Carl Neuerburg

RANKL-associated suppression of particle-induced osteolysis in an aged model of Calcitonin and α-CGRP deficiency.

An aging population with higher bone turnover intensifies the need for joint replacement surgery. However, particle-induced osteolysis (PIO) remains a major cause of early implant loosening. Differences in bone remodeling between young and aged Calcitonin (CT)- and α-CGRP (Calcitonin gene-related peptide)-deficient mice (Calca(-/-)) might modify our previous findings regarding CT/α-CGRP in PIO. This may have important implications for PIO in an aging population. Four groups of twelve-month-old wild-type and Calca(-/-) mice underwent either SHAM surgery with and without CT, or polyethylene-particle implantation with related treatment. Morphometric changes were detected using μ-CT, histomorphometric analysis and by counting TRAP(+) cells (osteoclast-staining). Bone remodeling was assessed using serum and urinary markers. There was no osteolysis in aged particle-treated Calca(-/-) animals and the effect of CT on PIO was reduced compared to wild-type mice. However, there were significantly higher numbers of TRAP(+) cells in Calca(-/-) animals, and bone remodeling markers revealed a significant increase in OPG/OCN and a significant reduction in RANKL compared to aged wild-type mice. CT/α-CGRP modulates bone cell activity in PIO in aged mice in a way that is distinct from young animals. This may have implications for the treatment of PIO in the periprosthetic surface of joint replacements in an aging population.

The use of augmentation techniques in osteoporotic fracture fixation

There are an increasing number of fragility fractures, which present a surgical challenge given the reduced bone quality of underlying osteoporosis. Particularly in aged patients, there is a need for early weight bearing and mobilization to avoid further complications such as loss of function or autonomy. As an attempt to improve fracture stability and ultimate healing, the use of biomaterials for augmentation of osseous voids and fracture fixation is a promising treatment option. Augmentation techniques can be applied in various locations, and fractures of the metaphyseal regions such as proximal humerus, femur, tibia and the distal radius remain the most common areas for its use. The current review, based on the available mechanical and biological data, provides an overview of the relevant treatment options and different composites used for augmentation of osteoporotic fractures.

Neue Osteoporose-Leitlinie DVO 2014 und ihre Bedeutung für den Unfallchirurgen

Osteoporosis-associated fractures represent a growing challenge in the treatment of orthopedic patients. In November 2014 a new revision of the guidelines on osteoporosis by the German Osteology Society (Dachverband Osteologie DVO) was adopted, in which additional risk factors for fractures and further treatment options have been included. On the one hand the existing model used to diagnose osteoporosis and estimate a high fracture risk as a guidance for the use of specific anti-osteoporotic therapy in patients without a fragility fracture was maintained and further refined. On the other hand the guideline includes the option to initiate a specific osteoporosis therapy without a prior bone densitometry in patients with typical radiographs of a proximal femur fracture and higher grade vertebral fractures, suspicious for osteoporosis, depending on the overall clinical context. This may reduce the treatment gap of osteoporosis in Germany. In this paper the changes in the DVO guidelines 2014 on osteoporosis are summarized, focusing on the most important changes with practical relevance for orthopedic surgeons.

Identifikation, Diagnostik und leitliniengerechte Osteoporosetherapie (DVO) unfallchirurgischer Patienten

Osteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated.ZusammenfassungOsteoporoseassoziierte Frakturen haben in der Unfallchirurgie eine zunehmende Bedeutung. Die Durchführung einer spezifischen Diagnostik und Therapie der Osteoporose während eines stationären Aufenthalts ist jedoch nach wie vor unzureichend. Daher wurde basierend auf der Dachverband-Osteologie(DVO)-Leitlinie 2014 ein spezifischer Algorithmus zur Diagnostik und Therapie der Osteoporose bei unfallchirurgischen Patienten entwickelt. Zunächst werden unter Berücksichtigung von Indikatorfrakturen, Alter und Risikoprofil Patienten mit Osteoporose identifiziert. Dazu wird den Patienten ein Fragebogen ausgehändigt, welcher spezifische Risikofaktoren erfasst. Zusätzlich werden die körperliche Aktivität, das Sturzrisiko, die Ernährungsgewohnheiten und die individuelle Medikamenteneinnahme erhoben, da diese einen entscheidenden Einfluss auf die spätere Therapieentscheidung haben können. Vor der individuellen Behandlung werden ein Basislabor, eine Knochendichtemessung mittels DXA sowie ggf. ein Röntgen der Wirbelsäule durchgeführt, um prävalente Wirbelkörperfrakturen zu erkennen. Im Falle einer niedrigtraumatischen proximalen Femurfraktur kann bereits eine Therapie indiziert sein. Im Falle einer Glukokortikoidtherapie, stattgehabter Frakturen oder anderweitiger Risikofaktoren gemäß Risikofragebogen muss die Therapiegrenze der mittels DXA detektierten T-Werte angehoben werden.Der Behandlungsalgorithmus zur Diagnostik und Therapie der Osteoporose stationärer unfallchirurgischer Patienten kann die Identifikation von Risikopatienten systematisch und effizienter gestalten. Weitere osteoporoseassoziierte Frakturen bzw. Versagen von Osteosynthesen können dadurch reduziert werden. Wir planen eine prospektive Validierung des Algorithmus.AbstractOsteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated.

Proximal femoral fractures in the elderly

Proximal femoral fractures represent an increasing major healthcare problem due to the demographic changes in this aging population and are associated with the highest mortality among fractures in elderly patients after suffering insufficiency injuries (so-called fragility fractures). The main aim in the treatment of orthogeriatric patients who suffered from a proximal femoral fracture is the preservation of function and independency. Given the high prevalence of comorbidities in these patients, interdisciplinary and interprofessional approaches are required. The use of modern osteosynthesis procedures can provide an improved, individualized surgical treatment with early full weight bearing of the affected extremity. Another aspect is the accompanying geriatric treatment which is associated with a significant reduction of perioperative and postoperative complications. In addition to acute treatment, the organization of secondary fracture prevention is a crucial pillar of treatment. This article provides an overview of the essential elements of orthogeriatric trauma surgery in elderly patients following proximal femoral fractures.ZusammenfassungHüftgelenknahe Femurfrakturen stellen eine der häufigsten und vital bedrohlichsten Frakturen nach inadäquatem Trauma des älteren Menschen dar (sog. Fragilitätsfrakturen) und sind aufgrund des demografischen Wandels von zunehmender Bedeutung. Das generelle Hauptziel der Behandlung orthogeriatrischer Patienten ist der Erhalt der Funktion und der Selbstständigkeit des Patienten. Daher bedarf es interdisziplinärer und interprofessioneller Konzepte. Durch die Verwendung moderner Osteosyntheseverfahren können, abhängig von der Frakturentität, individuelle chirurgische Therapieoptionen angeboten werden, die die Voraussetzung zur sofortigen vollbelastenden Mobilisation darstellen. Ein weiterer Aspekt ist die begleitende geriatrische Behandlung, die bei den häufig multimorbiden Patienten zu einer signifikanten Reduktion peri- und postoperativer Komplikationen führen kann. Neben der Akutversorgung stellt die Organisation einer Sekundärprophylaxe einen entscheidenden Behandlungspfeiler dar. Der vorliegende Beitrag gibt einen Überblick über die wesentlichen Elemente der Alterstraumatologie bei hüftgelenknahen Femurfrakturen des älteren Menschen.AbstractProximal femoral fractures represent an increasing major healthcare problem due to the demographic changes in this aging population and are associated with the highest mortality among fractures in elderly patients after suffering insufficiency injuries (so-called fragility fractures). The main aim in the treatment of orthogeriatric patients who suffered from a proximal femoral fracture is the preservation of function and independency. Given the high prevalence of comorbidities in these patients, interdisciplinary and interprofessional approaches are required. The use of modern osteosynthesis procedures can provide an improved, individualized surgical treatment with early full weight bearing of the affected extremity. Another aspect is the accompanying geriatric treatment which is associated with a significant reduction of perioperative and postoperative complications. In addition to acute treatment, the organization of secondary fracture prevention is a crucial pillar of treatment. This article provides an overview of the essential elements of orthogeriatric trauma surgery in elderly patients following proximal femoral fractures.

The role of calcitonin receptor signalling in polyethylene particle-induced osteolysis.

The detection of peptides from the calcitonin (CT) family in the periarticular tissue of loosened implants has raised hopes of opening new regenerative therapies in the process of aseptic loosening, which remains the major cause of early implant failure in endoprosthetic surgery. We have previously shown the roles of α-calcitonin gene-related peptide (α-CGRP) and the CALCA gene which encodes α-CGRP/CT in this process. To uncover the role of direct calcitonin receptor (CTR) mediated signalling, we studied particle-induced osteolysis (PIO) in a murine calvaria model with a global deletion of the CTR (CTR-KO) using μCT analysis and histomorphometry. As expected, CTR-KO mice revealed reduced bone volume compared to wild-type (WT) controls (p<0.05). In CTR-KO mice we found significantly higher RANKL (receptor activator of NF-κB ligand) expression in the particle group than in the control group. The increase in osteoclast numbers by the particles was twice as high as the increase of osteoclasts in the WT mice (400 vs. 200%). Changes in the eroded surface and actual osteolysis due to ultrahigh-molecular-weight polyethylene particles were similar in WTs and CTR-KOs. Taken together, our findings strengthen the relevance of the OPG/RANK/RANKL system in the PIO process. CTR seems to have an effect on osteoclast differentiation in this context. As there were no obvious changes of the amount of PIO in CTR deficiency, regenerative strategies in aseptic loosening of endoprosthetic implants based on peptides arising from the CT family should rather focus on the impact of α-CGRP.

Ultrathin sP(EO-stat-PO) hydrogel coatings are biocompatible and preserve functionality of surface bound growth factors in vivo

Hydrogel coatings prepared from reactive star shaped polyethylene oxide based prepolymers (NCO-sP(EO-stat-PO)) minimize unspecific protein adsorption in vitro, while proteins immobilized on NCO-sP(EO-stat-PO) coatings retain their structure and biological function. The aim of the present study was to assess biocompatibility and the effect on early osseointegrative properties of a NCO-sP(EO-stat-PO) coating with additional RGD-peptides and augmentation with bone morphogenetic protein-4 (BMP) used on a medical grade high-density polyethylene (HDPE) base under in vivo circumstances. For testing of biocompatibility dishes with large amounts of bulk NCO-sP(EO-stat-PO) were implanted subcutaneously into 14 Wistar rats. In a second set-up functionalization of implants with ultrathin surface layers by coating ammonia-plasma treated HDPE with NCO-sP(EO-stat-PO), functionalization with linear RGD-peptides, and augmentation with RGD and BMP-4 was analyzed. Therefore, implants were placed subcutaneously in the paravertebral tissue and transcortically in the distal femur of another 14 Wistar rats. Both tests revealed no signs of enhanced inflammation of the surrounding tissue analyzed by CD68, IL-1ß-/TNF-α-antibody staining, nor systemic toxic reactions according to histological analysis of various organs. The mean thickness of the fibrous tissue surrounding the femoral implants was highest in native HDPE-implants and tended to be lower in all NCO-sP(EO-stat-PO) modified implants. Micro-CT analysis revealed a significant increase of peri-implant bone volume in RGD/BMP-4 coated samples. These results demonstrate that even very low amounts of surface bound growth factors do have significant effects when immobilized in an environment that retains their biological function. Hence, NCO-sP(EO-stat-PO)-coatings could offer an attractive platform to improve integration of orthopedic implants.

Investigation and management of osteoporosis in aged trauma patients: a treatment algorithm adapted to the German guidelines for osteoporosis

BackgroundOsteoporosis-associated fractures are of increasing importance in trauma surgery. Systematic diagnostics and treatment of osteoporosis during a hospital stay, however, remain inadequate. Therefore, a specific algorithm for diagnosing and treating osteoporosis in trauma surgery patients was developed based on the DVO (German Osteology Society) guideline for osteoporosis from 2014.MethodsIn a first step, the individuals’ age and risk profile for osteoporosis is identified considering specific fractures indicating osteoporosis and risk factors assessed by a specific questionnaire. In addition, physical activity, risk of falls, dietary habits and the individuals’ medication are considered. Basic osteoporosis laboratory tests, a bone densitometry by dual-energy X-ray absorptiometry (DXA) and, if needed, X-rays of the spine are carried out to identify prevalent vertebral body fractures.ResultsBased on the treatment algorithm adapted to the new guidelines for osteoporosis in the majority of proximal femoral fractures, treatment of osteoporosis could already be indicated without prior DXA. In case of preexisting glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted given the table of T-scores.ConclusionsThe treatment algorithm for diagnosing and treating osteoporosis in in-patient trauma surgery patients can help identify high-risk patients systematically and efficiently. As a result, osteoporosis-associated fractures or failure of osteosynthesis could be reduced, yet a prospective validation of the algorithm has to be completed.

[Identification, diagnostics and guideline conform therapy of osteoporosis (DVO) in trauma patients : a treatment algorithm].

Osteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated.ZusammenfassungOsteoporoseassoziierte Frakturen haben in der Unfallchirurgie eine zunehmende Bedeutung. Die Durchführung einer spezifischen Diagnostik und Therapie der Osteoporose während eines stationären Aufenthalts ist jedoch nach wie vor unzureichend. Daher wurde basierend auf der Dachverband-Osteologie(DVO)-Leitlinie 2014 ein spezifischer Algorithmus zur Diagnostik und Therapie der Osteoporose bei unfallchirurgischen Patienten entwickelt. Zunächst werden unter Berücksichtigung von Indikatorfrakturen, Alter und Risikoprofil Patienten mit Osteoporose identifiziert. Dazu wird den Patienten ein Fragebogen ausgehändigt, welcher spezifische Risikofaktoren erfasst. Zusätzlich werden die körperliche Aktivität, das Sturzrisiko, die Ernährungsgewohnheiten und die individuelle Medikamenteneinnahme erhoben, da diese einen entscheidenden Einfluss auf die spätere Therapieentscheidung haben können. Vor der individuellen Behandlung werden ein Basislabor, eine Knochendichtemessung mittels DXA sowie ggf. ein Röntgen der Wirbelsäule durchgeführt, um prävalente Wirbelkörperfrakturen zu erkennen. Im Falle einer niedrigtraumatischen proximalen Femurfraktur kann bereits eine Therapie indiziert sein. Im Falle einer Glukokortikoidtherapie, stattgehabter Frakturen oder anderweitiger Risikofaktoren gemäß Risikofragebogen muss die Therapiegrenze der mittels DXA detektierten T-Werte angehoben werden.Der Behandlungsalgorithmus zur Diagnostik und Therapie der Osteoporose stationärer unfallchirurgischer Patienten kann die Identifikation von Risikopatienten systematisch und effizienter gestalten. Weitere osteoporoseassoziierte Frakturen bzw. Versagen von Osteosynthesen können dadurch reduziert werden. Wir planen eine prospektive Validierung des Algorithmus.AbstractOsteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated.

Impact of vitamin E-blended UHMWPE wear particles on the osseous microenvironment in polyethylene particle-induced osteolysis

Aseptic loosening mediated by wear particle-induced osteolysis (PIO) remains the major cause of implant loosening in endoprosthetic surgery. The development of new vitamin E (α-tocopherol)-blended ultra-high molecular weight polyethylene (VE-UHMWPE) with increased oxidation resistance and improved mechanical properties has raised hopes. Furthermore, regenerative approaches may be opened, as vitamin E supplementation has shown neuroprotective characteristics mediated via calcitonin gene-related peptide (CGRP), which is known to affect bone remodeling in PIO. Therefore, the present study aimed to further clarify the impact of VE-UHMWPE wear particles on the osseous microenvironment and to identify the potential modulatory pathways involved. Using an established murine calvaria model, mice were subjected to sham operation (SHAM group), or treated with UHMWPE or VE-UHMWPE particles for different experimental durations (7, 14 and 28 days; n=6/group). Morphometric analysis by micro-computed tomography detected significant (p<0.01) and comparable signs of PIO in all particle-treated groups, whereas markers of inflammation [tumor necrosis factor (TNF)-α/tartrate resistant acid phosphatase (TRAP) staining] and bone remodeling [Dickkopf-related protein 1 (DKK-1)/osteoprotegerin (OPG)] were most affected in the early stages following surgery. Taking the present data into account, VE-UHMWPE appears to have a promising biocompatibility and increased ageing resistance. According to the α-CGRP serum levels and immunohistochemistry, the impact of vitamin E on neuropeptidergic signaling and its chance for regenerative approaches requires further investigation.