RESUMO
Evidence on the management of rebound-associated vertebral fractures after denosumab discontinuation is scarce. This study describes seven patients retreated with denosumab, teriparatide or zoledronate for 24 months. Their bone mineral density remained stable or improved and no new fractures occurred suggesting that all three options might be adequate for their treatment. PURPOSE: To describe the densitometric and biochemical changes achieved with osteoactive treatment after 24 months of follow-up in patients who suffered rebound-associated vertebral fractures (RAVFs) after Dmab discontinuation, and to report the occurrence of new vertebral and non-vertebral fractures. METHODS: Patients with RAVFs who received retreatment (RT) for 24 months were included. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry at the lumbar spine (LS), femoral neck (FN) and total hip (TH), along with C-terminal cross-linked telopeptide of type I collagen, osteocalcin, and bone alkaline phosphatase. Data were collected at the start of the RT and after 24 months. RESULTS: Seven female patients were included. RT consisted in Dmab (n = 3), teriparatide (TPT) (n = 3) and zoledronate (Zol) (n = 1). At 24 months, the mean BMD change was 2.2% at LS, 6.8% at FN and 3.8% at TH in the Dmab group, 7.5% at LS, 1.4% at FN and 3.7% at TH in the TPT group and, 5.0% at LS, 0.6% at FN and 3.9% at TH in the patient with Zol. After 24 months of follow-up, no patient suffered new fractures. CONCLUSION: In this series of patients with RAVFs, we did not observe any new fractures and the BMD remained stable after 24 months of RT. Future studies are needed to evaluate the most suitable treatment approach after RAVFs but these preliminary data suggest that all denosumab, zoledronate and teriparatide might be adequate options.
Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose Pós-Menopausa , Fraturas da Coluna Vertebral , Feminino , Humanos , Denosumab/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Teriparatida/uso terapêutico , Ácido Zoledrônico/uso terapêutico , Seguimentos , Fraturas Ósseas/epidemiologia , Densidade Óssea , Fraturas da Coluna Vertebral/complicações , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative safety of denosumab and bisphosphonates in primary osteoporosis. Databases such as PubMed and Google Scholar were searched for relevant peer-reviewed randomized controlled trials published in English (as of December 2023). Trials comparing adverse events (AE) between denosumab and bisphosphonates in patients with primary osteoporosis were investigated. Data were pooled using a fixed- or random-effects model to determine the risk ratios (RR) and 95% confidence intervals (CIs) for various AEs in patients treated with denosumab in comparison to patients treated with bisphosphonates. Eleven trials (5,545 patients; follow-up period: 12-24 months) were included in this meta-analysis. All trials had a risk of bias (e.g., reporting bias linked to secondary endpoints and selection bias linked to random allocation). In comparison to bisphosphonates, denosumab was significantly associated with less withdrawal due to AEs (RR = 0.49; 95% CI 0.34-0.71), more five-point major adverse cardiovascular events (RR = 2.05; 95% CI 1.03-4.09), more cardiovascular AEs (RR = 1.61; 95% CI 1.07-2.41), more infections (RR = 1.14; 95% CI 1.02-1.27), more upper respiratory tract infections (RR = 1.56; 95% CI 1.08-2.25), less vertebral fractures (RR = 0.54; 95% CI 0.31-0.93), and less abdominal pain (RR = 0.44;95% CI 0.22-0.87). We explored the comparative safety of denosumab and bisphosphonates for primary osteoporosis, some of which could be attributed to their beneficial effects. However, all trials had a risk of bias. Further investigations are required to confirm our results.
Assuntos
Conservadores da Densidade Óssea , Denosumab , Difosfonatos , Osteoporose , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Difosfonatos/uso terapêutico , Difosfonatos/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controleRESUMO
Post hoc analysis of FRAME and ARCH revealed that on-study nonvertebral and vertebral fractures by Month 12 were less common in women initially treated with romosozumab versus placebo or alendronate. Recurrent fracture risk was also lower in romosozumabtreated patients, and there were no fracturerelated complications. Results support continuing romosozumab treatment postfracture. PURPOSE: Post hoc analysis evaluating efficacy and safety of romosozumab, administered in the immediate postfracture period, in the FRAME and ARCH phase 3 trials. METHODS: In FRAME (NCT01575834) and ARCH (NCT01631214), postmenopausal women with osteoporosis were randomized 1:1 to romosozumab 210 mg monthly or comparator (FRAME, placebo; ARCH, alendronate 70 mg weekly) for 12 months, followed by antiresorptive therapy (FRAME, denosumab; ARCH, alendronate). In patients who experienced on-study nonvertebral or new/worsening vertebral fracture by Month 12, we report the following: fracture and treatmentemergent adverse event (TEAE) incidence through 36 months, bone mineral density changes (BMD), and romosozumab timing. Due to the sample sizes employed, meaningful statistical comparisons between treatments were not possible. RESULTS: Incidence of on-study nonvertebral and vertebral fractures by Month 12 was numerically lower in romosozumab- versus comparator-treated patients (FRAME, 1.6% and 0.5% versus 2.1% and 1.6%; ARCH, 3.4% and 3.3% versus 4.6% and 4.9%, respectively). In those who experienced on-study nonvertebral fracture by Month 12, recurrent nonvertebral and subsequent vertebral fracture incidences were numerically lower in patients initially treated with romosozumab versus comparator (FRAME, 3.6% [2/56] and 1.8% [1/56] versus 9.2% [7/76] and 3.9% [3/76]; ARCH, 10.0% [7/70] and 5.7% [4/70] versus 12.6% [12/95] and 8.4% [8/95], respectively). Among those with on-study vertebral fracture by Month 12, recurrent vertebral and subsequent nonvertebral fracture incidences were numerically lower with romosozumab versus comparator (FRAME, 0.0% [0/17] and 0.0% [0/17] versus 11.9% [7/59] and 8.5% [5/59]; ARCH, 9.0% [6/67] and 7.5% [5/67] versus 15.0% [15/100] and 16.0% [16/100], respectively). In patients with fracture by Month 12, no fracturerelated complications were reported in romosozumab-treated patients. BMD gains were numerically greater with romosozumab than comparators. CONCLUSION: Data suggest support for the efficacy and safety of continuing romosozumab treatment following fracture. TRIAL REGISTRATIONS: NCT01575834; NCT01631214.
Assuntos
Alendronato , Anticorpos Monoclonais , Conservadores da Densidade Óssea , Denosumab , Osteoporose Pós-Menopausa , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Feminino , Fraturas por Osteoporose/prevenção & controle , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Fraturas da Coluna Vertebral/prevenção & controle , Fraturas da Coluna Vertebral/fisiopatologia , Idoso , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/fisiopatologia , Osteoporose Pós-Menopausa/complicações , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Pessoa de Meia-Idade , Alendronato/uso terapêutico , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Denosumab/administração & dosagem , Método Duplo-Cego , Densidade Óssea/efeitos dos fármacos , Idoso de 80 Anos ou mais , Esquema de Medicação , RecidivaRESUMO
This study investigates the effects of antiresorptive drugs and risk factors for medication-related osteonecrosis of the jaws in osteoporotic patients undergoing tooth extraction. Among the findings, antiresorptive-treated patients had thicker lamina dura and longer healing times. Additionally, corticosteroid intake and multi-rooted teeth carried a higher osteonecrosis risk. Bone sequestrum indicated osteonecrosis. PURPOSE: To describe the effects of antiresorptive drugs (ARD) in the maxilla and mandible and risk factors for medication-related osteonecrosis of the jaws (MRONJ) in osteoporotic patients undergoing tooth extractions using clinical data and cone beam computed tomography (CBCT). METHODS: This retrospective cohort study collected clinical and CBCT data from 176 patients. The study group (n = 78; 224 extractions) received ARD treatment, underwent tooth extraction, and had a pre-operative CBCT. Additionally, age-, sex-, and tooth-matched controls were selected (n = 98; 227 extractions). Radiographic examinations were performed independently by three calibrated examiners. Statistical analysis included Chi-square, Fisher's exact, Mann-Whitney U, and t-tests to contrast clinical and radiographic data between study and control, MRONJ + and MRONJ - , and bisphosphonate and denosumab patients/sites. Significance was set at p ≤ 0.05. RESULTS: From the study group, 4 patients (5%) and 5 sites (2%) developed MRONJ after tooth extraction. ARD-treated patients exhibited significantly more thickening of the lamina dura and a longer average mucosal healing time (4.4 weeks) than controls (2.6 weeks). In the study group, MRONJ risk significantly increased with corticosteroid intake and in multi-rooted teeth. No significant differences between bisphosphonates and denosumab use were seen in the tomographic features (p > 0.05). Lastly, bone sequestrum was exclusively observed in osteoporotic patients, who exhibited post-operative exposed bone or histological evidence of osteonecrosis. CONCLUSION: Osteoporotic patients under ARD may exhibit thickening of the lamina dura and prolonged post-operative healing. Among these patients, multi-rooted teeth are at higher risk for MRONJ than single-rooted teeth. Sequester formation is a radiographic indicator of osteonecrosis.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Tomografia Computadorizada de Feixe Cônico , Osteoporose , Extração Dentária , Humanos , Feminino , Extração Dentária/efeitos adversos , Extração Dentária/métodos , Tomografia Computadorizada de Feixe Cônico/métodos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/diagnóstico por imagem , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Estudos Retrospectivos , Masculino , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Osteoporose/fisiopatologia , Osteoporose/induzido quimicamente , Idoso de 80 Anos ou mais , Fatores de Risco , Cicatrização/efeitos dos fármacos , Denosumab/efeitos adversos , Denosumab/uso terapêuticoRESUMO
BACKGROUND: Bone metastases are frequently observed in advanced cancer, and bone modifying agents are used to prevent or treat skeletal-related events. Zoledronic acid is contraindicated in patients with severe renal impairment (Ccr < 30 mL/min), but it is not completely known whether denosumab can be used in them. We aimed to determine the association between renal function and hypocalcemia development during denosumab treatment. METHODS: We included patients with solid cancer and bone metastases who started denosumab treatment between April 2017 and March 2019. They were classified into four groups based on creatinine clearance (Ccr; mL/min): normal (Ccr ≥ 80), mild (50 ≤ Ccr Ë80), moderate (30 ≤ Ccr Ë50), and severe (Ccr Ë30). Hypocalcemia was evaluated using the Common Terminology Criteria for Adverse Events (v5.0) based on the albumin-adjusted serum calcium levels; its incidence (stratified by renal function) and risk factors were investigated using a Chi-square test and logistic regression analysis. RESULTS: Of 524 patients (age: 69 ± 11 years; 303 men), 153 had a normal renal function and 222, 117, and 32 had mild, moderate, and severe renal dysfunction. The albumin-adjusted serum calcium level was higher than the measured (total) calcium level in most patients. The incidence of grade ≥ 1 hypocalcemia was 32.0% in the normal group and 37.4%, 29.9%, and 62.5% in the mild, moderate, and severe renal dysfunction groups, respectively. It was, therefore, higher in the severe renal dysfunction groups than in the normal group (P = 0.002). The incidence of grade ≥ 3 hypocalcemia did not differ significantly among the groups. Pre-treatment low serum calcium levels and severe renal dysfunction were risk factors for hypocalcemia. CONCLUSIONS: Evaluating denosumab-induced hypocalcemia required albumin adjustment, and its incidence was high among patients with severe renal dysfunction. Reduced serum calcium levels and severely impaired renal function were associated with an elevated hypocalcemia risk.
Assuntos
Conservadores da Densidade Óssea , Neoplasias Ósseas , Hipocalcemia , Nefropatias , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Hipocalcemia/induzido quimicamente , Hipocalcemia/prevenção & controle , Denosumab/efeitos adversos , Cálcio/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Estudos Retrospectivos , Neoplasias Ósseas/tratamento farmacológico , Albuminas/efeitos adversos , Nefropatias/induzido quimicamenteRESUMO
AIM: To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long-term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all-cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta-analysis. METHODS: A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long-term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random-effects meta-analysis. Risk of bias and evidence quality were assessed using Cochrane-endorsed tools. RESULTS: Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78-0.88]). Secondary analysis showed significant risk reduction in all-cause mortality (0.79 [0.72-0.87]) and foot ulceration (0.67 [0.53-0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta-analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79-0.87]) (I2 = 10.76%). CONCLUSIONS: This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all-cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D.
Assuntos
Conservadores da Densidade Óssea , Denosumab , Diabetes Mellitus Tipo 2 , Difosfonatos , Osteoporose , Humanos , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Incidência , Estudos Retrospectivos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Feminino , Masculino , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Idoso , Difosfonatos/uso terapêutico , Pessoa de Meia-Idade , Pé Diabético/prevenção & controle , Pé Diabético/epidemiologia , Pé Diabético/mortalidade , Pé Diabético/tratamento farmacológico , Adulto , Estudos de CoortesRESUMO
INTRODUCTION: We aimed to investigate the effects of zinc deficiency and zinc medication in osteoporosis patients undergoing denosumab (DMAb). MATERIALS AND METHODS: This retrospective study was conducted at a single hospital. The participants were female osteoporosis patients visiting between April 2019 and April 2020. All patients were treated with DMAb and eldecalcitol and recommended zinc-rich food. Based on zinc medication and serum zinc levels at the 12th month of dietary guidance, patients were categorized into the following four groups: hypozincemia with zinc medication, latent zinc deficiency with zinc medication, without zinc medication, and control without zinc medication. Longitudinal serum zinc concentrations, bone mineral density (BMD), and occurrence of fractures were measured. We investigated the factors influencing no response to DMAb and eldecalcitol treatment. RESULTS: Among the 145 patients followed up for 24 months, dietary guidance did not change the serum zinc concentration; however, zinc medication significantly increased these levels. The hypozincemia group did not show a significant BMD increase in the lumbar spine and femoral neck after DMAb and eldecalcitol treatment during dietary guidance; however, zinc medication increased these to the same levels as the other groups. In multivariate analyses, hypozincemia and thyroid disease were identified as the factors affecting no response. While 28.2% of patients with latent zinc deficiency without zinc medication suffered fractures, no fractures occurred in hypozincemia patients with zinc medication. CONCLUSION: Hypozincemia may reduce the efficacy of DMAb and eldecalcitol in increasing BMD and fracture prevention.
Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose Pós-Menopausa , Osteoporose , Vitamina D/análogos & derivados , Humanos , Feminino , Masculino , Densidade Óssea , Denosumab/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Zinco/farmacologia , Zinco/uso terapêutico , Estudos Retrospectivos , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
OBJECTIVES: To investigate the protective effect of osteoporosis medications on the risk of developing rheumatoid arthritis (RA) in patients with osteoporosis. METHODS: We conducted a retrospective cohort study from 1 January, 2011 to 31 March, 2023. There was a total of 971901 patients from a hospital-based population in Taiwan. In this cohort, there was a total of 17065 osteoporosis patients with or without pathological fracture. In these patients, 7180 patients were osteoporosis medication users, and 9605 patients were non-osteoporosis medication users, after exclusion of previous RA. The risk of RA in the patients with osteoporosis medications was assessed, and stratified by sex and different medications, including bisphosphonates, denosumab, raloxifene and teriparatide. RESULTS: Patients with osteoporosis medication use had a reduced risk of RA compared with non-osteoporosis medication users [adjusted hazard ratio (aHR)=0.484, 95%CI: 0.270-0.867, p<0.05), after adjusting for age, comorbidites and medications. Specifically, patients with ever use of bisphosphonates (n=2069) or denosumab (n=4510) had a reduced risk of RA (aHR=0.405, 95%CI: 0.173-0.951, p<0.05, and aHR=0.394, 95%CI: 0.192-0.809, p<0.05, respectively). Notably, patients that only used denosumab (n=2938) had a further reduced risk of RA (aHR=0.32, 95%CI: 0.12-0.83, p<0.05), particularly in female patients (aHR=0.26, 95%CI: 0.09-0.74, p<0.05). Patients taking raloxifene or teriparatide did not have a significantly reduced risk of RA. CONCLUSIONS: Denosumab use reduces the risk of RA in patients with osteoporosis. Receptor activator of nuclear factor kappa B ligand (RANKL) mediated osteoclast joint damage may be involved in the pathogenesis of RA during the preclinical stage.
Assuntos
Artrite Reumatoide , Conservadores da Densidade Óssea , Denosumab , Osteoporose , Humanos , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Feminino , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Masculino , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Osteoporose/prevenção & controle , Estudos Retrospectivos , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Pessoa de Meia-Idade , Taiwan/epidemiologia , Fatores de Risco , Medição de Risco , Resultado do Tratamento , Fatores de Proteção , Difosfonatos/uso terapêuticoRESUMO
Kidney transplant recipients (KTR) are at an increased risk of developing Pneumocystis jirovecii pneumonia (PCP), especially during the first year after transplantation. This is the first reported pediatric KTR, with chronic kidney disease (CKD) secondary to kidney dysplasia and vesicoureteral reflux, who developed refractory and symptomatic hypercalcemia 5 years after transplantation. The hypercalcemia was resistant to treatment with intravenous hyperhydration, furosemide, and a low-calcium diet. A respiratory tract infection due to PCP treated with trimethoprim-sulfamethoxazole did not improve calcium levels. Due to the hypercalcemic symptom burden for the patient, a single dose of subcutaneous denosumab was used to achieve sustained clinical and biochemical improvement, without any severe adverse events. This case highlights the potential use of denosumab as a treatment option in pediatric KTR with refractory hypercalcemia related to PCP. Further study of denosumab in young people with CKD or kidney transplants is needed before routine use can be recommended.
Assuntos
Denosumab , Hipercalcemia , Transplante de Rim , Pneumocystis carinii , Pneumonia por Pneumocystis , Humanos , Hipercalcemia/etiologia , Hipercalcemia/tratamento farmacológico , Hipercalcemia/diagnóstico , Transplante de Rim/efeitos adversos , Denosumab/efeitos adversos , Denosumab/uso terapêutico , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/etiologia , Masculino , Insuficiência Renal Crônica/complicações , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Adolescente , Feminino , CriançaRESUMO
We present the case of a 9-year-old girl who developed striking bone changes following two years of denosumab therapy for giant cell lesions of the jaw.
Assuntos
Conservadores da Densidade Óssea , Denosumab , Humanos , Denosumab/efeitos adversos , Feminino , Criança , Conservadores da Densidade Óssea/efeitos adversosRESUMO
BACKGROUND: The prevalence of osteoporosis is increasing in the United States. PURPOSE: To evaluate low bone mass and osteoporosis treatments to prevent fractures. DATA SOURCES: Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022. STUDY SELECTION: Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies (n ≥1000) for harms. DATA EXTRACTION: Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE). DATA SYNTHESIS: We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE). LIMITATION: Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years. CONCLUSION: Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42021236220).
Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose Pós-Menopausa , Osteoporose , Médicos , Fraturas da Coluna Vertebral , Masculino , Adulto , Feminino , Humanos , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Teriparatida/efeitos adversos , Alendronato/efeitos adversos , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/tratamento farmacológico , Denosumab/efeitos adversos , Metanálise em Rede , Fraturas Ósseas/prevenção & controle , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Difosfonatos/efeitos adversos , Fraturas da Coluna Vertebral/prevenção & controleRESUMO
Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.
Assuntos
Conservadores da Densidade Óssea , Hipocalcemia , Osteoporose , Estados Unidos , Humanos , Idoso , Feminino , Hipocalcemia/induzido quimicamente , Hipocalcemia/sangue , Denosumab/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Cálcio/uso terapêutico , Estudos Retrospectivos , Diálise Renal , Medicare , Osteoporose/tratamento farmacológico , Difosfonatos/efeitos adversosRESUMO
Background and Objectives: Androgen deprivation therapy (ADT) for prostate cancer has greatly improved treatment outcomes. As patient survival rates have increased, reports of decreased bone density and increased bone fractures as side effects of ADT have emerged. The prevalence of osteoporosis in Japanese men was 4.6%. The purpose of this study was to evaluate the effect of osteoporosis treatment in prostate cancer patients who underwent ADT in Japan. Materials and Methods: The subjects were 33 male patients who had undergone ADT for prostate cancer, who were noted to have decreased bone density. Mean age was 76.2 ± 7.7 years (64-87). Medications included vitamin D in one case, bisphosphonates (BP) in 27 cases, and denosumab in five cases. The evaluation method examined the rate of change in bone mineral density (BMD) before osteoporosis treatment and 1 year after. For comparison, a group without osteoporosis treatment intervention (n = 33) was selected, and matched for prostate cancer treatment and age. The rate of change in trabecular bone score (TBS) was also calculated. Results: The percentage changes in BMD before and 1 year after treatment were as follows: lumbar spine, 7.1 ± 5.8% in the treatment group versus -3.9 ± 4.1% in the no treatment group; femoral neck, 5.5 ± 6.2% in the treatment group versus -0.9 ± 3.9% in the no treatment group; total femur, 6.6 ± 6.4% in the treatment group versus the no treatment group which was -1.7 ± 3.2%. In all cases, there was a clear significant difference (p < 0.01). The percent change in TBS was further calculated in the same manner. There was no significant difference between the two groups: +1.7 ± 3.8% in the treated group versus +0.3 ± 4.1% in the untreated group. Conclusions: Osteoporosis treatment in Japanese patients with prostate cancer on ADT therapy was found to significantly increase BMD compared to the untreated group. BP and denosumab were found to be very effective in increasing BMD.
Assuntos
Antagonistas de Androgênios , Conservadores da Densidade Óssea , Densidade Óssea , Denosumab , Osteoporose , Neoplasias da Próstata , Humanos , Masculino , Osteoporose/tratamento farmacológico , Idoso , Japão/epidemiologia , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Difosfonatos/efeitos adversos , Vitamina D/uso terapêuticoRESUMO
Denosumab is a human monoclonal antibody indicated for patients with osteoporosis and a high risk of fractures. It targets RANKL, the receptor activator of NF-κB (RANK) ligand, blocking RANKL-RANK interaction and leading to rapid osteoclast-mediated bone resorption inhibition. But RANK is widely expressed in neurons, microglia, and astrocytes. RANKL/RANK/NF-κB system can play an important role in the neuroinflammatory response, depressive behavior, memory impairments, and neurotrophism. We present two well-documented case reports of recurrent neuropsychiatric manifestations in patients treated with denosumab and a descriptive review of similar cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database between 2012 and 2022. Only those reported by healthcare professionals, coding denosumab as the only suspected drug, were retained. An 81-year-old woman with pre-existing mild cognitive impairment suffered two acute confusional episodes and another 81-year-old woman with depression in remission suffered two depressive recurrences with anxiety and psychomotor inhibition, in both cases following sequential administrations of denosumab without underlying calcium/phosphate imbalance. Scores on Naranjo Adverse Drug Reaction Probability Scale were 6 and 7, respectively, suggesting a probable causal relationship. Of the 91,151 cases with denosumab exposure reported to FAERS, 5.7% were related to psychiatric/neurological disorders and 23.8% of these corresponded to cognitive impairment, depressive/mood disturbances, or psychomotor retardation. Denosumab may cause transient but severe neuropsychiatric symptoms by several mechanisms involving RANKL blockade and subsequent immuno-inflammatory changes, at least in subjects with pre-existing neurobiological vulnerability. We recommend caution and careful monitoring of these patients following denosumab administrations.
Assuntos
Fraturas Ósseas , Osteoporose , Feminino , Humanos , Idoso de 80 Anos ou mais , Denosumab/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Ligante RANK , Anticorpos Monoclonais/uso terapêutico , Osteoporose/tratamento farmacológico , Fraturas Ósseas/tratamento farmacológicoRESUMO
A retrospective study of 121 patients who stopped denosumab (Dmab) then received no treatment (NT), risedronate (RIS), alendronate (ALN), or zoledronic acid (ZOL). Bone density (spine and hip) during and after Dmab discontinuation was measured. Treatment with ALN or ZOL, not NT and RIS, mitigated BMD loss after Dmab discontinuation. INTRODUCTION: Denosumab (Dmab) discontinuation is associated with bone loss and multiple vertebral fractures. The purpose was to compare bone mineral density (BMD) change in patients following Dmab discontinuation with no subsequent treatment (NT) and three bisphosphonate (BP) treatments: risedronate (RIS), alendronate (ALN), and zoledronic acid (ZOL). METHODS: In a review of 121 patients aged 71.2 ± 8.1 years, discontinuing Dmab (mean 5.4 doses), 33 received NT and 88 received BP (22 RIS; 34 ALN; 32 ZOL). BMD change after 1 year was compared between groups at the lumbar spine (LS), femoral neck (FN), and total hip (TH). Risk factors for bone loss after Dmab discontinuation were compared between groups and incidence of vertebral fractures was determined. RESULTS: Following Dmab discontinuation, LS mean change (g/cm2; 95% CI) was for NT: - 0.041 (- 0.062 to - 0.021); RIS: - 0.035 (- 0.052 to - 0.017); ALN: - 0.005 (- 0.020 to 0.009); and ZOL: - 0.009 (- 0.025 to 0.008). Differences in LS were found between NT and ALN (p = 0.015), and NT and ZOL (p=0.037), but not between NT and RIS. The only significant difference in TH was found between NT and ZOL (p 0.034) with no group differences in FN. BMD gains during Dmab treatment were associated with BMD loss after Dmab discontinuation. In a subset, discontinuation after Dmab treatment (> 5 doses) followed by ALN (n = 22) and ZOL (n = 11) showed no difference in BMD. Five of 7 vertebral fractures occurred after Dmab discontinuation in NT. CONCLUSION: Subsequent treatment with ALN or ZOL but not NT and RIS mitigates BMD loss after Dmab discontinuation.
Assuntos
Conservadores da Densidade Óssea , Doenças Ósseas Metabólicas , Osteoporose Pós-Menopausa , Fraturas da Coluna Vertebral , Feminino , Humanos , Alendronato , Densidade Óssea , Conservadores da Densidade Óssea/efeitos adversos , Doenças Ósseas Metabólicas/tratamento farmacológico , Denosumab/efeitos adversos , Difosfonatos/uso terapêutico , Vértebras Lombares , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/prevenção & controle , Osteoporose Pós-Menopausa/induzido quimicamente , Estudos Retrospectivos , Ácido Risedrônico , Fraturas da Coluna Vertebral/tratamento farmacológico , Ácido ZoledrônicoRESUMO
Twelve months following discontinuation of denosumab, the percent decrease in mean bone mineral density (BMD) values at the hip and knee regions were similar between both the denosumab and placebo groups. These findings emphasize the need for additional trials to understand the effect of continued administration of denosumab after subacute spinal cord injury (SCI) to avoid this demineralization. OBJECTIVE: To determine changes in BMD 1 year after denosumab was discontinued in participants with subacute SCI who had drug treatment initiated within 90 days post SCI and continued for 1 year. METHODS: Fourteen participants who completed a randomized, double-blinded, placebo-controlled drug trial (parent study: denosumab 60 mg (Prolia, Amgen Inc., n = 8) or placebo (n = 6); administered at baseline, 6, and 12 months) were followed 12 months after the 18 months from baseline primary end point was completed. The BMD of skeletal regions below the SCI at higher risk of fracture was measured [total hip, distal femur epiphysis (DFE), distal femur metaphysis (DFM), and proximal tibia epiphysis (PTE)] by dual energy X-ray absorptiometry. RESULTS: The percent decreases in mean BMD values at all regions of the hip and knee from 18 to 30 months were similar in both the denosumab and placebo groups. However, at 30 months, the absolute values for mean BMD remained significantly higher in the drug treatment than that of the placebo group at the DFM (p = 0.03), DFE (p = 0.04), and PTE (p = 0.05). CONCLUSIONS: In persons with SCI who initiated denosumab treatment during the subacute injury phase and maintained treatment for 1 year, the discontinuation of drug resulted in percent loss of mean BMD similar to that of the placebo group, with absolute mean BMD values at the knee regions at the 12-month follow-up visit significantly higher in the drug treatment than those in the placebo group. These data underscore the need to study continued administration of denosumab after subacute SCI to avoid marked demineralization in the sublesional skeleton upon discontinuation of this agent.
Assuntos
Conservadores da Densidade Óssea , Doenças Ósseas Metabólicas , Traumatismos da Medula Espinal , Humanos , Denosumab/efeitos adversos , Densidade Óssea , Doenças Ósseas Metabólicas/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Extremidade InferiorRESUMO
In patients with non-metastatic prostate cancer, treated with radiation therapy and androgen deprivation therapy for 3 years and DMAB on average for 5 years, BMD was in the normal or osteopenic range. Discontinuation of DMAB led to a bone loss of 2-5%. In men with osteopenia, the bone loss was prevented by zoledronate. PURPOSE: Patients with prostate cancer receiving androgen deprivation therapy (ADT) are treated with denosumab (DMAB) to prevent fractures and preserve bone mass. We wanted to investigate the change in BMD in men with non-metastatic prostate cancer discontinuing DMAB. METHODS: We conducted a retrospective cohort study based on medical records from patients referred to the Department of Endocrinology from the Department of Urology, Aarhus University Hospital between June 1, 2018, and June 1, 2021. We retrieved information on biochemistry and DXA performed 0-6 months after the last DMAB injection and a second DXA performed approximately 12 months after the first. In case of a BMD T-score ≤ - 1 at the lumbar spine or total hip at the first DXA, the patients were treated with zoledronate. The primary endpoint was change in lumbar spine BMD. RESULTS: We included 50 patients with non-metastatic prostate cancer. The mean DMAB treatment duration was 5 ± 0.1 years. Among the patients treated with zoledronate (n = 9), BMD was maintained at the spine and femoral neck after a mean of 16 months. We found a significant decrease in BMD; - 4.9 ± 4.2%, - 1.9 ± 3.5%, and - 2.4 ± 3.6% at the spine, total hip, and femoral neck between the first and second DXA in the patients not treated with zoledronate (n = 24) (p ≤ 0.01 for all). One patient who did not receive ZOL sustained multiple fragility vertebral fractures after DMAB discontinuation. CONCLUSION: In men with non-metastatic prostate cancer, discontinuation of DMAB after stopping ADT led to an average bone loss of 2-5%. Zoledronate prevented bone loss in men with osteopenia.
Assuntos
Conservadores da Densidade Óssea , Doenças Ósseas Metabólicas , Neoplasias da Próstata , Masculino , Humanos , Denosumab/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Ácido Zoledrônico/uso terapêutico , Estudos Retrospectivos , Antagonistas de Androgênios/efeitos adversos , Androgênios , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Densidade Óssea , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/tratamento farmacológicoRESUMO
In this multi-institutional retrospective cohort study, we compared the long-term risk of osteonecrosis of the jaw following the use of denosumab vs. bisphosphonates in osteoporotic patients. After 2-year use, the likelihood of osteonecrosis of the jaw is lower with denosumab compared to bisphosphonates, and the difference increases with time. PURPOSE: To compare the long-term risk of osteonecrosis of the jaw (ONJ) between osteoporotic patients treated with bisphosphonates (BPs) and denosumab. METHODS: This multi-institutional retrospective cohort study included patients aged > 40 years with osteoporosis between January 2010 and December 2018. Patients who met the eligibility criteria were divided into BPs and denosumab groups by propensity score matching (PSM). The risk of ONJ of denosumab vs. BPs was estimated using a Cox proportional hazards model and was described by the cumulative incidence rate using the Kaplan-Meier method. RESULTS: A total of 84,102 patients with osteoporosis were enrolled, among whom, 8962 were eligible for inclusion based on their first-line drug use (denosumab, n = 3,823; BPs, n = 5,139). Following PCM matching (1:1), the BPs and denosumab groups included 3665 patients each. The incidence density of ONJ in the denosumab and BPs matching groups was 1.47 vs. 2.49 events (per 1000 person-years), respectively. The hazard ratio of ONJ in the denosumab vs. BPs group was estimated as 0.581 (95% confidence interval: 0.33-1.04, p = 0.07). The cumulative incidence rates of ONJ in both groups were similar for the first and second years of drug use (p = 0.062), but significantly different from the third year onwards (p = 0.022). The severity of ONJ was not significantly different between the two groups. CONCLUSION: In osteoporotic patients, after 2 years of use, the likelihood of ONJ being induced by denosumab is lower than that of BPs, and the difference increases with time.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Osteonecrose , Osteoporose , Humanos , Difosfonatos/efeitos adversos , Denosumab/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Estudos Retrospectivos , Taiwan/epidemiologia , Osteonecrose/induzido quimicamente , Osteoporose/complicações , Fatores de Risco , Conservadores da Densidade Óssea/efeitos adversosRESUMO
We investigated the association between bisphosphonate and denosumab use and risk of hip fracture in Norway. These drugs protect against fractures in clinical trials, but their population-level effect is unknown. Our results showed lowered risk of hip fracture for treated women. Treatment of high-risk individuals could prevent future hip fractures. PURPOSE: To investigate whether bisphosphonates and denosumab reduced the risk of first-time hip fracture in Norwegian women when adjusting for a medication-based comorbidity index. METHODS: Norwegian women aged 50-89 in 2005-2016 were included. The Norwegian prescription database (NorPD) supplied data on exposures to bisphosphonates, denosumab, and other drugs for the calculation of the Rx-Risk Comorbidity Index. Information on all hip fractures treated in hospitals in Norway was available. Flexible parametric survival analysis was used with age as time scale and with time-varying exposure to bisphosphonates and denosumab. Individuals were followed until hip fracture or censoring (death, emigration, age 90 years), or 31 December 2016, whichever occurred first. Rx-Risk score was included as a time-varying covariate. Other covariates were marital status, education, and time-varying use of bisphosphonates or denosumab with other indications than osteoporosis. RESULTS: Of 1,044,661 women 77,755 (7.2%) were ever-exposed to bisphosphonate and 4483 (0.4%) to denosumab. The fully adjusted hazard ratios (HR) were 0.95 (95% confidence interval (CI): 0.91-0.99) for bisphosphonate use and 0.60 (95% CI: 0.47-0.76) for denosumab use. Bisphosphonate treatment gave a significantly reduced risk of hip fracture compared with the population after 3 years and denosumab after 6 months. Fracture risk was lowest in denosumab users who had previously used bisphosphonate: HR 0.42 (95% CI: 0.29-0.61) compared with the unexposed population. CONCLUSIONS: In population-wide real-world data, women exposed to bisphosphonates and denosumab had a lower hip fracture risk than the unexposed population after adjusting for comorbidity. Treatment duration and treatment history impacted fracture risk.
Assuntos
Conservadores da Densidade Óssea , Fraturas do Quadril , Osteoporose , Feminino , Humanos , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/efeitos adversos , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/prevenção & controle , Difosfonatos/efeitos adversos , Noruega/epidemiologiaRESUMO
This registry-based study of 3068 patients with osteoporosis compared the anti-fracture effectiveness of denosumab versus bisphosphonates. Denosumab was associated with significantly greater risk reduction than alendronate or ibandronate for vertebral and any fractures. No difference in fracture risk reduction was found between zoledronate and denosumab. PURPOSE: To analyse the fracture risk of patients with osteoporosis receiving bisphosphonates or denosumab in a real-world setting. METHODS: This registry-based cohort study evaluated patients taking denosumab, bisphosphonates or both sequentially. Fractures were analysed using rates, rate ratios and hazard ratios (HR), including both therapies as time-varying co-variates. Fracture risk hazards were adjusted (aHR) for baseline T-Scores and trabecular bone score (TBS) and were additionally analysed with inverse probability treatment weighting. RESULTS: A total of 3068 patients (89% female; median age at treatment onset, 69 years [63 to 76]) received denosumab (median duration 2.8 years, [2.2 to 4.7]), bisphosphonates (3.4 years, [2.1 to 5.7]) or both sequentially. Thus, 11,078 subject-years were assessed for bisphosphonates (41% alendronate, 36% ibandronate, 23% zoledronate) and 4216 for denosumab. Moreover, 48,375 subject-years were observed before treatment onset, in addition to 2593 years of drug holidays. A total of 1481 vertebral fractures (435 under therapy), 1508 non-vertebral fractures (499 under therapy) and 202 hip fractures (67 under therapy) occurred after age 50. The risks of vertebral, non-vertebral and hip fractures were significantly lower under all bisphosphonates, denosumab and drug holidays than before treatment onset (all p < 0.001). After adjusting for age, baseline T-scores and TBS, denosumab was associated with lower risk than alendronate or ibandronate for vertebral fractures (aHR 0.47 (0.35 to 0.64) and 0.70 [0.53 to 0.91], p < 0.001 and p = 0.009, respectively) and any fractures (aHR 0.62 [0.51 to 0.76] and 0.77 [0.64 to 0.92], p < 0.001 and p = 0.004). With propensity weighting, denosumab was associated with a lower hip fracture risk compared to alendronate (HR 0.54 [0.29 to 0.98], p = 0.044). No difference in fracture risk reduction (vertebral, non-vertebral or hip) was found between zoledronate and denosumab. CONCLUSIONS: When adjusting for disease severity, denosumab was associated with significantly greater risk reduction than alendronate and ibandronate for vertebral fractures. No difference in fracture risk reduction was found between zoledronate and denosumab.