The Genetics of Atypical Femur Fractures-a Systematic Review.
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ABSTRACT: Purpose of review
Atypical femur fractures (AFFs) are rare subtrochanteric or diaphyseal fractures regarded as side effects of bisphosphonates (BPs), possibly with a genetic background. Here, we summarize the most recent knowledge about genetics of AFFs.Recent findings
AFF has been reported in 57 patients with seven different monogenic bone disorders including hypophosphatasia and osteogenesis imperfecta; 56.1% had never used BPs, while 17.5% were diagnosed with the disorder only after the AFF. Gene mutation finding in familial and sporadic cases identified possible AFF-related variants in the GGPS1 and ATRAID genes respectively. Functional follow-up studies of mutant proteins showed possible roles in AFF. A recent small genome-wide association study on 51 AFF cases did not identify significant hits associated with AFF. Recent findings have strengthened the hypothesis that AFFs have underlying genetic components but more studies are needed in AFF families and larger cohorts of sporadic cases to confirm previous results and/or find novel gene variants involved in the pathogenesis of AFFs.
SUBMITTER: Zhou W
PROVIDER: S-EPMC8016774 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC7121199 | biostudies-literature
Project description:Hypophosphatasia (HPP) is a congenital, rare and heterogeneous bone disorder, characterized by a deficit of calcified tissue mineralization, leading to skeletal deformities and osteomalacia in adults, rickets in infants and children, and fragility fractures and premature loss of dentition in children and adults. The disease is caused by a reduced or absent expression and activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, derived from inactivating mutations of the alkaline phosphatase (ALPL) gene. Six different clinical variants have been reported, defined by the onset age and characterized by different degrees of severity. The adult form of HPP presents a wide range of clinical manifestations, many of which are non-specific, mild, and often overlapping with other metabolic bone diseases. Consequently, many cases of adult HPP are, commonly, undiagnosed or misdiagnosed, and, subsequently, wrongly or non-treated with severe consequences for patients and a very negative impact on their quality of life and life expectancy, as well as with costs due to the administration of wrong therapies and treatments of their side effects. The occurrence of a fragility atypical femur fracture in the adulthood can be suspected as a clinical indication of an undiagnosed adult mild form of HPP; and the presence of at least one of this kind of fracture can help in the diagnosis of adult HPP, together with conventional HPP biochemical signs.
| S-EPMC5762223 | biostudies-literature
Project description:IntroductionThe occurrence of atypical femur fractures (AFFs) in patients on prolonged bisphosphonate treatment has been gaining medical attention, but the use of pharmacotherapy for these fractures has not been explored in detail. The authors describe a case of AFFs successfully treated with once-weekly administration of 56.5 μg teriparatide (TPTD).Case presentationThe patient was a 74-year-old female patient who had been taking alendronate for approximately 6 years and who suffered with a fall while walking. X-rays revealed a subtrochanteric right femur fracture. The contralateral femur showed cortical thickening and a transverse radiolucent fracture line. Based on these specific features, the patient was diagnosed with AFF. The patient underwent osteosynthesis with intramedullary nailing for the right fracture. Alendronate treatment was discontinued. Low-intensity pulsed ultrasonography therapy did not affect the healing of the fracture with delayed union, even after 3 months of application. Prophylactic osteosynthesis was performed for the subtrochanteric left femur. Bone tissue collected from the left fracture site during surgery showed severe suppression of bone turnover. Union of bilateral femurs was achieved after 3 months of a once-weekly administration of TPTD.ConclusionOnce-weekly TPTD treatment is shown to be beneficial for improving the healing of AFFs showing delayed union.
| S-EPMC4254865 | biostudies-literature
Project description:Clinical factors that affect the likelihood of abuse in children with femur fractures have not been well elucidated. Consequently, specifying which children with femur fractures warrant an abuse evaluation is difficult. Therefore the purpose of this study is to estimate the proportion of femur fractures in young children attributable to abuse and to identify demographic, injury and presentation characteristics that affect the probability that femur fractures are secondary to abuse.We conducted a systematic review of published articles written in English between January 1990 and July 2013 on femur fracture etiology in children less than or equal to 5 years old based on searches in PubMed/MEDLINE and CINAHL databases. Data extraction was based on pre-defined data elements and included study quality indicators. A meta-analysis was not performed due to study population heterogeneity.Across the 24 studies reviewed, there were a total of 10,717 children less than or equal to 60 months old with femur fractures. Among children less than 12 months old with all types of femur fractures, investigators found abuse rates ranging from 16.7% to 35.2%. Among children 12 months old or greater with femur fractures, abuse rates were lower: from 1.5% - 6.0%. In multiple studies, age less than 12 months, non-ambulatory status, a suspicious history, and the presence of additional injuries were associated with findings of abuse. Diaphyseal fractures were associated with a lower abuse incidence in multiple studies. Fracture side and spiral fracture type, however, were not associated with abuse.Studies commonly find a high proportion of abuse among children less than 12 months old with femur fractures. The reported trauma history, physical examination findings and radiologic results must be examined for characteristics that increase or decrease the likelihood of abuse determination.
| S-EPMC4085378 | biostudies-literature
Project description: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.
| S-EPMC9382867 | biostudies-literature
Project description:BackgroundCase reports have linked adult hypophosphatasia as a possible cause of atypical femur fractures (AFF) associated with bisphosphonate use. Adult hypophosphatasia is an asymptomatic genetic condition which results in low alkaline phosphatase and elevated pyridoxal phosphate. We conducted a case-control study to assess the role of hypophosphatasia and atypical femur fracture.MethodsWe recruited 13 control patients who took long term bisphosphonates without complication and 10 patients who sustained atypical femur fractures (mean bisphosphonate use, 9 years both cohorts). Patients underwent clinical exam and measurement of alkaline phosphatase and pyridoxal phosphate (PLP) levels. In addition, DNA was extracted and the ALPL gene was sequenced in both cohorts.ResultsLow alkaline phosphatase levels (<55 U/L) were seen in 5/10 AFF patients and 5/13 control patients. Two control patients demonstrated low alkaline phosphatase levels and elevated PLP. The alkaline phosphatase (ALPL) gene exons and intron splice sites were sequenced in the atypical femur fracture and control cohorts and no coding mutations were identified in any subjects. Atypical femur fracture patients demonstrated more varus hip alignment (p < 0.048) with no significant difference in mechanical axis.ConclusionsWe found no evidence of hypophosphatasia as a risk factor for atypical femur fractures. Laboratory findings of mildly low alkaline phosphatase activity were equally common in atypical and control cohorts and may be due to long term bisphosphonate use.Trial registrationClinicaltrials.gov number NCT01360099 . Prospectively registered May 20, 2011. First patient enrolled June 14, 2011.
| S-EPMC4977896 | biostudies-literature
Project description: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.
| S-EPMC6124156 | biostudies-literature
Project description:Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral fractures (AFF). Recent published studies examining this potential association are conflicting regarding the existence and strength of this association. We conducted a systematic review and meta-analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random-effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta-analysis: five case-control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF, with adjusted RR of 1.70 (95% confidence interval [CI], 1.22-2.37). Subgroup analysis of studies using the American Society for Bone and Mineral Research criteria to define AFF suggests a higher risk of AFF, with bisphosphonate use with RR of 11.78 (95% CI, 0.39-359.69) as compared to studies using mainly diagnosis codes (RR, 1.62; 95% CI, 1.18-2.22), although there is a wide confidence interval and severe heterogeneity (I(2) ?=?96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI, 1.29-2.04). This meta-analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long-term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear.
| S-EPMC3713078 | biostudies-literature
Project description:ObjectivesThis review evaluates the safety and efficacy of submuscular plating (SMP) vs. elastic stable intramedullary nailing (ESIN) in the treatment of pediatric femur shaft fracture.MethodStudies comparing the efficacy and safety of SMP and ESIN in pediatric shaft fracture were retrieved from five databases (PubMed, Embase, Cochrane, OVID, and Web of Science) from inception to March 2023 using a systematic literature search strategy. A total of 13 outcome measures, such as perioperative parameters, clinical outcomes, and radiographic results, were included in the meta-analysis.ResultsEight eligible studies involving 491 patients were included in the narrative synthesis. There were no significant differences in baseline characteristics between the two groups. Meta-analysis showed reduced radiation time (RT), soft tissue irritation and angular deformation in the SMP group than in the ESIN group. However, the SMP group had greater estimated blood loss (EBL) than the ESIN group. The duration of surgery, length of hospital stay (LOS), implant removal, complications requiring surgery, Flynn score, incidence of infection, fracture healing time, and limb length discrepancy (LLD) were similar between the two groups. Only one study reported higher incidences of fracture nonunion or delayed healing in the ESIN group.ConclusionSMP is an effective and safe intervention superior to ESIN in reducing soft tissue irritation, angular deformation and radiation time. Given the presence of potential bias and heterogeneity, surgeons should select the treatment that would provide the best outcomes for EBL, LOS, operation time, and bone nonunion or delayed healing based on their experience.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023404118, Identifier PROSPERO (CRD42021228512).
| S-EPMC10663353 | biostudies-literature
Project description:Treatment of periprosthetic distal femur fractures and comminuted intraarticular distal femur fractures with previous arthritis remains a difficult challenge for orthopedic surgeons. Previous case series have shown that distal femur replacement (DFR) can effectively compensate for bone loss, relieve knee pain, and allow for early ambulation in both of these fracture patterns. Owing to the typical low-energy mechanism of these injuries, a bilateral injury treated with DFR is rarely encountered. We present a patient with traumatic open left Rorabeck III/Su III periprosthetic distal femur fracture and closed right intraarticular distal femur fracture (AO fcation 33-C2) with end-stage arthrosis treated with single-stage bilateral DFR. We suggest that in patients with similar injuries, single-stage bilateral DFR can provide the benefits of early mobilization and accelerated recovery.
| S-EPMC6470367 | biostudies-literature