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1.
Nutrients ; 11(4)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010176

RESUMO

Stroke is the second leading cause of death worldwide but also of disability. Stroke induces certain alterations of muscle metabolism associated with gross muscle atrophy and a decrease in muscle function, leading to sarcopenia. The vast majority of stroke cases occur in adults over 65 years of age, and the prevalence is expected to massively increase in the coming years in this population. Sarcopenia is associated with higher mortality and functional decline. Therefore, the identification of interventions that prevent muscle alterations after stroke is of great interest. The purpose of this review is to carry out a systematic literature review to identify evidence for nutritional and pharmacological interventions, which may prevent loss of muscle mass in the elderly after stroke. The search was performed on Medline in December 2018. Randomized controlled studies, observational studies and case reports conducted in the last 20 years on post-stroke patients aged 65 or older were included. In total, 684 studies were screened, and eight randomized control trials and two cohort studies were finally included and examined. This review reveals that interventions such as amino acid supplementation or anabolic steroid administration are efficient to prevent muscle mass. Little evidence is reported on nutritional aspects specifically in sarcopenia prevention after stroke. It pinpoints the need for future studies in this particular population.


Assuntos
Força Muscular , Músculo Esquelético , Sarcopenia/prevenção & controle , Acidente Vascular Cerebral/complicações , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/farmacologia , Aminoácidos/uso terapêutico , Anabolizantes/farmacologia , Anabolizantes/uso terapêutico , Suplementos Nutricionais , Humanos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Acidente Vascular Cerebral/terapia , Reabilitação do Acidente Vascular Cerebral
2.
J Pharmacol Exp Ther ; 369(2): 188-199, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30819762

RESUMO

The anabolic effects of ß 2-adrenoceptor (ß 2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of ß 2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived ß 2-AR agonist in comparison with formoterol as a representative ß 2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human ß 2-AR and selectivity over the ß 1-AR and ß 3-AR. 5-HOB also shows potent agonistic activity at the ß 2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue-derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional ß 2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Anabolizantes/efeitos adversos , Anabolizantes/química , Anabolizantes/farmacologia , Anabolizantes/uso terapêutico , Animais , Benzotiazóis/efeitos adversos , Benzotiazóis/uso terapêutico , Células CHO , Cricetulus , Coração/efeitos dos fármacos , Humanos , Hipertrofia/tratamento farmacológico , Cinética , Macaca mulatta , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos
3.
Nat Rev Rheumatol ; 15(4): 225-236, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30755735

RESUMO

Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.


Assuntos
Anabolizantes/uso terapêutico , Desmineralização Patológica Óssea/prevenção & controle , Conservadores da Densidade Óssea/uso terapêutico , Animais , Desmineralização Patológica Óssea/terapia , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Humanos
4.
Kidney Int ; 95(3): 506-517, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30598193

RESUMO

The past two decades have witnessed tremendous progress in our understanding of the mechanisms underlying wasting and cachexia in chronic kidney disease (CKD) and in other chronic illnesses, such as cancer and heart failure. In all these conditions wasting is an effect of the activation of protein degradation in muscle, a response that increases the risk of morbidity and mortality. Major recent advances in our knowledge on how CKD and inflammation affect cellular signaling include the identification of the myostatin (MSTN)/activin system, and its related transcriptional program that promotes protein degradation. In addition, the identification of the role of MSTN/activin in the vascular wall shows premise that its inhibition can better control or prevent some effects of CKD on vessels, such as accelerated atherosclerosis and vascular calcifications. In this review, we summarize the expanding role of MSTN activation in promoting muscle atrophy and the recent clinical studies that investigated the efficacy of MSTN/activin pathway antagonism in sarcopenic patients. Moreover, we also review the utility of MSTN inhibition in the experimental models of CKD and its potential advantages in CKD patients. Lessons learned from clinical studies on MSTN antagonism in sarcopenic patients tell us that the anabolic intervention is likely better if we use a block of the two ActRII receptors. At the same time, however, it is becoming clear that MSTN-targeted therapies should not be seen as a substitute for physical activity and nutritional supplementation which are mandatory to successfully manage patients with wasting.


Assuntos
Ativinas/metabolismo , Anabolizantes/farmacologia , Miostatina/metabolismo , Insuficiência Renal Crônica/complicações , Sarcopenia/patologia , Receptores de Activinas Tipo II/antagonistas & inibidores , Receptores de Activinas Tipo II/metabolismo , Anabolizantes/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Terapia por Exercício , Comportamento Alimentar/fisiologia , Humanos , Músculo Esquelético/patologia , Miostatina/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Insuficiência Renal Crônica/reabilitação , Sarcopenia/etiologia , Sarcopenia/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
5.
Burns ; 45(4): 841-848, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30527646

RESUMO

The purpose of this study is to use a retrospective cohort of burn patients to evaluate the contribution of oxandrolone on burn care outcomes. Longitudinal clinical data is used to analyze outcomes from a new perspective. Our random-effects longitudinal regression analysis model used temporal clinical data to evaluate oxandrolone's impact on outcomes (oxandrolone/non-oxandrolone n=50/11, median length of stay [LOS]=42.2/39.3, mean weight (kg)=192.2/207.6, mean initial prealbumin (mg/dL) 10.1/7.5). The resultant predictive models (p<0.001) described how certain factors influence clinically significant outcomes via a robust data analysis method. LOS was predicted and extended by a greater magnitude of 3rd-degree versus 2nd-degree burns (1.01 versus 0.85 additional days for each %TBSA, p<0.001). Weight was decreased by LOS (145.2g lost per day, p<0.001). Oxandrolone improved prealbumin (3.503mg/dL increase, p<0.001) but instead did not influence patient weight (p>0.05) nor LOS (5.27days shortening, p=0.361). Prealbumin over time was also influenced by initial value (0.293mg/dL, p=0.003), LOS (0.072mg/dL increase per additional day, p<0.001), and the presence of inhalation injury (2.652mg/dL decrease if present, p=0.009). Oxandrolone appears to benefit anabolic protein production. It is difficult to isolate the role of oxandrolone on major outcomes due to the concomitant influence of other variables.


Assuntos
Anabolizantes/uso terapêutico , Queimaduras/terapia , Tempo de Internação/estatística & dados numéricos , Oxandrolona/uso terapêutico , Pré-Albumina/metabolismo , Adulto , Peso Corporal , Queimaduras/metabolismo , Queimaduras/patologia , Queimaduras por Inalação , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índices de Gravidade do Trauma , Resultado do Tratamento , Adulto Jovem
6.
Clin Rheumatol ; 38(2): 385-395, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30542797

RESUMO

Osteoporosis is characterized by the loss of bone mass, deterioration of the bone microarchitecture, and an increased risk of fractures; these later complications are associated with significant morbidity and mortality. The asymptomatic and progressive nature of osteoporosis underscores the importance of identifying this entity in early stages. Despite the various treatments available, the prevention of the disease represents the most important aspect of management. An adequate intake of calcium and vitamin D as well as a healthy lifestyle is the basis for maintaining bone health. When osteoporosis is diagnosed, the choice of medications must be individualized considering characteristics of the patient and the risk of fractures. In this article, we review the main causes of osteoporosis, when and how to start treatment, and appropriate therapy and monitoring.


Assuntos
Fraturas Ósseas/epidemiologia , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Deficiência de Vitamina D/tratamento farmacológico , Anabolizantes/uso terapêutico , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Cálcio na Dieta/uso terapêutico , Feminino , Fraturas Ósseas/etiologia , Glucocorticoides/efeitos adversos , Estilo de Vida Saudável , Humanos , Masculino , Osteoporose/induzido quimicamente , Fatores Sexuais , Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações
7.
Int J Mol Sci ; 20(1)2018 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-30587780

RESUMO

Osteoporosis represents the most common bone disease worldwide and results in a significantly increased fracture risk. Extrinsic and intrinsic factors implicated in the development of osteoporosis are also associated with delayed fracture healing and impaired bone regeneration. Based on a steadily increasing life expectancy in modern societies, the global implications of osteoporosis and impaired bone healing are substantial. Research in the last decades has revealed several molecular pathways that stimulate bone formation and could be targeted to treat both osteoporosis and impaired fracture healing. The identification and development of therapeutic approaches modulating bone formation, rather than bone resorption, fulfils an essential clinical need, as treatment options for reversing bone loss and promoting bone regeneration are limited. This review focuses on currently available and future approaches that may have the potential to achieve these aims.


Assuntos
Anabolizantes/uso terapêutico , Regeneração Óssea/fisiologia , Osteoporose/tratamento farmacológico , Anticorpos Neutralizantes/uso terapêutico , Proteínas Morfogenéticas Ósseas/imunologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fraturas Ósseas/tratamento farmacológico , Humanos , Osteoporose/metabolismo , Osteoporose/patologia , Hormônio Paratireóideo/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Via de Sinalização Wnt
8.
Artif Organs ; 42(9): E259-E271, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30328628

RESUMO

Aseptic loosening due to wear particle-induced osteolysis is the main cause of arthroplasty failure and the influence of postmenopausal osteoporosis and anti-osteoporosis treatment on Titanium (Ti) particle-induced osteolysis remains unclear. 66 C57BL/6J female mice were used in this study. Ovariectomy (OVX) was performed to induce osteopenia mice and confirmed by micro-CT. The Ti particle-induced mouse calvaria osteolysis model was established subsequently and both OVX and Sham-OVX mice were divided into four groups, respectively: Ti (-) group, Ti group, Ti + zoledronic acid (ZOL) group (50ug/kg, local administration, single dose) and Ti + teriparatide (TPTD) group (40ug/kg/d, subcutaneous injection*14d). Mice calvarias were collected for micro-CT and histomorphometric analysis 2 weeks after particle induction. 8 weeks after bilateral OVX, significantly reduced BMD and microstructure parameters in both proximal tibia and calvaria were observed in OVX mice when comparing with Sham-OVX mice. OVX mice in Ti group had not only markly decreased BMD and BV/TV, but also significantly increased total porosity, eroded surface area and osteoclast numbers when comparing with Sham-OVX mice. Shown by Two-way ANOVA analysis, the interaction terms between OVX and Ti implantation on micro-CT and histomorphometry parameters didn't reach significant difference. As illustrated by micro-CT and histological analysis, ZOL treatment markedly inhibited Ti particle-induced osteolysis in OVX mice and Sham-OVX mice, and there were significant differences when comparing to both Ti and Ti+TPTD group. The combination of osteoporosis and Ti particle implantation result in aggravated bone resorption, accompanied with increased osteoclasts and excessive inflammation response. ZOL was more effective in preventing Ti particle-induced osteolysis in both OVX mice and Sham-OVX mice than TPTD in short-term administration. ZOL exert the protective effects on Ti particle-induced bone loss via the suppression of osteoclasts.


Assuntos
Anabolizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteólise/prevenção & controle , Crânio/efeitos dos fármacos , Titânio , Anabolizantes/farmacologia , Animais , Conservadores da Densidade Óssea/farmacologia , Feminino , Camundongos , Osteólise/induzido quimicamente , Ovariectomia
9.
Nat Rev Endocrinol ; 14(10): 605-623, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30181608

RESUMO

The WNT signalling pathway is a key regulator of bone metabolism, particularly bone formation, which has helped to define the role of osteocytes - the most abundant bone cells - as orchestrators of bone remodelling. Several molecules involved in the control of the WNT signalling pathway have been identified as potential targets for the development of bone-building therapeutics for patients with osteoporosis. Several of these molecules have been investigated in animal models, but only inhibitors of sclerostin (which is produced by osteocytes) have been investigated in phase III clinical studies. Here, we review the rationale for these developments and the specificity and potential off-target actions of WNT-based therapeutics. We also describe the available preclinical and clinical studies and discuss the benefits and risks of using sclerostin inhibitors for the management of patients with osteoporosis.


Assuntos
Anabolizantes/uso terapêutico , Osso e Ossos/metabolismo , Terapia de Alvo Molecular/métodos , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Via de Sinalização Wnt/efeitos dos fármacos , Idoso , Animais , Remodelação Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Haplorrinos , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese/efeitos dos fármacos , Osteoporose/diagnóstico por imagem , Prognóstico , Ratos , Índice de Gravidade de Doença , Proteínas Wnt/genética
10.
Nutrients ; 10(9)2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30149605

RESUMO

Canonical Wnt (Wingless/Integrated) signaling is crucial in bone development and the Wnt ligand can promote osteoblast differentiation from mesenchymal progenitor cells. Calcitriol, an active vitamin D3, is used clinically for treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients. The bone effects of calcitriol in SHPT remains uncertain. We hypothesized that calcitriol improves bone mass by suppressing osteoclast activity, and simultaneously promoting Wnt ligand secretion. We designed a cross-sectional study in maintenance hemodialysis patients to explore the effects of calcitriol on different bone turnover markers and specifically emphasized the Wnt 10b levels. Then, we explored the source of Wnt 10b secretion by using osteoclasts and osteoblasts treated with calcitriol in cell culture studies. Finally, we explored the effects of calcitriol on bone microarchitectures in CKD mice, using the 5/6 nephrectomy CKD animal model with analysis using micro-computed tomography. Calcitriol promoted the growth of both trabecular and cortical bones in the CKD mice. Wnt 10b and Procollagen 1 N-terminal Propeptide (P1NP) significantly increased, but Tartrate-resistant acid phosphatase 5b (Trap 5b) significantly decreased in the calcitriol-treated maintenance hemodialysis patients. Calcitriol enhanced Wnt 10b secretion from osteoclasts in a dose-dependent manner. Treatment of SHPT with calcitriol improved the bone anabolism by inhibiting osteoclasts and promoting osteoblasts that might be achieved by increasing the Wnt 10b level.


Assuntos
Anabolizantes/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Calcitriol/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Diálise Renal , Insuficiência Renal Crônica/terapia , Proteínas Wnt/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores/metabolismo , Células Cultivadas , Estudos Transversais , Modelos Animais de Doenças , Feminino , Humanos , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/metabolismo , Hiperparatireoidismo Secundário/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Via Secretória/efeitos dos fármacos
11.
Ann Surg ; 268(3): 431-441, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30048322

RESUMO

BACKGROUND: Massive burns induce a hypermetabolic response that leads to total body wasting and impaired physical and psychosocial recovery. The administration of propranolol or oxandrolone positively affects postburn metabolism and growth. The combined administration of oxandrolone and propranolol (OxProp) for 1 year restores growth in children with large burns. Here, we investigated whether the combined administration of OxProp for 1 year would reduce scarring and improve quality of life compared with control. STUDY DESIGN: Children with large burns (n = 480) were enrolled into this institutional review board-approved study; patients were randomized to control (n = 226) or administration of OxProp (n = 126) for 1 year postburn. Assessments were conducted at discharge and 6, 12, and 24 months postburn. Scar biopsies were obtained for histology. Physical scar assessments and patient reported outcome measures of physical and psychosocial function were obtained. RESULTS: Reductions in cellularity, vascular structures, inflammation, and abnormal collagen (P < 0.05) occurred in OxProp-treated scars. With OxProp, scar severity was attenuated and pliability increased (both P < 0.05). Analyses of patient-reported outcomes showed improved general and emotional health within the OxProp-treated group (P < 0.05). CONCLUSIONS: Here, we have shown improvements in objective and subjective measures of scarring and an increase in overall patient-reported physical function. The combined administration of OxProp for up to a year after burn injury should be considered for the reduction of postburn scarring and improvement of long-term psychosocial outcomes in children with massive burns.


Assuntos
Anabolizantes/uso terapêutico , Queimaduras/complicações , Cicatriz Hipertrófica/etiologia , Cicatriz Hipertrófica/prevenção & controle , Oxandrolona/uso terapêutico , Propranolol/uso terapêutico , Vasodilatadores/uso terapêutico , Adolescente , Anabolizantes/administração & dosagem , Biomarcadores/metabolismo , Biópsia , Criança , Cicatriz Hipertrófica/metabolismo , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Oxandrolona/administração & dosagem , Propranolol/administração & dosagem , Estudos Prospectivos , Qualidade de Vida , Recuperação de Função Fisiológica , Resultado do Tratamento , Vasodilatadores/administração & dosagem
12.
Expert Opin Drug Discov ; 13(8): 741-752, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29869573

RESUMO

INTRODUCTION: Osteoporosis is a growing health and health-economic problem due to the increased proportion of elderly people in the population. Basic and clinical advances in research over the past two decades have led to the development of different compounds with antiresorptive or anabolic activity on bone that improved substantially the management of patients with osteoporosis over calcitonin or estrogen replacement. New compounds are in preclinical and clinical development. Areas covered: In this review, the authors review the approaches for the preclinical and clinical development of antiresorptive and anabolic agents for osteoporosis, particularly focusing on the recent advances in technology and in the understanding of skeletal biology, together with their implications on novel osteoporosis drug discovery. Expert opinion: Based on the available evidence from the approved drugs for the treatment osteoporosis as well as from the different compounds under clinical development, it has become clear that long term nonclinical pharmacological studies with either bone quality and off-target effects as the main outcomes should be required for new drugs intended to treat osteoporosis. At the same time, basic and clinical advances in research have underlined the necessity to develop new technologies and new models for a thorough screening of the effects of new drugs on the different components of skeletal aging and bone fragility that cannot be assessed by bone mass measurement.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Osteoporose/tratamento farmacológico , Idoso , Anabolizantes/farmacologia , Anabolizantes/uso terapêutico , Animais , Conservadores da Densidade Óssea/farmacologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Osteoporose/patologia
13.
Nat Med ; 24(5): 667-678, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29662200

RESUMO

Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38-GSK3ß-ß-catenin and WNT5A-LRP5 pathways. Accordingly, S1P2-deficient mice were osteopenic and obese. In ovariectomy-induced osteopenia, S1P lyase inhibition was as effective as intermittent parathyroid hormone (iPTH) treatment in increasing bone mass and was superior to iPTH in enhancing bone strength. Furthermore, lyase inhibition in mice successfully corrected severe genetic osteoporosis caused by osteoprotegerin deficiency. Human data from 4,091 participants of the SHIP-Trend population-based study revealed a positive association between serum levels of S1P and bone formation markers, but not resorption markers. Furthermore, serum S1P levels were positively associated with serum calcium , negatively with PTH , and curvilinearly with body mass index. Bone stiffness, as determined through quantitative ultrasound, was inversely related to levels of both S1P and the bone formation marker PINP, suggesting that S1P stimulates osteoanabolic activity to counteract decreasing bone quality. S1P-based drugs should be considered as a promising therapeutic avenue for the treatment of osteoporotic diseases.


Assuntos
Aldeído Liases/antagonistas & inibidores , Anabolizantes/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/enzimologia , Terapia de Alvo Molecular , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Aldeído Liases/metabolismo , Anabolizantes/farmacologia , Animais , Reabsorção Óssea/sangue , Reabsorção Óssea/diagnóstico por imagem , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Fêmur/diagnóstico por imagem , Fêmur/patologia , Deleção de Genes , Lisofosfolipídeos/sangue , Camundongos Knockout , Obesidade/sangue , Obesidade/patologia , Tamanho do Órgão , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/metabolismo , Osteoporose/patologia , Osteoprotegerina/sangue , Osteoprotegerina/metabolismo , PPAR gama/metabolismo , Transdução de Sinais , Fator de Transcrição Sp7/metabolismo , Esfingosina/análogos & derivados , Esfingosina/sangue , Microtomografia por Raio-X
14.
Osteoporos Int ; 29(5): 1009-1022, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29627891

RESUMO

Osteoporosis is a common skeletal disorder characterized by low bone mass, which leads to reduced bone strength and an increased risk of fractures. Anabolic agents have been shown to improve bone mass and decrease fracture risk in osteoporosis patients by directly stimulating osteoblasts to produce new bone. Currently, two anabolic agents are available in the USA: recombinantly produced teriparatide (TPTD), which is the fully active (1-34) amino active sequence of human parathyroid hormone (PTH), and abaloparatide (APTD), a synthetic analog of parathyroid hormone-related peptide (PTHrP). At present, both agents are approved only for treatment of patients with osteoporosis at high risk of fracture. Nonetheless, their anabolic properties have led to off-label application in additional settings which include spine fusion, osteonecrosis of the jaw, arthroplasty, and fracture healing. In this article, we summarize available scientific literature regarding the efficacy, effectiveness, and safety of TPTD in these off-label settings.


Assuntos
Anabolizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Teriparatida/uso terapêutico , Artroplastia/métodos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Consolidação da Fratura/efeitos dos fármacos , Humanos , Uso Off-Label , Fusão Vertebral/métodos
15.
Curr Osteoporos Rep ; 16(3): 269-276, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29589203

RESUMO

PURPOSE OF REVIEW: Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis. RECENT FINDINGS: While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.


Assuntos
Anabolizantes/uso terapêutico , Androgênios/uso terapêutico , Anticorpos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Osteoporose/tratamento farmacológico , Vibração/uso terapêutico , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/imunologia , Criança , Marcadores Genéticos/imunologia , Humanos , Teriparatida/uso terapêutico , Testosterona/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia
16.
BMJ Open ; 8(3): e015187, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29500198

RESUMO

OBJECTIVE: We aimed to determine whether the concomitant combination therapy of anabolic agents and bisphosphonates produces more effects on bone mineral density (BMD) than anabolic agents alone in patients with osteoporosis. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library for publications from 1 January 1980 to 1 August 2016 to identify all the randomised controlled trials (RCTs) and quasi-RCTs. The primary outcome was the mean per cent changes in BMD at the lumbar spine, the total hip and the femoral neck with an optimal period of treatment (6 to 12 months). The secondary outcome was the mean per cent changes in BMD at the same sites with the full period of recommendation (18 to 24 months). A random-effects model was used to estimate the standardised mean differences (SMDs) and the 95% CIs. RESULTS: Seven studies, with 747 patients, were included. With the optimal period, the concomitant combination therapy demonstrated a significant advantage over a monotherapy in BMD improvement at the total hip (SMD 0.42; 95% CI 0.26 to 0.58) and the femoral neck (SMD 0.30; 95% CI 0.14 to 0.46), but not for the spine BMD (SMD 0.13; 95% CI -0.17 to 0.43). With the full period, the concomitant combination therapy did not improve the BMD at the lumbar spine (SMD -0.06; 95% CI -0.71 to 0.59), the total hip (SMD 0.05; 95% CI -0.71 to 0.82) and the femoral neck (SMD -0.32; 95% CI -1.15 to 0.50). CONCLUSIONS: Compared with anabolic monotherapy, the concomitant combination therapy of anabolic agents and bisphosphonates significantly improved the BMD at the total hip and femoral neck with a shorter term (6 to 12 months) and produced similar benefits on BMD for the longer term (18 to 24 months). Also, the effect of concomitant combination therapy might be affected by the dose of anabolic agents. PROSPERO REGISTRATION NUMBER: CRD42016041335.


Assuntos
Anabolizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Liver Transpl ; 24(1): 122-139, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29024353

RESUMO

Sarcopenia and physical deconditioning are frequent complications in patients with cirrhosis and end-stage liver disease (ESLD). They are the end result of impaired dietary intake, chronic inflammation, altered macronutrient and micronutrient metabolism, and low physical activity. Frailty is the end result of prolonged sarcopenia and physical deconditioning. It severely affects a patient's functional status and presents in approximately 1 in 5 patients on the liver transplantation waiting list. Sarcopenia, poor physical fitness/cardiopulmonary endurance (CPE), and frailty are all associated with increased mortality in ESLD. Clinical trials addressing the usefulness of exercise in patients with cirrhosis have shown that it improves the metabolic syndrome, sarcopenia, CPE, health-related quality of life, and hepatic venous pressure gradient. Although evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing, based on existing literature from multiple medical subspecialties, we believe that an exercise program coupled to a tailored nutritional intervention benefits both cardiopulmonary and musculoskeletal functions, ultimately translating into improved functional status, sense of well-being, and possibly less complications from portal hypertension. In conclusion, although supervised exercise training is the prevailing approach to manage ESLD patients, such intervention is not sustainable or feasible for most patients. Innovative home-based physical activity interventions may be able to effectively reach a larger number of patients. Liver Transplantation 24 122-139 2018 AASLD.


Assuntos
Doença Hepática Terminal/cirurgia , Cirrose Hepática/cirurgia , Transplante de Fígado , Sarcopenia/terapia , Listas de Espera , Anabolizantes/uso terapêutico , Doença Hepática Terminal/complicações , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/fisiopatologia , Exercício , Terapia por Exercício , Humanos , Fígado/fisiopatologia , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Cirrose Hepática/fisiopatologia , Desnutrição/etiologia , Desnutrição/fisiopatologia , Desnutrição/terapia , Estado Nutricional , Aptidão Física , Qualidade de Vida , Sarcopenia/etiologia , Sarcopenia/fisiopatologia , Testosterona/uso terapêutico , Fatores de Tempo
18.
J Cell Mol Med ; 22(1): 77-88, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28834244

RESUMO

Cartilage injury can trigger crucial pathomechanisms, including excessive cell death and expression of matrix-destructive enzymes, which contribute to the progression of a post-traumatic osteoarthritis (PTOA). With the intent to create a novel treatment strategy for alleviating trauma-induced cartilage damage, we complemented a promising antioxidative approach based on cell and chondroprotective N-acetyl cysteine (NAC) by chondroanabolic stimulation. Overall, three potential pro-anabolic growth factors - IGF-1, BMP7 and FGF18 - were tested comparatively with and without NAC in an ex vivo human cartilage trauma-model. For that purpose, full-thickness cartilage explants were subjected to a defined impact (0.59 J) and subsequently treated with the substances. Efficacy of the therapeutic approaches was evaluated by cell viability, as well as various catabolic and anabolic biomarkers, representing the present matrix turnover. Although monotherapy with NAC, FGF18 or BMP7 significantly prevented trauma-induced cell dead and breakdown of type II collagen, combination of NAC and one of the growth factors did not yield significant benefit as compared to NAC alone. IGF-1, which possessed only moderate cell protective and no chondroprotective qualities after cartilage trauma, even reduced NAC-mediated cell and chondroprotection. Despite significant promotion of type II collagen expression by IGF-1 and BMP7, addition of NAC completely suppressed this chondroanabolic effect. All in all, NAC and BMP7 emerged as best combination. As our findings indicate limited benefits of the simultaneous multidirectional therapy, a sequential application might circumvent adverse interferences, such as suppression of type II collagen biosynthesis, which was found to be reversed 7 days after NAC withdrawal.


Assuntos
Anabolizantes/uso terapêutico , Antioxidantes/uso terapêutico , Cartilagem Articular/patologia , Condrócitos/patologia , Ferimentos não Penetrantes/tratamento farmacológico , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anabolizantes/farmacologia , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Proteína Morfogenética Óssea 7/farmacologia , Proteína Morfogenética Óssea 7/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Citoproteção/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Fatores de Crescimento de Fibroblastos/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like I/uso terapêutico , Pessoa de Meia-Idade , Ferimentos não Penetrantes/patologia
19.
Braz J Phys Ther ; 22(1): 77-81, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28743567

RESUMO

BACKGROUND: There is evidence of hypertensive effects caused by anabolic androgenic steroids (AAS). A single exercise session promotes the acute reduction of blood pressure, but the effects of AAS on this phenomenon are unknown. OBJECTIVES: To investigate the post-exercise blood pressure response in androgenic-anabolic steroid users. METHODS: Thirteen AAS users (23.9±4.3 years old) and sixteen controls (22.1±4.5 years old) performed a session of aerobic exercise. Heart rate and blood pressure were assessed before exercise and during a 60min post-exercise resting period. Repeated ANOVA measures were used to determine differences between the groups. RESULTS: While the control group had a significant reduction in post-exercise systolic blood pressure of up to 13.9±11.6mmHg at 40min, this phenomenon was limited among AAS users who reached a maximum of 6.2±11.5mmHg at 60min. The between groups comparison revealed significant higher post-exercise hypotension (PEH) for the control group at 30min (-12.9±14.1mmHg versus -2.9±7.6mmHg), 40min (-13.9±11.6mmHg versus -2.5±8.3mmHg), 50min (-13.9±13.9mmHg versus -5.0±7.9mmHg) and 60min (-12.5±12.8mmHg versus -6.2±11.5mmHg). There was no significant diastolic PEH in any of the groups. CONCLUSIONS: This study demonstrated impaired systolic post-exercise hypotension as a new adverse effect of AAS usage.


Assuntos
Anabolizantes/uso terapêutico , Androgênios/uso terapêutico , Hipotensão Pós-Exercício/prevenção & controle , Hipotensão Pós-Exercício/fisiopatologia , Congêneres da Testosterona/uso terapêutico , Adulto , Anabolizantes/farmacologia , Androgênios/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Estudos de Casos e Controles , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Sístole/efeitos dos fármacos , Sístole/fisiologia , Congêneres da Testosterona/farmacologia , Adulto Jovem
20.
Curr Rheumatol Rev ; 14(1): 53-61, 2018 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-27908253

RESUMO

Osteoporosis is a chronic pathologic condition, particularly of the elderly, in which a reduction of bone mineral density (BMD) weakens bone, leading to the so-called fragility fractures, most often of spine and femur. The gold standard exam for the quantitative measurement of BMD is the dual X-ray photon absorptiometry (DXA), a radiological method. However, a relevant number of fragility fractures occurs in the range of normal BMD values, meaning that also qualitative aspects of bone play a role, namely bone architecture and bone geometry. Bone structure is investigated by microCT and histomorphometry, which necessitate an invasive approach with a biopsy, usually taken at the iliac crest, not the typical site of fragility fractures. New tools, trabecular bone score (TBS) and hip structural analysis (HSA), obtained during DXA, can supply informations about bone structure of spine and femur, respectively, in a not invasive way. Therapy of osteoporosis is based on two types of drugs leading to an increase of BMD: antiresorptive and anabolic treatments. The antiresorptive drugs inhibit the osteoclasts, whereas teriparatide and, in part, strontium ranelate ameliorate bone structure. The present review deals with the relation between the anabolic drugs for osteoporosis and the cited new tools which investigate bone architecture and geometry, in order to clarify if they represent a real advantage in monitoring efficacy of osteoporosis' treatment. Data from the studies show that increases of TBS and HSA values after anabolic therapy are small and very close to their least significant change at the end of the usual period of treatment. Therefore, it is questionable if TBS and HSA are really helpful in monitoring bone quality and in defining reduction of individual fragility fracture risk during osteoporosis treatment with bone anabolic agents.


Assuntos
Anabolizantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Osteoporose/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Humanos
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