Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.520
Filtrar
1.
JCO Glob Oncol ; 10: e2300396, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38452304

RESUMO

PURPOSE: Denosumab is clinically superior to zoledronic acid (ZA) for preventing and delaying time to first and subsequent skeletal-related events (SREs) among patients with breast cancer (BC) with bone metastases. We evaluated the cost and health benefits of denosumab and ZA (once every 4 weeks and once every 12 weeks) among four different molecular subtypes of BC with bone metastases in India. MATERIALS AND METHODS: A Markov model was developed in Microsoft Excel to estimate lifetime health consequences and resulting costs among cohort of 1,000 patients with BC with bone metastasis, for three intervention scenarios, namely denosumab (once every 4 weeks), ZA (once every 4 weeks), and ZA (once every 12 weeks). The health outcomes were measured in terms of SREs averted and quality-adjusted life-years (QALYs) gained. The cost of each intervention scenario was measured using both the health system and the patient's perspectives. Indirect costs because of lost productivity were not included. The future costs and outcomes were discounted at the standard rate of 3%. RESULTS: Over a lifetime, the incremental number of SREs averted with use of denosumab once every 4 weeks (compared with ZA once every 4 weeks and once every 12 weeks) among patients with luminal A, luminal B, human epidermal growth factor receptor 2-enriched, and triple negative breast cancer were estimated as 0.39, 0.26, 0.25, and 0.19, respectively. The number of QALYs lived were slightly higher in the denosumab arm (1.45-2.80) compared with ZA once every 4 weeks and once every 12 weeks arms (1.44-2.78). However, denosumab once every 4 weeks was not found to be a cost-effective alternative for either of the four molecular subtypes of breast cancer. ZA once every 12 weeks was found to be a cost-effective option with an average cost-effectiveness ratio ranging between ₹68,254 and ₹73,636. CONCLUSION: ZA once every 12 weeks is the cost-effective treatment option for BC with bone metastases in India. The present study findings hold significance for standard treatment guidelines under India's government-funded health insurance program.


Assuntos
Conservadores da Densidade Óssea , Neoplasias Ósseas , Neoplasias da Mama , Humanos , Feminino , Denosumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Difosfonatos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Análise de Custo-Efetividade , Imidazóis/uso terapêutico , Análise Custo-Benefício , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Ácido Zoledrônico/uso terapêutico
2.
Pediatr Rheumatol Online J ; 22(1): 37, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38481224

RESUMO

BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) is a rare genetic disorder characterized by the progressive loss of bone in the hands, feet, and other skeletal structures. It presents with symptoms that may resemble those of juvenile idiopathic arthritis, making diagnosis challenging for clinicians. The identification of MAF BZIP Transcription Factor B (MAFB) mutations as significant contributors to MCTO represents a major breakthrough in our understanding of the pathogenesis of this rare skeletal disorder. CASE PRESENTATION: Our objective was to present the phenotype, treatment, and outcome of a patient with a variant of MAFB-induced MCTO to broaden the range of clinical features associated with MCTO and share our clinical experience for improved diagnosis and treatment. In our case, early MRI examination of the bones and whole exome sequencing enabled an early and accurate MCTO diagnosis, and timely Denosumab administration resulted in no deterioration. CONCLUSION: This suggests that MRI examination and whole exome sequencing should be considered when MCTO is suspected, and Denosumab might be an option in the treatment of MCTO.


Assuntos
Osteólise , Humanos , Osteólise/diagnóstico por imagem , Osteólise/genética , Denosumab , Mutação , Fenótipo , Fator de Transcrição MafB/genética
3.
Support Care Cancer ; 32(3): 202, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427111

RESUMO

PURPOSE: Optimal use of bone-modifying agents (BMAs) in patients with bone metastases from solid tumors is uncertain in some aspects: the drug choice; the planned treatment duration and long-term therapy; the prevention and management of possible side effects, including renal toxicity, hypocalcaemia, and medication-related osteonecrosis of the jaw (MRONJ). METHODS: Italian oncologists were invited to fulfil a 24-question web survey about prescription of BMAs for bone metastases of breast cancer, prostate cancer, and other solid tumors. Prevention and management of side effects were also investigated. RESULTS: Answers of 191 oncologists were collected. BMAs are usually prescribed at the time of diagnosis of bone metastases by 87.0% (breast cancer) and 76.1% (solid tumors except breast and prostate cancers) of oncologists; the decision is more articulated for prostate cancer (endocrine-sensitive versus castration-resistant). The creatinine level (32.3%), the availability of patient venous access (15.8%), and the type of primary neoplasm (13.6%) are the most reported factors involved in choice between bisphosphonates and denosumab. Zoledronic acid every 3 months was considered as a valid alternative to monthly administration by 94% of Italian oncologists. Oncologists reported a good confidence with measures aimed to prevent MRONJ, whereas uncertainness about prevention and management of hypocalcemia was registered. CONCLUSION: Italian oncologists showed a high attitude in prescribing bisphosphonates or denosumab at the time of diagnosis of bone metastases, with a large application of preventive measures of side effects. Further studies are needed to investigate some controversial aspects, such as optimal drug treatment duration and long-term drug schedules.


Assuntos
Conservadores da Densidade Óssea , Neoplasias Ósseas , Neoplasias da Mama , Neoplasias da Próstata , Masculino , Humanos , Denosumab/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/secundário , Difosfonatos/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Mama/tratamento farmacológico , Prescrições de Medicamentos , Itália
4.
Br Dent J ; 236(6): 453-456, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38519674

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) is a known complication of antiresorptive and anti-angiogenic therapies in adults. Increasingly, these drugs are being prescribed for children with a variety of conditions, such as osteogenesis imperfecta and cancers of the bone. Review of the literature, however, reveals no reported paediatric MRONJ cases to date. We present such a case in a nine-year-old female patient with a vertebral aneurysmal bone cyst, who received dental extractions subsequent to denosumab therapy.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Neoplasias , Adulto , Feminino , Humanos , Criança , Denosumab/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/uso terapêutico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia
5.
Bone Res ; 12(1): 10, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378678

RESUMO

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191.


Assuntos
Denosumab , Displasia Fibrosa Óssea , Animais , Humanos , Camundongos , Denosumab/farmacologia , Displasia Fibrosa Óssea/tratamento farmacológico , Ligantes , Osteoblastos/metabolismo , Osteogênese/genética
7.
Rev Med Suisse ; 20(859): 255-258, 2024 Jan 31.
Artigo em Francês | MEDLINE | ID: mdl-38299957

RESUMO

The sequential effects of romosozumab and denosumab in osteoporosis are shown in real-life, while the mechanisms of post-denosumab rebound are reviewed extensively. A network meta-analysis confirms the superiority of anabolics vs anti-resorptives on fracture reduction, while the latter shown a reduction of mortality in a large population-based study. Fracture risk prediction by FRAXPlus is improved. New meta-analyses confirm the benefits of Vitamin D on fractures and falls. Finally, multiples trials with new molecules for the treatment of rare bone diseases, including osteogenesis imperfecta, fibrous dysplasia and hypoparathyroidism, shown promising results.


Dans l'ostéoporose, les effets séquentiels du romosozumab et du dénosumab se précisent et les mécanismes du rebond à l'arrêt de ce dernier font l'objet d'une revue détaillée. Une méta-analyse en réseau confirme la supériorité des traitements anaboliques sur les antirésorbtifs, alors que l'effet de ces derniers sur la réduction de la mortalité est démontré dans une large étude populationnelle. La prédiction du risque fracturaire est améliorée par l'outil FRAXPlus. De nouvelles méta-analyses des bénéfices de la vitamine D sur le risque de fractures et de chutes sont également disponibles. Enfin, de nombreuses études encourageantes sur l'efficacité de nouveaux traitements dans de multiples maladies osseuse rares, telles l'ostéogenèse imparfaite, la dysplasie fibreuse et l'hypoparathyroïdie, ont été publiées.


Assuntos
Doenças Ósseas Metabólicas , Fraturas Ósseas , Hipoparatireoidismo , Osteoporose , Humanos , Denosumab/uso terapêutico , Doenças Ósseas Metabólicas/tratamento farmacológico , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Doenças Raras
8.
Ugeskr Laeger ; 186(5)2024 Jan 29.
Artigo em Dinamarquês | MEDLINE | ID: mdl-38327195

RESUMO

Bone turnover markers (BTM) are highly responsive to initiation and changes in anti-osteoporotic therapy. In contrast to the slow treatment-induced changes in bone mineral density, the fast changes in BTM enable the clinician to adjust treatment management within a short timeframe. This review describes how BTM can be used for treatment monitoring, including monitoring during discontinuation of alendronate and denosumab therapy. In addition, sources of errors and pitfalls when using BTM monitoring will be described.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Humanos , Biomarcadores , Osteoporose/tratamento farmacológico , Densidade Óssea , Remodelação Óssea , Denosumab/uso terapêutico
9.
JAMA Netw Open ; 7(2): e2354734, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38335002

RESUMO

Importance: Denosumab, a humanized monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), is a widely used antiresorptive medication for osteoporosis treatment. Recent preclinical studies indicate that inhibition of RANKL signaling improves insulin sensitivity, glucose tolerance, and ß-cell proliferation, suggesting that denosumab may improve glucose homeostasis; however, whether denosumab reduces the risk of incident diabetes remains unclear. Objective: To evaluate whether denosumab use is associated with a lower risk of developing diabetes in patients with osteoporosis. Design, Setting, and Participants: This nationwide, propensity score-matched cohort study used administrative data from Taiwan's National Health Insurance Research Database. Adult patients who received denosumab for osteoporosis therapy in Taiwan between 2012 and 2019 were included. To eliminate the inherent bias from confounding by indication, the patients were categorized into a treatment group (34 255 patients who initiated denosumab treatment and adhered to it) and a comparison group (34 255 patients who initiated denosumab treatment but discontinued it after the initial dose) according to the administration status of the second dose of denosumab. Propensity score matching was performed to balance patient characteristics and to control for confounders. Exposure: Treatment with denosumab. Main Outcomes and Measures: The primary outcome was incident diabetes requiring treatment with antidiabetic drugs. A Cox proportional hazards model was used to estimate the hazard ratio (HR) for incident diabetes. Data were analyzed from January 1 to November 30, 2023. Results: After propensity score matching, 68 510 patients were included (mean [SD] age, 77.7 [9.8] years; 57 762 [84.3%] female). During a mean (SD) follow-up of 1.9 (1.6) years, 2016 patients developed diabetes in the treatment group and 3220 developed diabetes in the comparison group (incidence rate, 35.9 vs 43.6 per 1000 person-years). Compared with the comparison group, denosumab treatment was associated with a lower risk of incident diabetes (HR, 0.84; 95% CI, 0.78-0.90). Several sensitivity analyses also demonstrated similar results of lower diabetes risk associated with denosumab treatment. Conclusions and relevance: The results from this cohort study indicating that denosumab treatment was associated with lower risk of incident diabetes may help physicians choose an appropriate antiosteoporosis medication for patients with osteoporosis while also considering the risk of diabetes.


Assuntos
Conservadores da Densidade Óssea , Diabetes Mellitus , Osteoporose , Adulto , Humanos , Feminino , Idoso , Masculino , Denosumab/uso terapêutico , Estudos de Coortes , Osteoporose/tratamento farmacológico , Osteoporose/epidemiologia , Conservadores da Densidade Óssea/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Glucose
10.
Clin Orthop Surg ; 16(1): 149-156, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38304208

RESUMO

Background: Aneurysmal bone cysts (ABCs) are infrequent, benign, and locally destructive lesions that most commonly occur during the first two decades of life. They usually affect the metaphysis of the long bones, but the pelvis is involved in 8%-12% of the cases. The management of pelvic ABCs is a challenging issue due to difficulties in choosing the appropriate approach, adjacent neurovascular bundles, the risk of intraoperative bleeding with difficulty achieving good hemostasis, and the risk of injury to the hip or sacroiliac joints. Limited data exist concerning the use of denosumab as a non-surgical treatment for pelvic ABCs. Our hypothesis was that denosumab might be an effective and safe solo treatment of cases with ABCs in the pelvis. Methods: We retrospectively assessed 20 patients with ABCs in the pelvis, who were treated by denosumab as a solo agent without surgery. Patients were assessed regarding disease control, the incidence of recurrence and non-oncological complications, and functional outcome. Results: The mean follow-up period was 38.5 months. Disease control was achieved in 16 patients (80%), with no local recurrence. Tolerable drug-related complications occurred in 15% of cases. The mean Musculoskeletal Tumor Society score was 92.3%. Conclusions: Denosumab may provide a reliable option in the nonsurgical treatment of ABCs of pelvic origin with expected lower morbidity than the surgical solution and tolerable complications. Further studies on the safety profile and long-term effects of denosumab especially in skeletally immature patients are required.


Assuntos
Cistos Ósseos Aneurismáticos , Denosumab , Humanos , Denosumab/uso terapêutico , Cistos Ósseos Aneurismáticos/diagnóstico por imagem , Cistos Ósseos Aneurismáticos/tratamento farmacológico , Estudos Retrospectivos , Pelve , Osso e Ossos
11.
Exp Clin Transplant ; 22(Suppl 1): 342-344, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38385423

RESUMO

Deviations of calcium, phosphate, parathyroid hormone, and vitamin D levels are the basis for the diagnosis of calcium-phosphate metabolism disorders. The plasma concentration of the biologically active form known as free calcium is regulated in a harmonious manner by its exchange in the bones and reabsorption by the kidneys. These steps take place under the control of parathyroid hormone and calcitriol. In the process of chronic kidney disease, the kidney cannot synthesize adequate calcitriol, and the resulting hypocalcemia and hyperphosphatemia cause the development of secondary hyperparathyroidism. Osteoporosis is a metabolic bone disease and is essentially the consequence of osteoclastogenesis-induced bone resorption that exceeds bone formation. Osteoporosis is common after kidney transplant. However, hypocalcemia following kidney transplant is rare. The hungry bone syndrome after parathyroidectomy is often responsible for this condition in the pretransplant period. Denosumab is a human monoclonal antibody developed against the receptor activator of nuclear factor kappa-B ligand (known as RANKL). Denosumab exerts an antiresorptive effect on bones by reducing differentiation into osteoclasts. It is an effective treatment option for osteoporosis in the general population. There is insufficient scientific data regarding the use of denosumab in kidney transplant patients. Here, we present the case of a kidney transplant recipient who developed severe hypocalcemia (serum calcium 4.7 mg/dL) after denosumab treatment for osteoporosis.


Assuntos
Hipocalcemia , Transplante de Rim , Osteoporose , Humanos , Hipocalcemia/induzido quimicamente , Hipocalcemia/diagnóstico , Hipocalcemia/tratamento farmacológico , Denosumab/efeitos adversos , Calcitriol/efeitos adversos , Cálcio , Transplante de Rim/efeitos adversos , Osteoporose/diagnóstico , Osteoporose/tratamento farmacológico , Hormônio Paratireóideo , Fosfatos
12.
J Mol Med (Berl) ; 102(3): 353-364, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38302741

RESUMO

This study compiles the main hypotheses involved in the etiopathogenesis of medication-related osteonecrosis of the jaw (MRONJ). A narrative review of the literature was performed. The etiopathogenesis of MRONJ is multifactorial and not fully understood. The main hypothesis considers the disturbance of bone turnover caused by anti-resorptive drugs. Bisphosphonates and denosumab inhibit osteoclast activity through different action mechanisms, accumulating bone microfracture. Other hypotheses also consider oral infection and inflammation, the antiangiogenic effect and soft tissue toxicity of bisphosphonates, and the inhibition of lymphangiogenesis. Knowledge of the current theories for MRONJ is necessary to define future studies and protocols to minimize the incidence of this severe condition.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Humanos , Conservadores da Densidade Óssea/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Arcada Osseodentária
13.
BMC Cancer ; 24(1): 218, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360579

RESUMO

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 ˂80), moderate (30 ≤ Ccr ˂50), and severe (Ccr ˂30). 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 quimicamente
14.
Nat Med ; 30(3): 829-836, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38361122

RESUMO

Erosive hand osteoarthritis (OA) is a prevalent and disabling disease with limited treatment options. Here we present the results of a monocentric, placebo-controlled, double-blind, randomized phase 2a clinical trial with denosumab, a receptor activator of nuclear factor-κB ligand inhibitor, evaluating the effects on structure modification in erosive hand OA. Patients were randomized to 48 weeks treatment with denosumab 60 mg every 3 months (n = 51, 41 females) or placebo (n = 49, 37 females). The primary (radiographic) endpoint was the change in the total Ghent University Scoring System (GUSS) at week 24, where positive changes correspond to remodeling and negative changes to erosive progression. Secondary endpoints were the change in the GUSS at week 48 and the number of new erosive joints at week 48 by the anatomical phase scoring system. Baseline mean GUSS (standard deviation) of target joints was 155.9 (69.3) in the denosumab group and 158.7 (46.8) in the placebo group. The primary endpoint was met with an estimated difference between groups of 8.9 (95% confidence interval (CI) 1.0 to 16.9; P = 0.024) at week 24. This effect was confirmed at week 48 (baseline adjusted GUSS (standard error of the mean) denosumab and placebo were 163.5 (2.9) and 149.2 (3.9), respectively; with an estimated difference between groups of 14.3 (95% CI 4.6 to 24.0; P = 0.003)). At patient level, more new erosive joints were developed in the placebo group compared with denosumab at week 48 (odds ratio 0.24 (95% CI 0.08 to 0.72); P = 0.009). More adverse events occurred in the placebo group (125 events in 44 patients (90%)) compared with the denosumab group (97 events in 41 patients (80%)). These results demonstrate that denosumab has structure modifying effects in erosive hand OA by inducing remodeling and preventing new erosive joints. EU Clinical Trials Register identifier 2015-003223-53 .


Assuntos
Denosumab , Osteoartrite , Feminino , Humanos , Denosumab/efeitos adversos , Ligante RANK , Método Duplo-Cego , Osteoartrite/diagnóstico por imagem , Osteoartrite/tratamento farmacológico , Resultado do Tratamento
16.
Bone ; 181: 117045, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38341165

RESUMO

An 81-year-old Caucasian man who had commenced thrice weekly hemodialysis (HD) three months earlier, presented with a hip fracture, two vertebral fractures and a bone mineral density T-score of -3.6. He had received weekly iron sucrose infusions for 6 weeks and alphacalcidol on dialysis days. Although he suffered from coeliac disease and cirrhosis, he was fully ambulatory and well-nourished. He was normocalcaemic with a marginally low plasma phosphate and the PTH was 11.8 pmol/L (<2-times the upper range of the assay). In view of his severe osteoporosis, it was decided to treat him with denosumab (dmab). Laboratory assessment 2 weeks post dmab showed severe hypophosphatemia and hypocalcemia; phosphate 0.11 mmol/L and ionized calcium 0.83 mmol/L, and he was admitted for intravenous phosphate infusion. Three months later he remained on a phosphate supplement. The case illustrates that, in addition to the risks of hypocalcemia in patients with kidney failure and high bone turnover, kidney failure patients without evidence of high bone turnover, can also be at risk of hypocalcemia and severe hypophosphatemia requiring acute hospitalization and phosphate infusion. The potential role of compromised phosphate absorption versus increased deposition will be discussed. We recommend a cautious approach to dmab therapy in patients on dialysis, with evaluation of bone turnover and serum phosphate levels prior to initiation of treatment.


Assuntos
Conservadores da Densidade Óssea , Hipocalcemia , Hipofosfatemia , Insuficiência Renal , Humanos , Masculino , Idoso de 80 Anos ou mais , Denosumab/efeitos adversos , Hipocalcemia/induzido quimicamente , Hipofosfatemia/induzido quimicamente , Diálise Renal/efeitos adversos , Fosfatos , Insuficiência Renal/induzido quimicamente , Conservadores da Densidade Óssea/efeitos adversos , Densidade Óssea
17.
Sci Rep ; 14(1): 4140, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38374383

RESUMO

The present study aimed to compare clinical and radiological differences of ONFH patients who were treated with denosumab, and a control group. A total of 178 patients (272 hips) with symptomatic, nontraumatic ONFH were divided into a denosumab group (98 patients, 146 hips) and a control group (80 patients, 126 hips). Patients in the denosumab group received a 60 mg subcutaneous dose of denosumab every 6 months. For the clinical assessments, Harris hip scores (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were evaluated. Plain radiographs and MRI were performed before and a minimum of 1 year after administration of denosumab, which were evaluated for radiological results including femoral head collapse (≥ 2 mm) and volume change of necrotic lesion. Femoral head collapse occurred in 36 hips (24.7%) in the denosumab group, and 48 hips (38.1%) in the control group, which was statistically significant (P = 0.012). Twenty-three hips (15.8%) in the denosumab group and 29 hips (23%) in the control group required THA, which showed no significant difference (P = 0.086). At the final follow-up, 71.9% of hips in the denosumab group had a good or excellent HHS compared with 48.9% in the control group, showing a significant difference (P = 0.012). The denosumab group showed a significantly higher rate of necrotic lesion volume reductions compared with the control group (P < 0.001). Denosumab can significantly reduce the volume of necrotic lesions and prevent femoral head collapse in patients with ARCO stage I or II ONFH.


Assuntos
Denosumab , Necrose da Cabeça do Fêmur , Humanos , Denosumab/uso terapêutico , Estudos Retrospectivos , Cabeça do Fêmur/diagnóstico por imagem , Cabeça do Fêmur/patologia , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Necrose da Cabeça do Fêmur/tratamento farmacológico , Necrose da Cabeça do Fêmur/patologia , Quadril/patologia , Resultado do Tratamento
18.
JAMA Netw Open ; 7(1): e2350950, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38198137

RESUMO

Importance: Women with early breast cancer (EBC) exposed to aromatase inhibitors (AIs) may experience fragility fractures despite treatment with bone-active drugs. Risk factors for fractures in patients receiving AIs and denosumab have not been explored to date. Objectives: To evaluate whether an association exists between dual x-ray absorptiometry (DXA)-measured fat body mass (FBM) and vertebral fracture (VF) progression in postmenopausal women with EBC undergoing adjuvant therapy with AIs in combination with denosumab and to examine whether VF was associated with common risk factors for bone fracture and parameters of body composition other than FBM. Design, Setting, and Participants: For this prospective, single-center, cohort study, 237 patients with EBC who were undergoing adjuvant treatment with AIs and denosumab (60 mg every 6 months) were enrolled at the Breast Unit of the ASST Spedali Civili of Brescia from September 2014 to June 2018. Data analysis was conducted in June 2022. Exposure: Body composition parameters, bone mineral density, and morphometric VFs were assessed by DXA at study entry and after 18 months of therapy. Main Outcomes and Measures: VF progression, defined as either new or worsening of preexisting VFs, between the 2 time points. Results: Of the 237 patients enrolled (median [range] age, 61 [28-84] years), 17 (4.4%) reported VF progression. Univariable analysis found an association between VF progression and a history of clinical fractures (odds ratio [OR], 3.22; 95% CI, 1.19-8.74; P = .02), Fracture Risk Assessment Tool (FRAX) score for major fractures (OR, 4.42; 95% CI, 1.23-13.79; P = .04), percentage of FBM (OR, 6.04; 95% CI, 1.69-21.63; P = .006), and android fat (OR, 9.58; 95% CI, 1.17-78.21; P = .04) and an inverse association with appendicular lean mass index-FBM ratio (OR, 0.25, 95% CI, 0.08-0.82; P = .02). Multivariable analysis revealed percentage of FBM (OR, 5.41; 95% CI, 1.49-19.59; P = .01) and FRAX score (OR, 3.95; 95% CI, 1.09-14.39; P = .04) as independent variables associated with VF progression. Conclusions and Relevance: The findings of this study suggest that baseline FBM is an independent factor for VF progression in patients with EBC treated with adjuvant AIs and denosumab. This observation is new and indicates that diet and exercise may synergize with denosumab in the management of bone health in this patient setting.


Assuntos
Neoplasias da Mama , Fraturas Ósseas , Fraturas da Coluna Vertebral , Animais , Humanos , Feminino , Pessoa de Meia-Idade , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/etiologia , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Estudos de Coortes , Denosumab/uso terapêutico , Corpo Adiposo , Estudos Prospectivos , Adjuvantes Imunológicos
19.
Expert Opin Biol Ther ; 24(1-2): 91-100, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38269652

RESUMO

BACKGROUND: This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal antibody for specific pro-resorptive conditions). RESEARCH DESIGN AND METHODS: Healthy males (28-65 years, 50-90 kg) were randomized to a single sub-therapeutic subcutaneous injection of 35 mg GP2411, EU-Xgeva® or US-Xgeva®, and followed for 39 weeks. The primary endpoints were AUCinf, AUClast, and Cmax. RESULTS: Four hundred ninety-two participants completed treatment. The 90% confidence intervals (CIs) (AUCinf, AUClast, and Cmax) and 95% CI of the geometric mean ratios of AUEC of % change from baseline in serum CTX were fully contained within the prespecified equivalence margins (0.80, 1.25), demonstrating similarity. The occurrence of treatment-emergent adverse events (TEAEs) with GP2411, EU-Xgeva® and US-Xgeva® was similar (72.9%, 76.0%, and 71.0% of participants, respectively). Most were Grade 1 or 2, <30% were treatment-related, and there was only one TEAE-related study discontinuation. Rates of positive anti-drug antibodies (ADAs) were similar (57.8%, 64.9%, and 69.1% of participants respectively), but immunogenicity was only borderline detectable and of very low magnitude. Ninety-nine percent of positive ADAs were transient. CONCLUSION: GP2411 demonstrated similarity with EU-Xgeva® and US-Xgeva® in PK, PD, safety, and immunogenicity in this population. CLINICAL TRIAL REGISTRATION: EudraCT 2019-001651-39.


Denosumab is a biological treatment that inhibits bone degradation. It is very effective in conditions characterized by elevated bone degradation, such as osteoporosis in women who have gone through the menopause, and in the treatment of specific bone cancers. However, the cost of the original patented denosumab ('reference denosumab') treatment may result in fewer eligible patients receiving denosumab treatment. A biosimilar is highly similar to the original treatment but at a lower price, enabling more patients to benefit.GP2411 is being developed as a proposed biosimilar to denosumab. This Phase I clinical trial was the first clinical trial to compare GP2411 to the EU and US versions of the reference denosumab (EU-Xgeva® and US-Xgeva®). All three products were given at a dose of 35 mg to 502 healthy males. The dose was lower than the dose that would be used in clinical practice to provide a more sensitive evaluation of similarity. Healthy males were chosen because they have fewer hormonal fluctuations than females, and are considered the most appropriate population for detecting differences in pharmacological effects of denosumab.The results demonstrate that GP2411 proposed denosumab biosimilar is highly similar to the reference products in absorption, distribution, and elimination, and other outcomes, including bone turnover. The incidence of adverse events was also comparable, most adverse events were very mild, and GP2411 was not associated with a higher rate of immune reactions.These results support its continued development and GP2411 may, in future, enable more patients to benefit from denosumab treatment.


Assuntos
Medicamentos Biossimilares , Denosumab , Masculino , Humanos , Denosumab/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , Equivalência Terapêutica , Voluntários Saudáveis , Anticorpos Monoclonais , Método Duplo-Cego
20.
Pathol Res Pract ; 254: 155128, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38244437

RESUMO

INTRODUCTION: Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor characterized by the occurrence of multinucleated osteoclast-like giant cells that play a key role in GCTB pathogenesis. However, little is known about the molecular mechanisms underlying osteoclast differentiation in GCTB. Denosumab, a human monoclonal antibody against RANKL, is used for GCTB treatment. Here, we performed morphological and immunohistochemical examinations of pre- and post-denosumab treatment changes by analyzing each stage of osteoclast differentiation. METHODS: We retrieved 15 archival cases of GCTB with tumor samples from both pre- and post-denosumab treatment. We selected three immunohistochemical markers from the expression data from a previous single-cell RNA study: FOS, a progenitor osteoclast marker, and JDP2 and NFATc1, mature osteoclast markers. RESULTS: The mean positivity of the markers decreased after denosumab treatment from 11.1% to 8.9% for FOS, from 10.6% to 7.2% for JDP2, and from 10.0% to 0.2% for NFATc1. Only NFATc1 positivity decreased significantly (P < 0.001) after denosumab treatment. CONCLUSIONS: We identified a new differentiation stage of osteoclast maturation, intermediate cell, by comparing histological findings before and after denosumab treatment. We demonstrated that discrepancies exist between histological and molecular data and highlight the need for establishing an integrated definition of osteoclasts considering morphology and marker expression.


Assuntos
Neoplasias Ósseas , Tumor de Células Gigantes do Osso , Humanos , Denosumab/uso terapêutico , Osteoclastos/patologia , Tumor de Células Gigantes do Osso/tratamento farmacológico , Tumor de Células Gigantes do Osso/genética , Neoplasias Ósseas/patologia , Osso e Ossos/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...