Review: Epidemiology and Pathophysiology of Atypical Femur Fractures

The recent recognition of the clinical phenomenon of atypical femoral fractures has garnered significant scientific interest. In this review, we will discuss and summarize the salient developments in the current understanding of the epidemiology, pathophysiology, and radiology of atypical femoral fractures.     

Detection of Atypical Femur Fractures

The 2019 International Society for Clinical Densitometry (ISCD) Position Development Conference Task Force for monitoring with dual-energy X-ray absorptiometry (DXA) identified detection of atypical femur fractures (AFFs) as an important topic and established this working group to answer key questions in this area. The authors conducted a systematic review of the literature and deliberated on proposed ISCD positions, which were then reviewed by an external expert panel and vetted at the 2019 ISCD Position Development Conference in Kuala Lumpur on March 23, 2019. This paper summarizes the final ISCD positions and the rationale for supporting these positions. Default-length femur imaging or extended-length femur imaging as well as full-length femur imaging (FFI), both single-energy and dual-energy scans, by DXA can detect abnormalities in the spectrum of AFF. It is important to visually inspect all DXA scans of the hip and femur, and report on findings of focal periosteal and endosteal thickening at the lateral cortex (grade: Good, A, W). FFI is the preferred DXA scan mode for detecting abnormalities in the spectrum of AFF. The FFI report should state the absence or presence of abnormalities in the spectrum of AFF. If focal thickening is present on the lateral cortex, the report should state whether a lucent line is seen (grade: Fair, C, W). The ISCD recommends considering the use of bilateral FFI in patients who are currently or have been in the past year on potent antiresorptive therapy (ie, oral or intravenous bisphosphonate or subcutaneous denosumab therapy) for a cumulative period of 3 or more years, especially those on long-term glucocorticoid therapy (grade: Fair, B, W). More research is needed to determine the role of repeat testing and the optimal time interval for follow-up DXA scans, whether an automated measuring tool would perform better than visual inspection, whether FFI would change patient management and outcomes, and the cost-effectiveness of FFI.     

The Sydney AFF Score: A Simple Tool to Distinguish Females Presenting With Atypical Femur Fractures Versus Typical Femur Fractures

Atypical femur fractures (AFF) are a rare but serious complication of long-term bisphosphonate use. Although clearly defined by ASBMR criteria, a proportion of patients with AFFs may go unrecognized and the use of qualitative fracture criteria may lead to uncertainty in AFF diagnosis, with significant therapeutic implications. A score that rapidly and accurately identifies AFFs among subtrochanteric femur fractures using quantitative, measurable parameters is needed. In a retrospective cohort of 110 female patients presenting with AFFs or typical femur fractures (TFFs), multiple logistic regression and decision tree analysis were used to develop the Sydney AFF score. This score, based on demographic and femoral geometry variables, uses three dichotomized independent predictors and adds one point for each: (age ≤80 years) + (femoral neck width <37 mm) + (lateral cortical width at lesser trochanter ≥5 mm), (score, 0 to 3). In an independent validation set of 53 female patients at a different centre in Sydney, a score ≥2 demonstrated 73.3% sensitivity and 69.6% specificity for AFF (area under the receiver-operating characteristic curve [AUC] 0.775, SE 0.063) and remained independently associated with AFF after adjustment for bisphosphonate use. The Sydney AFF score provides a quantitative means of flagging female patients with atraumatic femur fractures who have sustained an AFF as opposed to a TFF. This distinction has clear management implications and may augment current ASBMR diagnostic criteria. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Screening for Atypical Femur Fractures Using Extended Femur Scans by DXA

Atypical femur fractures (AFFs) are a rare but serious complication associated with the use of antiresorptive drugs such as bisphosphonates. Assessment of incomplete AFFs on extended femur scans by dual‐energy X‐ray absorptiometry (DXA) may prevent the development of complete fractures. The aim of this study was to evaluate the potential of extended femur scans by DXA as a screening tool for incomplete AFFs. From June 2014 until September 2016, extended femur scans were routinely performed in all consecutive patients undergoing DXA scanning who had used bisphosphonates or denosumab at any given moment in the previous year. When “beaking” was found, defined as a localized periosteal or endosteal thickening of the lateral cortex, a radiograph of the femur was performed to confirm incomplete AFF. Beaking was detected in 12 of 282 patients (4.3%) with extended scans of both femora. In 9 patients (3.2%), beaking corresponded with the radiological presence of incomplete AFFs, of whom 4 already had an X‐ray made because of a previous complete AFF of the other leg. Five patients (1.8%) were newly diagnosed with 6 yet unknown incomplete AFFs. No additional X‐ray was performed in 2 patients because of loss of follow‐up. Beaking was explained by known soft tissue calcifications in 1 patient. The positive predictive value of beaking on extended femur scan was 83.3% in our study. Three cases in whom the new diagnosis of incomplete AFF has affected medical and surgical treatment are further discussed to illustrate the relevance of early detection. We conclude that extended femur scans by DXA can detect incomplete AFFs in patients on antiresorptive treatment and should therefore be considered a clinically relevant screening tool because early identification of AFFs has therapeutic consequences. © 2017 American Society for Bone and Mineral Research.     

Fractures of the Proximal Femur in Childhood: A Review

BackgroundFemoral neck fractures in children are rare injuries, occurring due to high-energy trauma. Due to the unique anatomy and blood supply of the proximal femur in growing children, these fractures are notorious for high rates of complications despite appropriate management. Classification of these fractures is according to the Delbet system, which not only guides management but also gives prognostic clues. Multiple fixation methods have been described and there is no consensus on what constitutes the best treatment. Osteonecrosis, non-union, coxa vara and premature physeal arrest are the most frequent complications.PurposeTo review the current knowledge, discuss controversial aspects, and provide suggestions for future research.MethodsWe have reviewed the literature on paediatric proximal femur fractures and have provided an evidence-based guide to the diagnosis and management of these injuries. Common complications have been elaborated and options for their prevention and/or management discussed.ConclusionThere is universal agreement that anatomic reduction and stable internal fixation, supplemented by spica immobilization in younger children, are essential to obtain good outcomes. The role of capsular decompression, choice and configuration of implant, and appropriate timing of surgery are aspects that continue to be debated. Multicenter prospective studies are necessary to standardize treatment of these challenging injuries.     

Evaluating Atypical Features of Femur Fractures: How Change in Radiological Criteria Influenced Incidence and Demography of Atypical Femur Fractures in a Community Setting

Identification of atypical femoral fractures (AFFs) can be challenging. To assist in the radiological assessment, an American Society for Bone and Mineral Research (ASBMR) Task Force developed a case definition for AFFs in 2010, revising it in 2013. How the revised definition performs in a community setting compared with the 2010 definition is unknown. We applied the 2013 criteria to 372 femoral fractures that occurred between January 1, 1996, and June 30, 2009, employing two independent expert physician reviewers. We used radiographs that had been categorized in a previous study on the incidence of atypical fractures using 2010 ASMBR criteria (BEAK1). In this follow‐up study (BEAK2), the same reviewers reviewed all previously identified femoral shaft fractures (FSFs) (n = 197) and distal femur fractures (n = 131) plus a 15% random sample of intertrochanteric fractures (n = 49). After initial review, agreement between the two reviewers ranged from 63% to 100% for specific features, and 84% of radiographs received the same overall classification. Fewer fractures met the 2013 compared with 2010 ASMBR case definition of AFFs (37 per 2013 criteria versus 74 per 2010 criteria). Forty‐three radiographs (58%) categorized as AFFs according to 2010 criteria were no longer AFFs when 2013 criteria were applied, and an additional 12 non‐atypical FSFs according to 2010 criteria were reclassified as AFFs according to 2013 criteria. The major cause of AFF reclassification was the change in the definition of transverse configuration. The modification of the comminution, non‐traumatic, and periosteal/endosteal thickness criteria resulted in the reclassification of non‐atypical FSFs to AFFs. Incidence rate of AFFs according to 2013 ASBMR criteria was lower overall during the 13 years of observation than when the 2010 ASBMR criteria were applied, although we saw a slight increase starting in 2000. As in BEAK1, we found that those with AFFs were younger, more often female, and had a higher exposure rate to bisphosphonates than those with non‐atypical FSFs. As we continue to unravel the demographics of those who suffer from AFFs, our study adds information about how the change in criteria influences epidemiological work. © 2017 American Society for Bone and Mineral Research.     

Clinical Outcomes Following Distal Femur Replacement for Periprosthetic Distal Femur Fractures: A Systematic Review and Meta-Analysis

BackgroundManagement of periprosthetic distal femur fractures (PDFFs) is often complicated by poor bone quality and limited bone stock making fixation attempts challenging and prone to failure. Distal femoral replacement (DFR) is being used to treat such injuries although outcome data are mostly from small case series. We sought to systematically review the literature on DFR for PDFF to summarize their outcomes.MethodsPubMed, MEDLINE (EBSCO), and Cochrane Central Database were searched to identify reports of PDFFs treated with DFR. Articles reporting on 5 or more knees were systematically reviewed for clinical function, complications, and mortality. Random effects meta-analysis was used to create summary estimates and publication bias also assessed.ResultsOf 287 identified and screened articles, 15 were included, 14 retrospective, reporting on 352 knees. Following DFR, 87% (95% confidence interval [CI] 71-95) of patients were able to ambulate. The mean postoperative Knee Society Score was 80 (95% CI 77-84). The risk of periprosthetic joint infection was 4.3% (95% CI 2.2-8.2). One-year postoperative mortality rate was 10% (95% CI 6-18). There was some evidence of publication bias with a trend toward smaller studies reporting lower infection risk and mortality.ConclusionDFR for PDFFs is associated with high functional outcomes and a relatively modest risk of infection. The periprosthetic joint infection and 1-year mortality rates reported here should be considered lower bounds estimates due to publication bias and loss to follow-up. Further investigation of long-term outcomes following DFR for PDFFs is warranted though short-term functional outcomes are promising.     

The Correlation Between Lateral Bowing Angle of the Femur and the Location of Atypical Femur Fractures

This study is the first to report the use of data on incomplete atypical femur fracture (AFF) to evaluate the curvature of femur and explore the relationship between lateral femoral bowing angle (FBA) and AAF location. In this study, we obtained 17 cases of incomplete AFF and calculated the accurate lateral FBA and location ratio of the incomplete fracture. Incomplete fracture location was defined as a percentage (length from lesion to greater trochanter tip/entire femur length %; greater trochanter tip: 0 %; femoral condyles: 100 %). A lateral FBA of 7° was set as the point of demarcation. Eleven femurs had a lateral FBA ≤ 7° (group 1), with a median lateral FBA of 4.75° (IQR 2.5–5.9°) and a median of incomplete AFF location at 25.2 % (IQR 23.4–30.1 %). Another six femurs had a FBA > 7° (group 2) with a median of 1.8° (IQR 10.2–14.3°) and a median location at 47.7 % (IQR 38.6–54.5 %). There was a significant statistical difference in location (p < 0.05) between the two groups. The rate of BP use was 87.5 % in group 1 which was higher than 60 % in group 2. There was some degree of positive correlation between the bowing angle and location in simple linear regression (r ² = 0.549, p < 0.001, ß = 1.789). AAFs located in diaphysis were associated with large lateral FBA. On the other hand, AAFs located in subtrochanteric region were more commonly found in femurs with smaller lateral FBA. In conclusion, the degree of the FBA was associated with AFF location.     

Incomplete Atypical Femoral Fractures: Assessing the Diagnostic Utility of DXA by Extending Femur Length

Atypical femoral fractures (AFFs) are associated with prolonged bisphosphonate therapy. A feature of incomplete AFF is a localized periosteal reaction. It has been suggested that extending the length of the femur image at the time of dual-energy X-ray absorptiometry (DXA) may diagnose an incomplete AFF. In patients older than 50 yr on bisphosphonate therapy for more than 5 yr, we extended femur length at the time of routine DXA. Abnormal DXA images were suggested in 19 of 257 patients (7.4%). On X-ray, 7 patients (2.7%) showed no abnormality, 7 patients (2.7%) showed evidence of AFF, and 5 patients (2.0%) showed an unrelated radiographic abnormality. Of the 7 cases with X-ray evidence of AFF, 5 had a periosteal flare and 2 had a visible fracture line, both of whom needed insertion of an intramedullary nail. We demonstrated that it is feasible to detect incomplete AFF early using extended femur length imaging with a prevalence in our sample of 2.7% (95% confidence interval: 1.7%–3.7%).     

Incidence of Atypical Femur Fractures in Cancer Patients: The MD Anderson Cancer Center Experience

Atypical femoral fractures (AFFs) are rare adverse events attributed to bisphosphonate (BP) use. Few cases of AFF in cancer have been described; the aim of this study is to identify the incidence and risk factors for AFF in a large cancer center. This retrospective study was conducted at the MD Anderson Cancer Center. The incidence rate of AFF among BP users was calculated from January 1, 2004 through December 31, 2013. The control group (n = 51) included 2 or 3 patients on BPs matched for age (≤1 year) and gender. Logistic regression analysis was used to assess the relationship between clinical characteristics and AFF. Twenty‐three AFF cases were identified radiographically among 10,587 BP users, the total BP exposure was 53,789 months (4482 years), and the incidence of AFF in BP users was 0.05 cases per 100,000 person‐years. Meanwhile, among 300,553 patients who did not receive BPs there were 2 cases of AFF as compared with the 23 cases noted above. The odds ratio (OR) of having AFF in BP users was 355.58 times higher (95% CI, 84.1 to 1501.4, p < 0.0001) than the risk in non‐BP users. The OR of having AFF in alendronate users was 5.54 times greater (OR 5.54 [95% CI, 1.60 to 19.112, p = 0.007]) than the odds of having AFF among other BP users. Patients who were on zoledronic acid (ZOL) had smaller odds of developing AFF compared with other BP users in this matched case control sample. AFFs are rare, serious adverse events that occur in patients with cancer who receive BP therapy. Patients with cancer who receive BPs for prior osteoporosis therapy or for metastatic cancer are at higher risk of AFF. © 2016 American Society for Bone and Mineral Research.     

Trabecular Bone Score and Hip Structural Analysis in Patients With Atypical Femur Fractures

Bisphosphonate use has declined dramatically in recent years, partly because of fear of rare side effects like atypical femur fractures (AFFs). It is therefore desirable to have a diagnostic method to identify those at risk of AFF to prevent this serious complication. We compared trabecular microarchitecture and hip geometry between 30 patients with AFF and 141 controls of similar age and sex, using bisphosphonates. Trabecular bone score (TBS) and hip structural analysis (HSA) were used to assess trabecular microarchitecture and macroscopic hip geometry from dual-energy X-ray absorptiometry images of the lumbar spine and hip, respectively. General characteristics, TBS, and HSA were compared between patients with AFF and controls using Student's t tests and chi-square statistics. Associations between AFF and TBS and femur geometric characteristics by HSA were adjusted for sex, age, height, weight, ethnicity, duration of bisphosphonate use, and glucocorticoid use. Additionally, the analysis of TBS was adjusted for lumbar spine bone mineral density and the time difference between dual-energy X-ray absorptiometry scanning and the diagnosis of AFF. Patients with AFF had significantly higher body mass index than controls, had used bisphosphonates longer, and glucocorticoids and proton pump inhibitors more frequently. Sex-specific T-score was significantly higher in patients with AFF at the lumbar spine (p?=?0.004), but not at the femoral neck (p?=?0.190) after adjustment for age, height, and weight. TBS did not differ significantly between patients with AFF and controls. Neither neck shaft angle nor any geometric variables at the femoral shaft measured by HSA differed between patients with AFF and controls. At the narrow neck, patients with AFF had lower buckling ratio and higher centroid position, consistent with a lower risk of classical fragility hip fractures. The findings at narrow neck and higher bone mineral density might be explained by the fact that the majority of patients with AFF used bisphosphonates to prevent glucocorticoid-induced osteoporosis. Based on our results, TBS and HSA do not appear to have value in detecting patients at risk of AFF.     

Current Understanding of Epidemiology,Pathophysiology, and Management of Atypical Femur Fractures

Purpose of Review

To summarize reports published since the 2013 American Society of Bone and Mineral Research Task Force Report on atypical femoral fractures (AFF).

Recent Findings

The absolute incidence of AFFs remains low. AFFs are primarily associated with prolonged bisphosphonate (BP) exposure, but have also been reported in unexposed patients and those receiving denosumab for osteoporosis and metastatic bone disease. Asians may be more susceptible to AFFs. Lateral femoral bowing and varus hip geometry, which increase loading forces on the lateral femoral cortex, may increase AFF risk. Altered bone material properties associated with BP therapy may predispose to AFFs by permitting initiation and increasing propagation of micro-cracks. Relevant genetic mutations have been reported in patients with AFFs. Single X-ray absorptiometry femur scans permit early detection of incomplete and/or asymptomatic AFFs. Orthopedists recommend intramedullary rods for complete AFFs and for incomplete, radiologically advanced AFFs associated with pain and/or marrow edema on MRI. Teriparatide may advance AFF healing but few data support its efficacy.

Summary

Greater understanding of biological and genetic predisposition to AFF may allow characterization of individual risk prior to initiating osteoporosis therapy and help allay fear in those at low risk for this complication, which remains rare in comparison to the osteoporotic fractures prevented by antiresorptive therapy.

     

ESIN in Femur Fractures

Abstract Background and Purpose: Elastic stable intramedullary nailing (ESIN) is gaining increasing popularity, but studies with high case loads are rare. It was the aim of four experienced pediatric trauma centers to give an update of indications for ESIN, postoperative management, and complications. Patients and Methods: Data of the last 100 ESIN cases of each department before June 30, 2003 were collected by reviewing the charts and X-rays. Among these 400 collected ESINs 65 femoral shaft fractures (16%) were found. The patients age ranged between 23/4 and 151/4 years. The middle third of the shaft was affected 42 times (65%), 13 fractures (20%) were in the proximal third of the diaphysis, and ten (15%) in the distal part of the femur, five dia- and five metaphyseal. Mainly transverse fractures were treated (52%), followed by 38% oblique or spiral fractures and 10% wedge or comminuted fractures. Two open reductions were required. Median hospitalization time was 6 days. Nails were extracted after a mean of 178 days. Results: Six skin irritations (wound infections, hematoma, seroma), one patient with myositis ossificans and one with constant pain at too long nail end were found. Three cosmetically relevant scarrings were observed during follow-up. Relevant axial deviations at fracture healing in two and shortening in one fracture could be seen, all caused by technical failure. Conclusion: ESIN meets all demands for an optimal fracture healing in children. Still, a considerable percentage of complications is observed, mainly caused by the surgeon himself, which can be avoided by exact indication and technique. Postoperative management has yet to be standardized.     

Responses to Treatment With Teriparatide in Patients With Atypical Femur Fractures Previously Treated With Bisphosphonates

If oversuppression of bone turnover explained the association between bisphosphonate use and atypical subtrochanteric femur fractures (AFF), this could be reversed with anabolic treatment such as teriparatide. We conducted a prospective, open‐label study in patients previously treated with bisphosphonates who sustained AFF, examining the response to 24‐month treatment with teriparatide on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers (BTM), and fracture healing as well as quantitative histomorphometry. We studied 14 patients. Baseline BMD, BTM, and TBS varied widely. On initial bone biopsies, 12 of 14 patients showed tetracycline labels, but mineralizing surface/bone surface was below published normal values in all but 2. Lumbar spine BMD increased significantly at month 24 (6.1% ± 4.3%, p < 0.05 versus baseline), whereas total hip BMD and TBS did not change significantly. Changes in BTM occurred as reported previously for patients without AFF treated with teriparatide after prior bisphosphonate treatment. At month 24, fractures were healed in 6 patients, showed partial healing in 3, were unchanged in 2, and showed nonunion in 1. In a patient with two fractures, the fracture that occurred before teriparatide treatment was reported as healed, but the fracture that occurred while on treatment showed only partial healing. Bisphosphonate‐treated patients who sustain AFF show heterogeneity of bone turnover. Treatment with teriparatide resulted in increases in BTM and lumbar spine BMD, as has been reported for patients without AFF. There was no significant effect of teriparatide on hip BMD, mineralizing surface to bone surface (MS/BS), or TBS and no consistent effect on fracture healing. In the context of a patient who has experienced an AFF after receiving bisphosphonate treatment, therapy with teriparatide for 24 months would be expected to increase BMD and BTM (and probably reduce the risk of fractures resulting from osteoporosis) but should not be relied on to aid in healing of the AFF. © 2017 American Society for Bone and Mineral Research.     

Mortality After Atypical Femoral Fractures: A Cohort Study

Although osteoporotic fracture rates can be reduced by bisphosphonates, prolonged therapy is associated with higher risk of atypical femoral fractures. Ordinary fragility fractures are linked to high mortality rates. We aimed to determine whether atypical femoral fractures also confer excess mortality. Radiographs were reviewed for all patients aged ≥55 years who had experienced a subtrochanteric or femoral shaft fracture in Sweden in 2008 to 2010. The fractures were classified as either atypical or ordinary. Data on medication use, coexisting conditions, and date of death were obtained from national registers. We estimated multivariable‐adjusted relative risks of death after atypical femoral fractures compared with ordinary subtrochanteric or femoral shaft fractures and calculated age‐ and sex‐standardized mortality ratios (SMRs) for atypical and ordinary fractures compared with the population average. During a mean of 4 years of follow‐up, 39 of 172 (23%) patients with an atypical fracture had died compared with 588 of 952 (62%) with an ordinary fracture, corresponding to a relative risk of 0.51 (95% confidence interval [CI] 0.38–0.68). The lower risk was evident in both users and nonusers of bisphosphonates. No patient with atypical fracture died in the first year after fracture. Individuals with an ordinary fracture had a higher mortality risk than the general population (SMR = 1.82; 95% CI 1.69–1.99), but no excess risk was found in patients with atypical fracture (SMR = 0.92; 95% CI 0.65–1.26). We conclude that in contrast to ordinary subtrochanteric and femoral shaft fractures, atypical femoral fractures are not associated with excess mortality. © 2015 American Society for Bone and Mineral Research.