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Schnurri-3 (Shn3) is an essential regulator of postnatal skeletal remodeling. Shn3-deficient mice (Shn3-/-) have high bone mass; however, their bone mechanical and material properties have not been investigated to date. We performed three-point bending of femora, compression tests of L3 vertebrae. We also measured intrinsic material properties, including bone mineralization density distribution (BMDD) and osteocyte lacunae section (OLS) characteristics by quantitative backscatter electron imaging, as well as collagen cross-linking by Fourier transform infrared microspectroscopy of femora from Shn3-/- and WT mice at different ages (6 weeks, 4 months, and 18 months). Moreover, computer modeling was performed for the interpretation of the BMDD outcomes. Femora and L3 vertebrae from Shn3-/- aged 6 weeks revealed increased ultimate force (2.2- and 3.2-fold, p < .01, respectively). Mineralized bone volume at the distal femoral metaphysis was about twofold (at 6 weeks) to eightfold (at 4 and 18 months of age) in Shn3-/- (p < .001). Compared with WT, the average degree of trabecular bone mineralization was similar at 6 weeks, but increased at 4 and 18 months of age (+12.6% and +7.7%, p < .01, respectively) in Shn3-/-. The analysis of OLS characteristics revealed a higher OLS area for Shn3-/- versus WT at all ages (+16%, +23%, +21%, respectively, p < .01). The collagen cross-link ratio was similar between groups. We conclude that femora and vertebrae from Shn3-/- had higher ultimate force in mechanical testing. Computer modeling demonstrated that in cases of highly increased bone volume, the average degree of bone matrix mineralization can be higher than in WT bone, which was actually measured in the older Shn3-/- groups. The area of 2D osteocyte lacunae sections was also increased in Shn3-deficiency, which could only partly be explained by larger remnant areas of primary cortical bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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BACKGROUND: Partially implantable active middle ear implants (aMEIs) offer a solution for individuals who have mild to severe sensorineural hearing loss and an outer ear medical condition that precludes the use of hearing aids. When otherwise left untreated, individuals report a lower quality of life, which may further decrease with increasing disability. In the lack of cost-effectiveness studies and long-term data, there is a need for decision modeling. OBJECTIVE: To explore individual-level variance in resource utilization patterns following aMEI implantation. METHODS: A Markov model was developed and analyzed as microsimulation to estimate the incremental cost utility ratio (ICUR) of partially implantable aMEIs compared with no (surgical) intervention in individuals with sensorineural hearing loss and an outer ear medical condition in Australia. Cost data were derived mostly from the Medicare Benefit Schedule and effectiveness data from published literature. A third-party payer perspective was adopted, and a 5% discount rate was applied over a 10-year time horizon. RESULTS: Compared with baseline strategy, aMEIs yielded an incremental cost of Australian dollars (AUD) 13,339.18, incremental quality-adjusted life-year (QALY) of 1.35, and an ICUR of AUD 9,913.72/QALY. Of the respective number of simulated patients who visited each health state, 75.73% never had a minor adverse event, 99.82% did not experience device failure, and 97.75% did not cease to use their aMEIs. Probabilistic sensitivity analyses showed the ICUR to differ by only 0.95%. CONCLUSIONS: In the Australian setting, partially implantable aMEIs offer a safe and cost-effective solution compared with no intervention and are also well accepted by users.
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Pérdida Auditiva Sensorineural/cirugía , Prótesis Osicular/economía , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Adolescente , Adulto , Anciano , Australia , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Femenino , Pérdida Auditiva Sensorineural/economía , Humanos , Reembolso de Seguro de Salud , Masculino , Cadenas de Markov , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
In the present work we examined the effect of teriparatide administration following bisphosphonate treatment on bone compositional properties by Raman and Fourier Transform Infrared Imaging (FTIR) microspectroscopic analysis. Thirty two paired iliac crest biopsies (before and after 1 year teriparatide) from sixteen osteoporotic women previously treated with either Alendronate (ALN) or Risedronate (RIS) and subsequently treated 12 months with teriparatide (TPTD) were analyzed at anatomical areas of similar tissue age in bone forming areas (within the fluorescent double labels). The outcomes that were monitored and reported were mineral to matrix ratio (corresponding to ash weight), mineral maturity (indicative of the mineral crystallite chemistry and stoichiometry, and having a direct bearing on crystallite shape and size), relative proteoglycan content (regulating mineralization commencement), and the ratio of two of the major enzymatic collagen cross-links (pyridinoline/divalent). Significant differences in mineral/matrix, mineral maturity/crystallinity, and collagen cross-link ratio bone quality indices after TPTD treatment were observed, indicating a specific response of these patients to TPTD treatment. Moreover differences between ALN and RIS treated patients at baseline in the collagen cross-link ratio were observed. Since tissue areas of similar tissue age were analyzed, these differences may not be attributed to differences in bone turnover.
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Alendronato/uso terapéutico , Huesos/fisiopatología , Ácido Etidrónico/análogos & derivados , Osteoporosis Posmenopáusica/tratamiento farmacológico , Osteoporosis Posmenopáusica/fisiopatología , Teriparatido/administración & dosificación , Teriparatido/uso terapéutico , Anciano , Alendronato/farmacología , Análisis de Varianza , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Matriz Ósea/efectos de los fármacos , Matriz Ósea/metabolismo , Huesos/patología , Cristalización , Esquema de Medicación , Ácido Etidrónico/farmacología , Ácido Etidrónico/uso terapéutico , Femenino , Humanos , Osteoporosis Posmenopáusica/patología , Ácido Risedrónico , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Teriparatido/farmacología , Resultado del TratamientoRESUMEN
CONTEXT: Mild primary hyperparathyroidism (PHPT) is characterized by asymptomatic hypercalcemia, most commonly in the absence of classical signs and symptoms. Hence, there is need to characterize this disorder with particular attention to the skeleton. DESIGN: We determined the ratio of pyridinium and dehydrodihydroxylysinonorleucine collagen cross-links in 46 iliac crest bone biopsies from patients with PHPT (14 men, aged 28-68 yr; 32 women, aged 26-74 yr) by Fourier transform infrared imaging. The results were compared with previously reported collagen cross-links ratio determined in iliac crest biopsies from normal subjects. RESULTS: PHPT patients exhibited significantly lower pyridinium to dehydrodihydroxylysinonorleucine collagen cross-links ratio, compared with normal controls. Parathyroidectomy restored values to those comparable with normal controls. Moreover, the differences among PHPT subjects were gender dependent, with female PHPT patients having a statistically significant lower ratio, compared with either male PHPT patients or normal controls. Comparison of the obtained outcomes with histomorphometry showed that the collagen cross-link ratio was strongly correlated with rate of bone formation, and mineralizing surface, in individual patients. This ratio was also correlated with bone mineralization density distribution parameters obtained in the same patients. The strongest correlations were with bone mineralization density distribution variables reflecting heterogeneity of mineralization and primary mineralization parameters. CONCLUSIONS: The results are consistent with the high turnover state manifested in PHPT patients. Reduced collagen cross-link ratio in patients with PHPT would be expected to reduce the stiffness of bone tissue. These observations provide a more complete assessment of bone material properties in this disorder.
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Huesos/diagnóstico por imagen , Hiperparatiroidismo Primario/diagnóstico por imagen , Adulto , Anciano , Biopsia , Remodelación Ósea/fisiología , Huesos/química , Huesos/patología , Calcificación Fisiológica/fisiología , Estudios de Cohortes , Colágeno/química , Diagnóstico por Imagen/métodos , Dipéptidos/análisis , Progresión de la Enfermedad , Femenino , Humanos , Hiperparatiroidismo Primario/patología , Masculino , Persona de Mediana Edad , Compuestos de Piridinio/análisis , Control de Calidad , Radiografía , Espectroscopía Infrarroja por Transformada de Fourier/métodosRESUMEN
UNLABELLED: Long-term effects of risedronate on bone mineral maturity/crystallinity and collagen cross-link ratio in triple iliac crest biopsies of osteoporotic women were evaluated. In this double-blinded study, 3- and 5-year treatment with risedronate arrested the tissue aging encountered in untreated osteoporosis and in osteoporosis treated with other antiresorptives. This effect may be contributing to risedronate's antifracture efficacy. INTRODUCTION: Risedronate is widely used in the treatment of osteoporosis. It reduces bone turnover, increases BMD, and decreases fracture risk. To date, there are no data available on the long-term effects of risedronate on bone material properties in humans. MATERIALS AND METHODS: Osteoporotic women enrolled in the VERT-NA trial received either risedronate (5 mg/day, orally) or placebo for up to 5 years. All subjects received calcium. They also received vitamin D supplementation if deficient at baseline. Triple iliac crest biopsies were collected from a subset of these subjects at baseline, 3 years, and 5 years. Mineral maturity/crystallinity and collagen cross-link ratio was measured in these biopsies using Fourier transform infrared imaging. RESULTS: Patients that received placebo exhibited increased mineral maturity/crystallinity and collagen cross-link ratio after 3 and 5 years compared with baseline values. On the contrary, patients that received risedronate retained baseline values in both bone material indices throughout. A more spatially detailed analysis revealed that this was achieved mainly through beneficial effects on active bone-forming areas. Surprisingly, patients that received risedronate achieved premenopausal values at bone-forming areas in both indices after 5 years of treatment. CONCLUSION: Long-term treatment with risedronate affects bone material properties (mineral maturity/crystallinity and collagen cross-link ratio) and arrests the tissue aging apparent in untreated osteoporosis. These changes at the material level of the bone matrix may contribute to risedronate's rapid and sustained antifracture efficacy in osteoporotic patients.
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Conservadores de la Densidad Ósea/uso terapéutico , Densidad Ósea/efectos de los fármacos , Ácido Etidrónico/análogos & derivados , Ilion/patología , Biopsia , Conservadores de la Densidad Ósea/administración & dosificación , Calcificación Fisiológica/efectos de los fármacos , Calcio/uso terapéutico , Colágeno/efectos de los fármacos , Colágeno/metabolismo , Ácido Etidrónico/administración & dosificación , Ácido Etidrónico/uso terapéutico , Femenino , Humanos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Ácido Risedrónico , Espectroscopía Infrarroja por Transformada de Fourier , Vitamina D/uso terapéuticoRESUMEN
UNLABELLED: Long-term effects of risedronate on bone mineralization density distribution in triple transiliac crest biopsies of osteoporotic women were evaluated. In this double-blinded study, 3- and 5-year treatment with risedronate increased the degree and homogeneity of mineralization without producing hypermineralization. These changes at the material level of bone could contribute to risedronate's antifracture efficacy. INTRODUCTION: Risedronate, a nitrogen-containing bisphosphonate, is widely used in the treatment of osteoporosis. It reduces bone turnover, increases BMD, and decreases fracture risk. To date, there are no data available on the long-term effects of risedronate on bone mineralization density distribution (BMDD) in humans. MATERIALS AND METHODS: Osteoporotic women enrolled in the VERT-NA trial received either risedronate (5 mg/day, orally) or placebo for up to 5 years. All subjects received calcium and vitamin D supplementation if deficient at baseline. Triple iliac crest biopsies were collected from a subset of these subjects at baseline and 3 and 5 years. BMDD was measured in these biopsies using quantitative backscattered electron imaging, and the data were also compared with a normal reference group. RESULTS: At baseline, both risedronate and placebo groups had a lower degree and a greater heterogeneity of mineralization as well as an increase in low mineralized bone compared with the normal reference group. The degree of mineralization increased significantly in the risedronate as well as in the placebo group after 3- and 5-year treatment compared with baseline. However, the degree of mineralization did not exceed that of normal. Three-year treatment with risedronate significantly increased the homogeneity of mineralization and slightly decreased low mineralized bone compared with placebo. Surprisingly with 5-year risedronate treatment, heterogeneity of mineralization increased compared with 3-year treatment, which might indicate an increase in newly formed bone. CONCLUSIONS: Long-term treatment with risedronate affects the homogeneity and degree of mineralization without inducing hypermineralization of the bone matrix. These changes at the material level of the bone matrix may contribute to risedronate's antifracture efficacy in osteoporotic patients.