In der vorliegenden Arbeit wurden drei unabhängige Problemfelder moderner biophysikalischer und materialwissenschaftlicher Forschung untersucht: Diffusion in binären Legierungen, der Umbauprozess in trabekulärem Knochen und die Voraussage mechanischer Eigenschaften, insbesonders der Biegesteifigkeit, selbstorganisierender, amphiphiler Membrane. Für alle drei Problemfelder wurden Gittermodelle gewählt, um ausgesuchte Fragestellungen zu untersuchen. Für den Fall der Diffusion in Legierungen war dies, inwieweit sich der Diffusionprozess, der sich auf atomarer Ebene als diskrete Platztäusche zwischen Atomen und Leerstellen manifestiert, auf einer größeren, makroskopischen, Ebene mit Hilfe einer kontinuumstheoretischen Theorie beschreiben lässt. Im Fall der Beschreibung des Umbauprozesses in in trabekulärem Knochen wurde die die spongiöse Architektur des Knochens auf ein Gitter abgebildet und mittels einer vereinfachten mechanischen Beschreibung die lokale Belastung in jedem Knochenelement bestimmt. Die zeitliche Entwicklung des Systems wurde mittels eines stochastischen Umbaugesetzes gesteuert, das die Wahrscheinlichkeit für Knochenan- bzw. -abbau als Funktion der lokalen Volumenänderung vorgab. Es wurde gezeigt, dass ein nicht-lineares Umbaugesetz bessere Übereinstimmung mit experimentellen Ergebnissen zeigt, als ein rein lineares. Weiters wurde das Krankheitsbild der Osteoporose untersucht und es konnte eine Unterscheidung zwischen einem normalen Alterungsprozess der Knochenstruktur und einer krankhaften Veränderung gezogen werden. Um die mechanischen Eigenschaften selbstorganisierender Membrane zu bestimmen, wurden linear elastische Federkräfte zwischen benachbarten Molekülen angenommen. Die volle elastische Matrix und daraus die gewünschten Eigenschaften wurden für unterschiedliche Zusammensetzungen der Membrane bestimmt. Es wurde gezeigt, dass die Biegesteifigkeit solcher Membrane in einem begrenzten Konzentrationsbereich um mehrere Größenordnungen variieren kann. / This thesis presents the results of investigations on three independent research topics of modern biophysical and materials science research: substitutional diffusion in binary alloys, the remodelling process in trabecular bone and the prediction of mechanical properties of self assembling, amphiphilic bilayers. The basic description of all three projects is based on lattice models, a highly successful class of models that are used in several fields of modern physics to describe physical processes. For the diffusional process in alloys, which on a microscopic scale manifests in a discrete site exchange between one atom and a neighbouring vacancy, it was investigated how this microscopic description can be reconciled with a macroscopic continuum model. For the investigations on remodelling of trabecular bone, the architecture of bone was mapped onto a lattice and the local mechanical state of each element was determined by a simplified mechanical model. A stochastic description was chosen to model the time evolution of the system, relating the probability of bone formation and resorption, respectively, to the local volume changes of the bone elements. It was shown that a non-linear remodelling law is a better candidate to describe the remodelling process in real bone than a linear one. Furthermore, applying the model to osteoporosis - a wide spread bone disease - it was shown that in the features attributed to osteoporosis one has to distinguish between normal ageing of bone''s architecture and additional changes that stem from pathological alterations in the regulatory system. A simple concept was introduced to model the mechanical properties of self-assembled membranes. The molecules forming the membrane are assumed to occupy a triangular lattice, nearest neighbours are connected by linear elastic springs. It was shown that the bending rigidity exhibits a pronounced concentration dependence, varying over orders of magnitude in a narrow concentration regime.

[Truncated abstract] Bone remodeling is an important process to maintain mechanical integrity. It is accomplished by two important steps, bone resorption followed by new bone formation. Osteoclasts and osteoblasts are the principal cells in bone resorption and bone formation, respectively. A multitude of local and systemic factors regulates this process by controlling the cellular activities in bone remodeling compartments (BRC). An imbalance of osteoblastic bone formation and osteoclastic bone destruction will result in the development of skeletal diseases. Recent studies suggested that angiogenesis is closely associated with bone remodeling. The vasculature in bone is important for skeletal development, growth and repair. During endochondral ossification, cartilage is invaded by blood vessels which bring in osteoblast and osteoclast precursor cells, nutrients, growth factors and differentiation factors. During fracture repair, it has been demonstrated that mature osteoclasts produce heparanase which can degrade heparin sulfate proteoglycans, a major component in extracellular matrix (ECM). The process leads to the release of heparin-binding growth factors including vascular endothelial growth factor (VEGF), a potent angiogenic factor which contributes largely to local angiogenesis. In recent studies, endothelial cells have been found to produce bone morphogenetic protein (BMP)-2 and BMP-4 when they are subjected to mechanical stimuli, or a hypoxia environment. Conversely, inhibition of angiogenesis has been shown to prevent fracture healing. In a distraction osteogenesis model, either inhibition of angiogenesis or disruption of the mechanical environment prevents normal osteogenesis and results in fibrous nonunion. .... A total of 42 mice from F1 and F2 generations were genotyped as transgene positive. Preliminary analysis using radiography did not reveal any difference between the gross structures of transgenic and wild type mice. Interestingly, the preliminary histology revealed a decrease in trabecular bone and an increase of lipid space in metaphysis of transgenic mice overexpressing EGFL6. However, further studies will need to be carried out to investigate the role of EGFL6 in angiogenesis and adipogenesis using a transgenic mice model. This will be a prime focus of future work. Collectively, the results presented in this thesis have identified EGFL6, a member of the EGF-like family, as a potential angiogenic factor which may play an important role in bone remodeling. EGFL6 has been found to be expressed highly in calvarial osteoblasts and upregulated during primary murine osteoblast differentiation. EGFL6 has been 8 characterized to be a secreted homomeric complex. More importantly, EGFL6 has been shown to induce angiogenic activity in endothelial cell migration, tube formation and in vivo chick embryo chorioallantoic membrane assay. Furthermore, conditioned medium containing the EGFL6 recombinant protein was shown to induce phosphorylation of ERK in endothelial cells. Inhibition of ERK impaired EGFL6-induced ERK activation and endothelial cell migration. Taken together these studies raise the possibility that EGFL6 has a potential role in angiogenesis, and mediates a paracrine mechanism of cross-talk between vascular endothelial cells and osteoblasts during osteogenesis. An understanding of this process offers the potential to facilitate the development of therapeutic treatments for bone disease.

Osteoporosis, a classical age-related disease and known to be more common in women than in men, has been reported increasingly often in men during the past few years. Although men at all ages after puberty have larger bones than women, resulting in greater bending strength, mortality after a hip fracture, one of the major complications of osteoporosis, is more common in men than in women. Sex hormone deficiency is associated with unrestrained osteoclast activity and bone loss. Even though estrogen deficiency is more pronounced in women, it appears to be a major factor in the pathogenesis of osteoporosis in both genders. In contrast to osteoporosis in postmenopausal women, the treatment of osteoporosis in men has been scarcely reported. Nevertheless, some drugs commonly used for the treatment of osteoporosis in women also appear to be effective in men. The aim of this study is to review primary osteoporosis in the elderly with particular emphasis on gender-related aspects. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Abstract Oral health among older people is shown to be worse compared to younger people. The aim of this study was to evaluate oral health and associating factors among ageing Finns. A cross-sectional, descriptive epidemiologic survey was performed in Kirkkonummi in southern Finland and in the Lakeus District in northern Finland. Altogether 1,191 subjects aged 60 to 78 years, 625 from Kirkkonummi and 566 from Lakeus, were examined and interviewed. Edentulousness and poor occlusal stability were recorded clinically. Gonial angle, ramus height, condylar height and the amount of residual ridge resorption in the mandible and the presence of fixed prostheses were evaluated from panoramic radiographs. Based on the radiographs the scoring of infection foci was performed with an infection focus index. The signs of infection recorded were deep caries, periapical lesions, furcal lesions, vertical bone pockets and horizontal bone loss. The prevalence of edentulousness was 37%, being significantly higher among women than among men and significantly higher in the northern compared to the southern region. Edentulousness was more prevalent among subjects with primary school education than among those with higher education. The mean of the gonial angle was smaller among dentate subjects than among edentulous ones. Dentate subjects had significantly greater ramus height and condylar height than edentulous subjects. Women had significantly more often than men severe residual ridge resorption in the mandible. Poor satisfaction with dentures associated significantly with poor occlusal stability in both genders. More than three quarters of the subjects had severe risk of infection, more in the southern than in the northern region. In the dentate sample women showed higher prevalence of fixed prostheses than men. In the Kirkkonummi region both men and women had more fixed prostheses than subjects in the Lakeus region. Edentulousness was very frequent among ageing Finns. Mandibular bone morphology changed as a consequence of tooth loss. The prevalence of fixed prostheses was low and the prevalence of signs of infection of dental origin was high. The geographical differences in oral health should be considered by health authorities in order to promote good oral health in rural areas, especially focusing on older people with low socio-economical status and poor health. / Tiivistelmä Vanhusväestön suun terveydentila on useassa tutkimuksessa todettu huonommaksi kuin nuoremmilla. Tämän tutkimuksen tarkoituksena oli selvittää suomalaisen ikääntyvän väestön suun terveydentilaa ja siihen liittyviä tekijöitä. Epidemiologinen poikkileikkaustutkimus tehtiin Kirkkonummella Etelä-Suomessa ja Lakeuden terveyskeskuksen alueella Pohjois-Suomessa. Tutkimukseen ja haastatteluun osallistui yhteensä 1191 iältään 60–78-vuotiasta henkilöä, 625 Kirkkonummelta ja 566 Lakeudelta. Kliinisessä tutkimuksessa selvitettiin hampaattomuus ja proteesien purentatasapaino. Alaleuan leukakulma, nousevan haaran ja nivellisäkkeen korkeus, hammasharjanteen korkeus ja kiinteiden proteesien esiintyminen arvioitiin panoraamaröntgenkuvista. Tulehdusriskiä kuvaava indeksi arvioitiin röntgenkuvien tulehdusmuutoksista, joina rekisteröitiin syvä karies, hampaan juurenpään tulehdus, tulehdus takahampaiden juurten haarautumassa, syventyneet luutaskut ja kiinnityskudoskato usean hampaan alueella. Hampaattomuuden vallitsevuus oli 37 %. Se oli tilastollisesti merkitsevästi korkeampi naisilla kuin miehillä ja pohjoisella alueella merkitsevästi korkeampi kuin eteläisellä. Hampaattomuus oli yleisempää vähiten koulutusta saaneilla kuin korkeamman koulutuksen saaneilla. Hampaallisilla oli pienempi alaleuan leukakulma kuin hampaattomilla, ja heillä oli myös korkeampi nouseva haara ja nivellisäke kuin hampaattomilla. Naisilla oli merkitsevästi useammin vakavaa hammasharjanteen madaltumista kuin miehillä. Molemmilla sukupuolilla tyytymättömyys proteeseihin liittyi merkitsevästi huonoon purentatasapainoon. Yli kolmella neljäsosalla tutkituista oli vakava tulehdusriski, eteläisellä alueella enemmän kuin pohjoisella. Hampaallisessa aineistossa naisilla oli enemmän kiinteitä proteeseja kuin miehillä. Kirkkonummen alueella tutkituilla oli enemmän kiinteitä proteeseja kuin Lakeuden alueella. Hampaattomuus oli hyvin yleistä 60–78-vuotiailla suomalaisilla. Alaleuanluun muoto muuttui hampaiden menetyksen seurauksena. Kiinteiden proteesien määrä oli vähäinen ja ikääntyvillä suomalaisilla oli röntgenkuvissa runsaasti hammasperäisten tulehdusten löydöksiä. Suun terveyden alueelliset erot tulisi ottaa huomioon suu- ja hammasterveyden edistämistyössä, jossa erityisesti tulisi huomioida alhaisen sosioekonomisen aseman ja huonon terveyden omaava vanhempi väestö.

INTRODUÇÃO: Os distúrbios minerais e ósseos da doença renal crônica (DMO-DRC) são influenciados por vários fatores, como idade, etiologia da DRC, toxinas urêmicas e modalidade dialítica. Os DMO-DRC são bem descritos em pacientes tratados com hemodiálise (HD). No entanto, na diálise peritoneal (DP) os estudos são escassos e, na maioria deles, não há dados de histologia óssea. OBJETIVOS: caracterizar os DMO-DRC em uma coorte de pacientes em DP; comparar os resultados com aqueles obtidos da HD; e analisar o desempenho de marcadores séricos para o diagnóstico das doenças de alto e baixo remodelamento ósseo. MÉTODOS: quarenta e um pacientes tratados com DP submeteram-se a avaliação clínica, bioquímica e biópsia óssea. RESULTADOS: a doença óssea adinâmica (DOA) foi o tipo de osteodistrofia renal (OR) predominante, correspondendo a 49% da amostra. Ao se analisar separadamente diabéticos e não diabéticos, a prevalência de DOA foi de 77,7% no primeiro grupo e 26% no segundo (p=0,001). Na comparação entre DP e HD, observou-se que os pacientes do primeiro grupo apresentavam 25(OH) vitamina D mais baixa, mineralização óssea mais comprometida e melhor volume ósseo. A fosfatase alcalina óssea (FAO) apresentou a melhor sensibilidade e especificidade tanto para o diagnóstico de alto, quanto de baixo remodelamento ósseo. CONCLUSÕES: a DOA é o tipo de OR mais prevalente na DP. No entanto, a influência do diabetes como fator de risco parece ser maior do que a própria modalidade dialítica / INTRODUCTION: Chronic kidney disease - mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins and dialysis modality. CKD-MBD has been extensively studied in hemodialysis (HD) patients. However, for peritoneal dialysis (PD), only a few, older studies exist, most of which contain no bone biopsy data. The present study sought to: characterize CKD-MBD in a cohort of prevalent PD patients; compare the results with that obtained from HD patients; and analyse performance of bone turnover serum markers to make the diagnosis of high or low bone turnover disease in PD patients. METHODS: Forty-one PD patients underwent to a clinical evaluation, biochemical analysis and bone biopsy. RESULTS: The most prevalent pattern of renal osteodystrophy (ROD) was adynamic bone disease (ABD), comprising 49% of the sample population. When we separately analyzed diabetic and non-diabetic patients, the ABD prevalence was 77.7% in the former group and 26% in the latter group (p=0.001). The comparison between DP and HD patients revealed low 25(OH) vitamin D level, worst bone mineralization and better bone volume parameters in the former group. Bone alkaline phosphatase (BAP) demonstrated the best sensitivity and specificity values to detect both high and low turnover disease. CONCLUSION: ABD is the most frequent type of ROD. However, the effect of diabetes on the development of ABD is more important than the dialysis modality itself

Ce mémoire présente l’évaluation du remodelage osseux autour des composantes acétabulaires non cimentées press-fit d’une arthroplastie de resurfaçage (RH) et d’une prothèse totale de hanche (PTH) après un minimum de 21 mois d’implantation. Nous avons mesuré par l’absorptiométrie à rayons X en double énergie (DEXA) la densité minérale osseuse (DMO) supra acétabulaire chez 60 patients (44 RH, 16 PTH). Aucune différence significative de la moyenne des DMO au niveau de la zone globale et de la zone centrale de l’acétabulum n’a été trouvée entre la hanche opérée et la hanche controlatérale, dans les deux groupes de traitement. Cependant, la DMO des zones corticospongieuses médiale et latérale est plus élevée du côté opéré par rapport au côté non opéré avec la cupule en chrome cobalt de la RH; (p=0,014 et 0,031 respectivement). Alors que pour la PTH avec une cupule en titane, la différence de la DMO au niveau de ces zones n’est pas significative; (p=0,130 et 0,733). Ces données semblent démontrer qu’avec des cupules plus rigides, il y a transfert des contraintes de charges vers la périphérie corticale. C’est la première étude à évaluer le remodelage osseux péri acétabulaire avec un RH. Cela montre que la DMO est relativement préservée et que le transfert des contraintes vers la périphérie peut être favorable au maintien de la stabilité de l’implant primaire et aux éventuelles révisions de la cupule press-fit du RH. / We undertook a retrospective study to evaluate bone remodeling around two uncemented press-fit acetabular components: (1. Hip resurfacing (HR) and 2. total hip replacement (THR)) at a minimum of 21 months after implantation. We measured by DEXA (Dual energy X ray absorptiometry) the bone mineral density (BMD) in the supra acetabular area in 60 patients (44 HR, 16 THR). We found no significant difference in the average BMD of the global zone and central zone of the acetabulum between the operated hip and the opposite non-operated hip in both treatment groups. However, the BMD of the medial and lateral cortico-cancellous areas on the side of surgery was significantly higher compared to non-operated side in HR group with the cobalt chrome cup; (p=0,014 and 0,031 respectively) As for THR with a titanium cup, we found no significant difference in BMD at these areas (p=0,130 and 0,733). These data show that with more rigid cups, there seems to be greater load transfer to the periphery of the acetabulum without significant stress shielding. This is the first study to assess peri-acetabular bone remodeling with HR. We showed that BMD is relatively preserved. Stress transfer to the periphery may be beneficial in maintaining the stability of the primary implant while conserving bone stock for possible revisions of the press-fit cup of the HR.

INTRODUÇÃO: Os distúrbios minerais e ósseos da doença renal crônica (DMO-DRC) são influenciados por vários fatores, como idade, etiologia da DRC, toxinas urêmicas e modalidade dialítica. Os DMO-DRC são bem descritos em pacientes tratados com hemodiálise (HD). No entanto, na diálise peritoneal (DP) os estudos são escassos e, na maioria deles, não há dados de histologia óssea. OBJETIVOS: caracterizar os DMO-DRC em uma coorte de pacientes em DP; comparar os resultados com aqueles obtidos da HD; e analisar o desempenho de marcadores séricos para o diagnóstico das doenças de alto e baixo remodelamento ósseo. MÉTODOS: quarenta e um pacientes tratados com DP submeteram-se a avaliação clínica, bioquímica e biópsia óssea. RESULTADOS: a doença óssea adinâmica (DOA) foi o tipo de osteodistrofia renal (OR) predominante, correspondendo a 49% da amostra. Ao se analisar separadamente diabéticos e não diabéticos, a prevalência de DOA foi de 77,7% no primeiro grupo e 26% no segundo (p=0,001). Na comparação entre DP e HD, observou-se que os pacientes do primeiro grupo apresentavam 25(OH) vitamina D mais baixa, mineralização óssea mais comprometida e melhor volume ósseo. A fosfatase alcalina óssea (FAO) apresentou a melhor sensibilidade e especificidade tanto para o diagnóstico de alto, quanto de baixo remodelamento ósseo. CONCLUSÕES: a DOA é o tipo de OR mais prevalente na DP. No entanto, a influência do diabetes como fator de risco parece ser maior do que a própria modalidade dialítica / INTRODUCTION: Chronic kidney disease - mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins and dialysis modality. CKD-MBD has been extensively studied in hemodialysis (HD) patients. However, for peritoneal dialysis (PD), only a few, older studies exist, most of which contain no bone biopsy data. The present study sought to: characterize CKD-MBD in a cohort of prevalent PD patients; compare the results with that obtained from HD patients; and analyse performance of bone turnover serum markers to make the diagnosis of high or low bone turnover disease in PD patients. METHODS: Forty-one PD patients underwent to a clinical evaluation, biochemical analysis and bone biopsy. RESULTS: The most prevalent pattern of renal osteodystrophy (ROD) was adynamic bone disease (ABD), comprising 49% of the sample population. When we separately analyzed diabetic and non-diabetic patients, the ABD prevalence was 77.7% in the former group and 26% in the latter group (p=0.001). The comparison between DP and HD patients revealed low 25(OH) vitamin D level, worst bone mineralization and better bone volume parameters in the former group. Bone alkaline phosphatase (BAP) demonstrated the best sensitivity and specificity values to detect both high and low turnover disease. CONCLUSION: ABD is the most frequent type of ROD. However, the effect of diabetes on the development of ABD is more important than the dialysis modality itself

No description available.

[ES] El acceso a una atención sanitaria de alta calidad es un marcador importante del desarrollo de las sociedades humanas. Los aportes tecnológicos a la medicina han mostrado un potencial relevante para descubrir procedimientos efectivos a nivel preventivo, diagnóstico y terapéutico. En particular, los métodos computacionales permiten el procesamiento eficaz de datos médicos y, por tanto, pueden modelar sistemas biológicos complejos. Esto ha influido en el desarrollo de la Medicina Personalizada (MP) durante las últimas décadas, donde la obtención de conocimiento específico de cada caso permite realizar intervenciones a medida, todo ello a un coste de recursos accesible. La simulación de remodelación ósea es un campo prometedor en el contexto de la MP. Predecir un proceso de adaptación ósea en un caso concreto puede dar lugar a numerosas aplicaciones en el campo de las enfermedades óseas, tanto a nivel clínico como experimental. Mediante la combinación del Método de Elementos Finitos (FEM) y los algoritmos de remodelación ósea, es posible obtener modelos numéricos de un hueso específico a partir de datos médicos (por ejemplo, una tomografía computarizada). Todo ello puede dar lugar a una revolución en la medicina personalizada. / [CA] L'accés a una atenció sanitària d'alta qualitat és un marcador important del desenvolupament de les societats humanes. Les aportacions tecnològiques a la medicina han mostrat un potencial rellevant per a descobrir procediments efectius a nivell preventiu, diagnòstic i terapèutic. En particular, els mètodes computacionals permeten el processament eficaç de dades mèdiques i, per tant, poden modelar sistemes biològics complexos. Això ha influït en el desenvolupament de la Medicina Personalitzada (MP) durant les últimes dècades, on l'obtenció de coneixement específic de cada cas permet realitzar intervencions a mesura, tot això a un cost de recursos accessible. La simulació de remodelació òssia és un camp prometedor en el context de la MP. Predir un procés d'adaptació òssia en un cas concret pot donar lloc a nombroses aplicacions en el camp de les malalties òssies, tant a nivell clínic com experimental. Mitjançant la combinació del Mètode d'Elements Finits (*FEM) i els algorismes de remodelació òssia, és possible obtindre models numèrics d'un os específic a partir de dades mèdiques (per exemple, una tomografia computada). Tot això pot donar lloc a una revolució en la medicina personalitzada. / [EN] Access to high-quality healthcare is an important marker of the development of human societies. Technological contributions to medicine have shown relevant potential to discover effective procedures at a preventive, diagnostic and therapeutic level. In particular, computational methods enable efficient processing of medical data and can therefore model complex biological systems. This has influenced the development of Personalized Medicine (PM) over recent decades, where obtaining specific knowledge of each case allows for tailored interventions, all at an affordable resource cost. Simulation of bone remodeling is a promising field in the context of PM. Predicting a bone adaptation process in a specific case can lead to numerous applications in the field of bone diseases, both clinically and experimentally. By combining the Finite Element Method (FEM) and bone remodeling algorithms, it is possible to obtain numerical models of a specific bone from medical data (for example, a CT scan). All of this can lead to a revolution in personalized medicine. / Thanks to the Valencian funding programme FDGENT/2018, for providing economic resources to develop this long-term work. / Gutiérrez Gil, J. (2023). Personalization of Bone Remodelling Simulation Models for Clinical Applications [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/202059