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1.
J Am Coll Cardiol ; 71(10): 1117-1126, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29519353

RESUMO

BACKGROUND: In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease. OBJECTIVES: The authors hypothesized that etidronate, a pyrophosphate analog, might reduce ectopic mineralization in PXE. METHODS: In the Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial, adults with PXE and leg arterial calcifications (n = 74) were randomly assigned to etidronate or placebo (cyclical 20 mg/kg for 2 weeks every 12 weeks). The primary outcome was ectopic mineralization, quantified with 18fluoride positron emission tomography scans as femoral arterial wall target-to-background ratios (TBRfemoral). Secondary outcomes were computed tomography arterial calcification and ophthalmological changes. Safety outcomes were bone density, serum calcium, and phosphate. RESULTS: During 12 months of follow-up, the TBRfemoral increased 6% (interquartile range [IQR]: -12% to 25%) in the etidronate group and 7% (IQR: -9% to 32%) in the placebo group (p = 0.465). Arterial calcification decreased 4% (IQR: -11% to 7%) in the etidronate group and increased 8% (IQR: -1% to 20%) in the placebo group (p = 0.001). Etidronate treatment was associated with significantly fewer subretinal neovascularization events (1 vs. 9, p = 0.007). Bone density decreased 4% ± 12% in the etidronate group and 6% ± 9% in the placebo group (p = 0.374). Hypocalcemia (<2.20 mmol/l) occurred in 3 versus 1 patient (8.1% vs. 2.7%, p = 0.304). Eighteen patients (48.6%) treated with etidronate, compared with 0 patients treated with placebo (p < 0.001), experienced hyperphosphatemia (>1.5 mmol/l) and recovered spontaneously. CONCLUSIONS: In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral 18fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180).


Assuntos
Ácido Etidrônico , Doença Arterial Periférica , Pseudoxantoma Elástico , Calcificação Vascular , Idoso , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacocinética , Cálcio/sangue , Cálcio/metabolismo , Monitoramento de Medicamentos/métodos , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/farmacocinética , Feminino , Fêmur/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etiologia , Doença Arterial Periférica/prevenção & controle , Fosfatos/sangue , Tomografia por Emissão de Pósitrons/métodos , Pseudoxantoma Elástico/complicações , Pseudoxantoma Elástico/diagnóstico , Pseudoxantoma Elástico/tratamento farmacológico , Pseudoxantoma Elástico/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Calcificação Vascular/diagnóstico , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/etiologia
2.
Acta otorrinolaringol. esp ; 66(3): 139-147, mayo-jun. 2015. tab, ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-137368

RESUMO

Introducción y objetivos: Los bisfosfonatos son fármacos con un amplio espectro de indicaciones cuya principal capacidad es la inhibición de la función osteoclástica. En el año 2003 se ha descrito una complicación asociada a su empleo, la osteonecrosis de los maxilares por bisfosfonatos (ONMB). Los objetivos del presente estudio son identificar los casos recogidos de ONMB en un hospital de tercer nivel durante 8 años, evaluando las principales variables en relación con la enfermedad, el bisfosfonato empleado y los factores de riesgo locales o generales que pudieran actuar como desencadenante en la patogénesis de la ONMB. Material y método: Se procedió a la selección los pacientes diagnosticados de ONMB en un centro de referencia para una población de 1.100.000 habitantes. Las variables analizadas se dividieron en 3 grupos: pacientes, fármaco (incluyendo el análisis de la dosis aplicada y la ponderación dosis/potencia) y osteonecrosis. Resultados: Se recogieron 70 casos (44 mujeres y 26 varones), con una media de 66,8 años. Dieciocho pacientes habían recibido un aminobisfosfonato oral y 52 por vía intravenosa. El tiempo medio de administración fue de 26,53 meses. En el 67,1% de los pacientes se pudo identificar un factor local desencadenante, siendo el más frecuente la exodoncia (48,6%). Aunque la exposición ósea estaba presente en el 75,7% de los casos, 8 enfermos padecieron una osteonecrosis sin exposición, manifestando la presencia de dolor y/o fístula crónica. El 58,6% experimentaron una resolución completa con un tiempo medio de control de 16,28 meses. Conclusiones: El 25% de las ONMB en nuestra serie se relacionaron con la administración de un bisfosfonato oral, especialmente el alendronato. El ácido zoledrónico es el agente que menos miligramos precisa para desarrollar la enfermedad. La exposición ósea solitaria fue el dato clínico más habitual, afectando especialmente a sectores posteriores mandibulares en pacientes con enfermedad metastásica (AU)


Background and objectives: Bisphosphonates are widely prescribed drugs whose principal capacity is inhibiting the osteoclast function. In 2003 a complication related to their administration, bisphosphonate-related osteonecrosis of the jaw (BRONJ), was described. The objectives of this study were to identify diagnosed cases of BRONJ in a third-level hospital over 8 years, evaluating the main features in relation to the disease, the bisphosphonate and the presence of local or general risk factors that could trigger the BRONJ. Material and method: Patients diagnosed with BRONJ in a centre of reference for a population of 1,100,000 inhabitants were selected. Variables analysed were classified into 3 groups: patients, bisphosphonate (focusing on dose and weighting dose/potency) and osteonecrosis. Results: Seventy cases were studied —44 women and 26 men—, with a mean age of 66.8 years. Eighteen patients received bisphosphonates orally and 52, intravenously. The mean time of administration was 26.53 months. In 67.1% of the patients it was possible to identify a local trigger, with the most common being tooth extraction (48.6%). Bone exposure was present in 89.2% of the cases, while 12 patients developed BRONJ without exposed bone, with only pain and/or chronic sinus tracts. Complete resolution was achieved in 58.6% of the patients, with a mean time of control of 16.28 months. Conclusions: 25% of the BRONJ cases were related to the administration of oral bisphosphonates, especially alendronate. Zoledronic acid was the bisphosphonate that required the fewest milligrams to induce osteonecrosis. Single bone exposure was the most common clinical finding, especially in the molar mandibular region in patients with metastatic disease (AU)


Assuntos
Feminino , Humanos , Masculino , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Fatores de Risco , Estudos Retrospectivos , Espanha/epidemiologia
3.
Int J Mol Med ; 36(1): 159-65, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25975272

RESUMO

Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder of spontaneous infantile arterial and periarticular calcification which is attributed to mutations in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) gene. Whilst the bisphosphonate, etidronate, is currently used off-label for the treatment for GACI, recent studies have highlighted its detrimental effects on bone mineralisation. In the present study, we used the Enpp1-/- mouse model of GACI to examine the effects of etidronate treatment (100 µg/kg), on vascular and skeletal calcification. Micro-computed tomography (µCT) analysis revealed a significant decrease in trabecular bone mass, as reflected by the decrease in trabecular bone volume/tissue volume (BV/TV; %), trabecular thickness, trabecular separation, trabecular number and pattern factor (P<0.05) in the Enpp1-/- mice in comparison to the wild-type (WT) mice. Mechanical testing revealed that in the WT mice, treatment with etidronate significantly improved work to fracture and increased work post-failure (P<0.05, in comparison to the vehicle-treated WT mice). This significant increase, however, was not observed in the Enpp1-/- mice. Treatment with etidronate had no effect on bone parameters in the WT mice; however, the Enpp1-/- mice displayed an increased structural model index (SMI; P<0.05). We used a recently developed 3D µCT protocol to reconstruct and quantify the extensive aortic calcification in Enpp1-/- mice in comparison to the WT mice. However, treatment with etidronate did not prevent de novo calcification, and did not arrest the progression of established calcification of the aorta.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Calcificação Fisiológica/efeitos dos fármacos , Ácido Etidrônico/efeitos adversos , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Calcificação Vascular/tratamento farmacológico , Animais , Aorta/patologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Modelos Animais de Doenças , Ácido Etidrônico/uso terapêutico , Predisposição Genética para Doença , Masculino , Camundongos , Camundongos Knockout , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Calcificação Vascular/genética , Microtomografia por Raio-X
4.
Arch Osteoporos ; 10: 213, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25792348

RESUMO

UNLABELLED: This case report highlights the potential severity of bisphosphonate-associated reactions. CASE REPORT: A 76-year-old lady underwent several hospital admissions for investigation of fever associated with rigors, abdominal pain, and vomiting. DISCUSSION: Despite multiple investigations, no cause was found, but the timing of the symptoms coincided with monthly risedronate administration.


Assuntos
Abscesso Abdominal/etiologia , Ácido Etidrônico/análogos & derivados , Sepse/etiologia , Abscesso Abdominal/induzido quimicamente , Abscesso Abdominal/diagnóstico , Idoso , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Feminino , Humanos , Osteoporose/tratamento farmacológico , Ácido Risedrônico , Sepse/induzido quimicamente , Sepse/diagnóstico
5.
Osteoporos Int ; 26(1): 327-37, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25304456

RESUMO

UNLABELLED: This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens. INTRODUCTION: The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate. METHODS: Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated. RESULTS: Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women. CONCLUSIONS: Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Ácido Etidrônico/análogos & derivados , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Biópsia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/patologia , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/farmacologia , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Osteoporose Pós-Menopausa/patologia , Osteoporose Pós-Menopausa/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Risedrônico
6.
Acta Otorrinolaringol Esp ; 66(3): 139-47, 2015.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-25308796

RESUMO

BACKGROUND AND OBJECTIVES: Bisphosphonates are widely prescribed drugs whose principal capacity is inhibiting the osteoclast function. In 2003 a complication related to their administration, bisphosphonate-related osteonecrosis of the jaw (BRONJ), was described. The objectives of this study were to identify diagnosed cases of BRONJ in a third-level hospital over 8 years, evaluating the main features in relation to the disease, the bisphosphonate and the presence of local or general risk factors that could trigger the BRONJ. METHODS: Patients diagnosed with BRONJ in a centre of reference for a population of 1,100,000 inhabitants were selected. Variables analysed were classified into 3 groups: patients, bisphosphonate (focusing on dose and weighting dose/potency) and osteonecrosis. RESULTS: Seventy cases were studied -44 women and 26 men-, with a mean age of 66.8 years. Eighteen patients received bisphosphonates orally and 52, intravenously. The mean time of administration was 26.53 months. In 67.1% of the patients it was possible to identify a local trigger, with the most common being tooth extraction (48.6%). Bone exposure was present in 89.2% of the cases, while 12 patients developed BRONJ without exposed bone, with only pain and/or chronic sinus tracts. Complete resolution was achieved in 58.6% of the patients, with a mean time of control of 16.28 months. CONCLUSIONS: 25% of the BRONJ cases were related to the administration of oral bisphosphonates, especially alendronate. Zoledronic acid was the bisphosphonate that required the fewest milligrams to induce osteonecrosis. Single bone exposure was the most common clinical finding, especially in the molar mandibular region in patients with metastatic disease.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Centros de Atenção Terciária , Ácido Zoledrônico
7.
J Endocrinol Invest ; 38(2): 189-92, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25412945

RESUMO

BACKGROUND: This study was aimed at comparing the safety of bisphosphonates in women with osteoporosis by application of equivalence testing. METHODS: Gastrointestinal and renal side effects were evaluated based on information published in randomized controlled trials. RESULTS: The data on gastrointestinal side effects (47 trials) indicated that alendronate, risedronate etidronate, and zolendronate have similar rates of the adverse effects; application of Bayesian network meta-analysis showed that equivalence was demonstrated according to margins around ±10%. The data on renal safety were more sparse and suffered from the use of different outcome measures; hence, a single trial could be evaluated. This trial showed a similar effect of alendronate and risedronate on renal function at 12 months; equivalence was based on differences between the two agents in renal function with margins of less than ±10.4 ml/min. CONCLUSION: Our study provided quantitative information to determine to what extent bisphosphonates can be considered equivalent in terms of gastrointestinal and renal side effects.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Gastroenteropatias/induzido quimicamente , Nefropatias/induzido quimicamente , Alendronato/efeitos adversos , Ácido Etidrônico/efeitos adversos , Feminino , Gastroenteropatias/epidemiologia , Humanos , Nefropatias/epidemiologia , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Int J Biol Macromol ; 70: 174-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24995633

RESUMO

Risedronate sodium (RA), a pyridinyl bisphosphonate, is widely used in the treatment of osteoporosis. However, the free acid form of the bisphosphonate below pH 3.5 has the potential to produce severe impatience of the upper gastrointestinal tract, particularly esophagitis. A pH-responsive raft-forming tablet (PRR-T) was designed to prevent the esophageal irritation, mainly consisting of low-molecular-weight alginate (LFR 5/60, 300 mg) as raft-forming polymer, sodium bicarbonate (1000 mg) as gas-generating agent and citrate and sodium citrate (600 and 200 mg, respectively) as buffer system. A PRR-T was rapidly liquefied in water within 80 s with a low viscosity 8.0 mPa s, offering ease of swallowing in patients. A formulation profoundly neutralized simulated gastric fluid over pH 5.5, leading to an ionization of the bisphosphonate, without raft formation. On the other hand, the raft was rapidly formed on the top layer preventing the reflux of RA, if the contact with acidic medium is much higher than 0.5 N of hydrochloric acid. Nevertheless, the release rate of the drug was equivalent, providing over 95% release within 5 min. Our study demonstrated the potential usefulness of alginate-based PRR-T for an oral therapy with bisphosphonates for reduced esophageal adverse experiences.


Assuntos
Alginatos/química , Desenho de Fármacos , Esôfago/efeitos dos fármacos , Ácido Etidrônico/análogos & derivados , Irritantes/química , Irritantes/farmacologia , Química Farmacêutica , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/química , Ácido Etidrônico/farmacologia , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Humanos , Concentração de Íons de Hidrogênio , Irritantes/efeitos adversos , Ácido Risedrônico , Comprimidos , Viscosidade
10.
Osteoporos Int ; 25(7): 1953-61, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24676847

RESUMO

UNLABELLED: Managing osteoporotic patients suboptimally adherent to bisphosphonates (BPs) is difficult. Such patients who remained at higher risk for fracture (≥1 risk factor) were transitioned to denosumab or a monthly oral BP. Denosumab-treated subjects had significantly greater increases in bone mineral density and decreases in bone turnover in this 12-month study. INTRODUCTION: A clinical need exists to manage patients who are suboptimally adherent to oral BPs and remain at higher risk for fracture. Here, we compare the effects on bone mineral density (BMD) and bone turnover of transitioning such patients to denosumab or monthly oral BP (ibandronate or risedronate). METHODS: In two previous multicenter, open-label studies, postmenopausal women ≥55 years previously treated with, though suboptimally adherent to, a daily or weekly BP were randomized to denosumab 60 mg subcutaneously every 6 months (N = 852) or oral BP 150 mg monthly (N = 851) for 12 months. In this combined post-hoc analysis, a subset of higher risk subjects was identified, and the percentage changes from baseline in BMD and serum C-telopeptide of type I collagen (sCTX-1) were assessed. RESULTS: In the overall population, denosumab was associated with greater gains in BMD at 12 months than monthly oral BP at the total hip, femoral neck, and lumbar spine (p < 0.0001 for all). In higher risk subjects, denosumab led to greater gains in BMD than oral BPs at the total hip (2.2 vs 0.8 %), femoral neck (1.8 vs 0.3 %), and lumbar spine (3.7 vs 1.4 %) (p < 0.0001 for all). Denosumab also led to greater decreases in sCTX-1 in the overall population and higher risk subjects at months 1 and 6 (p < 0.0001 for both). Adverse events and serious adverse events were generally similar between treatment groups. CONCLUSIONS: Transitioning to denosumab was well tolerated and more effective in increasing BMD and reducing bone turnover than cycling to a monthly oral BP treatment in subjects who remained at higher fracture risk despite suboptimal BP treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Administração Oral , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Biomarcadores/sangue , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/farmacologia , Remodelação Óssea/efeitos dos fármacos , Colágeno Tipo I/sangue , Denosumab , Difosfonatos/efeitos adversos , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Esquema de Medicação , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/análogos & derivados , Ácido Etidrônico/farmacologia , Ácido Etidrônico/uso terapêutico , Feminino , Colo do Fêmur/fisiopatologia , Articulação do Quadril/fisiopatologia , Humanos , Ácido Ibandrônico , Injeções Subcutâneas , Vértebras Lombares/fisiopatologia , Adesão à Medicação , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/fisiopatologia , Peptídeos/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Risedrônico , Fatores de Risco
11.
N Z Med J ; 127(1389): 81-5, 2014 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24548959

RESUMO

Bisphosphonates, drug of choice in the treatment of osteoporosis, have been associated with unusual skeletal side effects such as osteonecrosis of jaw and atypical femur fractures in recent years. We report two older patients with bisphosphonate-associated atypical femur fracture from a South Australian tertiary care hospital and a brief discussion of potential diagnostic complexities in this patient population.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Fraturas do Fêmur/etiologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Alendronato/efeitos adversos , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/análogos & derivados , Feminino , Fraturas do Fêmur/complicações , Fraturas do Fêmur/diagnóstico por imagem , Humanos , Osteoporose Pós-Menopausa/complicações , Radiografia , Ácido Risedrônico
12.
Bone ; 59: 44-52, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24184313

RESUMO

Oral risedronate has been shown to be effective in the treatment of osteoporosis when administered once-daily or once-weekly in Japan. This randomized, double-blind, multicenter 12-month study was conducted to compare the efficacy and tolerability of oral risedronate 75mg once-monthly with 2.5mg once-daily in Japanese patients with involutional osteoporosis. Bone mineral density (BMD), biochemical markers of bone metabolism, fractures, and adverse events (AEs) were evaluated. At the end of the study (Month 12, last observation carried forward [M12, LOCF]), mean percent change (SD) from baseline in lumbar spine (L2-L4) BMD, measured by dual energy X-ray absorptiometry (primary endpoint), was increased by 5.69 (4.00)% in the 2.5mg once-daily group (n=428), and 5.98 (4.54)% in the 75mg once-monthly group (n=422). In the non-inferiority t-test (non-inferiority margin Δ=1.5%), the 75mg once-monthly group was non-inferior to the 2.5mg once-daily group (p<0.0001). The difference between treatment groups was 0.28% (95% CI, -0.31% to 0.88%). Changes in biochemical markers of bone metabolism were generally comparable in the two groups, although decreases in the percent change from baseline in urinary NTX/CRN and CTX/CRN were statistically greater in the 2.5mg once-daily group than the 75mg once-monthly group. The frequency of new vertebral fractures (including aggravation of prevalent fractures) at the end of the study (M12, LOCF) was also similar in the two groups: 1.2% in the 2.5mg once-daily group and 1.3% in the 75mg once-monthly group. The incidence of mild/moderate/severe AEs was 75.5%/6.3%/0.5% in the 2.5mg once-daily group and 77.7%/8.1%/0.7% in the 75mg once-monthly group. AEs associated with gastrointestinal symptoms occurred in approximately 30% of subjects in each group but with no severe cases. AEs potentially associated with acute phase reaction (including symptoms of influenza-like illness or pyrexia starting within 3days of the first dose of the study drug and with a duration of 7days or less) only occurred in the 75mg once-monthly group (2.1%, 9/422 subjects; influenza-like symptoms in 1 subject and pyrexia in 8 subjects), although the incidence was low without any severe cases. In conclusion, risedronate 75mg once-monthly (a dosage which is 30 times higher than risedronate 2.5mg once-daily) had non-inferior efficacy in terms of BMD and was similarly well tolerated compared to the once-daily regimen in Japanese patients with involutional osteoporosis. Consistent with the once-daily and once-weekly dosage, the once-monthly dosage of risedronate 75mg was half that used outside Japan (150mg).


Assuntos
Grupo com Ancestrais do Continente Asiático , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Ácido Etidrônico/análogos & derivados , Osteoporose/tratamento farmacológico , Idoso , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Japão/epidemiologia , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Masculino , Ácido Risedrônico , Fraturas da Coluna Vertebral/epidemiologia , Resultado do Tratamento
13.
Lancet ; 382(9902): 1424-32, 2013 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-23927913

RESUMO

BACKGROUND: Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS: In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS: Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION: Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING: Alliance for Better Bone Health (Warner Chilcott and Sanofi).


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Ácido Etidrônico/análogos & derivados , Osteogênese Imperfeita/tratamento farmacológico , Administração Oral , Adolescente , Fosfatase Alcalina/metabolismo , Análise de Variância , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Criança , Pré-Escolar , Colágeno/metabolismo , Método Duplo-Cego , Esquema de Medicação , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Feminino , Humanos , Masculino , Osteogênese Imperfeita/fisiopatologia , Ácido Risedrônico , Resultado do Tratamento
14.
Bull Tokyo Dent Coll ; 54(2): 117-25, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23903583

RESUMO

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) affects quality of life and is an important problem for dentists. A Japanese position paper on BRONJ was published in 2010. The purpose of this study was to review clinical data on the treatment of BRONJ obtained at the Clinic of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba Hospital to further our understanding of this disease. A total of 13 patients (6 men and 7 women) were included. All the patients included in this study had received Bisphosphonate (BP) therapy and had BRONJ. Five of them (38.5%) had received oral BP therapy for osteoporosis, while the remaining 8 (61.5%) had received parenteral BP therapy for bone metastases from breast or prostate cancer. Osteoporosis patients were treated with risedronate or alendronate. Breast or prostate cancer patients were treated with zoledronate. Two patients with rheumatoid arthritis were treated with corticosteroid. Three patients had diabetes mellitus. Eleven patients were treated with antibiotics, while 5 underwent surgical treatment. Discontinuation of BP was recorded in 7 patients during dental treatment. Sequestration was observed in 6 patients during an 11-month follow-up. Eventually, healing and improvement of the oral mucosa were observed in 3 patients. The current standard treatment for BRONJ does not always provide good results. It is necessary to accumulate further clinical data to establish more effective treatment strategies for BRONJ.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Administração Oral , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Antibacterianos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/cirurgia , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Complicações do Diabetes , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/análogos & derivados , Feminino , Seguimentos , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Infusões Parenterais , Japão , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Bucais , Osteoporose/tratamento farmacológico , Neoplasias da Próstata/patologia , Ácido Risedrônico , Resultado do Tratamento , Cicatrização/fisiologia , Ácido Zoledrônico
15.
Br J Oral Maxillofac Surg ; 51(8): 874-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23866309

RESUMO

Bisphosphonates have been associated with a serious adverse reaction known as bisphosphonate-related osteonecrosis of the jaws (BRONJ). The aim of this study was to describe its clinical characteristics in patients with dental implants who were taking bisphosphonates orally. We made a retrospective multicentre study in 3 hospitals in Galicia, Spain. The medical records and clinical and radiological follow-up of the oral cavity were reviewed for those patients given bisphosphonates and diagnosed with BRONJ after the placement of dental implants within the previous 3 years. The series comprised 9 white patients (mean age 66 years). The bisphosphonates were alendronate (n=6), ibandronate (n=2), and risedronate (n=1), and the most common indication was osteoporosis (n=7). The mean interval between the initiation of treatment and the onset of BRONJ lesions was 60 months. Most of the lesions were located around the mandibular implants (n=8). The mean interval between placement of dental implants and the onset of BRONJ was 34 (range 1-96) months. After treatment 7/9 patients recovered completely. The prevalence of BRONJ secondary to treatment with bisphosphonates taken orally after placement of dental implants may be higher than expected in a particular geographical region, but to date specific risk factors have not been identified. Clinical characteristics and the outcomes of treatment of lesions are similar to those seen in patients with BRONJ that is unrelated to placement of dental implants.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Implantes Dentários , Administração Oral , Corticosteroides/uso terapêutico , Idoso , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/análogos & derivados , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Ácido Ibandrônico , Masculino , Doenças Mandibulares/etiologia , Doenças Maxilares/etiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Ácido Risedrônico , Fatores de Risco , Fatores de Tempo
16.
Eur J Cancer ; 49(15): 3176-83, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23849828

RESUMO

BACKGROUND: Prostate cancer truly is an age-associated disease. Due to the increased life expectancy and more sensitive diagnostic techniques in the Western world, prostate cancer is diagnosed more frequently and with rapidly increasing incidence and prevalence rates. However, age above 65 or 70 years has been an exclusion criterion in clinical trials for decades and the knowledge about chemotherapy tolerance in elderly is limited. METHODS: We performed a retrospective analysis of data acquired from the recently published Netherlands Prostate Study (NePro) to evaluate the influence of advanced age on docetaxel therapy in elderly men (>70 years) with castration resistant prostate cancer (CRPC) and bone metastases. Statistical analyses were performed stratified for age into four categories: <70 (n=315), 70-74 (n=150), 75-79 (n=85), and ≥80 years old (n=18). RESULTS: We analysed 568 patients (median age 68.1 years, range 46-89 years, 44.5% aged ≥70 years). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, time to progression (TTP), overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity and were five times less likely to complete the first three treatment cycles at the intended dose (Odds ratio (OR) 5.34, p=0.0052) and showed decreased overall survival (15.3 months versus 24.5 months in <80 years group, p=0.020). CONCLUSION: In CRPC patients up to the age of 80 years, docetaxel chemotherapy is well tolerated, with toxicity levels and TTP comparable to those of younger patients. For chemotherapeutic treatment of patients above the age of 80 years an individual assessment should be made.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Docetaxel , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Países Baixos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Ácido Risedrônico , Análise de Sobrevida , Taxoides/administração & dosagem , Taxoides/efeitos adversos
17.
Calcif Tissue Int ; 93(2): 137-46, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23644930

RESUMO

This randomized, double-blind study assessed the antifracture efficacy and safety of intermittent intravenous (IV) ibandronate versus oral daily risedronate in Japanese patients with primary osteoporosis. Ambulatory patients aged ≥60 years were randomized to receive 0.5 or 1 mg/month IV ibandronate plus oral daily placebo or 2.5 mg/day oral risedronate, the licensed dose in Japan, plus IV placebo. The primary end point was noninferiority of ibandronate versus risedronate for first new or worsening vertebral fracture over 3 years. A total of 1,265 patients were randomized. A total of 1,134 patients formed the per-protocol set. Both ibandronate doses were noninferior to risedronate: 0.5 mg, hazard ratio (HR) 1.09 [95 % confidence interval (CI) 0.77-1.54]; 1 mg, HR 0.88 (95 % CI 0.61-1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (95 % CI 12.8-20.8) for 0.5 mg ibandronate, 11.6 % (95 % CI 8.2-15.0) for 1 mg ibandronate, and 13.2 % (95 % CI 9.6-16.9) for risedronate. Significant increases in bone mineral density relative to baseline were observed with all treatments after 6 months, with substantial reductions in bone turnover markers after 3 months. Greatest efficacy was obtained with 1 mg ibandronate. Analyses in women only showed similar results to the overall population. No new safety concerns were identified. This study demonstrated the noninferiority of IV ibandronate to the licensed Japanese dose of oral risedronate and suggested that 1 mg/month is an effective dose in Japanese patients with primary osteoporosis.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Ácido Etidrônico/análogos & derivados , Fraturas Ósseas/prevenção & controle , Osteoporose/tratamento farmacológico , Administração Oral , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Método Duplo-Cego , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Feminino , Humanos , Ácido Ibandrônico , Infusões Intravenosas , Japão , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Ácido Risedrônico , Fraturas da Coluna Vertebral/prevenção & controle , Fatores de Tempo , Resultado do Tratamento
18.
J Intern Med ; 274(4): 342-50, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23679231

RESUMO

OBJECTIVES: The aim of this study was to investigate the occurrence of heart failure in patients treated with bisphosphonates. DESIGN: In this nationwide retrospective cohort study from Denmark, all users of bisphosphonates and raloxifene between 1996 and 2006 (n = 102 342) were included in the 'exposed' group and three age- and gender-matched subjects (n = 307.026) from the general population comprised the control group. The risk of heart failure was estimated by Cox proportional hazard analyses. RESULTS: The mean follow-up times were 2.8, 5.5 and 4.9 years for alendronate-, etidronate- and raloxifene-treated patients, respectively. The absolute risk of heart failure was 4.4% in the exposed group and 3.7% in the control group (P < 0.01). The relative risk (RR) of heart failure was significantly increased in users of bisphophonates: crude RR 1.71 [95% confidence interval (CI) 1.63-1.79]; adjusted hazard ratio (HR) 1.41 (95% CI 1.34-1.48). By comparison, raloxifene, which is used for the same indication but has a different mechanism of action, was not associated with an increased risk of heart failure: adjusted HR 1.07 (95% CI 0.76-1.50). When the two most commonly used bisphosphonates, alendronate and etidronate, were analysed separately, significant trends in the risk of heart failure were observed across refill compliance strata. The risk of heart failure increased significantly with increasing refill compliance for etidronate (P for trend < 0.01), whereas it decreased for alendronate (P for trend < 0.01). CONCLUSIONS: Bisphosphonate users were at increased risk of heart failure compared to age- and gender-matched control subjects. However, users of alendronate showed a dose-dependent reduction in this risk, suggesting that alendronate may reduce the risk of heart failure.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Estudos de Coortes , Dinamarca , Ácido Etidrônico/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Cloridrato de Raloxifeno/efeitos adversos , Estudos Retrospectivos , Fatores de Risco
20.
J Bone Miner Metab ; 31(2): 206-11, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23138352

RESUMO

This study was performed to investigate the effects of the co-administration of proton pump inhibitor (PPI) on the efficacy of bisphosphonate (BP) treatment for osteoporosis. A total of 180 women with low bone mineral density were randomly divided into four groups, one in which sodium risedronate was administered with sodium rabeprazole and one in which only risedronate was administered (BP + PPI and BP groups, respectively). The biomarkers were measured at the baseline and every 3 months, inlcuding: N-terminal telopeptide of type I collagen corrected for creatinine, bone-specific alkaline phosphatase (BAP), parathyroid hormone, bone mineral density (BMD) of the lumbar spine and physical parameters evaluated according to the SF-36v2™ Health Survey. Statistical comparisons of these parameters were performed after 9 months. Data were available for a total of 137 patients (62 in the BP group and 75 in the BP + PPI group). The Δ % value of increase in BMD and improvement of physical functioning in the BP + PPI group were significantly larger, and its decrease in BAP in the BP + PPI group was significantly smaller than that in the BP group. It is expected that risedronate administration in combination with a PPI may be more effective not only for treating osteoporosis but also improving physical fitness than treatment with risedronate alone.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Ácido Etidrônico/análogos & derivados , Osteoporose/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Quimioterapia Combinada , Ácido Etidrônico/administração & dosagem , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose/complicações , Fraturas por Osteoporose/complicações , Fraturas por Osteoporose/tratamento farmacológico , Inibidores da Bomba de Prótons/efeitos adversos , Ácido Risedrônico
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