The Outcome of Distal Radius Fractures with Concomitant Injuries Is Similar to those of Isolated Distal Radius Fractures Provided that an Arthroscopically Supported Treatment Is Performed.

BACKGROUND: Concomitant injuries of distal radius fractures (DRF) can have a fatal impact on the patients' outcome. However, wrist arthroscopy is a costly and complex procedure. It remains elusive whether patients benefit from an additional arthroscopy. METHODS: Patients with a DRF who were treated arthroscopically were enrolled. Fifty-six wrists were evaluated regarding their function by self-assessment with the Munich Wrist Questionnaire (MWQ). Thirty-nine patients were examined for postoperative strength and motion. Concomitant injuries were detected. RESULTS: A total of 75% of the DRF were type C injuries (AO classification). Twenty-four cases (43%) were triangular fibrocartilaginous complex (TFCC) lesion, eight cases (14%) of scapholunate ligament (SL) injuries and seven cases (12%) were a combination of TFCC and SL ligament lesion. No difference in function could be detected between DRF with surgically addressed concomitant lesions and isolated DRF. Dorsalextension, palmarflexion and grip strength were significantly reduced in patients with DRF and concomitant injuries compared to the healthy wrist. However, patients with DRF and arthroscopically treated concomitant injuries had similar results to those suffering only from an isolated DRF. CONCLUSION: The increased occurrence of concomitant injuries is to be expected in intraarticular DRF. Patients with concomitant injuries benefit from an arthroscopically assisted fracture treatment and show similar results compared to isolated DRF.

miRNAs in bone tissue correlate to bone mineral density and circulating miRNAs are gender independent in osteoporotic patients.

We previously demonstrated the aberrant expression of nine specific miRNAs in serum from osteoporotic patients. In the present study, we further evaluated the expression of these miRNAs in bone tissue, osteoblasts, and osteoclasts from 28 patients. We hypothesize that miRNA expression in serum from osteoporotic patients may be gender-independent. A further hypothesis is that the miRNA expression in bone could be correlated with BMD values. Moreover, intracellular expression of these osteoporosis-related miRNAs may indicate the role of these molecules during osteoporosis. Our results indeed show that miRNA expression in serum was gender-independent except for miR125b-5p. A correlation with BMD was confirmed for miR-21-5p, miR-24-3p, miR-93-5p, miR-100-5p and miR125b-5p with linear correlation coefficients r > 0.9. Intracellular studies revealed a simultaneous up-regulation of miR-21-5p, miR-93-5p, miR-100-5p and miR125b-5p in osteoblasts and in osteoclasts. miR-148a-3p up-regulation in cells was specific for osteoporotic osteoclasts. Altogether, miR-21-5p, miR-93-5p, miR-100-5p, and miR-125b-5p showed significant upregulation in serum, tissue and bone cells of osteoporotic patients. All except miR-125b-5p showed gender independent expression and good correlation to BMD values. Our results suggest that these miRNAs may be important for an earlier diagnosis of osteoporosis.

The Munich Wrist Questionnaire (MWQ) - development and validation of a new patient-reported outcome measurement tool for wrist disorders.

BACKGROUND: Although self-assessment questionnaires for the wrist joint are numerous, most validation studies focus on a specific pathology and patient collectives. In addition the available questionnaires focus on subjective parameters such as pain, usual and specific activities but the range of motion (ROM) as an essential objective parameter in wrist disorders is rarely considered. Therefore the purpose of the presented study was to develop and validate a new universally applicable self-assessment score, the Munich Wrist Questionnaire (MWQ), which allows for the assessment of subjective as well as objective parameters of the wrist joint. METHODS: The MWQ consists of 16 items addressing three domains: pain, work and activities of daily living and wrist function including range of motion and grip strength. In a prospective clinical study validity, reliability and responsiveness of the MWQ of physical active patients were evaluated. RESULTS: Validation study included 100 patients (mean age 41 years, SD 16.3 years; range, 18-77 years). Test-retest reliability was substantial, with intraclass correlation coefficients ranging from 0.75 to 0.83 for the three domains. Construct validity and responsiveness were confirmed by correlation coefficients of at least 0.86 for construct validity and for responsiveness ranging from 0.61 to 0.65. CONCLUSIONS: The MWQ presents a valid and reliable instrument for a qualitative self-assessment of subjective and objective parameters (e.g. range of motion) of the wrist joint. Quantitative measurement of wrist function may not longer be limited to specific wrist disorders or patient groups. The MWQ seems to allow for a broad application in clinical research and may facilitate the comparison of treatment results in wrist disorders.

HLA-DR expression on monocytes is decreased in polytraumatized patients.

BACKGROUND: Sepsis, systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) remain the most frequent causes of complications and death in severely injured patients. A main reason for the development of these syndromes is a post-traumatic dysregulation of the immune system. Several studies in intensive care unit (ICU) patients could detect a pivotal role of HLA-DR expression on monocytes. So far, its importance for development of SIRS, sepsis or MODS in the severely injured patient is not clear. METHODS: Therefore, we have analysed HLA-DR expression on monocytes from severely injured patients (ISS > 16) during the post-traumatic course, which was on the day of trauma, as well as on days 3, 7 and 14 post trauma. Clinical data were analysed and the HLA-DR expression levels of patients who developed post-traumatic sepsis, SIRS or MODS were compared to those with a more favourable outcome. Young and healthy volunteers as well as patients undergoing prosthetic hip replacement after trauma were enrolled as control groups. HLA-DR molecules on monocytes were marked with PE-conjugated antibodies and the mean fluorescence intensity (MFI) was analysed via flow cytometry. RESULTS: 24 severely injured patients (mean age 34 ± 2.7 years) mainly after high energy motor vehicle accidents as well as 8 controls (total hip replacement) and 9 healthy volunteers (mean age 26.2 ± 1.2 years) were enrolled. A total of eight patients suffered from sepsis (33.3 %) (six males, two females) and 17 patients suffered from SIRS (70.9 %) (10 males, 7 females). MODS was present in five patients (20.8 %), three male and two female patients. In four of these five patients the MODS developed subsequent to sepsis. HLA-DR expression significantly decreased after trauma and slowly returned to normal after 14 days, irrespective of the complications developed. CONCLUSION: In conclusion, post-traumatic HLA-DR expression on monocytes is significantly reduced after multiple trauma and it is back to normal on day 14. No significant changes in HLA-DR expression on monocytes from severely injured patients suffering from SIRS, MODS or sepsis compared to those who did not have complications could be detected. Nevertheless, HLA-DR expression on monocytes may be used to identify the immunological pro- or anti-inflammatory phase the patient is going through.

Signaling pathway STAT1 is strongly activated by IFN-ß in the pathogenesis of osteoporosis.

BACKGROUND: Despite extensive research, the underlying pathological mechanisms of osteoporosis are not completely understood. Recent studies have indicated a distinct role for the IFN-ß/STAT1 pathway in bone metabolism. An inhibitory effect of IFN-ß on osteoclastogenesis has been detected and STAT1/2 has been shown to influence osteoblastic bone metabolism. So far, no data concerning the IFN-ß/STAT1 pathways in osteoblasts and osteoclasts from osteoporotic and non-osteoporotic patients are available. The aim of the study was to analyze these pathways in both cell types. METHODS: Osteoblasts were isolated from the femoral heads of 12 osteoporotic and 11 non-osteoporotic patients and monocytes were differentiated into osteoclasts. After the differentiation period, cells were stimulated once with 20 and 100 ng/mL IFN-ß for 4 days. Viability, activity, bone metabolism-related genes, and the proteins Fra1, SOCS1, STAT1, p-STAT1, and TRAF6 were analyzed. RESULTS: Viability, activity, and gene expressions were not affected by stimulating the osteoblasts. However, in osteoporotic osteoclasts, which display a significantly higher basal osteoclastic activity, the stimulation with IFN-ß lead to significant inhibition. Further, an increased STAT1 activation was detected in both cell types with no significant differences between the groups. Regarding the phosphorylation of STAT1, no significant influence was detected in osteoblasts but the IFN-ß stimulation led to a significant increase of p-STAT1 in osteoclasts of both groups. CONCLUSIONS: IFN-ß is a principal mediator in the pathogenesis of osteoporosis by inhibiting osteoclasts and inducing and activating STAT1. Our results also confirm this in cells from osteoporotic and non-osteoporotic patients. Strong inhibitory effects on the osteoclastogenesis of osteoporotic osteoclasts were detectable. Nevertheless, osteoblast activity was not negatively affected by IFN-ß stimulation. These results may contribute to a better understanding of the underlying pathological signaling pathways of osteoporosis.

Green Tea Extract (GTE) improves differentiation in human osteoblasts during oxidative stress.

BACKGROUND: Oxidative stress is involved in the pathogenesis of bone diseases such as osteoporosis, which has a high coincidence with fractures in elderly. Several studies showed positive effects of herbal bioactive substances on oxidative stress. This study analyses the effect of green tea extract (GTE) Sunphenon 90LB on primary human osteoblasts differentiation and viability during H2O2-induced oxidative stress. Moreover, it was analyzed, whether GTE acts during the HO-1 signaling pathway. METHODS: Human osteoblasts were isolated from femoral heads of patients undergoing total hip replacement. Beneficial effects of GTE on osteoblasts were examined in a dose- and time-dependent manner. Furthermore, GTE was given before, simultaneous with and after induction of oxidative stress with 1 mM H2O2 to simulate prophylactic, acute and therapeutic use, respectively. Cell damage was measured by LDH leakage and cell viability by MTT assay. Flow cytometry was applied to measure formation of Reactive Oxygen Species by using 2`7`-dichlorofluorescein-diacetate. The formation of Extracellular Matrix after differentiation with GTE supplementation during oxidative stress was visualized with von Kossa and Alizarin Red staining. Last one was additionally photometrically quantified. To assess the effects of H2O2 and GTE on the osteogenic genes, RT-PCR was performed. To evaluate the intramolecular influence of GTE after the stimulation the protein levels of HO-1 were analyzed. RESULTS: Stimulation of primary human osteoblasts with low doses of GTE during oxidative stress over 21 days improved mineralization. Furthermore, GTE supplementation in combination with H2O2 leads to a higher gene expression of osteocalcin and collagen1α1 during osteoblasts differentiation. Both are important for bone quality. Pre-incubation, co-incubation and post-incubation of osteoblasts with high doses of GTE protect the osteoblasts against acute oxidative stress as shown by increased cell viability, decreased LDH leakage, and reduced production of intracellular free radicals. Functional analysis revealed an increased HO-1 protein synthesis after stimulation with GTE. CONCLUSIONS: Incubation of human primary osteoblasts with GTE significantly reduces oxidative stress and improves cell viability. GTE also has a beneficial effect on ECM production which might improve the bone quality. Our findings suggest that dietary supplementation of GTE might reduce inflammatory events in bone-associated diseases such as osteoporosis.

Increased oxidative stress response in granulocytes from older patients with a hip fracture may account for slow regeneration.

Proximal femur fracture, a typical fracture of the elderly, is often associated with morbidity, reduced quality of life, impaired physical function and increased mortality. There exists evidence that responses of the hematopoietic microenvironment to fractures change with age. Therefore, we investigated oxidative stress markers and oxidative stress-related MAPK activation in granulocytes from the young and the elderly with and without fractured long bones. Lipid peroxidation levels were increased in the elderly controls and patients. Aged granulocytes were more sensitive towards oxidative stress induced damage than young granulocytes. This might be due to the basally increased expression of SOD-1 in the elderly, which was not further induced by fractures, as observed in young patients. This might be caused by an altered MAPK activation. In aged granulocytes basal p38 and JNK activities were increased and basal ERK1/2 activity was decreased. Following fracture, JNK activity decreased, while ERK1/2 and p38 activities increased in both age groups. Control experiments with HL60 cells revealed that the observed p38 activation depends strongly on age. Summarizing, we observed age-dependent changes in the oxidative stress response system of granulocytes after fractures, for example, altered MAPK activation and SOD-1 expression. This makes aged granulocytes vulnerable to the stress stimuli of the fracture and following surgery.

Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures.

Osteoporosis as a systemic skeletal disorder is characterized by increased bone fragility and the risk of fractures. According to the World Health Organization, osteoporosis is one of the 10 most common diseases and affects approximately 75 million people in Europe, the United States, and Japan. In this context, the identification of specific microRNA (miRNA) signatures is an important step for new diagnostic and therapeutic approaches. The focus of interest on miRNAs as biomarkers came with new publications identifying free circulating extracellular miRNAs associated with various types of cancer. This study aimed to identify specific miRNAs in patients with osteoporotic fractures compared with nonosteoporotic fractures. For the array analysis, miRNAs were isolated from the serum of 20 patients with hip fractures, transcribed, and the samples were pooled into 10 osteoporotic and 10 nonosteoporotic specimens. With each pool of samples, human serum and plasma miRNA PCR arrays were performed, which are able to identify 83 different miRNAs. Subsequently, a separate validation analysis of each miRNA found to be regulated in the array followed with miRNA samples isolated from the serum of 30 osteoporotic and 30 nonosteoporotic patients and miRNA samples isolated from the bone tissue of 20 osteoporotic and 20 nonosteoporotic patients. With the validation analysis of the regulated miRNAs, we identified 9 miRNAs, namely miR-21, miR-23a, miR-24, miR-93, miR-100, miR-122a, miR-124a, miR-125b, and miR-148a, that were significantly upregulated in the serum of patients with osteoporosis. In the bone tissue of osteoporotic patients, we identified that miR-21, miR-23a, miR-24, miR-25, miR-100, and miR-125b displayed a significantly higher expression. A total of 5 miRNAs display an upregulation both in serum and bone tissue. This study reveals an important role for several miRNAs in osteoporotic patients and suggested that they may be used as biomarkers for diagnostic purposes and may be a target for treating bone loss and optimizing fracture healing in osteoporotic patients.

The immune response after fracture trauma is different in old compared to young patients.

BACKGROUND: Despite significant medical progress and improved treatment, surgical procedures of proximal femur fractures in older patients are still associated with a high postoperative complication and mortality rate. Recently, several authors investigated the phenomenon of immunoageing, indicating differences in the ageing immune system. The aim of the present multi-center prospective clinical trial was to analyze differences in the posttraumatic immune response of old patients compared to young patients. METHODS: Blood was collected from young patients (<50 y, n = 20) with long bone fractures (YF), old patients (>70 y, n = 21) with proximal femur fractures (OF) upon clinical admission and within 6 hours after surgery, and two healthy age matched control groups (YH & OH). Serum TRAIL- and cytokine concentrations were analyzed via cytometric bead array, Fas-Ligand and TNF-Receptor-I via ELISA. CD15(+) magnetic bead-isolated neutrophils (PMN) were TUNEL stained. RESULTS: IL-6 was significantly increased only in OF after trauma and surgery whereas YF patient exhibited a marked decrease of TNF after trauma. Interestingly, a significant increase of GM-CSF serum levels was observed in YF only, whereas OF exhibited a decrease of systemic IFN-γ concentrations after trauma and after surgery. The healthy controls, old and young, had more or less similar inflammation levels. Moreover, TRAIL serum levels were diminished in OF after trauma and even further after surgery whereas in YF this was only observed after the surgical procedure. Fas-L concentrations were reduced only in YF after surgery or trauma. PMN apoptosis was significantly reduced only in YF, indicating activation of the innate immune system. DISCUSSION: In summary, our data suggest that the posttraumatic immune response is differently regulated in old and young trauma patients. The operative procedure further impacts these differences after trauma. Whether the decreased activation of PMNs and phagocytes along with the observed dysregulation of the posttraumatic inflammatory response contributes to the high perioperative mortality rate of the elderly suffering from a proximal femoral fracture requires further investigation.

New method for detection of complex 3D fracture motion--verification of an optical motion analysis system for biomechanical studies.

BACKGROUND: Fracture-healing depends on interfragmentary motion. For improved osteosynthesis and fracture-healing, the micromotion between fracture fragments is undergoing intensive research. The detection of 3D micromotions at the fracture gap still presents a challenge for conventional tactile measurement systems. Optical measurement systems may be easier to use than conventional systems, but, as yet, cannot guarantee accuracy. The purpose of this study was to validate the optical measurement system PONTOS 5M for use in biomechanical research, including measurement of micromotion. METHODS: A standardized transverse fracture model was created to detect interfragmentary motions under axial loadings of up to 200 N. Measurements were performed using the optical measurement system and compared with a conventional high-accuracy tactile system consisting of 3 standard digital dial indicators (1 µm resolution; 5 µm error limit). RESULTS: We found that the deviation in the mean average motion detection between the systems was at most 5.3 µm, indicating that detection of micromotion was possible with the optical measurement system. Furthermore, we could show two considerable advantages while using the optical measurement system. Only with the optical system interfragmentary motion could be analyzed directly at the fracture gap. Furthermore, the calibration of the optical system could be performed faster, safer and easier than that of the tactile system. CONCLUSION: The PONTOS 5 M optical measurement system appears to be a favorable alternative to previously used tactile measurement systems for biomechanical applications. Easy handling, combined with a high accuracy for 3D detection of micromotions (≤ 5 µm), suggests the likelihood of high user acceptance. This study was performed in the context of the deployment of a new implant (dynamic locking screw; Synthes, Oberdorf, Switzerland).

TGF-ß1 as possible link between loss of bone mineral density and chronic inflammation.

BACKGROUND: The TGF family plays a key role in bone homeostasis. Systemic or topic application of proteins of this family apparently positively affects bone healing in vivo. However, patients with chronic inflammation, having increased TGF-ß(1) serum-levels, often show reduced bone mineral content and disturbed bone healing. Therefore, we wanted to identify intracellular mechanisms induced by chronic presence of TGF-ß(1) and their possible role in bone homeostasis in primary human osteoblasts. METHODOLOGY/PRINCIPAL FINDINGS: Osteoblasts were isolated from femur heads of patients undergoing total hip replacement. Adenoviral reporter assays showed that in primary human osteoblasts TGF-ß(1) mediates its signal via Smad2/3 and not Smad1/5/8. It induces proliferation as an intermediate response but decreases AP-activity and inorganic matrix production as a late response. In addition, expression levels of osteoblastic markers were strongly regulated (AP↓; Osteocalcin↓; Osteopontin↑; MGP↓; BMP 2↓; BSP2↓; OSF2↓; Osteoprotegerin↓; RANKL↑) towards an osteoclast recruiting phenotype. All effects were blocked by inhibition of Smad2/3 signaling with the Alk5-Inhibitor (SB431542). Interestingly, a rescue experiment showed that reduced AP-activities did not recover to base line levels, even 8 days after stopping the TGF-ß(1) application. CONCLUSIONS/SIGNIFICANCE: In spite of the initial positive effects on cell proliferation, it is questionable if continuous Smad2/3 phosphorylation is beneficial for bone healing, because decreased AP-activity and BMP2 levels indicate a loss of function of the osteoblasts. Thus, inhibition of Smad2/3 phosphorylation might positively influence functional activity of osteoblasts in patients with chronically elevated TGF-ß(1) levels and thus, could lead to an improved bone healing in vivo.

Clinical comparison of the second and third generation of intramedullary devices for trochanteric fractures of the hip--Blade vs screw.

With industrial societies getting older the incidence of femoral fractures is increasing. Complication rates up to 20% have led to a continuous improvement of intramedullar nailing systems and the third generation of implants is in clinical application. They seem superior to the second generation. But as clinical data is still fragmentary, we wanted to compare a second generation implant, the Proximal Femur Nail with three devices of the third generation: the Gleitnagel, Trochanter Fixation Nail and the Proximal Femur Nail Antirotation with a clinical study. We analysed whether fracture reduction and implant position could possibly be indicators for implant complications. Patients with a trochanteric fracture type A1-A3 (AO/ASIF classification) admitted at the department of traumatology Augsburg were enrolled. Postoperative X-rays were analysed in the matter of fracture reduction for the fracture gap, the Garden Alignment Index and for the matter of implant position in the femur head with the cleaveland zones and the Tip Apex Distance. 322 patients were enrolled. Most frequent was the A2 (n=240) and the A3 type of fracture (n=80) followed by A1 (n=29). Time to hospital discharge was 17 days (9/25), 12 patients died (3.2%). The complication rate (cutting out) in the third generation was lower (2.5-7%) than in the second generation (14%). The postoperative range of mobilisation compared to the old social status was in the groups with 34% similar after 3 months. The third generation nails are safe and reliable implants. Compared with second generation devices, fewer complications are observed. A correlation might be seen in the postoperative X-rays between the fracture reduction or implant position and implant related mechanical complications (cutting out).

Gentamycin delivered from a PDLLA coating of metallic implants: In vivo and in vitro characterisation for local prophylaxis of implant-related osteomyelitis.

Locally applied antibiotics support prophylaxis of highly feared implant associated infections. Implant coatings with poly(D,L-lactide) (PDLLA)/gentamicin seem to be a promising approach. Aims of this study were to analyse the release kinetics of gentamicin in vivo, in vitro, to analyse the antibacterial efficacy,the resistance development and its impact on osteoblasts. For the in vitro release experiments titanium implants were coated with PDLLA/gentamicin and the antibiotic release in aqueous solution was analysed at 20 time points (from 10 s to 110 days). For the in vivo experiments PDLLA/gentamicin-coated kirschner wires were implanted in the tibiae of 18 rats. Gentamicin concentration in the bone was analysed at several time points (n = 3 each, 1 h to 7 days). Bactericidal efficacy, bacterial adhesion on the implants and resistance development were tested. AP activity, cell count and CICP expression of osteoblasts were analysed. Gentamicin was released rapidly with an initial burst in aqueous solution and followed by a slow release. Similarly, in vivo gentamicin concentration reached a high peak initially followed by a decrease to a low level. No development of resistance was observed in the investigated setting, the antibacterial efficacy was not affected by the coating process and significantly fewer bacteria were attached to the implant. Osteoblasts were not negatively affected by the gentamicin released from the coating. PDLLA/gentamicin coating resulted in a desired antibiotic peak concentration within the bone. Bacterial adhesion was successfully prevented. No bacterial resistances were developed. This coating seems to be a suitable supplement for prophylaxis of implant-associated infections.

First report of a solid variant of aneurysmal bone cyst in the os sacrum.

We report on a 19-year-old woman with a rapidly growing, solid variant of aneurysmal bone cyst (solid ABC) in the right part of the lateral mass of the sacrum. On admission, the magnetic resonance imaging (MRI) scan disclosed an inhomogeneous low intensity mass right of the centre of the os sacrum with a diameter of 38 x 64 mm and a height of 56 mm on T1 and T2 weighted images. The mass showed homogenous high signal intensity on Gd-enhanced images. Computed tomography demonstrated an expansile osteolytic lesion and (99m)Tc-methylene diphosphonate bone scintigraphy revealed uniform accumulation in the lesion. The histological evaluation showed a proliferation of fibroblasts, histiocytes, chronic inflammatory cells and numerous multinucleated giant cells. Nevertheless, the cells were devoid of nuclear atypia. A cystic component was not observed. In spite of thorough curettage, the patient suffered from recurrence and severe neurological deficits. A review of the literature revealed no previous cases of solid ABC in the sacrum.