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Background: Some periprosthetic femoral fractures (PFFs) present history and radiographic aspect consistent with an atypical femoral fracture (AFF), fulfilling the criteria for AFF except that PFFs by themselves are excluded from the diagnosis of AFFs. The aim of this study is to evaluate in a single institution series of PFFs if any of them could be considered a periprosthetic atypical femoral fracture (PAFF), and their prevalence.Methods: Surgical records were searched for PFFs around a primary hip stem from January 2013 to December 2019. Cases were classified according to Vancouver classification. Demographic and medical history was extracted. Fisher's exact test was used for statistical analysis.Results: One hundred fifteen PFFs were identified, 59 of them were type B1 and 16 were type C. Radiographs and medical records were available for all patients. Twenty-four patients (32%) have been treated with bisphosphonates (BPs) for longer than 4 years. Four patients presented a fracture with characteristics of PAFF. When enlarged to all PFFs of the series, no other PAFF was found: prevalence of PAFFs was 5.3% for type B1 and C cases and 3.5% for all surgically treated PFFs. Statistical significative difference between PAFFs and PFFs was found for prolonged BP assumption and for the level of fracture clear of the stem.Conclusion: Fracture with characteristics of AFFs can also happen over a prosthetic stem, configuring themselves as PAFFs, and they are related to prolonged BP use. As a correct diagnosis is mandatory for proper treatment, a revision of criteria for AFFs should be considered, accepting that PAFFs exist. [ABSTRACT FROM AUTHOR]

Bisphosphonates have been the first drug of choice for osteoporosis in the recent years because of their known ability to suppress osteoclast activity. The adverse effect of long-term bisphosphonate administration in the fracture-healing process is controversial. The aim of our study was to observe not only morphology but also morphometry of the fracture site of atypical femoral fracture with and without long-term bisphosphonate administration, in a case study of two difficult-to-obtain human samples. The patients with insufficient healing of atypical femoral fracture were treated with valgus wedge osteotomy. Histomorphometrical analysis was performed in bone samples of fracture sites harvested during osteotomy. The thickness of the femoral cortex was measured in the fracture site and the adjacent, non-fracture site. A comparative analysis of the content of hypertrophic osteoclasts in fracture sites, shape and size of osteons, mass, and ratio of the woven bone to the total bone mass was performed, comparing bisphosphonatetreated and untreated samples. In bisphosphonate-treated samples, we observed femoral cortex thickening at the fracture site; the appearance of hypertrophic osteoclasts; decreased bone resorption surface, decreased osteoclast numbers on the bone resorption surface, and increased ratio of multinuclear osteoclasts; osteons were misshapen and thin; and the mass and ratio of the woven bone to the total bone mass were higher. This study demonstrated that long-term bisphosphonate administration can alter the morphological features of the fracture site compared to its physiological state. [ABSTRACT FROM AUTHOR]

Atypical femoral fractures (AFFs) are defined as atraumatic or low-trauma fractures located in the subtrochanteric or diaphyseal sites. Long-term bisphosphonates (BPs) are administered to prevent fragility fractures in patients with primary osteoporosis or collagen diseases who are already taking glucocorticoids (GCs). Long-term BP use is one of the most important risk factors for AFFs. Its pathogenesis is characterized by severely suppressed bone turnover (SSBT), but whether the characteristics of patients are different regarding to location of fracture site remains unknown. In this study, we compared the characteristics and bone histomorphometric findings between subtrochanteric and diaphyseal sites in patients with BP-associated AFFs. Nine women with BP-associated AFFs were recruited, including 3 with systemic lupus erythematosus, 2 with rheumatoid arthritis, 2 with primary osteoporosis, 1 with polymyalgia rheumatica, and 1 with sarcoidosis. Patients were divided into the subtrochanteric group (n = 5; average age, 52 years; BP treatment, 5.9 years) and the diaphyseal group (n = 4; average age, 77 years; BP treatment, 2.6 years). Compared with the diaphyseal group, the subtrochanteric group had significantly higher daily GC doses (average, 10.9 vs. 2.3 mg/day) and significantly lower serum 25-hydroxyvitamin-D levels (17.8 vs. 25.6 ng/mL). Bone histomorphometry of the biopsied iliac bone showed SSBT in 3 cases (subtrochanteric, n = 1; diaphyseal, n = 2). Osteoid volume and trabecular thickness were significantly lower in the subtrochanteric group than in the diaphyseal group. Bone formation was inhibited more severely in subtrochanteric than in the diaphyseal group due to the higher GC doses used. [ABSTRACT FROM AUTHOR]

Denosumab is a new standard treatment for bone disease caused by multiple myeloma. There are a few reports of atypical femoral fracture in patients with multiple myeloma, all of which were associated with long-term use of bisphosphonate. Here, we report the first case of denosumab-induced atypical femoral fracture in a patient with multiple myeloma. A 71-year-old woman with multiple myeloma developed dull pain in her right thigh 8 months after restarting high-dose denosumab following its initial administration for 4 months and subsequent withdrawal for 2 years. Fourteen months later, complete atypical femoral fracture occurred. Osteosynthesis was achieved using an intramedullary nail and she was switched to oral bisphosphonate 7 months after cessation of denosumab. There was no exacerbation of the multiple myeloma. Bone union was achieved and she recovered to her pre-injury level of activities. The oncological outcome was alive with disease at 2 years after surgery. Prodromal symptoms such as thigh pain and radiographical finding of thickening of the lateral cortex in the subtrochanteric region of the femur were attributed to denosumab-induced atypical femoral fracture in the case. A unique aspect of this case worth highlighting is that the fracture occurred after short-term denosumab use. This may be associated with multiple myeloma or other medication including dexamethasone and cyclophosphamide. Atypical femoral fracture may occur in patients with multiple myeloma who receive denosumab, even for a short period. Attending physicians should be cognizant of the early symptoms and signs of this fracture. [Display omitted] • Bisphosphonates are known to cause atypical femoral fractures in multiple myeloma. • First case of denosumab-induced atypical femoral fracture in multiple myeloma • These fractures should be suspected and treated based on typical signs and symptoms. • Consider atypical femoral fracture regardless of the disease treated with denosumab [ABSTRACT FROM AUTHOR]

• Atypical femoral fractures (AFFs) are suggested to have association with bone resorption inhibitors for osteoporosis. • Bone modifying agents (BMAs) for bone metastasis are also bone resorption inhibitors with more dosage. • It is difficult to cease BMA because of AFF occurrence. • Bone union time of AFF in BMA using patients was longer than ordinary AFF. • It would be important to prevent complete AFF via prophylactic internal fixation. Bone-modifying agents (BMAs), with bone-resorptive inhibitory effects, such as zoledronic acid and denosumab, are widely used at higher doses for bone-related events caused by bone metastasis of malignant tumors. These drugs have been suggested to be associated with atypical femoral fractures (AFFs), and the relationship between BMAs and AFFs has attracted attention. To investigate the clinical features including bone union time of AFFs in patients administered BMA for bone metastasis, we conducted a retrospective multicenter study. Thirty AFFs from 19 patients were enrolled in this study. Thirteen patients had bilateral AFFs, and nineteen AFFs had prodromal symptoms. Eighteen AFFs underwent surgery after complete fracture, three failed to achieve bone union and required nonunion surgery, and 11 AFFs that achieved bone union had an average period until bone union of 16.2 months, which was much longer than that previously reported for ordinary AFFs. Seven patients discontinued the BMAs, but not due to AFFs. Stopping BMAs in patients with bone metastasis would make it difficult to secure their performance of activities of daily living, and AFF with BMA administration might require a longer time for union. Therefore, it would be important to prevent incomplete AFF from becoming complete AFF via prophylactic internal fixation. [ABSTRACT FROM AUTHOR]

Atypical femoral fractures (AFFs) have been reported to occur with minimal or spontaneous subtrochanteric and femoral shaft fractures with a characteristic transverse pattern, compared with typical femoral fractures in young patients with high-energy trauma. AFFs are related to long-term use of bisphosphonates (BPs), glucocorticoids and rheumatic diseases. We have estimated a blind analysis of AFFs in rheumatic patients receiving BPs and glucocorticoids ordinary over a long time in all Yamagata prefectural area through radiographic examination. The 123 AFFs including suspected cases over six years were collected and reviewed by two independent orthopedic surgeons. We found 86 patients with a total of 99 AFFs between 2009 and 2014 (1.43 cases/100,000 person/year). Of these 99 AFFs, 11 were in 8 rheumatic patients including three patients with bilateral AFFs. The incidence of AFFs in rheumatic patients had trend to increase from 2012. The mean age of all 8 patients was 54.9 years. All 8 patients received BPs and 7/8 received prednisolone (PSL). The mean dose of PSL was 14 mg/day. Compared to patients with unilateral AFFs, those with bilateral AFFs in rheumatic patients were on a higher dose of PSL (20 mg/day vs. 7 mg/day) and had less femoral neck-shaft angle (129° vs. 136°, p < 0.05). In conclusion, the incidence of AFFs in rheumatic patients showed a trend to increase from 2012 to 2014 in Yamagata prefecture. Careful management of AFFs is of particular importance in rheumatic patients who have taken high doses of PSL and have small femoral neck-shaft angle. [ABSTRACT FROM AUTHOR]

Background: Atypical femoral fracture (AFF) is documented as a known but rare complication of bisphosphonate use for the treatment of osteoporosis. These present in an incomplete form prior to failure, which results in a complete fracture requiring surgical intervention. Dual energy x-ray absorptiometry (DXA) is the gold standard for the diagnosis of Osteoporosis and for monitoring the response to therapeutic interventions. This provides an opportunity to use routine DXA scans to identify incomplete atypical fractures, which can subsequently be monitored for progression and pre-fracture intramedullary nailing undertaken where necessary. DXA manufacturers have developed extended femur scans to assess and measure the femoral cortex for incipient atypical femoral fractures. The aim of this study was to evaluate the precision errors related to the cortical measurements and for hip bone mineral density using the extended femur setting. Methodology: A single operator performed duplicate same day in-vivo measurements of the femur in 30 consenting participants, with repositioning between scans, during their visit for routine DXA scanning. The study was performed on a single GE Lunar Prodigy scanner (GE Lunar, Bedford, UK). Root mean squared standard deviation (RMS SD) and coefficient of variation (RMS CV%) were calculated for the cortex measurements known as beaking index (BI) and hip bone mineral density (BMD) measurements. Results: The use of the extended femur scan software yielded an RMS SD (RMS CV%) of 0.011 (1.43%) for the total hip and 0.015 (2.05%) for the femoral neck. The BI measurement RMS SD (RMS CV%) was 0.473 (38.10%) Visual assessment of the femoral cortex discounted all positive BI anomalies as software generated in this dataset. Conclusions: The use of extended femur scan software did not affect the precision errors of the BMD measurements at the hip when compared to the literature on focused hip scans, however this study is unique with nothing similar being found in the published literature. The BI precision errors were much greater than those seen at the hip and therefore unreliable unless accompanied by visual assessment which is recommended to avoid unnecessary investigation in around one fifth of the scan population. [ABSTRACT FROM AUTHOR]

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Bisphosphonates remain the mainstay of the pharmacological approach to reduce the risk of fractures. Clinical trials have demonstrated their efficacy in reducing the frequency of osteoporosis-related vertebral and nonvertebral fractures. In the last few years, there have been several reports of increased risk of subtrochanteric and femoral shaft fractures also known as "atypical femoral fractures" (AFF) among patients receiving long-term bisphosphonate treatment. Most of these reports have been on alendronate, the most extensively used bisphosphonate. There is paucity of data to link ibandronate to AFF. We report a 66-year-old female presenting with AFF within three years of starting ibandronate and after receiving a total of 27 doses. Prescribers should be aware that AFF can happen even during the early course of bisphosphonate treatment and not necessarily only after prolonged treatment for several years. [ABSTRACT FROM AUTHOR]

Abstract: Atypical femoral fractures (AFFs) are associated with prolonged bisphosphonate therapy. A feature of incomplete AFF is a localized periosteal reaction. It has been suggested that extending the length of the femur image at the time of dual-energy X-ray absorptiometry (DXA) may diagnose an incomplete AFF. In patients older than 50 yr on bisphosphonate therapy for more than 5 yr, we extended femur length at the time of routine DXA. Abnormal DXA images were suggested in 19 of 257 patients (7.4%). On X-ray, 7 patients (2.7%) showed no abnormality, 7 patients (2.7%) showed evidence of AFF, and 5 patients (2.0%) showed an unrelated radiographic abnormality. Of the 7 cases with X-ray evidence of AFF, 5 had a periosteal flare and 2 had a visible fracture line, both of whom needed insertion of an intramedullary nail. We demonstrated that it is feasible to detect incomplete AFF early using extended femur length imaging with a prevalence in our sample of 2.7% (95% confidence interval: 1.7%–3.7%). [Copyright &y& Elsevier]

Abstract: Osteoporotic fractures and particularly hip fractures represent a considerable burden of illness in the elderly. Bisphosphonates (BP) have been used extensively over the past decade and a half for the management of osteoporosis with considerable clinical benefit in the reduction of fragility fractures. Although not apparent in clinical trials, rare associations of subtrochanteric atypical femoral fractures (AFF) have been reported postmarketing, often after long-term BP therapy. Here, we report a well-characterized Asian female patient with bilateral AFF after long-term etidronate and alendronate therapy. [Copyright &y& Elsevier]

Abstract: Administrative claims databases have large samples and high generalizability. They have been used to evaluate associations of atypical femoral fractures with bisphosphonates. We developed and assessed accuracy of claims-based algorithms with hospital and physician diagnosis codes for these fractures. Medical records and radiology reports of all adults admitted at University of Alabama at Birmingham Health System from 2004 to 2008 with International Classification of Diseases, Ninth Revision hospital discharges and surgeons’ fracture repair codes for subtrochanteric femoral fractures and random sample of other femoral fractures were reviewed. We identified 137 persons with suspected subtrochanteric femoral fractures and randomly selected 50 persons with either suspected diaphyseal femoral fractures or hip fractures other than subtrochanteric and diaphyseal femoral fractures (typical hip fractures). Eleven patients had radiographic features indicative of atypical femoral fractures. The positive predictive value (PPV) of claims-based algorithms varied with primary or secondary positions on discharge diagnoses and the sources of diagnosis codes. The PPV for fractures ranged 69–89% for subtrochanteric femoral, 89–98% for diaphyseal femoral, and 85–98% for typical hip fractures. The PPV of administrative codes for defining a femoral fracture as atypical was low and imprecise. Claims-based algorithms combining hospital discharges with surgeon’s diagnosis codes had high PPV to identify the site of subtrochanteric or diaphyseal femoral fractures vs typical hip fractures. However, claims-based data were not accurate in identifying atypical femoral fractures. These claims algorithms will be useful in future population-based observational studies to evaluate associations between osteoporosis medications and subtrochanteric and diaphyseal femoral fractures. [Copyright &y& Elsevier]

Antiresorptives such as bisphosphonates (BP) and denosumab are commonly used osteoporosis treatments that are effective in preventing osteoporotic fractures by suppressing bone turnover. Although these treatments reduce fracture risk, their long-term use has been associated with atypical femoral fracture (AFF), a rare potential side effect. Despite its rare occurrence, AFF has had a disproportionately significant adverse impact on society due to its severe outcomes such as loss of function and delayed healing. These severe outcomes have led to the decrease in the use and prescription of osteoporosis treatment drugs due to patient anxiety and clinician reluctance. This creates the risk for increasing osteoporotic fracture rates in the population. The existing information on the pathogenesis of AFF primarily relies on retrospective observational studies. However, these studies do not explain the underlying mechanisms that contribute to AFF, and therefore the mechanistic origins of AFF are still poorly understood. The purpose of this review is to outline the current state of knowledge of the mechanical mechanisms of AFF. The review focuses on three major potential mechanical mechanisms of AFF based on the current literature which are (1) macroscale femoral geometry which influences the stress/strain distribution in the femur under loading; (2) bone matrix composition, potentially altered by long-term remodeling suppression by BPs, which directly influences the material properties of bone and its mechanical behavior; and (3) microstructure, potentially altered by long-term remodeling suppression by BPs, which impacts fracture resistance through interaction with crack propagation. In addition, this review presents the critical knowledge gaps in understanding AFF and also discusses approaches to closing the knowledge gap in understanding the underlying mechanisms of AFF. [ABSTRACT FROM AUTHOR]

• Oncologic use of bone-modifying agents (BMAs) has been dramatically increasing. • Long-term BMA use is a risk factor for atypical femoral fracture (AFF). • We reviewed 721 patients with bone metastasis in a Japanese university hospital. • The incidence of critical AFF (n = 5) was 0.9% among 529 BMA-exposed patients. • The incidence was 6.6% when limited to breast cancer patients alone. As the life expectancy of cancer-bearing patients has increased, more patients with bone metastasis are receiving long-term treatment with bone-modifying agents (BMAs; e.g., zoledronate and denosumab), which are a risk factor for developing atypical femoral fracture (AFF). In this study, we surveyed the risk of iatrogenic AFF using a clinical database on treatment of bone metastasis in the past 10 years. From April 2011 through October 2019, 721 patients with bone metastasis (436 men, 285 women; mean age, 65.7 ± 12.4 years) were registered under the bone metastasis consultation system, which has been run by orthopaedic surgeons since 2011, at a university hospital in Japan. We retrospectively reviewed the database to identify patients who had received BMAs for treatment of bone metastasis, and we investigated the incidence of critical skeletal-related events (including AFF) which required surgical interventions by orthopaedic surgeons. BMAs were administered to 529 patients (73.4%). Orthopaedic surgery for the treatment of skeletal-related events was performed in 36 patients (5.0%): femur, 13 (1.8%); others, 23 (3.2%). Eight AFFs in 5 patients (breast cancer, n = 4; prostate cancer, n = 1), who all had prior exposure to zoledronate or denosumab before onset of AFF, were treated with internal fixation using intramedullary nailing. In 192 patients with no BMA exposure, critical (surgically treated) AFF was not detected. In summary, the incidence of critical AFF was 0.9% among 529 patients who received BMAs for treatment of bone metastasis, and the incidence was 6.6% when limited to breast cancer patients (4 of 61). In treatment of bone metastasis using BMAs, especially for breast cancer patients, attention should be paid to the risk of developing AFFs. Routine radiographic screening for AFF might be necessary in patients with prolonged BMA use for bone metastasis, even if asymptomatic. This report alerts all physicians and surgeons involved in the management of cancer patients, especially those with bone metastasis, regarding the risk of AFF following BMA use. [ABSTRACT FROM AUTHOR]