Curr Osteoporos Rep (2014) 12:446–453 DOI 10.1007/s11914-014-0239-7
ORTHOPEDIC MANAGEMENT OF FRACTURES (D LITTLE AND T MICLAU, SECTION EDITORS)
Atypical Femur Fractures: A Review Wesley H. Bronson & I. David Kaye & Kenneth A. Egol
Published online: 7 October 2014 # Springer Science+Business Media New York 2014
Abstract Bisphosphonates are one of the most commonly prescribed medications for the treatment of osteoporosis. Their use has greatly decreased the number of osteoporosisrelated vertebral and nonvertebral fractures. Recently, however, a relationship between long-term bisphosphonate use and subtrochanteric and femoral shaft fractures has been elucidated. These low-energy fractures, termed atypical femur fractures, exhibit unique characteristics in their pathophysiology, presentation, and radiographic appearance compared with more traditional high-energy femur fractures. Here we provide a review based on the most recent literature of the pathophysiology, presentation, evaluation, and management of these fractures. Despite an abundance of literature, atypical femur fractures remain difficult to treat, and surgeons must be aware of the tricks and complications associated with their management. Keywords Atypical femur fractures . Bisphosphonates . Subtrochanteric . Osteoporosis . Delayed healing . Intramedullary nail
Introduction Osteoporosis is a major source of disability and affects over 75 million individuals in the United States, Europe, and Japan [1]. The burden of this disease has both health and economic consequences. Nearly one in every four men and one in every two women will sustain an osteoporosis related fracture in their lifetime [2]. For those who suffer a hip fracture, 20 %– 30 % may die within the first year as a result of underlying W. H. Bronson : I. D. Kaye : K. A. Egol (*) Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, 301 E 17th St, New York, NY, USA e-mail: [email protected]
medical problems, and up to 50 % may never regain their prefracture level of function [3, 4]. From an economic perspective, the treatment of a single hip fracture may cost as much as $40,000 [5]. In 2002, the estimated cost of treating osteoporosis related fractures was nearly 20 billion USD [6]. Bisphosphonates have become widely used in the medical treatment for osteoporosis [7, 8]. This class of medications works by decreasing bone resorption, increasing bone mineral density, and subsequently has decreased the incidence of both vertebral and nonvertebral fractures [9–11]. In one study, single infusion of zoledronate decreased the incidence of vertebral fractures over a 3-year period by 70 % compared with placebo, decreased the risk of hip fractures by 41 %, increased bone mineral density, and improved biomarkers of bone metabolism [7]. Long-term bisphosphonate use, however, is not without consequences. In 2005, Odvina et al published the first case report of atypical fractures possibly related to bisphosphonate use [12]. They reported on nine patients who had been taking Alendronate who had sustained spontaneous nonvertebral fractures. Four of the nine patients had subtrochanteric femur fractures, and six of the nine demonstrated delayed or absent bone healing. Additionally, histologic analysis of iliac crest bone biopsy revealed oversuppression of bone turnover, raising the possibility of a causal relationship between bisphosphonate use and the resulting fractures. Despite the decrease in overall fracture risk with the initiation of bisphosphonate therapy, more and more evidence has revealed an association between bisphosphonate use and atypical femur fractures (AFF) [13–16].
Recognizing Atypical Femur Fractures Recently, the American Society for Bone and Mineral Research (ASBMR) has created a set of updated criteria for
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helping to diagnose an AFF (Table 1) [17, 18••]. The fracture must be located below the lesser trochanter and proximal to the supracondylar region of the distal femur. Femoral neck and intertrochanteric fractures with spiral subtrochanteric extension are excluded. This is in contrast to traditional osteoporotic femur fractures, which more commonly occur as femoral neck or intertrochanteric fractures. In addition, there are five major criteria, four of which must be met for the fracture to be classified as an atypical femur fracture. These include (1) no history of trauma, or if present, a low-energy trauma. Osteoporosis-related femoral neck or intertrochanteric fractures occur with low-energy as well, however, rarely occur without trauma. When a subtrochanteric fracture does occur, it is most commonly found after highenergy trauma; (2) the fracture originates at the lateral cortex, and the pattern is transverse or short oblique in configuration; (3) there is minimal or no evidence of comminution. Traditional osteoporotic fractures are classically spiral or long oblique, and high-energy subtrochanteric fractures occur with comminution; (4) they occur with a medial spike in complete fractures or, if an incomplete fracture, involves only the lateral cortex; and (5) there is periosteal or endosteal thickening on the lateral cortex at the fracture site with “beaking.” This is in contrast to bone surrounding an osteoporotic fracture, which tends to have thinned cortices (Figs. 1, 2, and 3). Minor features which do not need to be present but can help in the diagnosis include: generalized femoral cortical thickening, a history of prodromal pain, fractures occurring bilaterally, and evidence of delayed fracture healing. They may also be associated with comorbid conditions or medication use, including rheumatoid arthritis, rickets, osteomalacia, use of proton-pump-inhibitors or glucocorticoids.
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Mechanism The prodromal pain, bilateral occurrence, cortical thickening, and delayed bone healing suggest a separate pathophysiology when compared with osteoporotic fragility fractures [19]. The cause of bisphosphonate associated femur fractures is not entirely known, however, several proposed mechanisms exist. The most commonly accepted etiology is that severe, prolonged over-suppression of bone turnover leads to impaired bone remodeling and microdamage accumulation, resulting in skeletal fragility and thereby predisposing bone to spontaneous fracture [20–23]. Mashiba showed in a dog model that bisphosphonate-induced suppression in trabecular bone remodeling led to a 21 % decrease in bone toughness although no decrease in strength [21]. The majority of completed fractures are associated with low-energy falls.
Epidemiology As mentioned earlier, the introduction of bisphosphonate therapy has greatly decreased the number of typical femur fractures. A study in 2011 showed that from 1996 to 2006, the age-adjusted rates for hip fractures decreased by 31.6 %. At the same time, the number of subtrochanteric fractures increased by 31.2 % [24]. The increased use of bisphosphonates has, at least partly, been implicated in this trend. Nonetheless, the incidence of atypical femur fractures is extremely low. A recent case control study reported on the
Table 1 Major and minor features for the diagnosis of atypical femur fractures [18••] Major features (at least four must be present) Minimal or no trauma, such as fall from standing Fracture originates at lateral cortex and is largely transverse or short oblique Complete fractures associated with a medial spike; incomplete fractures involve only lateral cortex Minimal or no comminution Localized periosteal or endosteal thickening in lateral cortex (“beaking”) Minor features (none must be present but have been commonly associated) Generalized increase in cortical thickness of diaphysis Unilateral or bilateral prodromal symptoms Bilateral incomplete or complete fractures Delayed fracture healing
Fig. 1 Typical high energy subtrochanteric femur fracture with comminution
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Fig. 2 Complete atypical femur fracture
incidence of femur fractures in women over age 68 who took bisphosphonates for over 5 years. The authors found 9723 women who sustained a typical osteoporotic fracture of the intertrochanteric or femoral neck region and 716 who sustained a subtrochanteric or femoral shaft fracture (0.35 %) [25••]. This study, however, did not further evaluate which subtrochanteric or femoral shaft fractures had atypical features, so the incidence is only a fraction of this percentage. Another report was published recently on the effect of bisphosphonate use on the incidence of atypical femur
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fractures. Their study of the National Swedish Register found 12,777 women over age 55 with a femur fracture, 59 of which had atypical features [26]. They calculated that the ageadjusted relative risk of atypical fracture with any bisphosphonate use was 47.3. While the risk is substantially higher compared with nonusers, it is still incredibly low. They note that the difference in risk of atypical fracture between bisphosphonate users and nonusers was 5 per 10,000 patient-years, producing a number needed to harm of 2000 per year of use. Giusti et al looked at 906 patients with femur fractures [27]. Of those, 96 (10.6 %) occurred in the subtrochanteric or femoral shaft region. Of the 96, 63 were low-energy, and ten of those were atypical. Thus, 1.1 % of the femur fractures were atypical fractures. Although the atypical fractures were more frequent in the bisphosphonate users, with an odds ratio of 17.0, one-half of the patients in their cohort who had fractures with atypical features had never used bisphosphonates. Certain patient populations appear to be particularly at risk. Marcano et al identified patients with atypical femur fractures associated with bisphosphonate use (BFF) and patients who were on long term bisphosphonates but who suffered no associated fractures (BNF). After multivariate analysis, they found a higher percentage of Asians in the BFF group (17 %) than in the BNF group (3 %) with P value 0.004 [28•]. In addition, in comparing the BFF group with patients who suffered femur fractures not associated with bisphosphonate use, the patients in the BFF group were more likely to be women (14 % compared with 7 % male) and also tended to be younger. The authors suggest that Asians are at higher risks compared with other ethnicities, and they recommend closer follow-up for these patients. In other studies that analyzed the incidence of atypical fractures in both sexes, women accounted for 80 %–96 % of cases, with men making up a small minority [29, 30].
Presentation
Fig. 3 Bilateral incomplete atypical femur fractures
The majority of patients with atypical femur fractures present after minor trauma or fall from standing or less. But certain features of the patient history and presentation are unique to those with atypical femur fractures. Many patients experience prodromal pain leading up to the injury. In a study by Lo et al of 38 women presenting with atypical femur fractures, nearly one-third had prodromal pain [31]. Other studies show the number to be significantly higher, and a systematic review of case reports by Giusti et al of a total of 141 women with atypical femur fractures found that nearly 64 % had prodromal pain [32]. The duration of the pain is variable, lasting anywhere from days to years before fracture [33]. Patients may also have contralateral lower extremity symptoms or even bilateral fractures. A series by Kwek et al identified 17 patients with atypical femur fractures. Of the 17, nine
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had radiographs with evidence of bilateral stress reactions with lateral cortical thickening [34]. Capeci and Tejwani analyzed 65 patients with atypical femur fractures treated with intramedullary nail [13]. They found that seven patients sustained low-energy bilateral subtrochanteric or diaphyseal fractures while on long-term bisphosphonates. Of the seven, one presented with simultaneous bilateral fractures, two had sequential fractures with the second fracture occurring 12 and 18 months after initial injury, and four exhibited signs of stress reaction/impending fracture at time of initial injury. Lo et al found that patients with atypical femur fractures presented with contralateral stress reaction or complete fracture 39.5 % of the time, while only 2.4 % of the time when presenting with a typical femur fracture [31]. Atypical femur fractures may be associated with other medical comorbid conditions and medication use [31]. Over 75 % of women presenting with atypical femur fractures have one comorbid illness, and almost 25 % have over three. Chronic diseases found in more than 10 % of patients include COPD, asthma, rheumatoid arthritis, and diabetes. Over 25 % of patients report being on oral glucocorticoids and about 10 % on inhaled glucocorticoids for asthma or COPD. Additionally, almost 35 % report taking a proton pump inhibitor.
Imaging The diagnosis is often made easily from plain radiographs. As described previously, atypical femur fractures exhibit unique features on plain radiographs. They are commonly located in the subtrochanteric and proximal midshaft region of the femur. When complete and displaced they have simple transverse or short oblique patterns, lack comminution, have a medial spike, and have lateral cortical thickening, especially when incomplete. This is in contrast to stress fractures seen in athletes, which typically involve the medial cortex [35]. Not all patients with incomplete fractures present with radiographic findings. In the absence of radiographic abnormality, MRI is highly sensitive for detecting stress reaction and impending femur fracture. There may be a fracture line of low intensity on all sequences, the so-called “dreaded black line.” Additionally, decreased intensity on T1 images and increased T2 signal representing edema will be present around the fracture (Fig. 4) [36]. MRI is unnecessary in evaluating completed fractures, but becomes increasingly important in evaluating pain in the absence of radiographic changes, as well as evaluating the contralateral femur in patients who present with unilateral complete or incomplete fractures. Patients presenting with bisphosphonate-associated femur fractures, whether complete or incomplete, have a high rate of contralateral stress reaction, as high as 70 %. Some of these patients may have a history of prodromal pain, but some may
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Fig. 4 MRI demonstrating bone edema and stress fracture in the proximal femur
also be asymptomatic. Thus, many surgeons recommend routine imaging of the contralateral femur [13]. Imaging begins with plain radiographs. If radiographs are normal but clinical suspicion is high, then more advanced imaging with MRI or bone scan should be obtained. Nuclear scintigraphy can also identify incomplete and radiographically occult atypical fractures (Fig. 5). A study by Chan et al found that scintography demonstrated increased uptake in regions of lateral cortical thickening in incomplete fractures [37]. Perret et al demonstrated increased uptake in the contralateral femur of three patients, identifying two fractures that were radiographically occult [38]. As Aghbari and Egol point out, however, nuclear scintography is sensitive but lacks specificity, so correlation to clinical findings or other radiographic studies is required [39].
Treatment Nonoperative and Medical Management After being diagnosed with stress reaction, stress fracture, incomplete or complete fractures, patients should discontinue the offending agent [17]. The incidence of future atypical fracture is reduced by stopping the antiresorptive drug. In a study by Dell et al, the incidence of contralateral femur fracture was 53.9 % in those who were still taking bisphosphonates 3 years after the initial fracture and only 19.3 % in those who had stopped the bisphosphonate after injury [30]. Healing rates, however, do not appear to change during the immediate postinjury period despite discontinuation. In the systematic review by Giusti et al there was no statistically significant difference in delayed healing between those patients who discontinued the bisphosphonate after injury (5/8)
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Fig. 5 Nuclear scintography demonstrating increased uptake in the subtrochanteric region
and those who continued the bisphosphonate (6/13) [32]. This finding may be partially explained by the pharmacokinetics of bisphosphonates. All of the drugs remain present in the body for many years after administration. A single dose of zoledronate has been shown to have sustained antiresorptive effects at 3 years [40]. Similarly, animal models have shown varying metabolism of alendronate, with the drug still present anywhere from months to several years after administration [41]. Patients should also begin vitamin D and calcium supplementation. A recent study of patients with atypical fractures demonstrated that about half the patients had suboptimal levels of 25-hydroxyvitamin D, and 25 % had low levels [42]. Based on studies showing the efficacy of supplementation, it is
Fig. 6 AFF treated with intramedullary nail with abundant healing callus
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recommended now that patients take between 1000 and 2000 IU/day of Vitamin D3 [43]. This is significantly higher than the 400–800 IU/day dose recommended by the Institute of Medicine [44]. Additionally, patients should take 1000– 1200 mg/day of calcium [42]. Based on animal models showing accelerated bone healing, some researches also believe that vitamin C supplementation should be recommended during fracture healing in the elderly [45, 46]. For patients at high risk for fracture secondary to osteoporosis and those with oversuppression of bone turnover from bisphosphonates, some have suggested beginning Teriparatide, a recombinant parathyroid hormone. Teriparatide has been shown to increase callus formation and bone strength during fracture healing [47–52]. Reports of increased bone healing or bone mineral density, however, are inconsistent [53–58]. One study by Lin et al. analyzed femur nonunions in mice by using intramedullary implants and maintaining a 1.7 mm fracture gap while giving recombinant PTH or saline for 14 days. At 6 weeks, the group that had received PTH had significantly lower rates of nonunion measured both radiographically and histologically [59]. In the end, the ASBMR notes that given the varying data, no definite conclusion can be drawn, but they nonetheless consider Teriparatide therapy for those who do not heal with conservative therapy. Up until recently, it was suggested that medical management along with protected weight bearing with the use of assistive device could be considered until pain improved and healing occurred. While this strategy may be attempted in patients with incomplete fractures and mild pain, recent studies have demonstrated a high failure rate with nonoperative management. Banffy et al identified 12 patients with bisphosphonate associated incomplete stress fractures [60••]. Six were treated with prophylactic intramedullary nail and six were treated nonoperatively with nonweight- bearing or protected weightbearing. Of the six treated nonoperatively, five progressed to complete fracture at an average of 10 months. Additionally, they found that those who underwent prophylactic fixation had a total hospital length of stay of 3.7 days vs 6.0 days in those who were treated only after fracture completion. In another study of 14 fractures identified in 11 patients, five progressed to complete fracture at 10 months requiring operative intervention, and another five required surgery due to continued intractable pain [61]. In all, ten of the 14 fractures identified eventually required surgery. Egol similarly showed a 15 % progression rate for incomplete fractures treated nonoperatively [62•]. Nonoperative treatment with partial weight-bearing and medical management can be successful in some patients, but they must be monitored carefully to prevent fracture progression.
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Operative Management
Conclusions
Operative management is utilized in all complete fractures and select incomplete fractures. Potential techniques include plate fixation or intramedullary nail (IMN). Sometimes plate fixation is required because of technical difficulties with placing a nail. It has been reported that the thickened cortices of patients on bisphosphonates can, on occasion, make placing a nail impractical, as the proximal diameter of the nail either results in fracture of the brittle cortex or varus deformity [63]. But while there are no prospective trials comparing plate fixation with IMN, IMN is the preferred treatment of choice. This preference is partially a function of the different methods of healing with the implants. Fractures treated with intramedullary nails heal with abundant callus and through endochondral ossification. Bisphosphonates have not been shown to affect this stage of bone healing. They have been shown, however, to alter bone resorption and remodeling, thus, altering intramembranous bone healing and decreasing the mechanical properties of bone, potentially resulting in plate failure [64, 65]. Egol et al demonstrated successful outcomes with operative treatment of incomplete atypical femur fractures treated with intramedullary nail [62•]. In their study of 31 patients with 43 incomplete fractures, healing, pain, and disability scores were all superior in the operatively treated group. One-hundred percent progressed to radiographic healing compared with 18 % in the nonoperative group, 81 % became pain free vs 64 %, and scores on the Short Musculoskeletal Functional Assessment were better, 19.7 compared with 25.7 in the nonoperative group. The authors conclude that while operative intervention for incomplete fractures appears to provide successful and reliable results, no large scale prospective trial exists. Those who opt for nonoperative management, especially those who continue to have pain, should be counseled on the potential benefits of surgical treatment and the substantial risk of future fracture with continued observation. When conservative management fails or in cases of patient and surgeon mutual decision, operative management is best. For patients who sustain a complete fracture, operative fixation with IMN is the standard of care (Fig. 6). Results of fixation admittedly show mixed results. Weil et al identified 17 fractures in 15 patients that underwent surgery with IMN. seven patients (46 %) required reoperation with either nail dynamization, exchange nail, or revision with a blade plate, although all eventually healed successfully [66]. In the study by Egol et al at 12 months, 98 % demonstrated radiographic healing, but only 64 % of patients reported a return to functional baseline [62•].
Atypical femur fractures related to long-term bisphosphonate use, although still rare, are becoming an increasingly common phenomenon. Physicians and surgeons should be able to recognize the signs and symptoms of impending fracture, as well as the unique features of complete fractures in order to adequately counsel and treat patients. Treatment must include a multidisciplinary approach, with both surgical and medical interventions required in order to obtain a successful outcome. Despite a significant amount of retrospective literature, there is a paucity of prospective studies comparing different options for medical management or comparisons of operative vs nonoperative treatment. As such, recommendations on the management of these fractures are based on small studies and expert opinion. More research must be done on this topic in order to better create a reliable, evidence-based treatment paradigm. Compliance with Ethics Guidelines Conflict of Interest W. H. Bronson, I. D. Kaye, and K. A. Egol declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent All studies by K. A. Egol involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.
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ORTHOPEDIC MANAGEMENT OF FRACTURES (D LITTLE AND T MICLAU, SECTION EDITORS)
Atypical Femur Fractures: A Review Wesley H. Bronson & I. David Kaye & Kenneth A. Egol
Published online: 7 October 2014 # Springer Science+Business Media New York 2014
Abstract Bisphosphonates are one of the most commonly prescribed medications for the treatment of osteoporosis. Their use has greatly decreased the number of osteoporosisrelated vertebral and nonvertebral fractures. Recently, however, a relationship between long-term bisphosphonate use and subtrochanteric and femoral shaft fractures has been elucidated. These low-energy fractures, termed atypical femur fractures, exhibit unique characteristics in their pathophysiology, presentation, and radiographic appearance compared with more traditional high-energy femur fractures. Here we provide a review based on the most recent literature of the pathophysiology, presentation, evaluation, and management of these fractures. Despite an abundance of literature, atypical femur fractures remain difficult to treat, and surgeons must be aware of the tricks and complications associated with their management. Keywords Atypical femur fractures . Bisphosphonates . Subtrochanteric . Osteoporosis . Delayed healing . Intramedullary nail
Introduction Osteoporosis is a major source of disability and affects over 75 million individuals in the United States, Europe, and Japan [1]. The burden of this disease has both health and economic consequences. Nearly one in every four men and one in every two women will sustain an osteoporosis related fracture in their lifetime [2]. For those who suffer a hip fracture, 20 %– 30 % may die within the first year as a result of underlying W. H. Bronson : I. D. Kaye : K. A. Egol (*) Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, 301 E 17th St, New York, NY, USA e-mail: [email protected]
medical problems, and up to 50 % may never regain their prefracture level of function [3, 4]. From an economic perspective, the treatment of a single hip fracture may cost as much as $40,000 [5]. In 2002, the estimated cost of treating osteoporosis related fractures was nearly 20 billion USD [6]. Bisphosphonates have become widely used in the medical treatment for osteoporosis [7, 8]. This class of medications works by decreasing bone resorption, increasing bone mineral density, and subsequently has decreased the incidence of both vertebral and nonvertebral fractures [9–11]. In one study, single infusion of zoledronate decreased the incidence of vertebral fractures over a 3-year period by 70 % compared with placebo, decreased the risk of hip fractures by 41 %, increased bone mineral density, and improved biomarkers of bone metabolism [7]. Long-term bisphosphonate use, however, is not without consequences. In 2005, Odvina et al published the first case report of atypical fractures possibly related to bisphosphonate use [12]. They reported on nine patients who had been taking Alendronate who had sustained spontaneous nonvertebral fractures. Four of the nine patients had subtrochanteric femur fractures, and six of the nine demonstrated delayed or absent bone healing. Additionally, histologic analysis of iliac crest bone biopsy revealed oversuppression of bone turnover, raising the possibility of a causal relationship between bisphosphonate use and the resulting fractures. Despite the decrease in overall fracture risk with the initiation of bisphosphonate therapy, more and more evidence has revealed an association between bisphosphonate use and atypical femur fractures (AFF) [13–16].
Recognizing Atypical Femur Fractures Recently, the American Society for Bone and Mineral Research (ASBMR) has created a set of updated criteria for
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helping to diagnose an AFF (Table 1) [17, 18••]. The fracture must be located below the lesser trochanter and proximal to the supracondylar region of the distal femur. Femoral neck and intertrochanteric fractures with spiral subtrochanteric extension are excluded. This is in contrast to traditional osteoporotic femur fractures, which more commonly occur as femoral neck or intertrochanteric fractures. In addition, there are five major criteria, four of which must be met for the fracture to be classified as an atypical femur fracture. These include (1) no history of trauma, or if present, a low-energy trauma. Osteoporosis-related femoral neck or intertrochanteric fractures occur with low-energy as well, however, rarely occur without trauma. When a subtrochanteric fracture does occur, it is most commonly found after highenergy trauma; (2) the fracture originates at the lateral cortex, and the pattern is transverse or short oblique in configuration; (3) there is minimal or no evidence of comminution. Traditional osteoporotic fractures are classically spiral or long oblique, and high-energy subtrochanteric fractures occur with comminution; (4) they occur with a medial spike in complete fractures or, if an incomplete fracture, involves only the lateral cortex; and (5) there is periosteal or endosteal thickening on the lateral cortex at the fracture site with “beaking.” This is in contrast to bone surrounding an osteoporotic fracture, which tends to have thinned cortices (Figs. 1, 2, and 3). Minor features which do not need to be present but can help in the diagnosis include: generalized femoral cortical thickening, a history of prodromal pain, fractures occurring bilaterally, and evidence of delayed fracture healing. They may also be associated with comorbid conditions or medication use, including rheumatoid arthritis, rickets, osteomalacia, use of proton-pump-inhibitors or glucocorticoids.
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Mechanism The prodromal pain, bilateral occurrence, cortical thickening, and delayed bone healing suggest a separate pathophysiology when compared with osteoporotic fragility fractures [19]. The cause of bisphosphonate associated femur fractures is not entirely known, however, several proposed mechanisms exist. The most commonly accepted etiology is that severe, prolonged over-suppression of bone turnover leads to impaired bone remodeling and microdamage accumulation, resulting in skeletal fragility and thereby predisposing bone to spontaneous fracture [20–23]. Mashiba showed in a dog model that bisphosphonate-induced suppression in trabecular bone remodeling led to a 21 % decrease in bone toughness although no decrease in strength [21]. The majority of completed fractures are associated with low-energy falls.
Epidemiology As mentioned earlier, the introduction of bisphosphonate therapy has greatly decreased the number of typical femur fractures. A study in 2011 showed that from 1996 to 2006, the age-adjusted rates for hip fractures decreased by 31.6 %. At the same time, the number of subtrochanteric fractures increased by 31.2 % [24]. The increased use of bisphosphonates has, at least partly, been implicated in this trend. Nonetheless, the incidence of atypical femur fractures is extremely low. A recent case control study reported on the
Table 1 Major and minor features for the diagnosis of atypical femur fractures [18••] Major features (at least four must be present) Minimal or no trauma, such as fall from standing Fracture originates at lateral cortex and is largely transverse or short oblique Complete fractures associated with a medial spike; incomplete fractures involve only lateral cortex Minimal or no comminution Localized periosteal or endosteal thickening in lateral cortex (“beaking”) Minor features (none must be present but have been commonly associated) Generalized increase in cortical thickness of diaphysis Unilateral or bilateral prodromal symptoms Bilateral incomplete or complete fractures Delayed fracture healing
Fig. 1 Typical high energy subtrochanteric femur fracture with comminution
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Fig. 2 Complete atypical femur fracture
incidence of femur fractures in women over age 68 who took bisphosphonates for over 5 years. The authors found 9723 women who sustained a typical osteoporotic fracture of the intertrochanteric or femoral neck region and 716 who sustained a subtrochanteric or femoral shaft fracture (0.35 %) [25••]. This study, however, did not further evaluate which subtrochanteric or femoral shaft fractures had atypical features, so the incidence is only a fraction of this percentage. Another report was published recently on the effect of bisphosphonate use on the incidence of atypical femur
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fractures. Their study of the National Swedish Register found 12,777 women over age 55 with a femur fracture, 59 of which had atypical features [26]. They calculated that the ageadjusted relative risk of atypical fracture with any bisphosphonate use was 47.3. While the risk is substantially higher compared with nonusers, it is still incredibly low. They note that the difference in risk of atypical fracture between bisphosphonate users and nonusers was 5 per 10,000 patient-years, producing a number needed to harm of 2000 per year of use. Giusti et al looked at 906 patients with femur fractures [27]. Of those, 96 (10.6 %) occurred in the subtrochanteric or femoral shaft region. Of the 96, 63 were low-energy, and ten of those were atypical. Thus, 1.1 % of the femur fractures were atypical fractures. Although the atypical fractures were more frequent in the bisphosphonate users, with an odds ratio of 17.0, one-half of the patients in their cohort who had fractures with atypical features had never used bisphosphonates. Certain patient populations appear to be particularly at risk. Marcano et al identified patients with atypical femur fractures associated with bisphosphonate use (BFF) and patients who were on long term bisphosphonates but who suffered no associated fractures (BNF). After multivariate analysis, they found a higher percentage of Asians in the BFF group (17 %) than in the BNF group (3 %) with P value 0.004 [28•]. In addition, in comparing the BFF group with patients who suffered femur fractures not associated with bisphosphonate use, the patients in the BFF group were more likely to be women (14 % compared with 7 % male) and also tended to be younger. The authors suggest that Asians are at higher risks compared with other ethnicities, and they recommend closer follow-up for these patients. In other studies that analyzed the incidence of atypical fractures in both sexes, women accounted for 80 %–96 % of cases, with men making up a small minority [29, 30].
Presentation
Fig. 3 Bilateral incomplete atypical femur fractures
The majority of patients with atypical femur fractures present after minor trauma or fall from standing or less. But certain features of the patient history and presentation are unique to those with atypical femur fractures. Many patients experience prodromal pain leading up to the injury. In a study by Lo et al of 38 women presenting with atypical femur fractures, nearly one-third had prodromal pain [31]. Other studies show the number to be significantly higher, and a systematic review of case reports by Giusti et al of a total of 141 women with atypical femur fractures found that nearly 64 % had prodromal pain [32]. The duration of the pain is variable, lasting anywhere from days to years before fracture [33]. Patients may also have contralateral lower extremity symptoms or even bilateral fractures. A series by Kwek et al identified 17 patients with atypical femur fractures. Of the 17, nine
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had radiographs with evidence of bilateral stress reactions with lateral cortical thickening [34]. Capeci and Tejwani analyzed 65 patients with atypical femur fractures treated with intramedullary nail [13]. They found that seven patients sustained low-energy bilateral subtrochanteric or diaphyseal fractures while on long-term bisphosphonates. Of the seven, one presented with simultaneous bilateral fractures, two had sequential fractures with the second fracture occurring 12 and 18 months after initial injury, and four exhibited signs of stress reaction/impending fracture at time of initial injury. Lo et al found that patients with atypical femur fractures presented with contralateral stress reaction or complete fracture 39.5 % of the time, while only 2.4 % of the time when presenting with a typical femur fracture [31]. Atypical femur fractures may be associated with other medical comorbid conditions and medication use [31]. Over 75 % of women presenting with atypical femur fractures have one comorbid illness, and almost 25 % have over three. Chronic diseases found in more than 10 % of patients include COPD, asthma, rheumatoid arthritis, and diabetes. Over 25 % of patients report being on oral glucocorticoids and about 10 % on inhaled glucocorticoids for asthma or COPD. Additionally, almost 35 % report taking a proton pump inhibitor.
Imaging The diagnosis is often made easily from plain radiographs. As described previously, atypical femur fractures exhibit unique features on plain radiographs. They are commonly located in the subtrochanteric and proximal midshaft region of the femur. When complete and displaced they have simple transverse or short oblique patterns, lack comminution, have a medial spike, and have lateral cortical thickening, especially when incomplete. This is in contrast to stress fractures seen in athletes, which typically involve the medial cortex [35]. Not all patients with incomplete fractures present with radiographic findings. In the absence of radiographic abnormality, MRI is highly sensitive for detecting stress reaction and impending femur fracture. There may be a fracture line of low intensity on all sequences, the so-called “dreaded black line.” Additionally, decreased intensity on T1 images and increased T2 signal representing edema will be present around the fracture (Fig. 4) [36]. MRI is unnecessary in evaluating completed fractures, but becomes increasingly important in evaluating pain in the absence of radiographic changes, as well as evaluating the contralateral femur in patients who present with unilateral complete or incomplete fractures. Patients presenting with bisphosphonate-associated femur fractures, whether complete or incomplete, have a high rate of contralateral stress reaction, as high as 70 %. Some of these patients may have a history of prodromal pain, but some may
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Fig. 4 MRI demonstrating bone edema and stress fracture in the proximal femur
also be asymptomatic. Thus, many surgeons recommend routine imaging of the contralateral femur [13]. Imaging begins with plain radiographs. If radiographs are normal but clinical suspicion is high, then more advanced imaging with MRI or bone scan should be obtained. Nuclear scintigraphy can also identify incomplete and radiographically occult atypical fractures (Fig. 5). A study by Chan et al found that scintography demonstrated increased uptake in regions of lateral cortical thickening in incomplete fractures [37]. Perret et al demonstrated increased uptake in the contralateral femur of three patients, identifying two fractures that were radiographically occult [38]. As Aghbari and Egol point out, however, nuclear scintography is sensitive but lacks specificity, so correlation to clinical findings or other radiographic studies is required [39].
Treatment Nonoperative and Medical Management After being diagnosed with stress reaction, stress fracture, incomplete or complete fractures, patients should discontinue the offending agent [17]. The incidence of future atypical fracture is reduced by stopping the antiresorptive drug. In a study by Dell et al, the incidence of contralateral femur fracture was 53.9 % in those who were still taking bisphosphonates 3 years after the initial fracture and only 19.3 % in those who had stopped the bisphosphonate after injury [30]. Healing rates, however, do not appear to change during the immediate postinjury period despite discontinuation. In the systematic review by Giusti et al there was no statistically significant difference in delayed healing between those patients who discontinued the bisphosphonate after injury (5/8)
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Fig. 5 Nuclear scintography demonstrating increased uptake in the subtrochanteric region
and those who continued the bisphosphonate (6/13) [32]. This finding may be partially explained by the pharmacokinetics of bisphosphonates. All of the drugs remain present in the body for many years after administration. A single dose of zoledronate has been shown to have sustained antiresorptive effects at 3 years [40]. Similarly, animal models have shown varying metabolism of alendronate, with the drug still present anywhere from months to several years after administration [41]. Patients should also begin vitamin D and calcium supplementation. A recent study of patients with atypical fractures demonstrated that about half the patients had suboptimal levels of 25-hydroxyvitamin D, and 25 % had low levels [42]. Based on studies showing the efficacy of supplementation, it is
Fig. 6 AFF treated with intramedullary nail with abundant healing callus
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recommended now that patients take between 1000 and 2000 IU/day of Vitamin D3 [43]. This is significantly higher than the 400–800 IU/day dose recommended by the Institute of Medicine [44]. Additionally, patients should take 1000– 1200 mg/day of calcium [42]. Based on animal models showing accelerated bone healing, some researches also believe that vitamin C supplementation should be recommended during fracture healing in the elderly [45, 46]. For patients at high risk for fracture secondary to osteoporosis and those with oversuppression of bone turnover from bisphosphonates, some have suggested beginning Teriparatide, a recombinant parathyroid hormone. Teriparatide has been shown to increase callus formation and bone strength during fracture healing [47–52]. Reports of increased bone healing or bone mineral density, however, are inconsistent [53–58]. One study by Lin et al. analyzed femur nonunions in mice by using intramedullary implants and maintaining a 1.7 mm fracture gap while giving recombinant PTH or saline for 14 days. At 6 weeks, the group that had received PTH had significantly lower rates of nonunion measured both radiographically and histologically [59]. In the end, the ASBMR notes that given the varying data, no definite conclusion can be drawn, but they nonetheless consider Teriparatide therapy for those who do not heal with conservative therapy. Up until recently, it was suggested that medical management along with protected weight bearing with the use of assistive device could be considered until pain improved and healing occurred. While this strategy may be attempted in patients with incomplete fractures and mild pain, recent studies have demonstrated a high failure rate with nonoperative management. Banffy et al identified 12 patients with bisphosphonate associated incomplete stress fractures [60••]. Six were treated with prophylactic intramedullary nail and six were treated nonoperatively with nonweight- bearing or protected weightbearing. Of the six treated nonoperatively, five progressed to complete fracture at an average of 10 months. Additionally, they found that those who underwent prophylactic fixation had a total hospital length of stay of 3.7 days vs 6.0 days in those who were treated only after fracture completion. In another study of 14 fractures identified in 11 patients, five progressed to complete fracture at 10 months requiring operative intervention, and another five required surgery due to continued intractable pain [61]. In all, ten of the 14 fractures identified eventually required surgery. Egol similarly showed a 15 % progression rate for incomplete fractures treated nonoperatively [62•]. Nonoperative treatment with partial weight-bearing and medical management can be successful in some patients, but they must be monitored carefully to prevent fracture progression.
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Operative Management
Conclusions
Operative management is utilized in all complete fractures and select incomplete fractures. Potential techniques include plate fixation or intramedullary nail (IMN). Sometimes plate fixation is required because of technical difficulties with placing a nail. It has been reported that the thickened cortices of patients on bisphosphonates can, on occasion, make placing a nail impractical, as the proximal diameter of the nail either results in fracture of the brittle cortex or varus deformity [63]. But while there are no prospective trials comparing plate fixation with IMN, IMN is the preferred treatment of choice. This preference is partially a function of the different methods of healing with the implants. Fractures treated with intramedullary nails heal with abundant callus and through endochondral ossification. Bisphosphonates have not been shown to affect this stage of bone healing. They have been shown, however, to alter bone resorption and remodeling, thus, altering intramembranous bone healing and decreasing the mechanical properties of bone, potentially resulting in plate failure [64, 65]. Egol et al demonstrated successful outcomes with operative treatment of incomplete atypical femur fractures treated with intramedullary nail [62•]. In their study of 31 patients with 43 incomplete fractures, healing, pain, and disability scores were all superior in the operatively treated group. One-hundred percent progressed to radiographic healing compared with 18 % in the nonoperative group, 81 % became pain free vs 64 %, and scores on the Short Musculoskeletal Functional Assessment were better, 19.7 compared with 25.7 in the nonoperative group. The authors conclude that while operative intervention for incomplete fractures appears to provide successful and reliable results, no large scale prospective trial exists. Those who opt for nonoperative management, especially those who continue to have pain, should be counseled on the potential benefits of surgical treatment and the substantial risk of future fracture with continued observation. When conservative management fails or in cases of patient and surgeon mutual decision, operative management is best. For patients who sustain a complete fracture, operative fixation with IMN is the standard of care (Fig. 6). Results of fixation admittedly show mixed results. Weil et al identified 17 fractures in 15 patients that underwent surgery with IMN. seven patients (46 %) required reoperation with either nail dynamization, exchange nail, or revision with a blade plate, although all eventually healed successfully [66]. In the study by Egol et al at 12 months, 98 % demonstrated radiographic healing, but only 64 % of patients reported a return to functional baseline [62•].
Atypical femur fractures related to long-term bisphosphonate use, although still rare, are becoming an increasingly common phenomenon. Physicians and surgeons should be able to recognize the signs and symptoms of impending fracture, as well as the unique features of complete fractures in order to adequately counsel and treat patients. Treatment must include a multidisciplinary approach, with both surgical and medical interventions required in order to obtain a successful outcome. Despite a significant amount of retrospective literature, there is a paucity of prospective studies comparing different options for medical management or comparisons of operative vs nonoperative treatment. As such, recommendations on the management of these fractures are based on small studies and expert opinion. More research must be done on this topic in order to better create a reliable, evidence-based treatment paradigm. Compliance with Ethics Guidelines Conflict of Interest W. H. Bronson, I. D. Kaye, and K. A. Egol declare that they have no conflicts of interest. Human and Animal Rights and Informed Consent All studies by K. A. Egol involving animal and/or human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.
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