Injury, Int. J. Care Injured 45S (2014) S44–S48
Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Patient-important outcome for the assessment of fracture repair A. Hoang-Kim a,*, T. Miclau b, J. Goldhahn c, T.H. Nijman d, R.W. Poolman d a
St. Michael’s Hospital, Department of Surgery, University of Toronto, Institute of Medical Sciences, Toronto, ON, Canada Department of Orthopaedic Surgery, University of California, San Francisco, UCSF/SFGH Orthopaedic Trauma Institute, 2550 23rd Street, Bldg. 9, 2nd Floor, San Francisco, CA 94110, United States c Institute for Biomechanics of ETH Zurich, Switzerland d Onze Lieve Vrouwe Gasthuis, Joint Research, Department of Orthopaedic Surgery, Amsterdam, The Netherlands b
A R T I C L E I N F O
A B S T R A C T
Keywords: Fracture healing Outcome assessment (health care) Patient World health Safety Outcome and process assessment
Current evidence indicates that fracture healing assessment is limited to the use of one or two domains (such as pain, range of motion or mobility) in any single study. Functional outcome measures, which include physician-rated or observer-based impairment ratings and patient self-reported or observerbased activity limitation measures, better position the effectiveness of a given intervention towards patient-important outcomes. Health status measures, for example, cover a wide-range of physical, emotional, and social health dimensions. In this paper, we will examine the utility of metrics to assess fracture healing that are important to both the patient and provider, with selected examples from the recent literature. We recommend outcome measures with established and verified reliability and validity. Policy-makers and other stakeholders need to have an accurate assessment of treatment outcome that includes changes in function over time–adequate measures, should be re-applied at periodic intervals. ß 2014 Elsevier Ltd. All rights reserved.
Introduction Trauma is a major cause of disability worldwide, with skeletal injuries contributing to escalating treatment costs and loss of work [1]. The accurate assessment of fracture healing is fundamental to both clinical decision-making and fracture research. Despite advances in fracture care, however, the determination of bone union remains imprecise and the effectiveness of therapies is based on largely non-validated or unreliable measures [2]. Further, the clinical determination of delayed or non-union is widely variable, complicating clinical decision-making and research study design for the treatment of fractures with impaired healing [3]. The built-in capacity to repair bone fractures is a unique feature of vertebrates. It is a highly complex regeneration process that mimics stages of tissue differentiation during embryological development [4]. Bone has the capacity for full repair without any residual structural or functional deficit. Currently, the majority of fractures heal with appropriate clinical managmenet. However, there are fracture types, specific anatomical locations and combinations of risk
* Corresponding author at: St. Michael’s Hospital, 30 Bond Street (193-6T Yonge Street), M5B 1W8, Toronto, ON, United States. E-mail address: [email protected] (A. Hoang-Kim). http://dx.doi.org/10.1016/j.injury.2014.04.008 0020–1383/ß 2014 Elsevier Ltd. All rights reserved.
factors that increase the risk for delayed or failed healing. Examples include mechanical fixation failures due to poor bone quality, delayed bone healing due compromised blood supply or patient – specific factors like diabetes or smoking. Impaired healing leads to the potential need for salvage procedures, prolonged rehabilitation, and delayed return to function and to work. The socioeconomic impact of impaired healing justifies approaches to improve fracture repair. In principle, two different objectives can be targeted: (1) acceleration of fracture healing with subsequent earlier return to function and/or (2) reduction of healing complications. The first objective corresponds to efficacy the second one represents safety in clinical studies. In the following paper, we will review conceptual models used to define measurement need in fracture healing trials, the assessment of fracture repair (i.e. impairment and functional outcomes), and the safety and efficacy of choosing appropriate endpoints.
Comparison of two commonly-used conceptual models In medicine there are many measurements for diagnosis, prognosis and evaluation of medical interventions. Before choosing and using any of these measurements it is critical to understand
A. Hoang-Kim et al. / Injury, Int. J. Care Injured 45S (2014) S44–S48
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Fig. 1. An example of the Wilson and Cleary Model: relations between measures of patient outcome in hip fracture.*HRQOL: Health Related Quality of Live.
and explicitly define what you want to measure. In the following section we will discuss two commonly used conceptual models to determine the content of the measurement (the ‘what’). In short, a conceptual model is a schematic representation of a theory that acts as a heuristic device to provide a better understanding of a phenomenon (e.g. Health Related Quality Of Life (HRQOL)) by depicting interrelationships among concepts [5]. These conceptual models can, for example be helpful in structuring and developing a concrete research proposal or question. The term conceptual model has been used interchangeably with ‘‘conceptual framework, theoretical model, or theoretically based conceptual model [6]. There are many conceptual models applied and available across different health and illness conditions, and lifespans, and among individuals, their families, and communities [7]. The two conceptual models measuring HRQOL that will be discussed here are the Wilson and Cleary model [8] and the International Classification of Functioning, Disability and Health (ICF) model [9]. These models are most commonly used and are often considered to have more advantages than other models [3].
The International Classification of Functioning, Disability and Health (ICF) model The International Classification of Functioning, Disability and Health (ICF) model is a classification of the health components of functioning and disability. The ICF model is divided into four domains: (1) body functions, (2) body structure, (3) activities (related to tasks and actions by an individual) and participation (involvement in a life situation) and (4) additional information and environmental factors. Subsequently, every domain is divided into sub domains (Fig. 2), (http://www.who.int/classifications/icf/en/) [10]. When comparing the Wilson and Cleary model to the World Health Organization’s ICF model, there are some notable differences. Although the ICF model has been considered a model of HRQOL, it is more of a mapping and classification framework than a guide for hypothesis generation in the area of HRQOL. Use of the Wilson and Cleary model will provide more opportunities for testing and refinement of the model and more evidence about which relationships among HRQOL concepts are common to different populations [8].
The Wilson and Cleary model The Wilson and Cleary model proposes a taxonomy or classification scheme for different measures of health outcome (Fig. 1). The model suggest different levels of clinical and health measurements. These levels include biological and physiological factors, symptoms, functions, general health perceptions, and overall quality of life. As one moves from left to right in the model, one shifts outward from the cell to the individual to the interaction of the individual as a member of society.
Fig. 2. An example of a stepwise scheme as part of the International Classification of Functioning, Disability and Health, known more commonly as ICF.
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Example of using the Wilson and Cleary model To illustrate the use of conceptual models in more detail, we will use ‘‘hip fracture’’ as an example and the Wilson and Cleary model for demonstration. On the left side of the model (Fig. 1) the biological & physiological variables are depicted. Disturbances in this area can lead to changes in symptom and functional status. In patients with hip fracture, the disruption of cortical alignment of the femoral bone (biological & physiological variables) leads to pain and inability to use the affected leg (symptoms and signs). These symptoms and signs in turn affect the patients ‘functioning’. The World Health Organization (WHO) defines functioning as all aspects of physical, psychological and social functioning. In the case of hip fracture, walking will be impaired, social day trips with friends might be hard to arrange and patients may feel down because of their immobility. The way patients deal with these symptoms and functional limitations depend on the characteristics of the individual (e.g. is the patient a real ‘‘go-getter’’ in his coping style) and on the characteristics of the environment (e.g. how well is the development for less mobile people in a country). In the second to last box, general health perceptions, all previous aspects mentioned are integrated into HRQOL. Each patient will individually consider all these facets to form an idea about his/her HRQOL. Finally, the last box also takes non-medical factors into account, like the financial situation of the patient or the country of residence. Measurement instrument selection and examples When looking at the Wilson and Cleary figure, different kinds of measurements can be performed to acquire information for a certain aspect of the model (Fig. 1). For example, signs could probably be best diagnosed by clinician (e.g. inability to flex the hip in a patient with a hip fracture or assessing a hip X-ray), while symptoms like pain can only be reported by patients themselves. Physical functioning can be assessed by the clinician (e.g. walking test) or the patient (questionnaire about walking stairs). If information is obtained directly from the patient, we are talking about patient reported outcomes (PROMs). In the Wilson and Cleary model, in general, the further we go to the right the more we depend on PROMs because these factors (e.g. symptoms, perceived health, HRQOL) address the patient’s opinion and assessment of his/her current health status. Furthermore, on the left side of the model there are many possible one-dimensional measurements possible like haemoglobin level, heart rate etc. Going to the right of the model, there are more complex characteristics which cover different physical, social and psychological aspects. These are called multidimensional constructs [11]. Often, these constructs cannot be measured in a direct way (like counting white blood cells). For example, symptoms like pain, fatigue, mental functioning, and HRQOL are constructs that cannot be observed or measured directly. This is where PROMs come into play. PROMs are often multi-item instruments that try to measure these constructs in an indirect way. Using different items that are measurable and related to the construct provides for this. For example, the construct self esteem can be measured by assessing the items: self confidence, self worth, self disclosure and openness. In the case of hip fracture, a commonly used patient reported outcome measure [12–16] is the Low Extremity Measure [17]. This multi-item instrument was developed to assess the construct ‘physical functioning’ after hip fracture. It consists of 29 questions related to this specific construct: (1) Putting on a pair of pants is. . ., (2) Rising from a chair is. . .. Another well know generic HRQOL instrument is the Short Form 36 (SF-36). This questionnaire is a good example of a questionnaire that consists of multiple constructs. The SF-36 is a multi-purpose, short-form health survey
with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preferencebased health utility index [18]. The assessment of fracture repair Fracture healing is a dynamic process and dichotomizing this continuous event is not possible without introducing bias or losing data. However, clinical decision-making requires a recognizable endpoint, and research outcomes must be quantifiable. Plain radiography is the most common way of assessing fracture union, although more advanced options are available, including computerized tomography, quantitative computerized tomography, bone densitometry, bone scintigraphy, and ultrasound. Other common outcome measures include weight-bearing and palpation [19], manual assessment [20], and HRQOLs [2]. There is little information on the reliability of the various measures to determine fracture healing, and most studies do not address the reliability of the methods employed. There is a need for standard guidelines to accurately and reliably measure outcomes to improve patient care and clinical research design. Corrales et al. conducted a systematic review of outcome measures used in recently published long-bone fracture healing studies [2]. Specifically, they sought to establish the current definitions used for long bone union and the quantitative or qualitative reliability reporting in the orthopaedic trauma literature. They conducted a search of MEDLINE and computerized databases for the Journals of Bone and Joint Surgery (American and British) and the Journal of Orthopaedic Trauma between 1996 and 2006. The authors searched for therapeutic clinical studies of the appendicular skeleton in adults, and identified 123 studies for review. In this study [2], the authors found that union was defined using a combination of radiographic and clinical criteria in 62%, radiographic criteria only in 37%, and clinical criteria only in 1% of the articles. Eleven different radiographic measures were used to define fracture union, with the three most common being: bridging of fracture by callus, bone, or trabeculae (80%); obliteration of the fracture line or establishment of cortical continuity (18%); and bridging of the fracture at two cortices (6%). A quantitative measure of the reliability was noted in two studies. Twelve different clinical measures were used to determine healing, with the three most common being: absence of pain or tenderness with weight bearing (49%); absence of pain or tenderness on palpation or examination (39%); and ability to weight bear (18%). Therefore, the authors concluded that there is a lack of consensus in the definition of bone union. Functional assessment of fracture healing The choice of any one instrument will give you a partial view of the impact of a disease on a person. Several authors have reviewed the literature for fracture treatment in subspecialty fields including the wrist, hip and shoulder noting the importance of assessing functional outcomes with instruments of good psychometric [21–23]. For example, Goldhahn et al. reviewed the current use of measures and appropriate theoretical frameworks for health and disability to inform a consensus process that was focused on deriving the minimal set of core domains in distal radius [21]. International stakeholders, including patients, clinicians, physiotherapists, methodologists, researchers and industry, participated in two rounds of defining domains using the nominal group technique. Interestingly, the domains deemed relevant to clinical practice and research were a mirror-image of what had been found
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in the systematic review of frequently-used outcome instruments for interventions of the distal radius [21]. The group felt that pain and function were important domains and patient-important, while evidence from the literature indicated a prevalence of impairment-based assessments (i.e. radiological endpoints that tend to be physician-important). It was recommended that functional status of the injured wrist or upper extremity should be quantified with either the Quick disability of the arm, shoulder and hand questionnaire (QuickDASH), or the function subscale of the patient-reported wrist evaluation (PRWE). The QuickDASH is an 11-item scale made up of three items covering symptoms, and eight covering daily activities and roles (work, leisure, and social). The score is calculated out of 100. The PRWE is a15-item scale with 5 items on symptoms and 10 on function and roles. A direct comparison of the scales shows a strong degree of overlap in the content. Both scales are included in extensive reviews of their psychometric properties [24,25]. Core domains are minimal, but not exclusive, domains of outcomes agreed upon by professional groups as important to include in studies. The working group identified a return to participation in normal life roles an important outcome in assessing distal radius [21]. According to McDowell and Newell, the measurement of a concept like health or functional recovery relies on collating information from various indicators representing components of an overall concept [26]. A domain, in essence, is defined by the area of experience or behaviour one is trying to measure [27]. From a theoretical standpoint, ‘‘a person does not have a disability, a person experiences it’’ [28]. The high degree of variability is attributed to the perception that biology provides the foundation for impairment that subsequently causes the disability [29].
Efficacy and safety in fracture healing studies Efficacy Although the process of fracture healing always follows similar patterns, timing varies significantly. When a fracture has fully healed, including complete structural repair, full function and subsequent activities of daily living depend on a number of confounding factors. Complex fracture types, severe soft tissue, damaged blood supply or metabolic abnormalities represent risk factors for a prolonged course of fracture healing. In contrast, several drug candidates have shown potentially in preclinical studies to shorten the time to healing, (e.g. parathyroid hormone, antisclerostin or strontium ranelate) [30,31]. For proof of concept (phase IIa) or confirmation (phase III), efficacy has to be demonstrated in all domains of the ICF concept of health [9]. Whereas restoration of bone integrity corresponds to body structure and function, functional performance and activity scores cover activity limitation. Return to work and aspects of social activity represent aspects of participation restriction. In the past, radiological parameters of fracture healing, such as cortical bridging were mainly used to quantify differences in recovery in orthopaedic studies. In more recent work, differences in radiological healing must be complemented in by relevant functional improvement, such asm earlier functional recovery. In the absence of this evidence, patient benefit cannot be demonstrated and the study results will not convince health authorities and potential payers. Therefore, each comparative study about fracture healing should include a measure addressing restoration of bone integrity (most likely X-ray or computer tomography), function and activities of daily living (physical performance testing and/or patient reported outcome) and participation such as return to work (EQ-5D or SF-36). In the best case scenario, a clinical intervention
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can demonstrate earlier fracture bridging faster recovery and increased participation. In order to accomplish this, a number of challenges have to be considered and approached during trial planning. If differences in fracture healing are the target of a study, then repeated radiographic evaluations are necessary. Whereas the number of data points is limited by patient burden and cumulative radiation, an evaluation is complicated by fewer observations and low interrater reliability [32]. Predefined time points and evaluation criteria help to minimize variability [33]. Radiographic evaluations should be performed by an independent board following a standardized review protocol [34]. In contrast, PROMs can be collected more often. Here, the choice of the appropriate measure is critical. Instruments should be chosen that fulfil all criteria of outcomes research [22]. They should be validated for the fracture type under investigation, should reflect patient need and demonstrate sufficient psychometric properties, (e.g. high responsiveness, reliability, and content validity). The use of multiple PROMs is limited by burden for the patient and compliance. An appropriate infrastructure has to be established to process the large amount of data as a consequence of frequent patient self-assessment. Safety Complications in orthopaedic trials are an essential source of information. They may result in discontinuing unsuccessful treatment strategies, helping to identify potential for development, and forming the basis for shared decision-making with patients. In addition, they help to identify risk factors for treatment failure, and play a role in the quality control process to improve treatments, and must be reported according to the guidelines of Good Clinical Practice when performing clinical investigations [35]. The following approach has been proposed by Goldhahn et al. [31]: 1. Verification of Source data during monitoring visits. 2. Implementation of systematic assessment of any complication at each examination visit (e.g. using standard case report forms or asking whether another physician was visited other than for routine assessment). 3. Creation of a simple recording process and ensure anonymous reporting of complication statistics outside the involved clinics so that results cannot be traced back to the individual treating surgeon. 4. Exploration of additional information on putative events from the patient’s family doctor, if necessary. 5. Evaluation of reported complications by the study’s principal investigator, an independent experienced clinician, or any specifically established complication review board.
Risks for clinically relevant complications should be presented on the basis of the number of patients experiencing these complications (not the total number of documented complications) and for clearly defined follow-up periods [36]. Summary Future efforts will need to address how to standardize measures of fracture repair. These measures will likely use clinical findings, radiographic studies, and validated outcomes measures. The new methods must be quantifiable and reliable, providing for clinical recognizable and relevant outcomes measures. Care will also need to be taken to improve study designs, including the minimization of bias and loss of information. Technological advancements in imaging and molecular biology may enable more accurate
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measurements of union and the ability to follow the healing process in a patient longitudinally. Until better assessment techniques become available, clinicians and researchers should maintain awareness of the limitations of the current methods. Conceptual models are useful tools to help determine relevant aspects of disease. The models divide health in different aspects ranging from the cellular level to the functioning of a patient in his/ her environment. Once we have decided which aspect/construct we want to assess, we have to take a closer look at the construct. Some construct can be measured in a direct way, while other constructs are less easily measured and require multi-item questionnaires. Future considerations The selection of appropriate cohorts to study intervention is key for study success, with careful selection of inclusion and exclusion criteria. A number of variables are known to influence fracture healing [33]. These variables must be recorded to assess baseline characteristics and to provide possible explanations for unexpected treatment effects by randomization. Specifically, the following factors should be considered: specific fracture and injury characteristics method of fracture fixation; detailed soft tissue conditions; patient characteristics (e.g. age, sex, smoking status, co-morbidities, surgical intervention, pain treatment, including NSAID use, rehabilitation, and concomitant medications, including use of other bone active drugs), and the responsible surgeon’s experience [37–41]. Role of funding source A. Hoang-Kim, T. Miclau, J. Goldhahn, R. Poolman and T. Nijman have had no involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. Conflict of interest J. Goldhahn is employee of the Novartis Institutes for Biomedical Research Basel, Switzerland. References [1] Finkelstein EA, Corso PS, Miller T. The incidence and economic burden of injuries in the United States. New York: Oxford Press; 2006. [2] Corrales LA, Morshed S, Bhandari M, Miclau T. Variability in the assessment of fracture healing in orthopaedic trauma studies. J Bone Joint Surg Am 2008;90:1862–8. [3] Kooistra BK, Sprague S, Bhandari M, Schemitsch EH. Outcomes assessment in fracture healing trials: a primer. J Orthop Trauma 2010;24(3):S71–5. [4] Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 2003;88(April (5)):873–84. [5] Walker LOAK. Strategies for theory construction in nursing. 4th ed. New York: Prentice Hall; 2005. [6] Vallerand AH, Payne JK. Theories and conceptual models to guide quality of life related research, quality of life: from nursing and patient perspectives. 2nd ed. USA: Jones & Bartlett Publishers; 2003. p. 45–54. [7] Bakas T, McLennon SM, Carpenter JS, Buelow JM, Otte JL, Hanna KM, et al. Systematic review of health-related quality of life models. Health Qual Life Outcomes 2012;10:134. [8] Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA 1995;273(January (1)): 59–65. [9] International classification of functioning, disability and health (ICF). Geneva, Switzerland: World Health Organization; 2001. p. 10–20. [10] World Health Organization (WHO). International Classification of Functioning, Disability and Health (ICF). 2014. http://www.who.int/classifications/icf/en/ [accessed 17.04.14].
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Recommendation for measuring clinical outcome in distal radius fractures: a core set of domains for standardized reporting in clinical practice and research. Arch Orthop Trauma Surg 2014;134:197–205. [22] Hoang-Kim A, Beaton D, Bhandari M, Kulkarni AV, Schemitsch E. The need to standardize functional outcome in randomized trials of hip fracture: a review using the ICF framework. J Orthop Trauma 2013;27(January (1)):e1–8. [23] Swiontkowski MF. Outcomes measurement in orthopaedic trauma surgery. Injury 1995;26(10):653–7. [24] Beaton DE, Wright JG, Katz JN. Development of the QuickDASH: comparison of three-item reduction approaches. J Bone Joint Surg Am 2005;87:1038–46. Institute for Work and Health. The DASH outcome measure. www.dash.iwh.on.ca [accessed 12.04.12]. [25] Kennedy CA, Beaton DE, Solway S, McConnell S, Bombardier C. The DASH and QuickDASH outcome measures user’s manual. 3rd ed. Toronto: Institute for Work and Health; 2011. [26] McDowell I, Measuring Health:. 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GREES (group for respect of ethics and excellence in science) working group on bone fracture-healing, critical issues in translational and clinical research for the study of new technologies to enhance bone repair. J Bone Joint Surg Am 2008;90(February (1)):43–7. [33] Shisha T. Parameters for defining efficacy in fracture healing. Clin Cases Miner Bone Metab 2010;7(January (1)):15–6. [34] Goldhahn J, Scheele WH, Mitlak BH, Abadie E, Aspenberg P, Augat P, et al. Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis. Bone 2008;43(August (2)):343–7. [35] International Organization for Standardization ISO_14155. Clinical investigation of medical devices for human subjects. Good clinical practice. Geneva, Switzerland: International Standard Organization; 2011. [36] Audige´ L, Goldhahn S, Daigl M, Goldhahn J, Blauth M, Hanson B. How to document and report orthopedic complications in clinical studies? A proposal for standardization. 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Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Patient-important outcome for the assessment of fracture repair A. Hoang-Kim a,*, T. Miclau b, J. Goldhahn c, T.H. Nijman d, R.W. Poolman d a
St. Michael’s Hospital, Department of Surgery, University of Toronto, Institute of Medical Sciences, Toronto, ON, Canada Department of Orthopaedic Surgery, University of California, San Francisco, UCSF/SFGH Orthopaedic Trauma Institute, 2550 23rd Street, Bldg. 9, 2nd Floor, San Francisco, CA 94110, United States c Institute for Biomechanics of ETH Zurich, Switzerland d Onze Lieve Vrouwe Gasthuis, Joint Research, Department of Orthopaedic Surgery, Amsterdam, The Netherlands b
A R T I C L E I N F O
A B S T R A C T
Keywords: Fracture healing Outcome assessment (health care) Patient World health Safety Outcome and process assessment
Current evidence indicates that fracture healing assessment is limited to the use of one or two domains (such as pain, range of motion or mobility) in any single study. Functional outcome measures, which include physician-rated or observer-based impairment ratings and patient self-reported or observerbased activity limitation measures, better position the effectiveness of a given intervention towards patient-important outcomes. Health status measures, for example, cover a wide-range of physical, emotional, and social health dimensions. In this paper, we will examine the utility of metrics to assess fracture healing that are important to both the patient and provider, with selected examples from the recent literature. We recommend outcome measures with established and verified reliability and validity. Policy-makers and other stakeholders need to have an accurate assessment of treatment outcome that includes changes in function over time–adequate measures, should be re-applied at periodic intervals. ß 2014 Elsevier Ltd. All rights reserved.
Introduction Trauma is a major cause of disability worldwide, with skeletal injuries contributing to escalating treatment costs and loss of work [1]. The accurate assessment of fracture healing is fundamental to both clinical decision-making and fracture research. Despite advances in fracture care, however, the determination of bone union remains imprecise and the effectiveness of therapies is based on largely non-validated or unreliable measures [2]. Further, the clinical determination of delayed or non-union is widely variable, complicating clinical decision-making and research study design for the treatment of fractures with impaired healing [3]. The built-in capacity to repair bone fractures is a unique feature of vertebrates. It is a highly complex regeneration process that mimics stages of tissue differentiation during embryological development [4]. Bone has the capacity for full repair without any residual structural or functional deficit. Currently, the majority of fractures heal with appropriate clinical managmenet. However, there are fracture types, specific anatomical locations and combinations of risk
* Corresponding author at: St. Michael’s Hospital, 30 Bond Street (193-6T Yonge Street), M5B 1W8, Toronto, ON, United States. E-mail address: [email protected] (A. Hoang-Kim). http://dx.doi.org/10.1016/j.injury.2014.04.008 0020–1383/ß 2014 Elsevier Ltd. All rights reserved.
factors that increase the risk for delayed or failed healing. Examples include mechanical fixation failures due to poor bone quality, delayed bone healing due compromised blood supply or patient – specific factors like diabetes or smoking. Impaired healing leads to the potential need for salvage procedures, prolonged rehabilitation, and delayed return to function and to work. The socioeconomic impact of impaired healing justifies approaches to improve fracture repair. In principle, two different objectives can be targeted: (1) acceleration of fracture healing with subsequent earlier return to function and/or (2) reduction of healing complications. The first objective corresponds to efficacy the second one represents safety in clinical studies. In the following paper, we will review conceptual models used to define measurement need in fracture healing trials, the assessment of fracture repair (i.e. impairment and functional outcomes), and the safety and efficacy of choosing appropriate endpoints.
Comparison of two commonly-used conceptual models In medicine there are many measurements for diagnosis, prognosis and evaluation of medical interventions. Before choosing and using any of these measurements it is critical to understand
A. Hoang-Kim et al. / Injury, Int. J. Care Injured 45S (2014) S44–S48
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Fig. 1. An example of the Wilson and Cleary Model: relations between measures of patient outcome in hip fracture.*HRQOL: Health Related Quality of Live.
and explicitly define what you want to measure. In the following section we will discuss two commonly used conceptual models to determine the content of the measurement (the ‘what’). In short, a conceptual model is a schematic representation of a theory that acts as a heuristic device to provide a better understanding of a phenomenon (e.g. Health Related Quality Of Life (HRQOL)) by depicting interrelationships among concepts [5]. These conceptual models can, for example be helpful in structuring and developing a concrete research proposal or question. The term conceptual model has been used interchangeably with ‘‘conceptual framework, theoretical model, or theoretically based conceptual model [6]. There are many conceptual models applied and available across different health and illness conditions, and lifespans, and among individuals, their families, and communities [7]. The two conceptual models measuring HRQOL that will be discussed here are the Wilson and Cleary model [8] and the International Classification of Functioning, Disability and Health (ICF) model [9]. These models are most commonly used and are often considered to have more advantages than other models [3].
The International Classification of Functioning, Disability and Health (ICF) model The International Classification of Functioning, Disability and Health (ICF) model is a classification of the health components of functioning and disability. The ICF model is divided into four domains: (1) body functions, (2) body structure, (3) activities (related to tasks and actions by an individual) and participation (involvement in a life situation) and (4) additional information and environmental factors. Subsequently, every domain is divided into sub domains (Fig. 2), (http://www.who.int/classifications/icf/en/) [10]. When comparing the Wilson and Cleary model to the World Health Organization’s ICF model, there are some notable differences. Although the ICF model has been considered a model of HRQOL, it is more of a mapping and classification framework than a guide for hypothesis generation in the area of HRQOL. Use of the Wilson and Cleary model will provide more opportunities for testing and refinement of the model and more evidence about which relationships among HRQOL concepts are common to different populations [8].
The Wilson and Cleary model The Wilson and Cleary model proposes a taxonomy or classification scheme for different measures of health outcome (Fig. 1). The model suggest different levels of clinical and health measurements. These levels include biological and physiological factors, symptoms, functions, general health perceptions, and overall quality of life. As one moves from left to right in the model, one shifts outward from the cell to the individual to the interaction of the individual as a member of society.
Fig. 2. An example of a stepwise scheme as part of the International Classification of Functioning, Disability and Health, known more commonly as ICF.
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Example of using the Wilson and Cleary model To illustrate the use of conceptual models in more detail, we will use ‘‘hip fracture’’ as an example and the Wilson and Cleary model for demonstration. On the left side of the model (Fig. 1) the biological & physiological variables are depicted. Disturbances in this area can lead to changes in symptom and functional status. In patients with hip fracture, the disruption of cortical alignment of the femoral bone (biological & physiological variables) leads to pain and inability to use the affected leg (symptoms and signs). These symptoms and signs in turn affect the patients ‘functioning’. The World Health Organization (WHO) defines functioning as all aspects of physical, psychological and social functioning. In the case of hip fracture, walking will be impaired, social day trips with friends might be hard to arrange and patients may feel down because of their immobility. The way patients deal with these symptoms and functional limitations depend on the characteristics of the individual (e.g. is the patient a real ‘‘go-getter’’ in his coping style) and on the characteristics of the environment (e.g. how well is the development for less mobile people in a country). In the second to last box, general health perceptions, all previous aspects mentioned are integrated into HRQOL. Each patient will individually consider all these facets to form an idea about his/her HRQOL. Finally, the last box also takes non-medical factors into account, like the financial situation of the patient or the country of residence. Measurement instrument selection and examples When looking at the Wilson and Cleary figure, different kinds of measurements can be performed to acquire information for a certain aspect of the model (Fig. 1). For example, signs could probably be best diagnosed by clinician (e.g. inability to flex the hip in a patient with a hip fracture or assessing a hip X-ray), while symptoms like pain can only be reported by patients themselves. Physical functioning can be assessed by the clinician (e.g. walking test) or the patient (questionnaire about walking stairs). If information is obtained directly from the patient, we are talking about patient reported outcomes (PROMs). In the Wilson and Cleary model, in general, the further we go to the right the more we depend on PROMs because these factors (e.g. symptoms, perceived health, HRQOL) address the patient’s opinion and assessment of his/her current health status. Furthermore, on the left side of the model there are many possible one-dimensional measurements possible like haemoglobin level, heart rate etc. Going to the right of the model, there are more complex characteristics which cover different physical, social and psychological aspects. These are called multidimensional constructs [11]. Often, these constructs cannot be measured in a direct way (like counting white blood cells). For example, symptoms like pain, fatigue, mental functioning, and HRQOL are constructs that cannot be observed or measured directly. This is where PROMs come into play. PROMs are often multi-item instruments that try to measure these constructs in an indirect way. Using different items that are measurable and related to the construct provides for this. For example, the construct self esteem can be measured by assessing the items: self confidence, self worth, self disclosure and openness. In the case of hip fracture, a commonly used patient reported outcome measure [12–16] is the Low Extremity Measure [17]. This multi-item instrument was developed to assess the construct ‘physical functioning’ after hip fracture. It consists of 29 questions related to this specific construct: (1) Putting on a pair of pants is. . ., (2) Rising from a chair is. . .. Another well know generic HRQOL instrument is the Short Form 36 (SF-36). This questionnaire is a good example of a questionnaire that consists of multiple constructs. The SF-36 is a multi-purpose, short-form health survey
with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preferencebased health utility index [18]. The assessment of fracture repair Fracture healing is a dynamic process and dichotomizing this continuous event is not possible without introducing bias or losing data. However, clinical decision-making requires a recognizable endpoint, and research outcomes must be quantifiable. Plain radiography is the most common way of assessing fracture union, although more advanced options are available, including computerized tomography, quantitative computerized tomography, bone densitometry, bone scintigraphy, and ultrasound. Other common outcome measures include weight-bearing and palpation [19], manual assessment [20], and HRQOLs [2]. There is little information on the reliability of the various measures to determine fracture healing, and most studies do not address the reliability of the methods employed. There is a need for standard guidelines to accurately and reliably measure outcomes to improve patient care and clinical research design. Corrales et al. conducted a systematic review of outcome measures used in recently published long-bone fracture healing studies [2]. Specifically, they sought to establish the current definitions used for long bone union and the quantitative or qualitative reliability reporting in the orthopaedic trauma literature. They conducted a search of MEDLINE and computerized databases for the Journals of Bone and Joint Surgery (American and British) and the Journal of Orthopaedic Trauma between 1996 and 2006. The authors searched for therapeutic clinical studies of the appendicular skeleton in adults, and identified 123 studies for review. In this study [2], the authors found that union was defined using a combination of radiographic and clinical criteria in 62%, radiographic criteria only in 37%, and clinical criteria only in 1% of the articles. Eleven different radiographic measures were used to define fracture union, with the three most common being: bridging of fracture by callus, bone, or trabeculae (80%); obliteration of the fracture line or establishment of cortical continuity (18%); and bridging of the fracture at two cortices (6%). A quantitative measure of the reliability was noted in two studies. Twelve different clinical measures were used to determine healing, with the three most common being: absence of pain or tenderness with weight bearing (49%); absence of pain or tenderness on palpation or examination (39%); and ability to weight bear (18%). Therefore, the authors concluded that there is a lack of consensus in the definition of bone union. Functional assessment of fracture healing The choice of any one instrument will give you a partial view of the impact of a disease on a person. Several authors have reviewed the literature for fracture treatment in subspecialty fields including the wrist, hip and shoulder noting the importance of assessing functional outcomes with instruments of good psychometric [21–23]. For example, Goldhahn et al. reviewed the current use of measures and appropriate theoretical frameworks for health and disability to inform a consensus process that was focused on deriving the minimal set of core domains in distal radius [21]. International stakeholders, including patients, clinicians, physiotherapists, methodologists, researchers and industry, participated in two rounds of defining domains using the nominal group technique. Interestingly, the domains deemed relevant to clinical practice and research were a mirror-image of what had been found
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in the systematic review of frequently-used outcome instruments for interventions of the distal radius [21]. The group felt that pain and function were important domains and patient-important, while evidence from the literature indicated a prevalence of impairment-based assessments (i.e. radiological endpoints that tend to be physician-important). It was recommended that functional status of the injured wrist or upper extremity should be quantified with either the Quick disability of the arm, shoulder and hand questionnaire (QuickDASH), or the function subscale of the patient-reported wrist evaluation (PRWE). The QuickDASH is an 11-item scale made up of three items covering symptoms, and eight covering daily activities and roles (work, leisure, and social). The score is calculated out of 100. The PRWE is a15-item scale with 5 items on symptoms and 10 on function and roles. A direct comparison of the scales shows a strong degree of overlap in the content. Both scales are included in extensive reviews of their psychometric properties [24,25]. Core domains are minimal, but not exclusive, domains of outcomes agreed upon by professional groups as important to include in studies. The working group identified a return to participation in normal life roles an important outcome in assessing distal radius [21]. According to McDowell and Newell, the measurement of a concept like health or functional recovery relies on collating information from various indicators representing components of an overall concept [26]. A domain, in essence, is defined by the area of experience or behaviour one is trying to measure [27]. From a theoretical standpoint, ‘‘a person does not have a disability, a person experiences it’’ [28]. The high degree of variability is attributed to the perception that biology provides the foundation for impairment that subsequently causes the disability [29].
Efficacy and safety in fracture healing studies Efficacy Although the process of fracture healing always follows similar patterns, timing varies significantly. When a fracture has fully healed, including complete structural repair, full function and subsequent activities of daily living depend on a number of confounding factors. Complex fracture types, severe soft tissue, damaged blood supply or metabolic abnormalities represent risk factors for a prolonged course of fracture healing. In contrast, several drug candidates have shown potentially in preclinical studies to shorten the time to healing, (e.g. parathyroid hormone, antisclerostin or strontium ranelate) [30,31]. For proof of concept (phase IIa) or confirmation (phase III), efficacy has to be demonstrated in all domains of the ICF concept of health [9]. Whereas restoration of bone integrity corresponds to body structure and function, functional performance and activity scores cover activity limitation. Return to work and aspects of social activity represent aspects of participation restriction. In the past, radiological parameters of fracture healing, such as cortical bridging were mainly used to quantify differences in recovery in orthopaedic studies. In more recent work, differences in radiological healing must be complemented in by relevant functional improvement, such asm earlier functional recovery. In the absence of this evidence, patient benefit cannot be demonstrated and the study results will not convince health authorities and potential payers. Therefore, each comparative study about fracture healing should include a measure addressing restoration of bone integrity (most likely X-ray or computer tomography), function and activities of daily living (physical performance testing and/or patient reported outcome) and participation such as return to work (EQ-5D or SF-36). In the best case scenario, a clinical intervention
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can demonstrate earlier fracture bridging faster recovery and increased participation. In order to accomplish this, a number of challenges have to be considered and approached during trial planning. If differences in fracture healing are the target of a study, then repeated radiographic evaluations are necessary. Whereas the number of data points is limited by patient burden and cumulative radiation, an evaluation is complicated by fewer observations and low interrater reliability [32]. Predefined time points and evaluation criteria help to minimize variability [33]. Radiographic evaluations should be performed by an independent board following a standardized review protocol [34]. In contrast, PROMs can be collected more often. Here, the choice of the appropriate measure is critical. Instruments should be chosen that fulfil all criteria of outcomes research [22]. They should be validated for the fracture type under investigation, should reflect patient need and demonstrate sufficient psychometric properties, (e.g. high responsiveness, reliability, and content validity). The use of multiple PROMs is limited by burden for the patient and compliance. An appropriate infrastructure has to be established to process the large amount of data as a consequence of frequent patient self-assessment. Safety Complications in orthopaedic trials are an essential source of information. They may result in discontinuing unsuccessful treatment strategies, helping to identify potential for development, and forming the basis for shared decision-making with patients. In addition, they help to identify risk factors for treatment failure, and play a role in the quality control process to improve treatments, and must be reported according to the guidelines of Good Clinical Practice when performing clinical investigations [35]. The following approach has been proposed by Goldhahn et al. [31]: 1. Verification of Source data during monitoring visits. 2. Implementation of systematic assessment of any complication at each examination visit (e.g. using standard case report forms or asking whether another physician was visited other than for routine assessment). 3. Creation of a simple recording process and ensure anonymous reporting of complication statistics outside the involved clinics so that results cannot be traced back to the individual treating surgeon. 4. Exploration of additional information on putative events from the patient’s family doctor, if necessary. 5. Evaluation of reported complications by the study’s principal investigator, an independent experienced clinician, or any specifically established complication review board.
Risks for clinically relevant complications should be presented on the basis of the number of patients experiencing these complications (not the total number of documented complications) and for clearly defined follow-up periods [36]. Summary Future efforts will need to address how to standardize measures of fracture repair. These measures will likely use clinical findings, radiographic studies, and validated outcomes measures. The new methods must be quantifiable and reliable, providing for clinical recognizable and relevant outcomes measures. Care will also need to be taken to improve study designs, including the minimization of bias and loss of information. Technological advancements in imaging and molecular biology may enable more accurate
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measurements of union and the ability to follow the healing process in a patient longitudinally. Until better assessment techniques become available, clinicians and researchers should maintain awareness of the limitations of the current methods. Conceptual models are useful tools to help determine relevant aspects of disease. The models divide health in different aspects ranging from the cellular level to the functioning of a patient in his/ her environment. Once we have decided which aspect/construct we want to assess, we have to take a closer look at the construct. Some construct can be measured in a direct way, while other constructs are less easily measured and require multi-item questionnaires. Future considerations The selection of appropriate cohorts to study intervention is key for study success, with careful selection of inclusion and exclusion criteria. A number of variables are known to influence fracture healing [33]. These variables must be recorded to assess baseline characteristics and to provide possible explanations for unexpected treatment effects by randomization. Specifically, the following factors should be considered: specific fracture and injury characteristics method of fracture fixation; detailed soft tissue conditions; patient characteristics (e.g. age, sex, smoking status, co-morbidities, surgical intervention, pain treatment, including NSAID use, rehabilitation, and concomitant medications, including use of other bone active drugs), and the responsible surgeon’s experience [37–41]. Role of funding source A. Hoang-Kim, T. Miclau, J. Goldhahn, R. Poolman and T. Nijman have had no involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. Conflict of interest J. Goldhahn is employee of the Novartis Institutes for Biomedical Research Basel, Switzerland. References [1] Finkelstein EA, Corso PS, Miller T. The incidence and economic burden of injuries in the United States. New York: Oxford Press; 2006. [2] Corrales LA, Morshed S, Bhandari M, Miclau T. Variability in the assessment of fracture healing in orthopaedic trauma studies. J Bone Joint Surg Am 2008;90:1862–8. [3] Kooistra BK, Sprague S, Bhandari M, Schemitsch EH. Outcomes assessment in fracture healing trials: a primer. J Orthop Trauma 2010;24(3):S71–5. [4] Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 2003;88(April (5)):873–84. [5] Walker LOAK. Strategies for theory construction in nursing. 4th ed. New York: Prentice Hall; 2005. [6] Vallerand AH, Payne JK. Theories and conceptual models to guide quality of life related research, quality of life: from nursing and patient perspectives. 2nd ed. USA: Jones & Bartlett Publishers; 2003. p. 45–54. [7] Bakas T, McLennon SM, Carpenter JS, Buelow JM, Otte JL, Hanna KM, et al. Systematic review of health-related quality of life models. Health Qual Life Outcomes 2012;10:134. [8] Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA 1995;273(January (1)): 59–65. [9] International classification of functioning, disability and health (ICF). Geneva, Switzerland: World Health Organization; 2001. p. 10–20. [10] World Health Organization (WHO). International Classification of Functioning, Disability and Health (ICF). 2014. http://www.who.int/classifications/icf/en/ [accessed 17.04.14].
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