Injury, Int. J. Care Injured 45S (2014) S3–S7
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Injury journal homepage: www.elsevier.com/locate/injury
Delayed union and nonunions: Epidemiology, clinical issues, and financial aspects David J. Hak a,*, Daniel Fitzpatrick b, Julius A. Bishop c, J. Lawrence Marsh d, Susanne Tilp e, Reinhard Schnettler e, Hamish Simpson f, Volker Alt e a
Department of Orthopaedics Denver Health/University of Colorado, 777 Bannock Street, MC 0188, Denver, CO 80204, USA Slocum Center for Orthopedics and Sports Medicine, Eugene, OR, USA Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Pavilion A, Redwood City, CA, USA d Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA e Department of Orthopaedic Trauma Surgery, University Hospital Giessen-Marburg GmbH, Rudolf-Buchheim-Str. 7, 35385 Giessen, Germany f Department of Orthopaedics and Trauma, University of Edinburgh, Edinburgh, UK b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Non-union Aetiology Incidence Cost of treatment
Fracture healing is a critically important clinical event for fracture patients and for clinicians who take care of them. The clinical evaluation of fracture healing is based on both radiographic findings and clinical findings. Risk factors for delayed union and nonunion include patient dependent factors such as advanced age, medical comorbidities, smoking, non-steroidal anti-inflammatory use, various genetic disorders, metabolic disease and nutritional deficiency. Patient independent factors include fracture pattern, location, and displacement, severity of soft tissue injury, degree of bone loss, quality of surgical treatment and presence of infection. Established nonunions can be characterised in terms of biologic capacity, deformity, presence or absence of infection, and host status. Hypertrophic, oligotrophic and atrophic radiographic appearances allow the clinician to make inferences about the degree of fracture stability and the biologic viability of the fracture fragments while developing a treatment plan. Nonunions are difficult to treat and have a high financial impact. Indirect costs, such as productivity losses, are the key driver for the overall costs in fracture and non-union patients. Therefore, all strategies that help to reduce healing time with faster resumption of work and activities not only improve medical outcome for the patient, they also help reduce the financial burden in fracture and non-union patients. ß 2014 Elsevier Ltd. All rights reserved.
Introduction It has been estimated that 100,000 fractures go on to nonunion each year in the United States. [1]. The reported incidence and prevalence on nonunion vary significantly based on anatomic region and the criteria used to define nonunion. This variability reflects the overall complexity of understanding the epidemiology of nonunion. Risk factors for nonunion can be characterised as either patient dependent or patient independent. Established patient dependent risk factors include advanced age, various medical comorbidities, sex, smoking, non-steroidal anti-inflammatory use, various genetic disorders, metabolic disease and nutritional deficiency [2–5]. Patient independent factors include fracture pattern, location, and displacement, severity of soft tissue
* Corresponding author. Tel.: +1 303 436 6403; fax: +1 303 436 6572. E-mail address: [email protected] (D.J. Hak). http://dx.doi.org/10.1016/j.injury.2014.04.002 0020–1383/ß 2014 Elsevier Ltd. All rights reserved.
injury, degree of bone loss, quality of surgical treatment and presence or absence of infection [6]. Assessment of nonunion Assessing a patient with a suspected nonunion involves obtaining a clinical history and physical examination, imaging studies, as well as laboratory testing. Important elements of the patient history include pain with weight bearing and subjective fracture instability. Physical examination should focus on tenderness or motion at the fracture site, deformity, status of the soft tissue envelope, signs of infection, and range of motion at joints adjacent to the fracture site. Radiographic evaluation involves orthogonal views of the involved extremity to assess the state of fracture healing as well as the presence or absence of deformity. Radiographic findings suggestive of a healing problem include persistent fracture lines, absence of bony bridging, lack of progressive healing on serial radiographs, progressive deformity
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and the presence of loose or broken implants. Computed tomography (CT) scanning can also be undertaken to assess fracture union and has been shown to be highly sensitive in the identification of unhealed fractures, but this modality is somewhat limited by low specificity [7]. Laboratory evaluation is undertaken to assess for the presence of infection as well as for metabolic and endocrine abnormalities in the setting of unexpected or unexplained nonunion [8]. An established nonunion also needs to be characterised in terms of biologic capacity, deformity, presence or absence of infection, and host status. Hypertrophic, oligotrophic and atrophic radiographic appearances allow the clinician to make inferences about the degree of fracture stability and the biologic viability of the fracture fragments while developing a treatment plan. The presence of deformity increases the complexity of the problem, mandating not only fracture healing but deformity correction as well. When infection is present, it too must be eradicated prior to, or during, nonunion management. Finally, the patient’s overall ability to withstand and benefit from any proposed treatment must be considered. Although originally designed for osteomyelitis, the Cierny-Mader classification is also useful in making this assessment of patients with compromised fracture healing [9]. ‘‘Doctor, is my fracture healed yet?’’ Following a traumatic injury, patients most common question is whether their fracture is healed. The answer to this question has a very important impact for the patient because it may determine whether they can weight-bear, whether they can return to work, or whether additional surgery may be required. Not knowing whether their fracture is healing normally creates uncertainty as the patient plans their future. When the possibility of additional surgery is added to this uncertainty, significant anxiety may develop in some patients. Use of crutches or a walker to maintain non-weightbearing restrictions commonly leads to shoulder and wrist pain, along with exacerbation of any underlying shoulder or wrist pathology. Crutch or walker use may not even be feasible for obese patients or patients with limited upper extremity strength, restricting them to a wheelchair. Prolonged wheelchair use may compromise patients overall fitness and cardiac reserve, prolonging their future rehabilitation and recovery. When is a fracture healed? Clinical perspective The clinical evaluation of fracture healing is based on both radiographic findings and clinical findings. Plain radiographic findings that are used to define fracture union include the presence of bridging callus, the number of bridged cortices, and the disappearance of fracture lines. Depending on the fracture site, orientation, and the presence or absence of fixation it can be difficult to clearly evaluate these factors. Fractures that are rigidly fixed with interfragmentary compression may not show any visible evidence of callus. In these cases, it is easier to accurately identify failure of fracture healing, since this may be associated with hardware loosening or hardware failure. While plain radiographs are most commonly used to serially evaluate fracture healing, computed tomography may be used if nonunion is suspected [10]. Several clinical factors are thought to correlate with fracture healing. In a review of fracture healing trials, absence of pain or tenderness at the fracture site during weight-bearing was the most commonly used clinical criteria, while absence of pain or tenderness on palpation or examination was the second most common clinical criteria [11]. Ability to bear weight, walk, and
perform activities of daily living are also commonly used clinical criteria. However, some patients with stable internal fixation may not display abnormal clinical findings despite an absence of fracture union. Associated injuries may also confound the ability to use clinical criteria in the assessment of fracture healing. Do we need a better assessment of fracture healing? The answer to whether we need a better assessment of fracture healing is an unqualified yes. Fracture healing is a complex, dynamic process with both mechanical and biological components. There is tremendous variability in the characteristics of the patient, the fracture and the treatment all of which impact the time to healing and the chances of a successful repair. Although the end point is dichotomous (healed or not healed) the path to that endpoint may be long and varied, and predicting the final result at an early time point when clinical decisions are required is difficult and not reliable. Current technology allows many disease states to be quantitatively measured, but fracture healing is assessed subjectively, and frankly this assessment is not very good. Better assessment of the early phases of fracture healing would help clinicians better manage patients and to quantitatively assess fracture repair for clinical research. In current practice fracture healing is judged clinically and radiographically. Clinically assessing the patient is important and provides clues to progress towards fracture healing. A clinician assesses whether pain is improving, whether weight bearing is progressing and whether local reaction at the fracture site is decreasing. However these are at best subjective and usually not definitive. Motion at the fracture site present months after injury is a clear clinical sign of failure of repair, but not all nonunions have gross motion and in the presence of hardware this clinical sign is of limited value. Imaging is the cornerstone of fracture healing assessment. Serial radiographs, assessed for callus and cortical bridging, provide important information and are the most frequently used assessment of fracture healing. However difficult cases require prolonged observation with multiple sets of images to be certain of progress or failure to progress towards union. It is not uncommon for clinicians to find themselves asking: is there callus? Is it bridging? Is it mechanically sound? Will it become mechanically sound? Can I see it? Is there hardware in the way? Is it progressing? Can I judge it? CT scans add additional information and in current practice are frequently used. But CT is expensive, leads to large doses of radiation and has not been assessed as an early predictor of subsequent union. It provides more three dimensional detail than radiographs but is still an imperfect surrogate to judge how mechanically sound the repair has become. So our assessments are not very good but they are widely used and accepted in clinics around the world. Why is it important to look critically at the ability to assess fracture healing and why do clinicians need better tools to measure fracture repair? It is because better assessment will improve patient care and will result in better clinical research that will further improve patient care. Providing clinician’s tools to better assess fracture healing in the clinic would directly benefit patient care in many ways. Here are a few examples of the clinical problems that are poorly assessed with current methods. In the early weeks after injury clinicians predict the mechanical strength of the fracture and the fracture fixation construct and prescribe levels of patient function based on these predictions. Initially this judgement is made based on the construct achieved surgically. However after a few weeks has elapsed the progress of the repair process should increasingly contribute to the strength of the fracture and its ability to resist mechanical forces. Patient weight bearing and function need to progress or continue to be restricted based on how the clinician
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judges fracture repair. The clinician also needs to judge whether the fracture is adequately progressing to be able to predict and prevent healing delays, nonunion and hardware failure. In difficult fractures intervention with osteogenic stimuli may or may not be necessary based on these judgments. Judging the timing of removal of an external fixator is always challenging. Fixators removed before repair has gained adequate strength can result in angulation or lead to fracture motion and nonunion. Improving all of these clinical judgments with better assessment of fracture healing would directly improve patient care. Better fracture healing assessment will also improve clinical research to determine which clinical interventions are best for fracture healing. Because the rate of fracture repair cannot be measured, clinical research to demonstrate healing differences between treatment techniques has proven to be very difficult. Definitive healing takes time and the actual nonunion rate is low. A large number of patients need to be enrolled and they must be followed for a long time both of which provide important barriers to research to assess fracture healing interventions. Quantitatively measuring the repair process would lead to a new paradigm in clinical research in this important area. Fracture healing is a critically important clinical event for fracture patients and for clinicians who take care of them. While healing of low energy fractures is usually uneventful, high energy and complex fractures frequently lead to healing delays and failure of healing. Current fracture healing assessment based on the patient’s clinical progress and radiographs is subjective and has poor observer reliability. More robust quantitative assessments of fracture repair are within our reach. The research necessary to develop and validate these assessments is of fundamental importance to fracture treatment and would directly improve patient care and indirectly open the door for other enabling clinical investigations on interventions to optimise fracture repair. Markers of primary vs. secondary fracture healing Fracture healing occurs by different mechanisms largely dependent on the mechanical environment at the fracture site [12–15]. The fixation technique chosen by the surgeon defines the mechanical environment and determines how a fracture proceeds to consolidation. Two general mechanisms of bone healing are recognised in cortical bone. Primary bone healing occurs after surgical stabilization of a fracture with a rigid construct [16]. This type of fracture healing requires a perfect reduction and absolute stability obtained by interfragmentary compression of the fracture. Interfragmentary motion must be less than 0.15 mm for primary bone healing to reliably occur [16]. Fracture callus does not form during primary bone healing. In contrast, secondary bone healing with callus forms in a mechanical environment that permits motion at the fracture site [12,17]. Secondary bone healing may occur after surgical fixation with a flexible implant, such as an intramedullary nail or after nonsurgical management with a cast or brace. The goal of internal or external stabilization of the fracture is a functional rather than a perfect reduction. Interfragmentary motion is generally in the range of 0.2–1 mm [17–19], but healing has been shown to occur with greater than 10 mm in animal models [20]. Secondary bone healing begins with an initial inflammatory stage. Signalling molecules including TGF-B and PDGF are released from the fracture haematoma to promote bone healing. Additionally, VGEF, FGF-2, IL-1, IL-6 and TNF-A are released to promote vascular proliferation [21]. Mesenchymal stem cells derived from the periosteum and endosteum migrate to the fracture site [22]. Higher oxygen tension at the periosteal surface distant from the fracture site leads to preferred differentiation of these stem cells to osteoblasts resulting in eventual intramembranous bone formation. Low oxygen
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tension at the fracture site prefers chondroblasts, resulting in eventual enchondral bone formation. Mechanically, the healing construct is able to undergo 100% elongation and has a tensile strength of 0.1 Nm/mm2 [19]. The second stage of callus fracture healing is the development of soft callus. Hypertrophic chondrocytes and cartilage, consisting of predominately type 2 collagen, bridge the bone ends in the fracture gap. Bone begins to form by enchondral ossification with calcium derived from mitochondria deposited on the cartilage analogue. On the periosteal surface, bone forms by intramembranous ossification. The healing construct becomes semi-rigid in this stage with elongation of 10% and tensile strength between 4 and 19 Nm/mm2 [23]. The stability formed at the fracture site by calcified cartilage provides a mechanical environment suitable for vascular ingrowth. The third stage of callus healing is the development of hard callus. At the completion of this phase, the fracture is clinically healed. Vascular ingrowth to the fracture gap increases the oxygen level in the healing callus. A greater percentage of type 1 collagen is observed as the callus matures. The construct is now rigid, with a tensile strength of 130 Nm/mm2 and an elongation of 2% [23]. The final stage is remodelling, which takes place over a prolonged interval. In this stage, osteoclasts are active in the transition from woven bone to lamellar bone. Signalling molecules for osteoclast activation, including TNF-A, BMP, TGF-B, RANKL, and M-CSF are present in the remodelling tissue [17]. Primary bone healing requires a much different mechanical environment. Fracture gaps must be smaller than 0.1 mm and fracture strain should be less than 2% [24,25]. To obtain these high tolerances of fixation, a construct that provides rigid, compressive fixation is typically used. Alignment of the fracture ends to this degree of precision can only be obtained using open techniques which may require stripping of the fracture ends to allow adequate visualization. Modern fracture fixation techniques aim to limit the amount of soft tissue stripping to preserve the blood supply for fracture healing. Under conditions of absolute stability, synthesis of new bone occurs similar to the remodelling stage of secondary bone healing [24]. Osteoclast cutting cones form parallel to the long axis of the bone, crossing the fracture site. Vascular proliferation and osteoblast bone formation follow. Primary bone healing occurs slowly, with no visible on radiographs. True rigid, compressive fixation is difficult to achieve [26]. Additionally, using modern fracture fixation techniques that respect the blood supply often results in gaps greater that 0.1 mm [27]. A third form of fracture healing, termed gap healing is recognised to occur in these situations [24]. Gap healing requires rigid fixation with a fracture strain of less than 2% but allows gaps less than 1 mm at the fracture site. Bone is deposited perpendicular to the long axis of the bone by intramembranous bone formation. Woven bone is deposited in larger gaps. This immature bone is replaced by mature lamellar bone using the remodelling process. Different from cortical bone healing, fracture healing in metaphyseal bone occurs with very little visible callus. Metaphyseal bone has a large surface area for healing and high vascularity. In an animal fracture healing study, Claes showed that metaphyseal bone fractures respond to the mechanical environment similar to cortical bone fractures [28]. If the strain was less than 5%, there was little fracture healing response. When the strain increased to between 6% and 20%, abundant new bone was formed. If the strain was greater than 20%, fibrous cartilage formed at the fracture site. Financial aspects Health economics provide the theoretical background and practical tools to assess cost impact of different diseases and the
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‘‘health economic value’’ of different treatment options. Many countries such as Australia, Canada and the United Kingdom additionally demand sound health economic data that show the ‘‘cost-effectiveness’’ of a new treatment strategy to justify the overall higher treatment costs [29]. Therefore, the need for health economic data has clearly gained importance, which is also visible in orthopaedic surgery with a strong increase of health economic studies in our field [30]. Health economic studies on non-unions As for all health-economic studies, the type of the included cost data is essential for the interpretation and comparison of the results. In general, expenditures for medical treatment are considered as direct costs whereas loss of productivity is defined as an indirect cost. Kanakaris and Giannoudis reviewed the literature on health economic of long bone unions until 2006 [31]. The published health economic literature on non-unions can be separated into articles dealing with financial aspects of the prevention of nonunions after acute fracture and into works focusing on the actual costs of established non-unions. Financial aspects of prevention of non-unions after acute fracture Two studies have looked at the health economic aspects of acute tibia fractures, with a focus on fracture healing time in order to assess financial impact of time to fracture consolidation and to avoid development of non-unions [32,33]. In a retrospective study, Sprague and Bhandari compared medical and health economic results of patients with closed tibial shaft fractures who received early surgical treatment, defined as within 12 h of trauma (n = 16), with delayed treatment, defined as surgery more than 12 h from injury (n = 19) [34]. No patient in the early treatment group developed a nonunion compared to 8 patients in the delayed treatment group (p < 0.01). The early group achieved bone union in 28.2 9.4 weeks compared to 44.2 9.4 weeks in the second group. There were net savings for the early treatment group of 7330 Canadian dollars (CD$) per case compared to the delayed treated patients. This overall difference is mainly related to savings in productivity losses due to faster fracture healing in the early treatment group (CD$13,419.00 in the early treatment group compared to CD$21,830.00 in the delayed group). A similar approach was used by Alt et al. who analyzed the overall treatment costs for Gustilo-Anderson grade III open tibia fractures with respect to fracture healing time including indirect (productivity losses) and direct costs (secondary treatment costs) in patients treated with or without recombinant human bone morphogenetic protein-2 (rhBMP-2) for Germany, France and the UK [33]. For a 1 year perspective, overall treatment costs per patient after the initial surgery of the control vs. the rhBMP-2 group with s44.757 vs. s36,847 for the UK, s50,197 vs. s40,927 for Germany and s48,766 vs. s39,474 for France in favour of rhBMP-2 group. These effects were mainly caused by reduced productivity losses by significant faster fracture healing in the rhBMP-2 group with mean fracture healing time of 221 days in the rhBMP-2 group compared to the 266 days in the standard of care group (p = 0.01). Overall savings achieved per patient, including secondary interventions for delayed fracture healing and infection and productivity losses could be reduced with the use of rhBMP-2, resulting in total savings of s7911 for the UK), s9270 for Germany and s9291 for France. Furthermore, Busse et al. showed that the use of intramedullary nailing compared to casting, casting plus ultrasound, and nonreamed nailing resulted in significant reduction of non-union rates with reduction of overall treatment costs [34]. Costs for
non-unions were found to be approximately CN$11,800 per case including direct and indirect costs. Costs of established non-unions Regarding health economics of established non-unions, Beaver et al. determined the direct medical costs for the surgical and medical treatment of an established tibial diapyhseal non-union in 1997 to be US$11,333 for the US [35]. Patil and Montgomery calculated £29,204 for the direct costs of the Ilizarov frame technique in patients with aseptic and or septic tibial or femoral non-unions in the UK [36]. Dahabreh et al. showed that the use of BMP-7 reduces direct treatment costs in patients with complex and persisting fracture non-union tibia [37]. 25 nonunions of different anatomic regions were treated using BMP-7 alone (n = 9) alone or BMP-7 and bone grafting (n = 16). Financial differences between treatment episodes regarding hospital stays, number of procedures and costs before and after using BMP-7 were analyzed. Mean hospital stay and cost of treatment per fracture before receiving BMP-7 were 26.8 days and £13,845 vs. 7.8 days and £7338 after BMP-7 treatment. In summary, overall treatment cost of persistent fracture non-unions with BMP-7 was 47% less than that of the numerous previous unsuccessful treatments (p = 0.001). The authors concluded that treatment of fracture non-unions is costly but could be reduced by early BMP-7 administration. The same group published an analysis on direct costs from a UK hospital perspective for the treatment of aseptic nonunions after tibial fractures with autogenous bone grafting from the iliac crest (n = 12) compared to BMP-7 (n = 15) treatment [38]. The ICBG treatment added up to a total cost of £6831 per patient compared to BMP-7 with £7294 per patient, including the price for the growth factor of £3002. Besides the obviously elevated charges for the BMP-7 vial, all other costs (implant prices, hospital and theatre fees) were reduced, resulting in a difference of £464 in favour of ICBG treatment. All 27 patients healed their non-union, however, there was a statistically faster bone healing in the BMP-7 group of 5.5 months compared to 6.9 months in the ICBG group. This would have had considerable financial impact if the study had included indirect costs such as productivity losses. Financial summary Non-unions are difficult to treat and have a high financial impact. Average direct costs of the treatment of an established long bone non-union have been reported as CN$11,800, US$11,333 and £29,204 [34–36]. It is obvious that comparison of those figures needs to take into consideration the different health care systems, base year rates, and currencies. Indirect costs, such as productivity losses, are the key driver for the overall costs in fracture and non-union patients. It has been shown that indirect costs cause 67–79% of the total costs of a tibia fracture in the Canadian health care system. In a work for European health care systems the percentage of indirect costs were even greater, 82.8–93.3% of all costs for tibia fracture patients. Therefore, all strategies that help to reduce healing time with faster resumption of work and activities not only improve medical outcome for the patient, they also help reduce the financial burden in fracture and non-union patients. Conflicts of interest David J. Hak has received consultancy fees from RTI Biologics and Invibio. Daniel Fitzpatrick has received licensing and consulting income from Zimmer and Synthes CMF.
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Injury journal homepage: www.elsevier.com/locate/injury
Delayed union and nonunions: Epidemiology, clinical issues, and financial aspects David J. Hak a,*, Daniel Fitzpatrick b, Julius A. Bishop c, J. Lawrence Marsh d, Susanne Tilp e, Reinhard Schnettler e, Hamish Simpson f, Volker Alt e a
Department of Orthopaedics Denver Health/University of Colorado, 777 Bannock Street, MC 0188, Denver, CO 80204, USA Slocum Center for Orthopedics and Sports Medicine, Eugene, OR, USA Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Pavilion A, Redwood City, CA, USA d Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA e Department of Orthopaedic Trauma Surgery, University Hospital Giessen-Marburg GmbH, Rudolf-Buchheim-Str. 7, 35385 Giessen, Germany f Department of Orthopaedics and Trauma, University of Edinburgh, Edinburgh, UK b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Non-union Aetiology Incidence Cost of treatment
Fracture healing is a critically important clinical event for fracture patients and for clinicians who take care of them. The clinical evaluation of fracture healing is based on both radiographic findings and clinical findings. Risk factors for delayed union and nonunion include patient dependent factors such as advanced age, medical comorbidities, smoking, non-steroidal anti-inflammatory use, various genetic disorders, metabolic disease and nutritional deficiency. Patient independent factors include fracture pattern, location, and displacement, severity of soft tissue injury, degree of bone loss, quality of surgical treatment and presence of infection. Established nonunions can be characterised in terms of biologic capacity, deformity, presence or absence of infection, and host status. Hypertrophic, oligotrophic and atrophic radiographic appearances allow the clinician to make inferences about the degree of fracture stability and the biologic viability of the fracture fragments while developing a treatment plan. Nonunions are difficult to treat and have a high financial impact. Indirect costs, such as productivity losses, are the key driver for the overall costs in fracture and non-union patients. Therefore, all strategies that help to reduce healing time with faster resumption of work and activities not only improve medical outcome for the patient, they also help reduce the financial burden in fracture and non-union patients. ß 2014 Elsevier Ltd. All rights reserved.
Introduction It has been estimated that 100,000 fractures go on to nonunion each year in the United States. [1]. The reported incidence and prevalence on nonunion vary significantly based on anatomic region and the criteria used to define nonunion. This variability reflects the overall complexity of understanding the epidemiology of nonunion. Risk factors for nonunion can be characterised as either patient dependent or patient independent. Established patient dependent risk factors include advanced age, various medical comorbidities, sex, smoking, non-steroidal anti-inflammatory use, various genetic disorders, metabolic disease and nutritional deficiency [2–5]. Patient independent factors include fracture pattern, location, and displacement, severity of soft tissue
* Corresponding author. Tel.: +1 303 436 6403; fax: +1 303 436 6572. E-mail address: [email protected] (D.J. Hak). http://dx.doi.org/10.1016/j.injury.2014.04.002 0020–1383/ß 2014 Elsevier Ltd. All rights reserved.
injury, degree of bone loss, quality of surgical treatment and presence or absence of infection [6]. Assessment of nonunion Assessing a patient with a suspected nonunion involves obtaining a clinical history and physical examination, imaging studies, as well as laboratory testing. Important elements of the patient history include pain with weight bearing and subjective fracture instability. Physical examination should focus on tenderness or motion at the fracture site, deformity, status of the soft tissue envelope, signs of infection, and range of motion at joints adjacent to the fracture site. Radiographic evaluation involves orthogonal views of the involved extremity to assess the state of fracture healing as well as the presence or absence of deformity. Radiographic findings suggestive of a healing problem include persistent fracture lines, absence of bony bridging, lack of progressive healing on serial radiographs, progressive deformity
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and the presence of loose or broken implants. Computed tomography (CT) scanning can also be undertaken to assess fracture union and has been shown to be highly sensitive in the identification of unhealed fractures, but this modality is somewhat limited by low specificity [7]. Laboratory evaluation is undertaken to assess for the presence of infection as well as for metabolic and endocrine abnormalities in the setting of unexpected or unexplained nonunion [8]. An established nonunion also needs to be characterised in terms of biologic capacity, deformity, presence or absence of infection, and host status. Hypertrophic, oligotrophic and atrophic radiographic appearances allow the clinician to make inferences about the degree of fracture stability and the biologic viability of the fracture fragments while developing a treatment plan. The presence of deformity increases the complexity of the problem, mandating not only fracture healing but deformity correction as well. When infection is present, it too must be eradicated prior to, or during, nonunion management. Finally, the patient’s overall ability to withstand and benefit from any proposed treatment must be considered. Although originally designed for osteomyelitis, the Cierny-Mader classification is also useful in making this assessment of patients with compromised fracture healing [9]. ‘‘Doctor, is my fracture healed yet?’’ Following a traumatic injury, patients most common question is whether their fracture is healed. The answer to this question has a very important impact for the patient because it may determine whether they can weight-bear, whether they can return to work, or whether additional surgery may be required. Not knowing whether their fracture is healing normally creates uncertainty as the patient plans their future. When the possibility of additional surgery is added to this uncertainty, significant anxiety may develop in some patients. Use of crutches or a walker to maintain non-weightbearing restrictions commonly leads to shoulder and wrist pain, along with exacerbation of any underlying shoulder or wrist pathology. Crutch or walker use may not even be feasible for obese patients or patients with limited upper extremity strength, restricting them to a wheelchair. Prolonged wheelchair use may compromise patients overall fitness and cardiac reserve, prolonging their future rehabilitation and recovery. When is a fracture healed? Clinical perspective The clinical evaluation of fracture healing is based on both radiographic findings and clinical findings. Plain radiographic findings that are used to define fracture union include the presence of bridging callus, the number of bridged cortices, and the disappearance of fracture lines. Depending on the fracture site, orientation, and the presence or absence of fixation it can be difficult to clearly evaluate these factors. Fractures that are rigidly fixed with interfragmentary compression may not show any visible evidence of callus. In these cases, it is easier to accurately identify failure of fracture healing, since this may be associated with hardware loosening or hardware failure. While plain radiographs are most commonly used to serially evaluate fracture healing, computed tomography may be used if nonunion is suspected [10]. Several clinical factors are thought to correlate with fracture healing. In a review of fracture healing trials, absence of pain or tenderness at the fracture site during weight-bearing was the most commonly used clinical criteria, while absence of pain or tenderness on palpation or examination was the second most common clinical criteria [11]. Ability to bear weight, walk, and
perform activities of daily living are also commonly used clinical criteria. However, some patients with stable internal fixation may not display abnormal clinical findings despite an absence of fracture union. Associated injuries may also confound the ability to use clinical criteria in the assessment of fracture healing. Do we need a better assessment of fracture healing? The answer to whether we need a better assessment of fracture healing is an unqualified yes. Fracture healing is a complex, dynamic process with both mechanical and biological components. There is tremendous variability in the characteristics of the patient, the fracture and the treatment all of which impact the time to healing and the chances of a successful repair. Although the end point is dichotomous (healed or not healed) the path to that endpoint may be long and varied, and predicting the final result at an early time point when clinical decisions are required is difficult and not reliable. Current technology allows many disease states to be quantitatively measured, but fracture healing is assessed subjectively, and frankly this assessment is not very good. Better assessment of the early phases of fracture healing would help clinicians better manage patients and to quantitatively assess fracture repair for clinical research. In current practice fracture healing is judged clinically and radiographically. Clinically assessing the patient is important and provides clues to progress towards fracture healing. A clinician assesses whether pain is improving, whether weight bearing is progressing and whether local reaction at the fracture site is decreasing. However these are at best subjective and usually not definitive. Motion at the fracture site present months after injury is a clear clinical sign of failure of repair, but not all nonunions have gross motion and in the presence of hardware this clinical sign is of limited value. Imaging is the cornerstone of fracture healing assessment. Serial radiographs, assessed for callus and cortical bridging, provide important information and are the most frequently used assessment of fracture healing. However difficult cases require prolonged observation with multiple sets of images to be certain of progress or failure to progress towards union. It is not uncommon for clinicians to find themselves asking: is there callus? Is it bridging? Is it mechanically sound? Will it become mechanically sound? Can I see it? Is there hardware in the way? Is it progressing? Can I judge it? CT scans add additional information and in current practice are frequently used. But CT is expensive, leads to large doses of radiation and has not been assessed as an early predictor of subsequent union. It provides more three dimensional detail than radiographs but is still an imperfect surrogate to judge how mechanically sound the repair has become. So our assessments are not very good but they are widely used and accepted in clinics around the world. Why is it important to look critically at the ability to assess fracture healing and why do clinicians need better tools to measure fracture repair? It is because better assessment will improve patient care and will result in better clinical research that will further improve patient care. Providing clinician’s tools to better assess fracture healing in the clinic would directly benefit patient care in many ways. Here are a few examples of the clinical problems that are poorly assessed with current methods. In the early weeks after injury clinicians predict the mechanical strength of the fracture and the fracture fixation construct and prescribe levels of patient function based on these predictions. Initially this judgement is made based on the construct achieved surgically. However after a few weeks has elapsed the progress of the repair process should increasingly contribute to the strength of the fracture and its ability to resist mechanical forces. Patient weight bearing and function need to progress or continue to be restricted based on how the clinician
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judges fracture repair. The clinician also needs to judge whether the fracture is adequately progressing to be able to predict and prevent healing delays, nonunion and hardware failure. In difficult fractures intervention with osteogenic stimuli may or may not be necessary based on these judgments. Judging the timing of removal of an external fixator is always challenging. Fixators removed before repair has gained adequate strength can result in angulation or lead to fracture motion and nonunion. Improving all of these clinical judgments with better assessment of fracture healing would directly improve patient care. Better fracture healing assessment will also improve clinical research to determine which clinical interventions are best for fracture healing. Because the rate of fracture repair cannot be measured, clinical research to demonstrate healing differences between treatment techniques has proven to be very difficult. Definitive healing takes time and the actual nonunion rate is low. A large number of patients need to be enrolled and they must be followed for a long time both of which provide important barriers to research to assess fracture healing interventions. Quantitatively measuring the repair process would lead to a new paradigm in clinical research in this important area. Fracture healing is a critically important clinical event for fracture patients and for clinicians who take care of them. While healing of low energy fractures is usually uneventful, high energy and complex fractures frequently lead to healing delays and failure of healing. Current fracture healing assessment based on the patient’s clinical progress and radiographs is subjective and has poor observer reliability. More robust quantitative assessments of fracture repair are within our reach. The research necessary to develop and validate these assessments is of fundamental importance to fracture treatment and would directly improve patient care and indirectly open the door for other enabling clinical investigations on interventions to optimise fracture repair. Markers of primary vs. secondary fracture healing Fracture healing occurs by different mechanisms largely dependent on the mechanical environment at the fracture site [12–15]. The fixation technique chosen by the surgeon defines the mechanical environment and determines how a fracture proceeds to consolidation. Two general mechanisms of bone healing are recognised in cortical bone. Primary bone healing occurs after surgical stabilization of a fracture with a rigid construct [16]. This type of fracture healing requires a perfect reduction and absolute stability obtained by interfragmentary compression of the fracture. Interfragmentary motion must be less than 0.15 mm for primary bone healing to reliably occur [16]. Fracture callus does not form during primary bone healing. In contrast, secondary bone healing with callus forms in a mechanical environment that permits motion at the fracture site [12,17]. Secondary bone healing may occur after surgical fixation with a flexible implant, such as an intramedullary nail or after nonsurgical management with a cast or brace. The goal of internal or external stabilization of the fracture is a functional rather than a perfect reduction. Interfragmentary motion is generally in the range of 0.2–1 mm [17–19], but healing has been shown to occur with greater than 10 mm in animal models [20]. Secondary bone healing begins with an initial inflammatory stage. Signalling molecules including TGF-B and PDGF are released from the fracture haematoma to promote bone healing. Additionally, VGEF, FGF-2, IL-1, IL-6 and TNF-A are released to promote vascular proliferation [21]. Mesenchymal stem cells derived from the periosteum and endosteum migrate to the fracture site [22]. Higher oxygen tension at the periosteal surface distant from the fracture site leads to preferred differentiation of these stem cells to osteoblasts resulting in eventual intramembranous bone formation. Low oxygen
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tension at the fracture site prefers chondroblasts, resulting in eventual enchondral bone formation. Mechanically, the healing construct is able to undergo 100% elongation and has a tensile strength of 0.1 Nm/mm2 [19]. The second stage of callus fracture healing is the development of soft callus. Hypertrophic chondrocytes and cartilage, consisting of predominately type 2 collagen, bridge the bone ends in the fracture gap. Bone begins to form by enchondral ossification with calcium derived from mitochondria deposited on the cartilage analogue. On the periosteal surface, bone forms by intramembranous ossification. The healing construct becomes semi-rigid in this stage with elongation of 10% and tensile strength between 4 and 19 Nm/mm2 [23]. The stability formed at the fracture site by calcified cartilage provides a mechanical environment suitable for vascular ingrowth. The third stage of callus healing is the development of hard callus. At the completion of this phase, the fracture is clinically healed. Vascular ingrowth to the fracture gap increases the oxygen level in the healing callus. A greater percentage of type 1 collagen is observed as the callus matures. The construct is now rigid, with a tensile strength of 130 Nm/mm2 and an elongation of 2% [23]. The final stage is remodelling, which takes place over a prolonged interval. In this stage, osteoclasts are active in the transition from woven bone to lamellar bone. Signalling molecules for osteoclast activation, including TNF-A, BMP, TGF-B, RANKL, and M-CSF are present in the remodelling tissue [17]. Primary bone healing requires a much different mechanical environment. Fracture gaps must be smaller than 0.1 mm and fracture strain should be less than 2% [24,25]. To obtain these high tolerances of fixation, a construct that provides rigid, compressive fixation is typically used. Alignment of the fracture ends to this degree of precision can only be obtained using open techniques which may require stripping of the fracture ends to allow adequate visualization. Modern fracture fixation techniques aim to limit the amount of soft tissue stripping to preserve the blood supply for fracture healing. Under conditions of absolute stability, synthesis of new bone occurs similar to the remodelling stage of secondary bone healing [24]. Osteoclast cutting cones form parallel to the long axis of the bone, crossing the fracture site. Vascular proliferation and osteoblast bone formation follow. Primary bone healing occurs slowly, with no visible on radiographs. True rigid, compressive fixation is difficult to achieve [26]. Additionally, using modern fracture fixation techniques that respect the blood supply often results in gaps greater that 0.1 mm [27]. A third form of fracture healing, termed gap healing is recognised to occur in these situations [24]. Gap healing requires rigid fixation with a fracture strain of less than 2% but allows gaps less than 1 mm at the fracture site. Bone is deposited perpendicular to the long axis of the bone by intramembranous bone formation. Woven bone is deposited in larger gaps. This immature bone is replaced by mature lamellar bone using the remodelling process. Different from cortical bone healing, fracture healing in metaphyseal bone occurs with very little visible callus. Metaphyseal bone has a large surface area for healing and high vascularity. In an animal fracture healing study, Claes showed that metaphyseal bone fractures respond to the mechanical environment similar to cortical bone fractures [28]. If the strain was less than 5%, there was little fracture healing response. When the strain increased to between 6% and 20%, abundant new bone was formed. If the strain was greater than 20%, fibrous cartilage formed at the fracture site. Financial aspects Health economics provide the theoretical background and practical tools to assess cost impact of different diseases and the
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‘‘health economic value’’ of different treatment options. Many countries such as Australia, Canada and the United Kingdom additionally demand sound health economic data that show the ‘‘cost-effectiveness’’ of a new treatment strategy to justify the overall higher treatment costs [29]. Therefore, the need for health economic data has clearly gained importance, which is also visible in orthopaedic surgery with a strong increase of health economic studies in our field [30]. Health economic studies on non-unions As for all health-economic studies, the type of the included cost data is essential for the interpretation and comparison of the results. In general, expenditures for medical treatment are considered as direct costs whereas loss of productivity is defined as an indirect cost. Kanakaris and Giannoudis reviewed the literature on health economic of long bone unions until 2006 [31]. The published health economic literature on non-unions can be separated into articles dealing with financial aspects of the prevention of nonunions after acute fracture and into works focusing on the actual costs of established non-unions. Financial aspects of prevention of non-unions after acute fracture Two studies have looked at the health economic aspects of acute tibia fractures, with a focus on fracture healing time in order to assess financial impact of time to fracture consolidation and to avoid development of non-unions [32,33]. In a retrospective study, Sprague and Bhandari compared medical and health economic results of patients with closed tibial shaft fractures who received early surgical treatment, defined as within 12 h of trauma (n = 16), with delayed treatment, defined as surgery more than 12 h from injury (n = 19) [34]. No patient in the early treatment group developed a nonunion compared to 8 patients in the delayed treatment group (p < 0.01). The early group achieved bone union in 28.2 9.4 weeks compared to 44.2 9.4 weeks in the second group. There were net savings for the early treatment group of 7330 Canadian dollars (CD$) per case compared to the delayed treated patients. This overall difference is mainly related to savings in productivity losses due to faster fracture healing in the early treatment group (CD$13,419.00 in the early treatment group compared to CD$21,830.00 in the delayed group). A similar approach was used by Alt et al. who analyzed the overall treatment costs for Gustilo-Anderson grade III open tibia fractures with respect to fracture healing time including indirect (productivity losses) and direct costs (secondary treatment costs) in patients treated with or without recombinant human bone morphogenetic protein-2 (rhBMP-2) for Germany, France and the UK [33]. For a 1 year perspective, overall treatment costs per patient after the initial surgery of the control vs. the rhBMP-2 group with s44.757 vs. s36,847 for the UK, s50,197 vs. s40,927 for Germany and s48,766 vs. s39,474 for France in favour of rhBMP-2 group. These effects were mainly caused by reduced productivity losses by significant faster fracture healing in the rhBMP-2 group with mean fracture healing time of 221 days in the rhBMP-2 group compared to the 266 days in the standard of care group (p = 0.01). Overall savings achieved per patient, including secondary interventions for delayed fracture healing and infection and productivity losses could be reduced with the use of rhBMP-2, resulting in total savings of s7911 for the UK), s9270 for Germany and s9291 for France. Furthermore, Busse et al. showed that the use of intramedullary nailing compared to casting, casting plus ultrasound, and nonreamed nailing resulted in significant reduction of non-union rates with reduction of overall treatment costs [34]. Costs for
non-unions were found to be approximately CN$11,800 per case including direct and indirect costs. Costs of established non-unions Regarding health economics of established non-unions, Beaver et al. determined the direct medical costs for the surgical and medical treatment of an established tibial diapyhseal non-union in 1997 to be US$11,333 for the US [35]. Patil and Montgomery calculated £29,204 for the direct costs of the Ilizarov frame technique in patients with aseptic and or septic tibial or femoral non-unions in the UK [36]. Dahabreh et al. showed that the use of BMP-7 reduces direct treatment costs in patients with complex and persisting fracture non-union tibia [37]. 25 nonunions of different anatomic regions were treated using BMP-7 alone (n = 9) alone or BMP-7 and bone grafting (n = 16). Financial differences between treatment episodes regarding hospital stays, number of procedures and costs before and after using BMP-7 were analyzed. Mean hospital stay and cost of treatment per fracture before receiving BMP-7 were 26.8 days and £13,845 vs. 7.8 days and £7338 after BMP-7 treatment. In summary, overall treatment cost of persistent fracture non-unions with BMP-7 was 47% less than that of the numerous previous unsuccessful treatments (p = 0.001). The authors concluded that treatment of fracture non-unions is costly but could be reduced by early BMP-7 administration. The same group published an analysis on direct costs from a UK hospital perspective for the treatment of aseptic nonunions after tibial fractures with autogenous bone grafting from the iliac crest (n = 12) compared to BMP-7 (n = 15) treatment [38]. The ICBG treatment added up to a total cost of £6831 per patient compared to BMP-7 with £7294 per patient, including the price for the growth factor of £3002. Besides the obviously elevated charges for the BMP-7 vial, all other costs (implant prices, hospital and theatre fees) were reduced, resulting in a difference of £464 in favour of ICBG treatment. All 27 patients healed their non-union, however, there was a statistically faster bone healing in the BMP-7 group of 5.5 months compared to 6.9 months in the ICBG group. This would have had considerable financial impact if the study had included indirect costs such as productivity losses. Financial summary Non-unions are difficult to treat and have a high financial impact. Average direct costs of the treatment of an established long bone non-union have been reported as CN$11,800, US$11,333 and £29,204 [34–36]. It is obvious that comparison of those figures needs to take into consideration the different health care systems, base year rates, and currencies. Indirect costs, such as productivity losses, are the key driver for the overall costs in fracture and non-union patients. It has been shown that indirect costs cause 67–79% of the total costs of a tibia fracture in the Canadian health care system. In a work for European health care systems the percentage of indirect costs were even greater, 82.8–93.3% of all costs for tibia fracture patients. Therefore, all strategies that help to reduce healing time with faster resumption of work and activities not only improve medical outcome for the patient, they also help reduce the financial burden in fracture and non-union patients. Conflicts of interest David J. Hak has received consultancy fees from RTI Biologics and Invibio. Daniel Fitzpatrick has received licensing and consulting income from Zimmer and Synthes CMF.
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