„An sich ist nichts weder gut noch böse“: atypische Femurschaftfrakturen unter Bisphosphonattherapie - eine Frage der Zeit?

Die Studie untersucht die schwedische Population >55 J., welche 2008-2010 eine subtrochantäre-/Femurschaftfraktur erlitten hatte (n=5342). Röntgen wurden auf atypische Femurschaftfrakturen (n=172) gesichtet. Dem Register wurden Nebendiagnosen und Medikation entnommen. Es wird gezeigt, dass atypischen Femurschaftfrakturen auf die Bisphosphonattherapie zurückzuführen sind. Insbesondere die Langzeittherapie steigert das Risiko. Absetzten führt zu einer raschen Risikoreduktion. Alendronat birgt ein fast doppelt so hohes Risiko wie Risedronat. Frauen haben ein dreimal höheres Risiko als Männer.We reviewed radiographs of 5,342 Swedish patients >55 years with a fracture of the femoral shaft in 2008-2010, and found 172 atypical fractures (AF). We obtained data on medication and comorbidity. The age-adjusted relative risk (RR) of AF associated with bisphosphonate use was 55 in women and 54 in men. In bisphosphonate users, women had a 3-fold higher risk than men. Alendronate users had higher risk than risedronate users. The RR after 4 years or more of use reached 126, with a corresponding absolute risk of 11 fractures / 10,000 person-years of use. The risk decreased 70% / year since last use

IgG Conformer's Binding to Amyloidogenic Aggregates

Amyloid-reactive IgGs isolated from pooled blood of normal individuals (pAbs) have demonstrated clinical utility for amyloid diseases by in vivo targeting and clearing amyloidogenic proteins and peptides. We now report the following three novel findings on pAb conformer's binding to amyloidogenic aggregates: 1) pAb aggregates have greater activity than monomers (HMW species > dimers > monomers), 2) pAbs interactions with amyloidogenic aggregates at least partially involves unconventional (non-CDR) interactions of F(ab) regions, and 3) pAb's activity can be easily modulated by trace aggregates generated during sample processing. Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg), had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of Aβ- and Cibacron blue-isolated IVIg IgGs. Human pAb conformer's binding to amyloidogenic aggregates was retained in normal human sera, and mimicked by murine pAbs isolated from normal pooled plasmas. An unconventional (non-CDR) component to pAb's activity was indicated from control human mAbs, generated against non-amyloid targets, binding to aggregated Aβ and TTR. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Taken together, our findings strongly support further investigations on the physiological function and clinical utility of the inherent anti-amyloid activities of monomeric but not aggregated IgGs

Dichotomous location of 160 atypical femoral fractures

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.Funding Agencies|Swedish Research Council|VR 02031-47-5|Linkoping University||Ostergotland County Council||King Gustaf V and Queen Victoria Free Mason Foundation||Eli Lilly Co.||</p

Risk of atypical femoral fracture during and after bisphosphonate use Full report of a nationwide study

Background and purpose - Use of bisphosphonates in women is associated with higher risk of atypical femoral fractures. The risk in terms of timing of use and type of bisphosphonate, and in men, remains unclear. Patients and methods - We reviewed radiographs of 5,342 Swedish women and men aged 55 years or more who had had a fracture of the femoral shaft in the 3-year period 2008-2010 (97% of those eligible), and found 172 patients with atypical fractures (93% of them women). We obtained data on medication and comorbidity. The risk of atypical fracture associated with bisphosphonate use was estimated in a nationwide cohort analysis. In addition, we performed a case-control analysis with comparison to 952 patients with ordinary shaft fractures. A short report of the findings has recently been presented (Schilcher et al. 2014a). Here we provide full details. Results - The age-adjusted relative risk (RR) of atypical fracture associated with bisphosphonate use was 55 (95% CI: 39-79) in women and 54 (CI: 15-192) in men. In bisphosphonate users, women had a 3-fold higher risk than men ( RR = 3.1, CI: 1.1-8.4). Alendronate users had higher risk than risedronate users (RR = 1.9, CI: 1.1-3.3). The RR after 4 years or more of use reached 126 (CI: 55-288), with a corresponding absolute risk of 11 (CI: 7-14) fractures per 10,000 person-years of use. The risk decreased by 70% per year since last use. Interpretation - Women have a higher risk of atypical femoral fracture than men. The type of bisphosphonate used may affect risk estimates and the risk decreases rapidly after cessation.Funding Agencies|Swedish Research Council [VR 2009-6725]; Linkoping University; Ostergotland County Council; King Gustaf V and Queen Victoria Freemason Foundation; Eli Lilly Co.</p

Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls

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.Funding Agencies|Swedish Research Council|VR 2009-6725|Linkoping University||Ostergotland County Council||King Gustaf V and Queen Victoria Free Mason Foundation||Eli Lilly Co.||</p

Kinetics of tumor size and peritumoral brain edema before, during, and after systemic therapy in recurrent WHO grade II or III meningioma

The efficacy of systemic antineoplastic therapy on recurrent World Health Organization (WHO) grades II and III meningiomas is unclear.status: publishe

Unfractionated, Aβ- and Cibacron blue-isolated human IgGs binding to plate-immobilized PFs.

<p>¹Mon stands for IgG monomers.</p><p>^2,3SEC-isolated IgG monomers (mon), dimers, and HMW aggregates as shown in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137344#pone.0137344.g002" target="_blank">2</a> & <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137344#pone.0137344.g003" target="_blank">3</a>.</p><p>Each value for EC₅₀ and maximum signal amplitude was determined from the average of two to three sigmoidal fitted antibody binding curves, as shown in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137344#pone.0137344.g003" target="_blank">3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137344#pone.0137344.g008" target="_blank">8</a>.</p

Aβ-isolated but not heat-induced Avastin aggregates have enhanced avidity for PFs.

<p>(<b>A</b>) Left panel: SEC chromatograms for 0.3 mg/mL of Aβ-isolated Avastin IgGs, untreated Avastin, and for the antibody diluted into elution buffer (0.1 M glycine, pH 2.7) that was used to elute Aβ-bound Avastin IgGs. SEC was carried out using a Superdex 200 increase 10/300 GL column (GE Healthcare) that was equilibrated with PBS, pH 7.4. Right panel: Antibody binding curves against PFs for unfractionated IVIg and Avastin, and for Aβ-isolated Avastin IgGs. (<b>B</b>) Left panel: SEC chromatograms for ~5 mg/mL of unfractionated Avastin in PBS, pH 7.4, and for IgG conformers contained in supernatant of 71°C heated Avastin monomers (A_400nm 0.5 sup) in PBS, pH 7.4. Right panel: Antibody binding curves against PFs for soluble (A_400nm 0.5 sup) and insoluble (A_400nm 0.5 pellet) IgG conformers of heat-treated Avastin monomers, and for untreated Avastin and IVIg.</p