No description available.

No description available.

No description available.

No description available.

No description available.

The principal aim of this thesis was to develop and implement a standardised protocol for the fractal analysis of cancellous bone architecture. Cancellous bone structure from different skeletal sites in groups of osteoporotic, osteoarthritic and normal individuals was analysed. The results of fractal analysis were explained in the context of conventional bone histomorphometry and a priori knowledge to advance the understanding of cancellous bone architecture. There has been much effort devoted to the pursuit of descriptors of cancellous bone complexity. The aim of these endeavours has been to develop morphological descriptors of bone quality that explain the functional properties of the cancellous bone structure for age-related changes, the effect of disease processes or the effect of therapeutic agents on the diseased skeleton. The fractal analysis of the complexity of cancellous bone architecture promises to be an exciting addition to existing analytical techniques. The establishment of a standardised methodology for the fractal analysis of cancellous bone encompassed many components. Knowledge of the stereological and histomorphometric principles that are employed in currently available techniques enabled a comprehensive examination of the factors that effect the measurement of the fractal dimensions. The methodology presented in this thesis has been optimised specifically for measuring sectional fractal dimensions in histological sections of cancellous bone. The sectional fractal dimensions show that, over three ranges of scale, cancellous bone is effectively fractal at multiple sites in the normal skeleton. The three sectional fractal dimensions describe different morphological compartments of the cancellous bone structure. Fractal 1 describes the surface texture of the trabeculae, fractal 2 describes the shape or form of individual trabeculae and fractal 3 describes the spatial arrangement or overall architecture of the cancellous bone. This thesis reports that in the normal skeleton there are differences between skeletal sites for the fractal dimensions, which are dependent on the functional properties of the skeletal sites. Fractal 2 and fractal 3 for subchondral cancellous bone is greater than vertebral body and iliac crest cancellous bone, which indicates greater morphological complexity. Also, fractal 2 and fractal 3 in subchondral cancellous bone show an age-related decrease, which suggests that the cancellous bone structure becomes less complex with age. This interostotic variability in response to ageing is indicative of the heterogeneity in functional properties of cancellous bone in the skeleton. In this thesis, fractal analysis has been shown to detect morphological differences in the cancellous bone between normals, osteoporotics and osteoarthritics in the compressive and tensile trabeculae of the femoral head and the iliac crest. These data have provided new insights into the mechanisms of change to cancellous bone structure in ageing and in disease. Age-related changes in the structural parameters of cancellous bone are seen at all the skeletal sites in the normals but are only present in the compressive trabeculae of the femoral head in the osteoporotics and not at all in the osteoarthritics. These observations indicate that these disease processes are associated with an uncoupling of the control mechanisms that affect cancellous bone structural complexity. In the normals, the fractal dimensions only show age-related change in the tensile trabeculae of the femoral head, suggesting that fractal analysis is not suitable for detecting the age-related changes that are quantified by the structural parameters of cancellous bone in these study groups but the fractal dimensions detect underlying cancellous bone complexity independent of age. For the osteoporotics, fractal 1 is the same at all skeletal sites. This suggests that the relative levels of remodeling activity are the same for both normals and osteoporotics. Fractal 2 for both the compressive and tensile trabeculae in the femur is significantly lower for the osteoporotics than the normals but in the iliac crest, fractal 2 is the same. This implies that in the femoral head the osteoporotics have trabeculae that are significantly less complex in shape than the normals. This phenomenon is not seen in the iliac crest, which is usually the site of diagnostic biopsy. Therefore, biopsies for diagnosis of osteoporosis may not show changes in cancellous bone structural complexity that are evident in disease affected sites. The structural parameters of cancellous bone show that osteoporotics lose whole trabeculae due to perforation of trabeculae, through decreased Tb.N and increased Tb.Sp. This leads to less interconnection between trabeculae, loss of branching and more rounded trabeculae, hence the trabeculae are less complex in shape. For fractal 3, in compressive and tensile regions of the femur the osteoporotics are significantly lower than the normals and in the iliac crest the osteoporotics are the same as the normals. This indicates that in the femoral head the spatial arrangement of the trabeculae within the cancellous structure of the osteoporotics is less complex. The structural parameters of cancellous bone show that there is loss of whole trabeculae, which is associated with increased spatial separation between the trabeculae as bone is lost. For the osteoarthritics, fractal 1 is the same as the normals at all skeletal sites. Fractal 2 for the compressive trabeculae in the femoral head is significantly higher for the osteoarthritics than the normals but in the tensile trabeculae of the femoral head and the iliac crest fractal 2 for the osteoarthritics is the same as the normals. This implies that in the compressive trabeculae of the femoral head the osteoarthritics have trabeculae that are significantly more complex in shape than the normals. The structural parameters of cancellous bone show that the compressive trabeculae of the femoral head are thicker, more numerous and less widely separated with greater BV/TV than the normals. This leads to greater interconnectivity between trabeculae and more complex branching, hence the trabeculae are more complex in shape. For fractal 3, in the compressive and tensile regions of the femoral head the osteoarthritics and the normals are the same but in the iliac crest the osteoarthritics are lower than the normals. This indicates that the spatial arrangement of the trabeculae within the cancellous structure of the osteoarthritics does not change in response to the disease process in subchondral cancellous bone adjacent to the articular lesion but in the iliac crest the spatial arrangement of the trabeculae in osteoarthritics is less complex in shape. The structural parameters of cancellous bone show that BV/TV is increased in the compressive and tensile trabeculae of the femoral head but not in the iliac crest of the osteoarthritics. This indicates that the spatial complexity of the trabecular arrangement within the cancellous structure of osteoarthritics changes independently of changes in cancellous bone structure detected by the structural parameters of cancellous bone. The sectional fractal dimensions have detected differences in morphological complexity between the normals and disease groups and between the skeletal sites. These novel data have been obtained using an innovative technique that is not dependent on assumptions based on conceptual models of cancellous bone structure. A priori knowledge of bone biology is utilised to enable the fractal analysis to measure specific morphological entities within the cancellous bone structure. The fractal dimensions have identified changes in the morphological complexity of specific components of the cancellous structure, which are not identified by existing model-based morphometric techniques. This has enabled new understanding of how change to cancellous bone structure occurs as a result of a disease process. Fractal analysis is a novel tool that will prove useful for the study of changes in cancellous bone structure due to disease and to study the use of therapies to alter or maintain the quality of cancellous bone architecture. / Thesis (Ph.D.)--Medical School, 2002.

No description available.

Introdução: O quelante de fósforo (P) Osvaren® foi lançado recentemente no mercado internacional para tratamento da hiperfosfatemia nos pacientes com Doença Renal Crônica (DRC). Não existem estudos experimentais com esta medicação. Objetivo: Avaliar a ação deste quelante no tratamento do Distúrbio Mineral e Ósseo (DMO) de ratos com DRC induzida por adenina e por nefrectomia 5/6 (NX5/6). Métodos: Experimento 1: Durante 4 semanas, ratos Wistar receberam dieta com adenina [2 semanas (0,75%); 2 semanas (0,50%)] e então foram divididos em 3 grupos para receber dieta padrão (grupo DRC); dieta padrão com 3% de Acetato de Cálcio (grupo Ca); e dieta padrão com 3% de Osvaren® (grupo CaMg). Um grupo Controle (função renal normal) recebeu a dieta padrão durante todo o estudo. Ao final de cinco semanas de tratamento os animais foram sacrificados. Experimento 2: ratos da mesma espécie foram submetidos à NX5/6, divididos em grupos como no experimento 1 para receberem os quelantes de P imediatamente após a nefrectomia, e sacrificados após 9 semanas. Nos dois experimentos foram coletados soro, fêmures, aortas e paratireóides para análise bioquímica, histomorfometria óssea, pesquisa de calcificação vascular (CV) e imunohistoquímica de paratireóides, respectivamente. Resultados: Experimento 1: Os animais que receberam adenina apresentaram níveis maiores de creatinina, PTH, P e magnésio (Mg) que os do grupo Controle. Os quelantes de P reduziram a fração de excreção de P (FeP), mas não o P sérico, enquanto os níveis de PTH, FGF23 e calcitriol diminuíram de forma não significativa nos grupos tratados. O Mg sérico foi significativamente maior no grupo CaMg, enquanto maior calciúria, mais CV e menor marcação pelo PCNA nas paratireóides foram observadas no grupo Ca. Os animais que receberam adenina apresentaram doença óssea mista e ambos os quelantes de P melhoraram a remodelação, mas favoreceram a um acúmulo ainda maior de osteóide. Experimento 2: Da mesma forma que no experimento 1, o animais submetidos à NX5/6 evoluíram com uremia, e os efeitos dos quelantes no PTH, na CV e nas paratireóides foram similares. No entanto, o grupo CaMg apresentou mortalidade de 54% (vs 20% no grupo Ca), além de retardo na mineralização óssea. Conclusão: O tipo de nefropatia pode ter influência no efeito do quelante de P Osvaren®, já que o acúmulo de Mg provavelmente foi o responsável pela maior mortalidade e déficit de mineralização observados no experimento 2. Em relação ao efeito como quelante de P, o Osvaren® foi equivalente ao acetato de cálcio, mas este último está associado a maior sobrecarga de cálcio e a CV. O acúmulo de osteóide observado em ambos os experimentos parece ser o preço pago pela reduzida absorção intestinal de P favorecida pelos quelantes no hiperpatireoidismo secundário severo e esse efeito deveria ser avaliado em pacientes em diálise / Introduction: Osvaren® is a phosphate (P) binder that has been recently introduced for Chronic Kidney Disease (CKD) patients therapy. However, it has not been tested in experimental models yet. Aims: To study Osvaren® effects on mineral and bone metabolism in CKD experiment models. Methods: Experiment 1: For 4 weeks (wk), rats were fed normal chow or an adenine-enriched diet (0,75% for 2 wks; 0,50% for 2 wks). After that, adenine was discontinued and rats were divided into 3 groups: Ca (3% calcium acetate); CaMg (3% Osvaren®) and CKD (normal diet/untreated). A control group, with normal renal function was also studied. After 5 wks of therapy, animals were sacrificed. Experiment 2: Animals underwent 5/6 nephrectomy, and were submitted to different P binders treatment as in experiment 1 and then sacrificed 9 weeks after surgery. We performed biochemical and histomorphometric analyses, parathyroid PCNA imunohistochemistry, as well as Von Kossa staining and calcium content of aortic sections. Results: Experiment 1: Higher creatinine, PTH, FGF-23, P and Mg were found in all adenine-fed rats. P binders did not reduce serum P but decreased fractional excretion of P (FeP) and tended to reduce PTH, FGF23 and calcitriol levels. In the CaMg group, Mg was slightly elevated, whereas Ca group had greater urinary calcium as well as vascular calcification and smaller parathyroid PCNA staining. Adenine-fed rats presented features of mixed bone disease and P binders therapy was able to decrease bone resorption, but was associated with an osteoid accumulation. Experiment 2: As in experiment 1, nephrectomized rats were uremic and P binder effects on PTH, vascular calcification and parathyroid were very similar, except for the mortality rate, that was higher in CaMg group (54% vs 20% in Ca group). An increase in mineralization lag time was also found in CaMg group. Conclusions: Osvaren® may cause different effects on different types of nephropathy, as in experiment 2 the Mg was probably the responsible for higher mortality as well as for bone mineralization defect. In terms of P binding efficacy, Osvaren® was equivalent to calcium acetate, but the last one caused calcium overload and vascular calcification. The osteoid accumulation is probably related to the decrease in intestinal P absorption caused by the P binders in these models of secondary hyperparathyroidism. These effects should also be evaluated in dialysis patients

No description available.

Introdução: O quelante de fósforo (P) Osvaren® foi lançado recentemente no mercado internacional para tratamento da hiperfosfatemia nos pacientes com Doença Renal Crônica (DRC). Não existem estudos experimentais com esta medicação. Objetivo: Avaliar a ação deste quelante no tratamento do Distúrbio Mineral e Ósseo (DMO) de ratos com DRC induzida por adenina e por nefrectomia 5/6 (NX5/6). Métodos: Experimento 1: Durante 4 semanas, ratos Wistar receberam dieta com adenina [2 semanas (0,75%); 2 semanas (0,50%)] e então foram divididos em 3 grupos para receber dieta padrão (grupo DRC); dieta padrão com 3% de Acetato de Cálcio (grupo Ca); e dieta padrão com 3% de Osvaren® (grupo CaMg). Um grupo Controle (função renal normal) recebeu a dieta padrão durante todo o estudo. Ao final de cinco semanas de tratamento os animais foram sacrificados. Experimento 2: ratos da mesma espécie foram submetidos à NX5/6, divididos em grupos como no experimento 1 para receberem os quelantes de P imediatamente após a nefrectomia, e sacrificados após 9 semanas. Nos dois experimentos foram coletados soro, fêmures, aortas e paratireóides para análise bioquímica, histomorfometria óssea, pesquisa de calcificação vascular (CV) e imunohistoquímica de paratireóides, respectivamente. Resultados: Experimento 1: Os animais que receberam adenina apresentaram níveis maiores de creatinina, PTH, P e magnésio (Mg) que os do grupo Controle. Os quelantes de P reduziram a fração de excreção de P (FeP), mas não o P sérico, enquanto os níveis de PTH, FGF23 e calcitriol diminuíram de forma não significativa nos grupos tratados. O Mg sérico foi significativamente maior no grupo CaMg, enquanto maior calciúria, mais CV e menor marcação pelo PCNA nas paratireóides foram observadas no grupo Ca. Os animais que receberam adenina apresentaram doença óssea mista e ambos os quelantes de P melhoraram a remodelação, mas favoreceram a um acúmulo ainda maior de osteóide. Experimento 2: Da mesma forma que no experimento 1, o animais submetidos à NX5/6 evoluíram com uremia, e os efeitos dos quelantes no PTH, na CV e nas paratireóides foram similares. No entanto, o grupo CaMg apresentou mortalidade de 54% (vs 20% no grupo Ca), além de retardo na mineralização óssea. Conclusão: O tipo de nefropatia pode ter influência no efeito do quelante de P Osvaren®, já que o acúmulo de Mg provavelmente foi o responsável pela maior mortalidade e déficit de mineralização observados no experimento 2. Em relação ao efeito como quelante de P, o Osvaren® foi equivalente ao acetato de cálcio, mas este último está associado a maior sobrecarga de cálcio e a CV. O acúmulo de osteóide observado em ambos os experimentos parece ser o preço pago pela reduzida absorção intestinal de P favorecida pelos quelantes no hiperpatireoidismo secundário severo e esse efeito deveria ser avaliado em pacientes em diálise / Introduction: Osvaren® is a phosphate (P) binder that has been recently introduced for Chronic Kidney Disease (CKD) patients therapy. However, it has not been tested in experimental models yet. Aims: To study Osvaren® effects on mineral and bone metabolism in CKD experiment models. Methods: Experiment 1: For 4 weeks (wk), rats were fed normal chow or an adenine-enriched diet (0,75% for 2 wks; 0,50% for 2 wks). After that, adenine was discontinued and rats were divided into 3 groups: Ca (3% calcium acetate); CaMg (3% Osvaren®) and CKD (normal diet/untreated). A control group, with normal renal function was also studied. After 5 wks of therapy, animals were sacrificed. Experiment 2: Animals underwent 5/6 nephrectomy, and were submitted to different P binders treatment as in experiment 1 and then sacrificed 9 weeks after surgery. We performed biochemical and histomorphometric analyses, parathyroid PCNA imunohistochemistry, as well as Von Kossa staining and calcium content of aortic sections. Results: Experiment 1: Higher creatinine, PTH, FGF-23, P and Mg were found in all adenine-fed rats. P binders did not reduce serum P but decreased fractional excretion of P (FeP) and tended to reduce PTH, FGF23 and calcitriol levels. In the CaMg group, Mg was slightly elevated, whereas Ca group had greater urinary calcium as well as vascular calcification and smaller parathyroid PCNA staining. Adenine-fed rats presented features of mixed bone disease and P binders therapy was able to decrease bone resorption, but was associated with an osteoid accumulation. Experiment 2: As in experiment 1, nephrectomized rats were uremic and P binder effects on PTH, vascular calcification and parathyroid were very similar, except for the mortality rate, that was higher in CaMg group (54% vs 20% in Ca group). An increase in mineralization lag time was also found in CaMg group. Conclusions: Osvaren® may cause different effects on different types of nephropathy, as in experiment 2 the Mg was probably the responsible for higher mortality as well as for bone mineralization defect. In terms of P binding efficacy, Osvaren® was equivalent to calcium acetate, but the last one caused calcium overload and vascular calcification. The osteoid accumulation is probably related to the decrease in intestinal P absorption caused by the P binders in these models of secondary hyperparathyroidism. These effects should also be evaluated in dialysis patients