[Epidemiology and causes of Parkinson's disease]. / Epidemiologie und Ursachen der Parkinson-Erkrankung.

Parkinson's disease (PD) is the second most common neurodegenerative disease and has a growing socioeconomic impact due to demographic changes in the industrial nations. There are several forms of PD, a fraction of which (<5%) are monogenic, i. e. caused by mutations in single genes. At present, six genes have been established for the clinically classical form of parkinsonism including three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively inherited ones (Parkin, PINK1, DJ-1). In addition, there are a plethora of genes causing atypical forms of parkinsonism. In contrast, idiopathic PD is of a multifactorial nature. Genome-wide association studies have established a total of 26 genetic loci for this form of the disease; however, for most of these loci the underlying functional genetic variants have not yet been identified and the respective disease mechanisms remain unresolved. Furthermore, there are a number of environmental and life style factors that are associated with idiopathic PD. Exposure to pesticides and possibly a history of head trauma represent genuine risk factors. Other PD-associated factors, such as smoking and intake of coffee and alcohol may not represent risk factors per se and the cause-effect relationship has not yet been elucidated for most of these factors. A patient with a positive family history and/or an early age of disease onset should undergo counseling with respect to a possible monogenic form of the disease. Disease prediction based on genetic, environmental and life style factors is not yet possible for idiopathic PD and potential gene-specific therapies are currently in the development or early testing phase.

Effects of Facial Symmetry and Gaze Direction on Perception of Social Attributes: A Study in Experimental Art History.

This article explores the possibility of testing hypotheses about art production in the past by collecting data in the present. We call this enterprise "experimental art history". Why did medieval artists prefer to paint Christ with his face directed towards the beholder, while profane faces were noticeably more often painted in different degrees of profile? Is a preference for frontal faces motivated by deeper evolutionary and biological considerations? Head and gaze direction is a significant factor for detecting the intentions of others, and accurate detection of gaze direction depends on strong contrast between a dark iris and a bright sclera, a combination that is only found in humans among the primates. One uniquely human capacity is language acquisition, where the detection of shared or joint attention, for example through detection of gaze direction, contributes significantly to the ease of acquisition. The perceived face and gaze direction is also related to fundamental emotional reactions such as fear, aggression, empathy and sympathy. The fast-track modulator model presents a related fast and unconscious subcortical route that involves many central brain areas. Activity in this pathway mediates the affective valence of the stimulus. In particular, different sub-regions of the amygdala show specific activation as response to gaze direction, head orientation and the valence of facial expression. We present three experiments on the effects of face orientation and gaze direction on the judgments of social attributes. We observed that frontal faces with direct gaze were more highly associated with positive adjectives. Does this help to associate positive values to the Holy Face in a Western context? The formal result indicates that the Holy Face is perceived more positively than profiles with both direct and averted gaze. Two control studies, using a Brazilian and a Dutch database of photographs, showed a similar but weaker effect with a larger contrast between the gaze directions for profiles. Our findings indicate that many factors affect the impression of a face, and that eye contact in combination with face direction reinforce the general impression of portraits, rather than determine it.

Effects of neratinib and combination with irradiation and chemotherapy in head and neck cancer cells.

OBJECTIVE: Prognosis of patients with head and neck squamous cell carcinoma (HNSCC) is still poor. Novel therapeutic approaches are of great interest to improve the effects of radiochemotherapy. We evaluated the effects of tyrosine kinase inhibitor neratinib on HNSCC cell lines CAL27, SCC25 and FaDu as a single agent and in combination with irradiation and chemotherapy. METHODS: Effects of neratinib were evaluated in HNSCC cell lines CAL27, SCC25 and FaDu. Effect on cell viability of neratinib and combination with cisplatin and irradiation was measured using CCK-8 assays and clonogenic assays. Western blot analysis was performed to distinguish the effect on epithelial growth factor receptor and HER2 expression. Apoptosis was evaluated by flow cytometry analysis. RESULTS: Growth inhibition was achieved in all cell lines, whereas combination of cisplatin and neratinib showed greater inhibition than each agent alone. Apoptosis was induced in all cell lines. Combination of neratinib with irradiation or cisplatin showed significantly increased apoptosis. In clonogenic assays, significant growth inhibition was observed in all investigated cell lines. CONCLUSION: Neratinib, as a single agent or in combination with chemo-irradiation, may be a promising treatment option for patients with head and neck cancer.

Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.

The effect of cilengitide in combination with irradiation and chemotherapy in head and neck squamous cell carcinoma cell lines.

BACKGROUND: Integrins are highly attractive targets in oncology due to their involvement in angiogenesis in a wide spectrum of cancer entities. Among several integrin inhibitors under clinical evaluation, cilengitide is the most promising compound. However, little is known about the cellular processes induced during cilengitide therapy in combination with irradiation and cisplatin in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The cytostatic effect of cilengitide was assessed by proliferation assay in the three HNSCC cell lines SCC25, FaDu and CAL27. Combination experiments with cisplatin and irradiation were performed. Possible synergistic effects were calculated in combination index (CI) analyses. Colony forming inhibition was investigated in clonogenic assays. Real-time PCR arrays were used to evaluate target protein gene expression patterns. Flow cytometry was used to detect apoptosis. RESULTS: Used alone, cilengitide has only minor cytotoxic effects in HNSCC cell lines. However, combination with cisplatin resulted in synergistic growth inhibition in all three cell lines. Irradiation showed synergism in short-term experiments and in colony forming assays, an additive effect was detected. Real-time PCR assay detected downregulation of the antiapoptotic protein Bcl-2 after exposure of cells to cilengitide. CONCLUSION: Cilengitide in combination with cisplatin and irradiation may be a feasible option for the treatment of patients with head and neck cancer. However, further investigations are required to understand the exact mechanism that leads to synergistic cytotoxicity.

The effect of resveratrol in combination with irradiation and chemotherapy: study using Merkel cell carcinoma cell lines.

BACKGROUND AND PURPOSE: Merkel cell carcinoma (MCC) is a rare, but highly malignant tumor of the skin. In case of systemic disease, possible therapeutic options include irradiation or chemotherapy. The aim of this study was to evaluate whether the flavonoid resveratrol enhances the effect of radiotherapy or chemotherapy in MCC cell lines. MATERIALS AND METHODS: The two MCC cell lines MCC13 and MCC26 were treated with increasing doses of resveratrol. Combination experiments were conducted with cisplatin and etoposide. Colony forming assays were performed after sequential irradiation with 1, 2, 3, 4, 6, and 8 Gy and apoptosis was assessed with flow cytometry. Expression of cancer drug targets was analyzed by real-time PCR array. RESULTS: Resveratrol is cytotoxic in MCC cell lines. Cell growth is inhibited by induction of apoptosis. The combination with cisplatin and etoposide resulted in a partially synergistic inhibition of cell proliferation. Resveratrol and irradiation led to a synergistic reduction in colony formation compared to irradiation alone. Evaluation of gene expression did not show significant difference between the cell lines. CONCLUSION: Due to its radiosensitizing effect, resveratrol seems to be a promising agent in combination with radiation therapy. The amount of chemosensitizing depends on the cell lines tested.

[The genetic profile of multiple sclerosis: risk genes and the "dark matter"]. / Genetisches Profil der Multiplen Sklerose: Risikogene und die "dunkle Materie"

Multiple sclerosis (MS) is a genetically complex disease caused by the interplay of genetic and environmental factors. While it shows substantial familial accumulation, there is no evidence for typical Mendelian transmission within families. Instead, MS risk is likely governed by dozens to hundreds of genetic variants, which can also be present in the general population. The strongest genetic risk factor for MS was identified 40 years ago and lies within the HLA locus. It increases the risk of developing MS by two- to threefold. Within the last few years, genome-wide association studies (GWAS) have led to the identification of nearly 60 additional genetic risk loci. Each of these loci yields a modest to moderate risk increase (odds ratios of 1.1-1.3). Even in combination, however, the currently known risk variants merely account for a small fraction of the disease's heritability. It is likely that a major fraction of genetic MS risk that cannot be explained by GWAS, sometimes termed the "dark matter" of GWAS, is caused by other factors, such as structural variations of the genome, rare sequence variants, or inherited epigenetic modifications.

Bilateral stroke following pituitary apoplexy.

Pituitary apoplexy followed by cerebral infarction is rare. We report a 59-year-old male with a known pituitary macroadenoma who was admitted to our emergency department for treatment of an acute myocardial infarction. He underwent coronary angioplasty and was subsequently treated with aspirin, clopidogrel and full-dose enoxaparin. He developed pituitary apoplexy with bilateral compression of both internal carotid arteries, and infarction of both anterior and middle hemispheres; consequently, he died. This patient illustrates the difficulties of administering aggressive anticoagulative and antiplatelet therapy to patients who have a known pituitary adenoma.

Periodontal histomorphometry and status of aged sheep subjected to ovariectomy, malnutrition and glucocorticoid application.

OBJECTIVE: Ageing, hypogonadism, malnutrition, and the application of glucocorticoids have adverse effects on skeletal homeostasis. Herein we determined to which extent the periodontium undergoes catabolic changes under these conditions in a sheep model. METHODS: Six old sheep with a mean age of 7.5+/-1.0 years were subjected to ovariectomy, calcium/vitamin D-restricted diet, and intramuscular administration of approximately 2g methylprednisolone. Six adult sheep with a mean age of 3.8+/-0.9 years remained untreated and served as controls. First and second premolars of both jaws were subjected to histological analysis. The distances from the gingival margin (GM) and from the alveolar bone crest (ABC) to the cemento-enamel junction (CEJ) were determined. Periodontal attachment was given as the ratio between the dimension of the periodontal ligament and the alveolar bone. Clinical data were collected by counting the number of teeth missing, teeth with gingival recession, and teeth with a probing depth > 4 mm. RESULTS: We report that distance between GM and CEJ (2.1+/-1.7 mm and 6.6+/-2.6mm maxilla; -0.4+/-1.4 mm and 3.2+/-1.5 mm mandible), and between ABC and CEJ (-3.4+/-1.3mm and 1.8+/-2.7 mm maxilla; -3.5+/-1.1mm and -0.1+/-1.4mm mandible) are significantly lower in test than in control animals. In line with these findings, periodontal attachment was 67% in the maxilla and 86% in the mandible of the test group and almost completely preserved in the control group. Clinical evaluation showed that the overall number of teeth with recessions was significantly higher in the test compared to the control group (4.9+/-2.4 and 2.3+/-3.6), but not the number of teeth missing and teeth with a probing depth>4mm. CONCLUSIONS: Together these findings suggest that in sheep, the cumulating effects of ageing, hypogonadism, malnutrition and glucocorticoid application can cause substantial catabolic changes of the periodontium.

A sheep model for fracture treatment in osteoporosis: benefits of the model versus animal welfare.

Animal models are necessary to evaluate new options for the treatment of fractures in osteoporotic bone. They permit both the biological response of a living system and the influence of the pathological processes to be taken into account. A sheep model for osteoporosis was established by combining oestrogen deficiency, calcium and vitamin D-deficient diet with steroid medication. Bone mineral density (BMD) was reduced by >30% after 12 weeks of combined treatment. Osteoporosis similar to the human situation with corresponding changes in the micro-architecture and mechanical properties of bone was observed. This publication focuses on the impressive results obtained with the model and contrasts them with considerations of animal welfare. Considerable side-effects associated with steroid medication became manifest. Animals in the treatment groups showed signs of infection of various degrees due to the immunosuppressive effect of the medication. The infections were mostly caused by Corynebacterium pseudotuberculosis. Antibody testing revealed a 100% prevalence of infection in this breed of sheep. A modification of the steroid treatment, i.e. less-frequent injections, reduced the incidence of side-effects. This sheep model shows a significant and reproducible reduction in cancellous BMD of >30%, including relevant changes in biomechanical properties and increased fracture risk. However, the severity of the side-effects cannot be overlooked. The model must be improved if it is to be used in the future. Options to reduce the side-effects are discussed.

[Prevalence of allergic reactions to implant materials in total hip and knee arthroplasty]. / Häufigkeit von Allergien gegen Implantatwerkstoffe in der Hüft- und Knieendoprothetik.

INTRODUCTION: Several case reports have been published on allergic reactions like eczema, urticaria, persistent swelling, sterile osteomyelitis or aseptic implant loosening in the context of orthopaedic implants. There is, however, a lack of data concerning incidence or prevalence of allergies in this special group of patients. The aim of this study was to analyse a consecutive series of patients with a total hip or knee arthroplasty to gain information about prevalence of allergic reactions to constituents of the alloys or bone cement. MATERIAL AND METHOD: Between February and September 2005, a consecutive series of 300 patients after total hip (THA) or total knee (TKA) arthoplasty were interviewed during regular follow-up using the standardised questionnaire of the working group 20 "Implant and Allergy" of the DGOOC with respect to allergies, especially to different metals or constituents of bone cement. In this study 100 males and 200 females with 214 THA and 86 TKA were included. The mean follow-up time was 33.3 months (min: 3, max: 174). RESULTS: Different allergies were found in 39 patients. In 12 cases (4 %) allergic reactions against nickel, in 4 cases (1.3 %) against cobalt, in 2 cases (0.7 %) against chromium and in 2 cases (0.7 %) against benzoyl peroxide were detected by means of epicutaneous testing. One patient each suffering from a nickel allergy showed signs of osteolysis or recurrent effusion after THA with a metal-on-metal bearing. One patient each suffering from recurrent effusion or eczema following TKA showed allergic reactions to benzoyl peroxide. In all the other patients with allergies to the alloy constituents, the follow-up was uneventful. CONCLUSION: The prevalence of allergic reactions in an unselected group of orthopaedic patients is significantly lower in comparison to that in dermatological studies. Most patients suffering from allergies tolerated the implant uneventfully. Further studies are needed to identify those groups of patients with allergies who may not tolerate the implant in order to provide better care or use special implants.

Factors affecting the stability of screws in human cortical osteoporotic bone: a cadaver study.

We investigated several factors which affect the stability of cortical screws in osteoporotic bone using 18 femora from cadavers of women aged between 45 and 96 years (mean 76). We performed bone densitometry to measure the bone mineral density of the cortical and cancellous bone of the shaft and head of the femur, respectively. The thickness and overall bone mass of the cortical layer of the shaft of the femur were measured using a microCT scanner. The force required to pull-out a 3.5 mm titanium cortical bone screw was determined after standardised insertion into specimens of the cortex of the femoral shaft. A significant correlation was found between the pull-out strength and the overall bone mass of the cortical layer (r(2) = 0.867, p < 0.01) and also between its thickness (r(2) = 0.826, p < 0.01) and bone mineral density (r(2) = 0.861, p < 0.01). There was no statistically significant correlation between the age of the donor and the pull-out force (p = 0.246), the cortical thickness (p = 0.199), the bone mineral density (p = 0.697) or the level of osteoporosis (p = 0.378). We conclude that the overall bone mass, the thickness and the bone mineral density of the cortical layer, are the main factors which affect the stability of a screw in human female osteoporotic cortical bone.

Optimization of corticosteroid induced osteoporosis in ovariectomized sheep. A bone histomorphometric study.

During osteoporosis induction in sheep, side effects of the steroids were observed in previous studies. The aim of this study was to improve the induction regimen consisting of ovariectomy, calcium/vitamin D- restricted diet and methylprednisolone (-MP)- medication with respect to the bone metabolism and to reduce the adverse side effects. Thirty-six ewes (age 6.5 +/- 0.6 years) were divided into four MP-administration groups (n = 9) with a total dose of 1800 mg MP: group 1: 20 mg/day, group 2: 60 mg/every third day, group 3: 3 x 500 mg and 1 x 300 mg at intervals of three weeks, group 4: weekly administration, starting at 70 mg and weekly reduction by 10 mg. After double-labelling with Calcein Green and Xylenol Orange, bone biopsy specimens were taken from the iliac crest (IC) at the beginning and four weeks after the last MP injection, and additionally from the vertebral body (VB) at the end of the experiment. Bone samples were processed into stained and fluorescent sections, static and dynamic measurements were performed. There were no significant differences for static parameters between the groups initially. The bone perimeter and the bone area values were significantly higher in the VB than in the IC (Pm: 26%, p < 0.0001, Ar: 11%, p < 0.0166). A significant decrease (20%) of the bone area was observed after corticosteroid-induced osteoporosis (p < 0.0004). For the dynamic parameters, no significant difference between the groups was found. Presence of Calcein Green and Xylenol Orange labels were noted in 50% of the biopsies in the IC, 100% in the VB. Group 3 showed the lowest prevalence of adverse side effects. The bone metabolism changes were observed in all four groups, and the VB bone metabolism was higher when compared to the IC. In conclusion, when using equal amounts of steroids adverse side effects can be reduced by decreasing the number of administrations without reducing the effect regarding corticosteroid-induced osteoporosis. This information is useful to reduce the discomfort of the animals in this sheep model of corticosteroid-induced osteoporosis.

Mechanical performance of cylindrical and dual core pedicle screws in calf and human vertebrae.

INTRODUCTION: Failure of pedicle screws by loosening and back out remains a significant clinical problem. Pedicle screw fixation is determined by bone mineral density, pedicle morphology and screw design. The objective of this study was to compare the holding strength of newly developed dual core pedicle screws having a cylindrical design in terms of outer diameter and two cylindrical inner core regions connected by a conical transition with conventional cylindrical pedicle screws. MATERIALS AND METHODS: Fifty bovine lumbar vertebrae and 40 human lumbar vertebrae were used. Five different screws were tested in nine experimental "settings" and ten specimens each. The screws were tested for cranial displacement and pullout strength before and after 5,000 cycles of cranio-caudal loading. The tests included a setting with fully inserted and 4 mm backed out screws. For statistical analysis the incomplete balanced block design was used. RESULTS: Cyclic loading led to a decrease of pullout force between 24 and 31% and a 9% increase of displacement. The cylindrical screw designs were affected more than the dual core designs. The pullout force of cylindrical screws was smaller than of dual core screws. Even in a backed out condition dual core screws showed a significantly smaller displacement than cylindrical screws. CONCLUSION: Pedicle screws with the dual core design provide good anchorage in the vertebra.

[Experience in operations for scoliosis in patients with cerebral palsy]. / Erfahrungen mit operativer Skoliosekorrektur bei Patienten mit infantiler Zerebralparese.

AIM: Experiences in operation of scoliosis in cerebral palsy are very different. Therefore a therapeutic regiment does not exist. In this study we want to report our experiences. METHODS: This retrospective-clinical study (1986-2003) includes 46 patients with cerebral palsy who had been operated for scoliosis. The data focus in particular on the therapeutic strategies and its success and complications. Publications from 1946 to 2003 were reviewed and served for comparison. RESULTS: 28 female and 18 men during one period by median 3.4 years were after-observed. The post office-operationally reached correction of the curvature of all operation procedures was appropriate for median between 51 and 68 % depending upon localization of the curvature. In the last re-examination median a correction loss of 3-25 % existed. A fusion to S1 corrected a thoraco-lumbale or lumbale scoliosis significantly better than a fusion to L5. The posterior and the combined posterior-anterior operation procedure showed comparable correction results. The total complication rate was with 35 %. CONCLUSIONS: Due to good correction successes and smaller complication rate we favor a posterior-anterior operation procedure. A fusion to S1 is indicated with thoraco-lumbale and lumbale fusion. Altogether complication rate was reduced in patients with scoliosis and cerebral palsy after operation at the spinal column in the last years.

Direct adenoviral transfer of bone morphogenetic protein-2 cDNA enhances fracture healing in osteoporotic sheep.

Osteoporosis, a major public health burden, is associated with increased fracture risk. Fracture healing in osteoporosis is delayed, with reduced callus formation and impaired biomechanical properties of newly formed bone leading to high risk of fixation failure. Adenoviral gene transfer of bone morphogenetic protein-2 (BMP-2) has been shown to enhance fracture healing. This study evaluated the ability of gene transfer to enhance bone healing in osteoporosis. An established sheep model of osteoporosis with well-characterized alterations in fracture healing was used. Osteotomies were created surgically in the tibias of adult female sheep and monitored for 8 weeks, using radiographic, biomechanical, and histological methods. For pilot experiments, primary ovine osteoblasts and mesenchymal stem cells were transduced with a recombinant adenovirus carrying BMP-2 cDNA (Ad.BMP-2). Large increases in alkaline phosphatase production and mineralization confirmed the ability of human BMP-2 to stimulate osteoblastic differentiation in sheep. In vivo bending stiffness measurements during fracture healing as well as ex vivo torsional stiffness measurements demonstrated stiffer callus tissue after treatment with Ad.BMP-2. The differences were found mainly in the early fracture-healing period. Computed tomography demonstrated that animals receiving the BMP-2 cDNA had larger cross-sectional callus area and higher callus density. Histological examination of the tibias confirmed enhanced callus formation. Direct, local adenoviral delivery of an osteogenic gene thus led to enhanced healing of fractures in an ovine model of osteoporosis. These promising data encourage the further development of genetic approaches to enhance bone healing in patients suffering osteoporosis-associated fractures.

Effect of BMP-2 gene transfer on bone healing in sheep.

Critical size defects of bone and delayed fracture healing due to metabolic disorders are still problems in orthopaedic surgery. Adenoviral vectors encoding bone morphogenetic protein-2 (Ad.BMP-2) have been used to stimulate bone formation in small animals. The present study evaluated the use of direct adenoviral gene transfer for inducing bone formation in a large animal. Standardized iliac crest defects were created surgically on both sides of the pelvic bone of white mountain sheep. The efficiency of gene transfer was evaluated using recombinant adenoviruses carrying the cDNA for luciferase. High levels of transgene expression, restricted to the site of injection, were found for the 1st week. Transgene expression then fell considerably, but could still be detected for up to 5 weeks. To investigate the effect on bone healing, Ad.BMP-2 (10(11) particles in 200 mul saline) was unilaterally injected into iliac crest defects and into tibial osteotomies. The contralateral defects remained untreated to evaluate possible systemic effects. The controls were treated with saline solution. Bone formation within the defect, assessed by micro-computed tomography (CT) measurement at 8 weeks, and callus formation after osteotomy were significantly reduced following direct application of Ad.BMP-2. The retardation compared to untreated control animals was additionally found at the contralateral iliac crest indicating a systemic inhibitory effect. Histological analysis confirmed the CT measurement and showed an increased number of inflammatory cells within both defects. Antibodies against the adenovirus and the transgene product were detected in all treated animals. These data show a systemic retardation of bone formation following a single local injection of Ad.BMP-2 in sheep. This finding stands in contrast to the data obtained from small animal models. Further studies are needed to determine the contribution of the immune response to these results, and whether a lower dose of Ad.BMP-2 would be advantageous.

Image-based micro-finite-element modeling for improved distal radius strength diagnosis: moving from bench to bedside.

Although osteoporosis is characterized by quantitative (mass) and qualitative (structural) changes, standard clinical techniques (dual-energy X-ray absorptiometry, DXA) only measure the former. Three-dimensional micro-finite-element (micro-FE) models based on high-resolution images can account for structural aspects as well, and it has recently been shown that an improved prediction of distal radius strength is possible with micro-FE analysis. A clinical application of this technique, however, is limited by its high imaging and computational demands. The objective of this study is to investigate if an improved prediction of bone strength can be obtained as well when only a small part of the radius is used for micro-FE modeling. Images of a 1-cm region of the metaphysis of the distal radius of 54 cadaver arms (mean age: 82 +/- 9 SD) made with a three-dimensional peripheral quantitative computed tomography (pQCT) device at 165- micro m resolution formed the basis for micro-FE models that were used to predict the bone failure load. Following imaging, specimens were experimentally compressed to failure to produce a Colles'-type fracture. Failure loads predicted from micro-FE analyses agreed well with those measured experimentally (R2 = 0.66, p < 0.001). Lower correlations were observed with bone mass (R2 = 0.48, p < 0.001) and microstructural parameters (R2 = 0.47, p < 0.001). Hence, even when only a small region is modeled, micro-FE analysis provides an improved prediction of radius strength.

Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis.

Current methods for fracture treatment in osteoporosis are not always sufficient. To develop new fixation strategies (both mechanical and biological) requires pre-clinical testing utilizing appropriate models. The aim of this study was to apply a recently developed sheep model of osteoporosis to the study of healing in a non-critical long bone defect. A standardized transverse mid-shaft tibial osteotomy (with a fracture gap of 3 mm) was performed in seven osteoporotic and seven normal sheep and stabilized with a special external fixator for 8 weeks. The fixator was used for weekly in vivo bending stiffness measurements. Ex vivo bending stiffness and torsional stiffness of the callus zone were also determined. Callus area, callus density, and osteoporosis status were determined at 0, 4, and 8 weeks using peripheral quantitative computed tomography. The increase of in vivo bending stiffness of the callus was delayed approximately 2 weeks in osteoporotic animals. A significant difference (33%) in torsional stiffness was found between the osteotomized and contralateral intact tibia in osteoporotic animals, but no significant difference occurred in normal sheep (2%). In osteoporotic animals, ex vivo bending stiffness was reduced 21% (p=0.05). Bending stiffness was correlated with callus density (r=0.76, r=0.53); torsional stiffness was correlated with callus area (r=0.60) and to a lesser extent with callus density (r=0.53). This study demonstrated a delay of fracture healing in osteoporotic sheep tibiae with respect to callus formation, mineralization, and mechanical properties.