Marginal Bone Loss in Implants with External Connection versus Internal Conical Connection Prior to Prosthetic Loading. A Randomized Clinical Study

Round 1

Reviewer 1 Report

Introduction

1. Line 76 and 85: Please cite the several studies mentioned.

2. Line 93: Please keep the abbreviation uniform: ICC or CCI?

Both Materials and Methods as well as Discussion sections needs to be improved. Several details about the methodology are missing, which also needs to be explained and discussed with regard to the influence on the results. This includes:

3. Combining the date of crestal and subcrestal level implants. The amount of crestal bone loss differs between these two implants, i.e. placement protocols. 

4. What about the EC? Were the implants placed on a crestal level?

5. What was the healing period planned? For maxilla and for mandibule? When was the second surgery? How long were the healing abutments in place and when did the patients receive the final prosthodontics?

6. Why was there a combination of the type of restoration and how does this affect the results? It is important to notice and discuss that the loads transmitted to the crestal bone differs in case of SC than FDPs and overdentures. This must be explained and discussed well.

7. Was there a standard protocol for the fixed prosthetics? What type and material were the abutments and crowns? If it was not standardized, then it has an effect on the results as we know that the type and material of the restoration influence the amount of the force transmitted to the bone.

8. Was the planning of the implant done using an implant-planning software? Or only using the CBCT done before inclusion?
9. Was the placement of the implants done using a stent? If yes, guided or conventional stent?
Please mention these procedure and discuss them (choice of the treatment and its possible affects on the results).
If no computer guided planning and insertion was done, does this affect the accuracy of the implant placement? Especially that the insertion was not done by one operator but rather by several students with less experience. Please discuss this.

Author Response

Author's Point-by-Point response to Reviewer 1

In blue: answers to Referee.

In red: modifications and/or new paragraphs in the manuscript.

1. Line 76 and 85: Please cite the several studies mentioned.

Thanks for your comment.

We currently added clinical studies that comparing bone loss after one year of follow-up found a bone loss smaller or equal to 1mm. We added as well two systematic reviews where these articles are included. (Page 2– line 77-79)

Regarding the articles that describe the importance of choosing the connection, we have also cited authors describing it. (Page 2 – line 87-89)

2. Line 93: Please keep the uniform: ICC or CCI?

We corrected all the CCI for ICC. (Page 3 - line  96)

Both Materials and Methods as well as Discussion sections needs to be improved. Several details about the methodology are missing, which also needs to be explained and discussed with regard to the influence on the results. This includes:

3. Combining the date of crestal and subcrestal level implants. The amount of crestal bone loss differs between these two implants, i.e. placement protocols. 

Thanks for your comment. You are right that it is necessary to add information regarding bone loss between connections and crestal and subcrestal position. This information was already given in table 4 but we had not described anything in the text. In the results section, we currently added in the text that the bone loss did not differ significantly between the connections and the vertical position of the implant.

“Subsequently, a statistical analysis was carried out to assess whether the bone loss differed between the connections and the vertical position of the implant”

(Page 4– line 143-145).

“In the analysis of other possible determinants that may influence bone loss, no significant differences were found in relation to age, sex, jaw or maxilla, vertical placement of the ICC implant and tobacco consumption, considering implants of both type of connections”.

(Page 13 – line 335).

 4. What about the EC? Were the implants placed on a crestal level?

We have also specified that the external connection was always placed at the crestal level.

Thus, the three groups obtained were: (1) internal connection-crestal level, (2) internal connection-subcrestal level and (3) external connection (always placed at the level of the crest). With respect to the study reported in this article, when investigating only the type of connection, the data from the internal connection groups (1) and (2) were treated jointly.

(Page 4 – line 140 ).

5. What was the healing period planned? For maxilla and for mandibule? When was the second surgery? How long were the healing abutments in place and when did the patients receive the final prosthodontics?

 thank you for your comment. We omitted to specify this information by mistake. We now added this paragraph in the material and method section:

 “2.5. Surgical intervention and clinical follow-up

Regarding the healing period, the second surgery was performed 105 days after the implant placement, and a healing abutment was installed for two weeks. The prostheses could vary between single crowns or fixed dental prostheses (screw retained and metal ceramic) and overdentures (metal resin, Locator® system).

(Page 5– line 192-196 ).

In lines 204-206, the sentence “Standardized orthopantomographs were realized at the time of implant placement (T0), one month after implant placement (T1) and at the time of prosthesis placement (T2).” has been modified: “Standardized orthopantomographs were realized at the time of implant placement (T0), one month after implant placement (T1) and four months after implant placement, prior to the prosthetic procedures (T2).” 

6. Why was there a combination of the type of restoration and how does this affect the results? It is important to notice and discuss that the loads transmitted to the crestal bone differs in case of SC than FDPs and overdentures. This must be explained and discussed well. 

Thank you, you are right that depending on the type of prosthetic restoration, the occlusal loads transmitted to the implants may differ and this in turn influences bone loss. In this study we wanted to assess what happened to the marginal bone prior to prosthetic loading, however, we agree with you that prosthetic restoration is an important factor that we will have to take into account in the future follow-up of these implants.

In the discussion section we have added the following paragraph.

“The main limitation of this study is the short-term follow up (about 4 months) that does not provide a complete information with respect to the typical behaviour of bone biology during a larger period of time.

Moreover, the different prosthetic indications and materials used could have an effect on the possibility of marginal bone loss. Although, to account for it, all the measurements were done prior to the prosthetic procedures.

(Page 16– line 392-396 ).

7. Was there a standard protocol for the fixed prosthetics? What type and material were the abutments and crowns? If it was not standardized, then it has an effect on the results as we know that the type and material of the restoration influence the amount of the force transmitted to the bone.

The authors agree with the reviewer that the type and material has to be explained in the material and method’s section. 

 In line 230, a new subsection of the Material and method part has been added:  

“2.8 Restorative procedures

Silicone impressions were obtained two weeks later to the second surgery (T2). Mainly, in the implants indicated for single crown, a porcelain fused to metal restoration was screwed at 30N directly to the implant two weeks after impressions. In the implants indicated for a fixed dental prostheses, an abutment was screwed to the implant at 30N, and a porcelain fused to metal superstructure was screwed to the abutments two weeks after impressions. The implants indicated for an overdenture, received a machined titanium abutment at 30N two weeks after impressions”.

(Page 7– line 230-236).

8. Was the planning of the implant done using an implant-planning software? Or only using the CBCT done before inclusion?

9. Was the placement of the implants done using a stent? If yes, guided or conventional stent?

Please mention these procedure and discuss them (choice of the treatment and its possible affects on the results). If no computer guided planning and insertion was done, does this affect the accuracy of the implant placement? Especially that the insertion was not done by one operator but rather by several students with less experience. Please discuss this.

Thanks for your comment. In this study, an exhaustive planning of each case was carried out, using the diagnostic CBCT. The implant placement was done in a conventional way, always under the supervision of the researchers. Although you are right that the placement of implants by students could affect the results, the students who performed the surgeries were 3rd year students of the master of surgery, with a good experience in the placement of implants. In addition, the researchers ensured that the established protocol (described in section 2.4 of material and method) was followed at all times. We believe that it is an advantage because by always following the same guidelines, the results obtained do not depend on the possible experience and / or preference of the dentist.

We added a paragraph in the discussion to justify it.

We are also aware that implant placement performed by more than one operator could affect results. However, we believe that this fact can also be positive, since the same protocol is always followed, the results obtained do not depend on the possible experience and / or preference of the operator. (Page 15– line 398-400 ).

Reviewer 2 Report

１、Please explain why 1 month and 4 month were set to be the observation time point. I think the margin bone loss should be observed at least 3 month in mandibular and 6 month in maxilla.

２、Please explain whether the margin bone loss is influenced by the implant cover screw exposure  or semi exposure.

３、Some photos about the implant  used in this study should be offered, such as the photos of EC and ICC.

Author Response

Author's Point-by-Point response to Reviewer 2

In blue: answers to Referee.

In red: modifications and/or new paragraphs in the manuscript.

1. Please explain why 1 month and 4 month were set to be the observation time point. I think the margin bone loss should be observed at least 3 month in mandibular and 6 month in maxilla.

Thanks for your comments, you are right that the periods should be longer before taking the measurement. However, the objective of the present study was to determine if bone loss is different in EC and ICC implants at the time of prosthesis placement. This is the reason why the radiological follow-up was carried out in a relative short period. A sentence has been added to the discussion section to justify this issue.

The main limitation of this study is the short-term follow up (about 4 months) that does not provide a complete information with respect to the typical behaviour of bone biology during a larger period of time.

Moreover, the different prosthetic indications and materials used could have an effect on the possibility of marginal bone loss. Although, to account for it, all the measurements were done prior to the prosthetic procedures.

(Page 15- line 392-396)

Moreover, a sentence has been added as well in the conclusion section.

Taking into account the limitations of this study, particularly regarding the short follow-up period, it can be suggested that in implants with the similar surface, those with ICC show significantly better results regarding bone loss than those with EC (E.C = 0.57mm and I.C = 0.36mm). RFA stability values ​​were not related to bone loss.

(Page 15- line 421)

2. Please explain whether the margin bone loss is influenced by the implant cover screw exposure  or semi exposure.

Thanks for your comment. A possibility why the reabsorption of marginal bone loss is more pronounced by exposed or slightly exposed implant cover screws could be due to bone remodeling, caused by the formation of biological width.

The biological width process begins the same day of implant placement, if a healing abutment is placed immediately and the implant is exposed to the oral environment (one stage), or a second time if the abutment is placed later (two stages). Due to the design of the CE implant, the cover screw can be exposed or slightly exposed to the surface in the case of patients with a thin gingival biotype, stimulating the beginning of the bone remodeling necessary for the establishment of a biological width. This fact could explain why bone loss is greater in CE implants before prosthesis placement.

We have reformulated the wording of this paragraph in the discussion section.

A hypothesis as to why bone resorption is more pronounced during the first year could be due to bone remodeling, which in turn is influenced by a variety of factors, including facilitating the formation of biological width, with the aim of creating a barrier "against" oral flora (58). The biological width process begins on the same day as the implant placement, if a healing abutment is placed immediately and the implant is exposed to the oral environment (one stage), or at a second moment if the abutment is placed later (two stages) (59). We could speculate that in EC implants this remodeling could be anticipated, since the design of these implants has a hexagonal surface on top of the platform that measures 0.7mm in height. The hexagon is covered by the cover screw, resulting in a combined height of the components that might cause the cover screw to be exposed or slightly exposed to the surface in case of patients with thin gingival biotype, stimulating the initiation of bone remodeling necessary for the establishment of a biological width. In our study, 68% of EC implants were exposed to the oral environment prior to the second stage, and it is likely that bone loss was influenced by this fact. In implants with ICC, due to its design, little gingival thickness is required, so that the implant is completely submerged until the second stage 3 to 4 months later. This fact could explain why bone loss is greater in EC implants prior to prosthesis placement.

Page 14-line 358-372

3. Some photos about the implant  used in this study should be offered, such as the photos of EC and ICC.

Figure 1. Type of implants. (A) Naturactis®: ICC subcrestal-level;  (B) Uneva®: EC crestal level; (C) Naturall®: ICC crestal level .

Authors: Thank you. As recommended, we have added photos of the implants used in this study.

Author Response File: Author Response.docx

Reviewer 3 Report

Dear authors,

  thanks for having provided this manuscript.

Here you can find my comments in details:

1. Page 2 Line 81: about the micro gap please cite also thess articles: Meleo D, Baggi L, Di Girolamo M, Di Carlo F, Pecci R, Bedini R. Fixture-abutment surface and micro-gap measurements by 3D micro-tomographic technique analysis. Ann Ist Super Sanità. 2012;48(1):53-8; Ceruso FM, Barnaba P, Mazzoleni S, Ottria L, Gargari M, Zuccon A, Bruno G, Di Fiore A. Implant-abutment connections on single crowns: a systematic review. Oral Implantol (Rome). 2017 Jan 21;10(4):349-353; and Covani U, Marconcini S, Crespi R, Barone A. Bacterial plaque colonization around dental implant surfaces. implant Dent. 2006 Sep;15(3):298-304.
2. Page 2 Line 87: when talking about factors that can influence bone loss you should also cite the presence of specific microflora. Please cite appropriate references: Martellacci L, et al. Characterizing peri-implant and sub-gingival microbiota through culturomics. First isolation of some species in the oral cavity. A pilot study. Pathogens. 2020;9(5):365 AND Martellacci L, et al. A literature review of metagenomics and culturomics of the peri-implant microbiome: Current evidence and future perspectives. Materials. 2019;12(18):3010.
3. Page 3 Line 93-94: Please rephrase the aim according to the PICO format.
4. Page 4 Line 161: authors declared they have done radiographic measurements on orthopantomographies. How did you consider the distortion of the image typical of this exam in your measurements? Why did not you choose periapical radiographs?
5. Please give power analysis for sample size calculation.
6. Throughout the whole manuscript (especially in discussion and conclusion) you should always specify that all your measurements refer to an interval time of about 4 months and that all your conclusions cannot be considered as the typical behavior of bone biology in a larger period of time.
7. Please read accurately CONSORT guidelines as you will find that some points are not satisfied: 3a (allocation concealment is not given); 4b, 8b and 10 (data about randomization); 14a (dates defining the periods of recruitment and follow-up).

Warm regards

Author Response

Author's Point-by-Point response to Reviewer 2

In blue: answers to Referee.

In red: modifications and/or new paragraphs in the manuscript.

1.Page 2 Line 83: about the micro gap please cite also thess articles: Meleo D, Baggi L, Di Girolamo M, Di Carlo F, Pecci R, Bedini R. Fixture-abutment surface and micro-gap measurements by 3D micro-tomographic technique analysis. Ann Ist Super Sanità. 2012;48(1):53-8; Ceruso FM, Barnaba P, Mazzoleni S, Ottria L, Gargari M, Zuccon A, Bruno G, Di Fiore A. Implant-abutment connections on single crowns: a systematic review. Oral Implantol (Rome). 2017 Jan 21;10(4):349-353; and Covani U, Marconcini S, Crespi R, Barone A. Bacterial plaque colonization around dental implant surfaces. implant Dent. 2006 Sep;15(3):298-304.

 Thanks for your input. We have added the studies that you have suggested, referring to the connection between the implant and the abutment.

(Page 2 – line 83).

2. Page 2 Line 87: when talking about factors that can influence bone loss you should also cite the presence of specific microflora. Please cite appropriate references: Martellacci L, et al. Characterizing peri-implant and sub-gingival microbiota through culturomics. First isolation of some species in the oral cavity. A pilot study. Pathogens. 2020;9(5):365 AND Martellacci L, et al. A literature review of metagenomics and culturomics of the peri-implant microbiome: Current evidence and future perspectives. Materials. 2019;12(18):3010.

Thanks for your comment. Within the possible factors causing bone loss, we added the recommended references and the following sentence:

bacterial filtration, peri-implantitis caused by different potential etiologic agents (35–37); microgaps between implant-abutment (38–41); (Page 2 – line 83-84 ).

3. Page 3 Line 93-94: Please rephrase the aim according to the PICO format.

As you recommended, we have formulated the objective in the PICO format in the introduction. Moreover, we have developed the question in the material and method section. 

This clinical trial focused on answering a PICO format (52). In patients treated whit different implants connection, are there differences between EC and ICC in terms of bone loss?

 (Page 3 – line 98-99).

4. Page 4 Line 161: authors declared they have done radiographic measurements on orthopantomographies. How did you consider the distortion of the image typical of this exam in your measurements? Why did not you choose periapical radiographs?   

Thank you, we were aware that there could be differences in the measurements. Therefore, to control for it, the same researcher did all the measurements on the radiographs, so the bias could be reduced. The measurements were done using the Planmeca Romexis® software to process 2D images generated by the X-ray units. This tool ensured that the calibration carried out prior to the measurements was correct and this was verified taking into account the length of each implant.  

We have added the following paragraph:

Single-blind study.

For better reproducibility, the X-ray examiner (NPG) did all the measurements on the radiographs and was different from the surgeons who placed the implants, thus, the distortion bias of the measurements could be reduced.

(Page 7 – line 238-240).

As we have justified in the section on material and method 2.6, Radiographic monitoring of bone loss, all patients required a CBCT prior to surgery. Therefore, we decided to avoid cone beam radiographs in order to limit multiple exposures to radiation.

5. Please give power analysis for sample size calculation

Thank you for your comment. We added the information corresponding to the calculation of the sample size.

 2.4. Sample's size calculation

To test the hypothesis on the difference in bone loss in implants with internal connection vs implants with external connection, the following formula was used to quantify the size of the sample required.

 Where:

 = number of subjects needed in each of the two groups (i.e internal vs external)

 = Z -value correspondent to the desired level of risk of falsely rejecting a true null hypothesis

 = Z -value correspondent to the desired level of risk of failing to reject a false null hypothesis

 = Standard deviation in mm of bone loss in implants with internal connection

= Minimum desired value in mm of the difference in bone loss between the two groups

Thanks to the review of the literature, we knew that in previous studies the standard deviation in bone loss in internal connection was approximately 0.35 mm and that we would obtain a significant difference between the two treatments by achieving a difference in bone loss of approximately 0.25 mm - 0.30 mm.

We accept a risk of 5% and want a statistical power of 95% to detect differences, if they exist.

Finally, based on a recent systematic review (51) in which, from a qualitative point of view, no differences were identified between the two connections for randomized clinical studies with a larger sample number and greater longevity, we postulate a two-tailed hypothesis testing.

Substituting the data into the formula, we obtained that for each group (ICC and EC) we would need a minimum sample size of 28 observations.

(Page 4 – line 146-169).

6. Throughout the whole manuscript (especially in discussion and conclusion) you should always specify that all your measurements refer to an interval time of about 4 months and that all your conclusions cannot be considered as the typical behavior of bone biology in a larger period of time.

Thanks for your comment. You are right that we cannot extrapolate what happens in this short period of time with the general behavior of bone loss around implants. That is why we wanted to clarify it by adding a paragraph in the discussion section.

“The main limitation of this study is the short-term follow up (about 4 months) that does not provide a complete information with respect to the typical behaviour of bone biology during a larger period of time.  (Page 15 – line 392-396 ).

We have done the same in the conclusion.

“Taking into account the limitations of this study, particularly regarding the short follow-up period, it can be suggested that in implants with the similar surface, those with ICC show significantly better results regarding bone loss than those with EC (E.C = 0.57mm and I.C = 0.36mm). RFA stability values ​​were not related to bone loss.

 (Page 15 – line 422).

7. Please read accurately CONSORT guidelines as you will find that some points are not satisfied: 3a (allocation concealment is not given); 4b, 8b and 10 (data about randomization);

Thanks for your suggestion, we have corrected the points of the CONSORT guide

3a

Single-blind study. For better reproducibility, the X-ray examiner (NPG) did all the measurements on the radiographs and was different from the surgeons who placed the implants, thus, the distortion bias of the measurements could be reduced.

(Page 7 – line 238-240).

 4b

A randomized split-mouth clinical study was carried out at the University of Barcelona Dental Hospital. All participants were recruited from this center from May 2017 to November 2018. This was approved by the CEIC HOUB ethics committee [Ethics and Clinical Research Committee of the University of Barcelona Dental Hospital]. The criteria of the CONSORT guidelines were taken into account for conducting clinical trials and was included in the ClinicalTrials.gov database of clinical studies ID: NCT03232372. (Page 3 – line 101-105).

 8b and 10 (data about randomization)

Prior to surgery, the researcher (NPG) carried out the randomization and assignment of the implants through an application that generates random numbers (Random N - Version 4.2, 2015). In each jaw, each edentulous space was assigned a random letter (A, B,C, ..). Following the alphabetical order, each letter was randomly assigned to the corresponding connection.

(Page 3 – line 134-137).

 14a (dates defining the periods of recruitment and follow-up).

A randomized split-mouth clinical study was carried out at the University of Barcelona Dental Hospital. All participants were recruited from this center from May 2017 to November 2018.

(Page 3 – line 101-103).

Round 2

Reviewer 1 Report

Thank you for the reviewed version. I have some concerns about the study design. Therefore, it was important to mention the details as well as the limitations of the study in the manuscript. In the future, it would be helpful to improve the study design and minimize the factors that can influence the results of the study. 

Reviewer 2 Report

this is accept in present form.

Reviewer 3 Report

Dear authors,

  thanks for having provided all the requested information.

In my opinion the article can be accepted in its present form.

Best regards