Atypical Femur Fracture in the Setting of Long-Term Bisphosphonate use for Osteogenesis Imperfecta: A Case Report

Bisphosphonate (BP) therapy for moderate to severe osteogenesis imperfecta (OI) has become a mainstay of treatment in the last three decades. Given the significant improvements in bone mineral density and theoretical reductions in fracture risk, many patients are treated with bisphosphonates for prolonged periods of time. There currently lacks consensus in the optimal duration of BP therapy for patients with OI, and patients are often treated on a case-by-case basis. Long-term BP therapy has been associated with atypical femur fractures in adult patients treated for osteoporosis. The American Society for Bone and Mineral Research concluded that the median duration of BP therapy in patients with atypical femur fractures was 7 years. The role of long-term BP therapy in OI patients with atypical femur fractures remains unclear. Here, a case report is presented of an adolescent patient with type V OI that sustained a subtrochanteric femur fracture with features of an atypical pattern following treatment with intravenous pamidronate for 10.5 years. At the time of injury, the contralateral femur was also found to have atypical features suggestive of an impending fracture. The completed fracture was treated with closed reduction and cephalomedullary nail fixation. The impending fracture was prophylactically stabilized using the same technique. Prior to the injury, limb-length radiographs obtained to evaluate lower extremity alignment demonstrated features of an impending fracture but went unnoticed. Further studies are needed to clarify the role of long-term BP therapy in patients with OI suffering from atypical femur fractures.

ALPL genotypes in patients with atypical femur fractures or other biochemical and clinical signs of hypophosphatasia

Context Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue non-specific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the administration of contraindicated antiresorptive drugs that, in HPP patients, substantially increase the risk of atypical femur fractures (AFFs) and worsen fracture healing process that is usually already compromised in these patients. Objective Performing ALPL genetic testing to identify rare variants in suspected adult HPP patients. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP. Design Patients with suspected adult HPP were retrospectively selected for the genetic testing of the ALPL gene. Setting Patients included were from three main European Bone Units (Florence, Naples and Geneva). Patients 106 patients with biochemical and/or clinical signs suggestive of a mild form of HPP. Results and conclusions Genetic testing led to the identification of a heterozygote rare variant in 2.8% of cases, who were initially referred as suspected osteoporosis. The analysis of frequencies of ALPL common variants showed a high prevalence (30.8%) of homozygosity in subjects who developed an AFF, in association with normal serum total ALP activity, suggesting this as a possible genetic marker of risk for these fractures.

Differences in femur geometry and bone markers in atypical femur fractures and the general population

This study aimed to identify differences in femur geometry between patients with subtrochanteric/shaft atypical femur fractures (AFFs) and the general population, and to evaluate the biomechanical factors related to femoral bowing in AFFs. We retrospectively reviewed 46 patients. Data on age, and history and duration of bisphosphonate use were evaluated. Femur computed tomography images were reconstructed into a 3D model, which was analyzed with a geometry analysis program to obtain the femur length, femur width and length, and femoral bowing. Patients were divided into two groups according to fracture location: the subtrochanteric and shaft AFF groups. We compared all parameters between groups, and also between each group and a general population of 300 women ≥ 60 years. Thirty-five patients had a history of bisphosphonate use (average duration, 6.1 years; range, 0.8–20 years). There was no statistical difference in bone turnover markers between the two groups. The shaft AFF group had a lower radius of curvature (ROC) (P = 0.001), lower bone mineral density (BMD, T score) (P = 0.020), and lower calcium (P = 0.016). However, other parameters and rate of bisphosphonate use were not significantly different. There were no significant differences in the parameters of the subtrochanter AFF group and the general population, but the shaft AFF group demonstrated a wider femur width (P < 0.001), longer anteroposterior length (P = 0.001), and lower ROC (P < 0.001) than the general population. Femoral bowing and width increased in shaft AFFs, but similar to subtrochanter AFFs compared to the general population. Our results highlight the biomechanical factors of femur geometry in AFFs.

The Genetics of Atypical Femur Fractures—a Systematic Review

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. Summary 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.