The initial mechanical concept of osteosynthesis of long bone fractures was introduced by the Arbeitsgemeinschaft für Osteosynthesefragen (AO) group and aimed at perfect anatomic reduction and stable fixation.39,40 Stability could be achieved only by compression of the fracture. However, in multifragmentary comminuted fractures, stable fixation involves restoration of the structural continuity of the cortex, which requires extensive soft tissue stripping and subsequent damage to the blood supply at the fracture site.3,10,11,17,18,34 The favorable outcome of closed intramedullary (IM) nailing techniques indicated noninterference with the enhanced fracture healing potential of the comminution zone and accelerated bone union.14,16,20,25,67,73 These observations prompted a change in the therapeutic approach of extraarticular fractures of long bones. New techniques of indirect reduction and more elastic fixation with bridge plates generated the concept of biologic plate fixation.3,18,21,30,37,49,62,70 Many authors have reported favorable clinical results with this type of fixation.5,7,8,13,21,22,26-29,31,32,43,44,54,56,58-61,64,66,69-72 The inherent elasticity of biologic plate fixation allows micro- motion at the fracture level, resulting in an indirect bone healing process with abundant callus formation. Biologic plate fixation is mechanically stronger than the direct healing process after rigid fixation, which is characterized by minimal callus formation.4,6,16,46,47 These observations have revived the interest in using plates, particularly in patients in whom IM nails would be considered a less appropriate treatment.9,10,19,34,41,45,53,54,58,66 However, numerous reports had small cohorts,3,5,11,18,20,48,55 therefore the validity of their recommendations are limited. A meta-analysis of appropriately selected relevant randomized control trials would be a reasonable option. An improved estimate of the effect of size could be obtained by properly combining the results of the individual studies. Unfortunately, randomized controlled trials are difficult to do when acute trauma is involved, therefore the majority of articles regarding acute trauma are observational studies.
We systematically reviewed relevant studies on biologic plate fixation to clarify the union rate and time required for solid union. We also identified major complications (infection, malunion), reoperation rates, and the frequency of bone graft procedures.
MATERIALS AND METHODS
The methodologic guidelines for planning, conducting, and reporting systematic reviews are well described and we used such guidelines.2,38,65 We conducted an electronic search of the Medline database using the PubMed search engine (from January 1985 to January 2004) entering the following terms and Boolean operators: “biological fixation” OR “femoral plating” OR “indirect reduction” OR “LISS” AND “fracture.” The references of the retrieved articles also were reviewed. Only papers published in English or German were included. Articles were considered eligible if they met the inclusion criteria: (1) the target population consisted of adult patients with fractures in any of the three anatomic regions of the femur (subtrochanteric, diaphyseal, or supracondylar), either as an isolated injury or as a part of polytrauma; (2) each study included at least 12 patients; (3) the fracture treatment had been operative and in accordance with the principles of biologic plate fixation (indirect fracture reduction with no direct manipulation of the bony fragments of the comminution zone, limited surgical approach to the fracture site, and epiperiosteal application of the plate); and (4) for outcomes of interest, each paper had to provide complete information for union and infection rates. Papers dealing exclusively with pathologic or periprosthetic femoral fractures were excluded. Laboratory studies and case reports also were excluded. No unpublished papers were included.
All relevant data were collected by two investigators (CP, MG) working independently. We did not calculate the intrarater and interrater agreements regarding study selection and data extraction. Any discrepancies in the extracted data were resolved by discussion between the two reviewers. The authors, time of enrollment, and patient demographics were examined closely to avoid including patient data described in multiple reports. Reviewers were not blinded to the authors, journals, and institutions to avoid data duplication. The quality of each study was assessed using a self-made questionnaire asking: (1) Were the inclusion and exclusion criteria clearly defined?; (2) Was the number of dropouts known?; (3) Was the followup prespecified?; (4) Was the description of outcomes of interest complete?; and (5) Were details of pertinent data that might affect the outcome of interest available (eg, in case of open fractures, was this complication associated with the time needed for fracture union)? An affirmative answer covering all aspects of each question scored 2 points, an affirmative answer not providing all the anticipated information scored 1 point, and a negative answer scored 0 points. Each reviewer independently assigned a quality score to each study. The highest possible score was 10 points, and only studies with 5 points or greater were included. We evaluated interrater agreement by calculating the correlation between the two scores.
Categorical and numerical data were extracted from each manuscript. These included study population demographics, fracture pattern (simple or comminuted), type of injury (open or closed), followup rate, and bone graft procedures. The main outcome of interest was the union rate, but infection, malunion, and reoperation rates also were analyzed. Each outcome of interest in individual studies was expressed as a proportion of the total number of events or successes (eg, unions, infections, mal- unions, or reoperations) of the total number of the fractures in patients with adequate followup. We also calculated the 95% confidence intervals (95% CI). The union rate was the proportion of united fractures to the total number of fractures in patients with adequate followup. Infection, malunion, reoperation rates, and the frequency of autologous bone graft procedures also were calculated (Table 1). Details regarding infection rates were extracted from all 19 manuscripts.5,7,8,13,21,22,24,26-28,43,44,54,56,60,61,64,69,70
Data documenting the infection rate with respect to fracture location were available in 17 articles that documented 552 fractures.5,7,8,13,22,24,26-28,43,44,54,56,61,64,69,70 Data regarding the frequency of infection in open and closed fractures were abstracted from 12 papers that documented 421 fractures.5,13,21,22,24,26,44,54,56,60,61,69 Data on malunion were extracted from 15 papers of 522 fractures in patients with adequate followup.5,7,8,13,22,24,26-28,43,54,56,60,61,69 Information regarding re- operation rates could be derived from 14 studies of 459 fractures.5,7,13,21,22,24,27,28,43,54,56,60,61,70 Autologous bone graft procedures were described in 18 manuscripts,5,7,8,13,21,22,24,26-28,43,44,54,56,60,61,69,70 but no bone graft was used in 50%,7,8,22,26,27,43,44,60,69 and in another four studies, the bone graft rate was less than 5%.21,28,54,56 To ensure consistency of results across all studies, specific outcomes of interest (eg, malunion and reoperation rates) were clearly defined. The respective definition criteria were used during data extraction. A malunited fracture was based on the following criteria: (1) angulation greater than 5° in the coronal plane (varus-valgus deformity); (2) angulation greater than 5° in the sagittal plane (flexion-extension deformity); (3) malrotation greater than 15°; and (4) leg-length discrepancy greater than 1.5 cm. Reoperation was defined as at least one repeat surgical procedure after the index procedure. We also analyzed any association of infection with fracture location or type of injury (closed versus open).
We calculated a combined estimate of effect size for each outcome of interest. This constituted a weighted average of the individual study results using the inverse variance of each study as normalizing weight (W) (W 1/V), where V (variance) represents the square of the standard error (SE2) of the sample proportion (p). The latter was calculated according to the formula proposed by Agresti and Coul for proportions that are very close to 0 or 1: SE2 p'(1-p')/n+4 and p' s+2/n+4, where s represents the number of successes(eg, unions, infections) for a study and n represents the total number of observed fractures.1 Differences in treatment effects in the component studies (statistical heterogeneity) were formulated using the Cochran's chi square test (Q test)15 and I square test.23
Statistical analysis was performed on a personal computer using NCSS Statistical Software (Kaysville, UT). Graphs were created using the GraphPad Prism Version 3 software (GraphPad Software Inc, San Diego, CA). Chi square tests and Fisher's exact tests were used to estimate any relationship between nominal measures. Comparison of the weighted means of continuous parameters of interest across groups was performed using a two- tailed, unpaired t test. Differences were considered significant at p < 0.05. Significance was set at 0.1 for the Q test as this test is characterized by low sensitivity for detecting heterogeneity.33
Eighty-three papers were retrieved from the electronic search, but only 12 met the inclusion criteria.5,7,8,13,24,26,27,43,54,60,61,69 Another six eligible articles were found from the search of the reference lists of the electronically retrieved papers.21,22,44,56,64,70 One other article was included after a hand search of the last 10 years of the Journal of Orthopaedic Trauma.29 These papers represented retrospective, observational studies13,21,22,24,26,27,44,54,56,61,69,70 or prospective studies.5,7,8,29,43,60,64 The 19 manuscripts documented 750 patients with 760 femoral fractures,5,7,8,13,21,22,24,26,27,29,43,44,54,56,60,61,64,69,70 of which 687 patients with 697 femoral fractures were treated according to the principles of biologic plate fixation. The 19 studies differed regarding study design (prospective, retrospective), demographic characteristics, fracture location (subtrochanteric, diaphy- seal, supracondylar), proportion of open fractures, proportion of comminuted fractures, followup rate, and quality score. The impact of such diversity, commonly referred to as clinical and methodologic heterogeneity, on the observed results of the studies was explored by plotting the outcomes of interest against the various factors (in rank order scale) that were considered responsible for the heterogeneity. There were nonparametric correlations between mean age and mean time to union (Spearman r −0.69; p 0.0030) (Fig. 1), proportion of comminuted fractures in each study and mean time to union (Spearman r 0.64; p 0.0057) (Fig. 2), and proportion of supracondylar fractures and malunion rate (Spearman r 0.60; p 0.018) (Fig. 3). No other relationships were established between the recorded factors of clinical heterogeneity (mean age, proportion of comminuted fractures, proportion of supracondylar fractures, proportion of open fractures, bone graft rate, and quality score) and the various outcomes of interest. Study quality ranged from 5-10 points, with an average quality score of 5 points (Table 2). The correlation coefficient (r) for interrater agreement was 0.86, (p < 0.01). The mean difference between raters' scores was −0.0052 (Standard error [SE], 0.14; 95% confidence interval [CI], −0.35-0.25). The intraclass correlation coefficient (ICC) was 0.86 (95% CI, 0.66-0.94).
There were 659 fractures in patients with adequate followup until complete bone union. The union rate was 81- 100% across all studies. The Q and I squared values indicated a low to moderate degree of heterogeneity for union rate (Q 25.4; degrees of freedom 18; p > 0.1; I squared 29.1), therefore we calculated an estimated pooled union rate. The weighted mean union rate was 98.4% (95% CI, 98.3-98.4) (Fig. 4). To verify the robustness of our findings, we performed a sensitivity analysis by calculating the union rate after excluding studies that could have heavily influenced results. Repeat analysis after excluding the study by Huang et al24 (which seemed to be an outlier) yielded a weighted average union rate at 98.5% (95% CI, 98.46-98.56). However, an estimated union rate at 99% (95% CI, 98.96-99.05) was calculated after excluding the study by Schutz et al60 because it had the largest study group. The mean time to union ranged from 10.7-24 weeks (Table 3).
The infection rate across studies was 0-8%; there was a 2.1% estimated weighted mean infection rate (95% CI, 2.04-2.13) (Fig. 5). Excluding the studies by Schutz et al60 (the largest study group) and Schandelmaier et al56 (as an outlier) yielded estimated infection rates of 1.7% (95% CI, 1.7-1.8) and 1.9% (95 CI%, 1.8-1.9), respectively. The malunion rate across studies was 0-29%. Heterogeneity was detected with respect to malunion rate (Q 43.2; degrees of freedom 14; p < 0.01; and I2 67.6), therefore pooling of the results was considered inappropriate.
The reoperation rates of patients across the studies were 0-23%. The results of the individual studies varied (Q 26; degrees of freedom 13; p < 0.05; and I2 50), therefore a combined effect estimate could not be calculated. The bone graft rates were estimated as 0-55% across all 18 studies. We did not detect any association between the frequency of bone graft with union rate or mean time to union.
One hundred fifty-one fractures were subtrochanteric, 152 were diaphyseal, and 249 were supracondylar. Two subtrochanteric, one diaphyseal, and eight supracondylar fractures were infected. There was no association between fracture location and infection.
Three hundred thirty-three fractures were closed, and 89 fractures were open. Fourteen of these fractures were infected (11 open and three closed). Open injuries were associated (p 0.008) with an increased infection rate.
Malunion was observed in 78 fractures; most were supracondylar (83.3%). Subtrochanteric and diaphyseal fractures comprised 14.1% and 2.6% of the total number of malunited fractures, respectively (Table 4). We detected 89 malunions in the 78 malunited fractures, but in some patients the deformities represented a combination of mal- union in more than one plane of deformity. The most frequent type of malunion was angulation in the coronal plane (varus-valgus deformity) (53%), followed by flexion-extension deformity (21%), leg-length discrepancy (16%), and malrotation (10%) (Table 5).
The most common causes for reoperation were a secondary bone-grafting procedure (33.8%), implant failure (20%), and infection (18.5%) (Table 6).
The development of modern nailing techniques has improved the overall outcome and set new standards for operative treatment of fractures of long bones. Along with the evolution of nailing techniques, there has been a similar evolution of plating techniques. Clinical thinking has shifted from the mechanical concept of absolute stability to a more biologic concept of indirect reduction with limited or no approach at the fracture zone, and epiperiosteal plate application. Greater knowledge of bone circulation and its effect on fracture healing52,63,68 also has contributed to the development of atraumatic surgical techniques.
Our systematic review of the literature relied on observational studies and is subject to systematic and random error. There are certain limitations in comparing observational studies with a substantial number of uncontrolled parameters. A systematic review of observational studies inevitably will bring together material with an element of diversity. Studies differ in design, conduct, study population demographics (mean age and gender ratio), interventions, exposures, or outcomes studied. This diversity commonly is referred to as clinical heterogeneity and may be responsible for biased and invalid results. Sources of clinical heterogeneity were study type, fracture distribution according to location (subtrochanteric, diaphyseal, or supracondylar), proportion of open and comminuted fractures, and followup rate. We assessed how these limitations produced grossly dissimilar results by plotting them in rank order scale against the various outcomes of interest. A nonparametric correlation was established between mean age and mean time to union, proportion of comminuted fractures and mean time to union, and proportion of supracondylar fractures and malunion. To reduce bias and confounding results, our study design followed a certain methodologic procedure consisting of the search methodology, definition of certain inclusion and exclusion criteria, and an assessment of the quality of each study. In the inclusion criteria, a cut-off number of at least 12 patients in each eligible study was set. This was done to exclude studies with a small number of cases, whose results are not amenable to statistical interpretation.
The quality of each study was assessed by a self-made quality instrument, and poor quality studies initially were excluded (without previously exploring their influence to the outcome estimates) to avoid additional increase of the diversity and heterogeneity, almost always inherent with observational studies that comprised our material.
However, we explored the presence of excessive variation (beyond chance) of the individual estimates of treatment effect of the included studies (statistical heterogeneity), and we produced a combined estimate of effect size only in the absence of statistical heterogeneity. In addition, we evaluated the validity of our results by repeating the calculations of the pooled estimates of effect size after excluding studies considered to profoundly influence the results. Data synthesis from case series studies should be interpreted with caution.
Investigators of studies on biologic plating techniques report encouraging results.5,7,8,13,21,22,26-29,31,32,43,44,54,56,58-61,64,66,69-72 However, a cumulative evaluation of the results of biologic internal fixation with plates and screws has not been reported. A well-conducted meta-analysis of randomized controlled trials would be an appropriate scientific method for clarifying the role of biologic plate fixation in fracture treatment. Unfortunately, we could not identify any prospective randomized controlled trial that compared biologic plate fixation with mechanical plate fixation or biologic plate fixation with modern nailing techniques. This seems reasonable as it is difficult to organize and do well-designed randomized controlled trials in the context of acute trauma because of individual circumstances related to trauma severity and life-threatening conditions.
Most (81%) fractures were comminuted and there was a tendency to use biologic plate fixation for comminuted fracture patterns rather than simple patterns. This seems justified because the multifragmentary fracture pattern is more compatible with the elasticity of the biologic fixation and micromotion at the fracture site. As with this particular fracture pattern, the overall strain was kept within optimal limits.48,50,51,74 Extending the principles of indirect reduction and bridge plating to simpler fracture patterns was supported provided that the reduction of the fracture is not accurate.48 This allows for preservation of open gaps which keep strain to permissive levels for uneventful progress of bone healing.48
Only a small proportion of the fractures required bone graft (0-55%).5,13,21,24,29,54,56,61,70-72 Eliminating bone graft procedures is an advantage of biologic plating, particularly regarding donor-site morbidity.75 Almost ½ of the bone-grafting procedures were performed during the initial operation; the others were secondary procedures. Use of primary bone graft has been limited in open fractures such as fractures with metaphyseal bone loss and high energy, and multifragmentary fractures where reinforcement of the healing potential was considered necessary.13,21,70 Secondary grafting procedures were used in cases of disturbed union24,29 or as scheduled delayed procedures in cases of previous open fractures.22,29,61 Currently, the indications for bone grafting in the context of biologic plate fixation are limited. Primary indications for bone grafting include: open fractures with extensive devascularization and bone loss, large metaphyseal defects with imminent articular surface collapse, and severe comminution (particularly in the form of segmental) with compromised healing potential.34,54,57
There was an overall union rate of 98.4%, with a mean time to union ranging from 10.7 to 24 weeks. Investigators of various papers in the English literature report on the results of mechanical plate fixation12,35,36,42,55 or IM nailing16,20,25,67,73 for treating femoral fractures. However, our study design did not allow direct comparison of biologic plate fixation with either technique. Properly designed randomized controlled trials could directly compare the outcomes from different fixation techniques.
The malunion rates ranged from 0-29%. Heterogeneity was obvious in the results of the component studies with respect to this outcome. Subsequently, a combined estimate of effect size was not calculated. Most malunions angulated in the coronal (varus-valgus) plane, and most were supracondylar. True losses of reduction during followup were estimated at 2%. This implies most occur- rences of malunion were because of inaccurate intraoperative reduction. Kregor et al29 reported on 11 incorrect reductions detected during the postoperative period of 62 treated supracondylar fractures with the Less Invasive Stabilization System (LISS). Similarly, Schutz et al60 reported on 29 malreductions of 116 distal femoral and supracondylar fractures treated with the LISS. A comminuted fracture pattern and use of indirect reduction technique resulted in inaccurate reduction and malunion.60 Malunions mostly occurred in supracondylar fractures, which accounted for the increased overall malunion rate. There was a strong nonparametric relationship between the proportion of supracondylar fractures in each study and the respective malunion rates (Fig. 3). Because the component studies differed substantially with respect to fracture location, the correlation was attributed to heterogeneity of the malunion rates. Although minor deformities were considered in the overall calculation of malunion rate, they are probably of limited clinical significance.
The incidence of deep infection was 2.1% among all fractures with adequate followup. We attributed the relatively low infection rate to the minimally invasive nature of biologic plate fixation and the preservation of soft tissue and bone features at the fracture site.
Although the rate of fractures that needed reoperation (range, 0-23%) seems high, it likely reflects the complex nature of the injuries. It also reflects the occasional need for supplementary bone grafting procedures to eventually achieve bone union and acceptable function.
We presented the cumulative results of femoral biologic plate fixation reported in the literature. Although strict adherence to certain methodologic strategies aimed to reduce bias and invalid results, we are aware of the limitations and risks of pooling data extracted from observational studies. There were high union rates, low infection, and the bone graft procedures were infrequent. We think biologic plate fixation could be an alternative to IM nailing, especially when a nailing procedure is considered inappropriate. Results could be improved by strictly adhering to the biologic and mechanical principles of biologic plate fixation.
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