Occurrence Of Atypical Femoral Fractures Research Articles

Screening for the primary prevention of fragility fractures among adults aged 40 years and older in primary care: systematic reviews of the effects and acceptability of screening and treatment, and the accuracy of risk prediction tools

Screening for the primary prevention of fragility fractures among adults aged 40 years and older in primary care: systematic reviews of the effects and acceptability of screening and treatment, and the accuracy of risk prediction tools

Nontraumatic bilateral atypical femoral fractures associated with long-term alendronate therapy

Alendronate is a bisphosphonate commonly used in the treatment of post-menopausal and steroid-associated osteoporosis. Bisphosphonates have an evidence base for reducing the occurrence of typical osteoporotic fractures. However, there has been growing recognition of a correlation with the use of long-term therapy with bisphosphonates, and rare occurrence of atypical femoral fractures (AFFs). This report describes a 72-year-old caucasian woman presenting with evolving groin and thigh pains of two weeks duration. Plain X-rays noted features compatible with bilateral impending femoral subtrochanteric fractures. She had been taking oral alendronate 70mg weekly for ten consecutive years as treatment for osteoporosis. Based on the medication history, the absence of preceding trauma or a fall, and the presence of supportive radiological findings, the diagnosis was made of impending bilateral proximal femur fractures secondary to long-term bisphosphonate therapy. The alendronate was discontinued, and the patient managed with two planned successive surgeries involving the insertion of intertrochanteric antegrade nails (inter-TAN) to both femurs. Following a period of rehabilitation, she was successfully discharged home. Some pharmacokinetic and pharmacodynamic considerations of bisphosphonates are discussed. The write-up presents a brief literature review of AFFs. The index report is further reviewed in relation to the American society for bone and mineral research (ASBMR) task force’s recommended case definition of what constitutes AFFs. The discussion concludes with the application of two previously validated causality assessment systems (CAS). In this instance, both CAS indicated a ‘probable’ classification for the adverse drug reaction (ADR) to prolonged usage of oral alendronate.

Morphological profile of atypical femoral fractures: age‐related changes to the cross‐sectional geometry of the diaphysis

The use of bisphosphonates for osteoporosis patients has markedly decreased the incidence of femoral neck or trochanteric fractures. However, anti-osteoporosis drugs have been reported to increase the incidence of atypical femoral fractures, which involve stress fractures in the subtrochanteric region or the proximal diaphysis. In this study, the morphological characteristics of the cortical bone in human femoral diaphysis samples were analyzed from individuals who lived before bisphosphonate drugs were available in Japan. A total of 90 right femoral bones were arbitrarily selected (46 males and 44 females) from modern Japanese skeletal specimens. Full-length images of these femurs were acquired using a computed tomography scanner. An image processing method for binarization was used to calculate the threshold values of individual bones for determining their contours. The range between the lower end of the lesser trochanter and the adductor tubercle of each femur was divided at regular intervals to obtain 10 planes. The mean value of cortical bone thickness, periosteal border length, and the cortical cross-sectional area was evaluated for all planes. Moreover, the ratio of the area of the cortical bone to the total area of cross-section at the mid-diaphysis was calculated. A comparison between males and females demonstrated that most females had lower cortical bone area ratios at the mid-diaphysis. The femoral outer shape did not differ markedly according to age or sex; however, substantial individual differences were observed in the shape of the inner surface of the cortical bone. The cortical bone thickness and the cross-sectional area decreased with age in the femoral diaphysis; furthermore, in females, the decrease was higher for the former than for the latter. This may be due to a compensatory increase in the circumference of the femoral diaphysis. In addition, in about half of the subjects there was a discrepancy between the region with maximal value of the cortical bone thickness and that of the total cross-sectional area. Biological responses to mechanical stresses to the femoral diaphysis are thought not to be uniform. Bisphosphonates inhibit bone resorption and may promote non-physiological bone remodeling. Thus, a nonhomogeneous decrease in cortical thickness may be related to the fracture occurrence in the femoral diaphysis in some cases. Thus, long-term administration of bisphosphonates in patients with morphological vulnerability in the femoral cortical bones may increase the occurrence of atypical femoral fractures.

Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone

Bisphosphonates are widely used to treat osteoporosis, but have been associated with atypical femoral fractures (AFFs) in the long term, which raises a critical health problem for the aging population. Several clinical studies have suggested that the occurrence of AFFs may be related to the bisphosphonate-induced changes of bone turnover, but large discrepancies in the results of these studies indicate that the salient mechanisms responsible for any loss in fracture resistance are still unclear. Here the role of bisphosphonates is examined in terms of the potential deterioration in fracture resistance resulting from both intrinsic (plasticity) and extrinsic (shielding) toughening mechanisms, which operate over a wide range of length-scales. Specifically, we compare the mechanical properties of two groups of humeri from healthy beagles, one control group comprising eight females (oral doses of saline vehicle, 1mL/kg/day, 3years) and one treated group comprising nine females (oral doses of alendronate used to treat osteoporosis, 0.2mg/kg/day, 3years). Our data demonstrate treatment-specific reorganization of bone tissue identified at multiple length-scales mainly through advanced synchrotron x-ray experiments. We confirm that bisphosphonate treatments can increase non-enzymatic collagen cross-linking at molecular scales, which critically restricts plasticity associated with fibrillar sliding, and hence intrinsic toughening, at nanoscales. We also observe changes in the intracortical architecture of treated bone at microscales, with partial filling of the Haversian canals and reduction of osteon number. We hypothesize that the reduced plasticity associated with BP treatments may induce an increase in microcrack accumulation and growth under cyclic daily loadings, and potentially increase the susceptibility of cortical bone to atypical (fatigue-like) fractures.

Atypical femoral fractures and bisphosphonate use: current evidence and clinical implications.

Osteoporosis is a disease characterized by a low bone volume and deterioration of the bone quality, which increases the risk of low-energy fractures. Bisphosphonate (BP) treatment increases the bone mass and reduces the risk of fractures in patients with osteoporosis by suppressing bone resorption. In spite of its clinical benefits, the long-term use of BPs has been linked to the occurrence of atypical femoral fractures (AFFs). Although the evidence had been controversial regarding the association between the occurrence of AFFs and BP use, more recent studies with radiographic adjudication have indicated the significant associations between them. However, the pathogenesis of AFFs is not completely understood. The most popular hypothesis has suggested that the suppression of bone turnover by BPs is responsible; however, some recent reports have implied the involvement of pathophysiological alterations of the bone quality and fracture repair process. In this review, we summarize and discuss the epidemiology, risk factors and pathology of AFFs.

Increased risk for atypical fractures associated with bisphosphonate use.

Studies suggest an increasing occurrence of atypical femoral fractures with the use of bisphosphonates. To examine whether the use of bisphosphonates increases the risk for atypical fractures. Systematic review and meta-analysis. Literature search of MEDLINE, Embase and Cochrane CENTRAL (1948-June 2013). (i) randomized controlled trial or an observational study, (ii) evaluated bisphosphonate therapy versus no treatment and (iii) reported an incidence of subtrochanteric or diaphyseal fracture individually, or a composite of both. Two independent investigators completed study selection, data extraction and validity assessment. The Cochrane Risk of Bias Tool was used to assess the quality of included studies. Ten (n = 658497) studies were included in the meta-analysis which demonstrated a statistically significant increased risk of subtrochanteric or diaphyseal fracture with bisphosphonate use [adjusted odds ratios (AOR) = 1.99, 95% confidence intervals (CI)= 1.28-3.10] with I (2) = 84.3% (95% CI = 73.5%-89.5%) and Egger P = 0.01. Subtrochanteric fractures showed an AOR = 2.71 (95% CI = 1.86-3.95) with I (2) = 83.6% (95% CI = 64.3%-90.3%) and Egger's P = 2.29. Diaphyseal fractures had an AOR = 2.06 (95% CI = 1.70-2.50), I (2) = 29.7% (95% CI = 0%-73.7%) and Egger's P = 1.22. Results suggest there is an increased risk for atypical fractures associated with bisphosphonates and raises awareness to the potential complications related with bisphosphonates. These findings warrant the comprehensive evaluation of patients before initiating bisphosphonate therapy and highlights the need for additional medical decision analyses in future studies to compare the benefit over potential harms of bisphosphonate therapy.

Fracturas Femorais Atípicas e o Tratamento com Bifosfonatos: É um Factor de Risco?

Bisphosphonates are effective in preventing osteoporotic fracture, however atypical femoral fractures with a well-defined radiological pattern have been described in association with prolonged treatment with bisphosphonates. Our objectives in this study were to characterize patients ≥ 65 years old with femoral fractures (subtrochanteric/diaphyseal) considered typical and atypical and the relationship between the occurrence of atypical fractures and bisphosphonate use. We conducted a case-control study with patients admitted in our hospital with subtrochanteric or diaphyseal femur fracture in a period of five and a half years. After applying the exclusion criteria, the 92 fractures (91 patients) were classified as typical or atypical. The determination of prior bisphosphonate treatment was obtained through consultation of the individual medical history. We found 11 atypical fractures (10 patients) and 81 typical fractures (81 patients). The median age of both groups was statistically different (72 years - atypical vs. 80 years - typical, p < 0.01). The reason for the use of bisphosphonates was 0.60 in atypical fractures and 0.01 in typical, and an odds ratio of 101.1 was obtained (p < 0.01). Our results are supported and are in agreement with published studies relating to the occurrence of atypical femoral fractures associated with treatment with bisphosphonates. Despite the small number of cases it was possible to demonstrate a statistically significant relation between atypical femoral fractures and treatment with bisphosphonates. One should note that these atypical fractures occurred in patients significantly younger than patients with typical fractures.

Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs

Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in the cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than the bone's material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of the cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1ml/kg/day) or alendronate (ALN) at a clinical dose (0.2mg/kg/day). Treatment duration ranged from 3months to 3years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of the femoral cortical bone in humans.

Atypical Femoral Fracture in a Patient with Rheumatoid Arthritis

Atypical femoral fractures are characterized by a subtrochanteric or diaphyseal location. Recent studies have suggested that long-term treatment with bisphosphonates might be associated with the occurrence of atypical femoral fractures. The present report describes a case involving a 60-year-old woman with left buttock pain that was unassociated with trauma. Her hip pain was initially considered to be a symptom of her underlying rheumatoid arthritis, but a plain radiography, bone scintigraphy, and magnetic resonance imaging revealed an insufficiency fracture in the lateral shaft of the left proximal femur. She had been treated with a bisphosphonate for 4.5 years because of a previous vertebral fracture. Her chronic, long-term rheumatoid arthritis and history of bisphosphonate administration were considered to be associated with the development of her atypical femoral fracture. (Korean J Med 2014;87:240-244)

CORR Insights®: Are race and sex assessment associated with the occurrence of atypical femoral fractures?

This CORR Insights® is a commentary on the article “Are Race and Sex Assessment Associated With the Occurrence of Atypical Femoral Fractures?” by Marcano and colleagues available at: DOI 10.1007/s11999-013-3352-5. The author certifies that he, or a member of his immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR ® or the Association of Bone and Joint Surgeons®. This CORR Insights® comment refers to the article available at DOI: 10.1007/s11999-013-3352-5.

Are Race and Sex Associated With the Occurrence of Atypical Femoral Fractures?

Prior studies have suggested that Asian patients and women may be more likely to sustain atypical femoral fractures in association with bisphosphonate use. However, they do not account for confounders such as asymptomatic patients who are long-term bisphosphonate users or patients sustaining osteoporotic fractures. The purpose of this study was to determine the differences in sex and racial association with atypical femoral fractures by comparing demographic characteristics of patients who sustained an atypical bisphosphonate-associated fracture with patients on long-term bisphosphonates without fractures and with patients who sustained osteoporotic fractures. Three groups from prospective registries were identified: (1) patients with atypical femur fractures associated with long-term bisphosphonate use (BFF) (n=54); (2) patients on long-term bisphosphonates but with no associated fractures (BNF) (n=119); and (3) patients with osteoporotic proximal femur fractures not associated with bisphosphonates (PFF) (n=216). Age, sex, and self-reported race/ethnicity were documented and compared. Multivariate and univariate analyses were done as well as age- and sex-stratified analyses. Age and sex distributions of the BFF and BNF patients were similar. There was a higher percentage of Asian patients in the BFF group (17%) than in the BNF group (3%; p=0.004) as well as Hispanics (13% versus 3% in BNF; p=0.011). Patients in the BFF group were younger than those in the PFF group (67.5 versus 78.4years; p<0.001) and had fewer males (7% versus 14%; p<0.001). These data suggest that Asians are at higher risk for atypical bisphosphonate-associated fractures. We recommend closer followup in Asian patients who are taking bisphosphonates. Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Audit of atypical hip fractures at the Royal Berkshire Hospital

Audit of atypical hip fractures at the Royal Berkshire Hospital Shilpa Selvan,1 Tom Mills,2 Jeremy McNally1 1Rheumatology Department, 2Radiology Department, The Royal Berkshire Hospital, Reading, UK Background: There is increasing evidence suggesting an association between bisphosphonate use and the occurrence of atypical femoral fractures, which account for less than 1% of hip and femoral fractures overall. The aim of this audit was to assess the prevalence of atypical, bisphosphonate-related femoral fractures and adherence to regional (Fracture Reduction in South Central England [FRiSC]) guidelines in our departmental cohort. Methods: We retrospectively reviewed 1,803 patients from the National Hip Fracture Database (NHFD) with femoral fractures admitted to a district general hospital during a 49-month period. We studied all subtrochanteric fractures in patients admitted on bisphosphonates. Corresponding hip radiographs were examined for features of atypical fractures according to the American Society for Bone and Mineral Research diagnostic criteria. Results: The mean age of the patients included was 63 &plusmn; 8.08 years. One hundred and sixty-one femoral fractures were identified in patients on bisphosphonates; 73 intertrochanteric, 68 intracapsular, and 20 subtrochanteric. Ninety-three percent of these fractures were in women. Radiographs of the 20 subtrochanteric fractures were reviewed and five were classified as atypical, bisphosphonate-related fractures according to American Society for Bone and Mineral Research diagnostic criteria. Adherence with FRiSC guidelines was inconsistent. A repeat dual-energy X-ray absorptiometry scan was performed in only two cases. The bisphosphonate was stopped in only two of the five patients following fracture. No clinical assessment of the contralateral femur or radiological assessment was done in any of the five cases. Conclusion: Overall, five atypical femoral fractures were found in a cohort of 1,803 patients at our district general hospital. This is 0.3% of the population studied, consistent with the incidence reported in the literature. Improvements in adherence with local guidelines for the management of atypical femoral fractures, along with increasing awareness of the nature of these fractures is necessary amongst rheumatologists, orthopedic surgeons, and geriatricians. Keywords: fracture, bisphosphonate, atypical

Increasing Occurrence of Atypical Femoral Fractures Associated With Bisphosphonate Use

Current evidence suggests that there is an association between bisphosphonate therapy and atypical femoral fractures, but the extent of this risk remains unclear. Between 1999 and 2010, a total of 477 patients 50 years and older were hospitalized with a subtrochanteric or femoral shaft fracture at a single university medical center. Admission radiographs and medical and treatment records were examined, and patients were classified as having atypical or classic femoral fractures. A random sample of 200 healthy individuals without femoral fracture were also identified. Multivariate logistic regression was used to assess the association of bisphosphonate use and atypical femoral fracture, and the incidence rates of each type of fracture over time were calculated. Thirty-nine patients with atypical fractures and 438 patients with classic fractures were identified. Of the patients with atypical fractures, 32 (82.1%) had been treated with bisphosphonates compared with 28 (6.4%) in the classic fractures group (odds ratios [OR], 66.9; 95% CI, 27.1-165.1) and 11.5% in the group without fracture (OR, 35.2; 95% CI, 13.9-88.8). Bisphosphonate use was associated with a 47% reduction in risk of classic fracture (OR, 0.5; 95% CI, 0.3-0.9). Considering the duration of use, the ORs (95% CIs) for atypical fractures were 35.1 (10.0-123.6) for less than 2 years, 46.9 (14.2-154.4) for 2 to 5 years, 117.1 (34.2-401.7) for 5 to 9 years, and 175.7 (30.0-1027.6) for more than 9 years compared with no use. A contralateral fracture occurred in 28.2% of atypical cases and in 0.9% of classic cases (OR, 42.6; 95% CI, 12.8-142.4). The incidence rate of atypical fractures was low (32 cases per million person-years) and increased by 10.7% per year on average. Atypical femoral fractures were associated with bisphosphonate use; longer duration of treatment resulted in augmented risk. The incidence of atypical fractures increased over a 12-year period, but the absolute number of such fractures is very small.