4

Received: 1 December 2020 | Revised: 23 May 2021 | Accepted: 10 June 2021
DOI: 10.1111/clr.13860
REVIEW ARTICLE
Does the timing of implant placement and loading influence

biological outcomes of implant-supported multiple-unit fixed
dental prosthesis—A systematic review with meta-analyses
Louise Leite Aiquel1 | João Pitta2 | Georgios N. Antonoglou1 | Irene Mischak1 |

Irena Sailer2 | Michael Payer1
1
Department of Oral Surgery and
Orthodontics, University Clinic of Dental Abstract
Medicine and Oral Health, Medical
Objective: To investigate the impact of timing of implant placement and loading on
University of Graz, Graz, Austria
2
Division of Fixed Prosthodontics and
implant survival and biological outcomes of multiple-unit implant-supported fixed
Biomaterials, University Clinics for Dental dental prosthesis (FDPs).
Medicine, University of Geneva, Geneva,
Switzerland
Material and Methods: A literature search was performed by three independent re-
viewers for studies reporting on ≥10 patients with FPDs supported by ≥two implants
Correspondence
Georgios N. Antonoglou, Department of
over ≥3 years of follow-up. Data were analyzed on implant survival and biological
Oral Surgery and Orthodontics, University complications as primary outcomes and biological events, including changes in peri-
Clinic of Dental Medicine and Oral Health,
Billrothgasse 4, 8010 Graz, Austria.
implant marginal bone level (MBL), probing depth, soft-tissue level, and health condi-
Email: antonoglou.georgios@gmail.com tion as secondary outcomes.
Funding information
Results: 7002 titles were identified, 360 full-texts were screened, and 14 studies
Departmental funding was used were included. These comprised 6 randomized controlled studies (RCTs), 5 cohort
exclusively.
studies, and 3 case series with identifiable implant placement and loading protocols
in five of 09 possible combinations. All groups but one (IPIL) showed implant survival
rates >90%. A meta-analysis based on 3 RCTs found no differences in survival rate
between DPIL and DPDL (p = .227).
Conclusions: High survival rates for all studied implant placement and loading com-
binations were shown for FPDs over ≥3 years of follow-up. When a delayed implant
placement protocol is applied, immediate or delayed loading demonstrated similar
survival rates. The heterogeneity of the data did not allow to draw any further con-
clusions on the occurrence of biological complications related to timing of implant
placement/loading.
KEYWORDS
biological outcomes, bone level change, dental implant, implant loading protocols, implant
placement protocols, success rates, survival rate
Louise Leite Aiquel and Joao Pitta contributed equally to this manuscript.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2021 The Authors. Clinical Oral Implants Research published by John Wiley & Sons Ltd.
Clin Oral Impl Res. 2021;32(Suppl. 21):5–27. wileyonlinelibrary.com/journal/clr | 5

6 | AIQUEL et al.
1 | I NTRO D U C TI O N Thus, it cannot be excluded that immediately inserted implants

may be at higher risk of developing biological complications such as
Fixed dental prostheses supported by implants have become a well- peri-implant disease (Parvini et al., 2020).
documented and reliable treatment option. Excellent survival rates The influence of soft-tissue biotypes on the incidence of peri-
of both the multiple-unit prostheses and their supporting implants implant inflammation has been demonstrated in animal and clinical
have been reported notably for conventional metal-ceramic resto- studies, suggesting the need for grafting procedures simultaneously
rations (Sailer et al., 2018). Advances on the prosthetic materials, to immediate implant placement (Chappuis et al., 2017; Perussolo
along with the development of different implant surfaces, digital et al., 2018).
planning tools and surgical techniques have contributed to the cur- Reversible inflammation affecting the soft tissue around the im-
rent success rates of implant-supported restorations (Buser et al., plant (mucositis) is a highly frequent condition that can progress to
2017). progressive bone loss (peri-implantitis) and eventually implant loss.
All the contemporary treatment and fabrication concepts have (Lee et al., 2017). Local and systemic conditions, such as poor oral
aimed to minimize treatment durations and patient visits while main- hygiene, smoking, and diabetes, are already known risk factors for
taining optimal clinical and patient-related outcomes (Scheyer et al., peri-implant diseases, and the influence of recently developed im-
2017). This quest for greater efficiency also has resulted in a diversi- plant materials and surfaces has been studied (De Bruyn et al., 2017;
fication of implant placement and loading protocols. Contemporary Dreyer et al., 2018; Peixoto & Almas, 2016). However, the role of
options include immediate, early, or placement, as well as immediate, recently developed surgical techniques including placement and
early, or conventional loading (Gallucci et al., 2018). It is reasonable loading shorter time protocols and their combinations in the index
to assume that these expedited procedures and fewer patient visits of these biological complications and implant survival is little known.
involved in immediate or early placement or loading will reduce the Further discussed are flapless approaches, a particularly efficient
cost of treatment, and possibly increase efficiency (Scheyer et al., method often utilized for immediate procedures, offer advantages
2017). but are limited by local anatomy, ongoing infections and surgical
Numerous reviews have been published to classify these pro- skills (Barone et al., 2016).
tocols and define their indications (Gallucci et al., 2009, 2014, With efficiency (shorter treatment durations, fewer patient vis-
2018; Schrott et al., 2014). While both immediate/early placement its, better affordability) being more desirable than ever in times of
and immediate/early loading can yield excellent results, they are a pandemic crisis and global financial constraints, there is a need
subject to biological limitations and a need for careful patient se- for evidence-based insights into the biological indications and lim-
lection and site assessment (Gallucci et al., 2018). Immediate or itations of immediate/early placement and loading of implants, en-
early placement requires a fair amount of residual bone for good abling clinicians to make appropriately efficient treatment decisions
primary stability of the implant (Benic et al., 2014; Gallucci et al., in carefully selected patients.
2018). In this context, the present systematic review investigated the
Good primary stability is also crucial for immediate loading of im- question of whether different timing protocols of implant placement
plants. While surface modifications and advanced designs have im- and implant loading affect the biological outcomes and implant sur-
proved the outcomes of all placement and loading protocols (Benic vival related to implant-supported fixed partial dentures (FPDs) in
et al., 2014; Chu et al., 2020; Gallucci et al., 2018), immediate place- partially edentulous patients.
ment right after tooth extraction has repeatedly been shown not to
prevent physiological remodeling of the alveolar bone (Sanz et al.,
2017; Vignoletti et al., 2009). Thus, special care should be taken 2 | M ATE R I A L A N D M E TH O DS
by clinicians in order to prevent biological and esthetic complica-
tions due to the natural ridge resorption and bone remodeling that Ethics approval was not required for this systematic review and was
will occur independently of implant placement (Araújo et al., 2005; registered in PROSPERO (IRD42020179528) and conducted in ac-
Buser et al., 2009; Buser et al., 2013. These processes are accompa- cordance with PRISMA (Liberati et al., 2009), PRISMA extension
nied by volume changes of the peri-implant soft tissue, with loss of for abstracts (Beller et al., 2013), IOM (Institute of Medicine) stand-
mucosa seen more often after immediate than early placement (Lee ards (Institute of Medicine Committee on Standards for Developing
et al., 2020). Nonetheless, mucogingival tissue findings are contra- Trustworthy Clinical Practice, 2011), and the Cochrane Handbook
dictory. While they demonstrate that biotype (in addition to residual for Systematic Reviews of Interventions (Higgins & Green, 2017).
bone volume) is another major modifier of biological outcomes after
immediate/early placement or loading (Lee et al., 2020; Prati et al.,
2020; Sanz-Martín et al., 2019), some authors have found significant 2.1 | Focusing the question for review
mucosal recession around immediately placed and loaded implants
(Blanco et al., 2019; Kolerman et al., 2016) whereas others have not The PICOS (population, intervention, comparison, outcome, and stud-
(Chan et al., 2019; Östman et al., 2020; Parvini et al., 2020; Pohl ies) principle was applied to focus the question posed for this re-
et al., 2020; Yan et al., 2016). view. As population, the focus was on partially edentulous patients
AIQUEL et al. | 7
treated by implant-supported fixed partial dentures (FPDs). As in- by the 2017 World Workshop, co-sponsored by the American
tervention, the focus was on immediate or early placement or load- Academy of Periodontology and the European Federation of
ing as compared to delayed placement or delayed loading. Outcome Periodontology (Araujo & Lindhe, 2018; Caton et al., 2018; Heitz-
parameters included, as primary measures, implant survival and Mayfield & Salvi, 2018; Schwarz et al., 2018).
biological complications (e.g., peri-implantitis, peri-implant mu-
cositis, and apical peri-implantitis) and as secondary measures, the
radiographic parameter of marginal bone levels (MBL) and the clini- 2.3 | Search strategy
cal parameters of soft-tissue recession, bleeding on probing (BOP),
probing depths (PD), preservation or loss of width of keratinized The search strategy was developed in close collaboration with a re-
tissue (KT), and plaque index (PI) were analyzed (Vetter & Mascha, search methodologist (University of Malmö, Sweden) and a “refer-
2017). The study designs that were eligible for inclusion were pro- ence and education services librarian” (Medical University of Graz,
spective and retrospective comparative and non-comparative clini- Austria). The databases which were searched included PubMed/
cal trials. Medline, Embase, and Cochrane CENTER (Central Register of
The focused question was as follows: Does immediate or early Controlled Trials) databases. Publications in English language were
implant placement and loading influence the biological complication thus identified up to April 29, 2020. Whenever possible, controlled
rate and implant survival in partially edentulous patients when com- MeSH terms were included in the keyword combinations used for
pared with conventional protocols? these database searches. The electronic search was complemented
by an additional hand search that included the reference lists of all
included publications and, in addition, systematic reviews on related
2.2 | Protocols of implant placement and loading topics.
For a detailed overview of search terms used in Embase and
Timing possibilities for implant placement and loading were defined Cochrane, the reader is referred to Appendix S1. The basic terms
as proposed by Gallucci et al., 2018; Siebers et al., 2010): used in PubMed, Embase, and Cochrane were as follows:
• IPIL: immediate placement + immediate restoration/loading • (dental implant) AND (immediate OR early OR late OR delayed OR
• IPEL: immediate placement + early loading conventional OR post-extraction OR post-extractive)
• IPDL: immediate placement + delayed loading • Filters: English, humans, year from 2000 up to April 29, 2020.
• EPIL: early placement + immediate restoration/loading
• EPEL: early placement + early loading A reference management tool (EndNote X9.3.3; Clarivate
• EPDL: early placement + delayed loading Analytics, London, UK) was used for first entry of all references and
• DPIL: delayed placement + immediate restoration/loading elimination of double entries. Screening at the title, abstract, and
• DPEL: delayed placement + early loading full-text levels was accomplished using a web-based application for
• DPDL: delayed placement + delayed loading systematic reviews (rayyan.qcri.org) (Ouzzani et al., 2016).
Previous reports (Chen & Buser, 2009; Chen et al., 2004; Gallucci
et al., 2018; Hämmerle et al., 2004; Siebers et al., 2010) provided the 2.4 | Inclusion and exclusion criteria
blueprint for the definition of protocols to be reviewed.
Any multiple publications on the same populations were handled by
• Immediate implant placement (IP): The implant is placed at the considering only the results of the latest study (the one reporting the
same day of tooth extraction. longest follow-up) without making recourse to any of the preceding
• Early implant placement (EP): The implant is placed between 1 and studies unless to retrieve truly additional information.
4 months after tooth extraction. Studies meeting the criteria below were included:
• Delayed implant placement (DP): Implant is placed >6 months
after tooth extraction. • Randomized and non-randomized controlled trials
• Immediate loading (IL): The prosthesis is connected to the implant • cohort and case–control studies
within 1 week following implant placement. • Prospective or retrospective case series
• Early loading (EL): Loading is performed between 1 week and • FPDs supported by ≥2 implants in partially edentulous patients
2 months after implant placement. • Root-form or cylindrical implants supporting the FPDs
• Delayed loading (DL): Prosthesis is connected to the implant later • ≥ 10 patients in each study arm and ≥3 years of follow-up
than 2 months after implant placement. • Adequate reporting of implant placement protocols with timing
• Adequate reporting of implant loading protocols with timing
Definition of periodontal and peri-implant diseases, conditions, • Endosteal diameter of implant shoulder: 3−6 mm
health and complications were based on the proposed classification • Reporting of one or more biological outcomes
8 | AIQUEL et al.
Studies meeting the criteria below were excluded: • Soft-tissue recession (in mm)
• Width of keratinized tissue (KT) (in mm)
• Preclinical in vitro, experimental, or animal studies • Plaque index (PI)
• Full-arch dentures or removable superstructures • Probing depths (PD) (in mm)
• Implants placed in previously irradiated bone or in alveolar clefts
• Medication compromising bone metabolism Miscellaneous information
• Studies not based on clinical examinations (e.g., questionnaire
surveys) • Systemic condition of patients
• Studies published in languages other than English • Prescription of antibiotics
• Restorations other than permanently screw-retained or cemented • Time of implant placement after tooth loss or removal
FPDs • Time of implant loading (functional or nonfunctional)
• Studies with non-eligible designs • Mean follow-up period
• Inability to distinguish between placement/loading protocols • Implant numbers and locations
• Inability to rule out single-unit or full-arch restorations • Implant diameters, lengths, surface characteristics
• Implant materials, types and brands
• Use and design of surgical access flaps
2.5 | Screening and contacting • Use of bone grafting (material, technique)
• Healing protocol (submerged, transmucosal)
The retrieved reference publications were independently screened • Type and occlusal design of interim prosthesis
by three reviewers (LLA, JP, and GNA), including a first screening • Design of the definitive FPD
at the title/abstract level (LLA and JP) followed by a second run of • Implant survival rate(s)
full-text screening conducted in duplicate (LLA, JP, and GNA). Any • Prosthetic complications
disagreements were settled either by discussion between the three
reviewers or by obtaining a fourth and fifth opinion (IS and MP).
The default approach was to include or exclude studies based on 2.7 | Bias assessments and synthesis
these full-text screens, although this decision was deferred for stud-
ies regarded as potentially relevant. In these cases, the authors were Risk-of-bias assessments were conducted to rate the risk of bias in
emailed and asked to provide additional data. Likewise, authors of each individual study, using appropriate tools for each study de-
potentially relevant and already included studies were emailed as signs. The Cochrane RoB 2.0 tool was applied to RCTs [Sterne et al.,
needed to resolve issues and fill in missing bits of information for the 2019], the Newcastle-Ottawa scale to cohort studies (Wells et al.,
ensuing data extraction (see below). All this extra information was 2000), and the Joanna Briggs Institute's Critical Appraisal Checklist
analyzed, and the data integrated for the final datasets. to case series (The Joanna Briggs Institute, 2017). It was planned to
assess reporting biases by applying Egger's and Begg's tests to the
main outcomes, to interpret tests for funnel plot asymmetry with
2.6 | Data extraction visual inspection, and to perform post hoc sensitivity analyses by
excluding studies one by one from the global estimation. To judge
As per the Cochrane recommendations, standardized pre-piloted the strength of clinical recommendations derived from studies, their
forms were designed for data extraction from all included papers. overall qualities of evidence were assessed based on the GRADE ap-
Three reviewers (LLA, JP, and GNA) extracted in duplicate a defined proach (Guyatt et al., 2011).
set of study characteristics (design, setting, funding, country, patient
number, and mean age) and additional data pertinent to the PICO
question. 2.8 | Statistical analysis
Primary outcome measures
Cohen's kappa was used to determine inter-rater (i.e., between the
• Implant survival rate (%) three reviewers) agreement and descriptive statistics to elucidate
• Biological complication rate (peri-implant mucositis and peri- survival and biological complication rates and clinical outcomes. For
implantitis) (number of events) each protocol, a mean cumulative survival rate was planned to be
calculated and weighted by follow-up durations and implant num-
Secondary outcome measures bers. Thus, a weighted mean survival rate for each protocol was ob-
tained by applying this formula:
• Marginal bone levels (MBL) (in mm)
• Bleeding on probing (BOP); modified Bleeding Index; Gingival X1t1n1 + X2t2n2 + ⋯ + Xktknk
x = ∗ 100
Index; Sulcus Bleeding Index; Bleeding Index t1n1 + t2n2 + ⋯ + tknk
AIQUEL et al. | 9
where X is the reported survival rate, t the follow-up period, and n the 3 | R E S U LT S
number of implants reported in each study (study 1 to study k).
As the implant placement is bound to be affected by patient and 3.1 | Selected studies and their characteristics
treatment-related characteristics, a random-effects model was a pri-
ori deemed appropriate to calculate the average distribution of true The applied search strategy, returned a total of 7002 titles, after
effects, based on clinical and statistical reasoning (Papageorgiou the identification and exclusion of 1593 duplicated hits (Figure 1).
2014), and an inverse variance estimator with the DerSimonian- Screening at the title/abstract level left 360 articles for full-text
Laird estimator for tau2 was chosen (Langan et al., 2019). screening to assess their eligibility. Inter-rater agreement (kappa
Absolute and relative between-t rial heterogeneity was as- score) was 0.63 for the title/abstract and 0.96 for the full-text
2 2 2
sessed using the t and I indices, respectively. The latter (I ) index screens. A total of 153 studies were categorized as potentially rele-
was defined as percentage variation in the global estimate due vant, eight of which could be included upon contacting their authors
to heterogeneity, with I2 scores of 25%, 50%, or 75% indicating (Daher et al., 2019; Göthberg et al., 2018; Oxby et al., 2015; Payer
low, moderate, or high heterogeneity, respectively. Forest plots et al., 2010; Si et al., 2016; Siebers et al., 2010; Simons et al., 2015;
were created to illustrate the effects in a meta-a nalysis. SPSS Vogl et al., 2019). Fourteen studies were finally included: Six RCTs,
Statistics (v. 26, IBM, Armonk, NY, USA) and R (v. 1.3; R Project five cohort (four observational cohort and one case–control) stud-
for Statistical Computing, Vienna, Austria) software was used for ies, and three case series (two prospective and one retrospective).
all statistical operations. Differences were considered significant Each of these 14 studies was carefully selected based on parameters
at p ≤ .05. reported. In each assessment for eligibility, care was taken to identify
The potential of publication bias of this review was assessed by well-defined information on the placement and loading protocols used.
the funnel plot and an additional statistical test; the Egger’s test was Table 1 gives an overview of excluded studies and reasons for their ex-
performed (Figure 3). clusion. For additional information on the reasons for exclusion during
F I G U R E 1 PRISMA flow diagram

illustrating the search strategy
10 | AIQUEL et al.
TA B L E 1 Reasons for exclusion during data extraction TA B L E 1 (Continued)
Main reason for exclusion N Studies Main reason for exclusion N Studies
Insufficient data for 67 Agliardi et al. (2014) Cochran et al. (2011b)

screening assessment Al Amri et al. (2017) Esposito et al. (2018)
Alasqah et al. (2018) Bressan et al. (2017)
Arlin et al. (2007) Felice et al. (2019)
Bilhan et al. (2010) Gastaldi et al. (2017)
Bornstein et al. (2007) Maló and de Araújo Nobre
Bornstein et al. (2005) (2016)
Bruschi et al. (2017) Nedir et al. (2017)
Cassetta et al. (2016) Prosper et al. (2010)
Cesaretti et al. (2015) Queridinha et al. (2016)
Cochran et al. (2009) Testori et al. (2001)
Crespi et al. (2010) Zuffetti et al. (2016)
Degidi et al. (2009a) Mean follow-up less than 3 Schwartz-Arad et al. (2007)
Degidi et al. (2009b) 3 years Cordaro et al. (2010)
Ferrini et al. (2018) Degidi et al. (2008)
Glauser et al. (2013)
Less than 10 patients at 1 Ding and Wang (2017)
Glibert et al. (2016)
3 years
Gomez-Roman et al. (2001)
Han et al. (2017) Absence of FPDs supported 7 Prati et al. (2016)
Harel et al. (2013) by ≥2 implants Kolinsky et al. (2013)
Jungner et al. (2014) Merli et al. (2020)
Jungner et al. (2012) Romeo et al. (2012)
Kim et al. (2017) Salina et al. (2019)
Kokovic et al. (2014) Crespi et al. (2016)
Maddalone et al. (2018) Bruschi et al. (2014)
Malchiodi et al. (2011) Insufficient data do 4 Ferrini et al. (2018)
Montero et al. (2012) separate different Glauser et al. (2016)
Muelas-Jiménez et al. (2015) placement protocols Glauser et al. (2006)
Mura (2018) Degidi et al. (2018)
Nicolau et al. (2019)
Insufficient data to separate 44 Pozzi et al. (2014)
Nicolau et al. (2013)
single/full mouth from Anitua et al. (2016)
Peñarrocha-Diago et al. (2012)
multiple units Botticelli et al. (2018)
Pettersson and Sennerby (2013)
Cresp, et al. (2017)
Polizzi et al. (2000)
Crespi et al. (2016)
Polizzi et al. (2013)
Crespi et al. (2010a)
Pozzi et al. (2012)
Crespi et al. (2010b)
Pozzi et al. (2015)
Crespi et al. (2014)
Rammelsberg et al. (2016)
Degidi et al. (2012)
Rocci et al. (2012)
Roccuzzo et al. (2018)
Galindo-Moreno et al. (2014)
Rocha et al. (2016)
Liu et al. (2019)
Rossi et al. (2017)
Malchiodi et al. (2010)
Sato et al. (2014)
Maló et al. (2011)
Schliephake et al. (2012)
Maló et al. (2015)
Şener-Yamaner et al. (2017)
Maló et al. (2000)
Sullivan et al. (2005)
Malo et al. (2007)
Sullivan et al. (2001)
Maló et al. (2016)
Tallarico and Meloni (2017)
Malo et al. (2014)
Testori et al. (2017)
Martinez-Rodriguez et al. (2018)
Valerón and Valerón (2007)
Mengel et al. (2005)
Villa (2018)
Merli et al. (2020)
Wagenberg and Froum (2014)
Mura et al. (2012)
Zembić et al. (2010)
Madani et al. (2018)
Jung et al. (2016)
Cochran et al. (2011a)
(Continues) (Continues)
AIQUEL et al. | 11
TA B L E 1 (Continued)
inserted in healed (An et al., 2019; Degidi et al., 2011; Simons et al.,
Main reason for exclusion N Studies 2015; Vogl et al., 2019) or edentulous (Romanos et al., 2016) ridge
Nedir et al. (2004) areas. As most placement and loading protocols were covered by
Öskan et al. (2011) few or no studies, only one direct comparison was performed (DPIL
Paredes et al. (2018)
versus DPDL).
Pozzi et al. (2014)
Rocci et al. (2003a)
Rodrigo et al. (2012)
Soydan et al. (2013) 3.2 | Within-study risks of bias
Telleman et al. (2017)
Wilson et al. (2013)
Tables 3-5 summarizes the risk-of-bias assessments based on the
Bettach et al. (2018)
Cannizzaro et al. (2008) Cochrane RoB 2.0 tool, Newcastle-Ottawa scale, and Joanna Briggs
Crespi et al. (2016) Institute's Critical Appraisal Checklist.
Francetti et al. (2014) All cohort and case series were rated with low risk of bias.
Mendonca et al. (2017)
Regarding RCT studies, 3 of them (Daher et al., 2019; Fung et al.,
Wallkamm et al. (2015)
Felice et al. (2018) 2011; Van Nimwegen et al., 2015) were evaluated as having some
Felice et al. (2015) concerns in terms of risk bias. Two were rated with high risk of bias
Göthberg et al. (2016) (Romanos et al., 2016; Vogl et al., 2019), and only one was rated with
Balmer et al. (2018)
low risk of bias (Göthberg et al., 2018).
Temmerman et al. (2019)
Mertens et al. (2011)
Time of implant placement/ 13 Al Amri et al. (2017)
loading not reported ArReaje et al. (2019) 3.3 | Within-study results
Baelum et al. (2004)
Blus et al. (2010)
Table 6 lists the data extracted from the included studies. None of
Bornstein et al. (2003)
these reported on IPDL, EPIL, EPDL, or EPDL combinations of place-
Bornstein et al. (2010)
Cannizzaro et al. (2013) ment and loading. Given the unspecific wording by which many au-
Chiapasco et al. (2020) thors refer to the timing of implant placement, any studies reporting
Ibanes et al. (2003) on implants placed >3 months after tooth extraction without giving a
Östman et al. (2018)
time range (e.g., between 3 and 6 months) were considered delayed
Harel et al. (2013) placement. Thus, eleven cohort groups were available for DPIL (delayed
Rocci et al. (2003b) placement + immediate restoration/loading), seven for DPDL (delayed
placement + delayed loading), one for DPEL (delayed placement +early
loading), one for IPIL (immediate placement + immediate restoration/
full-text screening, the reader is referred to Appendix S2. Table 2 lists loading), and one for type IPEL (immediate placement + early loading).
the 14 included studies and their 21 cohort groups enabling us to ana-
lyze combined protocols of implant placement and loading.
All 14 studies included information on implant survival and on one 3.3.1 | IPIL (immediate placement + immediate
or more biological outcomes, but the biological outcomes reported restoration/loading)
across studies did differ. Since we would only consider MBL changes
from prosthetic loading to follow-up whereas some studies only re- Only one prospective cohort study was available on this combina-
ported MBL values measured at the time of implant placement, these tion of protocols [Siebers et al., 2010]. It gave a mean follow-up of
latter values were not evaluable. Details on peri-implant inflamma- 47.64 ± 6.48 months, two of these 20.
tion were reported based on clinical indices (Gingival Index, Sulcus Implants failed (implant survival rate: 90%). Even though immedi-
Bleeding Index, Bleeding on Probing (BOP), modified Bleeding Index, ate placement and immediate restoration/loading tended to produce
Bleeding Index) so heterogeneous as to preclude a comparison across a lower survival in this specific study, the MBL changes appeared
cohort groups. Group-specific mean Plaque Index (PI) scores and favorable compared to delayed placement protocols.
Probing Depths (PD) were reported in few of the 14 studies, while
mean soft-tissue recession and mean width of keratinized tissue (KT)
dimensions were reported in only one of them [Romanos et al., 2016]. 3.3.2 | IPEL (immediate placement + early loading)
Some studies indicated that implant placement had taken place
>3 months (Göthberg et al., 2018; Oxby et al., 2015; Van Nimwegen One prospective cohort study was available (Oxby et al., 2015).
et al., 2015), >4 months (Fung et al., 2011), or >3 to 6 months (Spies Based on a mean follow-up of 55 months, none of the 67 implants in
et al., 2015) after tooth extraction. Others were categorized as de- this category failed (survival rate: 100%) and merely one biological
layed placement based on statements that the implants had been complication (soft-tissue recession) was reported.
12 | AIQUEL et al.
TA B L E 2 Overview on study, patient and implant characteristics of included studies
Total Presence of Patients with history

number of smokers of periodontitis
Study Study design Setting/Country patients Drop-outs Yes/no (n) included (n)
An et al. (2019) Case series University/South 33 0 NR NR

(prospective) Korea
Daher et al. (2019) RCT (split-mouth) University/Lebanon 24 2 Yes (13) Yes (NR)
Degidi et al. (2011) Observational cohort Private practice/Italy 24 3 NR NR

(prospective)
Fung et al. (2011) RCT (split-mouth) University/USA 10 0 Yes (2) NR
Göthberg et al. (2018) RCT University/Sweden 50 0 NR Yes (NR)
Oxby et al. (2015) Observational Cohort Private practice/ 39 4 NR NR

(prospective) Sweden
Payer et al. (2010) Case Series University/Austria 24 0 NR NR

(prospective)
Romanos et al. (2016) RCT (split-mouth) University/Germany 24 4 NR NR
Si et al. (2016) Case Series University/China 10 0 Yes (24) Yes (41)

(retrospective)
Siebers et al. (2010) Observational cohort Private practice/ 45 NR Yes (15) Yes (45)
(prospective) Germany
Spies et al. (2015) Observational cohort University/Germany 13 0 NR

(prospective)
Simons et al. (2015) Case–control University/Belgium 70 NR Yes (29) Yes (267)
(retrospective)l
Van Nimwegen et al. RCT University/ 40 5 NR NR
(2015) Netherlands
Vogl et al. (2019) RCT University/Austria 20 0 NR NR
Abbreviation: NR, not reported.
3.3.3 | DPIL (delayed placement + immediate a weighted cumulative survival of 97.2% was obtained. Data for
loading) 378 implants revealed a mean MBL change of 0.71 ± 0.66 mm
and data for 361 implants a 2.6% rate of biological complications.
Data on this combination of protocols were available from five Probing depths were reported in four studies (An et al., 2019;
randomized controlled trials, three prospective cohort studies, Fung et al., 2011; Göthberg et al., 2018; Romanos et al., 2016) re-
and two prospective case series, including 11 cohort groups with sulting in a calculated mean of 2.83 ± 0.92 mm. A sub-a nalysis on
data on implant outcomes. Overall, 14 of 502 implants in this cat- the type of loading revealed an approximately similar MBL change
egory failed. Based on a mean follow-u p of 60.1 ± 37.8 months, for functional (0.65 mm) versus nonfunctional (0.62 mm) loading.
AIQUEL et al. | 13
Type of implant
Reported timing of Reported timing of restoration/ placement and Number of Implant Implant brand/
implant placement loading loading protocol implants material Manufacturer
NR Day of implant placement DPIL 68 Titanium NR
>9 months Immediately after implant DPIL 80 Titanium NobelActive/Nobel

placement Biocare
>9 months 3.5 months after implant DPDL 80 Titanium
placement
NR Immediately after implant DPIL 48 Titanium ANKYLOS/Dentsply
placement
≥4 months Within 24 h after implant DPIL 42 Titanium Brånemark System Mk IV
placement TiUnite/Nobel Biocare
>3 months Within 48 h after implant DPIL 78 Titanium Brånemark System
post-extraction placement TiUnite/Nobel Biocare
>3 months 3–4 months after implant DPDL 72 Titanium
post-extraction placement
≥3 months Within 60 days after implant DPEL 107 Titanium Astra Tech/Dentsply
Immediately Within 60 days after implant IPEL 67 Titanium
6 months post-extraction Immediately/within 1 week after DPIL 40 Titanium Xive/Dentsply
implant placement
NR Within 24 h after implant DPIL 36 Titanium ANKYLOS/Dentsply
placement
NR 3 months after healing DPDL 36 Titanium
>3 months after tooth 3–4 months after healing DPDL 21 Titanium Straumann AG
extraction
Immediately after tooth Within 48 h after implant IPIL 20 Titanium Camlog; 3i; Lifecore
extraction placement
Healed sites Within 48 h after implant DPIL 33 Titanium
placement
Healed sites 6 months after implant placement DPDL 46 Titanium
>3 months after tooth Immediately after implant DPIL 26 Zirconia Metoxit/Ziraldent
extraction placement
Healed sites 3–6 months after implant DPDL 151 Titanium Branemark MK III/Nobel
placement Biocare
≥3 months ≥3 months after implant placement DPDL 70 Titanium Nobel Perfect Groovy/
post-extraction Nobel Biocare
Healed sites Immediately after implant DPIL 19 Titanium Xive/Dentsply
placement
Healed sites Immediately after implant DPIL 32 Titanium
placement
3.3.4 | DPEL—(delayed placement + early loading) 3.3.5 | DPDL—(delayed placement + delayed

loading)
There was only one prospective cohort study [Oxby et al., 2015].
Based on a mean follow-up of 55 months, none of the 107 implants Data on this combination of protocols were available from three
in this category failed (survival rate: 100%) and merely one biological randomized controlled trials, one prospective cohort study, one
complication (soft-tissue recession) was reported. retrospective cohort study, and one retrospective case series.
14 | AIQUEL et al.
TA B L E 3 Risk of bias assessments of RCTs based on the Cochrane RoB 2.0 tool
ĞǀŝĂƟŽŶƐĨƌŽŵŝŶƚĞŶĚĞĚŝŶƚĞƌǀĞŶƟŽŶƐ
^ĞůĞĐƟŽŶŽĨƚŚĞƌĞƉŽƌƚĞĚƌĞƐƵůƚ
DĞĂƐƵƌĞŵĞŶƚŽĨƚŚĞŽƵƚĐŽŵĞ
ZĂŶĚŽŵŝǌĂƟŽŶƉƌŽĐĞƐƐ
DŝƐƐŝŶŐŽƵƚĐŽŵĞĚĂƚĂ
KǀĞƌĂůů
^ƚƵĚǇ KƵƚĐŽŵĞ
? + + + ? ! +
&ƵŶŐ͕ĞƚĂů͕͘ϮϬϭϭ ZĂĚŝŽŐƌĂƉŚŝĐďŽŶĞůĞǀĞů >ŽǁƌŝƐŬ
sĂŶEŝŵǁĞŐĞŶ͕ĞƚĂů͕͘
?
ϮϬϭϱ ZĂĚŝŽŐƌĂƉŚŝĐďŽŶĞůĞǀĞů ^ŽŵĞĐŽŶĐĞƌŶƐ
? + + ? ? !
ó
sŽŐů͕ĞƚĂů͕͘ϮϬϭϵ DĂƌŐŝŶĂůďŽŶĞĚĞĨĞĐƚ ,ŝŐŚƌŝƐŬ
? ó + + ? ó
'ŽƚŚďĞƌŐ͕ĞƚĂů͕͘ϮϬϭϴ ZĂĚŝŽŐƌĂƉŚŝĐďŽŶĞůĞǀĞů
ĂŚĞƌ͕ĞƚĂů͕͘ϮϬϭϵ ZĂĚŝŽŐƌĂƉŚŝĐďŽŶĞůĞǀĞů
+ + + + + +
ZŽŵĂŶŽƐ͕ĞƚĂů͕͘ϮϬϭϲ ZĂĚŝŽŐƌĂƉŚŝĐďŽŶĞůŽƐƐ
? + + + ? !
ó ó + + + ó
TA B L E 4 Risk of bias assessments of Cohort studies based on New Castle -Ottawa Quality Assessment Scale
Outcome not
Representativeness of the Selection of the non Ascertainment of present at the start
Study exposed cohort exposed cohort exposure of the study
Degidi et al. (2011), Oxby et al. (2015) * * * *

Oxby et al. (2015) * * * *
Siebers et al. (2010) * * * *
Simons et al. (2015) * * * *
Spies et al. (2015) * * * *
Note: Thresholds for converting the Newcastle-Ottawa scales to AHRQ standards (good, fair, and poor):
Good quality: 3 or 4 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain.
Fair quality: 2 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain.
Poor quality: 0 or 1 star in selection domain OR 0 stars in comparability domain OR 0 or 1 stars in outcome/exposure domain.
TA B L E 5 Risk of bias assessments of Case Series based on Joanna Briggs Institute's Critical Appraisal Checklist
Were there Was the condition measured Were valid methods used Did the case series Did the case series
clear criteria in a standard, reliable way for identification of the have consecutive have complete
for inclusion in for all participants included condition for all participants inclusion of inclusion of
Study the case series? in the case series? included in the case series? participants? participants?
An et al. Yes Yes Yes Unclear Yes

(2019)
Payer et al. Yes Yes Yes Unclear Yes
(2010)
Si et al. (2016) Yes Yes Yes Yes* Unclear
AIQUEL et al. | 15
Overall, 14 of 476 implants in this category failed. Based on a mean heterogeneity was minimal in absolute (t 2: 0.0022) and relative (I2:
follow-up of 74.2 ± 43.4 months, the weighted cumulative survival 0) terms (p = .77).
was 98.1%. Data for 217 implants yielded a mean MBL change of Regarding the publication bias assessment, Egger’s test does not
1.68 ± 0.97 mm and data for 242 implants a 3.7% cumulative rate indicate the presence of funnel plot asymmetry (Figure 3). However,
of biological complications. From 3 studies, in a mean probing depth since the meta-analysis contains three studies (k = 3) the Egger's test
of 3.12 ± 1.08 mm was calculated (Göthberg et al., 2018; Romanos may lack the statistical power to detect bias (i.e., k < 10).
et al., 2016; Van Nimwegen et al., 2015).
3.5 | Certainties of evidence

3.4 | Results of meta-analysis
Table 7 illustrates the overall quality of meta-evidence. The follow-
The reported results of analysis were based on data extracted di- ing outcome was assessed across the various combinations of im-
rectly from included studies but also on additional raw data provided plant placement and loading protocols: BOP, pocket depths, MBL
by some of the authors (Daher et al., 2019; Göthberg et al., 2018; changes, peri-implantitis, peri-implant mucositis, and implant sur-
Oxby et al., 2015; Payer et al., 2010; Siebers et al., 2010; Simons vival rates. A GRADE summary-of-evidence compilation is provided
et al., 2015; Vogl et al., 2019). Due to heterogeneity, mostly related (Table 7) for each of the four comparisons that could be made be-
to study designs and variable radiographic and clinical measures, tween any two of the evaluable placement-plus-loading combina-
only three RCTs comparing the same types of implant placement tions (DPIL vs. DPDL, IPIL vs. DPDL, DPEL vs. DPDL, and IPEL vs.
and implant loading protocols (DPIL vs. DPDL) were available for DPDL). Both direct and indirect study comparisons and all (avail-
a quantitative synthesis (Daher et al., 2019; Göthberg et al., 2018; able) biological outcomes have been entered. A low certainty was
Romanos et al., 2016). The meta-analysis revealed an overall effect identified for one comparison (DPIL vs. DPDL) and one outcome
size of 1.57 [95% CI: 0.19; 13.1], so that no significant difference in (BOP) based on one RCT exhibiting a high risk of bias (Romanos
terms of survival rate (p = .227) emerged between the type DPIL et al., 2016). Other than that, the certainty of evidence was rated
(74 patients/188 implants) and DPDL (182 implants/72 patients) as very low in all comparisons for all outcome parameters. In re-
combinations of placement and loading (Figure 2). Between-trial lation to the reference combination of protocols (type DPDL), all
Comparability of cases and Sufficient follow-up time for Adequacy of follow-up of

controls Assessment of outcome outcomes to occur cohorts Total
* * * * 8
* * * * 8
* * * 7
* * * 7
* * * * 8
Was there clear

reporting of the
Was there clear reporting Was there clear reporting Were the outcomes of presenting site(s)/ Was statistical
of the demographics of the of clinical information of follow-up results of cases clinic (s) demographic analysis Overall
participants in the study? the participants? clearly reported? information? appropriate? appraisal
Yes Yes Yes Yes* Yes Included
Yes Yes Yes Yes Yes Included
Yes Yes Yes Yes Yes Included

16 | AIQUEL et al.
TA B L E 6 Biological outcomes according to the implant placement and loading protocols (NA = not applicable; NR = not reported)
No.
Placement implants Mean ± SD on
and Mean ± SD No. available Implant Mean ± SD peri-implant
loading Type of follow-up implants at survival MBL changes at inflammation
Study protocol loading (months) placed follow-up rate follow-up (mm) (different indexes)
An et al. (2019) DPIL Non- 36 68 68 100% 0.42 ± 0.39 0.65 ± 0.81

functional (Gingival Index)
Daher et al. DPIL Functional 36 80 69 95.5% 0.78 ± 0.72 NR
(2019) DPDL NA 36 80 71 96.3% 0.91 ± 1.05 NR
Degidi et al. DPIL Non- 36 48 48 100% 0.57 ± 0.52 NR
(2011) functional
Fung et al. (2011) DPIL Functional 36 42 40 95.2% 0.26 ± 0.44 0.25 ± 0.30 (Sulcus
Bleeding Index)
Göthberg et al. DPIL Functional 60 78 62 94.9% NR NR
(2018) DPDL NA 60 72 64 97.2% NR NR
Oxby et al. DPEL NA 55 107 107 100% 0.28 ± 0.88 NR

(2015)
IPEL NA 55 67 67 100% 0.34 ± 1.48 NR
Payer et al. DPIL Non- 96 40 18 95% 0.88 ± 1.15 NR

(2010) functional
Romanos et al. DPIL Functional 145.7 ± 10.7 36 30 100% 0.57 ± 1.06 0.07 ± 0.25 (Sulcus
(2016) Bleeding Index)
DPDL NA 145.7 ± 10.7 36 30 100% 1.12 ± 1.30 0.00 ± 0.00 (Sulcus
Bleeding Index)
Si et al. (2016) DPDL NA 66 21 19 90.5% NR NR
Siebers et al. DPIL Both 45.1 ± 7.2 33 32 97% 2.15 ± 0.81 1.59 ± 1.39 (from
(2010) 0 to 6)
DPDL NA 55.7 ± 16.2 46 46 100% 2.46 ± 0.96 2.91 ± 2.11 (from
0 to 6)
IPIL Both 47.64 ± 6.48 20 17 90% 1.57 ± 0.91 1.76 ± 1.79 (from
0 to 6)
Simons et al. DPDL NA 48 151 151 98.3% 0.5 ± 0.68 NR
(2015)
Spies et al. DPIL Non- 60 26 26 100% 1.14 ± NR 1.1 ± NA (modified
(2015) functional Bleeding Index)
Van Nimwegen DPDL NA 60 70 58 97.1% NR 40 ± NR (Bleeding
et al. (2015) Index)
Vogl et al. (2019) DPIL Functional 36 19 17 100% 0.37 ± 0.46 NR
DPIL Non- 36 32 30 97% 0.39 ± 0.47 NR
functional
F I G U R E 2 Forest plot with individual effects and heterogeneity measures [Colour figure can be viewed at wileyonlinelibrary.com]
AIQUEL et al. | 17
Mean ± SD soft-tissue Mean (SD) PD Rate of biological

recession at follow-up Mean ± SD width KT Mean ± SD PI at follow-up No. of reported biological complications (%)
(mm) at follow-up (mm) at follow-up (mm) complications (except implant failure)
NR NR 0.35 ± 0.64 2.68 (1.00) 0 0%
NR NR NR NR 0 0%
NR NR NR NR 2 implants with peri-implantitis 2.8%
NR NR NR NR 0 0%
NR NR NR 2.82 (0.75) 0 0%
NR NR NR 3.15 (0.87) 3 implants with peri-implantitis 4.8%

2 implants with fistula
NR NR NR NR 1 implant with soft-tissue 0.9%
recession
NR NR NR NR 1 implant with soft-tissue 1.5%
recession
NR NR NR NR 1 implant with peri-implantitis 5.6%
0.30 ± 0.84 1.73 ± 1.36 mm 0.56 ± 0.94 2.53 (0.63) 0 0%
0.20 ±0.48 2.00 ± 1.23 mm 0.43 ± 0.63 2.6 (0.50) 0 0%
NR NR NR NR 2 implants with peri-implantitis 10.5%

NR NR NR NR NR -
NR NR NR NR NR -
NR NR NR NR NR -
NR NR NR NR NR -
NR NR 0.72 ± NR NR 0 0
NR NR 1.6 ± 0.7 NR 0 0%
NR NR 1.6 ± 0.7 NR 0 0%
alternative combinations seem to improve biological outcomes and

survival rates.
4 | DISCUSSION
It has been suggested as a fundamental principle in implant dentistry

that the implant-restoration complex should be considered as a sin-
gle variable in assessing clinical outcomes (Garber & Belser, 1995)
F I G U R E 3 Funnel plot describing the publication bias assessment and consequently success of treatment. In the present review, this
18 | AIQUEL et al.
TA B L E 7 GRADE I-IV summary-of-evidence compilation for each of the four comparisons that could be made between any two placement
and loading combinations (DPIL vs. DPDL, IPIL vs. DPDL, DPEL vs. DPDL, IPEL vs. DPDL)
Summary of findings: GRADE I
Delayed placement and immediate loading (DPIL) compared to delayed placement and delayed loading (DPDL) for implant treatment in partially
edentulous individuals
Patient or population: implant treatment in partially edentulous individuals (analysis at implant level)
Setting: University/private clinic
Intervention: delayed placement and immediate loading (DPIL)
Comparison: delayed placement and delayed loading (DPDL)
Anticipated absolute effects
Weighted effect with delayed placement and Weighted effect with delayed placement
Outcomes delayed loading (DPDL) and immediate loading (DPIL)
Rx bone loss around the implant platform The mean rx bone loss around the implant The mean rx bone loss around the implant
assessed with: Radiographic imaged platform was 1.68 mm ± 0.97 platform was 0.71 mm ± 0.66
Bleeding on probing assessed with: Sulcus The mean SBI was 0.066 (±0.253) The mean SBI was 0.00 (±0.00)
Bleeding Indexc
Peri-implant probing depth The mean peri-implant pocket depth was The mean peri-implant pocket depth was
3.12 mm ± 1.08 2.83 mm ± 0.92
Peri-implantitis prevalence assessed with: The mean percentage of implants with peri- The mean percentage of implants with peri-
Radiographic and clinical examinationd implantitis was 3.5% implantitis was 0.9%
Mucositis No muscositis was reported in all studies with data on peri-implantitis
Survival rate assessed with: Radiographic and The mean survival rate was 98.1.2% The mean survival rate was 97.2% %
clinical examinationd
GRADE Working Group grades of evidence: High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there
is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially
different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be
substantially different from the estimate of effect
Summary of findings: GRADE II
Immediate placement and immediate loading (IPIL) compared to delayed placement and delayed loading (DPDL) for implant treatment in
partially edentulous individuals
Patient or population: implant treatment in partially edentulous individuals

Intervention: immediate placement and immediate loading
Comparison: delayed placement and delayed loading
Weighted effect with delayed

placement and delayed loading Weighted effect with immediate placement and immediate
Outcomes (DPDL) loading (IPIL)
Rx bone loss around the implant The mean rx bone loss around The mean rx bone loss around the implant platform
platform assessed with: the implant platform was 1.57 mm ± 0.91
Radiographic imagef 1.68 mm ± 0.97
Bleeding on probing assessed with: 0 to Mean bleeding was 2.91 ± 2.11 Mean bleeding was 1.76 ± 1.79
6 scale (unknown reference)
AIQUEL et al. | 19
No. of implants (contributing arm/ Certainty of the

studies) evidence (GRADE) Comments
676 implants (4 RCTs, 6 observational ⨁◯◯◯ Immediate loading after delayed placement seems to reduce potential
studies) VERY LOWa bone loss after loading. Follow-up period varied from 3 years up to
15 years
60 implants (1 RCT) ⨁⨁◯◯ Immediate loading after delayed placement does not seems to affect the
LOWb Sulcus Bleeding Index. Follow-up was 15 years
352 (4 RCTs, 1 observational studies) ⨁◯◯◯ Peri-implant pocket depth does not exhibit substantial difference between
VERY LOWa immediate and delayed loading after delayed implant placement
535 (4 RCTs, 4 observational studies) ⨁◯◯◯ Evidence is scarce on peri-implantitis and low rates were reported in the
VERY LOWa included studies. This could be in part due to poor reporting of the
study of the clinical examination. Follow-up period varied from 3 years
up to 15 years
535 (4 RCTs, 4 observational studies) ⨁◯◯◯ Evidence is scarce on mucositis. No cases were reported in the included
VERY LOWa studies but this could be in part due to poor reporting of the study of
the clinical examination. Follow-up period varied from 3 years up to
15 years
879 implants (6 RCTs, 7 observational ⨁◯◯◯ Both delayed and immediate loading after delayed placement after
studies) VERY LOWa delayed implant placement present high survival rates. Follow-up
period varied from 3 years up to 15 years
Certainty of the evidence

No. of implants (contributing arm/studies) (GRADE) Comments
318 (2 RCTs, 3 observational studies) ⨁◯◯◯ Implants placed with immediate implant placement and
VERY LOWb immediate loading may exhibit comparable mean bone loss
after loading. Follow-up period varied from 3 years up to
15 years
53 (1 observational study) ⨁◯◯◯ Implants placed with immediate implant placement and
VERY LOWb immediate loading may exhibit decreased bleeding on probing.
Follow-up period varied from 3 years up to 15 years
(Continues)
20 | AIQUEL et al.
Summary of findings: GRADE II
Immediate placement and immediate loading (IPIL) compared to delayed placement and delayed loading (DPDL) for implant treatment in
partially edentulous individuals

Intervention: immediate placement and immediate loading
Weighted effect with delayed

placement and delayed loading Weighted effect with immediate placement and immediate
Outcomes (DPDL) loading (IPIL)
Peri-implant probing depth No comparison was possible

Peri-implantitis prevalence No comparison was possible
Mucositis No comparison was possible
Survival rate assessed with: Survival rate was 98.1% Survival rate was 75%
Radiographic and clinical
examinationf
Summary of findings: GRADE III
Delayed placement and early loading (DPEL) compared to delayed placement and delayed loading (DPDL) for implant treatment in partially
edentulous individuals

Intervention: delayed placement and early loading
Weighted effect with delayed placement Weighted effect with delayed placement and early
Outcomes and delayed loading (DPDL) loading (DPEL)
Rx bone loss around the implant platform The mean rx bone loss around the implant The mean rx bone loss around the implant platform
assessed with: Radiographic imagef platform was 1.68 mm ± 0.97 was 0.28 ± 0.88
Bleeding on probing No comparison was possible

Survival rate assessed with: Radiographic Survival rate was 98.1% Survival rate
and clinical examinationf was 100%
AIQUEL et al. | 21
Certainty of the evidence

No. of implants (contributing arm/studies) (GRADE) Comments
- - -
- - -
- - -
318 (2 RCTs, 3 observational studies) ⨁◯◯◯ Implants placed using both delayed placement with delayed
VERY LOWe loading may present higher survival rates compared to
immediate placement with immediate loading. Follow-up
period varied from 3 years up to 15 years
No. of participants (contributing arm/

studies) Certainty of the evidence (GRADE) Comments
298 + 107 (2 RCTs, 3 observational ⨁◯◯◯ Implants placed with delayed implant placement and
studies) VERY LOWb early loading may exhibit decreased mean bone
loss after loading. Follow-up period varied from
3 years up to 15 years
- - -
- - -
- - -
- - -
439 + 107 (3 RCTs, 3 observational ⨁◯◯◯ Implants placed using both delayed placement with
studies) VERY LOWe delayed loading and delayed placement with
early loading seem to present high survival rates.
Follow-up period varied from 3 years up to
15 years
22 | AIQUEL et al.
Summary of findings: GRADE IV
Immediate placement and early loading (IPEL) compared to delayed placement and delayed loading
(DPDL) for implant treatment in partially edentulous individuals

Intervention: immediate placement and early loading
Anticipated absolute effectsf (95% CI)
Weighted effect with delayed placement and delayed loading

Outcomes (DPDL)
Rx bone loss around the implant platform assessed with: Radiographic imagef The mean rx bone loss around the implant platform was
1.68 mm ± 0.97
Bleeding on probing No comparison was possible

f
Survival rate assessed with: Radiographic and clinical examination Survival rate was 98.1%
a
All studies except for one RCT (Gothberg et al., 2018) showed from some concerns to high risk of bias; only 3 direct comparisons.
b
The study Romanos et al. (2014) was rated with high risk of bias.
c
Based on withing study comparisons.
d
Based on within and between study comparisons
e
All studies except for one RCT (Gothberg et al., 2017) showed from some concerns to high risk of bias.
f
Based on between study comparisons.
principle was adopted by evaluating all outcomes of placement and implants) and DPDL (182 implants/72 patients) combinations of
loading from the 14 studies in combination, as recently suggested placement and loading.
(Gallucci et al., 2018). Five of the 9 categories are covered by the The only biological outcome measure that could be extracted
included studies: immediate placement combined with immediate or from pooled data was mean MBL. However, their heterogeneity
early loading (types IPIL and IPEL), and delayed placement combined and quality did not allow to draw any conclusions on the effect of
with immediate, early, or delayed loading (types DPIL, DPEL, and different timing of placement and loading protocols on peri-implant
DPDL). Three to 15 years after surgery, all groups showed implant marginal bone changes.
survival rates >90%, except one observational study representing Biological complications were poorly reported in the studies
type IPIL (Siebers et al., 2010). here reviewed. Low rates of 2.6% or 3.7% emerged in two groups
Heterogeneity in study designs, inconsistencies in outcome of delayed placement time combined with either immediate load-
reporting, and a lack of comparative studies, reflected by the low ing (type DPIL) or delayed loading (type DPDL). Our extraction
level of evidence in the GRADE table, allowed to include only three of data on biological outcomes and complications was based on
RCT’s in one quantitative synthesis (Daher et al., 2019; Göthberg definitions of peri-implant disease (Heitz-Mayfield & Salvi, 2018;
et al., 2018; Göthberg et al., 2010; Romanos et al., 2016). The meta- Schwarz et al., 2018) and health (Araujo & Lindhe, 2018) adopted
analysis revealed no significant difference in terms of survival by the 2017 World Workshop on the Classification of Periodontal
rate (p = .227) emerged between the type DPIL (74 patients/188 and Peri-implant Diseases and Conditions, co-sponsored by the
AIQUEL et al. | 23
Weighted effect with immediate No. of participants Certainty of the

placement and early loading (IPEL) (contributing arm/studies) evidence (GRADE) Comments
The mean rx bone loss around the 298+67 (2 RCTs, 3 ⨁◯◯◯ Implants placed with delayed implant
implant platform 0.99 ± 1.35 observational study) VERY LOWb placement and early loading may exhibit
decreased mean bone loss after loading.
Follow-up period varied from 3 years up to
15 years
- - -
- - -
- - -
- - -
Survival rate was 100% 439+67 (3 RCTs, 3 ⨁◯◯◯ Implants placed with both delayed placement
observational study) VERY LOWe with delayed loading and immediate
placement with early loading present high
survival rates. Follow-up period varied
from 3 years up to 15 years
American Academy of Periodontology and the European Federation options. History of periodontitis has been postulated as a risk factor
of Periodontology (Caton et al., 2018). Unfortunately, many studies for peri-implantitis (Schwarz et al., 2017), and there is some consen-
do not clearly define peri-implant diseases or do not consider clini- sus on this despite some conflicting reports (Canullo et al., 2016;
cal parameters in their definition, which can lead to inaccuracy and Dvorak et al., 2011; Marrone et al., 2013; Rokn et al., 2017; Schwarz
biased results. Thus, in this systematic review, only survival rates et al., 2017). The majority of studies in the present review had spe-
and mean bone level could be quantitatively assessed. cifically excluded patients with such histories or merely indicated
The results of this review are consistent with a previous finding of that all included patients had been periodontally stable.
overall treatment outcomes being similar for immediately placed and The integrity of the facial extraction socket wall has been re-
loaded implants as in control groups of delayed placement and/or garded as a critical factor in deciding upon an implant placement
delayed loading (Parvini et al., 2020). In addition, a systematic review protocol (Tonetti et al., 2019), and certainly, the anatomy of the
has reported survival rates >97% across all protocols of placement extraction socket is a useful consideration regarding implant suc-
and loading (Gallucci et al., 2018), while another systematic review cess and biological outcomes (Parvini et al., 2020). Most of the
focusing on placement protocols did not find a significant difference 14 studies dealt with healed sockets and yielded little information
between differently timed implant procedures (Bassir et al., 2018). on bone grafting, which usually was performed simultaneously with
No solid conclusions arise on how smoking and histories of peri- the implant surgery, either in immediate or in delayed placement
odontitis relate to the biological outcomes of the various timing protocols (Oxby et al., 2015; Siebers et al., 2010). This suggests the
24 | AIQUEL et al.
presence of less-than-ideal socket anatomies even during immedi- powered RCTs comparing biological outcomes of different implant
ate placement. Reference to post-extraction socket anatomy was placement and loading protocols in the long term.
made in only one study, to the effect that grafting was performed
when the buccal plate was “questionable” and preference given to AC K N OW L E D G E M E N T S
submerged healing in the presence of a bone defect >3 mm (Siebers This systematic review was performed in the context of the EAO
et al., 2010). Consensus Conference 2021. The reviewers would like to thank
One strength of this systematic review is its broad literature base the EAO for the trust and the assignment for the conduction of this
of over 7000 unique (i.e., deduplicated) publications which were re- review and in addition all contacted authors that provided detailed
turned by the search terms and carefully screened by the reviewers. information on their studies, that helped to complete the data set
Its methodology based on the Cochrane textbook is also a signif- analyzed in the present work. Namely we received additional in-
icant strength as well. Limitations arise from its inclusion of study formation and/or data from Dr. Susanne Vogl, Dr. Gert Oxby, Prof.
designs that might weaken conclusions, as non-RCT studies gener- Dr. Benedikt Spies, Dr. Zeina Majzoub, Dr. Paolo Capparé, Dr.
ally increase the risk of incurring biases in systematic reviews (Hoy Roberto Crespi, Dr. Derk Siebers, Prof. Dr. Georgios Romanos, Dr.
et al., 2012). As shown in the GRADE listings (Table 7), certainty of Willem-Frederik Simons, Prof. Dr. Andy Temmerman, Dr. Misi Si,
evidence was very low for all outcomes across all combinations of Prof. Vibaeke Baelum, Dr. Zeev Ormianer, Prof. David Cochrane,
protocols. One exception, with a low certainty of evidence based Prof. Ralf Kohal, Prof. Alessandro Pozzi, Dr. Marco Esposito, Prof.
on one RCT (Romanos, et al.), was bleeding on probing compared Luca Cordaro, and Dr. Tom Wilson. The Authors acknowledge and
between immediate and delayed loading in conjunction with delayed are grateful for the support and contributions from all the above.
placement (type DPIL versus DPDL). The conduction of this systematic was further supported by the
Another limiting factor was the small sample size (low number Division of Fixed Prosthodontics and Biomaterials University
of included studies) the small number of implants included, and that Clinics for Dental Medicine, University of Geneva, Switzerland
only three studies were available for meta-analysis. Thus, large parts (Chair: Prof. Dr. Irena Sailer) and the Department of Oral Surgery
of the conclusions from this systematic review are based on pooled and Orthodontics, University Clinic of Dental Medicine and Oral
data, which needs to mentioned as a limiting factor. Health, Medical University of Graz, Austria (Chair: Univ. Prof. DDr.
Yet this scarcity does reflect the current level of evidence on how Norbert Jakse). The authors would further like to thank Dr. Aron
different protocols of implant placement and loading may affect the Naimi-A kbar, DDS PhD research methodologist (University of
risk of biological complications related to implant-supported FPDs. Malmö, Sweden) for his expertise in developing the overall search
Given this inadequate base of evidence to shed light on these issues, strategy and Mag. Gregor Steinrisser reference and education ser-
this systematic review cannot possibly yield any robust conclusions. vices librarian (Medical University of Graz, Austria) for his help
The need for well-designed and adequately powered RCTs spe- with electronic literature databases used in the present review and
cifically reporting and evaluating biological outcomes of different Mag. Wielfried Preinfalk for his support editing the manuscript.
implant placement as well as loading protocols is warranted.
C O N FL I C T O F I N T E R E S T
None.
5 | CO N C LU S I O N
AU T H O R C O N T R I B U T I O N S
Within its limitations, this review showed high rates of survival of all Louise Leite Aiquel: Data curation (equal); formal analysis; method-
the studied implant placement and loading combinations for FPDs ology (equal); project administration (equal); software (lead); writing-
over ≥3 years of follow-up. The small number of studies (n = 14), al- original draft (equal); writing-review & editing. Joao Pitta: Data
lowing data synthesis from only 3 trials, revealed no differences in curation (equal); Formal analysis (equal); methodology (equal); soft-
terms of survival rates of implants immediately or delayed loaded ware (equal); writing-original draft (equal); writing-review & editing
after delayed placement. In addition, the analysis of pooled data (equal). Georgios N. Antonoglou: Data curation (equal); formal anal-
did not reveal differences in survival rates nor marginal bone levels ysis (equal); methodology (equal); validation (equal); writing-original
when DPDL and DPIM were compared. draft (equal); writing-review & editing (equal). Irene Mischak: Data
The heterogeneity and quality of the data did not allow to draw curation (lead); validation (equal). Irena Sailer: Conceptualization
any further conclusions on the occurrence of biological complica- (equal); supervision (equal); writing-original draft. Michael Payer:
tions related to timing of implant placement/loading. Most com- Conceptualization (equal); project administration (equal); supervi-
parisons across studies were precluded by major inconsistencies sion (equal); writing-review & editing (equal).
in outcome reporting, such as lack of definition of the peri-implant
diseases and scarcity of reported biological outcomes for each DATA AVA I L A B I L I T Y S TAT E M E N T
placement and loading combination. This suggests that the currently Data available on request from the authors. The data that support
available evidence on the PICO question which was investigated is the findings of this study are available from the corresponding au-
scarce and highlights the need for well-designed and adequately thor upon reasonable request.
AIQUEL et al. | 25
diseases and conditions - Introduction and key changes from the

ORCID 1999 classification. Journal of Periodontology, 89(Suppl 1), 1–8.
João Pitta https://orcid.org/0000-0002-2334-4688 https://doi.org/10.1002/JPER.18-0157.
Georgios N. Antonoglou https://orcid.org/0000-0002-8254-5471 Chan, H.-L ., George, F., Wang, I.-C ., Suárez López del Amo, F., Kinney,
J., & Wang, H.-L . (2019). A randomized controlled trial to compare
Irena Sailer https://orcid.org/0000-0002-4537-7624
aesthetic outcomes of immediately placed implants with and with-
Michael Payer https://orcid.org/0000-0003-4469-8335
out immediate provisionalization. Journal of Clinical Periodontology,
46, 1061–1069. https://doi.org/10.1111/jcpe.13171.
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Received: 1 December 2020 | Revised: 23 May 2021 | Accepted: 10 June 2021

Does the timing of implant placement and loading influence

Louise Leite Aiquel1 | João Pitta2 | Georgios N. Antonoglou1 | Irene Mischak1 |

Clin Oral Impl Res. 2021;32(Suppl. 21):5–27. ﻿ wileyonlinelibrary.com/journal/clr | 5

1 | I NTRO D U C TI O N Thus, it cannot be excluded that immediately inserted implants

F I G U R E 1 PRISMA flow diagram

TA B L E 1 Reasons for exclusion during data extraction TA B L E 1 (Continued)

Insufficient data for 67 Agliardi et al. (2014) Cochran et al. (2011b)

TA B L E 2 Overview on study, patient and implant characteristics of included studies

Total Presence of Patients with history

An et al. (2019) Case series University/South 33 0 NR NR

Degidi et al. (2011) Observational cohort Private practice/Italy 24 3 NR NR

Göthberg et al. (2018) RCT University/Sweden 50 0 NR Yes (NR)

Oxby et al. (2015) Observational Cohort Private practice/ 39 4 NR NR

Payer et al. (2010) Case Series University/Austria 24 0 NR NR

Si et al. (2016) Case Series University/China 10 0 Yes (24) Yes (41)

Spies et al. (2015) Observational cohort University/Germany 13 0 NR

Abbreviation: NR, not reported.

NR Day of implant placement DPIL 68 Titanium NR

>9 months Immediately after implant DPIL 80 Titanium NobelActive/Nobel

3.3.4 | DPEL—­(delayed placement + early loading) 3.3.5 | DPDL—­(delayed placement + delayed

Degidi et al. (2011), Oxby et al. (2015) * * * *

An et al. Yes Yes Yes Unclear Yes

3.5 | Certainties of evidence

Comparability of cases and Sufficient follow-­up time for Adequacy of follow-­up of

Was there clear

Yes Yes Yes Yes* Yes Included

Yes Yes Yes Yes Yes Included

Yes Yes Yes Yes Yes Included

An et al. (2019) DPIL Non-­ 36 68 68 100% 0.42 ± 0.39 0.65 ± 0.81

Oxby et al. DPEL NA 55 107 107 100% 0.28 ± 0.88 NR

Payer et al. DPIL Non-­ 96 40 18 95% 0.88 ± 1.15 NR

Mean ± SD soft-­tissue Mean (SD) PD Rate of biological

NR NR 0.35 ± 0.64 2.68 (1.00) 0 0%

NR NR NR 3.15 (0.87) 3 implants with peri-­implantitis 4.8%

0.30 ± 0.84 1.73 ± 1.36 mm 0.56 ± 0.94 2.53 (0.63) 0 0%

0.20 ±0.48 2.00 ± 1.23 mm 0.43 ± 0.63 2.6 (0.50) 0 0%

NR NR NR NR 2 implants with peri-­implantitis 10.5%

NR NR NR 3.33 (1.73) 2 implants with peri-­implantitis 3.4%

alternative combinations seem to improve biological outcomes and

It has been suggested as a fundamental principle in implant dentistry

Summary of findings: GRADE I

Anticipated absolute effects

Mucositis No muscositis was reported in all studies with data on peri-­implantitis

Summary of findings: GRADE II

Patient or population: implant treatment in partially edentulous individuals

Anticipated absolute effects

Weighted effect with delayed

No. of implants (contributing arm/ Certainty of the

Certainty of the evidence

Summary of findings: GRADE II

Patient or population: implant treatment in partially edentulous individuals

Anticipated absolute effects

Weighted effect with delayed

Peri-­implant probing depth No comparison was possible

Summary of findings: GRADE III

Patient or population: implant treatment in partially edentulous individuals

Anticipated absolute effects

Bleeding on probing No comparison was possible

Clin Oral Impl Res. 2021;32(Suppl. 21):5–27. wileyonlinelibrary.com/journal/clr | 5

3.3.4 | DPEL—(delayed placement + early loading) 3.3.5 | DPDL—(delayed placement + delayed

Comparability of cases and Sufficient follow-up time for Adequacy of follow-up of

An et al. (2019) DPIL Non- 36 68 68 100% 0.42 ± 0.39 0.65 ± 0.81

Payer et al. DPIL Non- 96 40 18 95% 0.88 ± 1.15 NR

Mean ± SD soft-tissue Mean (SD) PD Rate of biological

NR NR NR 3.15 (0.87) 3 implants with peri-implantitis 4.8%

NR NR NR NR 2 implants with peri-implantitis 10.5%

NR NR NR 3.33 (1.73) 2 implants with peri-implantitis 3.4%

Mucositis No muscositis was reported in all studies with data on peri-implantitis

Peri-implant probing depth No comparison was possible

diseases and conditions - Introduction and key changes from the