Atypical Femoral Fractures Research Articles

Differences in bone histomorphometry between White postmenopausal women with and without atypical femoral fracture after long-term bisphosphonate therapy.

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n= 20) and without (n= 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17yr. Despite the matched range of treatment duration (4-17yr), AFF patients received alendronate for significantly longer time (10.7yr) than non-AFF patients (8.0yr) (P= .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.

Impressive clinical improvement and disappearance of neuropathic pain in an adult patient with hypophosphatasia treated with asfotase alfa

Hypophosphatasia (HPP) is a rare disorder, resulting from loss-of-function variants of the ALPL gene encoding non-tissue specific alkaline phosphatase (TNSALP). Presentation varies largely, with increased severity usually occurring with earlier disease onset. Here we describe the clinical improvement of a 57-year-old woman with childhood onset HPP, after initiating treatment with asfotase alfa (Strensiq®). This was started because of the rapid and progressive radiological deterioration of bone structure after placement of nails in both upper legs for spontaneous atypical femur fracture (AFF) - like fractures. Initiation of treatment, not only resulted in stabilization of bone structure on X-rays, but within a few weeks there was a dramatic reduction of burning pain sensations in the lower legs, attributed in retrospect to neuropathic pain, and also almost complete disappearance of headaches. Additionally, unhealed metatarsal fractures finally healed after almost 10 years. Drug efficacy was further evaluated through -quality of life questionnaires and multiple tests conducted by the physiotherapist, and showed clear improvements. Within 3 months after starting asfotase alfa, the patient was able to carry out her daily tasks indoors without relying on a walker and even started electric bike rides for 20 km/day. In conclusion, treatment with asfotase alfa, halted rapid radiological bone deterioration after bilateral intramedullary femoral pen placement and strongly increased quality of life, marked by rapid disappearance of neuropathic pain, reduction in headaches and musculoskeletal pains, and enhanced muscle strength and mobility. The quick and almost complete disappearance of neuropathic pain and headache suggests a relation with disturbed levels of metabolites in HPP.

Bisphosphonate Use and Risk of Atypical Femoral Fractures: A Danish Case-Cohort Study With Blinded Radiographic Review.

Prolonged bisphosphonate (BP) treatment for osteoporosis prevents hip and other fractures but causes atypical femoral fractures (AFF). To establish the relationship between patterns of BP use and the risk of AFF and hip fractures. Other potential risk factors for AFF were also examined. This population-based case-cohort study utilized data from the Danish National Healthcare system, including longitudinal records of medication use, healthcare utilization, and x-ray images. Among all 1.9 million Danish adults ≥50, those with subtrochanteric or femoral shaft fractures between 2010 and 2015 (n = 4973) were identified and compared to a random sample (n = 37 021). Bisphosphonate use was collected from 1995-2015. Fracture radiographs (n = 4769) were reviewed by blinded study radiologists to identify AFFs (n = 189) using established criteria. Traditional hip fractures in the random sample (n = 691) were identified by ICD-10. Compared to <1 year of BP use, 5 to 7 years of use was associated with a 7-fold increase in AFF (adjusted HR = 7.29 [CI: 3.07, 17.30]); the risk of AFF fell quickly after discontinuation. The 5-year number needed to harm for one AFF was 1424, while the 5-year number needed to treat to prevent one hip fracture was 56. Glucocorticoid and proton pump inhibitor use were independently associated with increased AFF risk. Thirty-one percent of those with AFF had no BP exposure. The risk of AFF increases with duration of BP use but the beneficial effects of BP therapy in adults ≥50 dramatically exceed this increased risk. Nearly one-third of those with AFF have no BP exposure.

Atypical femur fracture in a male without history of bisphosphonate use: a case report

BackgroundAtypical femur fractures are a rare occurrence, especially in bisphosphonate-naïve men, and merit reporting owing to their unusual presentation and clinical implications. This case report highlights a unique instance of atypical femur fractures in a 73-year-old male with no prior bisphosphonate exposure.Case presentationThe patient, a 73-year-old Indian male with no history of bisphosphonate use, presented with left thigh pain and swelling following a minor fall. Radiographic assessment unveiled a closed left mid diaphyseal femoral shaft fracture. Subsequent imaging revealed an impending fracture in the contralateral femur. A comprehensive diagnostic evaluation, encompassing radiographic analysis, laboratory tests, and clinical assessment confirmed the diagnosis. Surgical management via intramedullary nailing was pursued for both fractures. Notably, the patient’s medical history was characterized by radiographic manifestations, the infrequent occurrence of atypical femur fractures in men, and associated risk factors. Treatment encompassed anabolic bone therapy employing teriparatide, alongside discontinuation of antiresorptive agents.ConclusionsThis case underscores the significance of considering atypical femur fractures in older individuals with limited trauma history. It accentuates the role of anabolic agents in the therapeutic regimen and contributes to the evolving understanding of atypical femur fractures. The report underscores the need for vigilant monitoring and tailored management strategies in similar cases, thereby enhancing clinical practice and patient care.

Does the Nonunion Rate of Atypical Femoral Fractures Differ According to Fracture Site?: A Meta-Analysis.

The nonunion rate for atypical femoral fractures (AFF) is known to be higher than that for typical fractures of the femur. We performed a meta-analysis to determine the incidence of nonunion necessitating reoperation following fixation for AFF and compare the rates according to the fracture site (subtrochanter or midshaft). A total of 742 AFFs from 29 studies were included. A proportion meta-analysis utilizing a random-effects model was conducted to estimate the prevalence of nonunion. The outcomes were the incidence of reoperations that included osteosynthesis. To determine the association of nonunion with patient mean age or average duration of bisphosphonate use, meta-regression analysis was done. In proportion meta-analysis, the estimated pooled prevalence of nonunion was 7% (95% confidence interval [CI], 5%-10%) from all studies. There was a significant difference in nonunion rate between the 2 groups (I2 = 34.4%, p = 0.02); the estimated prevalence of nonunion was 15% (95% CI, 10%-20%) in subtrochanteric AFFs and 4% (95% CI, 2%-6%) in midshaft AFFs. From meta-regression analysis, significant correlations were identified between nonunion rate and patient mean age (coefficient: -0.0071, p = 0.010), but not in the average duration of bisphosphonate use (coefficient: -0.0024, p = 0.744). A notable disparity existed in the nonunion rate among subtrochanteric AFFs and midshaft AFFs group. Therefore, it is critical for orthopedic surgeons to consider the complexity and challenges associated with AFF and to estimate the proper possibility of nonunion according to the fracture site.

How to Improve Fracture Healing in Atypical Femoral Fractures

How to Improve Fracture Healing in Atypical Femoral Fractures

Surgical Outcomes of Atypical Femoral Fracture

Surgical Outcomes of Atypical Femoral Fracture

Identifying Complete Atypical Femur Fractures in Adults with Bisphosphonate Exposure

Identifying Complete Atypical Femur Fractures in Adults with Bisphosphonate Exposure

Factors Affecting the Second Complete Atypical Femoral Fracture after the First Atypical Fracture

Objectives: Atypical femoral fracture (AFF) is an atypical low-energy subtrochanteric and diaphyseal femoral fracture. Even if bone fusion is achieved in patients with AFF, the risk of AFF in the contralateral femur must be considered. This study aimed to investigate the factors affecting complete AFF in the contralateral femur and conservatively treated incomplete AFF. Subject and Methods: Radiographs of 111 femurs in 104 AFF cases were examined, and the femurs were classified as follows: 85 contralateral femurs with complete AFF; 18 contralateral femurs with incomplete AFF; 8 femurs with incomplete AFF without surgical treatment. Various patients’ clinical data were collected, and we investigated the factors affecting the second complete AFF. Results: Complete fractures occurred in 10 (9.7%) of 103 femurs without incomplete AFF at the first visit and in 3 (37.5%) of 8 femurs with incomplete AFF. The Kaplan-Meier curve revealed that lateral cortical bone thickening and thigh pain were associated with significantly poorer prognoses (p = 0.026 and p = 0.013, respectively). Multivariate analyses revealed that eldecalcitol usage after AFF onset (p = 0.0094) and previous use of bisphosphonate or denosumab (p = 0.0126) were protective factors for second complete AFF and that the presence of thigh pain (p = 0.0134) was a risk factor for second complete AFF. Conclusions: Eldecalcitol administration after bone union of first AFF may prevent AFF recurrence. In addition, painful incomplete AFF has a high risk of developing a complete fracture.

Towards understanding how bisphosphonate-dependent alterations to nutrient canal integrity can contribute to risk for atypical femoral fractures: Biomechanical considerations and potential relationship to a real-world analogy.

Bisphosphonates are a class of drugs which have shown good efficacy in the treatment of post-menopausal osteoporosis, as well as a good safety profile. However, side-effects such as risk for atypical femoral fractures (AFF) have appeared, leading to a decline in use of the drugs by many patients who would benefit from the treatment. While patient characteristics have contributed to improved understanding of risk factors, the mechanisms involved that explain AFF risk have not appeared. Recently, the possibility that the mechanism(s) involved drug-induced modification of cells of the nutrient canals of the femur and subsequent compromise in the bone matrix has been published. The present Hypothesis article builds on the concept presented earlier and expands into biomechanical considerations. An analogy of the mechanisms involved to a real-life scenario is also presented. While this analogy has limitations, consideration of the biomechanical implications of progressive alterations to defects presented by compromised nutrient canal-bone matrix also presents potential relationships with AFF risk.

Biologic Antiresorptive: Denosumab.

Osteoporosis is an age-related common bone disorder characterized by low bone mineral density and increased fragility fracture risk. Various Antiresorptive medications are being used to target osteoclast mediated bone resorption to prevent bone loss and reduce fracture risk. Denosumab is a novel biological antiresorptive drug that belongs to the class of monoclonal antibodies. It binds to and inhibits the cytokine receptor activator of nuclear factor kappa-B ligand (RANKL), which is requisite for osteoclast differentiation, function and survival. Denosumab has been shown to be a potent and effective therapy for osteoporosis, with clinical trial data demonstrating significant improvement in bone mineral density (BMD) and reductions in fracture risk at various skeletal sites for more than 10 years of treatment. Denosumab has a favourable benefit/risk profile, with low rates of complications such as infection, atypical femoral fracture and osteonecrosis of the jawbone. However, denosumab treatment requires continuous administration, as discontinuation leads to rapid bone mineral loss and increased risk of multiple vertebral fractures due to rebound of bone turnover. Therefore, modification to another anti-osteoporosis drug therapy after denosumab discontinuation is required to maintain bone health. Denosumab is a promising biological antiresorptive therapy for osteoporosis that offers high efficacy and safety, but also poses challenges for long-term management.

Atypical femur fracture: A case study analysis and treatment implications

Atypical femur fracture: A case study analysis and treatment implications

Bilateral atypical femoral fracture in osteoporotic patient treated with bisphosphonates

Bilateral atypical femoral fracture in osteoporotic patient treated with bisphosphonates

Bilateral atypical femoral fracture in osteoporotic patient treated with bisphosphonates

Bilateral atypical femoral fracture in osteoporotic patient treated with bisphosphonates

Atypical Versus Typical Subtrochanteric Femoral Fractures: Disparate Patient Profiles, Similar Outcomes.

The purpose of the present study was to evaluate differences in demographic features and clinical outcomes between patients who sustained a typical versus atypical subtrochanteric femoral fracture. We reviewed the records for a cohort of consecutive patients who had undergone operative treatment of a subtrochanteric femoral fracture. Fractures were classified as either "typical" or "atypical" on the basis of the criteria of the American Society for Bone and Mineral Research (ASBMR). All patients were treated with a similar surgical algorithm and postoperative protocol. Groups were compared on the basis of demographic features, injury characteristics, operative quality measures, postoperative complications and outcomes, and radiographic time to healing. Comparative analyses were performed to compare the typical and atypical cohorts. Of 220 subtrochanteric fractures, 165 (75.0%) were classified as typical and 55 (25.0%) were classified as atypical. The atypical cohort was predominately female and more likely to have bisphosphonate usage (odds ratio [OR], 7.975; [95% confidence interval (CI), 3.994-15.922]; p < 0.001) and fractures with lower-energy mechanisms (p < 0.001). Patients in the atypical cohort were more likely to be treated with a 10-mm cephalomedullary nail (CMN) (OR, 2.100 [95% CI, 1.119-3.939]; p = 0.020), whereas patients in the typical cohort were treated more frequently with an 11-mm CMN (OR, 0.337 [95% CI, 0.168-0.674]; p = 0.002). There were no differences between the groups in terms of other operative parameters; however, anatomic fracture reduction in neutral lateral alignment was achieved more frequently in the typical cohort (OR, 0.438 [95% CI, 0.220-0.875]; p = 0.018). There were no differences between the groups in terms of hospital quality measures, mortality rates, readmission rates, or complication rates (including implant failure [broken screw or nail] and fracture nonunion) (p = 1.00). Interestingly, there was no significant difference between the groups in terms of time to radiographic healing (260.30 ± 187.97 days in the typical group, compared with 246.40 ± 116.33 days in the atypical group) (OR, 0.999 [95% CI, 0.997-1.002]; p = 0.606). Despite differences in terms of demographic and injury characteristics, patients who sustain a subtrochanteric femur fracture can expect similar outcome profiles regardless of fracture type. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Clinical characteristics, densitometric parameters and outcomes of patients with atypical femoral fractures related to bisphosphonate treatment for osteoporosis.

We described the clinical and densitometric characteristics and treatment outcomes of patients who developed atypical femoral fractures (AFF) while on bisphosphonate for osteoporosis. We performed a retrospective cohort study including all adults aged ≥50 years who developed AFF while on bisphosphonates between 1 January 2008 and 31 December 2020, and subsequently managed in the Osteoporosis Centre at Queen Mary Hospital in Hong Kong. A control group of patients who developed fragility hip fractures while on bisphosphonates in the same period was included for comparison. We compared the clinical and densitometric characteristics between the two groups, and described the clinical outcomes for the AFF group. In total, 75 patients were included (AFF: n = 35; fragility hip fracture: n = 40). All were related to oral bisphosphonates. The AFF group was characterised by a longer duration of bisphosphonate use (median of 5 years), higher bone mineral density (BMD) and more acute neck-shaft angle (all p < 0.05). Following AFF, 8 patients (22.9%) did not receive any subsequent bone-active agents: due to refusal to use an injectable, or BMD out of osteoporotic range. Most of those who received bone-active agents were given teriparatide, followed by raloxifene, and achieved stable BMD. However, subsequent fragility risk remained high. Nonetheless, AFF did not confer excess morbidity and mortality. AFF was characterised by usually long duration of bisphosphonate use, higher BMD and more acute neck-shaft angle. AFF did not confer significant impairment in mobility or mortality. Nonetheless, further research work is necessary to optimise bone health among patients who develop AFF.

Fusion of electronic health records and radiographic images for a multimodal deep learning prediction model of atypical femur fractures

Atypical femur fractures (AFF) represent a very rare type of fracture that can be difficult to discriminate radiologically from normal femur fractures (NFF). AFFs are associated with drugs that are administered to prevent osteoporosis-related fragility fractures, which are highly prevalent in the elderly population. Given that these fractures are rare and the radiologic changes are subtle currently only 7% of AFFs are correctly identified, which hinders adequate treatment for most patients with AFF. Deep learning models could be trained to classify automatically a fracture as AFF or NFF, thereby assisting radiologists in detecting these rare fractures. Historically, for this classification task, only imaging data have been used, using convolutional neural networks (CNN) or vision transformers applied to radiographs. However, to mimic situations in which all available data are used to arrive at a diagnosis, we adopted an approach of deep learning that is based on the integration of image data and tabular data (from electronic health records) for 159 patients with AFF and 914 patients with NFF. We hypothesized that the combinatorial data, compiled from all the radiology departments of 72 hospitals in Sweden and the Swedish National Patient Register, would improve classification accuracy, as compared to using only one modality. At the patient level, the area under the ROC curve (AUC) increased from 0.966 to 0.987 when using the integrated set of imaging data and seven pre-selected variables, as compared to only using imaging data. More importantly, the sensitivity increased from 0.796 to 0.903. We found a greater impact of data fusion when only a randomly selected subset of available images was used to make the image and tabular data more balanced for each patient. The AUC then increased from 0.949 to 0.984, and the sensitivity increased from 0.727 to 0.849.These AUC improvements are not large, mainly because of the already excellent performance of the CNN (AUC of 0.966) when only images are used. However, the improvement is clinically highly relevant considering the importance of accuracy in medical diagnostics. We expect an even greater effect when imaging data from a clinical workflow, comprising a more diverse set of diagnostic images, are used.

Bisphosphonates and Atypical Femur Fractures: Is the Relationship Causal or Casual?

Bisphosphonates (BPs) are a time-tested drug class with multivariate use cases. They are used in pathologies ranging from osteoporosis to Paget's disease, and also help in accelerated fracture healing. They have been used to treat both benign and malignant lesions of the skeletal system since a long time. However, there have been reports of increased incidences of atypical femoral fractures (AFFs) in patients exhibiting chronic use of bisphosphonates in the past years. This has led to the widespread dissuasion of physicians and practitioners from using the drug class. By means of this review of the literature, the authors aim to investigate the relationship between BP use and its association with AFFs. The review focuses on and elucidates the basic pharmacology of BPs and goes on to illustrate the indications of BPs in various pathologies of the musculoskeletal system, further exploring the effects of BPs on the healing of various bony fractures. The authors also explore the incidences of other pathologies, such as osteonecrosis of the jaw and nephropathies associated with BP use, and elaborate on their features. Through this review, the authors have tried to educate and induce critical thinking on the part of clinicians and medical professionals in regardto prescribing BPs to patients that need them, by keeping in mind the risk-reward relationship that accompanies their use.

Bisphosphonates and atypical femoral fractures: Is the location of the fracture associated with the time of consolidation?

IntroductionBisphosphonates are commonly prescribed to mitigate the effects of osteoporosis, a condition associated with an increased risk of fracture.However, despite their success, there has been growing concern regarding the long-term use of bisphosphonates because of the increased risk of atypical subtrochanteric fractures of the femur (AFFs).The objective of this study was to describe a cohort of patients with AFFs and evaluate the risk of evolving to non-union, the time of consolidation associated with the location of the fracture, the time of use of the drug, and the implant involved in its treatment. MethodsThis retrospective study recruited patients between June 2008 and May 2018. We identified patients with AFFs according to the task force criteria and a history of bisphosphonate use.We included all patients older than 65 years, with long-term use of bisphosphonates, AFF criteria according to the task force, and a follow-up of 12 months or longer.We studied the following variables: the time of use of bisphosphonates, localization of the fracture according to Hyodo et al., implant use, and fracture healing time, considering the presence of bone callus observed in two radiologic projections, which were measured in weeks. ResultsBetween June 2008 and May 2018, 72 patients met the task force criteria for AFFs.A total of 67 patients were included in this study. From this total, 37 were in the proximal region of the femur and 31 corresponded to the diaphyseal region.Univariate and multivariate analyses showed statistical significance in the time of bone healing compared with the different locations of the fracture along the femur. ConclusionAccording to our study, the localization of AFFs in patients with a history of bisphosphonate use influences the duration of bone healing.

Indication and adverse event profiles of denosumab and zoledronic acid: based on U.S. FDA adverse event reporting system (FAERS).

Objective: To investigate adverse events (AEs) associated with denosumab (Dmab) and zoledronic acid (ZA), compare their association strengths, and explore potential applications to provide clinical reference. Methods: We collected data from FAERS from January 2004 to November 2022 and mined AE signals for Dmab and ZA using ROR values. We compared signal intensity for same AEs and investigated off-label use. We also examined their AEs in adjuvant therapy for breast and prostate cancer. Results: 154,735 reports of primary suspect drugs were analyzed in the FAERS database (Dmab: 117,857; ZA: 36,878). Dmab and ZA had 333 and 1,379 AE signals, with 189 overlaps. The AEs of Dmab included death (ROR:3.478), osteonecrosis of jaw (ROR:53.025), back pain (ROR:2.432), tooth disorder (ROR:16.18), bone pain (ROR:6.523). For ZA, the AEs included osteonecrosis (ROR:104.866), death (ROR: 3.645), pain (ROR:3.963), osteonecrosis of jaw (ROR: 91.744), tooth extraction (ROR: 142.143). Among overlap signals, Dmab showed higher strength in exostosis of the jaw (ROR: 182.66 vs. 5.769), atypical fractures (ROR: 55.589 vs. 9.123), and atypical femur fractures (ROR:49.824 vs. 4.968). And ZA exhibited stronger associations in abscess jaw (ROR: 84.119 vs. 11.12), gingival ulceration (ROR: 74.125 vs. 4.827), increased bone formation (ROR: 69.344 vs. 3.218). Additionally, we identified 528 off-label uses for Dmab and 206 for ZA, with Dmab mainly used in prostate cancer (1.04%), breast cancer (1.03%), and arthritis (0.42%), while ZA in breast cancer (3.21%), prostate cancer (2.48%), and neoplasm malignant (0.52%). For Dmab in breast cancer treatment, AEs included death (11.6%), disease progression (3.3%), and neutropenia (2.7%), while for ZA included death (19.8%), emotional disorder (12.9%), osteomyelitis (11.7%). For prostate cancer treatment, Dmab`s AEs were death (8.9%), prostate cancer metastatic (1.6%), renal impairment (1.7%), while ZA`s included death (34.4%), general physical health deterioration (19.9%), and hemoglobin decreased (18.9%). Conclusion: Our analysis of FAERS database provided postmarketing surveillance data and revealed different strengths of reported AE signals between Dmab and ZA in some of their common AEs. It's also worth noting that both drugs have potential off-label applications, which could introduce new AEs. This highlights the necessity for safety monitoring when using Dmab and ZA off-label.