ2 = 10.27, df = 3, p = 0.02, I2 = 71.0%).
Outcome 4.2. Clinical vertical mid-­buccal bone change (mm):
There was evidence of a reduced amount of alveolar bone re-
sorption for CPBP + SS (with a porcine collagen membrane or au-
tologous tissue punch) compared to control therapy (p < 0.0001,
MD = 1.76 mm, 95% CI 1.29–2.23, χ2 = 14.15, df = 3, p = 0.003,
I2 = 79.0%).
Outcome 4.3. Clinical vertical mid-­lingual bone change (mm):
There was evidence of a reduced amount of alveolar bone resorp-
tion for CPBP + SS (with a porcine collagen membrane or autologous
tissue punch) compared to control therapy (p < 0.0001, MD = 1.82 mm,
95% CI 0.99–2.65, χ2 = 11.89, df = 3, p = 0.003 I2 = 83.0%).
Outcome 4.4. Clinical vertical mesial bone change (mm):
There was insufficient evidence of a difference between
CPBP + SS (with a porcine collagen membrane or autologous tissue
punch) and control (p = 0.18, MD = 0.40 mm, 95% CI −0.19 to 0.99,
χ2 = 4.91, df = 1, p = 0.03, I2 = 80.0%).
Outcome 4.5. Clinical vertical distal bone change (mm):
AVILA-­ORTIZ et al.
F I G U R E   7   Forest Plot for Outcome 1.3
There was insufficient evidence of a difference between
CPBP + SS (with a porcine collagen membrane or autologous tissue
punch) and control (p = 0.20, MD = 0.39 mm, 95% CI −0.20 to 0.97,
2 2
χ  = 5.00, df = 1, p = 0.03, I  = 80.0%).
3.6.5 | Comparison 5—AG with SS versus Control
Three outcomes of interest could be analysed.
Outcome 5.1. Clinical horizontal bone change (mm):
There was evidence of a reduced amount of alveolar bone re-
sorption for AG (freeze-­dried bone particles) + SS (with a collagen
membrane or sponge) compared to control therapy (p = 0.008,
MD = 2.01 mm, 95% CI 0.54–3.48, χ2 = 29.71, df = 2, p < 0.00001,
I2 = 93.0%). Noteworthy, data from one study (Spinato et al., 2014)
revealed that sites exhibiting >1 mm of buccal bone thickness at
baseline underwent less horizontal bone resorption, as compared
to sites presenting a buccal bone thickness of ≤1 mm (average
horizontal bone reduction values were 1.29 ± 0.2 mm in sites with
thick bone and 3.22 ± 0.2 mm in sites with thin bone).
Outcome 5.2. Clinical vertical mid-­buccal bone change (mm):
There was evidence of a reduced amount of alveolar bone re-
sorption for AG (freeze-­d ried bone particles) + SS (with a collagen
|
      21
membrane or sponge) compared to control therapy (p < 0.00001,
MD = 1.33 mm, 95% CI 0.81–1.86, χ2 = 3.35, df = 2, p = 0.19,
I 2 = 40.0%). Data from one study (Spinato et al., 2014) revealed
that sites exhibiting >1 mm of buccal bone thickness at baseline
underwent less vertical mid-­b uccal bone resorption, as compared
to sites presenting a buccal bone thickness of ≤1 mm (average
horizontal bone reduction values were 0.88 ± 0.3 mm in sites
with thick bone and 1.44 ± 0.2 mm in sites with thin bone).
Outcome 5.3. Clinical vertical mid-­lingual bone change (mm):
There was evidence of a reduced amount of alveolar bone re-
sorption for AG (freeze-­dried bone particles) + SS (with a collagen
membrane or sponge) compared to control therapy (p = 0.0001,
MD = 1.17 mm, 95% CI 0.57–1.78, χ2 = 4.09, df = 2, p = 0.13,
I2 = 51.0%). Buccal bone thickness did not appear to influence the
outcomes for this specific clinical parameter (Spinato et al., 2014).
3.6.6 | Comparison 6—AP with or without SS
versus Control
Three outcomes of interest could be analysed.
Outcome 6.1. Clinical horizontal bone change (mm):
 |
22       AVILA-­ORTIZ et al.
There was evidence of a reduced amount of alveolar bone re-
sorption for AP (calcium sulphate hemihydrate or calcium phospho-
silicate putty) with (rapidly absorbable collagen sponge) or without
SS compared to control therapy (p < 0.00001, MD = 1.25 mm, 95%
CI 0.79–1.71, χ2 = 0.02, df = 1, p = 0.90, I2 = 0%).
Outcome 6.2. Clinical vertical mid-­buccal bone change (mm):
Although the weighed MD showed a positive effect in fa-
vour of the ARP-­SG therapy, there was insufficient evidence of a
difference between AP (calcium sulphate hemihydrate or poly-
lactide–polyglycolide sponge) without SS and control therapy
(p = 0.14, MD = 2.21 mm, 95% CI −0.73 to 5.15, χ2 = 113.49, df = 1,
p < 0.00001, I2 = 99.0%).
Outcome 6.3. Clinical vertical mid-­lingual bone change (mm):
Although the weighed MD showed a positive effect in favour
of the ARP-­SG therapy, there was insufficient evidence of a differ-
ence between AP (calcium sulphate hemihydrate or polylactide–
polyglycolide sponge) without SS and control therapy (p = 0.12,
MD = 0.69 mm, 95% CI −0.17 to 1.54, χ2 = 8.70, df = 1, p = 0.003,
I2 = 89.0%).
4 |  D I S CU S S I O N
4.1 | General considerations on the scope of this
systematic review
This systematic review was focused on evaluating the effect of
different ARP therapeutic modalities performed immediately
after extraction of molar and non-­m olar teeth, when delayed
implant placement or the delivery of a tooth-­s upported FDP
is intended, in function of clinical, radiographic and patient-­
reported outcomes of interest, as compared to tooth extraction
alone. Clinical scenarios involving immediate implant placement
were outside of the scope of this review. In an effort to both ad-
here to high methodological standards and to maximize the clin-
ical applicability of the findings reported in this review, several
measures were taken. First, a priori eligibility criteria were es-
tablished with the objective of including proper RCTs performed
under conditions that would be reflective of standard of care
in contemporary daily practice (e.g. surgical re-­e ntry for im-
plant placement at 3–6 months after tooth extraction). Second,
qualitative and quantitative analyses of the extracted data were
conducted in function of nine different groups of ARP treat-
ment modalities identified in the 22 RCTs included in this sys-
tematic review (Aimetti et al., 2009; Alissa et al., 2010; Araujo
et al., 2015; Barone et al., 2013; Barone, Toti, Menchini-­Fabris,
et al., 2017; Barone, Toti, Quaranta, et al., 2017; Cardaropoli
et al., 2012, 2014, 2015; Festa et al., 2013; Fiorellini et al.,
2005; Guarnieri et al., 2017; Iasella et al., 2003; Iorio-­S iciliano
et al., 2017; Jung et al., 2013; Karaca et al., 2015; Kotsakis et al.,
2014; Madan et al., 2014; Pang et al., 2014; Pelegrine et al.,
2010; Rasperini et al., 2010; Schneider et al., 2014; Spinato
et al., 2014; Temmerman et al., 2016; Thalmair et al., 2013), as
shown in Table 2. Third, outcomes of interest relevant to the
aim of this review (i.e. critically analyse the available evidence
regarding the effect of different modalities of ARP as com-
pared to extraction alone) were selected and subdivided into
three categories (i.e. clinical, radiographic and patient-­r eported
outcomes). Histologic and histomorphometric outcomes were
intentionally not included in this systematic review. This is be-
cause, although pertinent to gain further understanding on the
biological characteristics of the tissue formed following the ap-
plication of different biomaterials (Barallat et al., 2014; Chan
et al., 2013; Corbella et al., 2017), they do not provide valuable
information to evaluate the effect of ARP as an approach that is
primarily aimed at minimizing the reduction of the alveolar ridge
after tooth extraction to subsequently facilitate implant place-
ment, and to enhance implant and patient-­r eported outcomes.
Fourth, quantitative analyses were only performed if at least
two studies within the same ARP treatment modality reported
on the same outcome of interest.
4.2 | Summary of main findings, applicability of
evidence and potential limitations
4.2.1 | Qualitative analyses of outcomes of interest
Qualitative analyses indicated that ARP consistently rendered
more favourable results in terms of horizontal, mid-­b uccal and
mid-­lingual bone preservation as compared to extraction alone,
with the exception of one clinical trial (Araujo et al., 2015). In
this study, although not clinically, nor statistically significant, the
control group exhibited slightly better results in terms of radio-
graphic mid-­b uccal and mid-­lingual vertical reduction as compared
to the experimental therapy (BBG/PC + SS using a porcine colla-
gen membrane). This could be explained due to methodological
discrepancies in the data collection and anatomical differences
(anterior vs. posterior) between the extraction sites included in
each group, as acknowledged by the authors of the original arti-
cle. ARP was also superior to the control in terms of feasibility of
implant placement without additional bone grafting upon surgi-
cal re-­e ntry, independently of the therapeutic modality applied.
On the contrary, other outcomes such as mesial and distal bone
height changes, implant success and survival rates, and marginal
bone loss after functional loading were not substantially different
between treatment groups.
PROMs were reported in two studies involving the use of autol-
ogous blood-­derived products (Alissa et al., 2010; Temmerman et al.,
2016). In these two studies, reported discomfort, perceived benefit
and quality-­of-­life scores, although marginally in favour of ARP ther-
apies, were very similar between the experimental and the control
group. The effect of other ARP modalities on PROMs could not be
investigated, as these outcomes were not reported in any other clin-
ical trial.
AVILA-­ORTIZ et al.
4.2.2 | Quantitative analyses of
outcomes of interest
Quantitative analyses for Comparison 1 revealed that ARP-­S G
using a bone substitute (i.e. xenograft with SS, allograft with SS
or alloplastic material with or without SS) was clearly superior
to the control in terms of preservation of horizontal bone width
(1.99 mm [95% CI: 1.54–2.44; p < 0.00001]), mid-­b uccal bone
height (1.72 mm [95% CI: 0.96–2.48; p < 0.00001]) and mid-­
lingual bone height (1.99 mm [95% CI: 0.81–1.52; p < 0.00001]),
measured clinically. Overall, these findings are in alignment
with the results of quantitative analyses reported in previous
systematic reviews on this topic (Atieh et al., 2015; Avila-­O rtiz
et al., 2014; MacBeth et al., 2017; Troiano et al., 2017; Vignoletti
et al., 2012; Vittorini Orgeas et al., 2013; Willenbacher et al.,
2016).
Additionally, this systematic review, which to our knowledge rep-
resents the most comprehensive analysis of the evidence regarding
the effect of ARP compared to extraction alone to date, involved
the conduction of pooled estimates exploring the effect of specific
ARP-­SG treatment modalities. Several of these specific analyses pro-
vided strong evidence indicating that ARP-­SG therapy was superior
to the control, particularly in terms of horizontal, mid-­buccal and
mid-­lingual bone preservation measured clinically. This is shown in
the forest plots for Outcomes 2.1 (clinical horizontal bone change
between control and BBP + SS for a MD of 2.24 mm), 4.1 (clinical
horizontal bone change between control and CPBP + SS for a MD
of 2.25 mm), 4.2 (clinical vertical mid-­buccal bone change between
control and CPBP + SS for a MD of 1.76 mm), 4.3 (clinical vertical
mid-­buccal bone change between control and CPBP + SS for a MD
of 1.82 mm), 5.1 (clinical horizontal bone change between control
and AG + SS for a MD of 2.01 mm), 5.2 (clinical vertical mid-­buccal
bone change between control and AG + SS for a MD of 1.33 mm),
5.3 (clinical vertical mid-­lingual bone change between control and
CPBP + SS for a MD of 1.17 mm) and 6.1 (clinical horizontal bone
change between control and AP with and without SS for a MD of
1.25 mm). For these comparisons, xenograft and allografts rendered
more favourable results than alloplastic materials, which is in agree-
ment with the findings from a previous systematic review (Avila-­
Ortiz et al., 2014).
Although the weighed MD showed a strong positive effect in
favour of the ARP-­S G therapy for Outcomes 3.1 (clinical horizon-
tal bone change between control and BBG/PC + SS for a MD of
2.62 mm) and 6.2 (clinical vertical mid-­b uccal bone change be-
tween control and AP for a MD of 2.21 mm), the strength of the
evidence may be questionable due to the marked heterogeneity
observed between pooled studies. This could be explained on
the basis of important methodological differences. For example,
one of the two RCTs that evaluated the effect of BBG/PC + SS in
terms of clinical horizontal bone change (i.e. Outcome 2.1) only
included molar sites (Rasperini et al., 2010), while the other trial
combined the data obtained from single-­rooted and multi-­rooted
sites (Iorio-­S iciliano et al., 2017). For the rest of the outcomes (i.e.
|
      23
3.2, 3.3, 4.4, 4.5 and 6.3), although in favour of ARP-­S G therapy,
there was insufficient evidence to claim superiority over the con-
trol, as the MD was ≤0.6 mm for all comparisons. Interestingly,
the vast majority of comparisons (16 out of 18) were based on
clinical outcome measures, which illustrates the need for further,
well-­conducted RCTs involving the collection of radiographic and
patient-­reported data using standardized methods. It is important
to remark that one of the potential limitations of this systematic
review is the total number of studies included in some of the sub-
category meta-­a nalyses, which calls for caution when interpreting
these findings.
Another option for the assessment of the effects of different
ARP treatment modalities would have been the use of Bayesian
network meta-­analysis. This type of estimates has been proposed
to increase the statistical power, as well as to permit indirect com-
parisons among different therapies with the purpose of facilitating
the clinical applicability of the findings (Ades et al., 2006; Faggion,
Chambrone, Listl, & Tu, 2013; Rabelo et al., 2015; Tu, Needleman,
Chambrone, Lu, & Faggion, 2012). Bayesian network meta-­
analyses may be conducted if the studies of interest present simi-
lar clinical scenarios and a comparable methodology. However, the
precision of these analyses can be significantly reduced if the in-
herent characteristics of the studies are substantially discrepant.
Therefore, in the light of the high degree of clinical heterogeneity
that exists between the majority of trials included (e.g. smoking
habits, anatomy and integrity of the sockets, flap elevation, fol-
low-­up period and methods use for the assessment of outcomes,
among others), the conduction of a network meta-­analysis was not
justified, which could be considered a limitation of this systematic
review.
4.2.3 | Potential influence of local and systemic
factors on outcomes of interest
With the exception of buccal bone thickness (in Comparison 5),
the effect of other local and systemic factors in the observed
outcomes could not be assessed as part of the quantitative
analyses. This is mainly due to insufficient data reported and/
or marked methodological discrepancies in the study protocols
of the selected clinical trials. For example, influence of history
of periodontitis could not be assessed, since it was not reported
in any of the articles included in this review. Also, feasibility of
implant placement with no need for ancillary grafting could not
be analysed because this is a dichotomic variable associated to
a high level of subjectivity. Whether the presence of an alveolar
bone defect influences the outcomes of ARP therapy could not
be ascertained either, due to the wide heterogeneity of eligibil-
ity criteria and clinical descriptions provided in the few selected
studies that included non-­intact extraction sites (Barone, Toti,
Quaranta, et al., 2017; Fiorellini et al., 2005; Guarnieri et al.,
2017; Jung et al., 2013; Rasperini et al., 2010; Schneider et al.,
2014; Temmerman et al., 2016). Similarly, the effect of sealing
the alveolar socket as a sole modality could not be assessed
 |
24       AVILA-­ORTIZ et al.
because it was frequently combined with socket grafting in the
majority of studies included in this systematic review (Araujo
et al., 2015; Barone et al., 2013; Barone, Toti, Menchini-­Fabris,
et al., 2017; Barone, Toti, Quaranta, et al., 2017; Cardaropoli
et al., 2012, 2014, 2015; Festa et al., 2013; Guarnieri et al.,
2017; Iasella et al., 2003; Iorio-­S iciliano et al., 2017; Jung et al.,
2013; Kotsakis et al., 2014; Pang et al., 2014; Rasperini et al.,
2010; Schneider et al., 2014; Spinato et al., 2014; Thalmair et al.,
2013).
Although the conduction of quantitative analyses was not
feasible for other variables aside from buccal bone thickness on
the basis of the selected evidence, some conclusions from a qual-
itative perspective may be withdrawn. Smoking did not seem to
significantly affect the observed outcomes in the selected studies
that allowed for the inclusion of smokers and had a comparable
distribution among treatment groups (Barone, Toti, Quaranta,
et al., 2017; Guarnieri et al., 2017; Thalmair et al., 2013). Regarding
socket anatomy, of the 22 RCTs, a total of 8 studies included a
mix of single-­and multi-­rooted teeth (Alissa et al., 2010; Barone
et al., 2013; Barone, Toti, Menchini-­Fabris, et al., 2017; Barone,
Toti, Quaranta, et al., 2017; Cardaropoli et al., 2012, 2014, 2015;
Guarnieri et al., 2017; Iorio-­S iciliano et al., 2017; Kotsakis et al.,
2014). Although none of these studies specifically aimed at evalu-
ating whether there were any differences in the outcomes of ARP
therapy in function of the anatomical features of the extraction
site (i.e. single-­vs. multi-­rooted sites), in the light of the available
evidence, this does not appear to be an influential factor (Walker
et al., 2017). In accordance with previously published clinical
studies (Engler-­H amm, Cheung, Yen, Stark, & Griffin, 2011; Kim
et al., 2013) and one systematic review (Avila-­O rtiz et al., 2014),
attempting primary closure following flap elevation did not ap-
pear to provide an additional benefit in terms of ARP (Alissa et al.,
2010; Festa et al., 2013; Fiorellini et al., 2005; Pang et al., 2014;
Pelegrine et al., 2010). Analysing implant-­related outcomes, it was
observed that ARP was strongly associated with a higher chance
of reducing the need for bone grafting prior to or at the time of
implant placement. This is in agreement with a previous system-
atic review (Mardas et al., 2015).
4.2.4 | Quality of the evidence
The overall quality of the evidence of the included studies was
average to low. None of the selected studies met all criteria of
the Cochrane Collaboration's tool for assessing risk of bias. In
fact, most of the included studies (n = 12) exhibited a high risk
of bias (Barone et al., 2013; Barone, Toti, Menchini-­Fabris, et al.,
2017; Barone, Toti, Quaranta, et al., 2017; Iasella et al., 2003;
Iorio-­Siciliano et al., 2017; Jung et al., 2013; Karaca et al., 2015;
Kotsakis et al., 2014; Madan et al., 2014; Pang et al., 2014; Spinato
et al., 2014; Temmerman et al., 2016); therefore, the information
presented in this systematic review should be interpreted with
caution.
5 | CO N C LU S I O N S
1. On the basis of the qualitative and quantitative analyses
performed as part of this systematic review, it can be con-
cluded that ARP is an effective approach to attenuate the
dimensional reduction of the alveolar ridge that normally
takes place after tooth extraction as compared to tooth ex-
traction alone. Therefore, in clinical scenarios in which min-
imizing alveolar ridge reduction is priority, ARP should be
considered in conjunction with minimally traumatic tooth
extraction.
2. Pooled analyses combining different ARP-SG treatment modalities
revealed that the beneficial effects of this therapy seem to be
more pronounced in preventing horizontal bone resorption, fol-
lowed by vertical mid-buccal and vertical mid-lingual bone
changes.
3. Whether there is a superior ARP-SG or SS approach could not be
determined on the basis of the selected evidence.
4. Based on the selected evidence, no further conclusions on the use
of cell therapy, rhBMP-2 and autologous blood-derived products
for ARP therapy may be extracted.
5. Although ARP-SG was strongly associated with a higher chance
of reducing the need for bone grafting prior to or at the time of
implant placement, no definite conclusions may be drawn on
the beneficial effects of ARP on implant-related outcomes,
such as implant survival/success rate and marginal bone level
changes.
6. Future research in this topic should involve the conduction of
properly designed randomized clinical trials adhering to the
most current version of the CONSORT statement (www.con-
sort-statement.org) aimed at evaluating the effect of different
ARP treatment modalities on the basis of relevant endpoints of
interest that go beyond conventional radiographic and clinical
linear assessments (e.g. volumetric dimensional outcomes, im-
plant-related and patient-reported outcome measures).
Additionally, these studies should incorporate well-described,
reproducible outcome assessment methods to allow for direct
comparisons of different ARP therapies in future systematic
reviews. There is also a need for clinical studies aimed at pre-
cisely evaluating the effect of local, systemic and surgical pro-
cedure-related variables (e.g. smoking status, history of
periodontitis, alveolar ridge anatomy and integrity, flap eleva-
tion, primary closure, SS modality) on the outcomes of ARP
therapy.
AC K N OW L E D G E M E N T S
Gustavo Avila-­Ortiz would like to acknowledge the American
Academy of Periodontology Foundation for the support provided
to pursue a career in academics. The authors would also like to ac-
knowledge Mr. Ken Rieger, graphic designer, for his contributions to
create Figures 1 and 2.
AVILA-­ORTIZ et al.
C O N FL I C T O F I N T E R E S T
Gustavo Avila-­Ortiz declares having received support for the con-
duction of research projects and lecture fees from Osteogenics
Biomedical, Geistlich Pharma and Dentsply Implants, and support
to conduct research from Sunstar Americas and BioHorizons. He is
also a member of the Osteology Foundation Expert Council and the
developing team of The Box (https://box.osteology.org).
Fabio Vignoletti declares having received support for the conduc-
tion of research projects and lecture fees from Sunstar, Osteogenics
Biomedical, Dentium, Osteology Foundation, Geistlich Pharma, MIS
Implants and Sweden Martina.
Dr. Leandro Chambrone declares no conflicts of interest.
ORCID
Gustavo Avila-Ortiz  https://orcid.org/0000-0002-5763-0201
Leandro Chambrone  https://orcid.org/0000-0002-2838-1015
Fabio Vignoletti  https://orcid.org/0000-0002-4574-3671
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 |
28       AVILA-­ORTIZ et al.

of Clinical Periodontology, 40, 721–727. https://doi.org/10.1111/ APPENDIX 1

jcpe.12111 Search Strategy
Troiano, G., Zhurakivska, K., Lo Muzio, L., Laino, L., Cicciu, M.,
#1 tooth extraction OR extraction OR dental extraction OR extrac-
& Lo Russo, L. (2017). Combination of bone graft and re-
sorbable membrane for alveolar ridge preservation: A sys- tion, tooth OR tooth socket
tematic review, meta-­ a nalysis and trial sequential analysis. #2 bone grafting OR biomaterial OR autogenous bone OR autologous
Journal of Periodontology, ???, 1–17. https://doi.org/10.1902/ bone OR xenogenous bone OR autograft OR allograft OR xenograft OR
jop.2017.170241
alloplastic OR bone substitutes OR soft tissue substitute OR cell
Trombelli, L., Farina, R., Marzola, A., Bozzi, L., Liljenberg, B., & Lindhe,
J. (2008). Modeling and remodeling of human extraction sock- therapy
ets. Journal of Clinical Periodontology, 35, 630–639. https://doi. #3 1#AND#2
org/10.1111/j.1600-051X.2008.01246.x #4 alveolar ridge preservation OR ridge preservation OR socket
Tu, Y. K., Needleman, I., Chambrone, L., Lu, H. K., & Faggion,
grafting OR socket filling OR socket preservation OR socket graft
C. M. Jr (2012). A Bayesian network meta-­a nalysis on
comparisons of enamel matrix derivatives, guided tis- OR guided bone regeneration OR alveolar ridge augmentation
sue regeneration and their combination therapies. Journal #5 #3AND#4
of Clinical Periodontology, 39, 303–314. https://doi.
org/10.1111/j.1600-051X.2011.01844.x
APPENDIX 2
Van der Weijden, F., Dell’Acqua, F., & Slot, D. E. (2009). Alveolar bone di-
List of articles excluded based on content after full-­text review
mensional changes of post-­extraction sockets in humans: A system-
atic review. Journal of Clinical Periodontology, 36, 1048–1058. https:// and reason for exclusion
doi.org/10.1111/j.1600-051X.2009.01482.x
Articles excluded Reason for exclusion
Vignoletti, F., Matesanz, P., Rodrigo, D., Figuero, E., Martin,
C., & Sanz, M. (2012). Surgical protocols for ridge preser- Kentros et al. (1985) Not an RCT—case series
vation after tooth extraction. A systematic review. Clinical No control group
Oral Implants Research, 23(Suppl 5), 22–38. https://doi. Kangvonkit et al. (1986) Data from the 3-­ and 6-­month time
org/10.1111/j.1600-0501.2011.02331.x points not reported
Vittorini Orgeas, G., Clementini, M., De Risi, V., & de Sanctis, M. (2013).
Bolouri et al. (1995) No outcomes of interest reported
Surgical techniques for alveolar socket preservation: A systematic
review. International Journal of Oral and Maxillofacial Implants, 28, Boyne et al. (1995) Animal study
1049–1061. https://doi.org/10.11607/jomi.2670 Lekovic et al. (1998) Non-­randomized clinical trial
Walker, C. J., Prihoda, T. J., Mealey, B. L., Lasho, D. J., Noujeim, M., &
Camargo et al. (2000) Non-­randomized clinical trial
Huynh-Ba, G. (2017). Evaluation of healing at molar extraction sites
with and without ridge preservation: A randomized controlled clinical Hahn et al. (2003) Not an RCT—case report
trial. Journal of Periodontology, 88, 241–249. https://doi.org/10.1902/ No control group
jop.2016.160445 Serino et al. (2003) Non-­randomized clinical trial
Weng, D., Stock, V., & Schliephake, H. (2011). Are socket and ridge
Nevins et al. (2006) No outcomes of interest reported
preservation techniques at the day of tooth extraction efficient in
(radiographic horizontal width
maintaining the tissues of the alveolar ridge? European Journal of Oral
changes measured at 6 mm
Implantology, 4, 59–66.
subcrestal)
Willenbacher, M., Al-Nawas, B., Berres, M., Kammerer, P. W., &
Schiegnitz, E. (2016). The effects of alveolar ridge preservation: A Barone et al. (2008) Assessment of outcomes at
meta-­analysis. Clinical Implant Dentistry and Related Research, 18, ≥7 months
1248–1268. https://doi.org/10.1111/cid.12364 Serino et al. (2008) No outcomes of interest reported
Wolleb, K., Sailer, I., Thoma, A., Menghini, G., & Hammerle, C. H.
Cardaropoli et al. (2010) Invalid control group (fibrin sponge
(2012). Clinical and radiographic evaluation of patients receiving
was applied)
both tooth-­and implant-­supported prosthodontic treatment after
5 years of function. The International Journal of Prosthodontics, 25, Casado et al. (2010) Non-­randomized clinical trial
252–259. Oghli et al. (2010) Included subjects younger than
18 years of age
Brownfield et al. (2012) Assessment of outcomes at
S U P P O R T I N G I N FO R M AT I O N
10–12 weeks
Additional supporting information may be found online in the Flipek et al. (2012) Invalid control group (socket was
Supporting Information section at the end of the article. Including all sealed by flap advancement)
forest plots corresponding to comparisons 2 to 6.  Sisti et al. (2012) Assessment of outcomes at 8 weeks
Canuto et al. (2013) No outcomes of interest reported

How to cite this article: Avila-Ortiz G, Chambrone L, Hauser et al. (2013) Surgical re-­entry at 8 weeks and no
outcomes of interest reported
Vignoletti F. Effect of alveolar ridge preservation
Suttapreyasri et al. (2013) Assessment of outcomes at 8 weeks
interventions following tooth extraction: A systematic review
maximum
and meta-­analysis. J Clin Periodontol. 2019;00:1–29. https://
doi.org/10.1111/jcpe.13057
AVILA-­ORTIZ et al.
Articles excluded
Avila-­Ortiz et al. (2014)
Barboza et al. (2014)
Kim et al. (2014)
Lindhe et al. (2014)
Mahesh et al. (2014)
De Sarkar et al. (2015)
Flügge et al. (2015)
Goh et al. (2015)
Loveless et al. (2015)
Ribeiro et al. (2015)
Abdelhamid et al. (2016)
Araujo-­Pires et al. (2016)
Joshi et al. (2016)
Mayer et al. (2016)
Pang et al. (2016)
Zadeh et al. (2016)
Alzahrani et al. (2017)
View publication stats
Reason for exclusion
Invalid control group (a collagen plug
was applied)
No outcomes of interest reported
Invalid control group (bone graft was
applied)
No outcomes of interest reported
No outcomes of interest reported
No outcomes of interest reported
No outcomes of interest reported
Invalid control group (socket was
sealed by flap advancement)
No outcomes of interest reported
No outcomes of interest reported
No outcomes of interest reported
No outcomes of interest reported
Invalid control group (socket was
sealed with a membrane)
Invalid control group (socket was
sealed by flap advancement)
Insufficient information to collect
data for any outcomes of
interest
No outcomes of interest reported
Assessment of outcomes at 8 weeks
maximum
|
      29
Articles excluded Reason for exclusion
Fickl et al. (2017) Outcomes of interest not reported as
a mean value and the corresponding
SD
Geishari et al. (2017) Invalid control group (bone graft was
applied)
Jiang et al. (2017) No outcomes of interest reported
Joshi et al. (2017) Invalid control group (socket was
sealed with a membrane)
Kivovics et al. (2017) No outcomes of interest reported
Levi et al. (2017) Assessment of outcomes between 6
and 11 months
Mozzati et al. (2017) No outcomes of interest reported
Assessment of outcomes at 8 weeks
maximum
Sbordone et al. (2017) Non-­randomized clinical trial
Walker et al. (2017) Invalid control group (a collagen plug
was applied)
Aimetti et al. (2018) Assessment of outcomes at
12 months
Al Qabbani et al. (2018) Invalid control group (socket was
sealed with a membrane)
Kumar et al. (2018) Not a proper split-­mouth RCT
Nunes et al. (2018) Invalid control group (a collagen
membrane was applied)
Tomasi et al. (2018) Invalid control group (a collagen
membrane was applied)
Zhao et al. (2018) Non-­randomized clinical trial