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1.
Eur J Endocrinol ; 184(3): 441-448, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33449911

RESUMO

Objective: Atrial fibrillation (AF) may be triggered by intravenous bisphosphonates (IVBPs) such as zoledronic acid or pamidronic acid. Our objective was to confirm the association between AF and IVBPs in a real-life large pharmacovigilance database. Design: A systematic analysis of VigiBase, the World Health Organization's pharmacovigilance database. Methods: Analysis of adverse events reported as 'atrial fibrillation' (according to the Medical Dictionary for Drug Regulatory Activities) associated with the use of zoledronic acid or pamidronic acid, in VigiBase, the World Health Organization's global Individual Case Safety Report (ICSR) database. All ICSRs reporting AF associated with zoledronic acid or pamidronic acid were included in a disproportionality analysis determining the lower end of the 95% credibility interval for the information component (IC025), showing a statistical association when >0. Results: 530 ICSRs reporting on the association between AF and IVBPs were extracted. Bayesian disproportionality analysis detected a significant association between AF and use of zoledronic acid (IC025 = 1.83) and pamidronic acid (IC025 = 2.16). Further analysis of these ICSRs determined that AF was severe in 85.0% of cases and with a mortality of 17.7%. The risk of severe AF was increased (OR: 2.98 (95% CI: 1.17-7.57), P = 0.02) following zoledronic acid vs pamidronic acid, after adjustment for age and gender. Conclusions: This is the first VigiBase pharmacoepidemiological study confirming the association between IVBPs and AF. Most AF were severe, with a high frequency of lethal outcome. The risk of severe AF was increased following zoledronic acid use compared to pamidronic acid, advocating for a cautious use of IVBPs.


Assuntos
Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Pamidronato/efeitos adversos , Ácido Zoledrônico/efeitos adversos , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , América do Norte/epidemiologia , Pamidronato/administração & dosagem , Farmacoepidemiologia , Farmacovigilância , Organização Mundial da Saúde , Ácido Zoledrônico/administração & dosagem
2.
N Z Med J ; 133(1527): 83-94, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33332330

RESUMO

AIM: Drug-induced ocular inflammation is rare and may be overlooked as a cause of uveitis. The main objective was to describe the causes of drug-induced ocular inflammation. Secondary objectives included uveitis complications and drug rechallenge reactions. METHODS: A retrospective chart review at Auckland District Health Board's tertiary uveitis clinic (Auckland, New Zealand) was performed. Participants were identified using the uveitis database, which consists of 2,750 subjects. Fifty eyes of 35 subjects had drug-induced inflammation. RESULTS: Drug-induced inflammation occurred in 1.3% of subjects with uveitis. Mean age was 66.8±15.6 years, and 25 subjects (71.4%) were female. Drugs responsible were bisphosphonates (24 subjects, 68.6%), brimonidine (one subject, 2.9%), etanercept (three subjects, 8.6%), immune checkpoint inhibitors (two subjects, 5.7%), BRAF inhibitors (three subjects, 8.6%), EGFR inhibitors (one subject, 2.9%) and allopurinol/perindopril (one subject, 2.9%). In subjects with bisphosphonate inflammation, anterior uveitis occurred in 22 (91.7%) and scleritis in two (8.3%). A positive rechallenge reaction occurred in two subjects with zoledronate and one with alendronate. Uveitis occurred in six subjects (17.1%) treated with cancer drugs including immune checkpoint inhibitors, BRAF inhibitors and EGFR protein kinase inhibitors. Subjects with cancer-drug-induced uveitis were managed with corticosteroids and five subjects were able to continue therapy; in one subject uveitis was uncontrollable and required drug cessation. CONCLUSIONS: Ocular inflammation caused by bisphosphonates is usually mild and resolves on medication withdrawal. Uveitis seen in association with newer cancer medications can be more severe, but in most cases it can be managed without medication cessation.


Assuntos
Difosfonatos/efeitos adversos , Uveíte Anterior/induzido quimicamente , Ácido Zoledrônico/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/efeitos adversos , Alopurinol/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Tartarato de Brimonidina/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/efeitos adversos , Etanercepte/efeitos adversos , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Esclerite/induzido quimicamente , Vemurafenib/efeitos adversos
3.
J Appl Oral Sci ; 28: e20200204, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32997086

RESUMO

OBJECTIVE: This study aims to evaluate bone repair and the development of the medication related osteonecrosis of the jaw (MRONJ) associated with the use of zoledronic acid in Wistar rats. METHODOLOGY: 48 male Wistar rats were divided into four groups: ZA, treated with intraperitoneal zoledronic acid, 0.6 mg/kg every 28 days, totaling five doses; control (C), treated with 0.9% sodium chloride; ZA-surgical (SZA) and C-surgical (SC), submitted to extraction of the right upper molars 45 days after the first application. Alveolar bone repair was evaluated by macroscopic and histological analysis. Protein expression evaluations were performed by qPCR. RESULTS: Macroscopic evaluation showed that 91.66% (11) of the animals in the SZA group and 41.66% (5) from the SC group presented solution of epithelium continuity (P<0.05). All animals in the SZA group and none in the SC group had bone sequestration. The area of osteonecrosis was higher in the SZA group than in the SC group (P<0.05). In molecular evaluation, the SZA group presented changes in the expression of markers for osteoclasts, with increased RANK and RANKL, and a decrease in OPG. CONCLUSION: The results highlighted strong and evident interference of zoledronic acid in bone repair of the socket, causing osteonecrosis and delayed bone remodeling.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/fisiopatologia , Conservadores da Densidade Óssea/efeitos adversos , Ácido Zoledrônico/efeitos adversos , Animais , Masculino , Ratos , Ratos Wistar , Extração Dentária/efeitos adversos
4.
J Bone Miner Metab ; 38(6): 894-902, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32656645

RESUMO

INTRODUCTION: Rapid descent in bone mineral density (BMD) and ascent in bone turnover marker (BTM) occur within the short period following denosumab (Dmab) discontinuation. In addition, the incidence of vertebral fracture also rises within the short period. The purpose of this study is to investigate the effects of sequential therapy using zoledronic acid (ZOL) on any adverse events after Dmab discontinuation. MATERIALS AND METHODS: This study was a multicenter retrospective observational study, and the subjects were osteoporosis patients who visited our institutions between 2013 and 2018. We performed sequential therapy using ZOL for 30 patients who had difficulty continuing Dmab, due to physical or social reasons, and investigated the fracture incidence and BMD/BTM changes at 4 time points (at the start of Dmab, the start of ZOL, 6 months after ZOL and 12 months after ZOL). RESULTS: No new vertebral/nonvertebral fractures were observed at each time point after switching from Dmab to ZOL in any of the 30 patients. The BMD/BTM changes were evaluated in 18 of the 30 cases, since all data of lumbar/femoral neck BMDs and TRACP-5b at 4 time points was only available in 18 cases. BMDs significantly increased at each time point compared with that at the start of Dmab. Serum TRACP-5b significantly decreased at each time point compared with that at the start of Dmab. CONCLUSION: It was suggested that sequential therapy using ZOL could suppress the decrease of BMD, and increase of BTM, if the period of Dmab administration was less than 3 years.


Assuntos
Denosumab/uso terapêutico , Suspensão de Tratamento , Ácido Zoledrônico/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Denosumab/efeitos adversos , Feminino , Fraturas Ósseas/sangue , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/sangue , Estudos Retrospectivos , Fosfatase Ácida Resistente a Tartarato/sangue , Ácido Zoledrônico/efeitos adversos
5.
PLoS One ; 15(6): e0234123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32492050

RESUMO

We aimed to evaluate the comparative efficacy and safety of drugs respectively for primary prevention and secondary prevention of osteoporotic fractures in postmenopausal women (PMW), and to further identify the optimal intervention(s) respectively for the two groups when efficacy and safety both considered. We searched three databases. Bayesian network meta-analyses were conducted for two efficacy outcomes (vertebral fractures and nonvertebral fractures) and two safety outcomes (tolerability and acceptability) respectively in primary prevention group and secondary prevention group. We synthesized hazard ratios (HRs) and 95% confidence intervals (CIs) for nonvertebral fractures, and risk ratios (RRs) for three others. Factor and cluster analyses on surface under the cumulative ranking curve (SUCRA) values were conducted to identify the best intervention(s) with efficacy and safety both considered. The study protocol has been registered in PROSPERO. We included 57 randomized trials involving fifteen anti-osteoporotic interventions and 106320 PMW. For primary prevention, only zoledronate (once per 18 months) reduced both vertebral (RR 0.46, 95% CI 0.28-0.74) and nonvertebral (HR 0.66, 95% CI 0.51-0.85) fractures. For secondary prevention, abaloparatide, alendronate, denosumab, lasofoxifene, risedronate, romosozumab, teriparatide, and zoledronate (once per 12 months) reduced both vertebral (RRs: from 0.17 to 0.62) and nonvertebral (HRs: from 0.54 to 0.81) fractures. PTH (1-84) and abaloparatide increased withdrawal risk. Romosozumab, teriparatide, denosumab and risedronate, with the greatest composite scores, constituted the optimal cluster having both superior efficacy and superior safety. Zoledronate used at 5 mg per 18 months, with the similar safety as placebo, is the only drug intervention which has been shown to significantly reduce both vertebral and nonvertebral fractures for primary prevention of osteoporotic fractures in PMW; while romosozumab, teriparatide, denosumab, and risedronate are the optimal treatments for secondary prevention when efficacy and safety both considered. A limitation is that safety outcomes failed to consider the severity of adverse effects.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Fraturas por Osteoporose/prevenção & controle , Teorema de Bayes , Conservadores da Densidade Óssea/efeitos adversos , Análise por Conglomerados , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Fraturas por Osteoporose/patologia , Pós-Menopausa , Modelos de Riscos Proporcionais , Risco , Prevenção Secundária , Resultado do Tratamento , Ácido Zoledrônico/efeitos adversos , Ácido Zoledrônico/uso terapêutico
6.
Medicine (Baltimore) ; 99(25): e20831, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569232

RESUMO

The objective was to investigate the association of different hydration doses and its effect on renal function in patients with primary osteoporosis treated with zoledronic acid.The subjects with primary osteoporosis treated with zoledronic acid at the First Affiliated Hospital of Chongqing Medical University, China, from January 2015 to December 2018 were included in this study. The subjects were classified according to different hydration doses. Renal function indexes before and after treatment were collected and adverse reactions recorded to analyze the changes in renal function associated with different hydration doses.The choice of the hydration dose treated with zoledronic acid deserves attention. The lower hydration dose is, the greater impact on renal function can be caused.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Rim/fisiopatologia , Osteoporose/tratamento farmacológico , Soluções para Reidratação/uso terapêutico , Ácido Zoledrônico/uso terapêutico , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Osteoporose/fisiopatologia , Soluções para Reidratação/administração & dosagem , Estudos Retrospectivos , Ácido Zoledrônico/efeitos adversos
8.
Med. oral patol. oral cir. bucal (Internet) ; 25(3): e326-e336, mayo 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-196318

RESUMO

BACKGROUND: The aim of the present study was to analyse the incidence, risk ratio (RR) and prognoses of two types of medication-related osteonecrosis of the jaws (MRONJ): denosumab-related osteonecrosis of the jaws (DRONJ) and Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) in cancer patients under treatment with deno-sumab or zoledronic acid (ZA). MATERIAL AND METHODS: An electronic and manual search was conducted for randomized controlled trials (RCTs) until May 2019. Assessment of the identified studies, risk of bias and data extraction were performed independently by two reviewers. The incidence of DRONJ and BRONJ and the RR to develop MRONJ were calculated at 1 year, 2 years and 3 years of exposure. It was also calculated the odds ratio (OR) of their respective prognoses. They were calculated normalizing the values of the individual studies to 1 year, 2 years or 3 years when necessary through robust regression models using a statistical program. RESULTS: From 1.277 references identified, 8 RCTs were included, which comprised a total of 13.857 patients with a variety of neoplasms. The incidence of DRONJ in cancer patients under treatment with denosumab ranged from 0.5 to 2.1% after 1 year, 1.1 to 3.0% after 2 years, and 1.3 to 3.2% after 3 years of exposure. The incidence of BRONJ in cancer patients under treatment with ZA ranged from 0.4 to 1.6% after 1 year of exposure, 0.8 to 2.1% after 2 years, and 1.0 to 2.3% after 3 years of exposure. Statistically significant differences were found between de-nosumab and ZA in the risk of developing MRONJ after 1, 2 and 3 years of exposure. Nevertheless, there were no significant differences in terms of patient prognosis. CONCLUSIONS: Denosumab is associated with a significantly higher risk of developing MRONJ compared to ZA. Nevertheless, no differences were found in its prognoses


No disponible


Assuntos
Humanos , Masculino , Feminino , Osteonecrose/induzido quimicamente , Denosumab/efeitos adversos , Ácido Zoledrônico/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Doenças Maxilomandibulares/induzido quimicamente , Medição de Risco , Fatores de Risco , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias/tratamento farmacológico , Fatores de Tempo
9.
Arch Osteoporos ; 15(1): 58, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32303862

RESUMO

This retrospective study reports 81% long-term (> 3 years) adherence to and 77% persistence with zoledronic acid (ZA) treatment in osteoporosis patients, with ZA being costfree for patients. Eight percent of patients discontinued treatment because of adverse events (AEs), with a tendency of higher discontinuation rate in older patients. PURPOSE: This study investigated (1) long-term adherence to and persistence with ZA treatment in a real-world setting, (2) extent to which an adverse reaction to ZA impacted on adherence and persistence, and (3) whether there were sex or age differences in patients that had early treatment termination (ETT) due to AEs and those who adhered to the regimen. METHODS: All patients treated with ZA at the Endocrinology Department at Linköping University Hospital, Linköping, Sweden between 2012 and 2017 were included. ETT was defined as < 3 ZA infusions, which was confirmed from patients' medical records. RESULTS: A total of 414 patients were treated with ZA, with 81% receiving > 3 ZA infusions. Three-year persistence was 77% for a treatment window of 365 days ± 90 days (75% with 365 days ± 60 days window). The most common reason for ETT was AEs (8%), followed by medical conditions (5%), biological aging (3%), and other (e.g., lost to follow-up [3%]). Most patients who discontinued treatment because of AEs reported symptoms of acute-phase reaction, and tended to be older than those who adhered to treatment (74 ± 9 vs 70 ± 13 years, p = 0.064). There was no difference in sex ratio between the 2 groups (85% vs 90% females, p = 0.367). CONCLUSION: Rates of long-term adherence to and persistence with ZA treatment were high with a pre-scheduled 3-year treatment regimen in the tax-financed Swedish healthcare system. AEs-mainly acute-phase reaction-were the most common reason for ETT, occurring in nearly 1 out of 10 patients.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Adesão à Medicação/estatística & dados numéricos , Osteoporose/tratamento farmacológico , Suspensão de Tratamento/estatística & dados numéricos , Ácido Zoledrônico/administração & dosagem , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Suécia , Fatores de Tempo , Ácido Zoledrônico/efeitos adversos
10.
Sci Rep ; 10(1): 5620, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221325

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) occurs in patients undergoing oral surgery while medicated with bisphosphonate, denosumab or anti-angiogenic agents. We employed a MRONJ-like rat model to investigate whether injecting fluvastatin at extraction sites prevents MRONJ-like lesion. A MRONJ-like model was created by treating rats with zoledronate and dexamethasone, extracting teeth, and immediately injecting fluvastatin at the extraction site. The experimental group comprised three subgroups treated with low (0.1 mg/kg; FS-L), medium (1.0 mg/kg; FS-M) and high concentrations (10 mg/kg; FS-H) of fluvastatin. Necrotic bone exposure was significantly lower in the FS-M (p = 0.028) and FS-H (p = 0.041) groups than in the MRONJ group. The distance between the edges of the epithelial surfaces was significantly shorter in the FS-M (p = 0.042) and FS-H (p = 0.041) groups. The area of necrotic bone and the necrotic bone ratio were significantly smaller in the FS-H group (p = 0.041 and p = 0.042 respectively). Bone volume fraction calculated on µ-CT images was significantly larger in the FS-H group than in the MRONJ group (p = 0.021). Our findings suggest that a single local injection of fluvastatin following tooth extraction can potentially reduce the chance of developing MRONJ-like lesion in rats.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Fluvastatina/farmacologia , Osteonecrose/prevenção & controle , Inibidores da Angiogênese/efeitos adversos , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Osso e Ossos/diagnóstico por imagem , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Modelos Animais de Doenças , Feminino , Osteonecrose/etiologia , Ratos , Ratos Wistar , Extração Dentária/efeitos adversos , Ácido Zoledrônico/efeitos adversos
11.
Drugs Aging ; 37(4): 311-320, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32026309

RESUMO

BACKGROUND AND OBJECTIVE: There is a relative lack of head-to-head comparisons of denosumab against other osteoporosis drugs on safety. We aimed to explore ocular outcomes in patients with osteoporosis initiating denosumab vs zoledronic acid. METHODS: We conducted a cohort study using claims data (2010-15) from two large US commercial insurance databases including patients with osteoporosis who were aged 50 years or older and initiators of denosumab or zoledronic acid. The primary outcomes were (1) receipt of cataract surgery and development of (2) wet age-related macular degeneration and (3) dry age-related macular degeneration within 365 days after initiation of denosumab vs zoledronic acid. Propensity score fine stratification and weighting were used to control for potential confounding, and we calculated the incidence rate and hazard ratio for each outcome in the cohorts. The estimates from the two databases were combined with a fixed-effects model meta-analysis. RESULTS: The study cohort included 50,821 denosumab and 67,471 zoledronic acid initiators. In the propensity score-weighted analysis, compared to zoledronic acid use, denosumab was associated with a modestly decreased risk of undergoing cataract surgery (hazard ratio 0.91; 95% confidence interval 0.85-0.98) but not with the risk of wet age-related macular degeneration (hazard ratio 1.29; 95% confidence interval 0.99-1.70) or dry age-related macular degeneration (hazard ratio 1.03; 95% confidence interval 0.98-1.09). CONCLUSIONS: In this large population-based cohort study of 118,292 patients with osteoporosis, initiation of denosumab was associated with a modestly decreased risk of cataract surgery vs zoledronic acid. The risk of age-related macular degeneration was similar between the two drugs.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Extração de Catarata/estatística & dados numéricos , Bases de Dados Factuais , Denosumab/efeitos adversos , Degeneração Macular/induzido quimicamente , Osteoporose/tratamento farmacológico , Ácido Zoledrônico/efeitos adversos , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Estudos de Coortes , Denosumab/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Ácido Zoledrônico/uso terapêutico
12.
J Stomatol Oral Maxillofac Surg ; 121(5): 523-526, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31863926

RESUMO

INTRODUCTION: The aim of the present study was to investigate the number of patients with Multiple Myeloma (MM) treated with intravenous Zoledronic Acid who presented an involvement of the jaws by Myeloma that mimicked an osteonecrosis. MATERIAL AND METHODS: A retrospective study was performed in a University Hospital reference for a population of 1.084.000 inhabitants. A 'case' Medication-Related Osteonecrosis of the jaw (MRONJ) was considered when the patient met diagnostic criteria established by the American Association of Oral and Maxillofacial Surgeons (AAOMS, 2014). We recorded data on the underlying disease, medications used, mode of Bisphosphonate administration (oral or intravenous), and timing of medication use. RESULTS: The sample size was 84 cases. 22 patients had MRONJ associated to MM treatment. Histopathological examination of pathological bone was characterized by the presence of necrotic osteitis in 82 patients. Only 2 patients with MRONJ suspicion were finally diagnosed as MM. These cases represented 9.09% of all patients with multiple myeloma initially labeled MRONJ in our hospital. CONCLUSION: The present study has shown that MM can be identified in jaw specimens of patients exposed to Bisphosphonates and clinically diagnosed as osteonecrosis. Biopsy examination should be considered in at least selected cases, for example, before surgical treatment in patients with MM and clinical stage 3 osteonecrosis (due to the detection of malignancy would alter the surgical strategy).


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Mieloma Múltiplo , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Difosfonatos/efeitos adversos , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Estudos Retrospectivos , Ácido Zoledrônico/efeitos adversos
13.
J Bone Miner Metab ; 38(2): 230-239, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31586241

RESUMO

INTRODUCTION: Zoledronic acid infusion is used to treat osteoporosis but patients, especially Japanese patients, often experience acute-phase reactions (APRs). In this multicenter, randomized, open-label, parallel-group study, we examined the efficacy of the most commonly used non-steroidal anti-inflammatory drug loxoprofen in Japan in reducing the incidence rate of zoledronic acid-induced APRs and body temperature, and investigated risk/protective factors for APRs in this population. MATERIALS AND METHODS: Patients aged ≥ 60 years with primary osteoporosis (n = 368) were allocated randomly to zoledronic acid plus loxoprofen (ZOL + LOX) or zoledronic acid alone (ZOL). All patients received 5-mg zoledronic acid infusion on day 1, and patients in the ZOL + LOX group also received 120 mg and 180 mg of oral loxoprofen on days 1 and 2, respectively. Adverse events and body temperature were recorded during the 7-day observation period. RESULTS: The incidence rates of APRs were 34.4% (64/186 patients) and 47.8% (87/182 patients) in the ZOL + LOX and ZOL groups, respectively (P = 0.0109). The proportions of patients with increased body temperature (≥ 1 °C and ≥ 37.5 °C) were similar in both groups (P = 0.1186). Past bisphosphonate users had a significantly lower incidence rate of APRs than treatment-naïve patients (odds ratio 0.444, 95% confidence interval 0.285-0.692, P = 0.0003). CONCLUSIONS: Zoledronic acid-induced APRs appeared to be suppressed by loxoprofen. Known risk/protective factors, including prior osteoporosis treatment, were applicable to Japanese patients.


Assuntos
Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Conservadores da Densidade Óssea/uso terapêutico , Ácido Zoledrônico/efeitos adversos , Reação de Fase Aguda/epidemiologia , Idoso , Temperatura Corporal , Difosfonatos/uso terapêutico , Feminino , Humanos , Incidência , Japão , Modelos Logísticos , Masculino , Análise Multivariada , Razão de Chances , Fatores de Risco , Resultado do Tratamento , Ácido Zoledrônico/uso terapêutico
15.
Support Care Cancer ; 28(1): 177-184, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31001696

RESUMO

PURPOSE: Crevicular fluid was used to assess interleukin-17 (IL-17) and vascular endothelial growth factor (VEGF) in cancer patients receiving zoledronic acid and/or bevacizumab. The markers were also assessed in the serum. METHODS: Twenty-five patients were included and comprised three groups: patients who received zoledronic acid (n = 9), patients who received bevacizumab (n = 9), and patients who received zoledronic acid combined with bevacizumab (n = 5). One patient received zoledronic acid and everolimus and another received zoledronic acid, bevacizumab, and temsirolimus. IL-17 and VEGF were measured by standard quantitative ELISA kits and assessed in two study points. RESULTS: Twenty-four patients maintained good periodontal health; one had asymptomatic osteonecrosis of the jaw. First assessment: 44 samples were collected; 21 from serum and 23 from crevicular fluid. Second assessment, 6 months later: 11 samples were collected; 6 from serum and 5 from crevicular fluid. IL-17 was detected in all samples, in serum and crevicular fluid, and remained unchanged at both time points. Serum VEGF in patients with bevacizumab alone or combined with zoledronic acid was significantly lower compared with that of patients who received zoledronic acid alone. VEGF was not detected in the crevicular fluid. CONCLUSIONS: Crevicular fluid might be an easy, non-invasive means to assess IL-17. The stable values of IL-17 in crevicular fluid and serum and the lack of VEGF in the crevicular fluid could be related to the good periodontal health of our patients. Further studies are needed to assess IL-17 and VEGF in the crevicular fluid in patients with and without periodontal disease.


Assuntos
Bevacizumab/administração & dosagem , Líquido do Sulco Gengival/química , Interleucina-17/análise , Neoplasias/tratamento farmacológico , Doenças Periodontais/diagnóstico , Fator A de Crescimento do Endotélio Vascular/análise , Ácido Zoledrônico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/efeitos adversos , Biomarcadores/análise , Biomarcadores/metabolismo , Quimioterapia Combinada/efeitos adversos , Feminino , Líquido do Sulco Gengival/metabolismo , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/diagnóstico , Neovascularização Patológica/metabolismo , Osteonecrose/induzido quimicamente , Osteonecrose/diagnóstico , Osteonecrose/metabolismo , Doenças Periodontais/induzido quimicamente , Doenças Periodontais/etiologia , Bolsa Periodontal/induzido quimicamente , Bolsa Periodontal/diagnóstico , Bolsa Periodontal/metabolismo , Valor Preditivo dos Testes , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ácido Zoledrônico/efeitos adversos
16.
Int J Cancer ; 146(2): 413-423, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31246277

RESUMO

In the OS2006 study, patients younger than 18 years were treated with a methotrexate-based regimen (MTX), patients older than 25 years with a doxorubicin-cisplatin-ifosfamide-based regimen (API-AI), whereas patients aged 18-25 years received either API-AI or MTX. We herein report the prespecified subgroup analysis of the outcome of 106 patients treated with API-AI. Preoperative chemotherapy combined three doxorubicin-ifosfamide-cisplatin (API) and two doxorubicin-ifosfamide (AI) courses. Postoperative chemotherapy was assigned by risk group: localised patients with a good histological response (<10% viable cells) received two AI and two cisplatin-ifosfamide (PI) courses; patients with synchronous metastases, poor histological response or unresectable primary received five cycles of etoposide-ifosfamide (EI). Of the 106 patients, 61 were randomised to receive or not zoledronate. Median age was 30 years (range 18-67), 66 (62%) patients were >25 years. The primary tumours were axial in 28 patients (26%), and 28 (26%) presented with metastases. Ninety-six patients (91%) had surgery, conservative in 82 (85%); 36 patients (38%, 95% CI 28-48%) were good responders. Toxicity was manageable, with no significant difference in severe acute toxicity between patients aged >25 years and those younger. With a median follow-up of 4.8 years, the 5-year event-free survival and overall survival rates were 46% (95% CI 36-56) and 57% (95% CI 47-67), respectively. The primary tumour size and initial metastases correlated with a higher risk of event. In these 106 osteosarcoma adult patients, API-AI proved feasible with no excess of toxicity, and favourable activity despite poor-prognosis factors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/terapia , Osteossarcoma/terapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Feminino , Seguimentos , França/epidemiologia , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Prognóstico , Taxa de Sobrevida , Adulto Jovem , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/efeitos adversos
18.
J Oncol Pharm Pract ; 25(8): 1846-1852, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31694497

RESUMO

OBJECTIVE: To identify the incidence of hypercalcemia and hypocalcemia in zoledronic acid and denosumab groups. Secondary objective was to determine the correlation between calcium supplement and calcium level control. METHODS: An observational retrospective cohort study was conducted by reviewing patient electronic records, laboratory results, and medication charts from 1 August 2015 to 31 July 2016. Adult cancer patients who were diagnosed with bone metastasis secondary to a solid tumor or multiple myeloma and who received either zoledronic acid or denosumab were included. Other indications for bone targeting agents were excluded. Data of bone targeting agents administration encounters were collected, evaluated, and analyzed. RESULTS: A total of 1141 encounters (for 271 patients) were included. The incidence of hypocalcemia was higher in denosumab compared to zoledronic acid group (5.5% vs. 3.1%, OR = 0.55, 95% CI [0.3-1.0]; P = 0.05). Hypercalcemia incidence was also higher in denosumab group (8.5% vs. 3.1%, OR = 2.9, 95% CI [1.68-5.03]; P < 0.0001). Breast cancer was the most common malignancy associated with hypocalcemia (27.3%) followed by ovarian cancer (25%) and multiple myeloma (22.7%). The risk of developing hypocalcemia was reduced by 16% in patients receiving calcium supplementation (RR = 0.84, 95% CI [0.55-1.20]; P = 0.39). CONCLUSION: Denosumab use was associated with higher rates of both hypercalcemia and hypocalcemia compared to zoledronic acid. Adequate supplementation with calcium substantially reduced the risk of hypocalcemia. Our results highlight the importance of taking preventative measures upon bone targeting agents initiation and during treatment including regular monitoring of calcium levels and providing supplements accordingly.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Denosumab/administração & dosagem , Ácido Zoledrônico/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/secundário , Cálcio/metabolismo , Estudos de Coortes , Denosumab/efeitos adversos , Feminino , Humanos , Hipercalcemia/induzido quimicamente , Hipocalcemia/induzido quimicamente , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ácido Zoledrônico/efeitos adversos
19.
Future Oncol ; 15(30): 3503-3511, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31580147

RESUMO

Aim: To investigate the risk factors for developing osteonecrosis of jaw (ONJ) in advanced cancer patients with bone metastases underwent zoledronic acid (ZA) treatment. Materials & methods: Univariate and multivariate logistic regression analyses were performed to investigate factors associated with developing ONJ in advanced cancer patients. Results: A total of 2214 advanced cancer patients were included. Univariate and multivariate logistic regression analyses for risk factors associated with ONJ were older age (≥66 years, hazards ratio [HR]: 3.21; p = 0.007), anemia (HR: 3.29; p = 0.006) and duration of ZA exposure (between 1 and 2 years, HR: 3.91, p = 0.01; ≥2 years, HR: 8.07, p < 0.001), respectively. Conclusion: Patients with older age, anemia and/or more than 1 year of ZA treatment are at high risk of developing ONJ.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Conservadores da Densidade Óssea/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Ácido Zoledrônico/administração & dosagem , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anemia/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/secundário , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Ácido Zoledrônico/efeitos adversos
20.
BMC Cancer ; 19(1): 980, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640606

RESUMO

BACKGROUND: While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy. METHODS: To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions. RESULTS: The study population consisted of 277 patients who had received a median of 10 doses (range, 1-79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77-4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF. CONCLUSIONS: We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Denosumab/uso terapêutico , Fraturas do Fêmur/epidemiologia , Fraturas do Fêmur/patologia , Osteoporose/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/administração & dosagem , Denosumab/efeitos adversos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Ácido Zoledrônico/efeitos adversos , Ácido Zoledrônico/uso terapêutico
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