The determination of fracture union is a key concept in clinical orthopaedics; however, there is no established gold standard for healing. This review provides an overview of the lack of consensus with regard to the consistent assessment of healing, examines currently available tools to determine union, discusses the role of functional outcomes in the assessment of fracture healing, and finally evaluates the assessment of healing as it pertains to fracture trials.
WHAT IS THE PROBLEM AND IS THERE A CONSENSUS?
There are several problems with the assessment of fracture union: there is no universally accepted gold standard for healing, most studies show low rates of interobserver and intraobserver reliability, and there is considerable variation in radiographic technique, methods, concepts, and scoring systems, making the interpretation of data from the literature difficult and confusing. For example, the subtrochanteric fracture illustrated in Figure 1 demonstrates a lack of healing medially with subsequent hardware failure, yet the fracture consolidates without further deformity and a good clinical result. Does the healing evident on the lateral cortex in the first radiograph justify the definition of “union” in this case? Corrales et al1 examined variability in the assessment of fracture healing in 12 orthopaedic trauma articles and found 11 different radiographic criteria for healing, with only 2 studies assessing the reliability of the radiographic outcomes; they noted the “lack of consensus” in this area. Mirić et al used 15 sets of plain radiographs and 7 surgeons to examine interobserver and intraobserver variability in the radiographic assessment of scaphoid nonunion healing and found kappa values in the 0.46 to 0.54 range (fair to moderate agreement). Their conclusion was that “radiographic assessment was not reliable or reproducible in this setting.”2
Surgeons have attempted to improve the accuracy of assessing radiographic healing by adding more advanced imaging studies. Bhattacharyya et al examined the accuracy of computed tomography (CT) scanning for the diagnosis of tibial nonunion in 35 patients with equivocal findings. They compared evaluations of the scans, by 2 radiologists and 1 surgeon, to the gold standard for union (namely union at the time of surgery or after 6 months of clinical observation).3 The reported kappa values were in the “excellent” range (0.89) with a sensitivity of 100% for nonunion. However, the authors did warn that there were 3 false positives (CT scan defined “nonunion” in a tibia subsequently found to be united) decreasing the specificity to only 62%.
Using a common clinical scenario, Whelan et al4 investigated the reliability of fracture healing in the tibia after intramedullary fixation using 30 sets of radiographs and 4 orthopaedic surgeons. Interestingly, they found excellent intraobserver reliability (kappa values of 0.82–0.83) and interobserver reliability (kappa values of 0.70–0.75) in the surgeons' ability to agree on the number of cortices bridged by callus and whether a fracture line was visible or not. They concluded that the “number of cortices bridged by callus was a reliable radiographic measure of healing after intramedullary fixation.” In a subsequent study, this same group then incorporated these findings into a new scoring system, the radiographic union score for tibial fractures (or RUST).5 By assigning a numerical grade of 1–3 (depending on fracture line visibility and the presence or absence of a bridging callus) to each of the 4 cortices of the tibia visible on standard anteroposterior and lateral radiographs, they produced a numerical “score” between 4 and 12. They found that this RUST score was very consistent, with an “overall agreement” kappa value of 0.86, and an intraobserver kappa value of 0.88. They proposed that, considering the lack of a gold standard score, the reliable and reproducible RUST score should be used and validated in the clinical setting.
In summary, the assessment of fracture healing is of critical importance to the practicing orthopaedic surgeon and his or her patient, as many treatment decisions will be made based on this information. The evaluation of fracture healing can be optimized using consistent radiographic technique, the judicious use of advanced imaging, and adherence to established, reproducible scoring systems.
CURRENT OPTIONS FOR DETERMINING UNION
Determining whether a bone fracture is healed is one of the most important and fundamental clinical determinations made in orthopaedics. Recent advancements in imaging techniques and the introduction of new radiographic scores have helped decrease the amount of disagreement among physicians on this topic. Furthermore, a deeper understanding of the molecular pathways involved in the bone healing process has led to the emergence of serologic markers as possible candidates in assessment of fracture union. In addition to current physician-centered methods, patient-centered approaches that evaluate quality of life and function are gaining popularity in the assessment of fracture union. Currently available tools in the assessment of fracture healing can be broadly divided into 4 categories: (1) imaging studies; (2) mechanical assessment; (3) serologic markers; and (4) clinical examination.
Despite its limitations, radiographic assessment has remained a crucial tool in determining fracture healing. Two radiographic scoring systems have been developed that assess the presence of a bridging callus and the disappearance of the fracture line; the radiographic union score for hip and the previously described RUST. The radiographic union score for hip and RUST increase agreement among surgeons and radiologists when assessing fracture repair.5–85–85–85–8 It has also been shown that for patients with diaphyseal tibia fractures, any cortical bridging on routine postoperative imaging by 4 months is 99% accurate in predicting union.9
CT is superior to plain radiography in the assessment of union and the visualizing of fracture in the presence of an abundant callus or overlaying cast,10 or in fractures involving metaphyseal bone that tend to heal with less callus.11,1211,12 Ultrasound is unable to penetrate cortical bone, but there is evidence that it is able to detect callus formation before radiographic changes are visible.13–1613–1613–1613–16
Mechanical testing measures fracture stiffness and stability.17,1817,18 With the increased use of internal fixation for fracture treatment, methods such as in vivo biomechanical testing and vibrational analysis cannot be used. However, information obtained from CT images or other modalities may allow for virtual stress testing, whereby a simulation using multiple loading conditions is developed after subtracting the mechanical contribution of fixation, which enables prediction of outcomes, such as axial compression, bending, and the area of tissue failure.19
Given what we know about the early local and systemic molecular changes after a fracture, serologic biomarkers are gaining popularity as possible early predictors of fracture healing.20–2420–2420–2420–2420–24 Current biomarkers under investigation assess either: (1) local or systemic factors regulating the healing process (transforming growth factor-beta1, vascular endothelial growth factor); or (2) extracellular matrix components that are produced or degraded during stages of repair (PIIINP, CTX). Further investigation is required to validate thresholds that are predictive of fracture repair failure.
Despite the many advancements in fracture assessment technologies reviewed above, physical examination remains one of the mainstays of determining fracture union in the clinical setting. In a recent international survey of 335 orthopaedic surgeons, 88% of participants agreed that radiographic and clinical data are required for adequate definition of union; the ability to bear weight being the most common criteria.25 Because patients are likely to regard the process of healing very differently from physicians, it is critical to use tools that evaluate patient-reported outcomes. The currently available patient-reported functional outcome assessment tools measure either general physical and psychological health, as in the Short Form-36, or are disease-specific, as in the disability of the arm, shoulder, and hand or Western Ontario McMaster Arthritis Index. In the future, computer-assisted tests that implement item response theory are likely to streamline the process of gathering patient-reported outcomes, as evidenced by the National Institutes of Health PROMISE initiative.26
Fracture healing is a complex process that requires an effective combination of clinical information and self-reported outcomes with imaging and, potentially, serologic biomarkers for accurate measurement.
WHAT IS THE ROLE FOR FUNCTIONAL OUTCOMES?
Clinical trials have often tried to mirror orthopaedic practice by defining fracture healing using a combination of radiographic and clinical parameters.27 Despite the apparent real-world generalizability of such an approach, clinical trials struggle with the added responsibility of trying to minimize bias within their study design and outcome adjudication. As a result, recent trials have used independent adjudication committees to determine radiographic union but still typically require a clinical assessment from the patient's treatment team.19
Functional outcome instruments offer a supplemental method for assessing fracture repair directly from the patient's perspective. This approach has potential advantages over clinician assessments as it minimizes investigator bias and measurement variation. Patient-reported outcomes are typically measured using well-developed questionnaires with established psychometric properties. The features of these instruments help to quantify the validity, reliability, and responsiveness to change that one can expect from the results. This establishes the limits of measurement error and thereby identifies true changes in function.
Generic health and disease-specific questionnaires have successfully been used in fracture healing trials. Analysis of the study to prospectively evaluate reamed intramedullary nails in tibial fractures trial data demonstrated that the Short Form-36 physical component summary (SF-36 PCS) and the Short Musculoskeletal Function Assessment Disability Index were able to distinguish between healed and nonhealed tibia fracture patients at 3, 6, and 12 months postinjury.28 Depending on the time from injury, comparisons between patient groups showed that healed patients had mean scores 4–8 points higher with the SF-36 PCS and 7–14 points higher with the Short Musculoskeletal Function Assessment Disability Index. These differences were clinically significant and consistent with the psychometrics of the instruments.
Although the study to prospectively evaluate reamed intramedullary nails in tibial fractures trial demonstrated significant differences between the patient-reported outcome scores of healed and nonhealed tibia fracture patients, using this information in a clinical trial to define fracture healing would require an a priori score threshold. The obvious problem is that a low score would not be specific for nonunion and would therefore need to be combined with radiographic determination as well. For example, a nonunion event could be defined as an SF-36 PCS score less than 45 and evidence of a persistent fracture line on the radiograph. In an attempt to achieve the psychometric benefits of a functional outcome questionnaire and the specificity of a focused clinical assessment for fracture healing, Bhandari et al29 have developed the Functional IndeX for Trauma. This clinician-based tool has explicit criteria and grading to assess lower extremity fracture healing based on weight bearing and pain. To date, a threshold score defining nonunion has not been published; however, the instrument has established its validity and interrater reliability, which is a great advancement over independent clinician assessments that can vary significantly.
In summary, a reliable and valid method to assess fracture healing is essential to minimizing bias in clinical trials and facilitating communication among surgeons. Functional outcomes have several advantages over previous clinical assessments and offer a potential alternative to increase the rigor of defining fracture union.
ARE FRACTURE HEALING TRIALS A THING OF THE PAST: THE CHALLENGE OF FDA
Accelerating fracture repair and achieving higher rates of union are 2 major concerns among orthopaedic surgeons. These clinical outcomes, however, are not commonly differentiated in fracture healing trials. Furthermore, the Food and Drug Administration (FDA) lacks guidelines for successful fracture healing, resulting in low-quality evidence and inconsistencies throughout the literature. To conduct research leading to higher-level evidence, guidelines for fracture healing trials must be established.
Study endpoints must be appropriately selected to allow for high-level evidence to be obtained from clinical trials. Time to union is a commonly reported endpoint; however, a specific time to union is difficult to define, as this measure is limited by the continuous nature of fracture healing, infrequent follow-up intervals, and the associated subjective assessment by surgeons and radiologists. For radiographs of tibial fractures treated with intramedullary nailing, Whelan et al4 reported sufficient agreement among orthopaedic surgeons on various parameters of fracture healing (κ = 0.57–0.75). However, when compared with musculoskeletal radiologists, orthopaedic surgeons reported earlier healing (10%–12% earlier),30,3130,31 and a greater number of patients having achieved union at 12 months (90% vs. 75% with union, as reported by orthopaedic surgeons and musculoskeletal radiologists, respectively).32 Percent united might provide a better measure of fracture repair, as specific time points for assessment can be standardized. Thus for fracture trials, better endpoints and more consistent assessment of radiographs by standard sets of reviewers are required to increase consistency and comparability across studies, and minimize interrater variability.
Although radiographs provide a noninvasive assessment of bone formation, functional strength and stability are the ultimate endpoints for clinical fracture healing. However, despite the critical importance of positive functional outcomes, surrogates for fracture healing, such as radiographs, CT, and ultrasound are often used and reported as primary outcomes in fracture trials. In a study by Hammer et al,33 127 tibia fractures were assessed by 7 radiologists for stability and the stage of radiographic union. Radiologic assessment did not correlate well with the measured stability, as 44% of the mechanically stable fractures were determined to have not achieved union, whereas 55% of the unstable fractures were read as united. More recently, a systematic review and meta-analysis by Busse et al34 identified 13 trials investigating the use of low-intensity pulsed ultrasound for fracture repair. Although pooled study data suggested a moderate improvement in time to radiographic union, only 5 studies directly measured functional outcomes, of which a single study demonstrated improved function. Radiographic imaging is an important clinical tool for evaluating fracture healing progression; however, radiographs alone cannot accurately ascertain functional repair. Because functional recovery is the ultimate goal in fracture healing, a composite measure consisting of comparable radiographic and functional outcomes is fundamental for the success of clinical trials involving bone fractures.
Fracture healing trials are critical to the improvement of patient care, yet they are often limited by insufficient or inappropriate endpoints and outcome measures. Consensus among orthopaedic surgeons and the FDA is lacking, and guidelines for fracture healing and trial design are limited. To increase the quality and consistency of fracture healing trials, with the ultimate goal of successfully enhancing orthopaedic practice, surgeon investigators along with the FDA must establish and implement consistent metrics for fracture healing.
There is currently no singular method to reliably determine fracture healing. A number of scoring systems for radiographic assessment have been developed to aid in the consistent assessment of union. However, to ensure fracture healing from the perspective of both the clinician and the patient, radiographic assessment must be combined with functional outcomes measured using well-developed questionnaires. This combined approach must furthermore be applied to the development of fracture healing trials, for which establishment of clear study endpoints is critical to the design of high-quality, reliable trials.
1. Corrales LA, Morshed S, Bhandari M, et al.. Variability in the assessment of fracture-healing in orthopaedic trauma studies. J Bone Joint Surg. 2008;90:1862–1868.
2. Mirić D, Vučković Č, Đorđević Z. Radiographic signs of scaphoid union after bone grafting: the analysis of inter-observer agreement and intra-observer reproducibility. Srp Arh Celok Lek. 2005;133:142–145.
3. Bhattacharyya T, Bouchard KA, Phadke A, et al.. The accuracy of computed tomography for the diagnosis of tibial nonunion
. J Bone Joint Surg. 2006;88:692–697.
4. Whelan D, Bhandari M, McKee M, et al.. Interobserver and intraobserver variation in the assessment of the healing of tibial fractures after intramedullary fixation. J Bone Joint Surg Br. 2002;84:15–18.
5. Whelan DB, Bhandari M, Stephen D, et al.. Development of the radiographic union score for tibial fractures for the assessment of tibial fracture healing after intramedullary fixation. J Trauma Acute Care Surg. 2010;68:629–632.
6. Bhandari M, Chiavaras MM, Parasu N, et al.. Radiographic union score for hip substantially improves agreement between surgeons and radiologists. BMC Musculoskelet Disord. 2013;14:70.
7. Kooistra BW, Dijkman BG, Busse JW, et al.. The radiographic union scale in tibial fractures: reliability and validity. J Orthop Trauma. 2010;24:S81–S86.
8. Chiavaras MM, Bains S, Choudur H, et al.. The radiographic union score for hip (rush): the use of a checklist to evaluate hip fracture healing improves agreement between radiologists and orthopedic surgeons. Skeletal Radiol. 2013;42:1079–1088.
9. Lack WD, Starman JS, Seymour R, et al.. Any cortical bridging predicts healing of tibial shaft fractures. J Bone Joint Surg Am. 2014;96:1066–1072.
10. Braunstein EM, Goldstein SA, Ku J, et al.. Computed tomography and plain radiography in experimental fracture healing. Skeletal Radiol. 1986;15:27–31.
11. Schnarkowski P, Rédei J, Peterfy CG, et al.. Tibial shaft fractures: assessment of fracture healing with computed tomography. J Comput Assist Tomogr. 1995;19:777–781.
12. Grigoryan M, Lynch JA, Fierlinger AL, et al.. Quantitative and qualitative assessment of closed fracture healing using computed tomography and conventional radiography 1. Acad Radiol. 2003;10:1267–1273.
13. Craig JG, Jacobson JA, Moed BR. Ultrasound of fracture and bone healing. Radiol Clin North Am. 1999;37:737–751.
14. Moed BR, Watson JT, Goldschmidt P, et al.. Ultrasound for the early diagnosis of fracture healing after interlocking nailing of the tibia without reaming. Clin Orthop Relat Res. 1995;310:137–144.
15. Moed BR, Kim EC, van Holsbeeck M, et al.. Ultrasound for the early diagnosis of tibial fracture healing after static interlocked nailing without reaming: histologic correlation using a canine model. J Orthopaedic Trauma. 1998;12:200–205.
16. Moed BR, Subramanian S, van Holsbeeck M, et al.. Ultrasound for the early diagnosis of tibial fracture healing after static interlocked nailing without reaming: clinical results. J Orthop Trauma. 1998;12:206–213.
17. Chehade MJ, Pohl AP, Pearcy MJ, et al.. Clinical implications of stiffness and strength changes in fracture healing. J Bone Joint Surg Br. 1997;79:9–12.
18. Richardson J, Cunningham J, Goodship A, et al.. Measuring stiffness can define healing of tibial fractures. J Bone Joint Surg Br. 1994;76:389–394.
19. FAITH Investigators. Fixation using alternative implants for the treatment of hip fractures (FAITH): design and rationale for a multi-centre randomized trial comparing sliding hip screws and cancellous screws on revision surgery rates and quality of life in the treatment of femoral neck fractures. BMC Musculoskelet Disord. 2014;15:219.
20. Bostrom MP. Expression of bone morphogenetic proteins in fracture healing. Clin Orthop Relat Res. 1998;355:S116–S123.
21. Cox G, Einhorn T, Tzioupis C, et al.. Bone-turnover markers in fracture healing. J Bone Joint Surg Br. 2010;92:329–334.
22. Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. 1998;355:S7–S21.
23. Moghaddam A, Müller U, Roth H, et al.. Tracp 5b and ctx as osteological markers of delayed fracture healing. Injury. 2011;42:758–764.
24. Zimmermann G, Henle P, Küsswetter M, et al.. Tgf-β1 as a marker of delayed fracture healing. Bone. 2005;36:779–785.
25. Bhandari M, Fong K, Sprague S, et al.. Variability in the definition and perceived causes of delayed unions and nonunions. J Bone Joint Surg Am. 2012;94:e109.
26. Promis: Dynamic Tools to Measure Health Outcomes from the Patient Perspective. Available at: http://www.nihpromis.org
. Accessed December 3, 2013.
27. Morshed S, Corrales L, Genant H, et al.. Outcome assessment in clinical trials of fracture-healing. J Bone Joint Surg Am. 2008;90(suppl 1):62–67.
28. Busse JW, Bhandari M, Guyatt GH, et al.. Use of both short musculoskeletal function assessment questionnaire and short form-36 among tibial-fracture patients was redundant. J Clin Epidemiol. 2009;62:1210–1217.
29. Bhandari M, Wasserman SM, Yurgin N, et al.. Development and preliminary validation of a function index for trauma (fix-it). Can J Surg. 2013;56:E114.
30. Emami A, Larsson A, Petrén-Mallmin M, et al.. Serum bone markers after intramedullary fixed tibial fractures. Clin Orthop Relat Res. 1999;368:220–229.
31. Kristiansen TK, Ryaby JP, McCabe J, et al.. Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study*. J Bone Joint Surg Am. 1997;79:961–973.
32. Jones AL, Bucholz RW, Bosse MJ, et al.. Recombinant human bmp-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. J Bone Joint Surg Am. 2006;88:1431–1441.
33. Hammer RR, Hammerby S, Lindholm B. Accuracy of radiologic assessment of tibial shaft fracture union
in humans. Clin Orthop Relat Res. 1985;199:233–238.
34. Busse JW, Kaur J, Mollon B, et al.. Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials. BMJ. 2009;338:b351.