Prevalence of Monogenic Bone Disorders in a Dutch Cohort of Atypical Femur Fracture Patients.

Atypical femur fractures (AFFs), considered rare associations of bisphosphonates, have also been reported in patients with monogenic bone disorders without bisphosphonate use. The exact association between AFFs and monogenic bone disorders remains unknown. Our aim was to determine the prevalence of monogenic bone disorders in a Dutch AFF cohort. AFF patients were recruited from two specialist bone centers in the Netherlands. Medical records of the AFF patients were reviewed for clinical features of monogenic bone disorders. Genetic variants identified by whole-exome sequencing in 37 candidate genes involved in monogenic bone disorders were classified based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines. Copy number variations overlapping the candidate genes were also evaluated using DNA array genotyping data. The cohort comprises 60 AFF patients (including a pair of siblings), with 95% having received bisphosphonates. Fifteen AFF patients (25%) had clinical features of monogenic bone disorders. Eight of them (54%), including the pair of siblings, had a (likely) pathogenic variant in either PLS3, COL1A2, LRP5, or ALPL. One patient carried a likely pathogenic variant in TCIRG1 among patients not suspected of monogenic bone disorders (2%). In total, nine patients in this AFF cohort (15%) had a (likely) pathogenic variant. In one patient, we identified a 12.7 Mb deletion in chromosome 6, encompassing TENT5A. The findings indicate a strong relationship between AFFs and monogenic bone disorders, particularly osteogenesis imperfecta and hypophosphatasia, but mainly in individuals with symptoms of these disorders. The high yield of (likely) pathogenic variants in AFF patients with a clinical suspicion of these disorders stresses the importance of careful clinical evaluation of AFF patients. Although the relevance of bisphosphonate use in this relationship is currently unclear, clinicians should consider these findings in medical management of these patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Whole Exome Sequencing in Two Southeast Asian Families With Atypical Femur Fractures.

Atypical femur fractures (AFFs) are rare complications of anti-resorptive therapy. Devastating to the affected individual, they pose a public health concern because of reduced uptake of an effective treatment for osteoporosis due to patient concern. The risk of AFF is increased sixfold to sevenfold in patients of Asian ethnicity compared with Europeans. Genetic factors may underlie the AFF phenotype. Given the rarity of AFFs, studying familial AFF cases is valuable in providing insights into any genetic predisposition. We present two Singaporean families, one comprising a mother (1-a) and a daughter (1-b), and the other comprising two sisters (2-a and 2-b). All four cases presented with bisphosphonate-associated AFF. Whole-exome sequencing (WES) was performed on 1-b, 2-a, and 2-b. DNA for 1-a was not available. Variants were examined using a candidate gene approach comprising a list of genes previously associated with AFF in the literature, as well as using unbiased filtering based on dominant and/or recessive inheritance patterns. Using a candidate gene approach, rare variants shared between all three cases were not identified. A rare variant in TMEM25, shared by the two sisters (2-a and 2-b), was identified. A rare heterozygous PLOD2 variant was present in the daughter case with AFF (1-b), but not in the sisters. A list of potential genetic variants for AFF was identified after variant filtering and annotation analysis of the two sisters (2-a and 2-b), including a Gly35Arg variant in TRAF4, a gene required for normal skeletal development. Although the findings from this genetic analysis are inconclusive, a familial aggregation of AFFs is suggestive of a genetic component in AFF pathogenesis. We provide a comprehensive list of rare variants identified in these AFF familial cases to aid future genetic studies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Medical Management of Patients After Atypical Femur Fractures: a Systematic Review and Recommendations From the European Calcified Tissue Society.

CONTEXT: Atypical femur fractures (AFFs) are serious adverse events associated with bisphosphonates and often show poor healing. EVIDENCE ACQUISITION: We performed a systematic review to evaluate effects of teriparatide, raloxifene, and denosumab on healing and occurrence of AFF. EVIDENCE SYNTHESIS: We retrieved 910 references and reviewed 67 papers, including 31 case reports, 9 retrospective and 3 prospective studies on teriparatide. There were no RCTs. We pooled data on fracture union (n = 98 AFFs on teriparatide) and found that radiological healing occurred within 6 months of teriparatide in 13 of 30 (43%) conservatively managed incomplete AFFs, 9 of 10 (90%) incomplete AFFs with surgical intervention, and 44 of 58 (75%) complete AFFs. In 9 of 30 (30%) nonoperated incomplete AFFs, no union was achieved after 12 months and 4 (13%) fractures became complete on teriparatide. Eight patients had new AFFs during or after teriparatide. AFF on denosumab was reported in 22 patients, including 11 patients treated for bone metastases and 8 without bisphosphonate exposure. Denosumab after AFF was associated with recurrent incomplete AFFs in 1 patient and 2 patients of contralateral complete AFF. Eight patients had used raloxifene before AFF occurred, including 1 bisphosphonate-naïve patient. CONCLUSIONS: There is no evidence-based indication in patients with AFF for teriparatide apart from reducing the risk of typical fragility fractures, although observational data suggest that teriparatide might result in faster healing of surgically treated AFFs. Awaiting further evidence, we formulate recommendations for treatment after an AFF based on expert opinion.

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.

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.

Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review.

Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long-term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate-naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand-searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X-linked osteoporosis (PLS3), osteopetrosis, X-linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate-naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X-linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole-exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well-phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition.

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.

Atypical femur fracture in an adolescent boy treated with bisphosphonates for X-linked osteoporosis based on PLS3 mutation.

Long-term use of bisphosphonates has raised concerns about the association with Atypical Femur Fractures (AFFs) that have been reported mainly in postmenopausal women. We report a case of an 18-year-old patient with juvenile osteoporosis based on X-linked osteoporosis due to a PLS3 mutation who developed a low trauma femoral fracture after seven years of intravenous and two years of oral bisphosphonate use, fulfilling the revised ASBMR diagnostic criteria of an AFF. The occurrence of AFFs has not been described previously in children or adolescents. The underlying monogenetic bone disease in our case strengthens the possibility of a genetic predisposition at least in some cases of AFF. We cannot exclude that a transverse fracture of the tibia that also occurred after a minor trauma at age 16 might be part of the same spectrum of atypical fractures related to the use of bisphosphonates. In retrospect our patient experienced prodromal pain prior to both the tibia and the femur fracture. Case reports of atypical fractures in children with a monogenetic bone disease such as Osteogenesis Imperfecta (OI) or juvenile osteoporosis are important to consider in the discussion about optimal duration of bisphosphonate therapy in growing children. In conclusion, this case report 1) highlights that AFFs also occur in adolescents treated with bisphosphonates during childhood and pain in weight-bearing bones can point towards this diagnosis 2) supports other reports suggesting that low trauma fractures of other long bones besides the femur may be related to long-term use of bisphosphonates 3) strengthens the concept of an underlying genetic predisposition in some cases of AFF, now for the first time reported in X-linked osteoporosis due to a mutation in PLS3 and 4) should be considered in decisions about the duration of bisphosphonate therapy in children with congenital bone disorders.

"Atypical" atypical femur fractures and use of bisphosphonates.

BACKGROUND: Atypical femur fractures (AFFs) present a rare but serious condition associated with use of bisphosphonates. Underlying mechanisms and clinical risk factors remain unclear. According to the diagnostic criteria formulated by the ASBMR, a lateral localization of an AFF is required. CASE HISTORY: We present a patient who developed bilateral leg pain while using an oral bisphosphonate and aromatase inhibitor in the course of adjuvant treatment for breast cancer. Initially she was diagnosed with bone metastases and received radiotherapy on the right femur. However, the bilateral periosteal reactions of the subtrochanteric femur are highly suggestive of AFFs. Our case meets all criteria for AFF except that she presented with lesions at the medial side of the femur. Therefore they could be best described as "atypical" atypical femur fractures. DISCUSSION: Since the pathogenesis of AFFs is not fully understood, we cannot rule out that AFFs also occur in the medial femur or in other weight-baring bones. Hence we propose that medial stress reactions belong to a spectrum of atypical fractures associated with use of antiresorptive drugs. The localization may depend on yet unknown biomechanical factors. CONCLUSION: We propose that these periosteal reactions of the subtrochanteric femur are in fact AFFs with uncommon medial localization and could hence be considered "atypical" AFFs. We recommend being alert of AFFs in patients with bone pain and medial subtrochanteric lesions. More epidemiological studies are needed to investigate the occurrence of both medial and lateral AFFs and to gain more insight into its frequency and pathogenesis.