RESUMEN
We have recently reported that risedronate preserves normal bone formation and decreases bone remodeling in women with postmenopausal osteoporosis after 3 years of treatment. We report now the results of a 2-year extension study. The primary objective of this study was to determine the effect of 5 years of risedronate treatment (5 mg daily) on bone quality and bone remodeling based on paired transiliac bone biopsies. There were additional measurements that included bone turnover markers and bone mineral density (BMD). Histologic evaluation of biopsy sections (placebo, n = 21; risedronate, n = 27) yielded no pathologic findings after 5 years in either treatment group. Histomorphometric assessment of paired biopsy specimens after 5 years (placebo, n =12; risedronate, n = 13) found no statistically significant differences between treatment groups in structural or resorption parameters. There was a significant reduction in osteoid (-27%) and mineralizing surfaces (-49%) from baseline values in the risedronate group that were also significantly different from placebo at 5 years. Similarly, activation frequency decreased significantly (-77%) in the risedronate group, although it was not significantly different from placebo at 5 years (0.09 vs. 0.21, respectively). Double tetracycline labels were identified in all biopsy specimens indicating continuous bone turnover. After 5 years of risedronate treatment, serum bone-specific alkaline phosphatase (bone ALP) and N-telopeptide (NTX) decreased significantly from baseline by 33.3% and 47.5%, respectively. In the placebo group, bone ALP decreased by 3.9% (P = NS), whereas NTX decreased by 27.0% (P < 0.005). Lumbar spine BMD increased significantly in the risedronate group (9.2%), whereas no significant change was seen in the placebo group (-0.26%). Risedronate was overall well tolerated; during the 2-year study extension nonvertebral fractures occurred in 7 patients in placebo and 2 patients in risedronate groups. The findings from this study are consistent with the antiremodeling effect of risedronate and support long-term bone safety and antifracture efficacy of risedronate treatment.
Asunto(s)
Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Anciano , Fosfatasa Alcalina/sangre , Fosfatasa Alcalina/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Canadá , Estudios de Cohortes , Colágeno/sangre , Colágeno/efectos de los fármacos , Colágeno Tipo I , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/prevención & control , Péptidos/sangre , Péptidos/efectos de los fármacos , Placebos , Ácido Risedrónico , Factores de TiempoRESUMEN
The effects of 3 years of oral risedronate treatment on bone quality and remodeling were assessed in women with postmenopausal osteoporosis. Transiliac bone biopsies were obtained at baseline and after treatment with placebo or risedronate 5 mg/day in 55 women (placebo, n = 27; risedronate 5 mg, n = 28); these pairs of samples allowed comparison of treatment effects vs. both baseline values and between treatment groups. A further 15 women (placebo, n = 6; risedronate 5 mg, n = 9) had measurements from a posttreatment biopsy, but not from a baseline biopsy. Samples were examined for qualitative changes (e.g., osteomalacia, peritrabecular fibrosis, and woven bone); no histological abnormalities were found to be associated with treatment. Among women with both baseline and posttreatment biopsies, risedronate-treated women experienced a moderate and expected reduction from baseline in bone turnover, which was reflected in mean decreases in mineralizing surface of 58% and in activation frequency of 47%. Histomorphometrical parameters indicated that bone formation rate decreased significantly from baseline with risedronate treatment, reflecting a decrease in bone turnover; bone mineralization was normal following treatment. Basic multicellular unit (BMU) balance tended to improve in the risedronate-treated women, whereas it tended to worsen in the placebo-treated women, although these changes were not statistically significant. There were no significant changes in structural parameters with treatment. The effects of 3 years of risedronate treatment on bone histology and histomorphometry reflect the antiresorptive mechanism of action, and are consistent with the antifracture efficacy and favorable bone safety profile demonstrated in large clinical trials.
Asunto(s)
Remodelación Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Ácido Etidrónico/análogos & derivados , Ácido Etidrónico/administración & dosificación , Osteogénesis/efectos de los fármacos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Remodelación Ósea/fisiología , Resorción Ósea/patología , Femenino , Humanos , Persona de Mediana Edad , Osteogénesis/fisiología , Ácido Risedrónico , Fracturas de la Columna Vertebral/tratamiento farmacológico , Fracturas de la Columna Vertebral/patología , Estadísticas no ParamétricasRESUMEN
With the proportion of elderly people increasing in many countries, osteoporosis has become a growing public health problem, with rising medical, social, and economic consequences. It is well recognized that a combination of low bone mass and the deterioration of the trabecular architecture underlies osteoporotic fractures. A comprehensive understanding of the relationships between bone mass, the three-dimensional (3D) architecture of bone and bone function is fundamental to the study of new and existing therapies for osteoporosis. Detailed analysis of 3D trabecular architecture, using high-resolution digital imaging techniques such as magnetic resonance microimaging (MRmicroI), micro-computed tomography (microCT), and direct image analysis, has become feasible only recently. Rapid prototyping technology is used to replicate the complex trabecular architecture on a macroscopic scale for visual or biomechanical analysis. Further, a complete set of 3D image data provides a basis for finite element modeling (FEM) to predict mechanical properties. The goal of this paper is to describe how we can integrate three-dimensional microimaging and image analysis techniques for quantitation of trabecular bone architecture, FEM for virtual biomechanics, and rapid prototyping for enhanced visualization. The integration of these techniques provide us with an unique ability to investigate the role of bone architecture in osteoporotic fractures and to support the development of new therapies.
Asunto(s)
Huesos/patología , Imagenología Tridimensional , Imagen por Resonancia Magnética/métodos , Osteoporosis/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Anciano , Animales , Fenómenos Biomecánicos , Huesos/diagnóstico por imagen , Huesos/fisiopatología , Femenino , Análisis de Elementos Finitos , Humanos , Masculino , Persona de Mediana Edad , RatasRESUMEN
The study objective was to analyze the three-dimensional (3D) trabecular architecture and mechanical properties in vertebral specimens of young and mature Sinclair minipigs to assess the relative contribution of architecture to bone strength. We used 3D magnetic resonance microimaging (MRmicroI) and direct image analysis to evaluate a set of standard structural measurements and new architectural descriptors of trabecular bone in biopsy specimens from L2, L3, and L4 vertebrae (n = 16 in each group) from young (mean age, 1.2 years) and mature (mean age, 4.8 years) minipigs. The measurements included bone volume/tissue volume (BV/TV), marrow star volume (Ma.St.V), connectivity density (ConnD), and two new parameters, percent platelike trabeculae (% plate) and percent bone in the load direction (% boneLD). The % plate, calculated from surface curvature, allowed the delineation of plates from rods. The % boneLD quantified the percentage of bone oriented along the long axis of the vertebral body. We showed that 3D MRmicroI can detect the subtle changes in trabecular architecture between the two age groups. ConnD, star volume, % plate, % boneLD, and BV/TV were found to be more effective than the model-based, derived indices (trabecular thickness [Tb.Th], trabecular separation [Tb.Sp], and trabecular number [Tb.N]) in differentiating the structural changes. BV/TV, % plate, and % boneLD significantly increased (p < 0.05) in all three vertebral sites of the mature minipigs. The significant decrease in ConnD and star volume in the mature vertebra was consistent with the concurrent increase of platelike trabecular bone (p < 0.05). Overall, ConnD, star volume, % plate, and % boneLD provided a coherent picture of the architectural changes between the two age groups. Apparent modulus and maximum stress were determined experimentally on biopsy specimens from L2 vertebrae (n = 16). When apparent modulus was predicted using 3D MRmicroI data sets as input for finite element modeling (FEM), the results were similar to the experimentally determined apparent modulus (p = 0.12). Both methods were then used to compare the young and the mature animals; the experimental and predicted apparent modulus were significantly higher for the mature group (p = 0.003 and 0.012, respectively). The experimental maximum stress in the vertebra of the mature animals was twice as high as that for the young animals (p = 0.006). Bone quantity (BV/TV or bone mineral content [BMC]) alone could explain approximately 74-85% of the total variability in stress and modulus. The inclusion of either ConnD or % boneLD with BV/TV in a multiple regression analysis significantly improved the predictability of maximum stress, indicating that architecture makes additional contributions to compressive strength in normal minipig vertebra.
Asunto(s)
Vértebras Lumbares/anatomía & histología , Vértebras Lumbares/fisiología , Imagen por Resonancia Magnética/métodos , Porcinos Enanos/fisiología , Envejecimiento/fisiología , Animales , Fuerza Compresiva , Simulación por Computador , Femenino , Procesamiento de Imagen Asistido por Computador , Vértebras Lumbares/crecimiento & desarrollo , Estadística como Asunto , Estrés Mecánico , PorcinosRESUMEN
Our objective was to investigate the efficacy and tolerability of risedronate in postmenopausal women with low bone mass. Women with a mean lumbar spine T-score of -2 or less (n = 543) received 24 months of placebo or risedronate (2.5 or 5 mg/day). All received calcium (1 g/day). The principal outcome measures were bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter. At 24 months, lumbar spine BMD increased from baseline by 4% with 5 mg risedronate and 1.4% in the 2.5-mg group, compared with no change with placebo. Efficacy was similar in women who were less than 5 yr and more than 5 yr postmenopausal. At 24 months, risedronate (5 mg) had also increased BMD at the femoral neck and trochanter, whereas BMD decreased in the placebo group. BMD increases were seen at all three sites with risedronate (5 mg) after only 6 months of therapy. Risedronate was well tolerated; upper gastrointestinal adverse events were similar to placebo. We conclude that risedronate (5 mg) increases BMD rapidly and effectively and is well tolerated in postmenopausal women with low bone mass, regardless of time since menopause.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/uso terapéutico , Ácido Etidrónico/análogos & derivados , Osteoporosis Posmenopáusica/tratamiento farmacológico , Anciano , Calcio/uso terapéutico , Bloqueadores de los Canales de Calcio/efectos adversos , Método Doble Ciego , Ácido Etidrónico/efectos adversos , Ácido Etidrónico/uso terapéutico , Europa (Continente) , Femenino , Fémur , Humanos , Vértebras Lumbares , Persona de Mediana Edad , Placebos , Ácido Risedrónico , Factores de TiempoRESUMEN
A mounting method utilizing an indium substrate is described for preparing freeze-dried cryosections of biological tissue for ion microscopic analysis. Using this procedure, a qualitative comparison between cryosection, conventional chemical, and freeze-substitution specimen preparations is made with rat liver tissue. Practical ion yield variations in cryosections are found to be minimal (+/- 13% relative standard deviation) in tissue-containing areas of rat liver and small intestine.