Cement augmentation for trochanteric femur fractures: A meta-analysis of randomized clinical trials and observational studies
Authors: Reto Babst
Nadine Diwersi
Ingmar F Rompen
Frank J P Beeres
Sven Nebelung
Matthias Knobe
Ralf Baumgaertner
Filippo Migliorini
Bryan J M van de Wall
Bjoern-Christian Link
Journal: PLoS ONE (2021)
Discipline: Multidisciplinary
Keywords: cement augmentation; trochanteric fractures; elderly patients; fixation; complications
Affiliations: Department of Orthopaedic and Trauma Surgery, Lucerne Cantonal Hospital, Lucerne, Switzerland., Department of Orthopaedics, RWTH Aachen University Hospital, Aachen, Germany., Department of Radiology, RWTH Aachen University Hospital, Aachen, Germany., Department of Health Science and Medicine, University of Lucerne, Lucerne, Switzerland.

Abstract:  Introduction: To date, it is unclear what the clinical benefit of cement augmentation in fixation for trochanteric fractures is. The aim of this meta-analysis is to compare cement augmentation to no augmentation in fixation of trochanteric femur fractures in the elderly patients (&gt;65 years) following low energy trauma. Methods: PubMed/Medline/Embase/CENTRAL/CINAHL were searched for both randomized clinical trials (RCT) and observational studies comparing both treatments. Effect estimates were pooled across studies using random effects models. Subgroup analysis was performed stratified by study design (RCTs and observational studies). The primary outcome is overall complication rate. Secondary outcomes include re-operation rate, mortality, operation duration, hospital stay, general quality of life, radiologic measures and functional hip scores. Results: A total of four RCT's (437 patients) and three observational studies (293 patients) were included. The effect estimates of RCTs were equal to those obtained from observational studies. Cement augmentation has a significantly lower overall complication rate (28.3% versus 47.2%) with an odds ratio (OR) of 0.3 (95%CI 0.1-0.7). The occurrence of device/fracture related complications was the largest contributing factor to this higher overall complication rate in the non-augmented group (19.9% versus 6.0%, OR 0.2, 95%CI 0.1-0.6). Cement augmentation also carries a lower risk for re-interventions (OR 0.2, 95%CI 0.1-0.7) and shortens the hospital stay with 2 days (95%CI -2.2 to -0.5 days). The mean operation time was 7 minutes longer in the augmented group (95%CI 1.3-12.9). Radiological scores (lag screw/blade sliding mean difference -3.1mm, 95%CI -4.6 to -1.7, varus deviation mean difference -6.15°, 95%CI; -7.4 to -4.9) and functional scores (standardized mean difference 0.31, 95%CI 0.0-0.6) were in favor of cement augmentation. Mortality was equal in both groups (OR 0.7, 95%CI 0.4-1.3) and cement related complications were rare. Conclusion: Cement augmentation in fixation of trochanteric femoral fractures leads to fewer complications, re-operations and shorter hospital stay at the expense of a slightly longer operation duration. Cementation related complications occur rarely and mortality is equal between treatment groups. Based on these results, cement augmentation should be considered for trochanteric fractures in elderly patients. 

Retracted: No

PubPeer comments:
 Comments on u201cCement augmentation for trochanteric femur fractures: A meta-analysis of randomized clinical trials and observational studies. PLoS One. 2021u201d We read the systematic review and meta-analysis (SRMA) by Rompen IF et al. [1] with great interest and appreciate the authorsu2019 efforts to investigate the effect of cement augmentation for geriatric trochanteric fractures. The primary outcome of interest was the overall complication rate. A total of four randomized control trials (RCT) were included in the study [1]. However, we would like to raise some concerns about the two RCTs among them [2,3]. In addition, we are concerned that they might have overestimated the effect of cement augmentation without the assessment for quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [4]. 1. Included RCTs We have some concerns about the two RCTs [2, 3]. 1-1. Lee PC et al. described u201ca prospective studyu201d and u201callocated into two treatment groupsu201d in the method [2]. However, they did not clearly describe u201crandom allocationu201d and u201cRCTu201d in the manuscript. Therefore, we cannot confirm that this study is an RCT. We recommend the inquiry to the authors of original studies for study design because this study significantly affects the overall complication [1]. This would substantially alter results and therefore the conclusion. 1-2. The study of Mattsson P et al. had the duplication of patient records in the two RCTs [3,5]. We contacted the authors of the studies directly and were informed of this fact. Rompen IF et al. [1] included a single-center RCT [3], not a multicenter RCT [5] that meets their inclusion criteria [1]. We think that a multicenter study should be included in their meta-analysis because a multicenter study is externally validated with many cases. Readers might find it helpful to know the selection criteria in studies associated with patient records duplication. 2. Forest plot for overall complications Incorrectly included RCTs for meta-analysis could have led to the incorrect results. Rompen IF et al. reported that the overall complication rate was significantly lower in the augmented group (28.3% versus 47.2%) with a weighted OR of 0.3 (95% CI 0.1u20130.7, I2: 75%) [1]. We re-analyzed considering the combination of included RCTs. In figure 1, we removed the uncertain RCT by Lee et al [2]. In figure 2, we added the multicenter RCT by Mattson et al. [5] where two nonunion events occurred in the cement augmentation group, although the single-center RCT by Mattson et al. [3] had no complications in both groups. In figure 3, we removed the RCT by Lee et al. [2] and added the multicenter RCT by Mattson et al [5]. Our results of re-analyze demonstrated that all the three patterns did not show a significant difference (Figure 1-3). We recommend creating the forest plot by adding the multicenter RCT by Mattson et al. [5] and removing the RCT by Lee et al. [2], if the study by Lee et al [2] is not RCT (Figure 3). Figure 3 shows inconsistent results in the studies and no significant effect in favor of the cement augmentation (OR 0.69, 95% CI 0.32u20131.47). Therefore, the results of these erroneous analyses by Rompen IF et al. [1] could change the interpretation, including the implications for clinical practice. 3. Overall assessments We are concerned that this SRMA by Rompen IF et al. [1] might have resulted in an outcome reporting bias. The reason for this is that there is no mention of registering this SRMA with PROSPERO, nor is there any mention of publishing the protocol to a platform such as Protocols.io . Readers need to compare the outcome items in the published SRMA with the outcome items listed in the pre-registered protocol before implementing SRMA to determine the outcome reporting bias [6]. Rompen IF et al. assessed RCTs using the MINORS-Criteria (Methodological Index for Non-Randomized [7] (S3 Table in S1 File [1]). On the other hand, we assessed the included two RCTs [2,8] using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) [9] (Figure 4). The overall risk of bias for the outcome of overall complication was assessed as u201chigh risku201d in the all included two RCTs. Finally, we evaluated evidence-based quality on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach [10]. The certainty of the evidence for overall complication was u201clowu201d for included RCTs due to the high risk of bias and small total sample size, and u201cvery lowu201d for included observational studies due to small total sample size [11]. Moreover, the methodological quality of the systematic review by Rompen IF et al.[1] was of critically low quality (Table 1). We applied AMSTAR 2 [12], a critical appraisal tool for systematic reviews of health care interventions, to the systematic review. 4. Summary There is no clear evidence on the overall complication suggesting a clinical benefit of cement augmentation in the SRMA by Rompen IF et al [1]. We are concerned about the selection process of the included studies and the risk of bias assessment, resulting in the misinterpretation of the reported outcomes. Conflict of interest None. Authors Norio Yamamoto, MD1, 2, 3, Takahisa Ogawa, MD, MPH4, Masahiro Banno, MD, PhD3, 5, 6, Jun Watanabe MD, PhD3, 7 1.tDepartment of Orthopedic Surgery, Miyamoto Orthopedic Hospital, 4-2-63, Kunitomi, Naka-ku, Okayama, Okayama 773-8236, Japan. 2.tDepartment of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan 3.tSystematic Review Workshop Peer Support Group (SRWS-PSG), Japan 4.tDepartment of Orthopedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan 5.tDepartment of Psychiatry, Seichiryo Hospital, Tsurumai 4-16-27, Showa-ku, Nagoya 466-0064, Japan 6.tDepartment of Psychiatry, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8560, Japan 7.tCenter for Community Medicine, Jichi Medical University, 3311-1 Yakushiji Shimotsuke City, Tochigi, 329-0498, Japan References 1. Rompen IF, Knobe M, Link BC, Beeres FJP, Baumgaertner R, Diwersi N, Migliorini F, Nebelung S, Babst R, van de Wall BJM. Cement augmentation for trochanteric femur fractures: A meta-analysis of randomized clinical trials and observational studies. PLoS One. 2021 Jun 15;16(6):e0251894. 2. Lee PC, Hsieh PH, Chou YC, Wu CC, Chen WJ. Dynamic hip screws for unstable intertrochanteric fractures in elderly patients--encouraging results with a cement augmentation technique. J Trauma. 2010 Apr;68(4):954-64. 3. Mattsson P, Larsson S. Unstable trochanteric fractures augmented with calcium phosphate cement. A prospective randomized study using radiostereometry to measure fracture stability. Scand J Surg. 2004;93(3):223-8. 4. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introductionu2014GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383u201394. 5. Mattsson P, Alberts A, Dahlberg G, Sohlman M, Hyldahl HC, Larsson S. Resorbable cement for the augmentation of internally-fixed unstable trochanteric fractures. A prospective, randomised multicentre study. J Bone Joint Surg Br. 2005 Sep;87(9):1203-9. 6. Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 2009;302:977e84. 7. Ou2019Neill F, Condon F, McGloughlin T, Lenehan B, Coffey JC, Walsh M. Dynamic hip screw versus DHS blade: a biomechanical comparison of the fixation achieved by each implant in bone. J Bone Joint Surg Br. 2011 May; 93(5):616u201321. 8. Kammerlander C, Hem ES, Klopfer T, Gebhard F, Sermon A, Dietrich M, et al. Cement augmentation of the Proximal Femoral Nail Antirotation (PFNA)u2013A multicentre randomized controlled trial. Injury [Internet]. 2018; 49(8):1436u201344. 9. Sterne JAC, Savoviu0107 J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. August 2019:l4898. doi:10.1136 bmj.l4898 10. Guyatt G, Oxman AD, Akl E a, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383-394. 11. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. www.cochrane-handbook.org. 12. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomized or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. Figure and Figure Legends Figure 1. Forest plot of comparison: Overall complications without the RCT by Lee et al. ![file] Figure 2. Forest plot of comparison: Overall complications adding the multicenter RCT by Mattson et al. ![file] Figure 3. Forest plot of comparison we recommended: Overall complications adding the multicenter RCT by Mattson et al. and removing the RCT by Lee et al. ![file] Figure 4. Risk of bias summary for overall complications. ![file] Table 1. AMSTAR 2 Checklist ![file] PICO, participants intervention control outcome; MINORS, Methodological Index for Non-Randomized Studies); RCT, randomized controlled trial. , 
 Comments on u201cCement augmentation for trochanteric femur fractures: A meta-analysis of randomized clinical trials and observational studies. PLoS One. 2021u201d We read the systematic review and meta-analysis (SRMA) by Rompen IF et al. [1] with great interest and appreciate the authorsu2019 efforts to investigate the effect of cement augmentation for geriatric trochanteric fractures. The primary outcome of interest was the overall complication rate. A total of four randomized control trials (RCT) were included in the study [1]. However, we would like to raise some concerns about the two RCTs among them [2,3]. In addition, we are concerned that they might have overestimated the effect of cement augmentation without the assessment for quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [4]. 1. Included RCTs We have some concerns about the two RCTs [2, 3]. 1-1. Lee PC et al. described u201ca prospective studyu201d and u201callocated into two treatment groupsu201d in the method [2]. However, they did not clearly describe u201crandom allocationu201d and u201cRCTu201d in the manuscript. Therefore, we cannot confirm that this study is an RCT. We recommend the inquiry to the authors of original studies for study design because this study significantly affects the overall complication [1]. This would substantially alter results and therefore the conclusion. 1-2. The study of Mattsson P et al. had the duplication of patient records in the two RCTs [3,5]. We contacted the authors of the studies directly and were informed of this fact. Rompen IF et al. [1] included a single-center RCT [3], not a multicenter RCT [5] that meets their inclusion criteria [1]. We think that a multicenter study should be included in their meta-analysis because a multicenter study is externally validated with many cases. Readers might find it helpful to know the selection criteria in studies associated with patient records duplication. 2. Forest plot for overall complications Incorrectly included RCTs for meta-analysis could have led to the incorrect results. Rompen IF et al. reported that the overall complication rate was significantly lower in the augmented group (28.3% versus 47.2%) with a weighted OR of 0.3 (95% CI 0.1u20130.7, I2: 75%) [1]. We re-analyzed considering the combination of included RCTs. In figure 1, we removed the uncertain RCT by Lee et al [2]. In figure 2, we added the multicenter RCT by Mattson et al. [5] where two nonunion events occurred in the cement augmentation group, although the single-center RCT by Mattson et al. [3] had no complications in both groups. In figure 3, we removed the RCT by Lee et al. [2] and added the multicenter RCT by Mattson et al [5]. Our results of re-analyze demonstrated that all the three patterns did not show a significant difference (Figure 1-3). We recommend creating the forest plot by adding the multicenter RCT by Mattson et al. [5] and removing the RCT by Lee et al. [2], if the study by Lee et al [2] is not RCT (Figure 3). Figure 3 shows inconsistent results in the studies and no significant effect in favor of the cement augmentation (OR 0.69, 95% CI 0.32u20131.47). Therefore, the results of these erroneous analyses by Rompen IF et al. [1] could change the interpretation, including the implications for clinical practice. 3. Overall assessments We are concerned that this SRMA by Rompen IF et al. [1] might have resulted in an outcome reporting bias. The reason for this is that there is no mention of registering this SRMA with PROSPERO, nor is there any mention of publishing the protocol to a platform such as Protocols.io . Readers need to compare the outcome items in the published SRMA with the outcome items listed in the pre-registered protocol before implementing SRMA to determine the outcome reporting bias [6]. Rompen IF et al. assessed RCTs using the MINORS-Criteria (Methodological Index for Non-Randomized [7] (S3 Table in S1 File [1]). On the other hand, we assessed the included two RCTs [2,8] using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) [9] (Figure 4). The overall risk of bias for the outcome of overall complication was assessed as u201chigh risku201d in the all included two RCTs. Finally, we evaluated evidence-based quality on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach [10]. The certainty of the evidence for overall complication was u201clowu201d for included RCTs due to the high risk of bias and small total sample size, and u201cvery lowu201d for included observational studies due to small total sample size [11]. Moreover, the methodological quality of the systematic review by Rompen IF et al.[1] was of critically low quality (Table 1). We applied AMSTAR 2 [12], a critical appraisal tool for systematic reviews of health care interventions, to the systematic review. 4. Summary There is no clear evidence on the overall complication suggesting a clinical benefit of cement augmentation in the SRMA by Rompen IF et al [1]. We are concerned about the selection process of the included studies and the risk of bias assessment, resulting in the misinterpretation of the reported outcomes. Conflict of interest None. Authors Norio Yamamoto, MD1, 2, 3, Takahisa Ogawa, MD, MPH4, Masahiro Banno, MD, PhD3, 5, 6, Jun Watanabe MD, PhD3, 7 1.tDepartment of Orthopedic Surgery, Miyamoto Orthopedic Hospital, 4-2-63, Kunitomi, Naka-ku, Okayama, Okayama 773-8236, Japan. 2.tDepartment of Epidemiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan 3.tSystematic Review Workshop Peer Support Group (SRWS-PSG), Japan 4.tDepartment of Orthopedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan 5.tDepartment of Psychiatry, Seichiryo Hospital, Tsurumai 4-16-27, Showa-ku, Nagoya 466-0064, Japan 6.tDepartment of Psychiatry, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8560, Japan 7.tCenter for Community Medicine, Jichi Medical University, 3311-1 Yakushiji Shimotsuke City, Tochigi, 329-0498, Japan References 1. Rompen IF, Knobe M, Link BC, Beeres FJP, Baumgaertner R, Diwersi N, Migliorini F, Nebelung S, Babst R, van de Wall BJM. Cement augmentation for trochanteric femur fractures: A meta-analysis of randomized clinical trials and observational studies. PLoS One. 2021 Jun 15;16(6):e0251894. 2. Lee PC, Hsieh PH, Chou YC, Wu CC, Chen WJ. Dynamic hip screws for unstable intertrochanteric fractures in elderly patients--encouraging results with a cement augmentation technique. J Trauma. 2010 Apr;68(4):954-64. 3. Mattsson P, Larsson S. Unstable trochanteric fractures augmented with calcium phosphate cement. A prospective randomized study using radiostereometry to measure fracture stability. Scand J Surg. 2004;93(3):223-8. 4. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introductionu2014GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383u201394. 5. Mattsson P, Alberts A, Dahlberg G, Sohlman M, Hyldahl HC, Larsson S. Resorbable cement for the augmentation of internally-fixed unstable trochanteric fractures. A prospective, randomised multicentre study. J Bone Joint Surg Br. 2005 Sep;87(9):1203-9. 6. Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 2009;302:977e84. 7. Ou2019Neill F, Condon F, McGloughlin T, Lenehan B, Coffey JC, Walsh M. Dynamic hip screw versus DHS blade: a biomechanical comparison of the fixation achieved by each implant in bone. J Bone Joint Surg Br. 2011 May; 93(5):616u201321. 8. Kammerlander C, Hem ES, Klopfer T, Gebhard F, Sermon A, Dietrich M, et al. Cement augmentation of the Proximal Femoral Nail Antirotation (PFNA)u2013A multicentre randomized controlled trial. Injury [Internet]. 2018; 49(8):1436u201344. 9. Sterne JAC, Savoviu0107 J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. August 2019:l4898. doi:10.1136 bmj.l4898 10. Guyatt G, Oxman AD, Akl E a, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383-394. 11. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. www.cochrane-handbook.org. 12. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomized or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. Figure and Figure Legends Figure 1. Forest plot of comparison: Overall complications without the RCT by Lee et al. ![file] Figure 2. Forest plot of comparison: Overall complications adding the multicenter RCT by Mattson et al. ![file] Figure 3. Forest plot of comparison we recommended: Overall complications adding the multicenter RCT by Mattson et al. and removing the RCT by Lee et al. ![file] Figure 4. Risk of bias summary for overall complications. ![file] Table 1. AMSTAR 2 Checklist ![file] PICO, participants intervention control outcome; MINORS, Methodological Index for Non-Randomized Studies); RCT, randomized controlled trial. ,