RESUMO
We examined serum IGF-1 in premenopausal IOP, finding relationships that were opposite to those expected: higher IGF-1 was associated with lower bone formation and higher body fat, and lower BMD response to teriparatide. These paradoxical relationships between serum IGF-1, bone, and fat may contribute to the mechanism of idiopathic osteoporosis in premenopausal women. INTRODUCTION: Premenopausal women with idiopathic osteoporosis (IOP) have marked deficits in bone microarchitecture but variable bone remodeling. We previously reported that those with low tissue-level bone formation rate (BFR) are less responsive to teriparatide and have higher serum IGF-1, a hormone anabolic for osteoblasts and other tissues. The IGF-1 data were unexpected because IGF-1 is low in other forms of low turnover osteoporosis-leading us to hypothesize that IGF-1 relationships are paradoxical in IOP. This study aimed to determine whether IOP women with low BFR have higher IGF-1 and paradoxical IGF-1 relationships in skeletal and non-skeletal tissues, and whether IGF-1 and the related measures predict teriparatide response. METHODS: This research is an ancillary study to a 24 month clinical trial of teriparatide for IOP. Baseline assessments were related to trial outcomes: BMD, bone remodeling. SUBJECTS: Premenopausal women with IOP(n = 34); bone remodeling status was defined by baseline cancellous BFR/BS on bone biopsy. MEASURES: Serum IGF-1 parameters, compartmental adiposity (DXA, CT, MRI), serum hormones, and cardiovascular-risk-markers related to fat distribution. RESULTS: As seen in other populations, lower BFR was associated with higher body fat and poorer teriparatide response. However, in contrast to observations in other populations, low BFR, higher body fat, and poorer teriparatide response were all related to higher IGF-1: IGF-1 Z-score was inversely related to BFR at all bone surfaces (r = - 0.39 to - 0.46; p < 0.05), directly related to central fat (p = 0.05) and leptin (p = 0.03). IGF-1 inversely related to 24 month hip BMD %change (r = - 0.46; p = 0.01). CONCLUSIONS: Paradoxical IGF-1 relationships suggest that abnormal or atypical regulation of bone and fat may contribute to osteoporosis mechanisms in premenopausal IOP.
Assuntos
Conservadores da Densidade Óssea , Osteoporose , Tecido Adiposo , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Fator de Crescimento Insulin-Like I , Osteogênese , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Teriparatida/uso terapêuticoRESUMO
SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.
Assuntos
Compostos de Bifenilo/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Idoso , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Catepsina K/antagonistas & inibidores , Método Duplo-Cego , Feminino , Colo do Fêmur/fisiopatologia , Articulação do Quadril/fisiopatologia , Humanos , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/fisiopatologia , Seleção de Pacientes , Projetos de Pesquisa , Resultado do TratamentoRESUMO
UNLABELLED: Measurement of marrow fat (MF) is important to the study of bone fragility. We measured MF on iliac biopsies and by spine/hip magnetic resonance spectroscopy in the same subjects. Noninvasively assessed spine MF and histomorphometrically assessed MF correlated well. MF quantity and relationships with bone volume differed by measurement site. INTRODUCTION: Excess marrow fat has been implicated in the pathogenesis of osteoporosis in several populations. In the bone marrow, adipocytes and osteoblasts share a common precursor and are reciprocally regulated. In addition, adipocytes may secrete toxic fatty acids and adipokines that adversely affect osteoblasts. Measurement of marrow fat is important to the study of mechanisms of bone fragility. Marrow fat can be quantified on bone biopsy samples by histomorphometry and noninvasively by proton magnetic resonance spectroscopy ((1)H-MRS). In this study, we evaluate relationships between marrow fat assessed using both methods in the same subjects for the first time. METHODS: Sixteen premenopausal women, nine with idiopathic osteoporosis and seven normal controls, had marrow fat measured at the iliac crest by bone biopsy and at the lumbar spine (L3) and proximal femur by (1)H-MRS. RESULTS: At L3, fat fraction by (1)H-MRS correlated directly and significantly with marrow fat variables on iliac crest biopsies (r = 0.5-0.8). In contrast, there were no significant correlations between fat fraction at the femur and marrow fat on biopsies. Marrow fat quantity (%) was greater at the femur than at L3 and the iliac crest and correlated inversely with total hip and femoral neck BMD by DXA. CONCLUSIONS: In summary, measurement of marrow fat in transiliac crest biopsies correlates with marrow fat at the spine but not the proximal femur by (1)H-MRS. There were site-specific differences in marrow fat quantity and in the relationships between marrow fat and bone volume.
Assuntos
Adiposidade/fisiologia , Medula Óssea/patologia , Fêmur/patologia , Vértebras Lombares/patologia , Adipócitos/patologia , Tecido Adiposo/patologia , Adolescente , Adulto , Biópsia , Densidade Óssea/fisiologia , Exame de Medula Óssea/métodos , Estudos de Casos e Controles , Feminino , Humanos , Ílio/patologia , Pessoa de Meia-Idade , Pré-Menopausa/fisiologia , Espectroscopia de Prótons por Ressonância Magnética/métodos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
The utility of HR-CT to study longitudinal changes in bone microarchitecture is limited by subject radiation exposure. Although MR is not subject to this limitation, it is limited both by patient movement that occurs during prolonged scanning at distal sites, and by the signal-to-noise ratio that is achievable for high-resolution images in a reasonable scan time at proximal sites. Recently, a novel MR-based technique, fine structure analysis (FSA) (Chase et al. Localised one-dimensional magnetic resonance spatial frequency spectroscopy. PCT/US2012/068284 2012, James and Chase Magnetic field gradient structure characteristic assessment using one-dimensional (1D) spatial frequency distribution analysis. 7932720 B2, 2011) has been developed which provides both high-resolution and fast scan times, but which generates at a designated set of spatial positions (voxels) a one-dimensional signal of spatial frequencies. Appendix 1 provides a brief introduction to FSA. This article describes an initial exploration of FSA for the rapid, non-invasive characterization of trabecular microarchitecture in a preclinical setting. For L4 vertebrae of sham and ovariectomized (OVX) rats, we compared FSA-generated metrics with those from CT datasets and from CT-derived histomorphometry parameters, trabecular number (Tb.N), bone volume density (BV/TV), trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp). OVX caused a reduction of the higher frequency structures that correspond to a denser trabecular lattice, while increasing the preponderance of lower frequency structures, which correspond to a more open lattice. As one example measure, the centroid of the FSA spectrum (which we refer to as fSAcB) showed strong correlation in the same region with CT-derived histomorphometry values: Tb.Sp: r -0.63, p < 0.001; Tb.N: r 0.71, p < 0.001; BV/TV: r 0.64, p < 0.001, Tb.Th: r 0.44, p < 0.05. Furthermore, we found a 17.5% reduction in fSAcB in OVX rats (p < 0.0001). In a longitudinal study, FSA showed that the age-related increase in higher frequency structures was abolished in OVX rats, being replaced with a 78-194% increase in lower frequency structures (2.4-2.8 objects/mm range), indicating a more sparse trabecular lattice (p < 0.05). The MR-based fine structure analysis enables high-resolution, radiation-free, rapid quantification of bone structures in one dimension (the specific point and direction being chosen by the clinician) of the spine.
Assuntos
Osso e Ossos/patologia , Imageamento por Ressonância Magnética/métodos , Animais , Feminino , Processamento de Imagem Assistida por Computador , Ratos , Ratos Sprague-DawleyRESUMO
Bone mineralization density distribution (BMDD) is an important determinant of bone mechanical properties. The most available skeletal site for access to the BMDD is the iliac crest. Compared to cancellous bone much less information on BMDD is available for cortical bone. Hence, we analyzed complete transiliac crest bone biopsy samples from premenopausal women (n = 73) aged 25-48 years, clinically classified as healthy, by quantitative backscattered electron imaging for cortical (Ct.) and cancellous (Cn.) BMDD. The Ct.BMDD was characterized by the arithmetic mean of the BMDD of the cortical plates. We found correlations between Ct. and Cn. BMDD variables with correlation coefficients r between 0.42 and 0.73 (all p < 0.001). Additionally to this synchronous behavior of cortical and cancellous compartments, we found that the heterogeneity of mineralization densities (Ct.Ca(Width)), as well as the cortical porosity (Ct.Po) was larger for a lower average degree of mineralization (Ct.Ca(Mean)). Moreover, Ct.Po correlated negatively with the percentage of highly mineralized bone areas (Ct.Ca(High)) and positively with the percentage of lowly mineralized bone areas (Ct.Ca(Low)). In conclusion, the correlation of cortical with cancellous BMDD in the iliac crest of the study cohort suggests coordinated regulation of bone turnover between both bone compartments. Only in a few cases, there was a difference in the degree of mineralization of >1wt % between both cortices suggesting a possible modeling situation. This normative dataset of healthy premenopausal women will provide a reference standard by which disease- and treatment-specific effects can be assessed at the level of cortical bone BMDD.
Assuntos
Densidade Óssea , Osso e Ossos/patologia , Calcificação Fisiológica , Ílio/patologia , Adulto , Biópsia , Estudos de Coortes , Elétrons , Feminino , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Porosidade , Pré-Menopausa , Probabilidade , Espalhamento de RadiaçãoRESUMO
INTRODUCTION: In men, idiopathic osteoporosis (IOP) is often associated with low serum insulin-like growth factor (IGF-1) and reduced bone formation. The characteristics of premenopausal women with IOP are not well defined. We aimed to define the clinical, reproductive, and biochemical characteristics of premenopausal women with unexplained osteoporosis. METHODS: This is a cross-sectional study of 64 women with unexplained osteoporosis, 45 with fragility fractures, 19 with low bone mineral density (BMD; Z-score less than or equal to -2.0) and 40 normal controls. The following are the main outcome measures: clinical and anthropometric characteristics, reproductive history, BMD, gonadal and calciotropic hormones, IGF-1, and bone turnover markers (BTMs). RESULTS: Subjects had lower BMI and BMD than controls, but serum and urinary calcium, serum estradiol, vitamin D metabolites, IGF-1, and most BTMs were similar. Serum parathyroid hormone (PTH) and the resorption marker, tartrate-resistant acid phosphatase (TRAP5b), were significantly higher in both groups of subjects than controls and directly associated in all groups. Serum IGF-1 and all BTMs were directly associated in controls, but the association was not significant after controlling for age. There was no relationship between serum IGF-1 and BTMs in subjects. There were few differences between women with fractures and low BMD. CONCLUSIONS: Higher serum TRAP5b and PTH suggest that increased bone turnover, possibly related to subclinical secondary hyperparathyroidism could contribute to the pathogenesis of IOP. The absence of differences between women with fractures and those with very low BMD indicates that this distinction may not be clinically useful to categorize young women with osteoporosis.
Assuntos
Osteoporose/fisiopatologia , Fraturas por Osteoporose/fisiopatologia , Pré-Menopausa/fisiologia , Absorciometria de Fóton/métodos , Fosfatase Ácida/sangue , Adolescente , Adulto , Antropometria/métodos , Biomarcadores/sangue , Índice de Massa Corporal , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Estudos de Casos e Controles , Estudos Transversais , Dieta , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Isoenzimas/sangue , Pessoa de Meia-Idade , Osteoporose/sangue , Fraturas por Osteoporose/sangue , Hormônio Paratireóideo/sangue , Pré-Menopausa/sangue , História Reprodutiva , Fosfatase Ácida Resistente a Tartarato , Adulto JovemAssuntos
Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Osteoporose/tratamento farmacológico , Anabolizantes/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/ultraestrutura , Ensaios Clínicos como Assunto , Humanos , Osteoporose/patologia , Teriparatida/uso terapêutico , Tiofenos/uso terapêutico , Resultado do Tratamento , Ácido Zoledrônico/uso terapêuticoRESUMO
UNLABELLED: We compared microarchitecture and mechanical competence parameters measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite-element analysis of radius and tibia to those measured by histomorphometry, micro-CT, and finite-element analysis of transiliac bone biopsies. Correlations were weak to moderate between parameters measured on biopsies and scans. INTRODUCTION: HR-pQCT is a new imaging technique that assesses trabecular and cortical bone microarchitecture of the radius and tibia in vivo. The purpose of this study was to determine the extent to which microarchitectural variables measured by HR-pQCT reflect those measured by the "gold standard," transiliac bone biopsy. METHODS: HR-pQCT scans (Xtreme CT, Scanco Medical AG) and iliac crest bone biopsies were performed in 54 subjects (aged 39 +/- 10 years). Biopsies were analyzed by 2D quantitative histomorphometry and 3D microcomputed tomography (microCT). Apparent Young's modulus, an estimate of mechanical competence or strength, was determined by micro-finite-element analysis (microFE) of biopsy microCT and HR-pQCT images. RESULTS: The strongest correlations observed were between trabecular parameters (bone volume fraction, number, separation) measured by microCT of biopsies and HR-pQCT of the radius (R 0.365-0.522; P < 0.01). Cortical width of biopsies correlated with cortical thickness by HR-pQCT, but only at the tibia (R = 0.360, P < 0.01). Apparent Young's modulus calculated by microFE of biopsies correlated with that calculated for both radius (R = 0.442; P < 0.001) and tibia (R = 0.380; P < 0.001) HR-pQCT scans. CONCLUSIONS: The associations between peripheral (HR-pQCT) and axial (transiliac biopsy) measures of microarchitecture and estimated mechanical competence are significant but modest.
Assuntos
Osteoporose/diagnóstico por imagem , Rádio (Anatomia)/diagnóstico por imagem , Tíbia/diagnóstico por imagem , Adulto , Idoso , Biópsia , Densidade Óssea/fisiologia , Estudos de Casos e Controles , Módulo de Elasticidade , Feminino , Humanos , Hipoparatireoidismo/diagnóstico por imagem , Hipoparatireoidismo/patologia , Hipoparatireoidismo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoporose/patologia , Osteoporose/fisiopatologia , Rádio (Anatomia)/patologia , Rádio (Anatomia)/fisiopatologia , Reprodutibilidade dos Testes , Tíbia/patologia , Tíbia/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Microtomografia por Raio-X/métodos , Adulto JovemRESUMO
To evaluate the potential use of a combination of antiresorption and bone formation-promoting agents as a treatment for postmenopausal osteoporosis, we examined the effects of combined and separate administration of estrogen (17 beta-estradiol, 30 micrograms/kg per d, s.c.) and parathyroid hormone (rPTH [1-34], 40 micrograms/kg per d, s.c.) on the proximal tibia of ovariectomized (Ovx) rats. The treatments lasted for 4 wk and were initiated 1, 3, and 5 wk after surgery. Ovx resulted in rapid loss of cancellous bone volume (Cn-BV/TV) as well as trabecular connectivity, as determined by two dimensional strut analysis. When administered in a preventive mode, treatment beginning 1 wk post-Ovx, estrogen or PTH treatment alone preserved Cn-BV/TV and trabecular connectivity, and combined estrogen and PTH treatment caused a 40% increment in Cn-BV/TV while maintaining comparable trabecular connectivity with that seen in the Sham-operated animals. When administered in a curative mode to rats with established osteoporosis, treatments beginning 3 or 5 wk post-Ovx, estrogen or PTH treatment alone prevented further loss of connectivity and Cn-BV/TV, whereas the combined treatment resulted in as much as a 300% improvement in one of the parameters of trabecular connectivity, node to node strut length, and a 106% increase in Cn-BV/TV, with respect to the bone status at the initiation of treatment. The beneficial effects of this combined treatment derive from estrogen's ability to prevent accelerated bone resorption and, simultaneously, PTH's promotion of bone formation. These data demonstrate, in an animal model, that therapies can be devised to cure the skeletal defects associated with established osteoporosis.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Estradiol/uso terapêutico , Osteoporose/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Estradiol/sangue , Estudos de Avaliação como Assunto , Feminino , Ovariectomia , Ratos , Ratos Sprague-Dawley , Tíbia/citologia , Tíbia/efeitos dos fármacos , Urina/químicaRESUMO
Intermittent administration of PTH has been found to be an effective anabolic agent in cancellous bone. We have reported previously that combined treatment with PTH and estrogen in estrogen-deficient rats was beneficial in correcting established osteopenia. To determine if the beneficial effects of PTH therapy can be preserved by estrogen alone and whether PTH therapy can be effective in treating osteopenic subjects stabilized with estrogen, we have undertaken a "crossover" study in the rat model of estrogen-deficiency induced osteopenia. Six-month-old female rats were ovariectomized and after 5 wk treated for 8 wk with vehicle, 30 micrograms/kg per day of rPTH(1-34) plus 15 micrograms/kg per day of 17 beta-estradiol or 17 beta-estradiol alone. One group from each treatment regimen was then sacrificed and for an additional 8 weeks the remaining rats were (a) maintained on their previous treatment; (b) "crossed over" to their reciprocal treatment; or (c) administered vehicle only. At the end of this second 8-wk treatment period all rats were sacrificed. Bone mineral density of the distal femur, histomorphometric measurements of the proximal tibia and mechanical testing of the distal femur and selected vertebral bodies were performed. Our results demonstrated that (a) the gains in bone mass, trabecular connectivity and mechanical strength induced by PTH can be maintained by estrogen alone, but are reversed when both agents are withdrawn; and (b) rats with established osteopenia, maintained on estrogen treatment alone, can derive the full beneficial effects from the addition of PTH to the treatment at a later date. These data indicate that combined and/or sequential use of antiresorptive and anabolic agents may be a promising approach to the treatment of osteoporosis.
Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Estradiol/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , Animais , Osso e Ossos/fisiopatologia , Modelos Animais de Doenças , Quimioterapia Combinada , Estradiol/administração & dosagem , Feminino , Humanos , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/fisiopatologia , Ovariectomia , Hormônio Paratireóideo/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone microarchitecture resulting in bone fragility, which increases the risk of fracture. The clinical efficacy of bisphosphonates is evaluated through improvements in bone mineral density (BMD) and reductions in the risk for fracture. However, as bisphosphonates are administered long term, there is increasing interest in their effects on bone quality, which includes bone mass, strength and architecture. Ibandronate is a potent, nitrogen-containing bisphosphonate with significant antifracture efficacy when administered daily and in regimens with extended between-dose intervals. Clinical studies with ibandronate are supported by an extensive preclinical program that investigated the efficacy and bone safety of ibandronate in various animal models of osteoporosis. In preclinical studies, treatment with ibandronate maintained, or improved the quality, strength and architecture of bone. Intermittent and daily ibandronate regimens provided similar benefits. During ibandronate treatment, the bone retains its capacity for repair and bone mineralization is not adversely affected. Notably, positive relationships among BMD, bone strength and bone architecture have been demonstrated. This review describes the preclinical evidence for the preservation of bone quality with ibandronate, irrespective of the dosing regimen and even when administered at doses higher than those used therapeutically.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/efeitos adversos , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Osso e Ossos/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Calcificação Fisiológica/fisiologia , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Ácido Ibandrônico , RatosRESUMO
By conventional 2-dimensional, histomorphometric analysis, we and others have previously shown that cancellous bone architecture is preserved in mild primary hyperparathyroidism (PHPT). We have now extended these observations to a 3-dimensional analysis using microcomputed tomography (microCT). Iliac crest bone biopsies were analyzed from the following subjects with PHPT: 22 postmenopausal women; 7 premenopausal women; similar numbers of normal pre- and postmenopausal women served as controls. Fifteen men with PHPT were also studied. Postmenopausal women with PHPT demonstrated features of preserved cancellous bone as shown by smaller age-related declines in cancellous bone volume (BV/TV) and connectivity density (Conn.D) and no change in bone surface/total volume (BS/TV) as compared to normal women. In postmenopausal women with PHPT, cancellous bone volume (BV/TV), bone surface/total volume, and connectivity density (Conn.D) were all higher, and trabecular separation (Tb.Sp) was lower than in postmenopausal controls. In sharp contrast to the findings in normal women, no structural variables in PHPT women were correlated with age. Also of note, there was no difference in any 3-dimensional index between women and men with PHPT. We conclude that three-dimensional, cancellous bone microarchitecture is preserved in patients with mild primary hyperparathyroidism.
Assuntos
Osso e Ossos/patologia , Hiperparatireoidismo Primário/patologia , Adulto , Fatores Etários , Idoso , Densidade Óssea , Remodelação Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Feminino , Humanos , Hiperparatireoidismo Primário/diagnóstico por imagem , Hiperparatireoidismo Primário/metabolismo , Ílio/diagnóstico por imagem , Ílio/metabolismo , Ílio/patologia , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
Parathyroid hormone (PTH) stimulates bone resorption as well as bone formation in vivo and in organ culture. The catabolic actions of PTH have been recognized in patients with hyperparathyroidism, or with acute infusion of the N-terminal 1-34 fragment of human PTH (hPTH1-34). Whereas the anabolic actions of daily injection with PTH have been well studied in both humans and mice, the catabolic actions of PTH on murine bone remain to be defined. To do this we sought to create a model with short-term, sustained hyperparathyroidism using osmotic infusion pumps. We treated 10-week-old female C57BL/J6 mice with continuous infusion of hPTH1-34 (8.1 pmol/0.25 microl per h, equivalent to 40 microg/kg per day) or vehicle for 2 weeks, using Alzet osmotic pumps. Bone mineral density (BMD), serum total calcium, hPTH1-34, mouse intact PTH (mPTH1-84), osteocalcin and mouse tartrate-resistant acid phosphatase (mTRAP) activity, and microarchitectural variables of the distal femur were measured. Separately, we compared the effects of intermittent daily injection of hPTH1-34 (40 microg/kg per day) with continuous infusion of hPTH1-34 on BMD and bone markers. Exogenous hPTH1-34 was detected only in the PTH-infused mice. Both intermittent and continuous treatment with hPTH1-34 markedly suppressed endogenous mPTH1-84, but only the latter induced hypercalcemia. Daily PTH injection significantly increased both serum osteocalcin and mTRAP, while continuous PTH infusion showed a strong trend to stimulate mTRAP, with a slight but non-significant increase in osteocalcin. There were significant differences in BMD at all sites between animals treated with the same daily dose of intermittent and continuous hPTH1-34. Micro-computed tomography (muCT) analysis of the distal femurs revealed that hPTH1-34 infusion significantly decreased trabecular connectivity density (P<0.05). Thus, the murine bone response to continuous PTH infusion was quite different from that seen with daily PTH injection. Short-term infusion of hPTH1-34 appears to be a good model to study the mechanisms underlying the catabolic action of PTH in mice.
Assuntos
Osso e Ossos/patologia , Hipercalcemia/induzido quimicamente , Teriparatida/administração & dosagem , Fosfatase Ácida/sangue , Animais , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Fêmur/patologia , Fêmur/fisiopatologia , Humanos , Hipercalcemia/patologia , Hipercalcemia/fisiopatologia , Bombas de Infusão Implantáveis , Injeções , Isoenzimas/sangue , Vértebras Lombares/patologia , Vértebras Lombares/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Osteocalcina/sangue , Distribuição Aleatória , Fosfatase Ácida Resistente a Tartarato , Teriparatida/farmacologia , Tíbia/patologia , Tíbia/fisiopatologia , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Patients on hemodialysis are at high risk for cardiovascular disease (CVD). Aspirin is an established therapy for primary and secondary prevention of CVD that may be underutilized in hemodialysis patients. To better understand the use of aspirin in hemodialysis patients, we examined the experience of an urban hemodialysis center. Guidelines for use as well as associated risks and benefits are reviewed. METHODS: Medical records for patients receiving hemodialysis treatment at our center (New York City, USA) in May 2004 were reviewed for aspirin use, presence of CVD, and potential contraindications to aspirin therapy. CVD was defined as a history of coronary artery disease, ischemic stroke, transient ischemic attack, or peripheral vascular disease. Potential contraindications to aspirin therapy included history of clinically significant bleeding or increased risk of bleeding, aspirin allergy and routine treatment with other anticoagulants. RESULTS: 176 patients were eligible for the study and 172 (98%) were included. Although 74 patients had a history of CVD, only 38 (51 %) of these were treated with aspirin. Among patients with a history of CVD who were not treated with aspirin, 19 (53%) had no identifiable contraindications to aspirin therapy for secondary prevention of CVD. Ninetyeight patients had no history of CVD, and 18 (18%) of these were treated with aspirin. Of patients without a history of CVD who were not treated with aspirin, 57 (71%) had no identifiable contraindications to aspirin therapy for primary prevention of CVD. CONCLUSIONS: Aspirin is underutilized in hemodialysis patients for the primary and secondary prevention of CVD. Given the high risk of CVD in hemodialysis patients, therapy with aspirin may be of significant benefit and prospective studies of aspirin therapy are needed.
Assuntos
Aspirina/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Inibidores de Ciclo-Oxigenase/administração & dosagem , Diálise Renal , Doenças Cardiovasculares/etiologia , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversosRESUMO
Chronic obstructive pulmonary disease (COPD) is associated with low aBMD as measured by DXA and altered microstructure as assessed by bone histomorphometry and microcomputed tomography. Knowledge of bone matrix mineralization is lacking in COPD. Using quantitative backscatter electron imaging (qBEI), we assessed cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) in 19 postmenopausal women (62.1 ± 7.3 years of age) with COPD. Eight had sustained fragility fractures, and 13 had received treatment with inhaled glucocorticoids. The BMDD outcomes from the patients were compared with healthy reference data and were correlated with previous clinical and histomorphometric findings. In general, the BMDD outcomes for the patients were not significantly different from the reference data. Neither the subgroups of with or without fragility fractures or of who did or did not receive inhaled glucocorticoid treatment, showed differences in BMDD. However, subgroup comparison according to severity revealed 10% decreased cancellous mineralization heterogeneity (Cn.CaWidth) for the most severely affected compared with less affected patients (p=0.042) and compared with healthy premenopausal controls (p=0.021). BMDD parameters were highly correlated with histomorphometric cancellous bone volume (BV/TV) and formation indices: mean degree of mineralization (Cn.CaMean) versus BV/TV (r=0.58, p=0.009), and Cn.CaMean and Ct.CaMean versus bone formation rate (BFR/BS) (r=-0.71, p<0.001). In particular, those with lower BV/TV (<50th percentile) had significantly lower Cn.CaMean (p=0.037) and higher Cn.CaLow (p=0.020) compared with those with higher (>50th percentile) BV/TV. The normality in most of the BMDD parameters and bone formation rates as well as the significant correlations between them suggests unaffected mineralization processes in COPD. Our findings also indicate no significant negative effect of treatment with inhaled glucocorticoids on the bone mineralization pattern. However, the observed concomitant occurrence of relatively lower bone volumes with lower bone matrix mineralization will both contribute to the reduced aBMD in some patients with COPD.
Assuntos
Densidade Óssea/fisiologia , Osso e Ossos/fisiopatologia , Calcificação Fisiológica/fisiologia , Doença Pulmonar Obstrutiva Crônica/complicações , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Ósseas Metabólicas/epidemiologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Feminino , Fraturas Ósseas/epidemiologia , Humanos , Pessoa de Meia-Idade , Osteoporose/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Microtomografia por Raio-XRESUMO
It is well established that zinc, an essential trace element, plays an important role in growth and stimulates bone formation. However, the effects of zinc on bone resorption have received little attention. We studied its effects on isolated rat osteoclasts. Unexpectedly, osteoclasts were exquisitely sensitive to zinc, with a significant decrease in bone resorption occurring at concentrations as low as 10(-14) M. This effect was specific for zinc and was not observed with the other transitional or alkaline metals studied. There was no evidence of toxicity at concentrations up to 10(-4) M. Zinc also completely abolished the stimulatory effect of parathyroid hormone. Zinc is therefore a highly potent and selective inhibitor of osteoclastic bone resorption in vitro. The mode of action remains to be established and may represent a novel inhibitory mechanism in the osteoclast.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Zinco/uso terapêutico , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Interações Medicamentosas , Osteoclastos/citologia , Hormônio Paratireóideo/farmacologia , Ratos , Zinco/farmacologiaRESUMO
We have examined the relationships among calcium intake, mechanical stress (activity) and axial (lumbar) and peripheral (midradius) bone mass in a population of 60 young normal, healthy eumenorrheic women (age 25-34 years), selected on the basis of weight for height (within 20% of expected). In this population, vertebral bone mineral density was significantly related (r = 0.41, p less than 0.005) to activity pattern but not to calcium intake. Elimination of the effects of activity, however, disclosed a significant correlation between total calcium intake and vertebral bone mass (r = 0.36, p less than 0.02). Closer examination of this relationship suggested that vertebral bone mineral density did not appear to increase with calcium intakes above 800-1000 mg/day, implying a threshold effect and vertebral density was better expressed as a function of the logarithm of calcium intake (r = p less than 0.01). Radial mineral content was not related to activity (which was mostly walking and running), but it was significantly affected by calcium intake. These data suggest that skeletal status in the vertebrae in young women may be influenced by modulation of mechanical stress. However, bone mineral density is probably also dependent on nutritional status such that the optimum calcium intake for this effect is 800-1000 mg/day. If such effects, observed here cross-sectionally, can be substantiated in longitudinal studies and persist into the aging postmenopausal population, then the average age of onset of osteoporotic fractures would be expected to be delayed approximately 10 years, by relatively simple modifications of diet and activity.
Assuntos
Osso e Ossos/anatomia & histologia , Cálcio da Dieta , Metabolismo Energético , Fenômenos Fisiológicos da Nutrição , Esforço Físico , Adulto , Feminino , Humanos , Valores de Referência , Medula Espinal/anatomia & histologiaRESUMO
The effect of heparin on osteoclastic bone resorption was studied in vitro using the disaggregated osteoclast resorption assay. Bone resorption was assessed by counting the resorption lacunae on bone slices by light microscopy. Low concentrations of heparin (5 micrograms/ml) increased bone resorption by isolated chick and rat osteoclasts. Among other glycosaminoglycans tested at 5 micrograms/ml, only dextran sulfate showed a small but significant stimulation of resorption. Chondroitin sulfates A, B, and C were without effect at 25 and 100 micrograms/ml, whereas resorption was increased by 100 micrograms/ml of heparan sulfate. With chick osteoclasts, which could be maintained in serum-free conditions, a stimulatory effect of heparin was found both in the presence of 5% fetal calf serum and in serum-free media containing insulin, transferrin, and selenium. The magnitude of the heparin-induced increase in resorption was similar in the presence or absence of serum. The stimulation of resorption was associated with an increase in the number of osteoclasts on bone slices. Pretreatment of the bone slices with heparin also enhanced resorption. In time course experiments, 5 micrograms/ml of heparin caused a doubling of chick osteoclast activity index (number of resorption pits per number of osteoclasts) at 12 and 24 h. In 24 h cultures, treatment with 10 micrograms/ml of the arginine-rich basic protein, protamine, 1 microgram/ml of the immunosuppressant, cyclosporine A, or 5 micrograms/ml of the cysteine-proteinase inhibitor, leupeptin, negated the heparin effect on bone resorption. Leupeptin also inhibited basal resorption.(ABSTRACT TRUNCATED AT 250 WORDS)