| 1. |
- Aspenberg, Per, et al.
(author)
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Atypical femoral fractures, bisphosphonates, and mechanical stress
- 2014
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In: Current osteoporosis reports. - : Springer. - 1544-1873 .- 1544-2241. ; 12:2, s. 189-193
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Journal article (peer-reviewed)abstract
- Atypical fractures are stress fractures occurring in the femoral shaft and closely related to bisphosphonate use. We here discuss their radiographic definition and different putative etiologies, apart from mechanical stress. Long time reduction of skeletal remodeling because of bisphosphonate use is thought to allow time for the bone to deteriorate mechanically, resulting in reduced toughness. However, the risk of atypical fracture diminishes rapidly after cessation of treatment, which suggests more acute effects of bisphosphonate use. Microdamage normally accumulates at areas of high stress. Possibly, ongoing bisphosphonate use reduces the ability to resorb and replace areas of microdamage by targeted remodeling. This could lead to crack propagation beyond a point of no return, ending in macroscopic stress fracture.
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| 2. |
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| 3. |
- Aspenberg, Per, et al.
(author)
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Stressfrakturer : hjulaxlar och idrottskarriärer brister
- 2014
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In: Läkartidningen. - Stockholm : Sveriges läkarförbund. - 0023-7205 .- 1652-7518. ; 111:36, s. 1436-1439
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Journal article (peer-reviewed)abstract
- Stress fractures are caused by material fatigue. Microcracks appear normally in bone, and are dealt with by remodeling, specifically targeting areas of microdamage. Inhibition of targeted remodeling can allow microcracks to grow and form fractures. Intensive athletic training can lead to an increased microcrack formation rate, which exceeds what can be balanced by remodeling. Stress fractures often heal poorly, possibly because they are so thin: normal deformation of the bone during loading has been shown to lead to strains within thin cracks that are incompatible with cell survival. If the patient can't reduce loading sufficiently to allow healing, surgical stabilization will therefore be required. If the crack is transformed into a larger defect, e.g. by drilling a hole, strains will be reduced and healing facilitated by a simple procedure.
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| 4. |
- Koeppen, V A, et al.
(author)
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Atypical fractures do not have a thicker cortex
- 2012
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In: Osteoporosis International. - : Springer Verlag (Germany). - 0937-941X .- 1433-2965. ; 23:12, s. 2893-2896
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Journal article (peer-reviewed)abstract
- An association between atypical fractures and general cortical thickness of the femoral shaft is often suggested in the literature. Our radiographic measurements of 59 atypical and 218 ordinary fractures now exclude a difference larger than 10 % in mean femoral cortical thickness (sum of lateral and medial) with 95 % confidence. less thanbrgreater than less thanbrgreater thanAn increased general cortical thickness in patients with fatigue fracture of the femoral shaft (atypical fractures) is commonly suggested. However, there are scarce data to support this. less thanbrgreater than less thanbrgreater thanIn a published nationwide Swedish study, we identified by radiographic review 59 women with an atypical fracture during 2008. The femoral cortical thickness index (thickness/femoral diameter) of these women was now compared with the 218 ordinary fractures that occurred in the same region of the femur in a case-control design. The cortical thickness index 5 cm below the lesser trochanter was the primary variable. less thanbrgreater than less thanbrgreater thanPatients with atypical fractures were younger. Without correction for age, they had a thicker cortex (i.e., higher index). However, the difference in cortical thickness disappeared after age correction. The 95 % CI excludes a group mean difference exceeding 10 % of total mean thickness. Similarly, there was no significant difference in cortical thickness between patients with or without bisphosphonate treatment or between the ipsi- and contralateral femurs in patients with an atypical fracture. less thanbrgreater than less thanbrgreater thanThe concept of a generally increased cortical thickness in patients with atypical fractures should be reconsidered.
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| 5. |
- Koeppen, Veronika A, et al.
(author)
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Dichotomous location of 160 atypical femoral fractures
- 2013
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In: Acta Orthopaedica. - : Informa Healthcare. - 1745-3674 .- 1745-3682. ; 84:6, s. 561-564
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Journal article (peer-reviewed)abstract
- Background and purpose The risk of atypical fracture of the femur is associated with bisphosphonate use. While characterizing atypical fractures from a previous nationwide study in radiographic detail, we had the impression that the fractures were located either in the subtrochanteric region or in the shaft. We determined whether there is a dichotomy in this respect. less thanbrgreater than less thanbrgreater thanPatients and methods The distance between the atypical fractures and the lesser trochanter was measured on plain radiographs from 129 of 160 patients with atypical fractures, taken from 2008 through 2010. Analysis of the distances measured showed 2 clusters, which were then analyzed with regard to bisphosphonate use and age. less thanbrgreater than less thanbrgreater thanResults The distribution of the distances would be best described as 2 clusters, with a dichotomy at 8 cm. The proximal (subtrochanteric) cluster comprised 25 patients who were generally younger (median 71 years) than the 104 patients in the cluster with shaft fractures (median 80 years). The 95% CI for the difference between medians was 4-11 years. Of the patients with subtrochanteric fractures, 18 of 25 used bisphosphonates as compared to 89 of 104 with shaft fractures. less thanbrgreater than less thanbrgreater thanInterpretation The younger age and possibly smaller proportion of bisphosphonate users in the subtrochanteric cluster may be compatible with a greater influence of mechanical stress in the underlying pathophysiology of proximal fractures.
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| 7. |
- Schilcher, Jörg, et al.
(author)
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Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls
- 2013
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In: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 52:1, s. 389-392
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Journal article (peer-reviewed)abstract
- Background: Estimations of the risk of bisphosphonate associated atypical femoral fractures vary between different population-based studies, from considerable to neglectable. A possible explanation for these discrepancies could be different definitions of atypical fractures. We aimed to identify specific radiographic fracture characteristics associated with bisphosphonate use. less thanbrgreater than less thanbrgreater thanMethods: In a previous nationwide study, 59 atypical and 218 ordinary fractures were diagnosed. The atypical fractures were defined by their stress-type fracture pattern. All fractures were now re-assessed by a physician in training, without information about bisphosphonate use. The fracture angle (0-180 degrees) was measured. Presence of local lateral cortical thickening (a callus reaction), more than 2 fragments, or a medial spike was noted. The reader then made a judgment whether the fracture appeared as an atypical fracture based on the ASBMR criteria. less thanbrgreater than less thanbrgreater thanResults: Frequency distribution analysis of the fracture angle showed a distinct subgroup, comprising 25% of all 277 fractures, with a mean of 89 and SD of 10 degrees. Forty-two of 57 patients in this subgroup used bisphosphonates, whereas only 27 of 213 others did (specificity 0.93; 95% CI 0.88-0.96). Presence of a callus reaction had also a high specificity for bisphosphonate use (0.96; 95% CI 0.92-0.98). The ASBMR criteria had a lower specificity, increasing the number of atypical fractures without bisphosphonate use from 13 to 31. This led to a decrease in age-adjusted relative risk associated with bisphosphonate use from 47 (95% CI 26-87) to 19 (95% CI 12-29). less thanbrgreater than less thanbrgreater thanInterpretation: Stress fractures of the femoral shaft are a specific entity, which is easily diagnosed on radiographs and strongly related to bisphosphonate use. Differences in diagnostic criteria may partially explain the large differences in relative risk between different population-based studies.
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| 9. |
- Schilcher, Jörg, et al.
(author)
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Bisphosphonate Use and Atypical Fractures of the Femoral Shaft
- 2011
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In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 364:18, s. 1728-1737
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Journal article (peer-reviewed)abstract
- BACKGROUND Studies show conflicting results regarding the possible excess risk of atypical fractures of the femoral shaft associated with bisphosphonate use. METHODS In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures. RESULTS The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). CONCLUSIONS These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small.
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| 10. |
- Schilcher, Jörg, 1978-
(author)
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Epidemiology, Radiology and Histology of Atypical Femoral Fractures : Development of understanding
- 2013
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In: Acta Orthopaedica. - Linköping : Linköping University Electronic Press. - 1745-3674 .- 1745-3682. ; 84:S352, s. 1-26
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Doctoral thesis (other academic/artistic)abstract
- Bisphosphonates have been used successfully in the prevention of osteoporosis-related fractures for over two decades. Only recently an association between bisphosphonate use and femoral insufficiency fractures – atypical femoral fractures – has been found.Bone remodeling is necessary to maintain a healthy skeleton. With age this process can get out of balance and bone resorption can outweigh formation of new bone. This can lead to osteoporosis and fractures that occur after minor trauma. Almost half of all women 50 years of age or older will suffer an osteoporosis related fracture during their remaining life. Bisphosphonates inhibit bone resorption, and after some years of treatment an increase in bone mass can be noted. This increase in bone mass can reduce fracture risk by as much as half. However, bisphosphonate use seems associated with the development of femoral insufficiency fractures, so called atypical femoral fractures. This thesis aimed to estimate the risk of atypical femoral fractures in the population and its association with bisphosphonate use. It also describes the radiographic and histologic features of these fractures in order to improve our understanding of the pathophysiological background.Study 1) All women 55 years of age and older, who had sustained a femoral shaft fracture during 2008, were identified through the Swedish National Patient Register. Radiographs of 1234 women were reviewed, and 59 patients with atypical fractures and 263 control patients with common femoral shaft fractures were identified. Atypical femoral fractures were defined by their stress fracture-like appearance. In a cohort analysis, we estimated an age-adjusted relative risk of 47 for bisphosphonate users to suffer an atypical femoral fracture compared to non-users. A total of 78% of the patients with an atypical fracture and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33. The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. These results indicate that bisphosphonate use is strongly associated with atypical femoral fractures. The absolute risk is low and benefits of treatment will outweigh the risks.Study 2) A transverse fracture line and a small but visible callus reaction are well established radiographic features of stress fractures. Radiographs from 59 atypical fracture patients and 218 control patients from Study 1 were re-reviewed to measure fracture angles and to detect callus reactions. The majority of the patients with a transverse fracture angle used bisphosphonates. Fracture angle and callus reaction had a high specificity to detect bisphosphonate treatment. When an oblique fracture line was chosen to define atypical femoral fractures in the cohort from Study 1, the association of atypical femoral fractures to bisphosphonate use became attenuated. Therefore, a correct case definition of atypical femoral fractures is necessary for adequate risk calculations.Study 3) Bone biopsies from 8 patients with atypical femoral fractures were obtained during surgical fixation. The histological analysis of the fracture site itself showed a thin fracture line running perpendicular to the long axis of the femur. Despite ongoing remodeling in the bone adjacent to the fracture gap, no healing occurred within the gap itself. Necrotic material in the gap suggests that strains within the gap might prohibit ingrowth of cells necessary for healing. This mechanism of inhibited healing might share similarities with that of stress fractures in athletes. Although it is highly likely that bisphosphonates play a causative role, the pathogenesis of these fractures is still unclear. It may involve a reduced capacity for targeted remodeling.
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| 11. |
- Schilcher, Jörg, et al.
(author)
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Histology of 8 atypical femoral fractures
- 2014
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In: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 85:3, s. 280-286
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Journal article (peer-reviewed)abstract
- Background and purpose - The pathophysiology behind bis-phosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself may provide clues. Patients and methods - Between 2008 and 2013, we collected bone biopsies including the fracture line from 4 complete and 4 incomplete atypical femoral fractures. 7 female patients reported continuous bisphosphonate use for 10 years on average. 1 patient was a man who was not using bisphosphonates. Dual-energy X-ray absorptiometry of the hip and spine showed no osteoporosis in 6 cases. The bone biopsies were evaluated by micro-computed tomography, infrared spectroscopy, and qualitative histology. Results - Incomplete fractures involved the whole cortical thickness and showed a continuous gap with a mean width of 180 m. The gap contained amorphous material and was devoid of living cells. In contrast, the adjacent bone contained living cells, including active osteoclasts. The fracture surfaces sometimes consisted of woven bone, which may have formed in localized defects caused by surface fragmentation or resorption. Interpretation - Atypical femoral fractures show signs of attempted healing at the fracture site. The narrow width of the fracture gap and its necrotic contents are compatible with the idea that micromotion prevents healing because it leads to strains within the fracture gap that preclude cell survival.
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