RESUMO
UNLABELLED: We report the results of alendronate ingestion plus exercise in preventing the declines in bone mass and strength and elevated levels of urinary calcium and bone resorption in astronauts during 5.5 months of spaceflight. INTRODUCTION: This investigation was an international collaboration between NASA and the JAXA space agencies to investigate the potential value of antiresorptive agents to mitigate the well-established bone changes associated with long-duration spaceflight. METHODS: We report the results from seven International Space Station (ISS) astronauts who spent a mean of 5.5 months on the ISS and who took an oral dose of 70 mg of alendronate weekly starting 3 weeks before flight and continuing throughout the mission. All crewmembers had available for exercise a treadmill, cycle ergometer, and a resistance exercise device. Our assessment included densitometry of multiple bone regions using X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and assays of biomarkers of bone metabolism. RESULTS: In addition to pre- and post-flight measurements, we compared our results to 18 astronauts who flew ISS missions and who exercised using an early model resistance exercise device, called the interim resistance exercise device, and to 11 ISS astronauts who exercised using the newer advanced resistance exercise device (ARED). Our findings indicate that the ARED provided significant attenuation of bone loss compared with the older device although post-flight decreases in the femur neck and hip remained. The combination of the ARED and bisphosphonate attenuated the expected decline in essentially all indices of altered bone physiology during spaceflight including: DXA-determined losses in bone mineral density of the spine, hip, and pelvis, QCT-determined compartmental losses in trabecular and cortical bone mass in the hip, calculated measures of fall and stance computed bone strength of the hip, elevated levels of bone resorption markers, and urinary excretion of calcium. CONCLUSIONS: The combination of exercise plus an antiresoptive drug may be useful for protecting bone health during long-duration spaceflight.
Assuntos
Alendronato/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Terapia por Exercício/métodos , Osteoporose/prevenção & controle , Voo Espacial , Absorciometria de Fóton/métodos , Adulto , Alendronato/administração & dosagem , Biomarcadores/sangue , Biomarcadores/urina , Composição Corporal/fisiologia , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/administração & dosagem , Reabsorção Óssea/etiologia , Reabsorção Óssea/prevenção & controle , Terapia Combinada , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/fisiopatologia , Ausência de Peso/efeitos adversosRESUMO
Quantitative computed tomography (QCT) based finite element (FE) models can compute subject-specific proximal femoral strengths, or fracture loads, that are associated with hip fracture risk. These fracture loads are more strongly associated with measured fracture loads than are DXA and QCT measures and are predictive of hip fracture independently of DXA bone mineral density (BMD). However, interpreting FE-computed fracture loads of younger subjects for the purpose of evaluating hip fracture risk in old age is challenging due to limited reference data. The goal of this study was to address this issue by providing reference data for male and female adult subjects of all ages. QCT-based FE models of the left proximal femur of 216 women and 181 men, age 27 to 90 years, from a cohort of Rochester, MN residents were used to compute proximal femoral load capacities, i.e. the maximum loads that can be supported, in single-limb stance and posterolateral fall loading (Stance_LC and Fall_LC, respectively) [US Patent No. 9,245,069] and yield load under fall loading (Fall_yield). To relate these measures to information about hip fracture, the CT scanner and calibration phantom were cross-calibrated with those from our previous prospective study of hip fracture in older fracture and control subjects, the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. We then plotted Stance_LC, Fall_LC and Fall_yield versus age for the two cohorts on the same graphs. Thus, proximal femoral strengths in individuals above 70 years of age can be assessed through direct comparison with the FE data from the AGES cohort which were analyzed using identical methods. To evaluate younger individuals, reductions in Stance_LC, Fall_LC and Fall_yield from the time of evaluation to age 70 years can be cautiously estimated from the average yearly cross-sectional decreases found in this study (108 N, 19.4 N and 14.4 N, respectively, in men and 120 N, 19.4 N and 21.6 N, respectively, in women), and the projected fracture loads can be compared with data from the AGES cohort. Although we did not set specific thresholds for identifying individuals at risk of hip fracture, these data provide some guidance and may be used to help establish diagnostic criteria in future. Additionally, given that these data were nearly entirely from Caucasian subjects, future research involving subjects of other races/ethnicities is necessary.
Assuntos
Fraturas do Quadril , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Estudos Transversais , Feminino , Fêmur/diagnóstico por imagem , Análise de Elementos Finitos , Fraturas do Quadril/diagnóstico por imagem , Fraturas do Quadril/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Bone loss in astronauts during spaceflight may be a risk factor for osteoporosis, fractures and renal stone formation. We previously reported that the bisphosphonate alendronate, combined with exercise that included an Advanced Resistive Exercise Device (ARED), can prevent or attenuate group mean declines in areal bone mineral density (aBMD) measured soon after ~ 6-month spaceflights aboard the International Space Station (ISS). It is unclear however if the beneficial effects on postflight aBMD were due to individual or combined effects of alendronate and ARED. Hence, 10 additional ISS astronauts were recruited who used the ARED (ARED group) without drug administration using similar measurements in the previous study, i.e., densitometry, biochemical assays and analysis of finite element (FE) models. In addition densitometry data (DXA and QCT only) were compared to published data from crewmembers (nâ¯=â¯14-18) flown prior to in-flight access to the ARED (Pre-ARED). Group mean changes from preflight (± SD %) were used to evaluate effects of countermeasures as sequentially modified on the ISS (i.e., Pre-ARED vs. ARED; ARED vs. Bis+ARED). Spaceflight durations were not significantly different between groups. Postflight bone density measurements were significantly reduced from preflight in the Pre-ARED group. As previously reported, combined Bis+ARED prevented declines in all DXA and QCT hip densitometry and in estimates of FE hip strengths; increased the aBMD of lumbar spine; and prevented elevations in urinary markers for bone resorption during spaceflight. ARED without alendronate partially attenuated declines in bone mass but did not suppress biomarkers for bone resorption or prevent trabecular bone loss. Resistive exercise in the ARED group did not prevent declines in hip trabecular vBMD, but prevented reductions in cortical vBMD of the femoral neck, in FE estimate of hip strength for non-linear stance (NLS) and in aBMD of the femoral neck. We conclude that a bisphosphonate, when combined with resistive exercise, enhances the preservation of bone mass because of the added suppression of bone resorption in trabecular bone compartment not evident with ARED alone.
Assuntos
Densidade Óssea/fisiologia , Terapia por Exercício/métodos , Voo Espacial , Absorciometria de Fóton , Adulto , Alendronato/uso terapêutico , Astronautas , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/prevenção & controle , Doenças Ósseas Metabólicas/terapia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Osteoporose/terapia , Ausência de Peso/efeitos adversosRESUMO
The loss of bone mineral in NASA astronauts during spaceflight has been investigated throughout the more than 40 years of space travel. Consequently, it is a medical requirement at NASA Johnson Space Center (JSC) that changes in bone mass be monitored in crew members by measuring bone mineral density (BMD), with dual-energy X-ray absorptiometry (DXA) before and after flight, of astronauts who serve on long-duration missions (4-6 months). We evaluated this repository of medical data to track whether there is recovery of bone mineral that was lost during spaceflight. Our analysis was supplemented by BMD data from cosmonauts (by convention, a space traveler formally employed by the Russia Aviation and Space Agency or by the previous Soviet Union) who had also flown on long-duration missions. Data from a total of 45 individual crew members - a small number of whom flew on more than one mission - were used in this analysis. Changes in BMD (between 56 different sets of pre- and postflight measurements) were plotted as a function of time (days after landing). Plotted BMD changes were fitted to an exponential mathematical function that estimated: (i) BMD change on landing day (day 0) and (ii) the number of days after landing when 50% of the lost bone would be recovered ("50% recovery time") in the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. In sum, averaged losses of bone mineral after long-duration spaceflight ranged between 2% and 9% across all sites with our recovery model predicting a 50% restoration of bone loss for all sites to be within 9 months.
Assuntos
Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Voo Espacial , Adulto , Feminino , Humanos , Masculino , Fatores de TempoRESUMO
The potential for loss of bone mineral mass due to space flight was recognized by space scientists even before man's first venture into micro-gravity. Early life science studies in both the U.S. and Russian space programs attempted to measure the effects of reduced gravity on skeletal homeostasis, and these measurements have become more sophisticated with time. Bone-related measurements have typically included: bone mineral density measured by X-ray absorptiometry and more recently CT scanning; bonerelated hormones and other biochemical markers of bone turnover; and calcium excretion and balance. These measurements, conducted over the last 4 decades, have shed light on the nature of disuse bone loss and have provided preliminary information regarding bone recovery. Ground-based analog (bed rest) studies have provided information complementary to the space flight data and have allowed the testing of various countermeasures to bone loss. In spite of the wealth of knowledge obtained thus far, many questions remain regarding bone loss, bone recovery, and the factors affecting these skeletal processes. This paper will summarize the skeletal data obtained to date by the U.S. and Russian space programs and in ground-based disuse studies. In addition, related body composition data will be briefly discussed, as will possible countermeasures to space flight-induced bone loss.
Assuntos
Repouso em Cama/efeitos adversos , Osso e Ossos/fisiologia , Voo Espacial , Ausência de Peso/efeitos adversos , Animais , Composição Corporal/fisiologia , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Difosfonatos/uso terapêutico , Humanos , Modelos Biológicos , Contramedidas de Ausência de PesoRESUMO
The objective of the study was to assess the time course of changes in bone mineralization and architecture using sequential triple biopsies from women with postmenopausal osteoporosis (PMO) who received long-term treatment with risedronate. Transiliac biopsies were obtained from the same subjects (n = 7) at baseline and after 3 and 5 years of treatment with 5 mg daily risedronate. Mineralization was measured using 3-dimensional (3D) micro-computed tomography (CT) with synchrotron radiation and was compared to levels in healthy premenopausal women (n = 12). Compared to the untreated PMO women at baseline, the premenopausal women had higher average mineralization (Avg-MIN) and peak mineralization (Peak-MIN) by 5.8% (P = 0.003) and 8.0% (P = 0.003), respectively, and lower ratio of low to high-mineralized bone volume (BMR-V) and surface area (BMR-S) by 73.3% (P = 0.005) and 61.7% (P = 0.003), respectively. Relative to baseline, 3 years of risedronate treatment significantly increased Avg-MIN (4.9 +/- 1.1%, P = 0.016) and Peak-MIN (6.2 +/- 1.5%, P = 0.016), and significantly decreased BMR-V (-68.4 +/- 7.3%, P = 0.016) and BMR-S (-50.2 +/- 5.7%, P = 0.016) in the PMO women. The changes were maintained at the same level when treatment was continued up to 5 years. These results are consistent with the significant reduction of turnover observed after 3 years of treatment and which was similarly maintained through 5 years of treatment. Risedronate restored the degree of mineralization and the ratios of low- to high-mineralized bone to premenopausal levels after 3 years of treatment, suggesting that treatment reduced bone turnover in PMO women to healthy premenopausal levels. Conventional micro-CT analysis further demonstrated that bone volume (BV/TV) and trabecular architecture did not change from baseline up to 5 years of treatment, suggesting that risedronate provided long-term preservation of trabecular architecture in the PMO women. Overall, risedronate provided sustained benefits on mineralization and architecture, two key determinants of bone strength, over 5 years lending support for its long-term efficacy in fracture risk reduction.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Ácido Etidrônico/análogos & derivados , Tomografia Computadorizada por Raios X , Adulto , Idoso , Biópsia , Estudos de Coortes , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/tratamento farmacológico , Pré-Menopausa , Ácido Risedrônico , Fatores de Tempo , Resultado do TratamentoRESUMO
Studies were performed to determine if the nonsteroidal anti-inflammatory drug ibuprofen alters bone and mineral metabolism in female rats. In experiment 1, four groups of growing rats underwent either sham operation or ovariectomy (OVX). One week later, controlled-release pellets with ibuprofen or placebo were implanted subcutaneously at the back of the neck. Following 3 weeks of treatment, rats were sacrificed and blood and bone samples were removed for serum assays and histomorphometric analysis. Body growth rate and the static cortical bone measurements made at the tibial diaphysis did not change in response to OVX. OVX, however, did increase radial bone growth, lowered serum 17beta-estradiol, reduced uterine weight, and decreased the cancellous bone area of the tibial metaphysis in the rats. Ibuprofen did not alter serum 17beta-estradiol or uterine weight but reduced radial bone growth as well as cancellous bone area of the tibial metaphysis in both sham-operated and OVX animals. In experiments 2 and 3, we tested the influence of ibuprofen on the effects of the tissue-selective estrogen agonist tamoxifen and of exogenous 17beta-estradiol in the OVX rat. Ibuprofen completely blocked the effects of tamoxifen and partially blocked the effects of 17beta-estradiol to prevent cancellous osteopenia. In contrast, ibuprofen did not influence the effects of tamoxifen and 17beta-estradiol to reduce radial bone growth. Besides the skeletal effects, ibuprofen suppressed estrogen-induced uterine growth. Our data suggest that ibuprofen blocks selective estrogen receptor-mediated activities in the rat.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Osso e Ossos/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Ibuprofeno/farmacologia , Tamoxifeno/antagonistas & inibidores , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Doenças Ósseas Metabólicas/prevenção & controle , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Osso e Ossos/metabolismo , Estradiol/farmacologia , Feminino , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/antagonistas & inibidores , Tamoxifeno/farmacologia , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimentoRESUMO
Chronic alcohol abuse is a major risk factor for osteoporosis but the effects of moderate drinking on bone metabolism are largely uninvestigated. Here, we studied the long-term dose-response (0, 3, 6, 13, and 35% caloric intake) effects of alcohol on cancellous bone in the proximal tibia of 8-month-old female rats. After 4 months of treatment, all alcohol-consuming groups of rats had decreased bone turnover. The inhibitory effects of alcohol on bone formation were dose dependent. A reduction in osteoclast number occurred at the lowest level of consumption but there were no further reductions with higher levels of consumption. An imbalance between bone formation and bone resorption at higher levels of consumption of alcohol resulted in trabecular thinning. Our observations in rats raise the concern that moderate consumption of alcoholic beverages in humans may reduce bone turnover and potentially have detrimental effects on the skeleton.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Regeneração Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Etanol/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Análise de Regressão , Útero/anatomia & histologia , Útero/efeitos dos fármacosRESUMO
Cell culture studies suggest that the aluminum silicate polymer sodium Zeolite A (SZA) increases bone cell proliferation and extracellular matrix production. This study in rats investigated the short-term (2 weeks) and long-term (18 weeks) in vivo effects of SZA on growth rate (weight gain) and tibia histomorphometry. In separate short-term experiments, female (experiment 1) or male (experiment 2) Sprague-Dawley rats grown and maintained on normal calcium diets were gavaged daily during a 2 week treatment period with 30 mg/kg, 100 mg/kg, or 500 mg of SZA/kg of rat body weight. In the long-term study (experiment 3) ovariectomized (OVX) rats were fed a low calcium diet containing 0, 1.80, and 9.00 g of SZA/kg of diet (0, 125, and 617 mg/kg of body weight, respectively). Short- and long-term treatment of growing rats with SZA resulted in a dose-dependent increase in bone aluminum. In the first experiment, growing intact female rats showed no significant SZA dose-dependent response in growth rate (weight gain) or histomorphometry of cortical bone in the tibial diaphysis or cancellous bone in the secondary spongiosa of the tibial metaphysis. In the second experiment, growing male rats, with right hind limbs immobilized by unilateral sciatic neurotomy, showed no SZA dose-dependent response in growth rate. The longitudinal growth of cancellous bone in the tibia of the denervated limb and the intact contralateral limb were not influenced by sciatic neurectomy and/or by treatment with SZA. Histomorphometry demonstrated that cortical bone mass and formation was reduced in the sciatic-sectioned limb when compared with the contralateral intact limb of vehicle-treated rats, as evidenced by significant reductions in static measurements of cortical bone area (-8.5%) and cross-sectional area (-4.8%) and in calculations of the periosteal formation rate (-33.8%) and mineral apposition rate (-31.6%), and the endocortical formation rate (-35.5%) and mineral apposition rate (-37.9%). The cancellous bone mass of denervated limbs of vehicle-treated rats was also deficient, as evidenced by decreased cancellous bone area (-39.1%) and perimeter (-31.9%). The bone mineral apposition rate was decreased (-26.7%) indicating reduced osteoblast activity. Treatment with SZA did not influence these indices in the tibiae of either sciatic-sectioned limbs or contralateral intact limbs. In the long-term experiment, OVX resulted in a dramatic 88% decrease in cancellous bone volume which was prevented by treatment with 17 beta-estradiol and not influenced by treatment with Zeolite A. The increases in osteoblast and osteoclast number following OVX were not influenced by SZA. The results indicate that SZA treatment has no anabolic effect on cortical and cancellous bone formation and mass in normal growing female rats and that this compound does not protect against osteopenia due to reduced load bearing in the growing male rat or gonadal hormone deficiency in adult female rats.
Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Tíbia/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacos , Zeolitas/farmacologia , Animais , Doenças Ósseas Metabólicas/prevenção & controle , Cálcio da Dieta/farmacologia , Denervação , Relação Dose-Resposta a Droga , Feminino , Membro Posterior/inervação , Masculino , Ovariectomia , Ovário/fisiologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/fisiologia , Tíbia/anatomia & histologia , Tíbia/crescimento & desenvolvimentoRESUMO
We examined the specificity of the steroidal antiestrogen ICI 182,780 (ICI) on bone and reproductive tissues in adult and growing female rats. Using a 1.5-mg/kg dose (s.c.), we evaluated the effects of ICI on the bone, body weight, uterine weight, serum cholesterol, and serum estradiol in either adult and/or growing rats. ICI increased serum estradiol cholesterol in ovary-intact rats, had no effect on uterine weight in ovariectomized rats, and resulted in uterine atrophy in ovary-intact animals comparable with ovariectomy. In contrast, ICI had no effect on body weight. In bone, ICI significantly increased the rate of periosteal bone formation in long bones of growing and mature female rats. In contrast, ICI had no effect on longitudinal bone growth in rapidly growing rats. When ICI was administered to mature rats with or without ovaries, two-factor ANOVA revealed significant interaction (P < or = 0.05) between ovariectomy and ICI treatment for cancellous bone area and labeled bone perimeter. ICI increased skeletal indices of bone turnover in the cancellous bone of ovary-intact rats but reduced these indices of bone turnover in the cancellous bone of ovariectomized rats. The increase in bone turnover was associated with a reduction in cancellous bone area in the ovary-intact rats. A reduction in bone turnover was similarly associated with an increase in bone area in the ICI-treated ovariectomized rats. In summary, ICI exhibited complete estrogen antagonism in cortical and cancellous bone, partial agonism in cancellous bone, and no activity on tibial longitudinal growth rate of growing ovary-intact rats. The effects in adult rats were influenced by circulating levels of estradiol. ICI had no activity on body weight and complete antagonism on uterine weight. These results demonstrate that a ligand with high binding affinity to the estrogen receptor(s) can elicit an array of estrogen-mediated regulation of bone metabolism.
Assuntos
Estradiol/análogos & derivados , Antagonistas de Estrogênios/farmacologia , Receptores de Estrogênio/metabolismo , Tíbia/efeitos dos fármacos , Animais , Ligação Competitiva , Colesterol/sangue , Estradiol/sangue , Estradiol/farmacologia , Feminino , Fulvestranto , Ligantes , Tamanho do Órgão/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Sprague-Dawley , Útero/anatomia & histologia , Útero/efeitos dos fármacosRESUMO
Trans-3,4,5-trihydroxystilbene (resveratrol), a polyphenolic compound found in juice and wine from dark-skinned grape cultivars, was recently shown to bind to estrogen receptors in vitro, where it activated transcription of estrogen-responsive reporter genes. The purpose of this 6-day study in weanling rats was to determine the dose response (1, 4, 10, 40, and 100 microg/day) effects of orally administered resveratrol on estrogen target tissues. The solvent (10% ethanol) had no significant effect on any measurement or derived value. 17Beta-estradiol treatment (100 microg/day) decreased the growth rate, final body weight, serum cholesterol, and radial bone growth (periosteal bone formation and mineral apposition rates) at the tibia-fibula synostosis. In the uterus, 17beta-estradiol treatment increased wet weight, epithelial cell height, and steady state messenger RNA levels for insulin-like growth factor I. In contrast, resveratrol treatment had no significant effect on body weight, serum cholesterol, radial bone growth, epithelial cell height, or messenger RNA levels for insulin-like growth factor I. Resveratrol treatment resulted in slight increases in uterine wet weight, but significance was achieved at the 10-microg dose only. A second experiment was performed to determine whether a high dose of resveratrol (1000 microg/day) antagonizes the ability of estrogen to lower serum cholesterol. As was shown for the lower doses, resveratrol had no effect on body weight, uterine wet weight, uterine epithelial cell height, cortical bone histomorphometry, or serum cholesterol. 17Beta-estradiol significantly lowered serum cholesterol, and this response was antagonized by cotreatment with resveratrol. These in vivo results suggest, in contrast to prior in vitro studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist.
Assuntos
Estrogênios/agonistas , Crescimento/efeitos dos fármacos , Estilbenos/farmacologia , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Relação Dose-Resposta a Droga , Estradiol/farmacologia , Feminino , Crescimento/fisiologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Resveratrol , Estilbenos/administração & dosagem , Útero/efeitos dos fármacos , DesmameRESUMO
In three experiments, we evaluated the pharmacological effects of 2-methoxyestradiol (2ME(2)) on several estrogen target tissues. Experiment 1: we gavaged recently ovariectomized (OVX) 9.5-wk-old rats with 2ME(2) at doses of 0, 0.1, 1, 4, 20, and 75 mg/kg in a 21-d dose-response study. 2ME(2) reduced body weight and serum cholesterol, increased uterine weight and epithelial cell height, and inhibited longitudinal and radial bone growth compared with values in the untreated OVX rat. All doses of 2ME(2) maintained cancellous bone mass at the baseline level, the lowest effective dose being 20-fold less than a uterotrophic dose. Experiment 2: in an 8-wk experiment in adult OVX rats, a nonuterotrophic dose of 2ME(2) (4 mg/kg x d) suppressed body weight gain, inhibited bone formation in cancellous bone and partially prevented bone loss in the tibial metaphysis. Experiment 3: in weanling rats, ICI 182,780 did not antagonize the effect of 2ME(2). We conclude that 2ME(2) antagonizes the skeletal changes that follow OVX at doses that have minimal or no effects in the uterus in both young and adult rats; 2ME(2) does not appear to act via estrogen receptors and is active on bone at doses well below those required for tumor suppression in mice. 2ME(2), through a novel pathway, may be a useful alternative to conventional hormone replacement therapy for prevention of postmenopausal bone loss.
Assuntos
Osso e Ossos/efeitos dos fármacos , Estradiol/administração & dosagem , Estrogênios/farmacologia , Ovariectomia , Útero/efeitos dos fármacos , 2-Metoxiestradiol , Envelhecimento , Animais , Peso Corporal/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Colesterol/sangue , Relação Dose-Resposta a Droga , Estradiol/análogos & derivados , Etinilestradiol/farmacologia , Feminino , Osteoporose/prevenção & controle , Ratos , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/fisiologia , DesmameRESUMO
Indirect measurements have suggested that spaceflight impairs bone elongation in rats. To test this possibility, our laboratory measured, by the fluorochrome labeling technique, bone elongation that occurred during a spaceflight experiment. The longitudinal growth rate (LGR) in the tibia of rats in spaceflight experiments (Physiological Space Experiments 1, 3, and 4 and Physiological-Anatomical Rodent Experiment 3) and in two models of skeletal unloading (hind-limb elevation and unilateral sciatic neurotomy) were calculated. The effects of an 11 day spaceflight on gene expression of cartilage matrix proteins in rat growth plates were also determined by northern analysis and are reported for the first time in this study. Measurements of longitudinal growth indicate that skeletal unloading generally did not affect LGR, regardless of age, strain, gender, duration of unloading, or method of unloading. There was, however, one exception with 34% suppression in LGR detected in slow-growing, ovariectomized rats skeletally unloaded for 8 days by hind-limb elevation. This detection of reduced LGR by hind-limb elevation is consistent with changes in steady-state mRNA levels for type II collagen (-33%) and for aggrecan (-53%) that were detected in rats unloaded by an 11 day spaceflight. The changes detected in gene expression raise concern that spaceflight may result in changes in the composition of extracellular matrix, which could have a negative impact on conversion of growth-plate cartilage into normal cancellous bone by endochondral ossification.
Assuntos
Desenvolvimento Ósseo , Voo Espacial , Ausência de Peso , Animais , Northern Blotting , Colágeno/genética , Feminino , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-DawleyRESUMO
2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17beta-estradiol, has been implicated as a physiological inhibitor of tumor cell proliferation. In this study, the effects of 2-ME on cultured osteosarcomatous cells were investigated. Dose-dependent growth inhibition was observed in MG63 and TE85 human osteosarcoma cells exposed to 2-ME. The cell killing by 2-ME was ligand-specific; the immediate precursor (2-hydroxyestradiol), the parent compound (17beta-estradiol), and the equivalent metabolite of estrone (2-methoxyestrone) exhibited less potency and efficacy. Furthermore, 2-ME was similarly effective at killing immortalized human fetal osteoblastic cells (hFOB) with and without estrogen receptor-alpha and -beta and rat osteosarcoma cells (ROS17/2.8). The cytotoxicity of 2-ME was selective to transformed and immortalized osteoblastic cells; 2-ME (2 microm) had no effect on the proliferation of primary cultures of human osteoblasts. Co-treatment with the potent estrogen receptor ligand, ICI-182,780, did not reduce 2-ME-induced osteosarcoma cell death, implying that this action is not mediated by conventional estrogen receptors. The expression levels of bone matrix protein genes, type 1 collagen and osteonectin, were transiently reduced after 2-ME treatment, suggesting that the surviving cells are capable of producing bone matrix. The 2-ME-mediated killing of osteosarcoma cells was due to the induction of apoptosis; treatment induced expression of interferon genes within 12 h and histological evidence of apoptosis within 48 h of 2-ME treatment. Thus, our results demonstrate that 2-ME is highly cytotoxic to osteosarcoma cells but not normal osteoblasts. These findings suggest that further study of 2-ME as a potential intervention for treatment of osteosarcoma is warranted.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas , Estradiol/análogos & derivados , Estradiol/farmacologia , Interferons/genética , Osteossarcoma , 2-Metoxiestradiol , Animais , Matriz Óssea/citologia , Matriz Óssea/efeitos dos fármacos , Matriz Óssea/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/genética , Antagonistas de Estrogênios/farmacologia , Estrogênios/farmacocinética , Fulvestranto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Substâncias de Crescimento/genética , Humanos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Ratos , Células Tumorais CultivadasRESUMO
There may be variability in the susceptibility of different individuals to osteolysis from wear debris, and it is not clear whether some individuals may have a genetic predisposition for a more marked osteolytic response. The purpose of this study in mice was to determine whether genetically determined obesity can alter the response to particulate debris. Polyethylene particles were implanted onto the calvaria of seven wild-type mice and seven obese mice (ob/ob). Calvaria from unimplanted wild-type and obese mice served as controls. Calvaria were harvested after 7 days, stained with toluidine blue and for tartrate-specific alkaline phosphatase, and analyzed by histomorphometry. The osteoclast number per mm total bone perimeter was 8.000+/-3.464 in wild-type animals with particles and 2.857+/-1.676 in ob/ob animals with particles (p=0.002; Fisher's PLSD). Bone resorption was 1.895+/-0.713 mm/mm(2) in wild-type animals with particles and 1.265+/-0.494 mm/mm(2) in ob/ob animals with particles (p=0.0438; Fisher's PLSD). Particles induced a diminished osteolytic response in genetically determined obese mice, suggesting that obesity may have a protective role against particle-induced bone resorption-similar to obesity and osteoporosis. These important new findings may help to stimulate clinical studies which may define criteria to better identify patients at risk to develop particle-induced osteolysis.
Assuntos
Reação a Corpo Estranho/patologia , Obesidade/patologia , Osteólise/patologia , Polietileno , Infecções Relacionadas à Prótese/patologia , Crânio/patologia , Crânio/cirurgia , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Reação a Corpo Estranho/complicações , Predisposição Genética para Doença/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/genética , Osteoclastos/patologia , Osteólise/complicações , Osteólise/genética , Tamanho da Partícula , Infecções Relacionadas à Prótese/complicações , Infecções Relacionadas à Prótese/genéticaRESUMO
Studies in humans and rats suggest that age impairs the ability to form bone. This impairment may be due to a depletion or deficit in osteoprogenitor stem cells. Such a deficit would be expected to reduce the ability of the skeleton to respond to therapy designed to restore lost bone. This study evaluated whether severely osteopenic senescent rats are capable of responding to a potent anabolic factor in bone, prostaglandin E2 (PGE). Growing female Sprague Dawley rats were ovariectomized at 3 months and aged until the start of treatment at 23 months. Rats were treated daily with PGE (3 mg/kg sc) or vehicle for 56 days. Tibiae were harvested for bone histomorphometry and femora were obtained for mRNA analysis of bone matrix proteins. The cancellous bone area was fivefold greater in PGE-treated rats than in vehicle-treated controls and not different from age-matched ovary-intact rats. PGE approximately doubled the bone-forming surface and the mineral apposition rate and increased the bone formation rate fourfold. The increased cancellous bone area in PGE-treated rats was primarily due to an increase in osteoblasts over osteoclasts. One hundred percent of the endocortical surface and 72 +/- 9% of the periosteal surface of cortical bone was undergoing mineralization in PGE-treated rats, whereas no mineratization was evident in vehicle-treated rats. An architectural analysis of cancellous bone indicates that trabecular number and thickness were increased and separation decreased in the treated rats. Imaging by microcomputed tomography further revealed that with PGE treatment, trabeculae in the medial plane of the proximal tibial metaphysis were more robust and continuous with the endocortical surface. PGE also significantly induced message levels for the prepro-alpha (I) subunit of type I collagen (collagen), osteonectin, and osteocalcin. In summary, bone mass can be restored to severely osteopenic senescent rats, suggesting that aging does not necessarily diminish the capacity of the skeleton to form bone.
Assuntos
Envelhecimento , Doenças Ósseas Metabólicas/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Dinoprostona/uso terapêutico , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Matriz Óssea/metabolismo , Osso e Ossos/patologia , Calcificação Fisiológica/efeitos dos fármacos , Estudos de Casos e Controles , Colágeno/análise , Colágeno/genética , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Microrradiografia , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteocalcina/análise , Osteocalcina/genética , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteonectina/análise , Osteonectina/genética , Ovariectomia , Periósteo/efeitos dos fármacos , Periósteo/patologia , Veículos Farmacêuticos , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Tíbia/efeitos dos fármacos , Tíbia/patologia , Tomografia Computadorizada por Raios XRESUMO
CONTEXT: Animal models and human studies suggest that osteocytes regulate the skeleton's response to mechanical unloading in part by an increase in sclerostin. However, few studies have reported changes in serum sclerostin in humans exposed to reduced mechanical loading. OBJECTIVE: We determined changes in serum sclerostin and bone turnover markers in healthy adult men undergoing controlled bed rest. DESIGN, SETTING, AND PARTICIPANTS: Seven healthy adult men (31 ± 3 yr old) underwent 90 d of 6° head down tilt bed rest at the University of Texas Medical Branch Institute for Translational Sciences-Clinical Research Center. OUTCOMES: Serum sclerostin, PTH, vitamin D, bone resorption and formation markers, urinary calcium and phosphorus excretion, and 24-h pooled urinary markers of bone resorption were evaluated before bed rest [baseline (BL)] and at bed rest d 28 (BR-28), d 60 (BR-60), and d 90 (BR-90). Bone mineral density was measured at BL, BR-60, and 5 d after the end of the study (BR+5). Data are reported as mean ± SD. RESULTS: Consistent with prior reports, bone mineral density declined significantly (1-2% per month) at weight-bearing skeletal sites. Serum sclerostin was elevated above BL at BR-28 (+29 ± 20%; P = 0.003) and BR-60 (+42 ± 31%; P < 0.001), with a lesser increase at BR-90 (+22 ± 21%; P = 0.07). Serum PTH levels were reduced at BR-28 (-17 ± 16%; P = 0.02) and BR-60 (-24 ± 14%; P = 0.03) and remained lower than BL at BR-90 (-21 ± 21%; P = 0.14), but did not reach statistical significance. Serum bone turnover markers were unchanged; however, urinary bone resorption markers and calcium were significantly elevated at all time points after bed rest (P < 0.01). CONCLUSIONS: In healthy men subjected to controlled bed rest for 90 d, serum sclerostin increased, with a peak at 60, whereas serum PTH declined, and urinary calcium and bone resorption markers increased.
Assuntos
Repouso em Cama , Proteínas Morfogenéticas Ósseas/sangue , Absorciometria de Fóton , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Biomarcadores/urina , Densidade Óssea , Reabsorção Óssea/metabolismo , Reabsorção Óssea/urina , Osso e Ossos/metabolismo , Cálcio/urina , Marcadores Genéticos , Decúbito Inclinado com Rebaixamento da Cabeça , Humanos , Estudos Longitudinais , Masculino , Hormônio Paratireóideo/sangue , Fósforo/urina , Aptidão Física , Vitamina D/sangueRESUMO
In marked contrast with men who drink, women who drink alcohol are found, as a group, to have higher bone mass compared with women who abstain. Furthermore, the apparent beneficial effects of alcohol use are more apparent in postmenopausal women than women of reproductive age, suggesting that there might be an interaction between alcohol and estrogen. Estrogen deficiency accompanying menopause leads to bone loss, which in turn predisposes women to osteoporosis later in life. Estrogen deficiency accelerates bone remodeling, which is the process by which small areas of bone are destroyed and rebuilt, and leads to an imbalance whereby bone resorption--the part of remodeling consisting of breaking down and assimilating--exceeds bone formation. Alcohol might reduce bone loss in postmenopausal women by increasing the circulating levels of estrogen. Alternatively, alcohol might slow bone loss by acting on bone cells to reduce bone remodeling. Alcohol use has a negative effect on the immature skeleton but current understanding suggests that small quantities of alcohol may have beneficial effects on bone in older women.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Desenvolvimento Ósseo/fisiologia , Remodelação Óssea/fisiologia , Estrogênios/fisiologia , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Alcoholism is a risk factor for osteoporosis and it is not clear whether the detrimental effects of alcohol on bone are reversible. Parathyroid hormone (PTH) is a potent stimulator of bone matrix synthesis and is being investigated as a therapeutic agent to reverse bone loss. The present investigation was designed to determine the effects of PTH on bone formation in a rat model for chronic alcohol abuse. METHODS AND RESULTS: Alcohol was administered in the diet of female rats (35% caloric intake) for 2 weeks. Human (1-34) PTH (80 microg/kg/day) was administered subcutaneously during the second week of the study. Alcohol resulted in a transient reduction in steady-state mRNA levels for the bone matrix proteins type 1 collagen, osteocalcin, and osteonectin compared with rats that were fed an alcohol-free (control) diet. As expected, alcohol decreased and PTH increased histologic indices of bone formation. Additionally, two-way ANOVA demonstrated that alcohol antagonized PTH-induced bone formation. Despite antagonism, bone formation and mRNA levels for bone matrix proteins in alcohol-fed rats treated with PTH greatly exceeded the values in rats fed the control diet. CONCLUSIONS: The results of this study contribute to a growing body of evidence that alcohol-induced bone loss is primarily due to reduced bone formation. We conclude that alcohol does not prevent the stimulatory effects of PTH on bone formation. This is evidence that the effects of alcohol on the skeleton are reversible. Additionally, the positive effects on bone formation in rats that consumed high concentrations of alcohol suggested that PTH may be useful as an intervention to treat alcohol-induced osteoporosis.
Assuntos
Alcoolismo/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Colágeno/efeitos dos fármacos , Etanol/farmacologia , Osteocalcina/efeitos dos fármacos , Osteonectina/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Alcoolismo/tratamento farmacológico , Animais , Matriz Óssea/efeitos dos fármacos , Matriz Óssea/metabolismo , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Colágeno/metabolismo , Feminino , Humanos , Modelos Animais , Osteocalcina/metabolismo , Osteonectina/metabolismo , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Hormônio Paratireóideo/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Animal models will continue to be important tools in the quest to understand the contribution of specific genes to establishment of peak bone mass and optimal bone architecture, as well as the genetic basis for a predisposition toward accelerated bone loss in the presence of co-morbidity factors such as estrogen deficiency. Existing animal models will continue to be useful for modeling changes in bone metabolism and architecture induced by well-defined local and systemic factors. However, there is a critical unfulfilled need to develop and validate better animal models to allow fruitful investigation of the interaction of the multitude of factors which precipitate senile osteoporosis. Well characterized and validated animal models that can be recommended for investigation of the etiology, prevention and treatment of several forms of osteoporosis have been listed in Table 1. Also listed are models which are provisionally recommended. These latter models have potential but are inadequately characterized, deviate significantly from the human response, require careful choice of strain or age, or are not practical for most investigators to adopt. It cannot be stressed strongly enough that the enormous potential of laboratory animals as models for osteoporosis can only be realized if great care is taken in the choice of an appropriate species, age, experimental design, and measurements. Poor choices will results in misinterpretation of results which ultimately can bring harm to patients who suffer from osteoporosis by delaying advancement of knowledge.