(b) Were all 72 participants symptoms free (i.e., non TMD patients) at time MRIs taken?

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1 Author s response to reviews Title: Disk displacement, eccentric condylar position, osteoarthrosis misnomers for variations of normality? Results and interpretations from an MRI study in two age cohorts Authors: Jens Türp (jens.tuerp@unibas.ch) Anna Schlenker (anna.schlenker@online.de) Johannes Schröder (johannes.schroeder@med.uni-heidelberg.de) Marco Essig (messig@exchange.hsc.mb.ca) Marc Schmitter (marc.schmitter@med.uni-heidelberg.de) Version: 1 Date: 25 Oct 2016 Author s response to reviews: We are grateful to the referees and appreciate their thorough and very helpful suggestions. We appreciate their time and effort. The insightful and constructive comments have helped us improve and strengthen our manuscript. In the following, we would like to comment on the recommendations. Our point-by-point responses are presented below. REVIEWER 1 (1) The methods section was sometimes not described in sufficient details: (a) The number of participants in the original cohort is not stated. Please report this information as the previous study was published in non-english language. Please also provide additional details regarding the selection process of the 72 individuals out of more than 1000 cohort? Our answer: The total number of participants in the original study was In order to recruit the participants of our study, the subjects from the Heidelberg cohorts had been asked to participate in the MRI examination until 72 individuals consented; 33 of them were from the birth cohort and 39 from the cohort We have added this information to the text of our manuscript. (b) Were all 72 participants symptoms free (i.e., non TMD patients) at time MRIs taken? Our answer: All subjects were examined according to the RDC/TMD. Three subjects reported pain in one TMJ. In five subjects, a reciprocal clicking was noticed during jaw opening,

2 closing, and protrusion, but not upon protrusive opening. No subject reported a functional limitation. We have added this information in the updated version. (c) How the remaining MRIs were assessed and agreed? Our answer: The remaining MRIs were assessed by one rater only. Based on the results of the reliability assessment, it was assumed that the measuring method was reliable. We have added this information in the updated version. (d) Because it is not likely that readers of the Journal will be familiar with the techniques used for assessing MRIs, it would be helpful to show a diagram explaining how the position of the mandibular condyle at closed jaw and another one showing the 11:30 and anterior positions of the disc at closed jaw were assessed. Our answer: We have added two new figures (now Fig 1 and 2). In addition, we have made a small modification in the labeling of the former Fig.1 (now Fig. 3). (e) There is no mention of the statistical test methods you used to analyse the data. Also nothing mentioned about the p value considered to be statistically significant in your study. Our answer: In the decription of the methods, we have added a new section entitled Statistical evaluation. (f) You may also rephrase your aim accordingly to address influence of age or sex. Likewise, the narrative in the results and discussion sections did not consistently describe the influence of age and sex on the three investigated variables in some areas. Please report all your findings in the results section and then discuss and interpret them briefly in the discussion section. Our answer: We have added in the introduction that we the cohorts were stratified to age and sex in order to investigate the possible influence of these two variables. We also extended the sections Results and Discussion by giving more information about our findings. (2) The technique (MRIs vs. CTs) used to asses bony changes is not the best method to investigate bony changes. The authors need to articulate a convincing reason why they used MRI rather than CT for assessing hard tissues. Our answer: The reason was that in this population-based investigation the use of CT scans would not have been allowed by the ethical committee. We have added this information as well as the main indication for MRIs and CTs, including appropriate references, in a new section in the Discussion. Coronal MRI views had been taken for the 72 subjects but not assessed in the current investigation?

3 Our answer: For the purpose of this paper, the coronal views were not considered. We have added this information in the Methods section. The authors stated that they assessed the morphology of the bony components of the TMJ. Since you actually only examined the depth of glenoid fossa, please rephrase TMJ morphology where necessary. Our answer: As far as the bony components of the TMJs are concerned, have indeed only focused on the depth of the mandibular fossa. Therefore, were suitable have replaced the expression TMJ morphology by depth of the glenoid fossa. Nonetheless, we would like to emphasize that flattening of joint surfaces is a typical sign of TMJ OA. In the Discussion, we have added a corresponding citation (DeLeeuw R et al. Oral Surg Oral Med Oral Pathol 1995; 79: ). Examination of the depth of the glenoid fossa (rather than the articular surfaces of condyle and eminence) is not the best method to infer flattening of condylar head and articular eminence and to diagnose the presence/absence of adaptive remodelling response or degenerative joint disease. Examining articular surfaces by CT or CBCT is more appropriate. Would it be more appropriate to re-analyse your TMJ morphology data by examining (in addition to GF depth) the articular surfaces of condyle and eminence on MRIs? Like the methods used in your cited reference [3] Schmitter et al., Our answer: We agree with the reviewer that flattening of bony structures may be assessed more directly and more precisely by other means (e.g. by resorting to radiographs, such as cone-beam computed tomography). However, in our investigation ionizing radiation was not an option. Unfortunately, reanalysis of the data is not possible. Is increasing depth of glenoid fossa indicate flattening of articular surfaces? I am not sure this is always the case. The authors need to take in their considerations other factors leading to variations in measurements of GF depth (and condyle position) such as: interindividual skeletal variations, loss of molar support, disc displacements...etc. Our answer: Since the morphology of the mandibular fossa remains more or less constant during age, we believe that decreasing (not increasing, which was obviously a typo) depth of the mandibular fossa may indeed be interpreted as a flattening of the posterior slope of the articular eminence. Did the authors use any standardisation for mouth opening? Our answer: For open jaw position, a mechanical mouth opener (Burnett BiDirectional TMJ Device, Medrad Inc. Pittsburgh, U.S.A.) was used to stabilize the opened jaw position and, therefore, to reduce blurred images due to mandibular motion. We added this important piece of information in the Methods section. Please report how you measured glenoid fossa depth? Is it (b+d)? This is neither mentioned in text nor in Table 5.

4 Our answer: The measurement of the glenoid fossa depth (=glenoid fossa height) has been described in the Methods section. You may also need to rephrase Table 5 legend from Height of the glenoid fossa (distance b )... To: Depth of glenoid fossa (b+d)...? Our answer: We have rephrased the legend to Table 5 from Height of the glenoid fossa (distance b ) to Depth of the glenoid fossa (distance b ). (3) Your reported result numbers were sometimes confusing. For example, the position of 142 mandibular condyles at closed jaw were analysed in the results, but you reported in the methods (Table 1) that 5 out of 144 MRIs were not accessible at closed jaw position. Our answer: Thank you for this observation. Out of 144 TMJs, analysis was possible for 139 at closed jaw and for 130 at opend jaw. To numbers were wrong in Table 1, right column: the correct numbers were 10 (not 8 ) in the row Cohort , and 14 (not 12 ) in the row Σ TMJs. On pg6, line3, it reads:...between approximately 20% and 40% of the disks were located anteriorly (Tab. 4). This information could not be found in Table 4. Our answer: The reviewer is right. We have reformulated the corresponding sentences in the Results section ( Position of the articular disk at closed jaw ). (4) Your discussion is lengthy and sometimes not directly relevant to your imaging study: Many of the cited studies in disc position discussion section were clinical studies using specific clinical criteria to diagnose disc displacements and, therefore, they are not directly comparable to your imaging study findings. The authors need to reference relevant radiographic studies and compare their results with the results from these studies briefly. Our answer: We have deleted the section about terminological inconsistencies. In addition, we have added pertinent literature. People having anterior disc position at closed jaw could have any type of disc displacements (with or without reduction) but the discussion focused mainly on the former. Our answer: This is true. In the new version, we have, therefore referred to both forms of disk behavior upon opening. Osteoarthrosis discussion section was excessively long. Our answer: We have deleted this part of the section. Please refer to Pullinger (2013) in your discussion.

5 Our answer: Thank you for mentioning this valuable reference. We have added suggestions from this paper (J Oral Rehabil 2013;40: ) in the discussion of our text. The authors did not consider other factors affecting their findings, such as skeletal variations among individuals like body stature, skeletal relationships...etc. For example, if some individuals have class III skeletal occlusion, will this affect your findings? Our answer: While interindividual variation and fluctuating intraindividual asymmetry exist, we do not see why a class III skeletal occlusion should have affected our results. In addition, The authors need to acknowledge the limitations of the study at the final paragraph of the discussion section, for example: retrospective, not using CT...etc. Our answer: We have followed this advice and acknowledged the limitations of our investigation in the new first part of the Discussion. (5) Readers may confuse statements of normal variation with abnormal pathology. Using the suggested terms (Table 6) may be problematic because they may also relate to pathology that requires treatment. My suggestion is to focus on the relevance of imaging findings with the presenting clinical signs and symptoms in terms of clinical decision-making process. Our answer: The reviewer rises an important point. We have considered his suggestion and discussed it in detail at the end of the paragraph entitled Position of the articular disk at closed jaw. (6) In a related point to above (point 5): I suggest reconsidering the discussion and conclusion statements and relate the findings to TMD patients complaints. How we know pathology does not exist? Imaging investigations should coincide patients complaints to confirm clinical diagnosis and manage patients. Our answer: We have considered this interesting point in our discussion. Therein, we came to a slightly different conclusion by arguing (a) that the decisive signs and symptoms that warrant therapy are pain and limited mandibular mobility, and (b) that sophisticated imaging (CBCT; MRI) is superfluous. (7) Additional issues that should be addressed: In the abstract, revisions are required: - You may add at opened jaw to this statement... joint surfaces was assessed [add: at opened jaw] by measuring the depth of the You may rephrase this statement...scans of the TMJs that had been made in 2005 and 2006 from 72 subjects... to:...scans of the TMJs that had been taken in 2005 and 2006 for 72 subjects....

6 - You may rephrase With another technique, a textbook-like disk position at closed jaw was distinguished from an anterior location. To: Another technique was used to distinguish textbook-like normal disc position from anterior disc position at closed jaw. - Also, the phrase Age had a statistically significant influence neither on condylar nor on disk position. should be revised to: Age had no statistically significant influence on condylar or disc position. - This statement...of the TMJs may be seen as bony adaptation to increased loading, instead of osteoarthrosis can be revised to:...of the TMJs may be considered as normal adaptive responses to increased loading rather than pathological degenerative changes. Our answer: Thank you very much for these linguistic comments. We have made all changes. - Also, you may add a phrase about data analysis methods in the abstract. Our answer: We have added more information about the methods that we have used. - The authors used the word articular fossa but typically referred to it as glenoid fossa and sometimes mandibular fossa. Consistency is needed. Please use one term, I would recommend using glenoid fossa. Our answer: We have now consistently used the term glenoid fossa. However, in the section Background, we have added mandibular to make it clear to readers, that glenoid fossa and mandibular fossa is the same, because the correct anatomical term is mandibular fossa ( Fossa mandibularis ). - Similarly sometimes you mentioned disk and sometimes disc in the manuscript. Pick one word and use it. I would suggest calling it disc. Our answer: We have now used the term disc consistently in the paper. - Keywords not cited that probably would be helpful: over diagnosis and it could replace diagnosis ; temporomandibular disorders could replace Temporomandibular joint. Our answer: We have followed the suggestions of the reviewer. - Although many epidemiological studies found that TMDs are most prevalent in young females, recent OPPERA studies found that the incidence of first-onset TMDs was more common among older age adults with only slightly greater incidence in females than males (see: Slade et al., 2013). Our answer: The reviewer is correct. We have added this new information, which the authors denote as unexpected demographic pattern (Slade et al. J Dent Res 2016;95: , here: 1086).

7 - The authors stated in the background page3, parag1: In contrast to musculoskeletal complaints located in other parts of the body, e.g. osteoarthritis [2], the incidence and prevalence of TMD symptoms decrease remarkably during menopause and in older age [1, 3-4]. However, contradictory statement was reported in the discussion section page9, line 24: The incidence of TMJ osteoarthrosis continues with increasing age [45-46],.... Please revise (first statement) and avoid such conflicting statements in the manuscript. Our answer: There is no contradiction between these two statements. TMD symptoms, mostly pain, are reported by the patients, whereas whereas TMJ osteoarthrosis are morphological findings identified on radiographs. While the former may indeed decrease with age, the latter may increase. In order to clarify this distinction, we have made some linguistic improvements. - Also in the background pg3, parag1, this statement TMD symptoms that usually require therapy are (a) temporomandibular pain i.e. masticatory muscle pain and/or temporomandibular joint (TMJ) pain, and (b) limitations of mandibular movements. Would it not be better to say: TMD symptoms that usually require therapy are (a) pain associated with masticatory muscles and/or temporomandibular joint (TMJ), and (b) limitations of jaw movements. Our answer: We have deleted the sentence from the Background section. Instead, we have added a similar sentence in the Discussion (at the end of the section Position of the articular disc at closed jaw ). - In pg3, parag2, would it be better to add to determine the prevalence of these variables and to reinterpret the clinical significance of the findings state the study s aims at the end of background by revising this statement to the sentence In the present investigation, these three anatomical variables were reanalyzed in two population-based birth cohorts. Our results form the basis for a new interpretation of the clinical meaning of these findings. Our answer: We have followed the reviewer s suggestions. By doing so, we have deleted our former sentence Our results form the basis for a new interpretation of the clinical meaning of these findings., because this information is now included in the reviewer s suggestions. - In pg4, line7, please delete this subheading: Position of the mandibular condyle at closed jaw under current study heading. Our answer: We have deleted the subheading. - In pg4, line 9, insert age range between brackets when reporting the two subsamples cohort & cohort , if possible? Our answer: We have added the age ranges. - In pg4 line12, in addition to referring to Table 1 please report in the text the total numbers of assessed MRIs at closed (n = 139?) and opened (n = 132?) jaw positions.

8 Our answer: We have added this information. - In pg4, would it be better to rephrase some statements, such as: the sagittal MRI views of the mandibular condyle and the articular disc of nine participants (open and closed jaw positions) were evaluated... to: were evaluated at opened and closed jaw positions.... There are numerous places throughout this manuscript where such kind of editing would be useful. Our answer: We have made the appropriate changes in this and other sentences. - In pg5, line3, please define textbook-like normal disk position when reporting it in the methods. Our answer: We have added the following definition: the posterior band is located at the top of the condyle (12 o clock position). In pg5, line14, please rephrase heading to: Depth of the glenoid fossa [add: at opened jaw]. Our answer: We have added this information. In pg5, line16, this statement: The depth of the glenoid fossa was assessed during open jaw by using... can be revised to: The depth of the glenoid fossa was assessed at opened jaw position by using... Our answer: We have revised the text accordingly. In pg5, please edit this phrase as follows: A perpendicular [add: line was drawn] from SE to P1 [add: and it] is equivalent [delete: with & add: to] the height of the fossa b. Then, a parallel [add: line] to SE touching the highest point of the condyle (C) in open jaw position was drawn (P2). A perpendicular [add: line] from SE to P2 was [add: drawn and] defined as the distance d (Fig. 1). Our answer: We have revised the text accord to the first suggestions. Since neither P2 nor d were needed for our analysis, we have deleted the corresponding sentence (in addition we have modified our figure). In Tables 2 & 4, please calculate and insert percentages of total numbers (in last row). Our answer: We have inserted these numbers in the two tables. In pg6, parag2 results, please report significant p values of age influence on GF depth. Our answer: We have done so.

9 In pg6, parag3, please revise this confusing statement in the discussion: While centric positions prevailed to a statistically significant degree, when all identified study articles were considered, no statistically significant predominance of any specific condylar position was observed when only the results of the six methodically best publications were observed [14]. Our answer: Our statement referred to the fact that the conclusion of a systematic review may change when only high-quality study articles are considered. We have revised our sentence by shortening it to the main message: No statistically significant predominance of any specific condylar position was observed when the results of the six methodically best study articles were observed [14]. In pg6, line 40, please delete c from this phrase Türp and Walter [c] evaluated.... Our answer: We replaced the c by the appropriate citation of the literature. In pg7, line 3, should the word studies added to the end of this phrase: Our observation...from the 1980s [23] and 1990s [24] studies. Our answer: With this suggestion, we disagree with the reviewer. We referred to imaging findings from the 1980s and 1990s. We just deleted the word classical. In pg8, please delete cf from these citations [cf. 38] [cf. 12]. Our answer: Done. In pg9, line53, acronym used TMJ OA but not clarified. Please state the full word as it can be understood as either osteoarthrosis or osteoarthritis. Our answer: We have replaced OA by osteoarthritis. In pg11, please report in the list all abbreviations you used in the manuscript such as: ms, Hz/Px, mm, cm...etc. Our answer: Done. Please use heading References instead of Literature. Our answer: Done. AAOP described in-advance DC/TMD criteria in the fifth edition textbook [de Leeuw and Klasser (2013). AAOP criteria for TMD diagnosis were described in the fourth edition textbook [de Leeuw (2008)]. Please change the former with the latter citation.

10 Our answer: We had cited the 2013 textbook four times. All citations were made in the discussion about inconsistencies in the current terminology (under the heading Osteoarthrosis ). While the first three citations were fully compatible with our text, the fourth one was omittable. In the new version, we have deleted our excursion about inconsistencies in the current terminology, which included the four citations of the 2013 book. Please translate titles of non-english references (e.g., citations 20, 29, 54...etc.) to English and insert them between brackets. Our answer: Done. We have first listed the original German or Dutch title, followed by the English translation between brackets. In Table 6, you may use term: Adaptive remodelling instead of Bony adaptation to increased loading. Our answer: This is a good suggestion. We have used now the term Adaptive remodelling due to increased loading. In Figure 1, please rephrase Points and lines used for measurements. To: Points and lines used for measuring glenoid fossa depth. Our answer: Done. REVIEWER 2 A mere bi-dimensional analysis risks being prone to this type of error. This needs to be addressed adequately in the discussion as a limitation of the method. Our answer: We have mentioned a sentence about the possible drawback or a bidimensional analysis in the first section of the Discussion. Page 3 lines Please reformulate some of the parameters of the MRI protocol since they are not being listed according to the common standards. Our answer: In our view, the variables have been mentioned. Otherwise, please specify. Page 4 line 13 How were the single slices oriented and selected according to which criteria? Our answer: We have added the following information in the Method section: The slices were orientated rectangular to the long axis of the condyle. The slice which was located in the middle of the long axis of the condyle had been chosen for assessment. How was the closed position defined and enforced?

11 Our answer: The subjects had been instructed to close their jaw habitually with slight tooth contacts. There was no enforcement of this position. We have added the first sentence in the text of the Method section. How was the open position stabilized? Our answer: For the stabilization of the open jaw position, a mechanical mouth opener (Burnett BiDirectional TMJ Device, Medrad Inc. Pittsburgh, U.S.A.) was used to stabilize the opened jaw position and, therefore, to reduce blurred images due to mandibular motion. We have added this piece of information in the Method section. Page 4 lines The position of the mandibular condyle at closed jaw should be explained and calculated more mathematically. How is this dependent on the shape of the condyle and the slice orientation/selection? Please use a formula with variables and not with words (the current formula is imprecise). Our answer: As the slices had been selected identically in each subject, the comparability of the results can be assumed to be valid. Without doubt, the orientation of the sliced has an influence on the measurement. However, as the orientation was standardized this approach seems to be acceptable. In this context, the shape of the condyle has certainly an impact on the measurement of the condylar position. We have added this text in the Discussion (Methodology). Page 5 line 16 How is the depth of the glenoid fossa invariant to the discrepancy between anatomical coordinates and those set for the analysis? This (and the choice of the slice) likely influences the values of "b". Our answer: Of course the anatomical depth of the glenoid fossa might be different from the calculated depth based on MRI data. However, this bias is true for all measurments in all subjects and might be acceptable for this reason. We have also added this text in the Discussion (Methodology). Why was "d" defined and why is it not reported? Our answer: The reviewer is right. We have deleted d as well as point C. Page 6 lines 14-16: The interpretation of the results belongs to the discussion. The authors should better explain how and where this flattening can occur and what the "upper joint surfaces" are. Last but not least, what would be the biological plausibility for a flattening of the fossa in older age. Our answer: We have shifted the interpretation to the Discussion section. Furthermore, we have explained that the upper joint surfaces, which we in the new version we refer to as temporal joint surfaces, relate particularly to the posterior slope of the articular eminence. Following the classical studies by Sandstedt (1904, 1905), we argue that continuous compressive forces may lead to resorption of bone, thus to flattening of formerly roundish joint surfaces, while traction may lead to bone apposition. Thus, we argue that repetitive compressive forces may lead to

12 resorption of bone, thus to flattening of formerly roundish joint surfaces. From a biological standpoint of plausibility, this would lead to a greater distribution of forces acting on the joint. We have added this to the existing text. Page 6 lines 46 less "frequently" Our answer: We have corrected this typo. Page 7 lines 55 The authors omit to mention papers of other authors who came to similar conclusions in the past, e.g. Rohlin M 1985, Westesson PL et al. 1989, Westesson PL et al. 1992, de Leeuw R et al. 1996, Molinari F et al. 2007, Ohrbach R and Greene C 2013, Vogl TJ et al 2016 Our answer: Thank you very much for this remark. We have added these citations in the Discussion of the paper. Page 9 lines 26: The speculation that loss of molar support would result in TMJ osteoarthrosis is not substantiated by citation 47. Correlation is not causation. Our answer: Indeed. Therefore, we have changed the text. It now reads: In contrast, the role of loss of occlusal support on such osseous changes remains controversial. Page 9 lines 51-60: The authors omit relevant literature, e.g. Brooks SL et al. 1992, Pereira FJ et al. 1994, de Leeuw R et al. 1996, Lee JY et al Our answer: Again, we appreciate this remark. We have considered these four and additional articles (Muir & Goss 1990a,b) in the discussion. Further, I suggest to include the commonly used Wilkes stages in the discussion, since in the oral and maxillofacial surgery community, Wilkes stages 3 and 4 are commonly hypothezised to indicate (surgical) treatment need, and some authors even use porcine models to support this hypothesis (see Matsuka AM et al. 2016) Our answer: We have considered and critically commented Clyde Wilkes staging (1989) in the part Position of the articular disc at closed jaw of the discussion.