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2.
J Bone Miner Metab ; 38(1): 44-53, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31297652

RESUMO

The objective of the present multicenter randomized study was to compare weekly teriparatide with alendronate in their inhibition of vertebral collapse, effects on delayed union, pain relief, and improvement of quality of life (QOL) in women with new osteoporotic vertebral fractures within 1 week after onset of the fracture. Patients were randomly allocated to the teriparatide and alendronate groups. Vertebral collapse, low back pain assessed by a visual analog scale, and QOL assessed by EuroQol 5 dimension at weeks 1, 2, 4, 8, and 12 after the start of the treatment were compared between the groups. Lumbar bone mineral density (BMD) at baseline and week 12 and the rate of delayed union at week 12 were also compared. Each group consisted of 48 subjects. Vertebral collapse progressed over time in both groups, with no significant difference between the groups. Pain on rising up from lying position, turning over in bed, and resting in the lying position improved over time in both groups, with no significant difference between the groups. There were no significant differences in increase in BMD and delayed union. QOL in the teriparatide group showed significant improvement in comparison with that in the alendronate group at week 12. The weekly formulation of teriparatide showed comparable inhibition of vertebral collapse, increase in BMD, promotion of bone union, and improvement of pain and significant improvement of QOL at week 12 in comparison with alendronate in patients with a new osteoporotic vertebral fracture within 1 week after onset of the fracture. The weekly formulation of teriparatide may have improved components of QOL other than pain at week 12.


Assuntos
Alendronato/uso terapêutico , Fraturas da Coluna Vertebral/tratamento farmacológico , Teriparatida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Alendronato/farmacologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Qualidade de Vida , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/fisiopatologia , Teriparatida/farmacologia , Escala Visual Analógica
3.
Medicine (Baltimore) ; 98(47): e18067, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764838

RESUMO

Osteoporosis is a complication of type 2 diabetes mellitus (T2DM). Blockade of receptor activator of nuclear factor kappa-B ligand (RANKL) improves osteoporosis, but might also improve glucose tolerance through reduction of hepatic insulin resistance. However, the effect of denosumab (a human monoclonal antibody of RANKL) upon glycemic and metabolic parameters is controversial. We revealed the effect of denosumab upon glycemic and metabolic parameters for 52 weeks. We evaluated 20 individuals diagnosed with both osteoporosis (male and female: postmenopausal) and T2DM. We measured glycemic and metabolic parameters before and 26/52 weeks after administration of denosumab (60 mg per 26 weeks) without changing any other medication each patient was taking. All patients completed the study without complications and the T-score (lumbar spine and femoral neck) improved significantly from baseline to 52 weeks after denosumab administration (P < .001, .001, respectively). None of the glycemic parameters changed significantly from baseline to 26 weeks after denosumab administration, but levels of glycated hemoglobin and homeostasis model assessment of insulin resistance improved significantly from baseline to 52 weeks after administration (P = .019, .008, respectively). The levels of liver enzymes did not change significantly from baseline to 26 weeks after denosumab administration, but levels of aspartate transaminase and alanine aminotransferase improved significantly from baseline to 52 weeks after administration (P = .014, .004, respectively). None of the markers of lipid metabolism and body mass index changed significantly from baseline to 26/52 weeks after denosumab administration. These data demonstrated that denosumab is useful for T2DM patients with osteoporosis for glycemic control via improvement of insulin resistance. Also, the effect of denosumab might be due to improvement of hepatic function.


Assuntos
Glicemia/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/farmacologia , Denosumab/uso terapêutico , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Osteoporose/metabolismo , Idoso , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Masculino , Osteoporose/etiologia , Ligante RANK/imunologia
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1045-1051, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640962

RESUMO

OBJECTIVE: To investigate the effects of continuous pumping of teriparatide (TPTD) on bone metabolism in ovariectomized and normal mice and provide experimental evidence for the selection of animal models for studying the effects of TPTD and its related peptides on osteoclasts. METHODS: Twenty-four female C57BL mice (6-weeks old) were subjected to ovariectomy (OVX) or sham operation followed 7 days later by continuous pumping of TPTD or the solvent vehicle (VEH) via a micropump (SHAM-VEH, SHAM-TPTD, OVX-VEH, and OVX-TPTD groups; n=6). Two weeks later, the tibial and femoral bones were harvested for micro-CT scanning to measure the parameters of the tibia and the femoral cortical bone. Histopathological examinations of the tibial tissue were conducted using HE staining and TRAP staining and the number of osteoclasts and the growth plate thickness were determined. The serum Ca2 + levels of the mice were measured. The primary osteoblasts from the cranial bone were treated with estradiol (E2) and TPTD for 48 h, and the expressions of ß-catenin and RANKL protein in the cells were analyzed. RESULTS: The trabecular bone mass of OVX mice was significantly lower than that of sham-operated mice (P < 0.05). Continuous TPTD pumping significantly reduced tibial cancellous bone mass and femoral cortical bone area in the sham-operated mice, while in the castrated mice, TPTD pumping increased the cancellous bone mass without changing the cortical bone area. TRAP staining showed that cancellous osteoblasts in the tibia increased significantly in the castrated mice as compared with the sham-operated mice, and TPTD pumping significantly increased the number of cancellous osteoblasts in the sham-operated mice (P < 0.05). In the primary cultured osteoblasts, treatment with both E2 and TPTD obviously lowered the expression of ß-catenin and increased the expression of RANKL as compared with TPTD treatment alone. CONCLUSIONS: Continuous pumping of TPTD promotes bone resorption in normal mice but does not produce obvious bone resorption effect in the ovariectomized mice, suggesting that castrated mice are not suitable models for studying the effect of TPTD and the related peptides on the osteoclasts.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea , Osso e Ossos/metabolismo , Osteoclastos/efeitos dos fármacos , Ovariectomia , Teriparatida/administração & dosagem , Animais , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Feminino , Lâmina de Crescimento/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ligante RANK/metabolismo , Teriparatida/farmacologia , beta Catenina/metabolismo
5.
Int J Mol Sci ; 20(19)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31623406

RESUMO

Malignant melanoma is one of the most metastatic cancer types, and despite recent success with novel treatment strategies, there is still a group of patients who do not respond to any therapies. Earlier, the prenylation inhibitor hydrophilic bisphosphonate zoledronic acid (ZA) was found to inhibit melanoma growth in vitro, but only a weaker effect was observed in vivo due to its hydrophilic properties. Recently, lipophilic bisphosphonates (such as BPH1222) were developed. Accordingly, for the first time, we compared the effect of BPH1222 to ZA in eight melanoma lines using viability, cell-cycle, clonogenic and spheroid assays, videomicroscopy, immunoblot, and xenograft experiments. Based on 2D and spheroid assays, the majority of cell lines were more sensitive to BPH. The activation of Akt and S6 proteins, but not Erk, was inhibited by BPH. Additionally, BPH had a stronger apoptotic effect than ZA, and the changes of Rheb showed a correlation with apoptosis. In vitro, only M24met cells were more sensitive to ZA than to BPH; however, in vivo growth of M24met was inhibited more strongly by BPH. Here, we present that lipophilic BPH is more effective on melanoma cells than ZA and identify the PI3K pathway, particularly Rheb as an important mediator of growth inhibition.


Assuntos
Antineoplásicos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Difosfonatos/farmacologia , Melanoma/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Melanoma/tratamento farmacológico , Melanoma/etiologia , Melanoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J R Soc Med ; 112(11): 472-475, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31526209

RESUMO

A significant loss of bone mineral density and the appearance of multiple vertebral fractures after discontinuation of denosumab treatment have been described. To date, no hip fractures have been reported. We present three cases of patients who suffered femoral fractures after denosumab suppression.


Assuntos
Densidade Óssea/efeitos dos fármacos , Denosumab/farmacologia , Fraturas do Quadril/etiologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Suspensão de Tratamento , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/farmacologia , Feminino , Fraturas do Quadril/diagnóstico , Humanos , Pessoa de Meia-Idade
7.
Braz Oral Res ; 33: e086, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31483052

RESUMO

Treatment of patients with bisphosphonate usage is a significant concern for oral surgeons because it interferes with jaw bone turnover and regeneration. In case of adverse effects manifesting related to bisphosphonate use, oral surgeons are usually treating and keep the patient's symptoms under control. In this study, we aimed to investigate a new treatment protocol for medication-related osteonecrosis of the jaw (MRONJ). This treatment protocol consisted of administering human parathyroid hormone (hPTH) loaded chitosan microspheres which were prepared by ionotropic gelation method or/and the prepared microspheres were suspended in a poloxamer gel. After in-vitro optimization studies, the efficacy of the chosen formulations was evaluated in-vivo studies. Zoledronic acid was administered daily to forty-eight adult female Sprague-Dawley rats, divided into four experimental groups, at a daily concentration of 0.11 mg/kg over three weeks to induce the MRONJ model. At the end of this period, maxillary left molar teeth were extracted. In the first group, the subjects received no treatment. In the negative control group, poloxamer hydrogel containing empty microspheres were immediately applied to the soft tissues surrounding the extraction socket. The treatment group-1 was treated with local injections of poloxamer hydrogel containing hPTH. The treatment group-2 was treated with a single local injection of poloxamer hydrogel containing hPTH-loaded chitosan microspheres. Both treatment groups received a total of 7 µg of hPTH at the end of the treatment protocol. Our study demonstrates successful attenuation of MRONJ through a local drug delivery system combined with hPTH, as opposed to previously attempted treatment strategies.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Quitosana/farmacologia , Maxila/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Quitosana/uso terapêutico , Preparações de Ação Retardada , Feminino , Humanos , Maxila/patologia , Microesferas , Modelos Animais , Hormônio Paratireóideo/uso terapêutico , Poloxâmero/administração & dosagem , Poloxâmero/química , Ratos Sprague-Dawley , Ácido Zoledrônico/efeitos adversos
8.
Maturitas ; 129: 12-22, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31547908

RESUMO

OBJECTIVE: To systematically evaluate the effects of bone anabolic therapies (BATs) - specifically, drug therapy with teriparatide, abaloparatide or romosozumab - on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis. METHODS: Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome. RESULTS: Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments. CONCLUSIONS: Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Teriparatida/uso terapêutico , Anticorpos Monoclonais/farmacologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Colágeno Tipo I/sangue , Feminino , Humanos , Meta-Análise em Rede , Osteoporose Pós-Menopausa/sangue , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Fragmentos de Peptídeos/sangue , Peptídeos/sangue , Pró-Colágeno/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Teriparatida/farmacologia
9.
J Biomed Sci ; 26(1): 51, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277646

RESUMO

BACKGROUND: Identifying bone anabolic agents is a superior strategy for the treatment of osteoporosis. Naturally, derived coumarin derivatives have shown osteoanabolic effect in vitro and in vivo. In this study, we investigated the effect of 5'-Hydroxy Auraptene (5'-HA), a coumarin derivative that newly isolated from Lotus lalambensis Schweinf on the differentiation of the mouse bone marrow-derived mesenchymal (skeletal) stem cells (mBMSCs) into osteoblast and adipocyte. METHODS: The effect of 5'-HA on mBMSCs cell proliferation and osteoblast differentiation was assessed by measuring cell viability, quantitative alkaline phosphatase (ALP) activity assay, Alizarin red staining for matrix mineralization and osteogenic gene array expression. Adipogenesis was measured by Oil Red O staining and quantitative real time PCR (qPCR) analysis of adipogenic markers. Regulation of BMPs signaling pathways by 5'-HA was measured by Western blot analysis and qPCR. RESULTS: 5'-HA showed to stimulate the differentiation of mBMSCs into osteogenic cell lineage in a dose-dependent manner, without affecting their differentiation into adipocytic cell lineage. Treatment of mBMSCs with 5'-HA showed to promote significantly the BMP2-induced osteogenesis in mBMSCs via activating Smad1/5/8 phosphorylation and increasing Smad4 expression. Blocking of BMP signaling using BMPR1 selective inhibitor LDN-193189 significantly inhibited the stimulatory effect of 5'-HA on osteogenesis. CONCLUSIONS: Our data identified 5'-HA, as a novel coumarin derivative that function to stimulate the differentiation of mBMSCs into osteoblasts in BMP-signaling dependent mechanism.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Proteína Morfogenética Óssea 2/genética , Cumarínicos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Lotus/química , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Transdução de Sinais
10.
Plast Reconstr Surg ; 144(2): 358-370, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31348344

RESUMO

BACKGROUND: Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds. METHODS: Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 µm of dipyridamole (n = 6), 10,000 µm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test. RESULTS: Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-µm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-µm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 µm versus 10,000 µm dipyridamole; p = 0.104), and rhBMP-2-coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 µm dipyridamole, and p = 0.938 versus 10,000 µm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone. CONCLUSION: Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.


Assuntos
Processo Alveolar/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Proteína Morfogenética Óssea 2/farmacologia , Regeneração Óssea/efeitos dos fármacos , Dipiridamol/farmacologia , Tecidos Suporte , Fator de Crescimento Transformador beta/farmacologia , Processo Alveolar/lesões , Animais , Conservadores da Densidade Óssea/administração & dosagem , Proteína Morfogenética Óssea 2/administração & dosagem , Transplante Ósseo/métodos , Dipiridamol/administração & dosagem , Modelos Animais de Doenças , Microscopia Eletrônica de Varredura , Modelos Animais , Osteogênese/efeitos dos fármacos , Impressão Tridimensional , Coelhos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Fator de Crescimento Transformador beta/administração & dosagem , Microtomografia por Raio-X
11.
Nutrients ; 11(8)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349732

RESUMO

The phenolic compounds of extra-virgin olive oil can act at various levels to protect individuals against cardiovascular and neurodegenerative diseases, cancer, and osteoporosis, among others. Polyphenols in extra-virgin olive oil can stimulate the proliferation of osteoblasts, modify their antigen profile, and promote alkaline phosphatase synthesis. The objective of this work was to determine the effect of different extra-virgin olive oil phenolic compounds on the gene expression of osteoblast-related markers. The cells of the MG63 osteoblast line were cultured for 24 h with 10-6 M of the phenolic compounds ferulic acid, caffeic acid, coumaric acid, apigenin, or luteolin. The expression of studied markers was quantified using quantitative real-time polymerase chain reaction (q-RT-PCR). The expression by MG63 osteoblasts of growth and differentiation/maturation markers was modified after 24 h of treatment with 10-6 M of the phenolic compounds under study, most of which increased the gene expression of the transforming growth factor ß1 (TGF-ß1), TGF-ß receptor 1,2 and 3 (TGF-ßR1, TGF-ßR2, TGF-ßR3), bone morphogenetic protein 2 and 7 (BMP2, BMP7), run-related transcription factor 2 (RUNX-2), Alkaline phosphatase (ALP), Osteocalcin (OSC), Osterix (OSX), Collagen type I (Col-I) and osteoprotegerin (OPN). The extra-virgin olive oil phenolic compounds may have a beneficial effect on bone by modulating osteoblast physiology, which would support their protective effect against bone pathologies.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Azeite de Oliva , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Fenóis/farmacologia , Adolescente , Conservadores da Densidade Óssea/isolamento & purificação , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Masculino , Azeite de Oliva/química , Osteoblastos/metabolismo , Osteogênese/genética , Fenóis/isolamento & purificação
12.
Nutrients ; 11(6)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234292

RESUMO

There is growing interest in bioactive substances from marine organisms for their potential use against diverse human diseases. Osteoporosis is a skeletal disorder associated with bone loss primarily occurring through enhanced osteoclast differentiation and resorption. Recently, we reported the anti-osteoclastogenic activity of fermented Pacific oyster (Crassostrea gigas) extract (FO) in vitro. The present study focused on investigating the anti-osteoporotic efficacy of FO in bone loss prevention in an experimental animal model of osteoporosis and elucidating the mechanism underlying its effects. Oral administration of FO significantly decreased ovariectomy-induced osteoclast formation and prevented bone loss, with reduced serum levels of bone turnover biomarkers including osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus (CTX). FO significantly suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts and attenuated the induction of osteoclast-specific genes required for osteoclastogenesis and bone resorption. Furthermore, FO inhibited RANKL-mediated IκBα and p65 phosphorylation in BMMs. Taken together, these results demonstrate that FO effectively suppresses osteoclastogenesis in vivo and in vitro, and that FO can be considered as a potential therapeutic option for the treatment of osteoporosis and osteoclast-mediated skeletal diseases.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Crassostrea/microbiologia , Fermentação , Lactobacillus brevis/fisiologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Ovariectomia , Alimentos Marinhos/microbiologia , Tíbia/efeitos dos fármacos , Actinas/metabolismo , Animais , Conservadores da Densidade Óssea/isolamento & purificação , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Osteoporose Pós-Menopausa/fisiopatologia , Transdução de Sinais , Tíbia/metabolismo , Tíbia/patologia , Tíbia/fisiopatologia
13.
Int J Mol Med ; 44(2): 582-592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173157

RESUMO

It is well known that extensive osteoclast formation plays a key role in osteoporosis in post­menopausal women and the elderly. The suppression of extensive osteoclastogenesis and bone resorption may be an effective preventive strategy for osteoporosis. Zoledronic acid (ZOL) has been indicated to play an essential role in regulating bone mineral density and has already been used in large clinical trials. However, the effects of ZOL on osteoclastogenesis remain to be fully elucidated. Therefore, the present study aimed to determine the effects of ZOL on osteoclastogenesis, and to explore the corresponding signalling pathways. By using a cell viability assay, as well as in vitro osteoclastogenesis, immunofluorescence and resorption pit assays, we demonstrated that ZOL (0.1­5 µM) suppressed receptor activator of nuclear factor­κB ligand (RANKL)­induced osteoclast differentiation and bone resorptive activity. Furthermore, western blot analysis and reverse transcription­quantitative PCR indicated that ZOL inhibited the RANKL­induced activation of NF­κB and the phosphorylation of JNK in RAW264.7 cells, and subsequently decreased the expression of osteoclastogenesis­associated genes, including calcitonin receptor, tartrate­resistant acid phosphatase and dendritic cell­specific transmembrane protein. ZOL inhibited osteoclast formation and resorption in vitro by specifically suppressing NF­κB and JNK signalling. On the whole, the findings of this study indicate that ZOL may serve as a potential agent for the treatment of osteoclast­associated diseases, including osteoporosis.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Osteogênese/efeitos dos fármacos , Ácido Zoledrônico/farmacologia , Animais , Camundongos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Células RAW 264.7
14.
Biol Pharm Bull ; 42(6): 929-936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155589

RESUMO

Bisphosphonates (BPs) containing nitrogen (N-BPs) exhibit far stronger anti-bone-resorptive effects than non-N-BPs. However, repeated administration of N-BPs causes osteonecrosis selectively in jawbones. As BPs accumulate in large amounts within inflamed bones, any N-BP released from the pool accumulated within jawbones might directly act on cells in the surrounding soft-tissues and induce inflammation or necrosis. Here, we examined the local and systemic effects of zoledronate (the most potent N-BP with the highest incidence of jawbone-necrosis) on inflammatory cytokines in mice. Locally within ear-pinnas: (i) zoledronate induced long-lasting accumulation of interleuikin-1ß (IL-1ß) and IL-18, but not tumor necrosis factor-α (TNF-α), (ii) zoledronate and lipopolysaccharide (LPS, a cell-wall component of Gram-negative bacteria) mutually augmented the productions of IL-1ß, IL-18, and TNF-α, and (iii) oxidronate (a toxic non-N-BP) by itself produced not only IL-1ß and IL-18, but also TNF-α. In systemic experiments using intraperitoneal injection of zoledronate and/or LPS, (i) zoledronate by itself increased none of the above cytokines in serum, and (ii) in mice pretreated (3 d before) with zoledronate, the LPS-induced increases in serum IL-1ß and IL-18 were greatly augmented with a delayed slight TNF-α augmentation. These results, together with previous ones, suggest that (a) pro-IL-1ß and pro-IL-18 accumulate within cells in soft-tissues exposed to N-BPs, and infection may augment not only their production, but also the release of their mature forms, (b) IL-1ß and IL-18 (possibly together with TNF-α) may play important roles in N-BP-induced inflammation and/or necrosis, and (c) mechanisms underlying the cytotoxic effects of BPs may differ between N-BPs and non-N-BPs.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Pavilhão Auricular/efeitos dos fármacos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ácido Zoledrônico/farmacologia , Animais , Pavilhão Auricular/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos BALB C
16.
Int J Mol Sci ; 20(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174394

RESUMO

Osteoporosis is an abnormal bone remodeling condition characterized by decreased bone density, which leads to high risks of fracture. Previous study has demonstrated that Lycii Radicis Cortex (LRC) extract inhibits bone loss in ovariectomized (OVX) mice by enhancing osteoblast differentiation. A bioactive compound, kukoamine B (KB), was identified from fractionation of an LRC extract as a candidate component responsible for an anti-osteoporotic effect. This study investigated the anti-osteoporotic effects of KB using in vitro and in vivo osteoporosis models. KB treatment significantly increased the osteoblastic differentiation and mineralized nodule formation of osteoblastic MC3T3-E1 cells, while it significantly decreased the osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. The effects of KB on osteoblastic and osteoclastic differentiations under more physiological conditions were also examined. In the co-culture of MC3T3-E1 cells and monocytes, KB promoted osteoblast differentiation but did not affect osteoclast differentiation. In vivo experiments revealed that KB significantly inhibited OVX-induced bone mineral density loss and restored the impaired bone structural properties in osteoporosis model mice. These results suggest that KB may be a potential therapeutic candidate for the treatment of osteoporosis.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Ácidos Cafeicos/uso terapêutico , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Espermina/análogos & derivados , Animais , Conservadores da Densidade Óssea/farmacologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Medicamentos de Ervas Chinesas/química , Feminino , Camundongos , Osteoblastos/citologia , Osteoclastos/citologia , Osteoporose/etiologia , Ovariectomia/efeitos adversos , Espermina/farmacologia , Espermina/uso terapêutico
17.
Int J Mol Sci ; 20(11)2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31181661

RESUMO

Several lines of evidence suggest that oxidative stress is one of the key pathogenic mechanisms of osteoporosis. We aimed to elucidate the bone protective effects of petunidin, one of the most common anthocyanidins, considering its potent antioxidative activity. Petunidin (>5 µg/mL) significantly inhibited osteoclastogenesis and downregulated c-fos, Nfatc1, Mmp9, Ctsk, and Dc-stamp mRNA expression in RAW264.7 cells. Conversely, petunidin (>16 µg/mL) stimulated mineralized matrix formation and gene expression of Bmp2 and Ocn, whereas it suppressed Mmp13, Mmp2, and Mmp9 mRNA expression and proteolytic activities of MMP13 and MMP9 in MC3T3-E1 cells. Micro-CT and bone histomorphometry analyses of sRANKL-induced osteopenic C57BL/6J mice showed that daily oral administration of petunidin (7.5 mg/kg/day) increased bone volume to tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), the ratio of osteoid volume to tissue volume (OV/TV), osteoid thickness (O.Th), the ratio of osteoid surface to bone surface (OS/BS), the ratio of osteoblast surface to bone surface (Ob.S/BS), and the number of osteoblast per unit of bone surface (N.Ob/BS), and decreased trabecular separation (Tb.Sp), the ratio of eroded surface to bone surface (ES/BS), the ratio of osteoclast surface to bone surface (Oc.S/BS), and number of osteoclast per unit of bone surface (N.Oc/BS), compared to untreated mice. Furthermore, histological sections of the femurs showed that oral administration of petunidin to sRANKL-induced osteopenic mice increased the size of osteoblasts located along the bone surface and the volume of osteoid was consistent with the in vitro osteoblast differentiation and MMP inhibition. These results suggest that petunidin is a promising natural agent to improve sRANKL-induced osteopenia in mice through increased osteoid formation, reflecting accelerated osteoblastogenesis, concomitant with suppressed bone resorption.


Assuntos
Antocianinas/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoblastos/efeitos dos fármacos , Osteogênese , Osteoporose/tratamento farmacológico , Animais , Antocianinas/farmacologia , Conservadores da Densidade Óssea/farmacologia , Proteína Morfogenética Óssea 2/metabolismo , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/metabolismo , Feminino , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo , Osteoporose/metabolismo , Ligante RANK/metabolismo , Células RAW 264.7
18.
Osteoporos Int ; 30(8): 1581-1589, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31115592

RESUMO

INTRODUCTION: To investigate the effect of zoledronic acid on periprosthetic bone mineral density (BMD) and bone metabolism markers after primary total hip arthroplasty in females with postmenopausal osteoporosis. METHODS: From November 2015 to April 2016, 40 female patients who met the inclusion criteria were randomized into two groups: a control group (calcium + calcitriol) and a zoledronic acid group (calcium + calcitriol + zoledronic acid). At 1 week and 3, 6, and 12 months after operation, BMD was obtained through dual-energy X-ray absorptiometry (DEXA). At pre-operation and at 3, 6, and 12 months after the operation, levels of bone metabolism markers were obtained by serum examination. RESULTS: Loss of BMD was significantly more pronounced in the control group than in the ZOL group in zones 1, 4, 6, and 7 at 6 months and in zones 1, 2, 4, 6, and 7 at 12 months after the operation. The levels of bone-resorption marker (ß-CTX) were significantly lower in the ZOL group than in the control group at 3, 6, and 12 months after operation. The levels of bone-formation marker (TP1NP) performed statistically differences only at 12 months after the operation in these two groups. CONCLUSIONS: Receiving an intravenous infusion of 5 mg zoledronic acid after THA can effectively reduce periprosthetic BMD loss and improve bone remodeling in females with postmenopausal osteoporosis. Zoledronic acid significantly inhibited bone mass loss in zones 1, 2, 4, 6, and 7 after THA and inhibited bone-resorption marker (ß-CTX) to improve bone remodeling. Zoledronic acid treatment is potentially important for patients with osteoporosis after THA.


Assuntos
Artroplastia de Quadril/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Prótese de Quadril , Osteoporose Pós-Menopausa/tratamento farmacológico , Ácido Zoledrônico/farmacologia , Absorciometria de Fóton/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/fisiopatologia , Reabsorção Óssea/prevenção & controle , Calcitriol/uso terapêutico , Carbonato de Cálcio/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Cuidados Pós-Operatórios/métodos , Método Simples-Cego , Ácido Zoledrônico/uso terapêutico
19.
Osteoporos Int ; 30(8): 1607-1616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31053927

RESUMO

Glucorticoid (GC) therapy is the commonest cause of secondary osteoporosis. Ovariectomized rabbits receiving the GC methylprednisolone for 6 weeks exhibited relatively lower vertebral and femoral bone mass. Treatment with the PTH receptor agonist abaloparatide for 12 weeks during ongoing methylprednisolone administration increased cortical and trabecular bone mass and femur bending strength. INTRODUCTION: Abaloparatide, an osteoanabolic PTHrP analog, increases bone mineral density (BMD) and reduces fracture risk in women with postmenopausal osteoporosis. This study assessed abaloparatide effects on BMD and bone strength in ovariectomized (OVX) rabbits with glucocorticoid (GC)-induced osteopenia. METHODS: Thirty-two rabbits underwent OVX and 8 underwent sham surgery. One day later, 24 OVX rabbits began daily s.c. GC injections (methylprednisolone, 1 mg/kg/day) for 6 weeks, while 8 OVX and 8 sham controls received no GC. GC-challenged rabbits (8/group) then received GC (0.5 mg/kg/day) along with daily s.c. vehicle (GC-OVX), abaloparatide 5 µg/kg/day (ABL5), or 25 µg/kg/day (ABL25) for 12 weeks, and the no-GC OVX and sham controls received daily vehicle. RESULTS: GC-OVX rabbits showed significant deficits in vertebral and proximal femur areal BMD, lower cortical area, thickness and volumetric BMD of the femur diaphysis, and reduced trabecular bone volume and volumetric BMD in the vertebra and distal femur versus sham controls. These deficits were significantly reversed in the ABL25 group, which also showed enhanced trabecular micro-architecture versus GC-OVX controls. Destructive bending tests showed significantly lower femur diaphysis ultimate load and bending rigidity of the femoral diaphysis in the GC-OVX group versus sham controls, whereas these parameters were similar in the ABL25 group vs sham controls. CONCLUSIONS: Abaloparatide 25 µg/kg/day mitigated the adverse effects of GC administration on cortical and trabecular bone and improved femoral strength in OVX rabbits. These results suggest potential promise for abaloparatide as an investigational therapy for glucocorticoid-induced osteoporosis.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Absorciometria de Fóton , Animais , Fenômenos Biomecânicos , Conservadores da Densidade Óssea/farmacologia , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/fisiopatologia , Feminino , Fêmur/fisiopatologia , Glucocorticoides , Vértebras Lombares/fisiopatologia , Metilprednisolona , Ovariectomia , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Coelhos , Microtomografia por Raio-X
20.
J Bone Miner Metab ; 37(6): 1036-1047, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31087185

RESUMO

Eldecalcitol increased bone mineral density (BMD) and prevented vertebral fractures in vitamin D-sufficient osteoporotic subjects. However, the effect of eldecalcitol on BMD under vitamin D insufficiency is unknown. We examined the effect of eldecalcitol on BMD compared with alfacalcidol in osteoporotic patients without vitamin D or calcium supplementation. This is a randomized, double-blind, active comparator trial. 265 Chinese osteoporotic patients were randomly assigned to receive 0.75 µg eldecalcitol or 1.0 µg alfacalcidol for 12 months without vitamin D or calcium supplementation. Baseline calcium intakes were less than 550 mg/day and mean serum 25-hydroxyvitamin D [25(OH)D] was below 43 nmol/L in both groups. Baseline BMD tended to be lower in patients with lower calcium intake and serum 25(OH)D. Lumbar BMD increased by 2.05% higher in eldecalcitol than alfacalcidol group at 12 months. Total hip and femoral neck BMD also increased by 1.33 and 1.78%, respectively, in the eldecalcitol than the alfacalcidol group. The effect of eldecalcitol on BMD was not affected by serum 25(OH)D or calcium intake. The incidence of adverse events was not different between the two groups. Incidence of hypercalcemia in the edecalcitol group was not affected by serum 25(OH)D. In conclusion, baseline BMD tended to be lower in patients with low calcium intake and serum 25(OH)D. Eldecalcitol increased lumbar and hip BMD more than alfacalcidol regardless of serum 25(OH)D or calcium intake without vitamin D or calcium supplementation. These results suggest that eldecalcitol is effective in increasing the BMD of osteoporotic patients regardless of vitamin D status or calcium intake.Clinical Trial Registration number JAPIC CTI 152904.


Assuntos
Densidade Óssea/efeitos dos fármacos , Cálcio/farmacologia , Suplementos Nutricionais , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologia , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Idoso , Biomarcadores/sangue , Conservadores da Densidade Óssea/farmacologia , Remodelação Óssea/efeitos dos fármacos , Cálcio/sangue , Cálcio/urina , Método Duplo-Cego , Feminino , Colo do Fêmur/efeitos dos fármacos , Colo do Fêmur/fisiopatologia , Quadril/fisiopatologia , Humanos , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoporose/sangue , Osteoporose/urina , Vitamina D/efeitos adversos , Vitamina D/sangue , Vitamina D/uso terapêutico
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