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[PMID]:29442028
[Au] Autor:Ng PY; Ong AJ; Gale LS; Dass CR
[Ti] Título:Treatment of bone disorders with parathyroid hormone: success and pitfalls.
[So] Source:Pharmazie;71(8):427-433, 2016 08 01.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Bone diseases such as osteoporosis, osteoarthritis, bone tumours and bone fractures are rather common and not just in the elderly. Parathyroid hormone (PTH) is responsible for maintaining calcium homeostasis, increasing bone mineral density (BMD), increasing cortical and trabecular bone thickness and thus increasing bone strength. Teriparatide (PTH 1-34) has the same effects as endogenous PTH and is pharmacologically used to treat bone diseases such as osteoporosis, osteoarthritis, bone fractures and bone tumours. This review discusses how PTH 1-34 plays a role in managing bone diseases. Clinical studies have shown that short or intermittent dosing of PTH 1-34 has minimal adverse effects, while long-term dosing (over two years) has been linked to de novo osteoarthritis and bone deformation. Currently PTH therapy is only approved in the treatment of post-menopausal osteoporosis, however it is also proven to have effects in treating osteoarthritis, bone tumours and bone fractures. If the patient undergoing therapy is closely monitored, the major pitfalls are very unlikely to take place, thus it is highly recommended that patients be closely monitored by a medical practitioner.
[Mh] Termos MeSH primário: Doenças Ósseas/tratamento farmacológico
Hormônio Paratireóideo/efeitos adversos
Hormônio Paratireóideo/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Conservadores da Densidade Óssea/uso terapêutico
Difosfonatos/uso terapêutico
Seres Humanos
Hormônio Paratireóideo/fisiologia
Ensaios Clínicos Controlados Aleatórios como Assunto
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates); 0 (Parathyroid Hormone)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6008


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[PMID]:29403337
[Au] Autor:Umunakwe OC; Herren D; Kim SJ; Kohanim S
[Ad] Endereço:Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.
[Ti] Título:Diffuse ocular and orbital inflammation after zoledronate infusion-case report and review of the literature.
[So] Source:Digit J Ophthalmol;23(4):18-21, 2017.
[Is] ISSN:1542-8958
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bisphosphonates have become a commonly used class of medications to treat osteoporosis and other bone diseases. Zoledronate (zoledronic acid) can be dosed annually via intravenous infusion, making it an appealing option for patients and physicians. We report the case of a 68-year-old woman who developed severe, unilateral, ocular inflammation, including corneal endotheliitis, anterior uveitis with hyphema, scleritis, and orbital inflammation beginning 12 hours after receiving her first zoledronate infusion. Symptoms escalated but ultimately resolved with topical steroids and high-dose systemic corticosteroids. To our knowledge, this is the first report of unilateral diffuse inflammation of the eye and orbit, including corneal inflammation developing within 12 hours of a first zoledronate infusion.
[Mh] Termos MeSH primário: Difosfonatos/efeitos adversos
Imidazóis/efeitos adversos
Doenças Orbitárias/induzido quimicamente
Osteoporose/tratamento farmacológico
Uveíte Anterior/induzido quimicamente
[Mh] Termos MeSH secundário: Doença Aguda
Idoso
Conservadores da Densidade Óssea/administração & dosagem
Conservadores da Densidade Óssea/efeitos adversos
Difosfonatos/administração & dosagem
Feminino
Seres Humanos
Imidazóis/administração & dosagem
Inflamação/induzido quimicamente
Inflamação/diagnóstico
Infusões Intravenosas
Doenças Orbitárias/diagnóstico
Tomografia Computadorizada por Raios X
Uveíte Anterior/diagnóstico
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates); 0 (Imidazoles); 6XC1PAD3KF (zoledronic acid)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE
[do] DOI:10.5693/djo.02.2017.08.002


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[PMID]:28458336
[Au] Autor:Nakamura Y; Suzuki T; Kamimura M; Ikegami S; Uchiyama S; Kato H
[Ad] Endereço:Department of Orthopaedic Surgery, Shinshu University School of Medicine.
[Ti] Título:Alfacalcidol Increases the Therapeutic Efficacy of Ibandronate on Bone Mineral Density in Japanese Women with Primary Osteoporosis.
[So] Source:Tohoku J Exp Med;241(4):319-326, 2017 04.
[Is] ISSN:1349-3329
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Bisphosphonates (BPs) increase bone mineral density (BMD) through the inhibition of osteoclast activity. Among BPs, ibandronate (IBN) is a strong inhibitor of bone resorption. However, the effects of a vitamin D analogue, alfacalcidol (ALF), on IBN treatment for osteoporosis is unknown. Fifty-three treatment-naïve post-menopausal women with primary osteoporosis were recruited and divided into IBN-treatment group (IBN group) and IBN with ALF group (IBN/ALF group). IBN (1.0 mg) was intravenously injected once a month, with or without oral ALF (1.0 µg/day). Ultimately, 19 subjects in IBN group and 26 in IBN/ALF group were analyzed. Bone turnover markers were examined at 4, 6, 12, and 18 months, and BMD was measured at 6, 12, and 18 months. Compared with pre-treatment, bone turnover markers significantly decreased in both groups after 4 months. The levels of serum N-terminal propeptide of type-1 procollagen and tartrate-resistant acid phosphatase-5b, and urinary N-terminal telopeptide of type-I collagen were significantly lower in IBN/ALF group than those in IBN group at 12 months. Lumbar 1-4 (L)-BMD significantly increased from 6 months in IBN/ALF group and at 18 months in IBN group. L-BMD was significantly higher in IBN/ALF group (6.6% increase) than in IBN group (3.4%) at 18 months. Total hip (H)-BMD significantly increased from 6 months in IBN/ALF group and tended to improve in IBN group. H-BMD was significantly higher in IBN/ALF group (4.8%) than in IBN group (3.2%) at 18 months. In conclusion, treatment with ALF in combination with IBN improves BMD in post-menopausal women with osteoporosis.
[Mh] Termos MeSH primário: Conservadores da Densidade Óssea/uso terapêutico
Densidade Óssea/efeitos dos fármacos
Difosfonatos/uso terapêutico
Hidroxicolecalciferóis/uso terapêutico
Osteoporose/tratamento farmacológico
[Mh] Termos MeSH secundário: Absorciometria de Fóton
Administração Intravenosa
Administração Oral
Idoso
Grupo com Ancestrais do Continente Asiático
Sinergismo Farmacológico
Feminino
Quadril/diagnóstico por imagem
Seres Humanos
Hidroxicolecalciferóis/efeitos adversos
Pós-Menopausa
Fosfatase Ácida Resistente a Tartarato/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates); 0 (Hydroxycholecalciferols); EC 3.1.3.2 (Tartrate-Resistant Acid Phosphatase); UMD7G2653W (ibandronic acid); URQ2517572 (alfacalcidol)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1620/tjem.241.319


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[PMID]:29370211
[Au] Autor:Hayes AR; Brungs D; Pavlakis N
[Ad] Endereço:Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
[Ti] Título:Osteoclast inhibitors to prevent bone metastases in men with high-risk, non-metastatic prostate cancer: A systematic review and meta-analysis.
[So] Source:PLoS One;13(1):e0191455, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: In advanced prostate cancer, osteoclast inhibitors prevent and palliate skeletal related events associated with bone metastases. However, it is uncertain whether they play a disease-modifying role earlier in the course of the disease. METHODS: Medline, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and ASCO conference proceedings were searched for randomized controlled trials that compared osteoclast inhibitors with placebo and/or standard of care (SOC) in patients with high-risk, non-metastatic prostate cancer. The primary outcome measure was incidence of new bone metastases; secondary outcomes included overall survival (OS), prostate cancer specific survival, mortality unrelated to prostate cancer, toxicity and health related quality of life outcomes. Results are presented as relative risk (RR) with 95% confidence intervals (CI). RESULTS: Six randomized controlled trials (5947 participants) were included, five evaluating bisphosphonates and one denosumab. Overall, there was no difference in incidence of bone metastases between participants treated with osteoclast inhibitors versus placebo/SOC (RR 1.09, 95%CI 0.84-1.41, p = 0.51) however significant heterogeneity was observed between studies. The denosumab trial was the largest and only positive trial amongst the included studies (RR 0.83, 95%CI 0.73-0.95, p = 0.007). No significant difference was observed in OS (RR 0.99 95% CI 0.89-1.10, p = 0.84) nor prostate cancer specific survival (RR 1.12 95%CI 0.93-1.36, p = 0.24). Most studies reported increased rates of osteonecrosis of the jaw (5% or less) and hypocalcemia (2% or less) with osteoclast inhibitors. CONCLUSIONS: While there is limited evidence that bisphosphonates alter the natural history of high-risk, non-metastatic prostate cancer, denosumab delays onset of bone metastases in this patient population. Neither class of osteoclast inhibitor demonstrated an impact on survival outcomes. Future trials with better defined patient selection and a robust definition for high risk disease is critical.
[Mh] Termos MeSH primário: Conservadores da Densidade Óssea/uso terapêutico
Neoplasias Ósseas/prevenção & controle
Neoplasias Ósseas/secundário
Osteoclastos/efeitos dos fármacos
Neoplasias da Próstata/tratamento farmacológico
[Mh] Termos MeSH secundário: Denosumab/uso terapêutico
Difosfonatos/uso terapêutico
Seres Humanos
Masculino
Osteoclastos/patologia
Avaliação de Resultados (Cuidados de Saúde)
Neoplasias da Próstata/patologia
Qualidade de Vida
Ensaios Clínicos Controlados Aleatórios como Assunto
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates); 4EQZ6YO2HI (Denosumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180126
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191455


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[PMID]:28459066
[Au] Autor:Jang SP; Yeo I; So SY; Kim K; Moon YW; Park YS; Lim SJ
[Ad] Endereço:Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
[Ti] Título:Atypical Femoral Shaft Fractures in Female Bisphosphonate Users Were Associated with an Increased Anterolateral Femoral Bow and a Thicker Lateral Cortex: A Case-Control Study.
[So] Source:Biomed Res Int;2017:5932496, 2017.
[Is] ISSN:2314-6141
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The purpose of our study was to investigate the radiographic characteristics of atypical femoral shaft fractures (AFSFs) in females with a particular focus on femoral bow and cortical thickness. We performed a fracture location-, age-, gender-, and ethnicity-matched case-control study. Forty-two AFSFs in 29 patients and 22 typical osteoporotic femoral shaft fractures in 22 patients were enrolled in AFSF group and control group, respectively. With comparing demographics between two groups, radiographically measured femoral bow and cortical thicknesses of AFSF group were compared with control group. All AFSF patients were females with a mean age of 74.4 years (range, 58-85 years). All had a history of bisphosphonate (BP) use with a mean duration of 7.3 years (range 1-17 years). Femoral bow of AFSF group was significantly higher than control group on both anteroposterior (AP) and lateral radiographs after age correction. Mean femoral bow on an AP radiograph was 12.39° ± 5.38° in AFSF group and 3.97 ± 3.62° in control group ( < 0.0001). Mean femoral bow on the lateral radiograph was 15.71° ± 5.62° in AFSF group and 10.72° ± 4.61° in control group (after age correction = 0.003). And cortical thicknesses of AFSF group demonstrated marked disparity between tensile and compressive side of bowed femurs in this study. An adjusted lateral cortical thickness was 10.5 ± 1.4 mm in AFSF group and 8.1 ± 1.3 mm in control group (after age correction < 0.0001) while medial cortical thickness of AFSF group was not statistically different from control group. Correlation analysis showed that the lateral femoral bow on the AP radiograph was solely related to lateral CTI ( = 0.378, = 0.002). AFSFs in female BP users were associated with an increased anterolateral femoral bow and a thicker lateral cortex of femurs.
[Mh] Termos MeSH primário: Conservadores da Densidade Óssea
Difosfonatos
Fraturas do Fêmur/diagnóstico por imagem
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Conservadores da Densidade Óssea/efeitos adversos
Conservadores da Densidade Óssea/uso terapêutico
Estudos de Casos e Controles
Difosfonatos/efeitos adversos
Difosfonatos/uso terapêutico
Feminino
Fraturas do Fêmur/epidemiologia
Fêmur/diagnóstico por imagem
Seres Humanos
Meia-Idade
Osteoporose/tratamento farmacológico
Osteoporose/prevenção & controle
Radiografia
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1155/2017/5932496


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[PMID]:29304080
[Au] Autor:Hong C; Quach A; Lin L; Olson J; Kwon T; Bezouglaia O; Tran J; Hoang M; Bui K; Kim RH; Tetradis S
[Ad] Endereço:Section of Orthodontics, Division of Growth and Development, UCLA School of Dentistry, Los Angeles, California, United States of America.
[Ti] Título:Local vs. systemic administration of bisphosphonates in rat cleft bone graft: A comparative study.
[So] Source:PLoS One;13(1):e0190901, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A majority of patients with orofacial cleft deformity requires cleft repair through a bone graft. However, elevated amount of bone resorption and subsequent bone graft failure remains a significant clinical challenge. Bisphosphonates (BPs), a class of anti-resorptive drugs, may offer great promise in enhancing the clinical success of bone grafting. In this study, we compared the effects of systemic and local delivery of BPs in an intraoral bone graft model in rats. We randomly divided 34 female 20-week-old Fischer F344 Inbred rats into four groups to repair an intraoral critical-sized defect (CSD): (1) Control: CSD without graft (n = 4); (2) Graft/Saline: bone graft with systemic administration of saline 1 week post-operatively (n = 10); (3) Graft/Systemic: bone graft with systemic administration of zoledronic acid 1 week post-operatively (n = 10); and (4) Graft/Local: bone graft pre-treated with zoledronic acid (n = 10). At 6-weeks post-operatively, microCT volumetric analysis showed a significant increase in bone fraction volume (BV/TV) in the Graft/Systemic (62.99 ±14.31%) and Graft/Local (69.35 ±13.18%) groups compared to the Graft/Saline (39.18±10.18%). Similarly, histological analysis demonstrated a significant increase in bone volume in the Graft/Systemic (78.76 ±18.00%) and Graft/Local (89.95 ±4.93%) groups compared to the Graft/Saline (19.74±18.89%). The local delivery approach resulted in the clinical success of bone grafts, with reduced graft resorption and enhanced osteogenesis and bony integration with defect margins while avoiding the effects of BPs on peripheral osteoclastic function. In addition, local delivery of BPs may be superior to systemic delivery with its ease of procedure as it involves simple soaking of bone graft materials in BP solution prior to graft placement into the defect. This new approach may provide convenient and promising clinical applications towards effectively managing cleft patients.
[Mh] Termos MeSH primário: Transplante Ósseo
Fissura Palatina/cirurgia
Difosfonatos/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Fissura Palatina/tratamento farmacológico
Feminino
Osteoclastos/efeitos dos fármacos
Ratos
Ratos Endogâmicos F344
Microtomografia por Raio-X
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Diphosphonates)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190901


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[PMID]:29384970
[Au] Autor:Lou S; Wang L; Wang Y; Jiang Y; Liu J; Wang Y
[Ad] Endereço:Department of Spine Surgery.
[Ti] Título:Combination therapy of anabolic and nonbisphosphonates antiresorptive agents for the treatment of osteoporosis: A meta-analysis.
[So] Source:Medicine (Baltimore);96(52):e9534, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: According to the mechanisms of action, combination therapy of anabolic and antiresorptive agents may produce more effect for the treatment of osteoporosis. However, the combination therapy of anabolic agents and bisphosphonates reports no benefit and even reduced the anabolic effects of anabolic agents. This study aims to assess the effect of combination therapy of anabolic and nonbisphosphonates antiresorptive agents in adults with osteoporosis. METHODS: Medline, EMBASE, and Cochrane Library were searched from January 1, 1980 to November 1, 2017 for randomized controlled trials (RCTs) of adults with osteoporosis treated in combination therapy of anabolic and nonbisphosphonates antiresorptive agents compared with monotherapy of either agent alone. The primary outcome was the incidence of fractures. The secondary outcomes were the bone mineral density (BMD) changes at lumbar spine and total hip. Continuous outcomes were expressed as standardized mean difference (SMD) and 95% confidence interval (CI), while dichotomous outcomes were expressed as risk ratio (RR) and 95% CI. The meta-analysis was performed using a random-effects model. I statistic (I > 50% as a threshold indicates significant heterogeneity) was used to assess the heterogeneity. RESULTS: A total of 10 trials with a total of 1042 patients were included. The pooled results showed that the combination therapy demonstrated a significant advantage over a monotherapy in the BMD improvement at the lumbar spine (SMD 1.18; 95% CI, 0.63 to 1.72; I = 93%) and the total hip (SMD 0.89; 95% CI, 0.48 to 1.29; I = 88%) and further reduce the fracture risk (RR, 0.45; 95%CI, 0.21 to 0.94; I = 0%). CONCLUSIONS: Low-to-moderate-quality evidence shows that the combination therapy of anabolic and nonbisphosphonates antiresorptive agents is superior to monotherapy in improving the BMD and reducing the fracture risk. However, further high methodological quality studies are needed to determine the antifracture efficacy, cost-effectiveness and safety of this strategy of combination therapy.
[Mh] Termos MeSH primário: Conservadores da Densidade Óssea/uso terapêutico
Fraturas Ósseas/prevenção & controle
Osteoporose/tratamento farmacológico
[Mh] Termos MeSH secundário: Densidade Óssea/efeitos dos fármacos
Conservadores da Densidade Óssea/administração & dosagem
Difosfonatos/uso terapêutico
Quimioterapia Combinada
Seres Humanos
Hormônio Paratireóideo/uso terapêutico
Ensaios Clínicos Controlados Aleatórios como Assunto
Teriparatida/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates); 0 (Parathyroid Hormone); 10T9CSU89I (Teriparatide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009534


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[PMID]:29339529
[Au] Autor:Adler RA
[Ad] Endereço:Endocrinology and Metabolism SectionMcGuire Veterans Affairs Medical Center, Division of Endocrinology,Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA Robert.adler@va.gov.
[Ti] Título:MANAGEMENT OF ENDOCRINE DISEASE: Atypical femoral fractures: risks and benefits of long-term treatment of osteoporosis with anti-resorptive therapy.
[So] Source:Eur J Endocrinol;178(3):R81-R87, 2018 Mar.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Modern osteoporosis treatment began in the mid-1990s with the approval of amino-bisphosphonates, anti-resorptive agents that have been shown to decrease osteoporotic fracture risk by about half. In 2005, the first cases of atypical femoral fractures (AFF), occurring in the shaft of the femur, were reported. Since then, more cases have been found, leading to great concern among patients and a dramatic decrease in bisphosphonate prescribing. The pathogenesis and incidence of AFF are reviewed herein. Management and an approach to prevention or early detection of AFF are also provided. Denosumab, a more recently approved anti-resorptive medication has also been associated with AFF. Long-term management of osteoporosis and prevention of fracture are challenging in light of this serious but uncommon side effect, yet with an aging population osteoporotic fracture is destined to increase in frequency.
[Mh] Termos MeSH primário: Conservadores da Densidade Óssea/efeitos adversos
Fraturas do Fêmur/induzido quimicamente
Osteoporose/tratamento farmacológico
Fraturas por Osteoporose/prevenção & controle
[Mh] Termos MeSH secundário: Conservadores da Densidade Óssea/uso terapêutico
Denosumab/efeitos adversos
Denosumab/uso terapêutico
Difosfonatos/efeitos adversos
Difosfonatos/uso terapêutico
Seres Humanos
Medição de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates); 4EQZ6YO2HI (Denosumab)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.1530/EJE-17-1002


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[PMID]:29248353
[Au] Autor:Matthiesen RA; Varney ML; Xu PC; Rier AS; Wiemer DF; Holstein SA
[Ad] Endereço:Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States.
[Ti] Título:α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.
[So] Source:Bioorg Med Chem;26(2):376-385, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates.
[Mh] Termos MeSH primário: Difosfonatos/farmacologia
Inibidores Enzimáticos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Terpenos/farmacologia
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Difosfonatos/síntese química
Difosfonatos/química
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Farnesiltranstransferase/metabolismo
Seres Humanos
Metilação
Estrutura Molecular
Relação Estrutura-Atividade
Terpenos/síntese química
Terpenos/química
Triazóis/síntese química
Triazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Diphosphonates); 0 (Enzyme Inhibitors); 0 (Terpenes); 0 (Triazoles); EC 2.5.1.29 (Farnesyltranstransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:28744112
[Au] Autor:Pan WL; Chen PL; Lin CY; Pan YC; Ju YR; Chan CP; Hsu RW
[Ad] Endereço:Department of Periodontics, Chang Gung Memorial Hospital, Taipei, Taiwan.
[Ti] Título:Strontium ranelate treatment in a postmenopausal woman with osteonecrosis of the jaw after long-term oral bisphosphonate administration: a case report.
[So] Source:Clin Interv Aging;12:1089-1093, 2017.
[Is] ISSN:1178-1998
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Bisphosphonates (BPs) suppress bone resorption and increase bone strength, thus reducing the risk of fracture. Oral BPs are widely used for the prevention and treatment of osteoporosis and osteopenia. Here, we describe the case of a postmenopausal woman who took oral alendronate for >3 years for osteoporosis. The patient presented at the clinic with sharp jaw pain and swelling on the left mandible 4 months after extraction of the third molar. Clinical examinations identified an inflamed mucosal opening with pus over an area of necrotic bone. Initial images of cone beam computed tomography revealed a sequestrum at the extracted socket. The condition did not improve after 1 week of antibiotic treatment; therefore, the alendronate treatment was terminated and the patient was prescribed strontium ranelate instead. The patient gradually recovered and, at the 2-year follow-up, the site of BP-related osteonecrosis of the jaw healed completely as determined by both clinical and cone beam computed tomography measures. The bone mineral densities in the femoral neck and lumbar spine improved after 1 year, and were maintained at the 3-year follow-up. The serum C-terminal cross-linking telopeptide values also gradually increased from the initial 130 pg/mL to 320 pg/mL at the 3-year follow-up. Taken together, this case supports the use of strontium ranelate as an alternative treatment for postmenopausal women who receive long-term oral BP treatments and are at risk for serious complications of BP-related osteonecrosis of the jaw.
[Mh] Termos MeSH primário: Alendronato/efeitos adversos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico
Conservadores da Densidade Óssea/efeitos adversos
Osteoporose Pós-Menopausa/tratamento farmacológico
Tiofenos/uso terapêutico
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Alendronato/uso terapêutico
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia
Conservadores da Densidade Óssea/uso terapêutico
Difosfonatos/efeitos adversos
Feminino
Seres Humanos
Pós-Menopausa
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bone Density Conservation Agents); 0 (Diphosphonates); 0 (Thiophenes); 04NQ160FRU (strontium ranelate); X1J18R4W8P (Alendronate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.2147/CIA.S141753



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