Immediate nonfunctional versus immediate functional loading and dental implant failure rates: A systematic review and meta-analysis

Immediate nonfunctional versus immediate functional loading and dental implant failure rates: A systematic review and meta-analysis

Journal of Dentistry, 2014-09-01, Volume 42, Issue 9, Pages 1052-1059, Copyright © 2014 Elsevier Ltd

Abstract

Objectives

The purpose of the present review was to test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for patients being rehabilitated using dental implants with immediate nonfunctional loading (INFL) compared to immediate functional loading (IFL), against the alternative hypothesis of a difference.

Methods

An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomized or not. The estimates of relative effect were expressed in risk ratio (RR) and mean difference (MD) in millimeters.

Results

1059 studies were identified and 11 studies were included, of which 7 were of high risk of bias, whereas four studies were of low risk of bias. The results showed that the procedure used (nonfunctional vs. functional) did not significantly affect the implant failure rates ( P = 0.70), with a RR of 0.87 (95% CI 0.44–1.75). The wide CI demonstrates uncertainty about the effect size. The analysis of postoperative infection was not possible due to lack of data. No apparent significant effects of non-occlusal loading on the marginal bone loss (MD 0.01 mm, 95% CI -0.04–0.06; P = 0.74) were observed.

Conclusions

The results of this study suggest that the differences in occlusal loading between INFL and IFL might not affect the survival of these dental implants and that there is no apparent significant effect on the marginal bone loss.

Clinical Significance: There has been a controversy concerning whether dental implants should be subjected to immediate functional or nonfunctional loading. As the philosophies of treatment may alter over time, a periodic review of the different concepts is necessary to refine techniques and eliminate unnecessary procedures. This would form a basis for optimum treatment.

Introduction

The desire for fewer surgical interventions and shorter implant treatment times has led to the development of revised placement and loading protocols. A healing period of 4–6 months was initially proposed to ensure osseointegration of endosseous dental implants. With the improvements in oral implantology resulting in improved prognosis and outcomes, the traditional protocol for implant dentistry has been constantly reevaluated. Recent steps include reduction of the treatment time through immediate placement of implants into fresh extraction sockets and by loading the implants immediately. Immediate loading protocols have since been extensively discussed in the literature and found to be a viable treatment approach in selected cases.

Two types of immediate loading have been described in the literature. One is the immediate functional loading (IFL), or immediate occlusal loading, which refers to the use of a temporary or definitive prosthesis seated the same day as the surgery in occlusal contact with the opposing arch. An alternative approach consists modifying the immediate temporary restoration to avoid occlusal contacts in centric and lateral excursions, in order to reduce the early risks of mechanical overload caused by functional or parafunctional forces, the immediate nonfunctional loading (INFL), or immediate non-occlusal loading. Thus, the modified restoration would still be involved in the masticatory process, but the mechanical loading stress is reduced.

Theoretically, it has been suggested that IFL could be associated with an increased rate of implant failure. Thus, the aim of this systematic review and meta-analysis was to compare the survival rate of dental implants submitted to IFL and INFL protocols, in order to test the hypothesis that the immediate full occlusal load would compromise or jeopardize the osseointegration process. This study presents a more detailed analysis of the influence of IFL and INFL protocols on the implant failure rates, previously assessed in a systematic review addressing the reasons for failures of oral implants.

Materials and methods

This study followed the PRISMA Statement guidelines. A review protocol does not exist.

Objective

The purpose of the present review was to test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for patients being rehabilitated by dental implants with INFL compared to IFL, against the alternative hypothesis of a difference.

Search strategies

An electronic search without time or language restrictions was undertaken in March 2014 in the following databases: PubMed, Web of Science, and the Cochrane Oral Health Group Trials Register. The following terms were used in the search strategy on PubMed:

{Subject AND Adjective}

{ Subject : (dental implant OR dental implant failure OR dental implant survival OR dental implant success [text words])

AND

Adjective : (immediate occlusal loading OR immediate non-occlusal loading OR immediate functional loading OR immediate nonfunctional loading [text words])}

The following terms were used in the search strategy on Web of Science:

{Subject AND Adjective}

{ Subject : (dental implant OR dental implant failure OR dental implant survival OR dental implant success [title])

AND

Adjective : (immediate occlusal loading OR immediate non-occlusal loading OR immediate functional loading OR immediate nonfunctional loading [title])}

The following terms were used in the search strategy on the Cochrane Oral Health Group Trials Register:

(dental implant OR dental implant failure OR dental implant survival OR dental implant success AND (immediate occlusal loading OR immediate non-occlusal loading OR immediate functional loading OR immediate nonfunctional loading))

A manual search of dental implant-related journals, including British Journal of Oral and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, European Journal of Oral Implantology, Implant Dentistry, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, International Journal of Periodontics and Restorative Dentistry, International Journal of Prosthodontics, Journal of Clinical Periodontology, Journal of Dental Research, Journal of Dentistry, Journal of Oral Implantology, Journal of Craniofacial Surgery, Journal of Cranio-Maxillofacial Surgery, Journal of Maxillofacial and Oral Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Oral Rehabilitation, Journal of Periodontology, and Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology , was also performed.

The reference list of the identified studies and the relevant reviews on the subject were also scanned for possible additional studies. Moreover, online databases providing information about clinical trials in progress were checked (clinicaltrials.gov; www.centerwatch.com/clinicaltrials; www.clinicalconnection.com ).

Inclusion and exclusion criteria

Eligibility criteria included clinical human studies, either randomized or not, comparing implant failure rates in any group of patients receiving dental implants with non-occlusal immediate loading compared to occlusal immediate loading. For this review, implant failure represents the complete loss of the implant. The exclusion criteria were case reports, technical reports, animal studies, in vitro studies, and reviews papers.

Study selection

The titles and abstracts of all reports identified through the electronic searches were read independently by the three authors. For studies appearing to meet the inclusion criteria, or for which there were insufficient data in the title and abstract to make a clear decision, the full report was obtained. Disagreements were resolved by discussion between the authors.

Quality assessment

The quality assessment was performed by using the recommended approach for assessing risk of bias in studies included in Cochrane reviews. The classification of the risk of bias potential for each study was based on the four following criteria: sequence generation (random selection in the population), allocation concealment (steps must be taken to secure strict implementation of the schedule of random assignments by preventing foreknowledge of the forthcoming allocations), incomplete outcome data (clear explanation of withdrawals and exclusions), and blinding (measures to blind study participants and personnel from knowledge of which intervention a participant received). The incomplete outcome data will also be considered addressed when there are no withdrawals and/or exclusions. A study that met all the criteria mentioned above was classified as having a low risk of bias, whereas a study that did not meet one of these criteria was classified as having a moderate risk of bias. When two or more criteria were not met, the study was considered to have a high risk of bias.

Data extraction and meta-analysis

From the studies included in the final analysis, the following data was extracted (when available): year of publication, study design, unicenter or multicenter study, number of patients, patient’s age, follow-up, days of antibiotic prophylaxis, mouth rinse, implant healing period, failed and placed implants, postoperative infection, marginal bone loss, and implant surface modification. Contact with authors for possible missing data was performed.

Implant failure and postoperative infection were the dichotomous outcomes measures evaluated. Weighted mean differences were used to construct forest plots of marginal bone loss, a continuous outcome. The statistical unit for ‘implant failure’ and ‘marginal bone loss’ was the implant, and for ‘postoperative infection’ was the patient. Whenever outcomes of interest were not clearly stated, the data were not used for analysis. The I 2 statistic was used to express the percentage of the total variation across studies due to heterogeneity, with 25% corresponding to low heterogeneity, 50% to moderate and 75% to high. The inverse variance method was used for random-effects or fixed-effects model. Where statistically significant ( P < .10) heterogeneity is detected, a random-effects model was used to assess the significance of treatment effects. Where no statistically significant heterogeneity was found, analysis was performed using a fixed-effects model. The estimates of relative effect for dichotomous outcomes were expressed in risk ratio (RR) and in mean difference (MD) in millimeters for continuous outcomes, both with a 95% confidence interval (CI). Only if there were studies with similar comparisons reporting the same outcome measures was meta-analysis to be attempted. In the cases where no events (or all events) were observed in both groups, the study provides no information about relative probability of the event and is automatically omitted from the meta-analysis. In such cases, the term ‘not estimable’ is shown under the RR column of the forest plot table. The software used here automatically checks for problematic zero counts and adds a fixed value of 0.5 to all cells of study results tables where the problems occur.

A funnel plot (plot of effect size versus standard error) will be drawn. Asymmetry of the funnel plot may indicate publication bias and other biases related to sample size, although the asymmetry may also represent a true relationship between trial size and effect size.

The data were analyzed using the statistical software Review Manager (version 5.2.8, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2014).

Results

Literature search

The study selection process is summarized in Fig. 1 . The search strategy resulted in 1059 papers. The three reviewers independently screened the abstracts for those articles related to the focus question. The initial screening of titles and abstracts resulted in 51 full-text papers; 33 were cited in more than one search of terms. The full-text reports of the remaining 18 articles led to the exclusion of 9 articles because they did not meet the inclusion criteria: 6 articles were conducted in animals, and 3 articles compared non-occlusal vs. occlusal loading, but only in one group the loading was immediate. Additional hand-searching of the reference lists of selected studies yielded 2 additional papers. Thus, a total of 11 publications were included in the review.

Study screening process.
Fig. 1
Study screening process.

Description of the studies

Detailed data of the eleven included studies are listed in Table 1 . Six RCTs, and five CCT were included in the meta-analysis. In two studies both patients and operators/outcome assessors were blinded to the tested intervention, whereas in three studies it was unclear whether blinding was performed. Four studies had a follow-up of up to 1 year.

Table 1
Detailed data of the included studies.
Authors Published Study design Patients ( n ) Patients’ age range (average) (years) Follow-up visits (or range) Antibiotics/mouth rinse (days) Fully occluding final restoration after Failed/placed implants (n) Implant failure rate (%) P value (for failure rate) Marginal bone loss
(mean ± SD) (mm)
Implant surface modification (brand) Observations
Degidi and Piattelli 2003 CCT
(unicenter)
151 (116, G1; 65, G2) 18–75 (NM) 1, 2, 12, 18, 24, 36, 48, and 60 months NM NM 2/224 (G1)
6/422 (G2)
0.9 (G1)
1.4 (G2)
NM NM (G1)
1.1 ± 0.2 (G2) ( n = 87)
Several a No grafted patients
Implants placed in fresh extraction sockets: 97 (G1), 187 (G2)
Degidi and Piattelli 2005 CCT
(unicenter)
97 (253 b ) (63, G1; 34, G2) 20–78 (53) 1, 3, 5, 12, 18, and 24 months NM NM 1/135 (G1)
2/253 (G2)
0.7 (G1)
0.8 (G2)
NM 0.7 ± 0.2 (G1 + G2) Grit-blasted and acid-etched (XiVe, Dentsply-Friadent, Mannheim, Germany) No grafted patients
Some implants placed in fresh extraction sockets
Degidi et al. 2006 CCT
(unicenter)
29 (12, G1; 17, G2) 23–65 (52) 12 and 36 months 5 / NM Mean of 28 weeks 0/23 (G1)
0/119 (G2)
0 (G1)
0 (G2)
NM 1.0 ± NM (G1 + G2) Porous anodized surface (TiUnite, Nobel Biocare, Göteborg, Sweden) No grafted patients
Some implants placed in fresh extraction sockets
Lindeboom et al. 2006 RCT
(unicenter)
48 (24, G1; 24; G2) 19–78 (42.3 ± 13.1) 1, 2, 4, and 6 weeks, 2, 3, 4, 5, and 6 months, 1 year Only before surgery / NP 6 months 3/25 (G1)
2/25 (G2)
12 (G1)
8 (G2)
NM Mesial
0.28 ± 0.22 (G1)
0.27 ± 0.2 (G2)
Distal
0.2 ± 0.11 (G1)
0.19 ± 0.15 (G2)
Sandblasted and etched (BioComp, BioComp Industries BV, Vught, The Netherlands) Only in maxilla (excluding molar regions)
32 implants grafted (16 from each group)
Machtei et al. 2007 CCT
(unicenter)
20 (NM) 31–68 (55.7) 7-10 days, 1, 2, 3, 6, and 12 months 7 / 21 12 months 1/26 (G1)
4/23 (G2)
3.8 (G1)
17.4 (G2)
0.2755 0.91 ± 0.17 (G1 + G2) Acid-etched (Osseotite TG, 3i Implant Innovations, Palm Beach Gardens, USA) Implants placed in periodontally susceptible patients. Xenograft in some patients
Degidi et al. 2009 RCT
(unicenter)
82 (155 c ) (63, G1; 19, G2) 18–78 (54) 4 and 6 months, 1, 2, 3, 4, and 5 years 3 / 7 4–6 months 3/132 (G1)
0/130 (G2)
2.3 (G1)
0 (G2)
NM d 0.5 ± NM (G1)
0.6 ± NM (G2)
Blasted with calcium phosphate (Maestro, BioHorizons, Birmingham, USA) No grafted patients
Some implants placed in fresh extraction sockets
Cannizzaro et al. 2010 RCT
(multicenter)
40 (20, G1; 20, G2) 18–55 (39) 3, 10, and 14 days, 4/5 months, 1 year Only before surgery (6 days for the grafted) / 14 4–5 months 2/20 (G1)
3/20 (G2)
10 (G1)
15 (G2)
1.0 0.72 ± 0.59 (G1)
0.90 ± 0.48 (G2)
Zirconia sandblasted (Z-Look3, Z-Systems, Oensingen, Switzerland) Use of zirconia implants, 10 patients grafted (5 of each group), 10 implants placed in fresh extraction sockets (5 of each group)
Degidi et al. 2010 RCT
(unicenter)
50 (25, G1; 25, G2) 35–54 (45.1 ± 9.1) 5 and 7 weeks, 6, 12, 24, and 36 months 5 / NP 6 months 1/50 (G1)
1/50 (G2)
2 (G1)
2 (G2)
NM 0.987 ± 0.375 (G1)
0.947 ± 0.323 (G2)
Grit-blasted and acid-etched (XiVe Plus, Dentsply-Friadent, Mannheim, Germany) Only in posterior mandible
No grafted patients
Siebers et al. 2010 CCT
(unicenter)
45 (76 e ) (NM) 22–85 (52 ± 13) Mean of 38 months NM 6–8 months 4/47 (G1)
1/64 (G2) f
8.5 (G1)
1.6 (G2)
0.083 f NM Sandblasted and acid-etched (Camlog Rootline and Screw Line, Camlog Biotechnologies, Basel, Switzerland), acid-etched (Osseotite, Biomet 3i, Palm Beach Gardens, USA), blasted with HA and calcium phosphate (Restore RBM, Lifecore Biomedical, Chaska, USA) No grafted patients
46 implants placed in fresh extraction sockets
Margossian et al. 2012 RCT
(unicenter)
80 (117 g ) (40, G1; 40, G2) NM 2, 4, 8, 12, 20, and 24 weeks, 1 and 2 years Only before surgery / 14 4 months 0/105 (G1)
7/104 (G2)
0 (G1)
6.7 (G2)
NM NM Acid-etched (Osseotite NT, 3i Implant Innovations, Palm Beach Gardens, USA) No grafted patients
Vogl et al. 2013 RCT
(unicenter)
20 (11, G1; 9, G2) 33–70 (54 ± 11.9) 1 week, 1, 2, 3, 6, and 12 months 5 / only before surgery 6–8 months 0/34 (G1)
0/21 (G2)
0 (G1)
0 (G2)
NM 0.4 ± 0.5 (G1)
0.4 ± 0.4 (G2)
Grit-blasted and acid-etched (XiVe, Dentsply-Friadent, Mannheim, Germany) Only in posterior mandible.
Use of stereolithographic tooth-supported guides. No grafted patients

a Frialit 2, IMZ, Frialoc (Friadent, Mannheim, Germany), Brånemark (Nobel Biocare, Göteborg, Sweden), Restore (Lifecore Biomedical, Chaska, USA), Maestro (Biohorizons, Birmingham, USA), 3i (Implant Innovations, West Palm Beach, USA).

b There were 253 patients in the study, however, in 156 patients the implants were inserted using the traditional technique.

c There were 155 patients in the study, however, only in 82 of them the implants were inserted in immediate function.

d A P value was 0.196 when a comparison of the implant survival rate between the immediately loaded group and delayed loaded group was performed, but not between the INFL and IFL groups.

e There were 76 patients in the study, however, only in 45 of them the implants were inserted in immediate function.

f Unpublished information was obtained by personal communication with one of the authors.

g There were 117 patients in the study, however, in 37 patients the implants were inserted using the traditional technique. NM–not mentioned; CCT–controlled clinical trial; RCT–randomized controlled trial; G1–group immediately nonfunctional loaded implants (INFL); G2–group immediately functional loaded implants (IFL); NP – not performed.

All studies with available data of patients’ age included only adult patients. Eight studies did not perform grafting procedures in any of the patients. One study used only zirconia implants, in another study the implants were inserted in periodontally susceptible patients, in two studies the implants were inserted only in the posterior mandible, and in one study the implants were inserted only in the maxilla.

Not every article provided information about the number of failed implants by group. Unpublished information concerning the number of failed implants in each group was obtained by personal communication with one of the authors in one study. From the eleven studies, a total of 821 dental implants received non-occlusal immediate loading, with 17 failures (2.1%), and 1231 implants received occlusal immediate loading, with 26 failures (2.1%). Eight studies did not inform whether there was a statistically significant difference or not between the techniques concerning implant failure, whereas the other three studies did not find statistically significant difference. There were no implant failures in two studies. Only three studies informed of the incidence of postoperative infection, all with no occurrences in a total of 89 patients receiving 237 implants. Nine studies provided information about the marginal bone loss.

Quality assessment

Each trial was assessed for risk of bias, and the scores are summarized in Table 2 . Seven studies were judged to be at high risk of bias and four studies of low risk of bias.

Table 2
Results of quality assessment.
Authors Published Sequence generation (randomized?) Allocation concealment Incomplete outcome data addressed Blinding Estimated potential risk of bias
Degidi and Piattelli 2003 No Inadequate Yes No High
Degidi and Piattelli 2005 No Inadequate Yes No High
Degidi et al. 2006 No Inadequate No No High
Lindeboom et al. 2006 Yes Inadequate Yes No High
Machtei et al. 2007 No Inadequate Yes No High
Degidi et al. 2009 Yes Unclear Yes Unclear High
Cannizzaro et al. 2010 Yes Adequate Yes Yes Low
Degidi et al. 2010 Yes Adequate Yes Yes Low
Siebers et al. 2010 No Inadequate No No High
Margossian et al. 2012 Yes Adequate Yes Yes a Low
Vogl et al. 2013 Yes Adequate Yes Yes a Low

a Unpublished information was obtained by personal communication with one of the authors.

Meta-analysis

In this study, a fixed-effects model was used to evaluate the implant failure, since statistically significant heterogeneity was not found ( P = 0.26; I 2 = 21%). The results showed a RR of 0.87 (95% CI 0.44–1.75; Fig. 2 ) for the INFL, suggesting that implant failures in patients receiving implants under the INFL protocol are 0.87 times likely to happen when compared to implant failures in patients receiving implants under the IFL protocol (relative risk reduction of 13% for INFL). However, the procedure used (INFL vs. IFL) did not significantly affect the implant failure rates ( P = 0.70).

Forest plot of comparison of INFL versus IFL for the event ‘implant failure’.
Fig. 2
Forest plot of comparison of INFL versus IFL for the event ‘implant failure’.

As only three studies informed of the incidence of postoperative infection, and all with no events, no meta-analysis was possible for this outcome.

Only four studies (245 implants) provided information about the marginal bone loss with standard deviation, necessary for the calculation of comparisons in continuous outcomes ( Fig. 3 ). A fixed-effects model was used to evaluate this outcome, since statistically significant heterogeneity was not found ( P = 0.84; I 2 = 0%). There was no statistically significant difference ( P = 0.74) between the different techniques concerning the marginal bone loss.

Forest plot of comparison of INFL versus IFL for the event ‘marginal bone loss’.
Fig. 3
Forest plot of comparison of INFL versus IFL for the event ‘marginal bone loss’.

Publication bias

The funnel plot did not show asymmetry when the studies reporting the outcome ‘implant failure’ were analyzed ( Fig. 4 ), indicating absence of publication bias.

Funnel plot for the studies reporting the outcome event ‘implant failure’.
Fig. 4
Funnel plot for the studies reporting the outcome event ‘implant failure’.

Discussion

The present study proposed to test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for patients being rehabilitated with dental implants comparing INFL to IFL, against the alternative hypothesis of a difference.

Concerning the implant failure rates, the idea behind the concept of keeping the temporary restoration out of occlusion is to control the load on the prosthesis in order to allow undisturbed healing. The role of tongue pressure and perioral musculature may be an underestimated factor in immediately provisionalized but unloaded implants. Moreover, occlusion might not be the only determinant of implant survival. The results of the present meta-analysis showed that there was no statistically significant difference between the INFL and IFL concerning implant failures. The increase of load, applied to the prosthesis caused by the presence of the normal occlusal contact, seems to be unable to jeopardize or alter the healing process of the implant. Some factors may have contributed to such outcome in some studies, that include the use of a resilient acrylic resin for the fabrication of the temporary restoration, the exclusion of parafunctional bruxist patients from the study, and the splinting of the temporary prosthetic work. It has been suggested that it is not the absence of loading per se that is critical for osseointegration, but rather the absence of excessive micromotion at the interface. Micromotion consists of a relative movement between the implant surface and surrounding bone during functional loading and it is believed that, above a certain threshold, excessive interfacial micromotion early after the implantation interferes with local bone healing, predisposing to a fibrous tissue interface, preventing the fibrin clot from adhering to the implant surface during healing. Splinting the provisional restoration might have protected the implants from micromotion.

The small sample size in many studies may also have affected the results concerning implant failure. Even though the importance of meta-analyses is to increase sample size of individual trials to reach more precise estimates of the effects of interventions, in this particular analysis no statistically significant difference was found when comparing these two techniques concerning the implant failure rates ( P = 0.70). As there is a wide CI for the RR (RR 0.87; 95% CI 0.44–1.75), the uncertainty about the effect size is greater than if the CI was narrower, although there might still be enough precision to make decisions about the utility of the intervention.

In four studies the patients were followed for a short period (1 year). Thus, only early failures could be assessed. A longer follow-up period may lead to an increase in the failure rate. Moreover, the results found in the studies differed from each other, and such discrepancies could be due to factors such as differences in the patients included in the study or the between clinicians placing and restoring the implants.

Only three studies provided information regarding the incidence of postoperative infection, all of them with no events. Therefore, no meta-analysis was possible for this outcome.

The third outcome analyzed was the marginal bone loss. Marginal bone levels might vary with load distribution patterns between natural teeth and implants, with access for hygiene instruments in splinted provisional restorations or with iatrogenic manipulation of the implant during initial healing. Early functional loading during the healing phase may have a positive effect on marginal bone levels. Early loading stimuli at the bone-implant interface leads to functional adaptation of the bone (remodeling) and to an improved differentiation of the bone structures, resulting in a higher marginal bone level. However, the present meta-analysis did not find a statistically significant difference ( P = 0.74) between the techniques in what concerns the marginal bone loss. The reason for that may be the short postoperative follow-up period of 1 year found in three of the four studies with available data to produce a comparison, and/or the small sample size in all four studies. The biological differences in peri-implant tissue responses between IFL and INFL implants have been analyzed in animal models, where no differences were observed between the ultrastructural morphology of the cells at the interface of implants from both groups in the early phases of osseointegration in minipigs, and no statistically significant differences in the bone-to-implant contact percentages were found between groups, in a study performed in dogs.

The present meta-analysis included non-RCT studies, which is not usually performed. Potential biases are likely to be greater for non-randomized studies compared with RCTs, so results should always be interpreted with caution when they are included in reviews and meta-analyses. So what was the reason to include non-randomized studies in the present meta-analysis? The issue is important because meta-analyses are frequently conducted on a limited number of RCTs. Shrier reviewed a random 1% sample of meta-analyses published by the Cochrane Collaboration in 2003 and found that 6 of 16 reviews included two studies or fewer. Furthermore, 158 of 183 analyses conducted in 7 additional studies were limited to two or fewer studies. In meta-analyses such as these, adding more information from observational studies may aid in clinical reasoning and establish a more solid foundation for causal inferences. In a meta-analysis, homogeneity implies a mathematical compatibility between the results of each individual trial. Narrowing the inclusion criteria increases homogeneity but also excludes the results of more trials and thus risks the exclusion of significant data.

One of the strengths of meta-analysis as a technique for synthesizing research findings on the effectiveness of intervention programs is that it allows those findings to be systematically compared and contrasted across studies. What complicates the investigation is the presence of confounding variables in the analyzed studies. The use of grafting in some studies is a confounding factor, as well as inserting the implants only in periodontally susceptible patients, in particular regions of the mouth, such as only in the posterior mandible or only in the maxilla, the insertion of some implants in fresh extraction sockets, the use of zirconia implants, and the insertion of implants from different brands and surface treatments. Titanium implants with different surface modifications show a wide range of chemical, physical properties, and surface topographies and morphologies, depending on how they are prepared and handled, while it is not clear whether, in general, one surface modification is better than the other.

The results of the present study should be interpreted with caution considering its limitations. The presence of confounding factors may have affected the long-term outcomes, regardless of whether the implants were submitted to INFL or IFL. The impact of such variables on the implant survival rate, postoperative infection and marginal bone loss outcomes is difficult to estimate if these factors are not identified separately between the two different procedures in order to perform a meta-regression analysis. Therefore, lack of control of the confounding factors limited the potential to draw robust conclusions.

Conclusions

The results of this meta-analysis suggest that the differences in occlusal loading between INFL and IFL might not affect the survival of these dental implants. There was also no statistically significant difference between the two techniques concerning the marginal bone loss.

Acknowledgements

This work was supported by CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico–Brazil. The authors would like to thank Dr. Derk Siebers, Dr. Patrice Margossian, and Dr. Marlene Stopper, who provided us some missing information about their studies.

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Immediate nonfunctional versus immediate functional loading and dental implant failure rates: A systematic review and meta-analysis Bruno Ramos Chrcanovic , Tomas Albrektsson and Ann Wennerberg Journal of Dentistry, 2014-09-01, Volume 42, Issue 9, Pages 1052-1059, Copyright © 2014 Elsevier Ltd Abstract Objectives The purpose of the present review was to test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for patients being rehabilitated using dental implants with immediate nonfunctional loading (INFL) compared to immediate functional loading (IFL), against the alternative hypothesis of a difference. Methods An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomized or not. The estimates of relative effect were expressed in risk ratio (RR) and mean difference (MD) in millimeters. Results 1059 studies were identified and 11 studies were included, of which 7 were of high risk of bias, whereas four studies were of low risk of bias. The results showed that the procedure used (nonfunctional vs. functional) did not significantly affect the implant failure rates ( P = 0.70), with a RR of 0.87 (95% CI 0.44–1.75). The wide CI demonstrates uncertainty about the effect size. The analysis of postoperative infection was not possible due to lack of data. No apparent significant effects of non-occlusal loading on the marginal bone loss (MD 0.01 mm, 95% CI -0.04–0.06; P = 0.74) were observed. Conclusions The results of this study suggest that the differences in occlusal loading between INFL and IFL might not affect the survival of these dental implants and that there is no apparent significant effect on the marginal bone loss. Clinical Significance: There has been a controversy concerning whether dental implants should be subjected to immediate functional or nonfunctional loading. As the philosophies of treatment may alter over time, a periodic review of the different concepts is necessary to refine techniques and eliminate unnecessary procedures. This would form a basis for optimum treatment. 1 Introduction The desire for fewer surgical interventions and shorter implant treatment times has led to the development of revised placement and loading protocols. A healing period of 4–6 months was initially proposed to ensure osseointegration of endosseous dental implants. With the improvements in oral implantology resulting in improved prognosis and outcomes, the traditional protocol for implant dentistry has been constantly reevaluated. Recent steps include reduction of the treatment time through immediate placement of implants into fresh extraction sockets and by loading the implants immediately. Immediate loading protocols have since been extensively discussed in the literature and found to be a viable treatment approach in selected cases. Two types of immediate loading have been described in the literature. One is the immediate functional loading (IFL), or immediate occlusal loading, which refers to the use of a temporary or definitive prosthesis seated the same day as the surgery in occlusal contact with the opposing arch. An alternative approach consists modifying the immediate temporary restoration to avoid occlusal contacts in centric and lateral excursions, in order to reduce the early risks of mechanical overload caused by functional or parafunctional forces, the immediate nonfunctional loading (INFL), or immediate non-occlusal loading. Thus, the modified restoration would still be involved in the masticatory process, but the mechanical loading stress is reduced. Theoretically, it has been suggested that IFL could be associated with an increased rate of implant failure. Thus, the aim of this systematic review and meta-analysis was to compare the survival rate of dental implants submitted to IFL and INFL protocols, in order to test the hypothesis that the immediate full occlusal load would compromise or jeopardize the osseointegration process. This study presents a more detailed analysis of the influence of IFL and INFL protocols on the implant failure rates, previously assessed in a systematic review addressing the reasons for failures of oral implants. 2 Materials and methods This study followed the PRISMA Statement guidelines. A review protocol does not exist. 2.1 Objective The purpose of the present review was to test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for patients being rehabilitated by dental implants with INFL compared to IFL, against the alternative hypothesis of a difference. 2.2 Search strategies An electronic search without time or language restrictions was undertaken in March 2014 in the following databases: PubMed, Web of Science, and the Cochrane Oral Health Group Trials Register. The following terms were used in the search strategy on PubMed: {Subject AND Adjective} { Subject : (dental implant OR dental implant failure OR dental implant survival OR dental implant success [text words]) AND Adjective : (immediate occlusal loading OR immediate non-occlusal loading OR immediate functional loading OR immediate nonfunctional loading [text words])} The following terms were used in the search strategy on Web of Science: {Subject AND Adjective} { Subject : (dental implant OR dental implant failure OR dental implant survival OR dental implant success [title]) AND Adjective : (immediate occlusal loading OR immediate non-occlusal loading OR immediate functional loading OR immediate nonfunctional loading [title])} The following terms were used in the search strategy on the Cochrane Oral Health Group Trials Register: (dental implant OR dental implant failure OR dental implant survival OR dental implant success AND (immediate occlusal loading OR immediate non-occlusal loading OR immediate functional loading OR immediate nonfunctional loading)) A manual search of dental implant-related journals, including British Journal of Oral and Maxillofacial Surgery, Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, European Journal of Oral Implantology, Implant Dentistry, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, International Journal of Periodontics and Restorative Dentistry, International Journal of Prosthodontics, Journal of Clinical Periodontology, Journal of Dental Research, Journal of Dentistry, Journal of Oral Implantology, Journal of Craniofacial Surgery, Journal of Cranio-Maxillofacial Surgery, Journal of Maxillofacial and Oral Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Oral Rehabilitation, Journal of Periodontology, and Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology , was also performed. The reference list of the identified studies and the relevant reviews on the subject were also scanned for possible additional studies. Moreover, online databases providing information about clinical trials in progress were checked (clinicaltrials.gov; www.centerwatch.com/clinicaltrials; www.clinicalconnection.com ). 2.3 Inclusion and exclusion criteria Eligibility criteria included clinical human studies, either randomized or not, comparing implant failure rates in any group of patients receiving dental implants with non-occlusal immediate loading compared to occlusal immediate loading. For this review, implant failure represents the complete loss of the implant. The exclusion criteria were case reports, technical reports, animal studies, in vitro studies, and reviews papers. 2.4 Study selection The titles and abstracts of all reports identified through the electronic searches were read independently by the three authors. For studies appearing to meet the inclusion criteria, or for which there were insufficient data in the title and abstract to make a clear decision, the full report was obtained. Disagreements were resolved by discussion between the authors. 2.5 Quality assessment The quality assessment was performed by using the recommended approach for assessing risk of bias in studies included in Cochrane reviews. The classification of the risk of bias potential for each study was based on the four following criteria: sequence generation (random selection in the population), allocation concealment (steps must be taken to secure strict implementation of the schedule of random assignments by preventing foreknowledge of the forthcoming allocations), incomplete outcome data (clear explanation of withdrawals and exclusions), and blinding (measures to blind study participants and personnel from knowledge of which intervention a participant received). The incomplete outcome data will also be considered addressed when there are no withdrawals and/or exclusions. A study that met all the criteria mentioned above was classified as having a low risk of bias, whereas a study that did not meet one of these criteria was classified as having a moderate risk of bias. When two or more criteria were not met, the study was considered to have a high risk of bias. 2.6 Data extraction and meta-analysis From the studies included in the final analysis, the following data was extracted (when available): year of publication, study design, unicenter or multicenter study, number of patients, patient's age, follow-up, days of antibiotic prophylaxis, mouth rinse, implant healing period, failed and placed implants, postoperative infection, marginal bone loss, and implant surface modification. Contact with authors for possible missing data was performed. Implant failure and postoperative infection were the dichotomous outcomes measures evaluated. Weighted mean differences were used to construct forest plots of marginal bone loss, a continuous outcome. The statistical unit for ‘implant failure’ and ‘marginal bone loss’ was the implant, and for ‘postoperative infection’ was the patient. Whenever outcomes of interest were not clearly stated, the data were not used for analysis. The I 2 statistic was used to express the percentage of the total variation across studies due to heterogeneity, with 25% corresponding to low heterogeneity, 50% to moderate and 75% to high. The inverse variance method was used for random-effects or fixed-effects model. Where statistically significant ( P < .10) heterogeneity is detected, a random-effects model was used to assess the significance of treatment effects. Where no statistically significant heterogeneity was found, analysis was performed using a fixed-effects model. The estimates of relative effect for dichotomous outcomes were expressed in risk ratio (RR) and in mean difference (MD) in millimeters for continuous outcomes, both with a 95% confidence interval (CI). Only if there were studies with similar comparisons reporting the same outcome measures was meta-analysis to be attempted. In the cases where no events (or all events) were observed in both groups, the study provides no information about relative probability of the event and is automatically omitted from the meta-analysis. In such cases, the term ‘not estimable’ is shown under the RR column of the forest plot table. The software used here automatically checks for problematic zero counts and adds a fixed value of 0.5 to all cells of study results tables where the problems occur. A funnel plot (plot of effect size versus standard error) will be drawn. Asymmetry of the funnel plot may indicate publication bias and other biases related to sample size, although the asymmetry may also represent a true relationship between trial size and effect size. The data were analyzed using the statistical software Review Manager (version 5.2.8, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2014). 3 Results 3.1 Literature search The study selection process is summarized in Fig. 1 . The search strategy resulted in 1059 papers. The three reviewers independently screened the abstracts for those articles related to the focus question. The initial screening of titles and abstracts resulted in 51 full-text papers; 33 were cited in more than one search of terms. The full-text reports of the remaining 18 articles led to the exclusion of 9 articles because they did not meet the inclusion criteria: 6 articles were conducted in animals, and 3 articles compared non-occlusal vs. occlusal loading, but only in one group the loading was immediate. Additional hand-searching of the reference lists of selected studies yielded 2 additional papers. Thus, a total of 11 publications were included in the review. Fig. 1 Study screening process. 3.2 Description of the studies Detailed data of the eleven included studies are listed in Table 1 . Six RCTs, and five CCT were included in the meta-analysis. In two studies both patients and operators/outcome assessors were blinded to the tested intervention, whereas in three studies it was unclear whether blinding was performed. Four studies had a follow-up of up to 1 year. Table 1 Detailed data of the included studies. Authors Published Study design Patients ( n ) Patients’ age range (average) (years) Follow-up visits (or range) Antibiotics/mouth rinse (days) Fully occluding final restoration after Failed/placed implants (n) Implant failure rate (%) P value (for failure rate) Marginal bone loss (mean ± SD) (mm) Implant surface modification (brand) Observations Degidi and Piattelli 2003 CCT (unicenter) 151 (116, G1; 65, G2) 18–75 (NM) 1, 2, 12, 18, 24, 36, 48, and 60 months NM NM 2/224 (G1) 6/422 (G2) 0.9 (G1) 1.4 (G2) NM NM (G1) 1.1 ± 0.2 (G2) ( n = 87) Several a No grafted patients Implants placed in fresh extraction sockets: 97 (G1), 187 (G2) Degidi and Piattelli 2005 CCT (unicenter) 97 (253 b ) (63, G1; 34, G2) 20–78 (53) 1, 3, 5, 12, 18, and 24 months NM NM 1/135 (G1) 2/253 (G2) 0.7 (G1) 0.8 (G2) NM 0.7 ± 0.2 (G1 + G2) Grit-blasted and acid-etched (XiVe, Dentsply-Friadent, Mannheim, Germany) No grafted patients Some implants placed in fresh extraction sockets Degidi et al. 2006 CCT (unicenter) 29 (12, G1; 17, G2) 23–65 (52) 12 and 36 months 5 / NM Mean of 28 weeks 0/23 (G1) 0/119 (G2) 0 (G1) 0 (G2) NM 1.0 ± NM (G1 + G2) Porous anodized surface (TiUnite, Nobel Biocare, Göteborg, Sweden) No grafted patients Some implants placed in fresh extraction sockets Lindeboom et al. 2006 RCT (unicenter) 48 (24, G1; 24; G2) 19–78 (42.3 ± 13.1) 1, 2, 4, and 6 weeks, 2, 3, 4, 5, and 6 months, 1 year Only before surgery / NP 6 months 3/25 (G1) 2/25 (G2) 12 (G1) 8 (G2) NM Mesial 0.28 ± 0.22 (G1) 0.27 ± 0.2 (G2) Distal 0.2 ± 0.11 (G1) 0.19 ± 0.15 (G2) Sandblasted and etched (BioComp, BioComp Industries BV, Vught, The Netherlands) Only in maxilla (excluding molar regions) 32 implants grafted (16 from each group) Machtei et al. 2007 CCT (unicenter) 20 (NM) 31–68 (55.7) 7-10 days, 1, 2, 3, 6, and 12 months 7 / 21 12 months 1/26 (G1) 4/23 (G2) 3.8 (G1) 17.4 (G2) 0.2755 0.91 ± 0.17 (G1 + G2) Acid-etched (Osseotite TG, 3i Implant Innovations, Palm Beach Gardens, USA) Implants placed in periodontally susceptible patients. Xenograft in some patients Degidi et al. 2009 RCT (unicenter) 82 (155 c ) (63, G1; 19, G2) 18–78 (54) 4 and 6 months, 1, 2, 3, 4, and 5 years 3 / 7 4–6 months 3/132 (G1) 0/130 (G2) 2.3 (G1) 0 (G2) NM d 0.5 ± NM (G1) 0.6 ± NM (G2) Blasted with calcium phosphate (Maestro, BioHorizons, Birmingham, USA) No grafted patients Some implants placed in fresh extraction sockets Cannizzaro et al. 2010 RCT (multicenter) 40 (20, G1; 20, G2) 18–55 (39) 3, 10, and 14 days, 4/5 months, 1 year Only before surgery (6 days for the grafted) / 14 4–5 months 2/20 (G1) 3/20 (G2) 10 (G1) 15 (G2) 1.0 0.72 ± 0.59 (G1) 0.90 ± 0.48 (G2) Zirconia sandblasted (Z-Look3, Z-Systems, Oensingen, Switzerland) Use of zirconia implants, 10 patients grafted (5 of each group), 10 implants placed in fresh extraction sockets (5 of each group) Degidi et al. 2010 RCT (unicenter) 50 (25, G1; 25, G2) 35–54 (45.1 ± 9.1) 5 and 7 weeks, 6, 12, 24, and 36 months 5 / NP 6 months 1/50 (G1) 1/50 (G2) 2 (G1) 2 (G2) NM 0.987 ± 0.375 (G1) 0.947 ± 0.323 (G2) Grit-blasted and acid-etched (XiVe Plus, Dentsply-Friadent, Mannheim, Germany) Only in posterior mandible No grafted patients Siebers et al. 2010 CCT (unicenter) 45 (76 e ) (NM) 22–85 (52 ± 13) Mean of 38 months NM 6–8 months 4/47 (G1) 1/64 (G2) f 8.5 (G1) 1.6 (G2) 0.083 f NM Sandblasted and acid-etched (Camlog Rootline and Screw Line, Camlog Biotechnologies, Basel, Switzerland), acid-etched (Osseotite, Biomet 3i, Palm Beach Gardens, USA), blasted with HA and calcium phosphate (Restore RBM, Lifecore Biomedical, Chaska, USA) No grafted patients 46 implants placed in fresh extraction sockets Margossian et al. 2012 RCT (unicenter) 80 (117 g ) (40, G1; 40, G2) NM 2, 4, 8, 12, 20, and 24 weeks, 1 and 2 years Only before surgery / 14 4 months 0/105 (G1) 7/104 (G2) 0 (G1) 6.7 (G2) NM NM Acid-etched (Osseotite NT, 3i Implant Innovations, Palm Beach Gardens, USA) No grafted patients Vogl et al. 2013 RCT (unicenter) 20 (11, G1; 9, G2) 33–70 (54 ± 11.9) 1 week, 1, 2, 3, 6, and 12 months 5 / only before surgery 6–8 months 0/34 (G1) 0/21 (G2) 0 (G1) 0 (G2) NM 0.4 ± 0.5 (G1) 0.4 ± 0.4 (G2) Grit-blasted and acid-etched (XiVe, Dentsply-Friadent, Mannheim, Germany) Only in posterior mandible. Use of stereolithographic tooth-supported guides. No grafted patients a Frialit 2, IMZ, Frialoc (Friadent, Mannheim, Germany), Brånemark (Nobel Biocare, Göteborg, Sweden), Restore (Lifecore Biomedical, Chaska, USA), Maestro (Biohorizons, Birmingham, USA), 3i (Implant Innovations, West Palm Beach, USA). b There were 253 patients in the study, however, in 156 patients the implants were inserted using the traditional technique. c There were 155 patients in the study, however, only in 82 of them the implants were inserted in immediate function. d A P value was 0.196 when a comparison of the implant survival rate between the immediately loaded group and delayed loaded group was performed, but not between the INFL and IFL groups. e There were 76 patients in the study, however, only in 45 of them the implants were inserted in immediate function. f Unpublished information was obtained by personal communication with one of the authors. g There were 117 patients in the study, however, in 37 patients the implants were inserted using the traditional technique. NM–not mentioned; CCT–controlled clinical trial; RCT–randomized controlled trial; G1–group immediately nonfunctional loaded implants (INFL); G2–group immediately functional loaded implants (IFL); NP - not performed. All studies with available data of patients’ age included only adult patients. Eight studies did not perform grafting procedures in any of the patients. One study used only zirconia implants, in another study the implants were inserted in periodontally susceptible patients, in two studies the implants were inserted only in the posterior mandible, and in one study the implants were inserted only in the maxilla. Not every article provided information about the number of failed implants by group. Unpublished information concerning the number of failed implants in each group was obtained by personal communication with one of the authors in one study. From the eleven studies, a total of 821 dental implants received non-occlusal immediate loading, with 17 failures (2.1%), and 1231 implants received occlusal immediate loading, with 26 failures (2.1%). Eight studies did not inform whether there was a statistically significant difference or not between the techniques concerning implant failure, whereas the other three studies did not find statistically significant difference. There were no implant failures in two studies. Only three studies informed of the incidence of postoperative infection, all with no occurrences in a total of 89 patients receiving 237 implants. Nine studies provided information about the marginal bone loss. 3.3 Quality assessment Each trial was assessed for risk of bias, and the scores are summarized in Table 2 . Seven studies were judged to be at high risk of bias and four studies of low risk of bias. Table 2 Results of quality assessment. Authors Published Sequence generation (randomized?) Allocation concealment Incomplete outcome data addressed Blinding Estimated potential risk of bias Degidi and Piattelli 2003 No Inadequate Yes No High Degidi and Piattelli 2005 No Inadequate Yes No High Degidi et al. 2006 No Inadequate No No High Lindeboom et al. 2006 Yes Inadequate Yes No High Machtei et al. 2007 No Inadequate Yes No High Degidi et al. 2009 Yes Unclear Yes Unclear High Cannizzaro et al. 2010 Yes Adequate Yes Yes Low Degidi et al. 2010 Yes Adequate Yes Yes Low Siebers et al. 2010 No Inadequate No No High Margossian et al. 2012 Yes Adequate Yes Yes a Low Vogl et al. 2013 Yes Adequate Yes Yes a Low a Unpublished information was obtained by personal communication with one of the authors. 3.4 Meta-analysis In this study, a fixed-effects model was used to evaluate the implant failure, since statistically significant heterogeneity was not found ( P = 0.26; I 2 = 21%). The results showed a RR of 0.87 (95% CI 0.44–1.75; Fig. 2 ) for the INFL, suggesting that implant failures in patients receiving implants under the INFL protocol are 0.87 times likely to happen when compared to implant failures in patients receiving implants under the IFL protocol (relative risk reduction of 13% for INFL). However, the procedure used (INFL vs. IFL) did not significantly affect the implant failure rates ( P = 0.70). Fig. 2 Forest plot of comparison of INFL versus IFL for the event ‘implant failure’. As only three studies informed of the incidence of postoperative infection, and all with no events, no meta-analysis was possible for this outcome. Only four studies (245 implants) provided information about the marginal bone loss with standard deviation, necessary for the calculation of comparisons in continuous outcomes ( Fig. 3 ). A fixed-effects model was used to evaluate this outcome, since statistically significant heterogeneity was not found ( P = 0.84; I 2 = 0%). There was no statistically significant difference ( P = 0.74) between the different techniques concerning the marginal bone loss. Fig. 3 Forest plot of comparison of INFL versus IFL for the event ‘marginal bone loss’. 3.5 Publication bias The funnel plot did not show asymmetry when the studies reporting the outcome ‘implant failure’ were analyzed ( Fig. 4 ), indicating absence of publication bias. Fig. 4 Funnel plot for the studies reporting the outcome event ‘implant failure’. 4 Discussion The present study proposed to test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for patients being rehabilitated with dental implants comparing INFL to IFL, against the alternative hypothesis of a difference. Concerning the implant failure rates, the idea behind the concept of keeping the temporary restoration out of occlusion is to control the load on the prosthesis in order to allow undisturbed healing. The role of tongue pressure and perioral musculature may be an underestimated factor in immediately provisionalized but unloaded implants. Moreover, occlusion might not be the only determinant of implant survival. The results of the present meta-analysis showed that there was no statistically significant difference between the INFL and IFL concerning implant failures. The increase of load, applied to the prosthesis caused by the presence of the normal occlusal contact, seems to be unable to jeopardize or alter the healing process of the implant. Some factors may have contributed to such outcome in some studies, that include the use of a resilient acrylic resin for the fabrication of the temporary restoration, the exclusion of parafunctional bruxist patients from the study, and the splinting of the temporary prosthetic work. It has been suggested that it is not the absence of loading per se that is critical for osseointegration, but rather the absence of excessive micromotion at the interface. Micromotion consists of a relative movement between the implant surface and surrounding bone during functional loading and it is believed that, above a certain threshold, excessive interfacial micromotion early after the implantation interferes with local bone healing, predisposing to a fibrous tissue interface, preventing the fibrin clot from adhering to the implant surface during healing. Splinting the provisional restoration might have protected the implants from micromotion. The small sample size in many studies may also have affected the results concerning implant failure. Even though the importance of meta-analyses is to increase sample size of individual trials to reach more precise estimates of the effects of interventions, in this particular analysis no statistically significant difference was found when comparing these two techniques concerning the implant failure rates ( P = 0.70). As there is a wide CI for the RR (RR 0.87; 95% CI 0.44–1.75), the uncertainty about the effect size is greater than if the CI was narrower, although there might still be enough precision to make decisions about the utility of the intervention. In four studies the patients were followed for a short period (1 year). Thus, only early failures could be assessed. A longer follow-up period may lead to an increase in the failure rate. Moreover, the results found in the studies differed from each other, and such discrepancies could be due to factors such as differences in the patients included in the study or the between clinicians placing and restoring the implants. Only three studies provided information regarding the incidence of postoperative infection, all of them with no events. Therefore, no meta-analysis was possible for this outcome. The third outcome analyzed was the marginal bone loss. Marginal bone levels might vary with load distribution patterns between natural teeth and implants, with access for hygiene instruments in splinted provisional restorations or with iatrogenic manipulation of the implant during initial healing. Early functional loading during the healing phase may have a positive effect on marginal bone levels. Early loading stimuli at the bone-implant interface leads to functional adaptation of the bone (remodeling) and to an improved differentiation of the bone structures, resulting in a higher marginal bone level. However, the present meta-analysis did not find a statistically significant difference ( P = 0.74) between the techniques in what concerns the marginal bone loss. The reason for that may be the short postoperative follow-up period of 1 year found in three of the four studies with available data to produce a comparison, and/or the small sample size in all four studies. The biological differences in peri-implant tissue responses between IFL and INFL implants have been analyzed in animal models, where no differences were observed between the ultrastructural morphology of the cells at the interface of implants from both groups in the early phases of osseointegration in minipigs, and no statistically significant differences in the bone-to-implant contact percentages were found between groups, in a study performed in dogs. The present meta-analysis included non-RCT studies, which is not usually performed. Potential biases are likely to be greater for non-randomized studies compared with RCTs, so results should always be interpreted with caution when they are included in reviews and meta-analyses. So what was the reason to include non-randomized studies in the present meta-analysis? The issue is important because meta-analyses are frequently conducted on a limited number of RCTs. Shrier reviewed a random 1% sample of meta-analyses published by the Cochrane Collaboration in 2003 and found that 6 of 16 reviews included two studies or fewer. Furthermore, 158 of 183 analyses conducted in 7 additional studies were limited to two or fewer studies. In meta-analyses such as these, adding more information from observational studies may aid in clinical reasoning and establish a more solid foundation for causal inferences. In a meta-analysis, homogeneity implies a mathematical compatibility between the results of each individual trial. Narrowing the inclusion criteria increases homogeneity but also excludes the results of more trials and thus risks the exclusion of significant data. One of the strengths of meta-analysis as a technique for synthesizing research findings on the effectiveness of intervention programs is that it allows those findings to be systematically compared and contrasted across studies. What complicates the investigation is the presence of confounding variables in the analyzed studies. The use of grafting in some studies is a confounding factor, as well as inserting the implants only in periodontally susceptible patients, in particular regions of the mouth, such as only in the posterior mandible or only in the maxilla, the insertion of some implants in fresh extraction sockets, the use of zirconia implants, and the insertion of implants from different brands and surface treatments. Titanium implants with different surface modifications show a wide range of chemical, physical properties, and surface topographies and morphologies, depending on how they are prepared and handled, while it is not clear whether, in general, one surface modification is better than the other. The results of the present study should be interpreted with caution considering its limitations. The presence of confounding factors may have affected the long-term outcomes, regardless of whether the implants were submitted to INFL or IFL. The impact of such variables on the implant survival rate, postoperative infection and marginal bone loss outcomes is difficult to estimate if these factors are not identified separately between the two different procedures in order to perform a meta-regression analysis. 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