RESUMO
Estrogen deficiency arising with the menopause promotes marked acceleration of bone resorption, which can be restored by hormone replacement therapy. The inhibitory effects of estrogen seem to involve indirect cytokine- mediated effects via supporting bone marrow cells, but direct estrogen-receptor mediated effects on the bone-resorbing osteoclasts have also been proposed. Little information is available on whether estrogens modulate human osteoclastogenesis or merely inhibit the functional activity of osteoclasts. To clarify whether estrogens directly modulate osteoclastic activities human CD14+ monocytes were cultured in the presence of M-CSF and RANKL to induce osteoclast differentiation. Addition of 0.1-10 nM 17beta-estradiol to differentiating osteoclasts resulted in a dose-dependent reduction in tartrate resistant acid phosphatase (TRACP) activity reaching 60% at 0.1 nM. In addition, 17beta-estradiol inhibited bone resorption, as measured by the release of the C-terminal crosslinked telopeptide (CTX), by 60% at 0.1 nM, but had no effect on the overall cell viability. In contrast to the results obtained with differentiating osteoclasts, addition of 17beta-estradiol (0.001-10 nM) to mature osteoclasts did not affect bone resorption or TRACP activity. We investigated expression of the estrogen receptors, using immunocytochemistry and Western blotting. We found that ER-alpha is expressed in osteoclast precursors, whereas ER- beta is expressed at all stages, indicating that the inhibitory effect of estrogen on osteoclastogenesis is mediated by ER-alpha for the major part. In conclusion, these results suggest that the in vivo effects of estrogen are mediated by reduction of osteoclastogenesis rather than direct inhibition of the resorptive activity of mature osteoclasts.
Assuntos
Reabsorção Óssea , Estradiol/farmacologia , Osteoclastos/efeitos dos fármacos , Western Blotting , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Humanos , Imuno-Histoquímica , Osteoclastos/citologia , Osteoclastos/metabolismoRESUMO
Although our approach to the clinical management of osteoporosis (OP) and degenerative joint diseases (DJD)-major causes of disability and morbidity in the elderly-has greatly advanced in the past decades, curative treatments that could bring ultimate solutions have yet to be found or developed. Effective and timely development of candidate drugs is a critical function of the availability of sensitive and accurate methodological arsenal enabling the recognition and quantification of pharmacodynamic effects. The established concept that both OP and DJD arise from an imbalance in processes of tissue formation and degradation draws attention to need of establishing in vitro, ex vivo, and in vivo experimental settings, which allow obtaining insights into the mechanisms driving increased bone and cartilage degradation at cellular, organ, and organism levels. When addressing changes in bone or cartilage turnover at the organ or organism level, monitoring tools adequately reflecting the outcome of tissue homeostasis become particularly critical. In this context, bioassays targeting the quantification of various degradation and formation products of bone and cartilage matrix elements represent a useful approach. In this review, a comprehensive overview of widely used and recently established in vitro, ex vivo, and in vivo set-ups is provided, which in many cases effectively take advantage of the potentials of biomarkers. In addition to describing and discussing the advantages and limitations of each assay and their methods of evaluation, we added experimental and clinical data illustrating the utility of biomarkers for these methodological approaches.
Assuntos
Anti-Inflamatórios/uso terapêutico , Biomarcadores/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Animais , Bioensaio/métodos , Desenho de Fármacos , Humanos , Osteoartrite/diagnóstico , Osteoporose/diagnóstico , Resultado do TratamentoRESUMO
We have previously shown that angiotensin II (Ang II) and pressure increase extracellular signal-regulated kinase (ERK) 1/2 activity synergistically in intact, pressurized resistance arteries in vitro. However, the mechanisms by which pressure and Ang II activate ERK1/2 in intact resistance arteries remain to be determined. The purpose of the present study was to investigate the involvement of Rho-kinase and the actin filament network in Ang II- and pressure-induced ERK1/2 activation, as well as in the contractile response induced by Ang II. Mesenteric resistance arteries (200 to 300 microm) were isolated, mounted in an arteriograph, and stimulated by pressure, Ang II, or both. Activation of ERK1/2 was then measured by an in-gel assay. In mesenteric resistance arteries maintained at 70 mm Hg, Ang II (0.1 micromol/L) induced contraction (29+/-1.4% of phenylephrine, 10 micromol/L-induced contraction) and significantly increased ERK1/2 activity. Selective inhibition of Rho-kinase by Y-27632 (10 micromol/L) and selective disruption of the actin filament network by cytochalasin B (10 micromol/L) both decreased the Ang II-induced contraction by 78+/-1.2% and 87+/-1.9%, respectively, and significantly diminished ERK1/2 activity. In the absence of Ang II, increasing intraluminal pressure from 0 to 70 or 120 mm Hg increased ERK1/2 activity. ERK1/2 activity at 120 mm Hg was similar to that observed at 70 mm Hg in the presence of Ang II. Pressure-induced ERK1/2 activation was markedly attenuated by cytochalasin B but not by Y-27632. These results indicate that whereas pressure-induced ERK1/2 activation requires an intact actin filament network, but not Rho-kinase, the activation of ERK1/2 and the contraction induced by Ang II require both Rho-kinase and an intact actin filament network in isolated, intact mesenteric resistance arteries.
Assuntos
Citoesqueleto de Actina/fisiologia , Músculo Liso Vascular/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Vasoconstrição/fisiologia , Amidas/farmacologia , Angiotensina II/farmacologia , Animais , Citocalasina B/farmacologia , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos , Quinases Associadas a rhoRESUMO
Recent in vitro and animal studies suggest that cholesterol and its metabolites inhibit the functional activity of osteoblasts and thereby induce reduced bone mineralization. However, scant information is available on the clinical implication of these findings with special regard to postmenopausal bone loss. Therefore, the aim of the present study was to investigate cross-sectional and longitudinal associations between serum cholesterol, bone mineral density (BMD), and bone turnover in 340 postmenopausal women aged 50-75 years (mean 59 years), who were followed for 8.3 +/- 1.1 years. BMD in the lumbar spine, distal forearm, and total hip was measured by dual energy X-ray absorptiometry. Other study variables were physical measures, serum cholesterol, serum markers of bone turnover, and self-reported information on various risk factors for osteoporosis. At baseline, serum cholesterol showed significant negative correlation with BMD at the lumbar spine (r = -0.21, P < 0.0001) and distal forearm (r = -0.14, P = 0.013), but not at the hip. No associations of serum cholesterol with serum osteocalcin (r = 0.054, P = 0.317) and CTX (r = -0.027, P = 0.623) were, however, noted. After adjustment for age and BMI, the negative correlation remained significant at the lumbar spine (r = -0.16, P = 0.004), but not at the distal forearm (r = -0.018, P = 0.738). At the end of the 8-year follow-up, the correlation between serum cholesterol and spine BMD was not observed. Those with the largest increases in serum cholesterol, however, showed the greatest decreases in spine BMD independently of the changes in BMI (r = -0.16, P = 0.004). The correlation between the changes in serum cholesterol and the simultaneous changes in osteocalcin (r = 0.081, P = 0.140) and CTX (r = 0.042, P = 0.441) were statistically insignificant. Thus, our results suggest that the weak associations between spine BMD and serum cholesterol can be explained by the fact that both variables are simultaneously affected by estrogen deficiency rather than by a direct influence of serum cholesterol on osteoblast function.
Assuntos
Colesterol/sangue , Vértebras Lombares/metabolismo , Osteoporose Pós-Menopausa/sangue , Idoso , Análise de Variância , Densidade Óssea/fisiologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Coluna VertebralRESUMO
Since effective prevention and treatment of osteoporosis demands a high degree of long-term compliance, optimization of the dosing regimen in terms of efficacy and convenience of drug intake is a critical issue of oral bisphosphonate treatment. The purpose of the present study was to investigate whether the efficacy of the treatment with oral ibandronate, 2.5 mg daily, can be maintained if changing the postdose fast from 60 to 30 min. This was a 48-week, multicenter, open-label, randomized, parallel-group noninferiority study. Subjects were postmenopausal women 55-80 years old with lumbar spine (L1-L4) bone mineral density (BMD) corresponding to a T score < or =2.5. Women were randomly assigned to take 2.5 mg ibandronate exactly 30 or 60 min before breakfast. Lumbar spine and proximal femur (trochanter, femoral neck, total hip) BMD were measured by dual energy X-ray absorptiometry; serum osteocalcin and creatinine-corrected urinary C-telopeptide of type I collagen (u-CTX/Cr) excretion were measured by ELISA. After 48 weeks of treatment, the relative increase in lumbar spine BMD from baseline in the 30-min fast group was lower than that in the 60-min fast group (3.07% versus 4.95%, one-sided 97.5% CI = -2.89%) such that the prespecified noninferiority criteria were not met. The mean relative increases in BMD at the trochanter (3.04% versus 4.36%), femoral neck (1.82% versus 2.19%), and total hip (2.35% versus 3.21%) in the 30-min fast group were also lower than those in the 60-min fast group. Less suppression of the markers of bone turnover (u-CTX/Cr, -48.5% vs -61.8%; serum osteocalcin, -34.8% vs 43.8%) was observed in the 30-min compared with the 60-min group. In conclusion, if reducing the postdose fasting interval, dose-increase compensation would likely to be required to maintain efficacy of oral ibandronate treatment. Another potential solution for improving the convenience with bisphosphonate treatment is expected from weekly or monthly dosing regimens currently under clinical investigations.
Assuntos
Densidade Óssea/efeitos dos fármacos , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Absorciometria de Fóton , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Colágeno/urina , Colágeno Tipo I , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Ácido Ibandrônico , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteoporose Pós-Menopausa/prevenção & controle , Peptídeos/urina , Fatores de TempoRESUMO
The aims of the present study were to investigate how changes in the cumulative dose and the frequency of dosing influence the short-term antiresorptive efficacy of oral ibandronate treatment and whether serial measurements of bone markers could provide a useful diagnostic tool for the revelation of noncompliance to established treatments with antiresorptive drugs. Study participants were 200 healthy women 50-70 years old (mean 63.1 years) with a lumbar spine BMD t-score of -1 to -5. Women were randomly allocated to receive treatment with oral ibandronate according to one of the following eight dosing regimes: (1) 2.5 mg daily for 84 days; (2) 20 mg weekly for 84 days; (3) 2.5 mg daily for 28 days + no treatment for 56 days; (4) 2.5 mg daily for 28 days + 2.5 mg weekly for 56 days; (5) 2.5 mg daily for 28 days + 2.5 mg three times weekly for 56 days; (6) 2.5 mg daily for 14 days + 2.5 mg three times weekly for 56 days; (7) 2.5 mg three times weekly for 84 days; (8) no treatment for 168 days. Study parameters were the serum concentration of the C-terminal telopeptide of collagen type I (s-CTX, resorption marker) and N-MID osteocalcin (formation marker) measured by enzyme-linked immunosorbent assay. Oral treatment with ibandronate 20 mg weekly (cumulative dose 240 mg) resulted in greater final inhibition in s-CTX and area under the curve (AUC) compared to the 2.5 mg daily treatment (cumulative dose 210 mg), indicating that as long as optimal doses are administered the frequency of dosing has secondary importance for overall efficacy. When the cumulative dose was 130 mg or less, the final degree of inhibition was still the function of the cumulative dose, but the overall efficacy estimated by the AUC was also under the influence of the frequency of dosing. These observations suggest that serial measurements of s-CTX may provide a useful diagnostic tool for the early revelation of suboptimal dosing or noncompliance to already optimized therapies with antiresorptive agents.
Assuntos
Difosfonatos/administração & dosagem , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Administração Oral , Idoso , Análise de Variância , Biomarcadores/sangue , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/fisiologia , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Esquema de Medicação , Feminino , Humanos , Ácido Ibandrônico , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
1. The aim of this study was to investigate whether the balloon-based impedance planimetry technique could be a useful tool in endothelium-dependent investigations. 2. Porcine large coronary arteries contracted with prostaglandin F2alpha (PGF2alpha, 10 microM) did not relax to bradykinin (0.1 nM - 0.1 microM), but did relax to sodium nitroprusside (SNP, 10 microM). However, after eversion of the segments, bradykinin induced relaxations with pD2 values and maximal responses of 8.78+/-0.09 and 75+/-2% (n=6), respectively. 3. Incubation with captopril (1 microM) did not reveal a relaxation to bradykinin in the normal vessel configuration and had no influence on the concentration-relaxation relationship in everted segments. 4. Lowering the luminal pressure in contracted segments from 131+/-5 mmHg (isometric, n=5) to 60 mmHg (isobaric, n=5) did not facilitate the action of bradykinin. 5. Eversion of segments did not influence the concentration-response relationship for K+ (4.7 - 125 mM), PGF2alpha (0.3 - 30 microM), and SNP (30 nM - 30 microM), although the time-courses of responses were faster when the agents were added from the intimal compared to the adventitial side of the preparation. 6. In the same everted segment contracted with PGF2alpha, the concentration-response relationship for bradykinin was not different under isometric and isobaric conditions. 7. These results indicate that, (1) reduced endothelium-dependent relaxations to adventitially administered substances can be ascribed to a diffusion barrier in the vessel wall, while enzymatic degradation, luminal pressure and precontractile responses seem not to play a role, (2) impedance planimetry applied to everted cylindrical segments could be a useful experimental approach in pharmacological studies of endothelium-dependent responses under isobaric and isometric conditions.
Assuntos
Bradicinina/farmacologia , Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Bradicinina/administração & dosagem , Bradicinina/metabolismo , Calcimicina/farmacologia , Captopril/farmacologia , Vasos Coronários/lesões , Vasos Coronários/metabolismo , Difusão , Dinoprosta/farmacologia , Relação Dose-Resposta a Droga , Impedância Elétrica , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Nitroprussiato/farmacologia , Peptidil Dipeptidase A/metabolismo , Potássio/farmacologia , Pressão , Substância P/farmacologia , Suínos , Fatores de Tempo , Vasoconstrição/efeitos dos fármacosRESUMO
The purpose of the study was to investigate the influence of preactivation, wall tension and geometry on the reactivity of porcine coronary arteries to nifedipine and extracellular Ca(2+) in vitro. Porcine large coronary arteries were mounted as ring and cylindrical preparations and studied by wire- and balloon-based techniques. The sensitivity and maximal responses to nifedipine were more pronounced in 25 mM K(+) compared to 10 microM prostaglandin F(2alpha)-contracted preparations. Vascular sensitivity to nifedipine and Ca(2+) was enhanced under isometric compared to isobaric conditions. Under isometric conditions in the presence of 25 mM K(+), coronary rings were more sensitive to nifedipine, but less sensitive to Ca(2+) compared to cylindrical segments. In cylindrical segments, circumferential and axial tension increases augmented the extracellular Ca(2+)-dependent spontaneous resting tone and the sensitivity to extracellular Ca(2+). Coronary rings showed no resting tone at various resting tensions. These results suggest that preactivation, wall tension and vessel geometry are important determinants of Ca(2+)-influxes via nifedipine-sensitive voltage-gated Ca(2+) channels. Furthermore, axial wall tension appears to be a modulator of nifedipine-insensitive transmembrane Ca(2+)-influx that may play a role for the tone and reactivity in large coronary arteries.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Vasos Coronários/efeitos dos fármacos , Nifedipino/farmacologia , Animais , Canais de Cálcio Tipo L/fisiologia , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Técnicas In Vitro , Potássio/farmacologia , Suínos , Vasoconstrição/efeitos dos fármacosRESUMO
OBJECTIVE: Glucosamine sulphate has been shown in a large double-blind, placebo-controlled clinical trial to prevent structural damage and improve clinical symptoms of osteoarthritis (OA). We investigated whether early response in a newly developed biochemical marker of collagen type II degradation (CTX-II, CartiLaps ELISA) could reflect the long-term preservation of hyaline cartilage. METHODS: Study subjects comprised 212 knee OA patients participating in a clinical trial of the effects of glucosamine sulphate. Disease symptoms were assessed quarterly by WOMAC scoring and X-ray analysis was performed at baseline and after 3 years. Urine samples were obtained at baseline and after 1, 2 and 3 years for measurement in the CartiLaps assay. The measurements were corrected for creatinine. RESULTS: At baseline the patients had an average concentration of urinary CTX-II of 222.4 +/- 159.5 ng/mmol creatinine. This was significantly above the CTX-II levels measured in urine samples from 415 healthy controls (169.1 +/- 92.3 ng/mmol, p < 0.0001). There was no significant difference in the CTX-II response in the placebo group and the glucosamine treated group. However, those with high cartilage turnover presented a significant decrease in CTX-II after 12-month glucosamine treatment. Thus, three group with CTX II concentrations above normal average + 1SD decreased 15.5% after 12-month therapy. The 12 months change in CTX-II in OA patients with elevated CTX-II at baseline correlated with the change in average joint space width observed after 36 months (R = 0.43, p < 0.05). Increased baseline levels of CTX-II were associated with a worsening of the WOMAC index (p < 0.01). CONCLUSION: The data indicate that measurement of urinary collagen type II C-telopeptide fragments enables the identification of OA patients with high cartilage turnover who at the same time are most responsive to therapy with structure modifying drugs.
Assuntos
Cartilagem Articular/metabolismo , Glucosamina/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/urina , Idoso , Artrografia , Biomarcadores/urina , Cartilagem Articular/patologia , Colágeno/urina , Colágeno Tipo I , Método Duplo-Cego , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/fisiopatologia , Peptídeos/urina , Índice de Gravidade de DoençaRESUMO
The vasorelaxant effects of nicorandil, a K(+)-channel opener, and amlodipine, a dihydropyridine-type Ca(2+)-channel blocker, were investigated on partially and maximally K(+)-depolarized ring preparations from the porcine left anterior descending coronary artery. By comparing vascular responses in the proximal and distal parts of the epicardial segment, the scope of the study was to evaluate regional differences in the action of nicorandil and amlodipine. Nicorandil (10(-7)-10(-4) M) shifted the K+ concentration-response curves to the right and depressed the maximal contractile responses in a concentration-dependent manner, consistent with K(+)-channel opening and secondary non-K(+)-channel opening mechanisms of action. Nicorandil had a significantly more potent relaxant effect in the proximal compared to the distal arterial rings contracted with 85 mM K+. Pretreatment with methylene blue (10(-5) M) did not significantly influence the regional difference in the action of nicorandil. Amlodipine (10(-9)-10(-6) M) had a significantly more potent and effective inhibitory and relaxant effect than nicorandil under the same conditions. In contrast to nicorandil, the effect of amlodipine was more prominent in the distal compared to the proximal vessel rings. The cumulative addition of extracellular Ca2+ exhibited a more potent contractile response in the distal rather than in the proximal rings. Nicorandil totally and amlodipine partly eliminated the contractile responses to the lowest concentration of Ca2+. The inhibitory effect of amlodipine on the contractile responses to higher Ca2+ concentrations was more pronounced than that of nicorandil. The results show that there are regional differences in the responsiveness of porcine coronary arteries to Ca2+, nicorandil and amlodipine. Our findings indicate that the regional difference in nicorandil-induced vasodilation was caused neither by the K(+)-channel opening nor by the nitrate-like mechanism of action, but could be due to a direct Ca(2+)-influx blocking effect of the drug.
Assuntos
Anlodipino/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Vasos Coronários/efeitos dos fármacos , Niacinamida/análogos & derivados , Canais de Potássio/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Cálcio/metabolismo , Vasos Coronários/fisiologia , Ativação Enzimática/efeitos dos fármacos , Espaço Extracelular/metabolismo , Guanilato Ciclase/antagonistas & inibidores , Técnicas In Vitro , Azul de Metileno/farmacologia , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Niacinamida/farmacologia , Nicorandil , Pericárdio , Potássio/farmacologia , SuínosRESUMO
The aim of the study was to compare the onset, incidence and frequency/intensity of hot flushes during androgen-deprivation therapy with a gonadotropin-releasing hormone antagonist (GnRH) blocker versus an agonist using data from a randomized Phase 3 clinical trial. In total, 610 prostate cancer patients received monthly degarelix (s.c., 240/80 mg, n=207, or 240/160 mg, n=202) or leuprolide (i.m., 7.5 mg, n=201) for 12 months. Data on hot flushes was collected as self-reported adverse events and in a subgroup of 254 patients with electronic diaries. The onset of hot flushes was faster on degarelix versus leuprolide, and was accompanied by higher median hot flush scores during the first 3 months. However, there were no significant differences in overall incidence rates and median hot flush scores over the entire 12 months. After the third month, incidence rates dropped below 6%, whereas prevalence rates remained constant in all the three treatment arms. In multivariate analysis, body weight and heart rate at baseline were independent predictors of hot flushes (P<0.05). Except for a more rapid onset with the GnRH antagonist, there were no major differences in the overall pattern of hot flushes between treatment options. Weight control may help to minimize the incidence of hot flushes.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Rubor/induzido quimicamente , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Leuprolida/uso terapêutico , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/efeitos adversos , Peso Corporal , Rubor/epidemiologia , Seguimentos , Frequência Cardíaca , Humanos , Leuprolida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Fatores de Risco , Autorrelato , Resultado do TratamentoRESUMO
OBJECTIVES: First, to compare the impact of nasally and orally dosed estradiol on breast density; second, to investigate the utility of computer-based automated approaches to the assessment of breast density with reference to traditional methods. METHODS: Digitized images from two 2-year, randomized, placebo-controlled trials formed the basis of the present post hoc analysis. Active treatments were 1 mg estradiol continuously combined with 0.125 mg trimegestone (oral hormone replacement therapy, HRT) or low-dose (150 or 300 microg estradiol) nasal estradiol cyclically combined with 200 mg micronized progesterone (nasal HRT). The effects on breast density were assessed by a radiologist, providing the BI-RADS score and the interactive threshold, and by a computer-based approach, providing the measure of stripiness and the HRT-effect specific measure of breast density. RESULTS: In the oral HRT trial, active treatment induced a significant increase in breast density, which was consistent in all methods used (all p < 0.05). In contrast, none of the methods detected significant changes in women receiving nasal HRT. The sensitivity of automated methods to discriminate HRT- from placebo-treated women was equal or better than the sensitivity of methods performed by the radiologist. CONCLUSIONS: The markedly different pharmacokinetic profile of nasal estrogen seems to be associated with better breast safety. Automated computer-based analysis of digitized mammograms provides a sensitive measure of changes in breast density induced by hormones and could serve as a useful tool in future clinical trials.
Assuntos
Mama/efeitos dos fármacos , Estrogênios/administração & dosagem , Terapia de Reposição Hormonal , Progestinas/administração & dosagem , Administração Intranasal , Administração Oral , Idoso , Relação Dose-Resposta a Droga , Estradiol/administração & dosagem , Estradiol/farmacocinética , Estrogênios/farmacocinética , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Mamografia , Pessoa de Meia-Idade , Pós-Menopausa , Progesterona/administração & dosagem , Progesterona/farmacocinética , Progestinas/farmacocinética , Promegestona/administração & dosagem , Promegestona/análogos & derivados , Promegestona/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE: To review cellular mechanisms that have been proposed to mediate the indirect and direct effects of estrogen on articular cartilage, and to outline the remaining clinical questions that need to be clarified before utilizing the beneficial effects of estrogen for the prevention of osteoarthritis in early postmenopausal women. DESIGN: Summary of original research papers and reviews listed in Pubmed (1980-2007). RESULTS: Estrogen receptors have been identified in articular chondrocytes from various animals and humans. Molecular studies showed that estrogen can elicit genomic and rapid non-genomic effects on various cell types, including chondrocytes, and the latter effects are only inducible in females. In addition to direct effects, estrogen can also affect the homeostasis of articular cartilage by modulating the expression/production of different molecules such as various growth factors, inflammatory cytokines, matrix metalloproteinases, and reactive oxygen species. Moreover, in vivo observation argues for the notion that inhibition of subchondral bone turnover is also part of the mechanisms by which estrogen (and antiresorptive agents in general) can protect against joint degradation. Published studies undertaken at cellular, tissue, and in vivo levels illustrate that the effect of estrogen on cartilage may depend on the dose applied, the administration route, the time of initiation, and whether it is combined with a progestin. CONCLUSIONS: The herein reviewed direct and indirect effects of estrogen on articular cartilage further corroborate the due consideration of estrogen therapy for maintaining not only bone but also cartilage health in postmenopausal women. Future studies in postmenopausal women are needed to clarify whether the efficacy of estrogen therapy can be further optimized by using other forms of estrogen, other progestins, or by initiating the therapy in the peri- or early postmenopausal period.
Assuntos
Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Estrogênios/farmacologia , Estrogênios/fisiologia , Osteoartrite/prevenção & controle , Cartilagem Articular/citologia , Feminino , Humanos , Osteoartrite/sangue , Pós-Menopausa , Progestinas/farmacologia , Progestinas/fisiologia , Receptores de Estrogênio/metabolismoRESUMO
The presence of peripheral fat mass (PFM) appears to counteract the atherogenic trends of central fat mass through mechanisms presently poorly understood. In elderly women with distinct forms of body fat distribution, we wanted to study whether physical activity and aortic calcification are related to plasma levels of cortisol, 17-alpha-hydroxyprogesterone (17-alpha-OHP), dehydroepiandrosterone (DHEA), androstenedione (ASD), and interleukin 6 (IL6) accomplishing an anti-atherogenic milieu. A total of 276 well-defined generally healthy women aged 60-85 years were included. Categorization of body fat distribution was based on the relative presence of central to PFM measured by dual-energy X-ray absorptiometry. Women meticulously reported weekly physical activity. Outcome measures were aortic calcification between lumbar vertebra L1 and L4, plasma levels of hormones, and IL6. In peripheral adipose women, plasma DHEA and ASD increased with the degree of physical activity. This was also mirrored in the ratios of cortisol/DHEA and cortisol/17-alpha-OHP. Peripheral adipose women with high DHEA relative to cortisol had less severe aortic calcification, and in the same group a higher level of physical activity was associated with lower levels of plasma IL6. In conclusion, this study demonstrates that high physical activity is associated with a high circulating androgen to cortisol ratio, low IL6, and less severe aortic calcification. Since androgens inhibit IL6 secretion, the activity-induced increase of these hormones might be an anti-atherogenic signal.
Assuntos
Valva Aórtica/patologia , Calcinose/patologia , Interleucina-6/sangue , Atividade Motora/fisiologia , Obesidade/sangue , Obesidade/patologia , 17-alfa-Hidroxiprogesterona/sangue , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Androstenodiona/sangue , Estudos de Coortes , Desidroepiandrosterona/sangue , Feminino , Humanos , Hidrocortisona/sangue , Pessoa de Meia-Idade , Obesidade/fisiopatologiaRESUMO
UNLABELLED: Prevalent fracture and BMD are core elements of fracture prediction. In this control study case, we demonstrate that a simple computer-based estimation of local irregularities in the alignment of the lumbar vertebrae independently contributes to the fracture risk, thus supplementing current diagnostic tools. INTRODUCTION: We tested the hypothesis that degree of lordosis and/or irregularity in the alignment of lumbar vertebrae could be contributors to the risk of fragility fractures. METHODS: This was a case-control analysis including 144 elderly women; 108 maintaining skeletal integrity, whereas 36 sustaining a lumbar vertebral fracture during a 7.5-year observation period. The two groups of women were carefully matched for age, BMI, spine BMD and numerous classic risk factors. Lateral X-rays of the lumbar spine were digitized and the four corner points of endplates on each vertebra from Th12 to L5 were annotated. The degree of lordosis and irregularity of vertebral alignment was assessed by image analysis software. RESULTS: Degree of lordosis was not predictive for fractures. In contrast, irregularity was significantly higher in those who later sustained a fracture (1.6 x 10(-2)vs. 2.0 x 10(-3) cm(-1), p < 0.001), and further increased upon a sustained fracture (2.8 x 10(-2) cm(-1), p < 0.001), but was unchanged in controls (1.6 x 10(-2) cm(-1)). The predictive value of irregularity was independent of classic risk factors of fractures, including BMD (p < 0.01). CONCLUSION: Our results suggest that the herein introduced simple measure of irregularities in vertebral alignment could provide useful supplement to the currently used diagnostic tools of fracture prediction in elderly women.
Assuntos
Lordose/complicações , Lordose/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Fraturas da Coluna Vertebral/etiologia , Idoso , Índice de Massa Corporal , Densidade Óssea , Progressão da Doença , Métodos Epidemiológicos , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/lesões , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Prognóstico , Fraturas da Coluna Vertebral/fisiopatologiaRESUMO
INTRODUCTION AND HYPOTHESIS: Epidemiological observations suggest links between osteoporosis and risk of acute cardiovascular events and vice versa. Whether the two clinical conditions are linked by common pathogenic factors or atherosclerosis per se remains incompletely understood. We investigated whether serum lipids and polymorphism in the ApoE gene modifying serum lipids could be a biological linkage. METHODS: This was an observational study including 1176 elderly women 60-85 years old. Women were genotyped for epsilon (epsilon) allelic variants of the ApoE gene, and data concerning serum lipids (total cholesterol, triglycerides, HDL-C, LDL-C, apoA1, ApoB, Lp(a)), hip and spine BMD, aorta calcification (AC), radiographic vertebral fracture and self-reported wrist and hip fractures, cardiovascular events together with a wide array of demographic and lifestyle characteristics were collected. RESULTS: Presence of the ApoE epsilon 4 allele had a significant impact on serum lipid profile, yet no association with spine/hip BMD or AC could be established. In multiple regression models, apoA1 was a significant independent contributor to the variation in AC. However, none of the lipid components were independent contributors to the variation in spine or hip BMD. When comparing the women with or without vertebral fractures, serum triglycerides showed significant differences. This finding was however not applicable to hip or wrist fractures. After adjustment for age, severe AC score (>or=6) and/or manifest cardiovascular disease increased the risk of hip but not vertebral or wrist fractures. CONCLUSION: The contribution of serum lipids to the modulators of BMD does not seem to be direct but rather indirect via promotion of atherosclerosis, which in turn can affect bone metabolism locally, especially when skeletal sites supplied by end-arteries are concerned. Further studies are needed to explore the genetic or environmental risk factors underlying the association of low triglyceride levels to vertebral fractures.
Assuntos
Doenças Cardiovasculares/complicações , Lipídeos/sangue , Osteoporose Pós-Menopausa/complicações , Idoso , Idoso de 80 Anos ou mais , Doenças da Aorta/complicações , Doenças da Aorta/fisiopatologia , Apolipoproteínas E/genética , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Densidade Óssea/fisiologia , Calcinose/complicações , Calcinose/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Feminino , Fraturas Ósseas/etiologia , Fraturas Ósseas/fisiopatologia , Frequência do Gene/genética , Quadril , Fraturas do Quadril/etiologia , Fraturas do Quadril/fisiopatologia , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Polimorfismo Genético/genética , Fatores de Risco , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/fisiopatologia , Coluna Vertebral/fisiopatologiaRESUMO
Numerous experimental and clinical observations suggest that overall changes in bone resorption during menopause or treatment with hormone replacement therapy (HRT) are combined effects of changes in osteoclast number and function. Moreover, due to a coupling between osteoclastic bone resorption and osteoblastic bone formation, pronounced alteration of osteoclast number will eventually lead to alteration of osteoblastic bone formation. Fragments of type I collagen, such as the C- and N-terminal telopeptides of collagen type I (CTX and NTX, respectively), are generated during bone resorption and hence can be used as surrogate markers of osteoclast function. Circulating levels of different enzymes in the serum, such as TRAP 5b and cathepsin K are proportional to the number of osteoclasts, and hence can be used as surrogate markers of osteoclast number. Since antiresorptive effects can be obtained in different ways, we felt it was timely to discuss the different scenarios, highlight differences specific to different pharmacological interventions with different mechanisms of action, and discuss how these bone markers can assist us in a deeper analysis of the pharmacodynamics and safety profile of existing and upcoming drug candidates.
Assuntos
Reabsorção Óssea/fisiopatologia , Osteoclastos/fisiologia , Fosfatase Ácida/análise , Biomarcadores/análise , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/prevenção & controle , Catepsina K , Catepsinas/análise , Contagem de Células , Diferenciação Celular/fisiologia , Colágeno Tipo I/análise , Feminino , Humanos , Isoenzimas/análise , Osteopetrose/tratamento farmacológico , Osteopetrose/prevenção & controle , Osteoporose/tratamento farmacológico , Peptídeos/análise , Fosfatase Ácida Resistente a TartaratoRESUMO
OBJECTIVE: The aim of the present study was to investigate collagen metabolism after anabolic and catabolic stimulation of chondrocytes ex vivo. DESIGN: Metabolic activities in ex vivo bovine cartilage explants were stimulated with insulin-like growth factor I (IGF-I) or a combination of tumor necrosis factor alpha (TNFalpha) and oncostatin M (OSM). Supernatants were assessed for changes in biochemical markers, N-terminal propeptide of type II (PIINP) collagen and fragments of C-telopeptide of type II collagen (CTX-II). Matrix metalloproteinases (MMP) were added to metabolic inactivated cartilage and evaluated by the two biochemical markers for formation or degradation, respectively. Finally, urinary CTX-II and PIINP were evaluated for assessment of type II collagen turnover in patients with rheumatoid arthritis (RA). RESULTS: In the bovine articular cartilage explants, IGF-I induced an increase in PIINP level up to 4.8+/-1.1[ng/ml]/mg cartilage whereas CTX-II remained below 0.1+/-0.1[ng/ml]/mg cartilage. In the catabolic stimulated explants both PIINP and CTX-II were released to the supernatant, reaching concentrations of 9.0+/-1.4 and 9.1+/-2.2[ng/ml]/mg cartilage, respectively. RA patients had significantly lower serum concentrations of PIINP (3.4+/-3.7 ng/ml) compared with those healthy individuals (18.7+/-12.41 ng/ml, P<0.001). In contrast, RA patients had significantly higher urinary CTX-II (0.8+/-0.8 mg/mmol) compared to the healthy controls (0.1+/-0.08 mg/mmol, P=0.004). CONCLUSIONS: This study is the first to demonstrate that precursors and degradation products of type II collagen released into the supernatant can effectively reflect the anabolic and catabolic activities of stimulated cartilage explants.
Assuntos
Artrite Reumatoide/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Animais , Biomarcadores , Bovinos , Fator de Crescimento Insulin-Like I , Fator de Necrose Tumoral alfaRESUMO
OBJECTIVE: To summarize recent findings providing mechanistic insight into why the relative presence of central to peripheral fat mass is a critical determinant of atherogenesis and why postmenopausal women with android obesity represent a risk population with increased susceptibility to the cardiovascular harm of estrogen plus progestin therapy (EPT). METHODS: Review of own research and related literature in PubMed. RESULTS: In postmenopausal women, android obesity characterized by excessive upper-body combined with relatively poorly developed lower-body fat mass is frequently associated with insulin resistance, low-grade inflammation, and early atherosclerosis. Underlying mechanisms involve disequilibrium between proinflammatory cytokines (high interleukin-6/C-reactive protein) and the anti-inflammatory adipokine (low adiponectin). Recent findings point out that women with abnormal glucose tolerance, a metabolic alteration closely linked to android adiposity, respond with increases in low-grade inflammation and accelerated atherogenesis to EPT that collectively may promote acute complications. We recently pointed out that a progestin could exert a dose-dependent inhibitory effect on circulating adiponectin. Thus, when EPT is prescribed to women with android obesity, further decreases in the protective adiponectin pool may become critical and act as a promoter of thromboembolic complications via its effects on plaque formation and stability. Since android obesity is associated with the highest levels of free estradiol, women with this phenotype might not be trivial candidates for EPT. CONCLUSIONS: The herein summarized findings shed light on important interactions between sex steroids and body fat mass, with functional implications for cardiovascular risk. Since previous trials have not optimized the dose of the progestin for its effect on circulating adiponectin, utmost caution should be exercised in the prescription of available estrogen plus progestin therapies to women with android obesity and/or symptoms of the insulin resistance syndrome.
Assuntos
Tecido Adiposo/metabolismo , Arteriosclerose/etiologia , Doenças Cardiovasculares/etiologia , Terapia de Reposição de Estrogênios/efeitos adversos , Resistência à Insulina , Obesidade/complicações , Adiponectina/sangue , Índice de Massa Corporal , Citocinas/sangue , Relação Dose-Resposta a Droga , Estrogênios/efeitos adversos , Feminino , Humanos , Hipertensão/etiologia , Obesidade/classificação , Progestinas/efeitos adversos , Fatores de RiscoRESUMO
OBJECTIVE: The effect of hormone replacement therapy (HRT) on cardiovascular risk is intensely debated. The aim of this study was to investigate the long-term effects of HRT given for a few years on all-cause and cardiovascular mortality and the severity of atherosclerosis. METHODS: This analysis was based on a cohort of 1,458 postmenopausal women (55.8 +/- 6.1 years old) who previously participated in a number of randomized, placebo-controlled, clinical trials assessing the efficacy of 2-3 years of therapy with various estrogen plus progestin combinations for preventing bone loss. Women were followed on average for 9.8 years and came for a follow-up visit. Outcome variables were all-cause and cardiovascular mortality and the severity of atherosclerosis, as estimated by semi-quantitative scoring of vascular calcification in the lumbar aorta on lateral radiographs. RESULTS: A total of 174 women died during the observation period. All-cause mortality was decreased by 30% in the HRT+ group compared with the HRT- group (hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.50-0.97) after adjusting for age, body mass index and smoking. Under the same conditions, similar results characterized mortality from cardiovascular disease (n = 61 deaths; 35.1% of all deaths) and coronary heart disease (n = 39 deaths; 22.4% of all deaths), which were decreased by 46% (HR 0.54, 95% CI 0.29-0.98, p = 0.045) and 53% (HR 0.47, 95% CI 0.21-1.03, p = 0.062), respectively. Furthermore, the mean severity score of aortic calcification at follow-up was significantly lower in hormone-treated compared to non-treated women (p < 0.0001). CONCLUSION: Women who receive 2-3 years of HRT after menopause do not have increased all-cause mortality, and results of the present study suggest relative cardiovascular benefits compared to those who had not used hormones.