Atypical Femoral Fractures Research Articles

Family-based whole-exome sequencing implicates a variant in lysyl oxidase like 4 in atypical femur fractures.

Atypical femur fractures (AFFs) are rare adverse events associated with bisphosphonate use, having unclear pathophysiology. AFFs also cluster in families and have occurred in patients with monogenetic bone diseases sometimes without bisphosphonate use, suggesting an underlying genetic susceptibility. Our aim was to identify a genetic cause for AFF in a Caucasian family with seven members affected by osteoporosis, including three siblings with bisphosphonate-associated AFFs. Using whole-exome sequencing, we identified a rare pathogenic variant c.G1063A (p.Gly355Ser) in lysyl oxidase like 4 (LOXL4) among 64 heterozygous rare, protein-altering variants shared by the three siblings with AFFs. The same variant was also found in a fourth sibling with a low-trauma femur fracture above the knee, not fulfilling all the ASBMR criteria of AFF and in one of 73 unrelated European AFF patients. LOXL4 is involved in collagen cross-linking and may be relevant for microcrack formation and bone repair mechanisms. Preliminary functional analysis showed that skin fibroblast-derived osteoblasts from the unrelated patient with the LOXL4 variant expressed less collagen type I and elastin, while osteogenic differentiation and mineralization were enhanced compared with two controls. In conclusion, this LOXL4 variant may underlie AFF susceptibility possibly due to abnormal collagen metabolism leading to increased formation of microdamage or compromised healing of microcracks in the femur.

Using DEXA to diagnose impending atypical femoral fracture in an asymptomatic patient on long term bisphosphonates: A case report of a missed opportunity for fracture prevention.

We report a patient who sustained an AFF (Atypical femoral fractures) after 15 years of bisphosphonate treatment. DEXA scans can be utilized to identify early evidence of AFF in asymptomatic patients up to 9 years before the development of an AFF.

Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis.

To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis. We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype. Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age ± standard deviation 42.4 ± 10.9years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm2) at the femoral neck (0.72 vs 0.85, p = < 0.001) and total hip (0.79 vs 0.88, p = 0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357g/cm2 (p = 0.028) in those on alendronate for > 5years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4years. In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for < 5years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.

8079 PPI Breaks a Leg! An Unusual Case of Atypical Femur Fracture

Abstract Disclosure: M. Sedghian: None. M. Flanagan: None. D. Pinkhasova: None. K. Selk: None. G. Moloney: None. Background: Atypical femur fractures (AFF) occur along the shaft of the femur extending from the subtrochanteric region proximally to the distal femoral metaphysis. These fractures have an increased incidence in patients taking bisphosphonates and denosumab for osteoporosis and develop as stress reactions in the lateral cortex of the femoral shaft (beaking). However, few cases that meet the characteristics of these fractures have occurred in patients who have never used antiresorptive drugs. We present a case with a history of long-term proton pump inhibitor (PPI) use and possible association with AFF. Clinical Case: The patient is a 68-year-old female with a past medical history of hypothyroidism who presented to the emergency department (ED) after an atraumatic femur fracture and consequently ground level fall. The patient reported experiencing a distinctive cracking sound in her femur while leaning over to wash her feet, resulting in a fall that prompted her to seek immediate care in the ED. Upon initial evaluation, radiographic imaging was significant for displaced left mid-femoral diaphyseal fracture and right femur lateral cortex thickening consistent with AFF. Labs were consistent with elevated PTH to 100.7 [18.4-80.1], Vit D2 1,25 (OH)2 &amp;lt;8 pg/mL, Vit D 25OH 34 ng/ml [30-100], and Calcium level of 9.5. Upon further history taking, the patient stated that she has been taking PPIs intermittently for more than 10 years. She denied a history of bisphosphonate and denosumab exposure, non-Hodgkin's lymphoma, rheumatoid arthritis, and COL1A2 variant mutations as main predisposing factors for atypical femur fractures. She had potential steroid exposure for less than a year before hospitalization as she was on "adrenal complex" from her functional medicine provider. The patient underwent open reduction and internal fixation of the left femur with placement of intramedullary nail and prophylactic fixation with placement of intramedullary nail of the right femur as there was radiographic evidence of beaking. Discussion/Conclusion: Several studies suggested a possible association between PPIs and fracture risk, especially hip fractures, but the relationship remains contentious. Overall, PPIs are positively associated with elevated fracture risk in multiple studies. Increased gastrin production and hypochlorhydria are the two main mechanisms that affect bone remodeling, decreasing bone turnover, impairing calcium absorption, and altering homocysteine levels through impairment of folate and vitamin B12 absorption.This case supports a potential association between long-term PPI use and atypical femur fractures. There have been other case reports that also highlight this potential risk of PPI use. This shows the importance of more comprehensive research on this topic as the number of patients on long-term PPIs is growing in outpatient settings. Presentation: 6/2/2024

7740 Adult-Onset Hypophosphatasia Presenting As Low Alkaline Phosphatase Level Following Denosumab Use For Osteoporosis

Abstract Disclosure: J. Ocampo Mascaro: None. P. Wax: None. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Incyte Research Funding. Background: Hypophosphatasia (HPP) is a genetic disease characterized by low activity of the tissue non-specific alkaline phosphatase. It has a broad range of clinical phenotypes, with adults usually presenting with an incidental low alkaline phosphatase (ALP) finding. Differentiating this from other causes of low ALP is challenging, especially when treating osteoporosis, as antiresorptive therapy such as denosumab and bisphosphonates may cause low ALP and carry the potential of increasing risk of atypical femoral fractures in patients with undiagnosed HPP. Clinical Case: A 64-year-old woman with history of nephrolithiasis, hypercalciuria, and osteoporosis (screening DXA lowest T-score -3.3 in femoral neck (FN)) but no prior fractures or dental issues was seen in clinic. Initial bloodwork showed normal range calcium, 25-OH vitamin D, and intact PTH. Pre-treatment ALP was 42 IU/L (N 39-117). Work up for secondary causes of osteoporosis was negative. Three yearly doses of IV zoledronic acid resulted in +4.2% BMD increase in lumbar spine (LS) but no changes in FN. She had no side effects but was found to have a decrease in ALP to 33 IU/L. This normalized back to 42 IU/L during a three-year drug holiday. Follow up DXA noted significant decline in BMD, hence denosumab was initiated. ALP decreased back to the 30-35 IU/L range. Fasting Vitamin B6 level (off B6 supplements for 1 week) was 23.4 ng/ml (N 2.1-21). Urine phosphoethanolamine was mildly elevated at 5 mmol/mol creatinine (N ≤4). Genetic testing evidenced a pathogenic ALPL variant (Exon 6, c.575T&amp;gt;C (p.Met192Thr), heterozygous) compatible with HPP. She had tolerated three doses of denosumab by then with BMD improvement of 5.0% in LS but no changes in FN and no atypical femoral fracture. Denosumab was stopped. Abaloparatide was started for osteoporosis with close monitoring for worsening hypercalciuria. Conclusion: This case demonstrates that adult HPP patients may present with subtle findings and lower range of normal ALP and may tolerate short courses of antiresorptive agents. There is a need for better screening and diagnostic criteria for adult HPP patients whose ALP levels may not be initially low before initiating antiresorptive drugs for osteoporosis. The risk of adverse effects from therapy will likely vary significantly based on the clinical severity/presentation of HPP as some adults with lower ALP ranges might be more susceptible to developing atypical femur fractures (1). Balancing atypical femur fracture risk with the benefits of antiresorptive treatment in decreasing risk of osteoporotic fractures highlights the need for better risk stratification to prevent undertreatment of osteoporosis. Reference: 1. Warren AM, Ebeling PR, Grill V, Seeman E, Sztal-Mazer S. Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia. Endocrinol Diabetes Metab Case Rep. 2021 Sep 1;2021:21-0096. Presentation: 6/2/2024

7336 Decades In The Dark: The Long Road To Diagnosing And Treating Hypophosphatasia

Abstract Disclosure: V.A. Mendpara: None. G. Madrigal Loria: None. L.Z. Khan: None. Background: Hypophosphatasia (HPP) is a rare bone disorder that results from deficient activity of the tissue non-specific isoenzyme alkaline phosphatase (ALP).[1] This case highlights a patient whose diagnosis of this treatable genetic condition was significantly delayed for almost two decades, despite receiving care at a prominent academic institution. The patient's persistently low ALP levels in routine lab tests were overlooked by multiple clinicians, leading to a delay in her care and eventual treatment. Case presentation: A 61-year-old Caucasian woman presented at the endocrinology clinic with complaints of severe fatigue, generalized pain, multiple childhood fractures, and ongoing dental issues. The rheumatology clinic to which she was referred for polyarthralgia diagnosed her with Hypophosphatasia (HPP) after noting chronically low alkaline phosphatase (ALP) levels from her previous charts ranging from 15 to 24 U/L (normal range: 34 to 123 U/L) over two decades. Her serum calcium, parathyroid hormone (PTH), and 25-hydroxy vitamin D levels were within normal ranges. A DEXA scan revealed normal bone density, effectively ruling out osteoporosis. Further investigation showed elevated Vitamin B6 levels at 219.6 nmol/L (normal range: 20.0 to 125.0 nmol/L), raising suspicion for HPP. The patient's family history provided additional insight, with her mother having a history of short stature and fractures and her son experiencing premature tooth loss at the age of 2. A genetic evaluation identified a heterozygous pathogenic variant in the ALPL gene (c.881A&amp;gt;C, p.Asp294Ala), confirming the diagnosis of autosomal dominant HPP. Initiating treatment with Asfotase alfa, a medication targeting HPP, resulted in a marked improvement in the patient's symptoms. Discussion: This case shows the diagnostic complexities of HPP, stressing the significance of actively screening for this condition via ALP levels in routine laboratory testing or during osteoporosis evaluations. The diagnostic process is critical to distinguish HPP from primary osteoporosis, as treatment and potential risks differ significantly. Inadvertent use of bisphosphonates can worsen hypomineralization and lead to atypical femoral fractures in HPP patients. Asfotase alfa enzyme replacement therapy, available since 2015, offers a targeted approach by replacing the enzyme defect, thereby mitigating symptoms. Heightened awareness among healthcare providers of HPP in adults holds the potential to enhance diagnosis rates and facilitate improved treatment outcomes for this highly treatable condition.[1] Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. ASBMR. Presentation: 6/2/2024

7077 A Rare Case Of Hypophosphatasia Presenting With Osteoporosis In A Young Female Patient- Diagnostic Delay In Hypophosphatasia

Abstract Disclosure: R. Abdelmasih: None. I. Ali: None. Introduction: Hypophosphatasia is a rare hereditary cause of secondary osteoporosis that affects 1/100.000 individuals. The rate of osteoporosis due to hypophosphatasia is probably underestimated as it likely goes undiagnosed in heterogeneous or milder cases. We present a case of Hypophosphatasia that presented initially with osteoporosis and went misdiagnosed for years with intermittent treatment of Bisphosphonate, luckily with no atypical fractures that prompted different course of management for osteoporosis. Case Presentation: A 44-year-old female with a history of rheumatoid arthritis and osteoporosis diagnosed 7 years prior and treated with intermittent bisphosphonate which was discontinued due to side effects including muscle aches and bone pains, presented to our endocrinology clinic to establish care for osteoporosis. Patient denied prior fractures. She reported jaw pain that is being evaluated by otolaryngology and a dentist. Family history is negative. DEXA scan showed Z scores of -1.1, -1.8, and -2.2 of the lumbar spine, femoral neck, and total femur respectively. Laboratory workup showed consistently low alkaline phosphatase (ALP) 25, 20, &amp;lt;20 U/L (ref range 34-123), elevated Vitamin B6 of 167 nmol/L (ref range 20-125), normal parathormone, calcium, phosphate, Vit D, magnesium, and liver enzymes. Genetic testing was sent for Tissue non-specific alkaline phosphatase (TNALP). Hypophosphatasia was diagnosed based on clinical and laboratory findings, patient was started on Asfotase alfa. Clinical course is to be followed. Discussion: Hypophosphatasia is a rare hereditary disorder due to mutation of (TNALP). In normal induvial, TNALP breaks down pyrophosphate to phosphate. It also plays a role in transferring Vit B6 into the tissues. Hence, clinical presentation due to impaired calcium-phosphate hemostasis is broad including musculoskeletal pain, pseudofractues, dental abscess, and neurological symptoms (due to accumulation of Vit B6). The clinical picture varies depending on the heterogenicity of ALPL mutation. Genetic testing is not mandated to establish diagnosis, clinical presentation and laboratory testing including low ALP and elevated Vit B6 are sufficient. However, genetic testing and counseling are recommended for the patient’s sake and their family members. Antiresorptive bone therapy is contraindicated due to a further decrease of bone turnover with reported cases of increased risk of atypical femur fracture, Bone density is reported to improve with enzyme replacement therapy with bone-targeting recombinant alkaline phosphatase (Asfotase Alpha), if further treatment is needed, anabolic treatment is preferred. We present this case to shed light on such a rare disease to decrease rates of underdiagnosis or delayed diagnosis in young patients presenting with osteoporosis for prompt treatment and improved quality of life of these patients. Presentation: 6/2/2024

Bilateral atypical femur fracture in a patient with breast cancer taking zoledronic acid and denosumab: a case report.

A 54-year-old woman developed stage IV breast cancer 8 years prior. Chemotherapy was administered, and she was started on zoledronic acid treatment for her bone metastases. Her chemotherapy regimen was then switched, owing to disease progression. Fifty-seven months after starting treatment with zoledronic acid, the patient suffered an atypical femoral fracture of her right femur, for which she underwent surgery. Twenty months later, she developed another atypical femoral fracture in her left femur and underwent intramedullary nail fixation. Zoledronic acid and denosumab use in patients with metastatic bone tumors caused by breast cancer should be done cautiously, considering atypical femoral fracture risk.

Long-term administration of alendronate sodium caused an atypical femoral shaft fracture in a 36-year-old woman: a case report and literature review.

Long-term bisphosphonate therapy is associated with atypical or insufficiency fractures, particularly in the proximal femur. We observed a case of an atypical femoral shaft fracture in a patient with a long-term history of alendronate therapy. A 36-year-old woman was admitted with a complaint of pain in her right mid-thigh following low-energy trauma. She had been taking alendronate for more than 15 years. X-rays indicated a fracture of the right femoral shaft. The patient was treated with proximal femoral nail antirotation (PFNA) fixation. This case highlights concerns regarding long-term bisphosphonate therapy and its potential complications.

Total Hip Arthroplasty in Hip Osteoarthritis with Subtrochanteric Localized Periosteal Thickening: Preoperative Planning Using Finite Element Analysis to Determine the Optimal Stem Length

Background: Owing to the risk of atypical femoral fractures, total hip arthroplasty presents unique challenges for patients with ipsilateral osteoarthritis and localized periosteal thickening in the femoral subtrochanteric region. Stem length selection is critical for minimizing stress concentration in the thickened cortex to avoid such fractures. Herein, we report the case of a 78-year-old woman with ipsilateral hip osteoarthritis and localized subtrochanteric periosteal thickening. Methods: Preoperative planning included a finite element analysis to assess the stress distribution across various stem lengths. A simulation was conducted to determine the optimal stem length to span the cortical thickening and reduce the risk of postoperative complications. Results: The finite element analysis indicated that a stem length of &gt;150 mm was required to effectively reduce the stress at the site of cortical thickening. A 175 mm stem was selected for total hip arthroplasty, which provided a favorable stress distribution and avoided the risk of stress concentration. Conclusions: In cases of ipsilateral osteoarthritis with localized subtrochanteric periosteal thickening, finite element analysis can be valuable for preoperative planning to determine the optimal stem length, thereby reducing the risk of atypical femoral fractures. Further studies with multiple cases are recommended to validate these findings and improve surgical outcomes.

Atypical fractures at non-classical sites associated with anti-resorptive therapy: A Systematic Review.

Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50 (1). Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described. We aimed to systematically identify atypical fracture cases, excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than three years. A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane and Web of Sciences, and hand-searching of conference abstracts was undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18years) and receiving anti-resorptive medication for >3years were included, with data extracted and analysed by two independent reviewers. Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following atypical fracture in the majority (89%). Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence, at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.

Irish Hip Fracture Database Frailty Index Predicts Delirium Incidence and Length of Stay in Older Adults Admitted with Hip Fractures

Abstract Background The Irish Hip Fracture Database (IHFD) Frailty Index was developed with the National Office for Clinical Audit has been shown to predict adverse outcomes in older adults with fractures in retrospective review of national data. Here we examined the tool prospectively in clinical practice and its ability to predict delirium and length of stay. Methods We prospectively collected data on all hip fracture patients admitted to an acute orthopaedic floor from October 2022 to May 2024. Patients aged &amp;lt; 60 years or those with atypical femoral or peri-prosthetic fractures were excluded. The 21-item frailty index was applied to all eligible patients. Delirium diagnosis was based on a composite of clinical diagnosis and a 4AT score ≥ 4. Regression analysis was used to examine the relationship between delirium and length of stay with Frailty Index, age and sex. Results A total of 260 patients were included in the study, of whom 72% were female. The mean age was 80 ± 10 years, and 7.7% were nursing home residents. Additionally, 24.2% of patients were discharged directly home, while 40.3% were discharged to rehabilitation. Delirium developed in 24.6% of patients, and 24.9% of patients had a LOS exceeding 30 days. Higher frailty index scores were significantly associated with both LOS (p = 0.001) and delirium (p = 0.013) in both unadjusted and adjusted analyses. There was no significant association between age or sex and LOS or delirium in adjusted analysis. Conclusion The IHFD Frailty Index facilitates a pro-active risk stratification that is based on comorbidities and functional status. IHFD Frailty index independently predicted delirium and length of stay while age did not. Further studies integrating this tool into everyday practice in the care of older patients with hip fractures is warranted.

Treating Osteoporosis in Patients with Atypical Femoral Fracture.

Patients who have suffered an atypical femoral fracture while on bisphosphonates or denosumab may continue to be at risk for typical osteoporotic fractures. There are no studies to provide guidance on safe treatment for such patients. Instead, using an illustrative case, 5 principles of management are provided that may lead to decreased osteoporotic fracture risk. The first principle is to discontinue the anti-resorptive medications, which may be challenging in the patient on denosumab because of rebound vertebral fractures reported in patients stopping denosumab. The second principle is to maximize non-pharmacologic management to reduce falls and fractures. Home safety, other methods of fall risk reduction, adequate nutrition, and an exercise prescription should help reduce fracture risk. Investigating potential secondary causes of osteoporosis, particularly if the original workup was not comprehensive, is the third principle because treatment of some specific causes may lower fracture risk. Reviewing the medication list is the fourth principle, with the goal of eliminating drugs that may increase fracture risk; and considering thiazides for some patients, which may lower fracture risk. Finally, some patients may benefit from anabolic therapy. One potential (but not FDA-approved) method is to use long-term cyclic teriparatide or abaloparatide on a three-months on, three-months off schedule. Tailoring the approach to each patient is important, based on the five clinical principles, in the absence of evidence-based management recommendations.

Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures.

Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF.

Prevalence of atypical femoral fractures, a clinical update: A comparative retrospective study 7 years later.

Atypical femoral fractures (AFFs) are a rare type of subtrochanteric or diaphyseal fracture frequently associated with the use of bisphosphonates (BPs). They are a clinical entity often overlooked, for which a correct clinical-instrumental classification is essential for a successful treatment. Nowadays, there is no accurate data on their real incidence. The aim of this work is to evaluate the period prevalence of AFFs and their risk factors, and to compare actual results with a previous study conducted at the same Institution seven years previously. The same methodology used in the previous study, conducted by the same Authors, was applied. Radiographs of all subtrochanteric and diaphyseal femoral fractures in patients over 60 years treated at a single Institution between January 2018 and February 2020 were reviewed, and cases that displayed the AFFs definition criteria were identified. Current and previous medical and pharmacological history were collected, and osteometabolic evaluation through the execution of first level blood tests, with the addition of a valuation of 25(OH)-vitamin D and parathormone was performed. Out of 40 subtrochanteric or diaphyseal femoral fractures in patient aged 60 years or older, four cases (10 %) presented a characteristic radiographic pattern significative for AFFs, in comparison with a 5 % observed in the previous study. All four patients were women with a positive (current or previous) history of BPs consumption. The efficacy of BPs for the prevention of osteoporotic fractures is widely demonstrated. However, particularly prolonged use of these drugs may increase the risk of developing AFFs in some patients. The incidence of AFFs is higher than that reported in the literature, if evaluated only for the subtrochanteric and diaphyseal sites (essential diagnostic criterion in the definition of AFFs). In our study, the incidence of AFFs doubled after seven years. The present data also confirm the frequent association between the use of BPs and the onset of AFFs.

Comparison of bone turnover suppression in atypical femoral fractures and osteoporotic hip fractures

We aimed to compare the extent of bone turnover suppression between patients with atypical femoral fractures (AFFs) and osteoporotic hip fractures (typical femur fractures, TFFs) using a one-to-one matching strategy. A single-center retrospective comparison of females aged ≥ 60 years who underwent operative treatment for AFFs and TFFs between January 2010 and March 2021 was conducted. Demographic characteristics and clinical data including fracture site, past medical history, bone mineral density (BMD), bisphosphonate (BP) medication history, and serum bone turnover marker (BTM) levels were examined. Moreover, we performed a logistic regression analysis to determine the risk factors for AFFs and a one-to-one matched-pair analysis to compare various BTMs. Overall, 336 consecutive females were included: 113 with AFFs and 213 with TFFs. The mean age, BMI, and lowest BMD T-score were 78.6 years, 22.8 kg/m2, and −3.3, respectively. Patients with AFF were younger, had lower BMD, higher BMI, higher prevalence of rheumatoid arthritis, a greater proportion with previous steroid or BP use, and a longer history of BP use than patients with TFF. The 48:48 matched-pair analysis revealed higher serum 25(OH) vitamin-D (30.5 vs 18.2 ng/mL, P < 0.001) and calcium levels (8.8 vs 8.3 ng/dL, P = 0.009) and lower serum CTX levels (0.33 vs 0.54 ng/mL, P = 0.010) in the AFF group than in the TFF group, suggesting a more suppressed bone remodeling. No differences in the other BTM levels were found. Despite identical histories and durations of BP use, the AFF group exhibited lower CTX levels, suggesting more suppressed bone remodeling. This observation leads us to infer that more suppressed bone remodeling, indicated by lower CTX levels, could be linked to the occurrence of AFFs.

Update on Atypical Femoral Fractures.

➤ Atypical femoral fractures (AFFs) are stress fractures between the lesser trochanter and the metaphyseal flare that are most commonly related to prolonged (3 to 5 years) antiresorptive medication use.➤ An important finding is a visible transverse line in the lateral cortex, known as the "dreaded black line." Complete fractures are transverse and have minimal comminution.➤ Prodromal symptoms including hip, groin, thigh, and knee pain are present in more than one-half of cases and are usually misdiagnosed.➤ Nonoperative treatment for all patients with AFF includes withdrawal of bisphosphonates, assessment for secondary causes of osteoporosis, and optimization of vitamin D and calcium.➤ Incomplete fractures without a visible line can initially be treated nonoperatively with protected weight-bearing.➤ Intramedullary nailing is indicated for complete fractures and incomplete fractures with a visible fracture line. Delayed healing after fixation should be anticipated.➤ Treatment with parathyroid hormone (PTH) analogs (teriparatide and abaloparatide) after AFF prevents other fractures in high-risk patients, but the effect on healing of the fracture is unclear.

Assessing the contribution of genes involved in monogenic bone disorders to the etiology of atypical femoral fractures

BackgroundRecent studies suggested that genetic variants associated with monogenic bone disorders were involved in the pathogenesis of atypical femoral fractures (AFF). Here, we aim to identify rare genetic variants by whole exome sequencing in genes involved in monogenic rare skeletal diseases in 12 women with AFF and 4 controls without any fracture.ResultsOut of 33 genetic variants identified in women with AFF, eleven (33.3%) were found in genes belonging to the Wnt pathway (LRP5, LRP6, DAAM2, WNT1, and WNT3A). One of them was rated as pathogenic (p.Pro582His in DAAM2), while all others were rated as variants of uncertain significance according to ClinVar and ACMG criteria.ConclusionsOsteoporosis, rare bone diseases, and AFFs may share the same genes, thus making it even more difficult to identify unique risk factors.

Operative Management of Atypical Femur Fractures.

https://ota.org/education/ota-online-resources/video-library-procedures-techniques/operative-management-atypical#/+/0/score,date_na_dt/desc/.

Atypical Periprosthetic Femoral Fracture Might be Considered a Distinct Subtype of Atypical Femoral Fracture: A Retrospective Study.

The exact relationship among atypical periprosthetic femoral fractures (APFFs), typical periprosthetic femoral fractures (PFFs), and atypical femur fractures (AFFs) remains unclear. This study aimed to investigate the prevalence of APFFs among PFFs and to identify the clinical characteristics, management, and prognosis that distinguish APFFs from typical PFFs and AFFs to further determine the relationship among these three fracture types. In this retrospective study, we reviewed the clinical data of 117 consecutive patients who had PFFs after hip arthroplasty between January 2012 and December 2022 and further classified them into an APFF group and a typical PFF group according to the revised ASBMR diagnostic criteria for AFF. Moreover, patients who had subtrochanteric or femoral shaft fractures in the same period and met the diagnostic criteria for AFF were recruited and classified into the AFF group. Demographic information, minor features of AFF, comorbidities, history of medication usage, management, and complications were collected and compared among patients with typical PFFs, APFFs, and AFFs. Eleven PFFs were identified as APFFs, and the prevalence of APFFs among PFFs was 9.4%. Significant differences were found in generalized increase in cortical thickness (p = 0.019), prodromal symptoms (p < 0.001), and the incidence of bilateral fractures (p = 0.010) among the groups, where the incidences of these minor features in the APFF group and the AFF group were higher than those in the typical PFF group. Of note, the duration of fracture healing of APFFs was significantly longer than that of typical PFFs and AFFs (p < 0.001 and p = 0.004, respectively). In addition, the APFF group and the AFF group had higher proportions of patients with rheumatoid arthritis (p = 0.004 and p = 0.027, respectively), bisphosphonate (BP) usage (p = 0.026 and p < 0.001, respectively), and longer duration of BP usage (p = 0.003 and p = 0.007, respectively) than the typical PFF group. Furthermore, significant differences were found in management (p < 0.001) and complication rate (p = 0.020) among the groups, and the rate of complications in the APFF group and the AFF group was higher than that in the typical PFF group. APFFs not only fulfilled the mandatory and major diagnostic criteria for AFF but also had many clinical characteristics, management and prognosis distinguishing them from typical PFFs but resembling AFFs; hence, the diagnostic criteria for AFF might be revised to incorporate APFF as a distinct subtype of the condition.