Clinical Oral Investigations

https://doi.org/10.1007/s00784-021-04248-1

REVIEW

Dimensional and histomorphometric evaluation of biomaterials used

for alveolar ridge preservation: a systematic review and network
meta-analysis
L. Canullo1   · M. Del Fabbro2,3 · S. Khijmatgar2 · S. Panda2,4 · A. Ravidà5 · G. Tommasato3 · A. Sculean1 · P. Pesce6

Received: 22 April 2021 / Accepted: 23 October 2021

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Objectives  This systematic review and network meta-analysis aimed to answer to the following questions: (a) In patients
undergoing alveolar ridge preservation after tooth extraction, which grafting material best attenuates horizontal and vertical
ridge resorption, as compared to spontaneous healing?, and (b) which material(s) promotes bone formation in the extraction
socket?
Materials and methods  The MEDLINE, SCOPUS, CENTRAL, and EMBASE databases were screened in duplicate for
RCTs up to March 2021. Two independent authors extracted the data and assessed the risk of bias of the included studies.
Primary outcomes were ridge horizontal and vertical dimension changes and new bone formation into the socket. Both pair-
wise and network meta-analysis (NMA) were undertaken to obtain estimates for primary outcomes and compare different
grafting materials.
Results  Eighty-eight RCTs were included, with a total of 2805 patients and 3073 sockets. Overall, a total of 1740 sockets
underwent alveolar ridge preservation with different materials (1432 were covered by a membrane). Pairwise meta-analysis
showed that, as compared to spontaneous healing, all materials statistically significantly reduced horizontal and vertical
shrinkage. According to the multidimensional scale ranking of the NMA, xenografts (XG) and allografts (AG), alone or
combined with bioactive agents (Bio + AG), were the most predictable materials for horizontal and vertical ridge dimension
preservation, while platelet concentrates performed best in the percentage of new bone formation.
Conclusions  Alveolar ridge preservation is effective in reducing both horizontal and vertical shrinkage, as compared to
untreated sockets. NMA confirmed the consistency of XG for ridge dimension preservation, but several other materials and
combinations like AG, Bio + AG, and AG + alloplasts, produced even better results than XG in clinical comparisons. Further
evidence is needed to confirm the value of such alternatives to XG for alveolar ridge preservation. Bio + AG performed better
than the other materials in preserving ridge dimension and platelet concentrates in new bone formation. However, alloplasts,
xenografts, and AG + AP performed consistently good in majority of the clinical comparisons.
Clinical relevance  XG and Bio + AG demonstrated significantly better performance in minimizing post-extraction horizontal
and vertical ridge dimension changes as compared with other grafting materials or with spontaneous healing, even if they
presented the worst histological outcomes. Allografts and other materials or combinations (AG + AP) presented similar
performances while spontaneous healing ranked last.

Keywords  Alveolar ridge preservation · Bone graft · Xenograft · Alloplast · Allograft · Platelet concentrate · Systematic
review · Network meta-analysis

Introduction
L. Canullo and M. Del Fabbro contributed equally to this work.
Tooth loss is classified among the most prevalent conditions
The manuscript represents the proceedings of a consensus that affect the global population [1]. Even if preservation
conference of the Italian Society of Osseointegration (IAO, https://​
of the dentition should always be the first treatment choice
www.​iao-​online.​com).
at the time of treating patients [2], dental extractions are
Extended author information available on the last page of the article unavoidable when a tooth cannot be successfully treated [3,

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 Clinical Oral Investigations

4]. It has been demonstrated that after tooth explanation, the biomaterials were incorporated within newly formed bone
surrounding alveolar bone resorbs both on the vestibular and and were inactive until the resorption of these particles took
lingual aspects [5–9]. Araujo and Lindhe concluded in an place.
animal study that the buccal bone plates both in the maxilla Several systematic reviews and meta-analyses of rand-
and the mandible resorbed considerably more than the cor- omized clinical trials compared specific preservation modal-
responding palatal/lingual bony walls and that the center of ities and tooth extraction followed by spontaneous healing
the ridge shifted palatally/lingually as a result [9]. Huynh-Ba [3, 4, 26]. However, to the best of our knowledge, only two
[10] demonstrated that the vertical reduction of the buccal network meta-analyses (NMA) have been published so far
bony crest is more evident in the aesthetic zone, due to the on alveolar ridge preservation [27, 28]. As opposed to tra-
thin buccal wall predominantly composed of bundle bone in ditional pairwise meta-analysis, NMA combines indirect
this area. Schropp [11] stated that approximately two-thirds evidence, in order to make inferences on the effects of treat-
of this reduction occurred in the first 3 months after sur- ments that have not been directly compared. Iocca et al. [28]
gery. Moreover, a systematic review by Van der Weijden [8] evaluated bone height (only on the buccal side) and width
reported a weighted mean alveolar ridge reduction of 3.87 reduction and included only six RCTs published up to Janu-
mm in width and 1.67 mm in height in the first 3 months and ary 1, 2016; hence, missing several materials were more
a 63% and 22% reduction after 6 months. Recently, the most recently documented. Canellas et al. [27] only focused on
important aspects of bone biology and the healing outcomes histomorphometric outcomes. In the latter study, the authors
related to the self-regenerative capacity (i.e., without the did not attempt aggregation of similar materials (they esti-
placement of any biomaterial) of bone defects that occur mated the probability of a given material of being ranked
following tooth extraction have been reviewed. The current first among 34 different grafting materials and sealing tech-
evidence from animal and human studies indicates that intra- niques), which resulted in high fragmentation of the results,
oral bone defects possess a high self-regenerative capacity with consequent low strength of the findings. No NMA
but a number of factors such as extent of bone loss, presence investigated the dimensional clinical changes together with
of bony walls, closed healing environment, space provision, percentage of newly formed bone after ridge preservation
and mechanical wound stability substantially influence heal- with different grafting materials, to date. Hence, the aim of
ing/regeneration [12]. the present updated systematic review and network meta-
In order to reduce bone resorption and the necessity for analysis was to evaluate and compare the efficacy of different
bone augmentation prior to implant placement, different grafting materials for alveolar ridge preservation after tooth
techniques such as socket shield [13–15], orthodontic extru- extraction.
sion [14–16], orthodontic extrusion [16–18], and alveolar
ridge preservation (ARP) have been proposed.
A wide variety of ARP treatment modalities and graft Materials and methods
materials have been described in the past 25 years; however,
none of these approaches is considered ideal [19, 20]. Bio- This review was conducted following the PRISMA guide-
materials such as autogenous bone, allografts (demineral- lines (http://​www.​prisma-​state​ment.​org/). The review pro-
ized freeze-dried bone allograft (DFDBA), or freeze-dried tocol was registered with PROSPERO (submission no.
bone allograft (FDBA)), xenografts (deproteinized bovine CRD42020196275).
bone mineral (DBBM), porcine bone, coralline calcium
carbonate), alloplastic materials (bioactive glass particles, Focused questions (dimensional changes)
hydroxyapatite, tricalcium phosphate), absorbable collagen
sponges, biologics (recombinant human bone morphogenetic 1) After alveolar ridge preservation, what is the material
protein-2 (rhBMP-2) and platelet-rich plasma/platelet-rich that best preserves the dimensions of the ridge horizon-
fibrin (PRP/PRF)), and tooth-derived grafts have been used tally and vertically assessed clinically or radiographi-
[21–23]. cally at any follow-up after the surgical intervention?
Recent review by Atieh concluded after reviewing 16 2) Does ARP decrease the horizontal and vertical resorp-
RCTs that ARP may minimize the overall changes in height tion of the ridge compared with spontaneous healing?
and width in 6 months but stated evidence was uncertain.
The review also found that there was no significant difference Patient, intervention, comparison, outcome, time
between grafting materials and barriers used for ARP [20]. question — dimensional changes
From a histological point of view, controversial results
have been observed when comparing the percentage of The focused questions were elaborated following the PICOT
newly formed bone in natural healing and ridge preservation format (Stone, 2002 [29]), where:
sites [24]. Araujo [25] demonstrated that several of these Patients (P): adult patients undergoing tooth extraction

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Clinical Oral Investigations

Intervention (I): ARP using different grafting materi- or vertical dimensional changes of the alveolar bone with
als: autogenous AU, bone marrow aspirates (MA), xeno- any follow-up after extraction or quantitative morphometric
grafts (XG), allografts (AG), alloplastic grafts (including data regarding the amount of newly formed vital bone after
synthetic bioceramics, polymers, and other synthetic bio- extraction. Non-RCTs, animal studies, and in vitro studies
materials) (AP), autogenous tooth grafts (ATG), bioactive were excluded.
agents (including autologous platelet concentrates, recom-
binant factors, statins, or other substances enhancing bone Search strategy
regeneration) (BIO)
Comparison (C): All possible comparisons among the A literature search was carried out using electronic data-
included interventions were explored, including non-inter- bases (MEDLINE (PubMed), EMBASE, Cochrane Cen-
vention (spontaneous healing). tral Register of Controlled Trials, and Scopus), using an
Outcome (O): Horizontal and vertical dimensional ad hoc search string that was adapted to each database:
changes, clinically or radiographically assessed (((((((“tooth extraction”) OR “socket”) OR “alveolus”)
Time (T): Any follow-up after the surgical intervention OR “dental extraction”)) AND ((((((((((“bone grafts”) OR
“biomaterials”) OR “autografts”) OR “collagen”) OR “cell
Focused questions (new bone formation) therapy”) OR “platelet concentrates”) OR “alloplasts”) OR
“allografts”) OR “xenograft”) OR “bioceramic scaffolds”)))
1) After alveolar ridge preservation, what is the mate- AND (((((“alveolar ridge preservation”) OR “socket pres-
rial that best consent to produce more bone formation ervation”) OR “socket grafting”) OR “socket filling”) OR
assessed histologically at any follow-up after the surgi- “ridge maintenance”). The last electronic search was car-
cal intervention? ried out on March 2021. A hand search was also performed
2) Does ARP affect the percentage of new bone formation in the following journals: British Dental Journal; British
compared with spontaneous healing? Journal of Oral and Maxillofacial Surgery; Clinical Implant
Dentistry and Related Research; Clinical Oral Implants
Patient, intervention, comparison, outcome, time Research; Clinical Oral Investigations; European Journal
question — new bone formation of Oral Implantology; European Journal of Oral Sciences;
Implant Dentistry; International Journal of Oral and Maxil-
Patients (P), intervention (I), and comparison (C) were the lofacial Implants; International Journal of Oral and Maxil-
same of the aforementioned PICOT. lofacial Surgery; International Journal of Periodontics and
Outcome (O): percentage of new bone formation evalu- Restorative Dentistry; Journal of Clinical Periodontology;
ated from a bone biopsy, histologically assessed Journal of Dental Research; Journal of Dentistry; Journal of
Time (T): Any follow-up period after the surgical Maxillofacial & Oral Surgery; Journal of Oral and Maxillo-
intervention facial Surgery; Journal of Periodontal Research; Journal of
Periodontology; Oral Surgery, Oral Medicine, Oral Pathol-
Eligibility criteria ogy, and Oral Radiology; and Endodontology.
The reference lists of all identified RCTs and relevant sys-
Only randomized controlled trials assessing the efficacy of tematic reviews were scanned for possible additional studies.
grafting materials for preservation of hard tissues in patients Online registries providing information about in progress
undergoing tooth extraction were included. Both parallel and clinical trials were checked (http://​clini​caltr​ials.​gov/; http://​
split-mouth designs were considered. Studies were included www.c​ enter​ watch.c​ om/c​ linic​ altri​ als/; http:// www.c​ linic​ alco​
only if a test group used one grafting material, or combina- nnecti​ on.c​ om/). No language restriction was placed. We also
tions of such materials in various proportions, and was com- searched for grey literature, such as conference abstracts,
pared with a control group represented by spontaneous heal- proceedings, and theses, on the following databases: www.​
ing (SH) (with/without a rapidly absorbable collagen plug greyl​it.​org; www.​openg​rey.​eu.
inside the socket) or a different grafting material. The studies
which included the same material in both test and control Study selection
groups (e.g., xenograft vs. collagenated xenograft, or xeno-
graft of bovine vs. porcine origin, or synthetic bioceramics Two reviewers (SP, GT) independently screened the titles
in different proportions, or the same material covered by a and abstracts of the retrieved articles to identify all eligi-
resorbable vs. a non-resorbable membrane) were excluded. ble studies that met the inclusion criteria. The agreement
Studies with more than two arms, treating at least 10 patients between examiners was assessed by using the Cohen’s
(at least 5 patients per each group), were considered. Stud- Kappa statistics. When the abstract was not available or was
ies were included only if they presented data of horizontal not sufficient to allow unequivocal evaluation, the full text

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 Clinical Oral Investigations

was obtained. Publications that did not meet the selection Blinding of participants and personnel (performance bias)
criteria were excluded. Disagreements were resolved by dis- was not considered, because in socket preservation, neither
cussion or by consulting a third reviewer (MDF). The full the surgeon nor the patient can be efficiently masked to the
text of all the eligible articles was obtained. Three reviewers bone graft material used, especially if it is autogenous bone.
(SP, GT, SK) assessed the features of each study to confirm The reviewers contacted the authors of the identified studies
inclusion for data analysis or to exclude the study. The rea- for clarification or to provide missing information.
sons for exclusion at this stage were noted. Studies were classified as follows: low risk of bias (plau-
sible bias unlikely to seriously alter results) if all criteria
Data collection were judged adequate; moderate risk of bias (plausible bias
that raises some doubt about the results) if one or more cri-
Relevant data relative to the study protocol (e.g., study teria were considered unclear; or high risk of bias (plausi-
design, country, sponsor, use of flap or flapless technique, ble bias that seriously weakens confidence in the results) if
antibiotic prescription, material used, coverage employed, one or more criteria were judged inadequate. The criteria
presence or absence of the buccal wall, smoking status of for assessing the risk of bias of RCTs were adapted from
included patients, percentage of new bone, complications) the tool reported in the Cochrane Handbook for Systematic
were extracted from the included studies and collected on Reviews of Interventions. Disagreement between the two
a predetermined datasheet for subsequent analysis. Two reviewers was resolved by discussion or by consulting with
authors (GT, PP) independently extracted the data, and a a third reviewer (MDF). Publication bias for the main com-
third author (MDF) finally reviewed the dataset. parisons was assessed using funnel plot.
The studied outcome measures were:
Data analysis
1) Horizontal dimensional changes of the alveolar socket
(in mm), measured clinically or radiographically at Since the outcome of socket preservation may be affected by
the level of the crest, or at different vertical distances a number of factors like the position of the tooth, the bone
from the crest or from landmarks (i.e., adjacent teeth or graft material, the surgical technique (e.g., flap or flapless or
implants). Only data at comparable level (i.e., crestal, or the use of a membrane), the baseline condition of the socket
at the level of 3 mm from the crest) were merged. (e.g., presence or absence of buccal or vestibular/lingual walls
2) Vertical dimensional changes of the alveolar socket (in and wall thickness), the post-operative management (e.g., tak-
mm) measured clinically or radiographically either at ing antibiotics or not), and the patient’s individual response,
the level of the crest or at the buccal and palatal/lingual a random-effects model according to DerSimonian and Laird
aspect. [30] was considered appropriate to address this variability.
3) Percentage of newly formed bone. Both pairwise and network meta-analysis were undertaken to
obtain estimates for primary outcomes. The estimate of effect
Mean values and standard deviations for primary out- of an intervention was expressed as mean differences (MDs)
comes were extracted or, when possible, estimated. When an along with 95% confidence intervals (CIs). Heterogeneity
article did not provide the mean values and standard devia- among included studies was assessed using Cochran’s test
tions, or when data were missing, the corresponding author for heterogeneity, considering a significance threshold of P
was contacted in order to provide missing information. In < 0.1. Quantification of the heterogeneity was estimated with
case of no or unsatisfactory reply, the study was excluded. I2 statistics, which describes the total percentage of variation
across studies that is due to heterogeneity rather than chance.
Risk of bias assessment Substantial heterogeneity was considered when I2 > 50%. The
software RevMan (Review Manager Version 5.4, 2020; The
Two reviewers (SP, SK) evaluated the methodological qual- Nordic Cochrane Center, The Cochrane Collaboration, Copen-
ity of the included studies independently and in duplicate as hagen, Denmark) was used for pairwise meta-analysis com-
part of the data extraction process. The risk of bias of the putations. Data from split-mouth and parallel group studies
included trials was assessed based on the following criteria: were combined using the generic inverse variance procedure
randomization method, concealed allocation of treatment, in RevMan. Meta-analysis was undertaken only when at least
blinding of outcome assessors, completeness of outcome three studies with similar comparisons and reporting the same
assessment reporting, completeness of information on rea- outcome measures were found. When feasible, missing stand-
sons for withdrawal by trial group, other biases (sample ard deviations were estimated using the methods described in
size calculation, definition of inclusion/exclusion criteria, the Section 7.7.3 of the Cochrane Handbook for Systematic
and comparability of control and test groups at entry). All Reviews of Interventions, Version 5.1.0 (Higgins 2011). In
such criteria were scored as adequate/inadequate/unclear. addition, a subgroup and meta-regression meta-analysis was

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Clinical Oral Investigations

performed considering confounders impact of heterogeneity studies or grey literature were found. After screening based
and results. on title and abstract, 179 studies were identified as eligible.
For network meta-analysis, prediction intervals (PrIs) After full text evaluation of these studies, 91 studies were
were calculated to predict effects in a future clinical set- excluded, the main reason for exclusion being summarized in
ting by incorporating heterogeneity. The results of all direct Supplementary Table 1. The kappa value for inter-reviewer
and mixed comparisons were presented in forest plots. The agreement was 0.88 and 0.90 for title/abstract screening
latter were augmented with contours of effect magnitude and full-text articles selection, respectively, thus indicating
based on multiples of the mean standard deviation of the very good agreement. Eighty-eight RCTs were included, and
included outcome (10%): 0–10%—clinically irrelevant the main features are briefly described in Supplementary
effect, 10–20%—moderate effect, 20–30%—large effect, Table 2. Supplementary Tables 3 and 4 describe the main
and >30%—very large effect. In order to estimate the rela- outcomes of these studies. Sixty-six studies had a parallel
tive ranking of treatments using probabilities, surface under design, and 22 had a split-mouth design. Sponsorship was
the cumulative ranking curves (SUCRA) was used. SUCRA declared in 27 studies. Almost all studies were conducted
is a simple transformation of the mean rank and is used to in university. Overall, 2805 patients were treated, and the
provide a hierarchy of the interventions, accounting both mean age of included patients ranged from 30.2 to 67.8 years
for the location and the variance of all relative treatment (total age range 18–84 years). The follow-up duration ranged
effects. The larger the SUCRA value, the better the rank of from 2 to 24 months. A total of 1333 sockets were used as
the treatment. Multidimensional ranking (MDS rank) was controls, of which 1012 were left to heal spontaneously. The
also used to rank the competing treatments, based on the number of sockets treated in test groups was 1740. In total,
similarities and dissimilarities between any two treatments. 1432 sites were covered by a membrane. Only three stud-
MDS consists of multivariate techniques for the analysis ies specifically included sockets in which the buccal wall
of proximity data and synthesizes the results on a 2-axis was absent [32–34], while information on the presence or
plot. It provides some insights on the differences in effect absence of the buccal wall was not reported in two studies
size among treatments, also accounting for the inconsist- [35, 36]. Fifty-one studies used a flapless approach. Thirty-
ency in the network of interventions. The MDS rank graph four studies left the sockets heal by primary intention, 53
would have “0” value in the centre and the left side would by secondary intention, and one [37] did not specify the
have negative values (more favorable outcome) and right healing type. Antibiotics were prescribed in 66 studies.
side positive values (less favorable outcome). All analyses Twenty-nine studies did not report about complications, 46
were done with Stata version 16 (StataCorp, College Station, studies reported no complications, 11 studies reported very
TX, USA) by one author (SK), with the commands xtgee, few complications like extra-alveolar hematoma, or swelling
metan, mvmeta, network, and the routines from Chaimani in 1 to 3 patients per group, and one study [38] reported a
et al. [31]. A two-tailed P-value of 0.05 was considered sig- very detailed analysis of adverse events, listing a total of 52
nificant for hypothesis testing. mild events and 2 moderate events.
The number of studies selected for network meta-analysis
was based on the different materials used in each group. Dimensional changes
Information regarding the mean difference, SD, type of treat-
ment, and number of subjects was extracted from clinical After full text evaluation of these studies, 74 RCTs inves-
studies. Three separate network meta-analyses were under- tigating dimensional changes after socket preservation pro-
taken, one for horizontal changes, one for vertical dimension cedures were included and their main outcomes are synthe-
changes, and one for histological data. In situations where sized in Supplementary Table 3 [22, 32–34, 37–106].
only one study was identified for a given comparison, the
study was excluded from the analysis because there would Histological data
be network (geometry) disconnection and no further analysis
would be possible. The reason for exclusion of such studies Forty-five RCTs investigating histological and histomorpho-
was “data not comparable to other studies.” metric changes of bone biopsies taken after socket preser-
vation procedures were included, and their main outcomes
are synthesized in Supplementary Table 4. One study used
Results micro-CT to evaluate new bone formation [37]. The data of
four studies [32, 35, 70, 107] could not be used for network
Study selection meta-analysis, because they caused network disconnection.
In total, 45 studies were included in quantitative analysis.
Figure 1 is a flowchart of the study selection process. The Thirty-two studies had a parallel design [22, 35, 37, 38, 41,
search strategy yielded a total of 2730 items. No ongoing 45, 47, 49, 51, 55, 56, 58, 59, 75, 82, 85, 86, 88–90, 92–94,

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 Clinical Oral Investigations

Fig. 1  PRISMA flowchart of
the study selection process

98, 100, 103, 105, 108–115], and 10 studies had split-mouth Nineteen studies were judged as exhibiting a low risk of
design [32, 36, 63, 66, 71, 104, 107, 116–118]. bias [35, 37–40, 44–48, 53, 54, 58, 59, 83–88, 97, 98,
107–111, 117, 118], fourteen were associated with a high
Risk of bias analysis risk [39, 42, 51, 60, 64, 76, 79, 83, 85, 87, 94, 96], and the
remaining fifty-five had a moderate risk.
Figure 2 and Supplementary Fig. 1 show the risk of bias
graph and table, respectively, of the included studies.

Fig. 2  Risk of bias (ROB)

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Clinical Oral Investigations

Funnel plots showed for both SH vs. XG and SH vs. AG [22, 36, 45, 49, 56, 58, 63, 103, 110, 112, 114, 115]. There
comparisons the presence of a publication bias, suggestive was a significant lower new bone formation when using xen-
of substantial between-study heterogeneity (Fig. 3). ografts, as compared to blood clot at 3–4 months (−13.11%
(95% CI [−25.52 to −0.71], p = 0.04)), and a non-significant
Alveolar ridge preservation vs. spontaneous healing trend for lower new bone formation when using xenografts
(pairwise meta‑analysis) at 5–7 months (−10.37% (95% CI [−34.12 to 13.38], p =
0.39)). Six studies showed a significant effect in favor of
The following comparisons underwent traditional unassisted healing [22, 45, 103, 110, 112, 115], and two
meta-analysis: studies showed a significant effect in favor of xenografts [56,
116]. There was highly significantly heterogeneity among
Spontaneous healing vs. xenografts — dimensional studies (p < 0.00001). A multiple subgroup analysis was
changes (Suppl Fig. 2A‑B) demonstrated in supplementary file (Suppl Fig. 2D). Meta-
regression analysis was carried out using random effect
Twenty studies were divided according to the follow-up models to assess the relationship between study level covari-
duration into two subgroups: 3–4 months and 5–7 months’ ates and effect size. The covariate-like method was found to
post-extraction. One study provided data for both 3 and 6 be significant (p < 0.0001).
months [43]. Overall, there was evidence of a significantly
reduced horizontal bone loss in favor of xenografts at 3 Spontaneous healing vs. allografts — dimensional changes
(−1.89 mm (95% CI [−2.55 to −1.23], p < 0.01)) and 6 (Suppl Fig. 3A‑B)
months (−0.87 mm (95% CI [−1.57 to −0.17], p = 0.01))
(Suppl Fig. 2). Similar results were found for the changes in Based on ten studies, there was a trend for a reduced dimen-
the vertical dimension at 3 (−0.72 mm (95% CI [−1.03 to sional shrinkage in groups using allografts, as compared to
−0.40], p < 0.01)) and 6 months (−0.40 mm (95% CI [−0.81 spontaneous healing. There was a not-significant reduced
to −0.02], p = 0.06)) (Suppl Fig. 2B). Significant heteroge- horizontal bone change at 3–4 months (−0.42 mm (95% CI
neity among studies was found in all cases (p < 0.00001). [−0.92 to −0.09], p = 0.11)) in favor of allograft and at 6
months (−0.19 mm (95% CI [−1.01 to 0.63], p = 0.65))
Spontaneous healing vs. xenografts — new bone formation (Suppl Fig. 3A). However, significance was reached for ver-
(Suppl Fig. 2C) tical changes at both 3–4 months (−0.85 (95% CI [−1.13
to −0.56], p < 0.00001)) and 6 months (−0.81 mm (95%
Twelve studies were included and divided according to the CI [−1.21 to −0.42], p < 0.0001)), with an overall effect in
follow-up time in two groups (3–4 months and 5–7 months). favor of allografts (−0.95 mm (95% CI [−1.07 to −0.63], p

Fig. 3  A Publication bias for SH vs. XG in dimensional outcome. metric, more weightage was given to smaller studies. If larger studies
The funnel plot is clearly asymmetric with larger standard errors need to be given weightage, then inverse standard error metric should
reporting larger effective sizes than the more precise studies sugges- be used as shown below. B Publication bias for SH vs. AG. Majority
tive of publication bias. In the absence of publication bias and het- of the studies are outside the given pseudo 95% CIs, showing that a
erogeneity, the studies expected to lie within the pseudo 95% CIs and publication bias exists
hence inverted funnel plot shape. Since we have used standard error

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 Clinical Oral Investigations

< 0.00001)) (Suppl Fig. 3B). There was moderate hetero- Spontaneous healing vs. platelet concentrates —
geneity among studies, but not for the vertical change at 6 dimensional changes (Suppl Fig. 5A‑B)
months.
Based on eight studies, there was a significant reduced
Spontaneous healing vs. allografts — new bone formation dimensional shrinkage in groups using platelet concentrates,
(Suppl Fig. 3C) as compared spontaneous healing. This comparison achieved
significance for both horizontal (−0.26 mm (95% CI [−0.35
Based on eight studies, there was a significant difference to −0.18], p < 0.0001)) (Suppl Fig. 5A) and vertical changes
in new bone formation between groups using allografts, (−0.53 mm (95% CI [−0.62 to −0.44], p < 0.00001)) (Suppl
as compared to blood clot both in the 3–4-month group Fig. 5B). Significant heterogeneity among studies was found
(−15.19% (95% CI [−29.68 to −0.69], p = 0.04)) and a not for both horizontal and vertical changes (p < 0.0001).
statistically significant difference in the 5–6-month group
(−2.69% (95% CI [−16.55 to −11.17], p = 0.70)), with a Spontaneous healing vs. platelet concentrates — new bone
slight trend in favor of the latter. There was highly significant formation (Suppl Fig. 5C)
heterogeneity among studies (I2 = 80%, p < 0.0001).
A multiple subgroup analysis was demonstrated in sup- Based on five studies, there was significant evidence for a
plementary file (Suppl Fig. 3D). Meta-regression analysis beneficial effect of using platelet concentrates as an adjunct
was carried out using random effect models to assess the to favor healing of the post-extraction socket (14.22% (95%
relationship between study level covariates and effect size. CI [3.95 to 24.48], p = 0.007)). Anitua et al. and Stumbras
The covariate-like method was found to be significant (p et al. [111, 115] used PRGF (plasma rich in growth fac-
< 0.0001). The meta-regression for SH vs. AG in vertical tors), Clark et al. [41] and Hauser et al. [37] used A-PRF
outcomes was not possible due to collinearity. (advanced-platelet-rich fibrin), and the study by Ntounis
et al. [35] used PRP (platelet-rich plasma). In the latter
Spontaneous healing vs. alloplasts — dimensional changes study, PRP was mixed to FDBA and compared to FDBA
(Suppl Fig. 4A‑B) alone. Significant heterogeneity was found among studies
(p = 0.007).
Based on eleven studies, there was a trend for a reduced
dimensional shrinkage in groups using alloplasts, as com- Comparison between the different grafting
pared to spontaneous healing. Similar to allografts, this materials and spontaneous healing — dimensional
trend reached significance for horizontal changes at 3–4 changes (network meta‑analysis)
months (−0.90 mm (95% CI [−1.65 to −0.14], p = 0.02))
but not at 6 months (0.76 mm (95% CI [−0.84 to 2.35], p = Figure 4 A shows the network geometrical plot for overall
0.35)) (Suppl Fig. 4A). Significance was reached for verti- horizontal dimension changes. The size of the blue circles is
cal changes at both 3–4 months (−0.93 mm (95% CI [−1.78 proportional to sample size for any given material, while the
to −0.08], p = 0.03)) and at 6 months (−0.92 mm (95% CI thickness of the lines connecting two circles is proportional
[−1.37 to −0.47], p < 0.0001)) (Suppl Fig. 4B). Significant to the number of studies comparing the two treatments. Xen-
heterogeneity among studies was found (p < 0.0001). ografts, allografts, platelet concentrates, and alloplasts were
in that order the most highly represented materials among
Spontaneous healing vs. alloplasts — new bone formation those compared with spontaneous healing. Figure 4B shows
(Suppl Fig. 4C) the effect size and the confidence interval for each material
as compared with spontaneous healing (“Con”). Values to
Based on six studies [36, 45, 51, 85, 109, 113], there was no the left of the vertical blue line indicate favorable outcomes
significant difference in new bone formation between groups for the test material. Confidence intervals (black horizontal
using alloplasts, as compared to blood clot in the 3–4-month lines), not crossing the blue line, indicate significant differ-
group (63.8% (95% CI [−10.90 to 5.72], p = 0.54)); how- ences with respect to control groups and demonstrate that
ever, there was a statistically significant difference in the most materials displayed a significantly favorable outcome
5–6-month groups (36.2% (95% CI [1.11 to 27.12], p = as compared to spontaneous healing. Based on Fig. 4C,
0.03)). Highly significant heterogeneity was found among xenografts and Bio + AG displayed the most favorable out-
studies. Alloplasts used were the following: biphasic cal- come in the preservation of alveolar sockets in the horizon-
cium sulfate (CaS) with hydroxyapatite (HA) [45], biphasic tal dimension, followed by allografts, alloplasts, and other
CaS/HA and beta-tricalcium phosphate (TCP) [85], HA and materials, or combinations. Figure 4D illustrates the multi-
TCP [109], magnesium-HA [36], bioactive glass [113], and dimensional scale ranking for all the biomaterials, and XG
medical-grade calcium sulfate hemihydrate [51]. and AG ranked least dissimilar materials.

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Clinical Oral Investigations

Fig. 4  A Network geometrical plot for overall horizontal dimension ranked material 76.7% in overall and 81.3% in long-term follow-up
changes. B The effect size and the confidence interval for each mate- (>6 months) followed by alloplast 79.0% in short-term follow-up
rial as compared with spontaneous healing. C The SUCRA ranking (2–4 months) suggestive of better clinical performance. Xenograft
for the horizontal dimension clinical outcome for various graft mate- was ranked consistently better in all the comparisons. D Multidimen-
rials used for alveolar ridge preservation. Bio + AG was the highest sional scale ranking for overall horizontal dimension changes

Figure 5 A illustrates the network geometrical plot for Comparison based on short‑ and long‑term
overall vertical dimensional changes. Figure  5B shows follow‑ups
the effect size and predictive and the confidence intervals
for each material as compared with spontaneous healing Horizontal dimension
(“Con”). Values to the left of the vertical blue line indicate
favorable outcomes for the test material. Confidence inter- Suppl Fig.  6A illustrates the network geometry plot for
vals (black horizontal lines) not crossing the blue line indi- horizontal outcome with a follow-up period between 2 and
cate significant differences with respect to control groups. 4 months in socket preservation. Suppl Fig. 6B illustrates
Bio + AG, XG, AG, and AP resulted in significantly bet- predictive interval (Prl) and confidence interval plot (Crl).
ter outcomes compared to spontaneous healing. Based on Values to the left of the vertical blue line indicate favorable
SUCRA ranking in Fig. 5C, Bio + AG showed the most outcomes for the test material. Confidence intervals (black
favorable outcome for the preservation of the alveolar socket horizontal lines) not crossing the blue line indicate signifi-
in the vertical dimension, followed by allografts, allografts cant differences with respect to control groups. Xenografts
combined with bioactive agents, alloplasts, and other mate- would be the most likely material that would perform better
rials. Spontaneous healing was clearly in the last position. in short term in future clinical studies. Xenografts (XG),
Figure 5 D graphically illustrates the multidimensional allografts (AG), allografts + bioactive agents (Bio + AG),
ranking of the different materials. and alloplasts (AP) have better outcomes as compared to
control group (Con). Suppl Fig. 6C illustrates the multidi-
mensional scale ranking for different materials. Xenografts
followed by alloplasts and combination of allograft with
biologic showed the most favorable outcome for the preser-
vation of the alveolar socket in short-term follow-up based
on SUCRA rankings.

Fig. 5  A Network geometrical plot for overall vertical dimensional overall, 91.6 in short-term follow-up (2–4 months), and 84.5% in
changes. B The effect size and the confidence intervals for each mate- long-term follow-up. Among buccal and lingual regeneration, AG
rial as compared with spontaneous healing. C SUCRA ranking for + AP (buccal) and alloplast (lingual) ranked higher. D Multidimen-
vertical dimension clinical outcome for various graft materials used sional scale ranking for overall vertical dimensional changes.
for alveolar ridge preservation. Bio + AG ranked highest 86.8% in

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 Clinical Oral Investigations

Similarly, Suppl Fig. 7A and Suppl Fig. 7B illustrate net- better in future clinical studies (Suppl Fig. 9B). Mul-
work geometry plot and predictive interval plot, respectively, tidimensional scale ranking (Suppl Fig. 9C) suggests
for ≥6-month follow-up period for horizontal outcome. In that the combination of allografts with biologics and
Fig. 3C, SUCRA ranking, with Bio + AG and XG group, xenografts (2) are the most dissimilar materials among
shows the most favorable horizontal outcome for preserva- the materials used in the clinical studies.
tion of alveolar socket after ≥6-month follow-up. Suppl In summary, Bio + AG performed better in over-
Fig. 7C illustrates the multidimensional scale rank for the all and long-term (≥6 months) horizontal outcome in
materials which were followed for ≥6 months. AP and Bio preserving alveolar socket and alloplast short term
+ AP are ranked higher in dissimilarity and XG ranked least. (Fig. 3C). Also, for short-term and long-term follow-
ups in vertical dimension outcome, Bio + AG and XG
Vertical dimension have favorable outcomes in preserving alveolar socket
(Fig. 4C).
Suppl Fig. 8A, Suppl 8B, and Suppl 8C illustrate network
geometry plot, predictive interval plot, and multidimen-
sional ranking for vertical dimension outcome in socket New bone formation data
preservation with a follow-up period of 2–4 months,
respectively. SUCRA ranking is illustrated in Fig. 4C. Prl Figure 6 A shows the network geometrical plot for all the
and Crl plot (Suppl Fig. 8B) illustrates platelet concen- comparisons. Xenografts, allografts, and alloplasts were
trates (PC) along with xenografts (XG), allografts (AG), the most represented materials among those compared
and alloplasts (AP) most likely to perform better in future with blood clot.
clinical studies as compared to control group. Bio + AG Figure 6 B is the predictive interval plot and PC group
ranked highest 86.8% in overall, 91.6 in short-term follow- resulted significantly superior to XG, AG, AP, and control.
up (2–4 months), 84.5% in long-term follow-up. Among More detailed explanations are given in the figure legend.
buccal and lingual regeneration, AG + AP (buccal) and Based on the outcomes of the in the SUCRA ranking, the
alloplast (lingual) ranked higher (Fig. 4C). Xenografts and platelet concentrates category of materials showing the
combination with biologics displayed the higher proba- most favorable outcome regarding the percentage of new
bility to perform better than other materials and control bone formation, while xenografts rank in the last position
group (Suppl Fig. 8C). (Fig. 6C).
Suppl Fig. 9A, Suppl 9B, and Suppl 9C depict the Figure 6 D illustrates graphically the multidimen-
network geometry plot, predictive interval plot, and sional ranking of the different materials. Most nega-
multidimensional scale ranking for vertical dimension tive values to the left side represent the materials
outcome in socket preservation with a follow-up period associated with the highest probability to achieve
of ≥6 months, respectively. Bio + AG, AG + AP, and the lowest values of the outcome (new bone forma-
alloplast have favorable outcomes as compared to con- tion %). Hence, on the left side are the least osteo-
trol group based on SUCRA ranking. In addition, xeno- promoting materials, while materials associated with
grafts and allografts have consistence performance to positive values are the most osteo-promoting ones
have favorable outcomes (Fig. 4C). Combination of XG (right side).
and AP with biologics would be most likely to perform

Fig. 6  A Network geometrical plot for overall histological data. B materials in all the comparisons (overall: 97.9%; 2–4 months: 97.5%
The effect size and the confidence intervals for each material. C The and >6 months: 100.0%). Bio + AG in addition to platelet concen-
SUCRA Ranking for histomorphometric outcome for various regen- trates ranked better in overall (74.3%) and short-term (74.1%) follow-
erative materials used for alveolar ridge preservation. Platelet concen- up outcomes. D Multidimensional scale ranking for overall histologi-
trates were ranked best in clinical performance as compared to other cal data

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Clinical Oral Investigations

Comparison between short‑term (<4 months) comparison was between XG and AG as compared to con-
and long‑term (≥6 months) follow‑ups trol group. A loop was formed between Con, XG, and AG
(Fig. 8A). The predictive interval plot suggests that AP vs.
Follow‑up <4 months XG, AP vs. AG, Con vs. AP, and Con vs. AG are more
likely to perform better in future clinical studies in increased
Figure 7A, B, and C illustrate network geometry plot, pre- percentage of NBF (Fig. 8B). Platelet concentrates ranked
dictive interval plot, and multidimensional scale ranking for higher among all the materials in longer duration outcome
new bone formation, respectively. Figure 6C illustrates the based on SUCRA ranking (Fig. 6C). The multidimensional
SUCRA ranking. The most representative direct compari- scale ranking demonstrates Con followed by XG ranked
son is between control and XG, PC, and AP. The predic- higher (Fig. 8C) and suggestive of more favorable outcome
tive interval plot illustrates that PC and Bio + AG are most in ARP during follow-up ≥6 months.
likely to perform better (achieve higher NBF) in future clini-
cal studies (Fig. 7B). The multidimensional scale ranking
illustrates that PC is the least dissimilar and more favorable Discussion
option for NBF in ARP procedures (Fig. 7C) in short-term
follow-up. The SUCRA ranking for different materials is The outcomes of the present systematic review and network
illustrated in Fig. 6C that suggests that platelet concentrates meta-analysis confirmed that there is no evident superior-
ranked higher compared to all other materials. ity of any material or combination of materials for preser-
vation of both horizontal and vertical dimensions in post-
Follow‑up ≥ 6 months extraction sockets. However, all the materials provided better
results than spontaneous healing. This result is in agreement
Less biomaterials were available than the longer follow-up with a recently published systematic review where the data
for ≥6 months for this analysis. The most common direct was analyzed without employing a network meta-analysis

Fig. 7  A Network geometrical plot for histological data (2–4 months). B The effect size and the confidence intervals for each material. C Multi-
dimensional scale ranking for histological data (2–4 months)

Fig. 8  A Network geometrical plot for histological data (5–6 months). B The effect size and the confidence intervals for each material. C Multi-
dimensional scale ranking for histological data (5–6 months)

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 Clinical Oral Investigations

methodology [3]. The improved clinical outcomes of ARP Regardless of our strict methodological selection criteria
compared to spontaneous healing can be explained by the aimed at maintaining a high quality of evidence, 179 eligible
scaffold effect of the grafting material and the diminished randomized studies were found, and 74 were included for
volume to be regenerated. assessment of dimensional changes while 45 were included
Concerning the material, the most robust analysis was for histomorphometric analysis. With network meta-analysis
performed with xenografts and allografts due to the highest software, network geometry plots and predictive interval
number of comparable articles. The results clearly demon- plots (Prl) were generated, and multidimensional ranking
strated a better clinical behavior compared to spontaneous was used to estimate the ranking of different competing
healing. This can be explained by the fact that xenografts materials. This statistical method allowed confirmation that
have been demonstrated to be resistant to resorption due to most active treatments appeared more effective than control
de-antigenation that occurs during processing [119]. This groups.
characteristic may, in fact, stabilize the coagulum, mini- Overall, the most effective and predictable treatment
mizing bone resorption. Significant differences for vertical interventions for horizontal preservation were xenografts,
and horizontal changes at 6 months between xenograft and allografts, and alloplasts, which are also the three most fre-
spontaneous healing were noted. Similarly, allografts dem- quently used biomaterials.
onstrated to be reliable material at the time of performing Regarding vertical changes, the overall geometry network
ARP. It has been described that this material incorporates appeared as complex as the horizontal changes. The results
growth factors which may lead to an increase in regeneration demonstrated that allografts and xenograft were effective in
at the site [120]. However, the actual role of these molecules the control of vertical bone loss.
in the bone regeneration process is still controversial. However, if the attention is focused on histological
At the same time, an increasing number of reports for response, pairwise meta-analysis showed no significant
platelet concentrates (mainly platelet-rich fibrin), together difference in the percentage of new bone formation over a
with osteoconductive materials and bioactive agents like 5–6-month period in groups using allografts, as compared
rhPDGF-BB and rhBMP, were published. Even though the to self-healing, similar to a previous meta-analysis [124].
latter have shown promising results in some clinical appli- The network meta-analysis confirmed this trend. At the
cations, more evidence is needed to estimate with greater same time, AG materials are ranked 8th out of nine, among
precision their value in preserving post-extraction sock- the investigated materials. It must be underlined that the
ets [121–123]. Additionally, some of these agents are not combination of AG with a bioactive agent showed a trend
approved in all countries and clinicians need to be aware towards increased new bone formation. In fact, the use of
of that. bioactivated AG is ranked at the second position among the
On the other hand, based on the histomorphometric best materials. Clark et al. [41] added an advanced platelet-
results, xenograft materials displayed poor results in terms of rich fibrin (A-PRF) to freeze-dried bone allograft (FDBA)
new bone formation, as found in both pairwise and network obtaining an increase of vital bone, reaching values similar
meta-analysis. This finding is in agreement with a previous to the blood clot alone. Ntounis et al. [35] similarly evalu-
systematic review and meta-analysis of histomorphometric ated the combination of FDBA with platelet-rich plasma or
studies on ridge preservation [124]. The main explanation recombinant human platelet-derived growth factor reaching
for this finding could be the very low resorption rate of such in both cases values of new bone greater than using FDBA
biomaterials. In fact, the persistence of xenogeneic granules alone.
in the socket may leave a limited space for the growth of new The present article is not exempt from limitations. First,
bone tissue. On the contrary, the use of xenografts consents there is a big heterogeneity among the included studies.
to reduce consistently the dimensional shrinkage of the bone Despite a common aim (preservation of the post-extraction
after the tooth extraction [4]. The clinical significance of this socket) and study design, the included studies showed a high
lower amount of newly formed bone must be questioned. degree of variability especially regarding materials and tech-
Future research should analyze if this may impair or delay niques tested, as well as timing of assessment and outcome
the osseointegration of an implant placed in a ridge pre- variables investigated. In fact, even when the aim is to esti-
served with xenograft material. mate dimensional changes at the socket level, one has to
All the other treatments present similar results. As dif- consider that some studies evaluated the overall change in
ferent reviews suggest [4], leaving the socket heal spontane- the vertical or horizontal dimensions, others distinguished
ously, without bone substitutes, provides the worst results in between the buccal and lingual plates, and some measured at
terms of bone dimension preservation. At the same time, the the crestal level, while others are at different vertical levels
data failed to reveal a superiority of any material or combi- apically from the crest.
nation of materials over the others, for both horizontal and The outcomes of this review would also depend on the
vertical preservation of the post-extraction socket. confounders like different populations examined, antibiotic

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Clinical Oral Investigations

prescription, presence or absence of buccal wall, type of demonstrates that CBCT has more accuracy in determin-
flap, single- and multi-rooted teeth, smoking, primary or sec- ing changes along with clinical methods. Another method
ondary healing, and the method by which the measurements is optical coherence tomography which is based on optical
were recorded. There is significant impact of “method” of phenomenon and can detect changes at 7% bone changes.
covariate that would impact the outcomes of the clinical
studies. CBCT, clinical methods, and cast methods were
most commonly employed by the clinicians. Based on the
meta-regression and sensitivity analysis, it was found that Conclusion
CBCT method would be most appropriate method of record-
ing the change. Cast analysis is most unreliable as the bone When compared with untreated sockets, alveolar ridge pres-
change would be over expressed. ervation is effective in reducing both horizontal and vertical
Furthermore, the interval between extraction and assess- shrinkage, with respect to untreated sockets. In the network
ment varied between 2 weeks and several months (up to meta-analysis, xenografts performed better than the other
24 months in one case). Finally, the assessments of bone materials in preserving ridge dimension. On the other hand,
dimensional changes were based on direct radiographs statistically and significantly better histomorphometric out-
(either 2D or 3D), digital scan of casts obtained by impres- comes (higher % of vital bone) were achieved by platelet
sions, or clinical measurements using calipers. Same could concentrate.
be highlighted for histomorphometric outcomes: Most of the
Supplementary Information  The online version contains supplemen-
selected studies presented a small sample size limiting the tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00784-0​ 21-0​ 4248-1.
possibility of drawing strong conclusions and they did not
report the power of studies and drawing conclusions from Declarations 
such study should be done carefully. Additionally, a lack of
standardization in the biopsy sample collection was present Ethical approval  Not applicable
among the examined papers.
This heterogeneity prevented a more robust analysis and Informed consent  Not applicable
made it difficult to consider the contribution of all confound-
ing factors to the outcomes. Conflict of interest  The authors declare no competing interests.
All the interpretation from the analysis and models should
be done carefully by considering factors like the risk of bias
of the included studies, uncertainty in the estimates (con-
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Authors and Affiliations

L. Canullo1   · M. Del Fabbro2,3 · S. Khijmatgar2 · S. Panda2,4 · A. Ravidà5 · G. Tommasato3 · A. Sculean1 · P. Pesce6

4
* P. Pesce Department of Periodontics and Oral Implantology, Siksha
[email protected] ‘O’ Anusandhan University, Bhubaneswar, India
5
1 Department of Periodontics and Oral Medicine, University
Department of Periodontology, University of Bern, Bern,
of Michigan School of Dentistry, Ann Arbor, MI, USA
Switzerland
6
2 Department of Surgical Sciences and Integrated Diagnostics,
Department of Biomedical, Surgical and Dental Sciences,
University of Genoa, Genoa, Italy
Università degli Studi di Milano, Milan, Italy
3
IRCCS Orthopedic Institute Galeazzi, Milan, Italy

13

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