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Incomplete atypical femur fractures (iAFFs) are associated with the long-term use of anti-resorptive therapies. Although X-rays are typically used to screen for iAFFs, images from dual-energy X-ray absorptiometry (DXA) offer an alternate method for detecting iAFFs. Although a previous 2019 ISCD Official Position on this subject exists, our task force aimed to update the literature review and to propose recommendations on reporting findings related to iAFFs that may be observed on DXA images. The task force recommended that full-length femur imaging (FFI) from DXA can be used as a screening tool for iAFFs. The presence of focal lateral cortical thickening and transverse lucencies should be reported, if identified on the FFI. This task force proposed a classification system to determine the likelihood of an iAFF, based on radiographic features seen on the FFI. Lastly, the task force recommended that the clinical assessment of prodromal symptoms (pain) is not required for the assessment of FFI.

The earliest reports of atypical femur fractures (AFF) emerged from Asia. In the West, epidemiologic studies report a greater incidence of AFFs among subjects of Asian background. Asian ethnicity is an established risk factor for AFF, but clear mechanisms to explain this risk and implications for the general development of AFF are open questions. Ethno-specific differences in bisphosphonate action and femoral geometry have been proposed as hypotheses. In a retrospective cohort of 163 female patients presenting with AFFs or typical femur fractures (TFF), relative contributions of Asian ethnicity, proximal femoral geometry, and bisphosphonate use in AFF status were examined. There was a fourfold higher proportion of Asian subjects in the AFF compared with TFF groups (31.6%, 30/95 versus 7.4%, 5/68). Asian subjects had smaller femurs in femoral head, neck, and axial dimensions. A multiple logistic regression model for AFF status was fitted adding Asian ethnicity to three previously reported independent predictors of AFF including femoral geometry, which together comprise the Sydney AFF Score (age ≤80 years, femoral neck width <37 mm than non-Asian, lateral cortical width at lesser trochanter ≥5 mm). Asian ethnicity was a robust independent predictor of AFF, imparting sevenfold increase in the odds of AFF after adjusting for all three variables (95% confidence interval [CI] 2.2-23.2, p = 0.001) or for overall AFF score (95% CI 2.2-22.3 p = 0.001). Overall Asian subjects had higher rates of bisphosphonate use than non-Asian subjects (67.6% versus 47.2%, p = 0.034). Among AFF bisphosphonate users, Asian subjects had lower AFF scores than non-Asians (Sydney AFF Score ≤1, 45.5% Asian subjects versus 22.2% non-Asian subjects, p = 0.05). Asian ethnicity is a strong independent risk factor for AFF, unaccounted for by ethno-specific differences in proximal femoral geometry. Bisphosphonate use may be associated with a greater predisposition for AFF in Asian subjects compared with non-Asian subjects. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP), its manifestations may include atypical femoral fractures (AFF). However, the prevalence of low serum ALP and HPP in patients with AFF remains unknown. We retrospectively analyzed ALP levels and clinical manifestations compatible with HPP in 72 adult patients with confirmed AFF by chart review. ALP values were compared with those of a control group of patients with prior proximal femoral fracture during antiresorptive treatment (n = 20). Among the AFF patients, 18 (25%) had at least one serum ALP value ≤ 40 IU/L, although in all but one case, at least one ALP value > 40 IU/L was also detected at another time point. Most low ALP values were associated with antiresorptive treatment (P = 0.049) and lowest levels of ALP did not differ between the AFF and the control groups (P = 0.129). However, low ALP values among AFF patients were associated with a higher rate of bilateral AFF (50% vs 22%, P = 0.025), metatarsal fracture (33% vs 7%, P = 0.006), and with trends for more frequent use of glucocorticoid (22% vs 8%, P = 0.089) and proton pump inhibitor (61% vs 44%, P = 0.220). In one AFF patient with low ALP and clinical suspicion of HPP, a rare pathogenic heterozygous variant of the ALPL gene was identified. In conclusion, low ALP values are common among subjects with AFF and mainly related to concomitant antiresorptive medication. Hence, low serum ALP has low specificity for HPP among AFF patients.

Atypical femoral fractures (AFFs) are categorized as low-energy fractures of the femoral shaft or subtrochanteric region. The use of computed tomography-based finite element analysis demonstrated that the femoral weakest point against tensile stress coincided with AFF location, which was determined by the lower limb axis and femoral bowing.
BACKGROUND: This study aimed to assess the relationship between the femoral weakest point against tensile stress and the lower limb axis and geometry, including femoral bowing, using a computed tomography (CT)-based finite element analysis (FEA) model.
METHODS: We retrospectively reviewed 19 patients with AFFs and analyzed their CT images of the contralateral intact femur. We performed FEA to find the maximum principal stress (MPS) and maximal tensile stress loading area (femoral weakest point, FWP) of each patient and matched the FWP with the real location of AFF. We applied mechanical axes differently, as neutral, varus, and valgus, in the FEA model, when we analyzed the change in MPS and FWP based on lower limb alignment. We compared the degree of agreement between the real fracture location and FWP before and after knee mechanical axis adjustment.
RESULTS: The average participant age was 75.9 (range, 61-87) years, and all participants were women. In the 19 patients included, we observed 20 and 7 shaft and subtrochanteric AFFs, respectively. The average mechanical axis at the knee joint level was 22.6 mm (range, 0-70 mm) of the varus. All the patients showed an increasing trend of MPS and a distal movement of FWP when the mechanical axis of the knee was applied from the valgus to varus alignment. The root mean square errors between the FWP and real fracture location were 14.58% and 10.87% before and after adjustment, respectively, implying that the degree of agreement was better in patients who underwent mechanical adjustment.
CONCLUSIONS: The use of CT/FEA demonstrated that the FWP against tensile stress coincided with AFF location, which was determined by the lower limb axis and femoral bowing.

Bisphosphonates are effective in reducing hip and other fractures. However, concerns about atypical femur fractures (AFFs) have contributed to substantially decreased bisphosphonate use, and hip fracture rates may be increasing. Despite this impact, important uncertainties remain regarding AFF risks including the association between bisphosphonate use and other risk factors such as BMD, age, weight, and race. To address this evidence gap, a cohort study of 196,129 women ≥50 years of age in the Southern California Kaiser Permanente HMO women (with ≥1 bisphosphonate prescription) were studied; the primary outcome was radiographically-adjudicated AFF between 2007 and 2017. Risk factors including bisphosphonate use and race were obtained from electronic health records. Multivariable Cox models were used for analysis. Benefit-risk was modeled for 1-10 years of bisphosphonates to compare fractures prevented vs. AFFs associated. Among 196,129 women, 277 (0.1%) sustained AFFs. After multivariable adjustment, AFF risk increased with longer bisphosphonate duration: hazard ratio (HR) increased from HR = 8.9 (95%CI: 2.8,28) for 3-5 years to HR = 43.5 (13.7138.1) for >8 years. Hip BMD, surprisingly, was not associated with AFF risk. Other risk factors included Asian ancestry (HR = 4.8 (3.6, 6.6)), short stature, overweight, and glucocorticoid use. Bisphosphonate discontinuation was associated with rapid decrease in AFF risk. Decreases in osteoporotic and hip fractures risk during 1-10 years of bisphosphonates far outweighed the increase AFF risk in Caucasians, but less so in Asians. In Caucasians, after 3 years 149 hip fractures were prevented with 2 AFFs associated compared to 91 and 8 in Asians. The evidence for several potential mechanisms is summarized with femoral geometry being the most likely to explain AFF risk differences between Asians and Caucasians. The results from this new study add to the evidence base for AFF risk factors and will help inform clinical decision-making for individual patients about initiation and duration of bisphosphonate therapy and drug holidays.

The 2021 Virtual Santa Fe Bone Symposium was held August 5-8, with over 300 registered attendees from throughout the USA, and at least 18 other countries. This annual meeting focuses on applying advances in basic science and clinical research to the care of patients with osteoporosis and those with inherited and acquired disorders of bone metabolism. Participants represented a broad range of medical disciplines with an interest in skeletal diseases. These included physicians of many specialties and practice settings, fellows, advanced practice providers, fracture liaison service (FLS) coordinators, clinical researchers, and bone density technologists. There were lectures, case presentations, and panel discussions, all followed by interactive discussions. Breakout sessions included an FLS workshop, Bone Health TeleECHO workshop, special interest groups, meet-and-greet the faculty, and satellite symposia. The agenda covered topics of interest such as strategies for the use of osteoanabolic therapy, prevention of periprosthetic fractures, management of atypical femur fractures, what we know and don\'t know about vitamin D, advances in the use of dual-energy X-ray absorptiometry in the assessment of skeletal health, controversies and conundrums in osteoporosis care, skeletal health in transgender patients, management of patients with hypophosphatasia and hypophosphatemia, and treat-to-target approaches for managing patients with osteoporosis. The Proceedings of the 2021 Virtual Santa Fe Bone Symposium consists of highlights of each presentation with current strategies for optimizing the care of patients with skeletal disorders.

The objective of this study was to examine the health-related quality of life (HRQOL) outcomes for surgically-treated atypical femur fractures (AFFs) compared to typical femoral diaphyseal fractures. Two large trauma center databases were retrospectively queried for surgically-treated femur fractures. Fractures were grouped into AFFs and compared to a control cohort. Controls for the AFF group included women with diaphyseal fractures without additional AFF characteristics. Patients were contacted for administration of the Short Form-36v2 Health Survey. Surveys were completed an average of 30.3 months (range, 6-138 months) and 25.5 months (range, 5-77 months) postoperatively for the AFF and non-AFF groups, respectively. All patients were female, with 46 patients in the AFF and 26 patients in the non-AFF group. The average age of the AFF group was 70.1 years compared with an average age of 67.4 years in the non-AFF group (p = 0.287). Over 90% (91.3%) of patients in the AFF group had a history of bisphosphonate use while 26.9% of patients in the non-AFF group had used bisphosphonates (p < 0.0001). Patients with AFF reported their postoperative physical and mental health to be no different than similarly aged patients with femoral diaphyseal fractures, as measured by the Short Form 36, version 2 (SF-36v2) Health Survey. These data suggest that mid-term patient-reported quality of life outcomes are similar among women who sustain an AFF compared to a cohort of more typical femoral diaphyseal fractures. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Atypical femur fractures (AFFs) are well-established serious complication of long-term bisphosphonate and denosumab therapy in patients with osteopenia or osteoporosis. To elucidate underlying mechanism(s) for the development of AFF, we performed a nested case-control study to investigate bone tissue nanomechanical properties and prevailing bone microstructure and tissue-level remodeling status as assessed by bone histomorphometry. We hypothesized that there would be differences in nanomechanical properties between patients with and without AFF and that bone microstructure and remodeling would be related to nanomechanical properties. Thirty-two full-thickness transiliac bone biopsies were obtained from age- and sex-matched patients on long-term bisphosphonate therapy with (n = 16) and without an AFF (n = 16). Standard histomorphometric measurements were made in each sample on three different bone envelopes (cancellous, intracortical, and endosteal). Iliac bone wall thickness was significantly lower on all three bone surfaces in patients with AFF than in those without AFF. Surface-based bone formation rate was suppressed similarly in both groups in comparison to healthy premenopausal and postmenopausal women, with no significant difference between the two groups. Nanoindentation was used to assess material properties of cortical and cancellous bone separately. Elastic modulus was higher in cortical than in cancellous bone in patients with AFF as well as compared to the elastic modulus of cortical bone from non-AFF patients. However, the elastic modulus of the cancellous bone was not different between AFF and non-AFF groups or between cortical and cancellous bone of non-AFF patients. Resistance to plastic deformation was decreased in cortical bone in both AFF and non-AFF groups compared to cancellous bone, but to a greater extent in AFF patients. We conclude that long-term bisphosphonate therapy is associated with prolonged suppression of bone turnover resulting in altered cortical remodeling and tissue nanomechanical properties leading to AFF. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.