BACKGROUND Bone is a major site of metastasis in nasopharyngeal carcinoma(NPC).Recently,nuclear factor kappa-beta ligand(RANKL)inhibitors have garnered attention for their ability to inhibit osteoclast formation and b...BACKGROUND Bone is a major site of metastasis in nasopharyngeal carcinoma(NPC).Recently,nuclear factor kappa-beta ligand(RANKL)inhibitors have garnered attention for their ability to inhibit osteoclast formation and bone resorption,as well as their potential to modulate immune functions and thereby enhance the efficacy of programmed cell death protein 1(PD-1)inhibitor therapy.CASE SUMMARY We present a case of a patient with NPC who developed sternal stalk metastasis and multiple bone metastases with soft tissue invasion following radical chemoradiotherapy and targeted therapy.Prior to chemotherapy,the patient experienced severe bone marrow suppression and opted out of further chemotherapy sessions.However,the patient received combination therapy,including RANKL inhibitors(denosumab)alongside PD-1,radiotherapy,and granulocyte-macrophage colonystimulating factor(PRaG)therapy(NCT05435768),and achieved 16 months of progression-free survival and more than 35 months of overall survival,without encountering any grade 2 or higher treatment-related adverse events.CONCLUSION Denosumab combined with PRaG therapy could be a new therapeutic approach for the second-line treatment in patients with bone metastases.展开更多
Objective This systematic review examines recent pharmacoeconomic literature on denosumab'cost-effectiveness for bone metastasis treatment,providing evidence-based insights to guide healthcare policy decisions.Met...Objective This systematic review examines recent pharmacoeconomic literature on denosumab'cost-effectiveness for bone metastasis treatment,providing evidence-based insights to guide healthcare policy decisions.Methods A comprehensive literature search was performed across Cochrane,PubMed,EMBASE(Ovid),CNKI,and Wanfang databases to identify original articles published between 2017 and 2023.Key words consisted of bone metastases,denosumab,and cost-effectiveness in the search strategy.The methodological quality of the included studies was assessed utilizing the revised Consolidated Health Economic Evaluation Reporting Standards(CHEERS 2022).Data was extracted regarding methodological characteristics and cost-effectiveness analyses.Results A total of 111 studies were retrieved,of which 6 met the inclusion criteria.All included studies were based on clinical trials and published literature data and exhibited high methodological quality.Up to 83%(5 out of 6)of comparisons demonstrated that denosumab was more cost-effective or dominant compared to zoledronic acid.The adjusted incremental cost-effectiveness ratios varied substantially by tumor type,ranging from CZK 436,339.09 to USD 136,234 per skeletal-related event avoided and from CZK 61,580.95 to USD 118,392.11 per quality-adjusted life year gained.Conclusions The majority of the included studies support denosumab as a more cost-effective treatment option for bone metastases in solid tumors compared to zoledronic acid.The application of CHEER(2022)enhances the reliability of pharmacoeconomic evaluations.展开更多
In this study,injectable bone graft putty samples were developed using fine and coarse melt-quenched 45S5 bioactive glass(BG)incorporated into a carrier system composed of glycerol and polyethylene glycol(PEG)with dif...In this study,injectable bone graft putty samples were developed using fine and coarse melt-quenched 45S5 bioactive glass(BG)incorporated into a carrier system composed of glycerol and polyethylene glycol(PEG)with different average molecular weights.Selected putty samples were further incorporated with varying amounts of Denosumab(5wt%-10wt%)to investigate its influence on rhe-ological behavior and flow properties using mathematical modeling.All PEG/glycerol/45S5-based putty samples exhibited viscoelastic behavior(storage modulus>loss modulus)and pseudoplastic behavior(n<1),with viscosity values required for optimal flow remaining below 1000 Pa∙s.Both viscosity and thixotropic area increased proportionally with higher BG content and smaller-sized BG particles.All putty samples showed more than 98%injectability through a 12G cannula,suggesting potential clinical suitability.However,injectability decreased with smaller cannulas,dropping to 34.7%-58.3%with a 19G cannula and further decreasing with a 23G cannula at higher BG contents.Incorporation of Denosumab preserved viscoelasticity and injectability but modified the flow behavior,shifting it from pseudo-plastic to more Newtonian with higher Denosumab content,while also reducing viscosity and thixotropic area values.Among all tested samples,putty containing a lower amount of Denosumab and smaller-sized BG exhibited the most suitable combination of injectability and rheological features.All putty samples were well described by both the Power law and Herschel-Bulkley rheological models(coeffi-cient of determination>0.95).This study highlights the influence of Denosumab on flowability and rheological relationships and sug-gests potential improvements in bioactivity through a dual synergistic effect of BG and Denosumab in minimally invasive bone graft sys-tems.展开更多
BACKGROUND Aneurysmal bone cysts(ABCs)are usually treated with curettage or various minimally invasive percutaneous procedures.Patient refractory to these treatments,as well as those with locally advanced or unresecta...BACKGROUND Aneurysmal bone cysts(ABCs)are usually treated with curettage or various minimally invasive percutaneous procedures.Patient refractory to these treatments,as well as those with locally advanced or unresectable tumors,present a challenge for orthopedic surgeons and require new treatment approaches.Antiresorptive drugs inhibit osteoclastic resorption and increase intralesional osteogenesis.Denosumab induces tumor ossification,but this effect may disappear after drug withdrawal due to limited impact on neoplastic cells.Bisphosphonates(BPs)may induce apoptosis of tumor cells and allow for long-term local control.We hypothesized that after denosumab treatment,BPs would better accumulate in the tumor and exert an irreversible antitumor effect.AIM To test the hypothesis that the sequential use of BPs after denosumab induction improves treatment outcomes in surgically unsalvageable ABCs.METHODS Using data from five electronic databases(Scopus,MEDLINE,EMBASE,PubMed,Web of Science),we aimed to identify all patients who received denosumab therapy(DT)for unresectable ABCs.Among published case reports and case series,we identified patients who discontinued denosumab for various reasons and divided them into two groups:Group 1 included 31 patients without further anti-resorptive therapy and Group 2 included 12 patients who received BPs in the context of rebound hypercalcemia.Local control rates in both groups were analyzed.RESULTS As of December 2024,43 patients have been reported in the literature who received DT for locally advanced/unresectable ABCs.There were 27 males and 16 females with a mean age of 15.8 years.At a median follow-up time of 15.5 months,there were 10 confirmed and two pathologically unconfirmed relapses after denosumab discontinuation.All 10 relapses occurred in patients in Group 1 at a median time of 13.5 months.Among patients in Group 2,with a median follow-up time of 12.5 months after completion of therapy,no local relapses were observed.The difference between local recurrence rates(32%vs 0%)is statistically significant(P value=0.02).Kaplan-Meier estimates show the same trend with marginal statistical significance(P value=0.085).Here we put forward a novel treatment algorithm.CONCLUSION BPs used in post-denosumab ossifying ABCs appear to improve treatment outcomes,presumably by targeting residual tumor cells.Prospective clinical studies are warranted to validate this promising two-stage conceptual strategy in difficult-to-treat ABC.展开更多
BACKGROUND Giant cell tumor of bone(GCTB)is a rare,locally aggressive neoplasm that should be treated surgically,whenever possible.This treatment approach may be linked with greater morbidity besides functional impair...BACKGROUND Giant cell tumor of bone(GCTB)is a rare,locally aggressive neoplasm that should be treated surgically,whenever possible.This treatment approach may be linked with greater morbidity besides functional impairment.Denosumab is a human monoclonal antibody.Its administration inhibits bone resorption and has become part of the therapeutic armamentarium against GCTB,as it allows local control with a view to downstaging for a more conservative surgical procedure.However,there is no consensus in the literature regarding the optimal denosumab regimen for GCTB.Therefore,a wide discussion of denosumab regimen is necessary.AIM To assess the effectiveness of various therapy protocols employing denosumab in individuals with GCTB.METHODS A broad and systematic literature search was carried out using the PRISMA guidelines.We analyzed studies that reported skeletally mature patients with GCTB regardless of sex or ethnicity treated with denosumab.Articles with fewer than five patients and in languages except Spanish,Portuguese and English were excluded.Statistical analysis with proportion meta-analysis was performed due to the dichotomous nature of the data.RESULTS 1005 articles were screened,of which 26 articles met the inclusion criteria and were selected,totaling 1742 patients,51.8%women and 48.2%men,with an average of 35 years of age.Treatment with denosumab was associated with high rates of clinical benefit(CB)and imaging response(IR),without changing local recurrence rates when compared to patients treated without denosumab,regardless of the therapeutic regimen adopted and the number of doses applied.The adverse events(AE)presented were mostly mild,with the exception of a malignant transformation to osteosarcoma.CONCLUSION Treatment of GCTB with denosumab is effective,showing high rates of CB and IR.The AE that occurred were mostly mild.We found no differences between the articles considering the researched outcomes regardless of the therapeutic regimen adopted.展开更多
Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT045...Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.展开更多
BACKGROUND Denosumab inhibits the receptor activator of nuclear factor kappa-ligand.It markedly increases bone mineral density and has been proven to reduce the risk of fractures.However,numerous adverse effects,notab...BACKGROUND Denosumab inhibits the receptor activator of nuclear factor kappa-ligand.It markedly increases bone mineral density and has been proven to reduce the risk of fractures.However,numerous adverse effects,notably hypocalcemia,are prevalent in patients with end-stage renal disease(ESRD).AIM To analyze the incidence and predictors of hypocalcemia caused by denosumab compared to control in patients with ESRD.METHODS We conducted this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.PubMed,Scopus,Cochrane Central,and EMBASE were systematically searched from inception through March 2024.All original studies investigating the effects of denosumab on patients with ESRD compared to control were extracted.The primary outcomes of our study were the incidence of mild,severe,and very severe hypocalcemia.Secondary outcomes included serum levels of intact parathyroid hormone,calcium,and phosphate.The results were pooled and analyzed using a random-effects model.RESULTS Seven articles comprising 3240 patients were included in our study.Patients treated with denosumab had a significantly increased incidence of mild hypocalcemia[risk ratio(RR):2.79;95%confidence interval(CI):0.99-7.91;P=0.05;I^(2)=37%]and of very severe hypocalcemia(RR:9.58;95%CI:1.58-57.98;P=0.01;I^(2)=49%).However,an increase in the occurrence of severe hypocalcemia was non-significant(RR:4.23;95%CI:0.47-38.34;P=0.20;I^(2)=96%).Alternatively,denosumab showed a significant decrease in serum intact parathyroid hormone[mean difference(MD):-433.20,95%CI:-775.12 to-91.28,I2=98%,P=0.01],while there was a non-significant decrease in phosphate(MD:-0.47,95%CI:-1.35 to 0.41,I^(2)=88%,P=0.30)and calcium levels(MD:-0.33,95%CI:-0.95 to 0.29,I^(2)=94%,P=0.29).CONCLUSION Our study demonstrated that denosumab is significantly associated with mild and very severe hypocalcemia in patients with ESRD making it necessary to detect and prevent this side effect of treatment.展开更多
To evaluate the differences in outcomes of treatment with denosumab alone or denosumab combined with vitamin D and calcium supplementation in patients with primary osteoporosis. Patients were split into a denosumab mo...To evaluate the differences in outcomes of treatment with denosumab alone or denosumab combined with vitamin D and calcium supplementation in patients with primary osteoporosis. Patients were split into a denosumab monotherapy group （18 cases） or a denosumab plus vitamin D supplementation group （combination group; 23 cases）. We measured serum bone alkaline phosphatase （BAP）, tartrate-resistant acid phosphatase （TRACP）-5b and urinary N-terminal telopeptide of type-I collagen （NTX） at baseline, 1 week, as well as at I month and 2, 4, 8 and 12 months. We also measured bone mineral density （BMD） of L1-4 lumbar vertebrae （L）-BMD and bilateral hips （H）-BMD at baseline and at 4, 8 and 12 months. There was no significant difference in patient background. TRACP-5b and urinary NTX were significantly suppressed in both groups from I week to 12 months （except at 12 months for NTX）. In the combination group, TRACP-5b was significantly decreased compared with the denosumab monotherapy group at 2 and 4 months （P 〈 0.05）. BAP was significantly suppressed in both groups at 2-12 months. L-BMD significantly increased at 8 and 12 months （8.9%） in the combination group and at 4, 8 and 12 months （6.0%） in the denosumab monotherapy group, compared with those before treatment. H-BMD was significantly increased in the combination group （3.6%） compared with the denosumab group （1.2%） at 12 months （P 〈 0.05）. Compared with denosumab monotherapy, combination therapy of denosumab with vitamin D and calcium stopped the decrease in calcium caused by denosumab, inhibited bone metabolism to a greater extent, and increased BMD （especially at the hips）.展开更多
BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease(CLD)patients.Denosumab has been shown to increase bone mineral density(BM...BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease(CLD)patients.Denosumab has been shown to increase bone mineral density(BMD)and decrease the risk of osteoporotic fracture in the general population.However,there are few reports evaluating the efficacy of denosumab in CLD patients.AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo.The study period for evaluating efficacy and safety was 12 mo.Changes from baseline in BMD at the lumbar spine,femoral neck,and total hip were evaluated at 12 mo of denosumab treatment.Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b(bone resorption marker),serum total procollagen type I N-terminal propeptide(bone formation maker),and plasma pentosidine(bone quality marker).RESULTS Among the 405 CLD patients,138(34.1%)patients were diagnosed with osteoporosis;among these,78 patients met the exclusion criteria and thus 60 patients were finally included in the present study.The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine,femoral neck,and total hip were+4.44%,+3.71%,and+4.03%,respectively.Denosumab significantly improved BMD,regardless of sex,patient age,and presence of liver cirrhosis.Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment(P<0.001).Plasma pentosidine levels were also significantly lower at 12 mo of treatment(P=0.010).No patients experienced fractures and moderate-to-severe adverse events,except for transient hypocalcemia.CONCLUSION Denosumab treatment was safe and increased BMD,suppressed bone turnover,and improved bone quality marker levels in CLD patients with osteoporosis,irrespective of differences in baseline characteristics.展开更多
This randomized prospective study aimed to evaluate the clinical outcome of denosumab treatment alone and in combination with teriparatide in treatment-naive postmenopausal Japanese female patients with osteoporosis. ...This randomized prospective study aimed to evaluate the clinical outcome of denosumab treatment alone and in combination with teriparatide in treatment-naive postmenopausal Japanese female patients with osteoporosis. Thirty patients were randomly assigned to two groups:(1) denosumab group(denosumab alone, n=13); and(2) combination group(denosumab+teriparatide, n=17). Serum bone-specific alkaline phosphatase(BAP), serum tartrate-resistant acid phosphatase(TRACP)-5b, urinary cross-linked N-terminal telopeptides of type I collagen(NTX), and bone mineral density(BMD) of L1–4 lumbar vertebrae(L-BMD)and bilateral total hips(H-BMD) were determined at the first visit and at various time points up to 24 months post-treatment to determine percentage changes. Serum TRACP-5b and urinary NTX were equally suppressed in both groups and maintained at low levels, with slight increases at 12, 18 and 24 months. BAP was significantly decreased in both groups from 4 to 24 months, with significant differences between the groups at 4, 8 and 15 months(P<0.05). L-BMD was significantly increased at most time points in both groups, with a significant difference between the combination group and denosumab group at 24 months(17.2% increase versus 9.6% increase; P<0.05). There was no significant difference in H-BMD between the two groups, although the levels tended to be higher in the combination group than in the denosumab group(9.5% increase versus 5.6% increase). These findings suggest that denosumab+teriparatide combination therapy may represent an important treatment for primary osteoporotic patients at high risk of vertebral fracture.展开更多
Background: Receptor activator of nuclear factor- κ B ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162)- b...Background: Receptor activator of nuclear factor- κ B ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162)- binds RANKL with high affinity and specificity and inhibits RANKL action. Methods: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of- 1.8 to - 4.0 at the lumbar spine or- 1.8 to- 3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open- label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Results: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C- telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. Conclusions: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis.展开更多
Target-mediated drug disposition (TMDD)model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK)ofmonoclonal antibodies.However,there are too many parameters in full TMDD model to be esti...Target-mediated drug disposition (TMDD)model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK)ofmonoclonal antibodies.However,there are too many parameters in full TMDD model to be estimated based on limited clinical data,leading to instability of the final model.In the present study,we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS)model with the assumption that the total target concentration was a constant parameter during treatment with monoelonal antibody in clinical data modeling.Based on the parameters of a published TMDD model of denosumab,simulations were performed at population and individual levels.Then,a simplified TMDD model,QSS model, was used to examine the effects of hypotheses,in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation.Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses,the total receptor concentration had little influence on changes in drug concentration,and the model with constant total receptor concentration had the same predictive power.The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.展开更多
Intrapelvic prosthetic migration prosthesis following hip arthroplasty can occur due to aseptic loosening, infection, injury and malposition of the cup with chronic instability. Revision surgery is the treatment optio...Intrapelvic prosthetic migration prosthesis following hip arthroplasty can occur due to aseptic loosening, infection, injury and malposition of the cup with chronic instability. Revision surgery is the treatment option, but is often complex, is high risk owing to the co-morbidities of the patient, has higher complications and sometimes even patients refuse for the surgery. Osteoclast mediated bone resorption at the prosthetic bone interface is the main pathophysiology process involved in aseptic loosening associated intrapelvic migration. RANK/RANKL (Receptor Activated Nuclear factor κB Ligand) is the primary pathway responsible for the periprosthetic osteolysis, therefore, we have offered Denosumab which binds to RANKL and inhibits osteoclasts mediated bone resorption, to our two patients with intrapelvic prosthetic migration who have refused for the revision surgery. Here, we report the outcome of these two cases of Intrapelvic prosthetic migration following a hip arthroplasty that was treated using subcutaneous injection of 120 mg denosumab monthly for 3 months. Both the cases had good functional outcomes and radiographs showed good consolidation of bone around the prosthesis. These cases suggest denosumab can be repurposed to arrest further intrapelvic prosthetic migration due to its anti-resorptive and bone forming action and can avoid the need for a complex revision surgery.展开更多
基金Supported by The Suzhou Medical Center,No.Szlcyxzx202103The National Natural Science Foundation of China,No.82171828+15 种基金The Key R and D Plan of Jiangsu Province(Development of Social),No.BE2021652The Subject Construction Support Project of The Second Affiliated Hospital of Soochow University,No.XKTJHRC20210011The Wu Jieping Medical Foundation,No.320.6750.2021-01-12The Special Project of"Technological Innovation"Project of CNNC Medical Industry Co.Ltd,No.ZHYLTD2021001The Suzhou Science and Education Health Project,No.KJXW2021018Foundation of Chinese Society of Clinical Oncology,No.Y-pierrefabre202102-0113 and No.Y-XD202002/zb-0015The Beijing Bethune Charitable Foundation,No.STLKY0016The Research Projects of China Baoyuan Investment Co.Ltd,No.270004The Suzhou Gusu Health Talent Program,No.GSWS2022028The Open Project of State Key Laboratory of Radiation Medicine and Protection of Soochow University,No.GZN1202302The New Medical Technology Project of the Second Affiliated Hospital of Soochow University,No.23zl001The Multi-center Clinical Research Project for Major Diseases in Suzhou,No.DZXYJ202304The Postgraduate Research and Practice Innovation Program of Jiangsu Province,No.SJCX24_1814The Gusu Health Talent Research Fund,No.GSWS2022053The National Natural Science Foundation of China,No.82102824The Scientific Research Program for Young Talents of China National Nuclear Corporation。
文摘BACKGROUND Bone is a major site of metastasis in nasopharyngeal carcinoma(NPC).Recently,nuclear factor kappa-beta ligand(RANKL)inhibitors have garnered attention for their ability to inhibit osteoclast formation and bone resorption,as well as their potential to modulate immune functions and thereby enhance the efficacy of programmed cell death protein 1(PD-1)inhibitor therapy.CASE SUMMARY We present a case of a patient with NPC who developed sternal stalk metastasis and multiple bone metastases with soft tissue invasion following radical chemoradiotherapy and targeted therapy.Prior to chemotherapy,the patient experienced severe bone marrow suppression and opted out of further chemotherapy sessions.However,the patient received combination therapy,including RANKL inhibitors(denosumab)alongside PD-1,radiotherapy,and granulocyte-macrophage colonystimulating factor(PRaG)therapy(NCT05435768),and achieved 16 months of progression-free survival and more than 35 months of overall survival,without encountering any grade 2 or higher treatment-related adverse events.CONCLUSION Denosumab combined with PRaG therapy could be a new therapeutic approach for the second-line treatment in patients with bone metastases.
文摘Objective This systematic review examines recent pharmacoeconomic literature on denosumab'cost-effectiveness for bone metastasis treatment,providing evidence-based insights to guide healthcare policy decisions.Methods A comprehensive literature search was performed across Cochrane,PubMed,EMBASE(Ovid),CNKI,and Wanfang databases to identify original articles published between 2017 and 2023.Key words consisted of bone metastases,denosumab,and cost-effectiveness in the search strategy.The methodological quality of the included studies was assessed utilizing the revised Consolidated Health Economic Evaluation Reporting Standards(CHEERS 2022).Data was extracted regarding methodological characteristics and cost-effectiveness analyses.Results A total of 111 studies were retrieved,of which 6 met the inclusion criteria.All included studies were based on clinical trials and published literature data and exhibited high methodological quality.Up to 83%(5 out of 6)of comparisons demonstrated that denosumab was more cost-effective or dominant compared to zoledronic acid.The adjusted incremental cost-effectiveness ratios varied substantially by tumor type,ranging from CZK 436,339.09 to USD 136,234 per skeletal-related event avoided and from CZK 61,580.95 to USD 118,392.11 per quality-adjusted life year gained.Conclusions The majority of the included studies support denosumab as a more cost-effective treatment option for bone metastases in solid tumors compared to zoledronic acid.The application of CHEER(2022)enhances the reliability of pharmacoeconomic evaluations.
基金supported by Yildiz Technical University Scientific Research Projects Coordination Unit under project number FBA-2023-5377support from the Scientific and Technological Research Council of Turkey(TUBITAK)under the BIDEB/2211-A National PhD Scholarship Program and 2250-Performance-Based Scholarships Program for PhD.
文摘In this study,injectable bone graft putty samples were developed using fine and coarse melt-quenched 45S5 bioactive glass(BG)incorporated into a carrier system composed of glycerol and polyethylene glycol(PEG)with different average molecular weights.Selected putty samples were further incorporated with varying amounts of Denosumab(5wt%-10wt%)to investigate its influence on rhe-ological behavior and flow properties using mathematical modeling.All PEG/glycerol/45S5-based putty samples exhibited viscoelastic behavior(storage modulus>loss modulus)and pseudoplastic behavior(n<1),with viscosity values required for optimal flow remaining below 1000 Pa∙s.Both viscosity and thixotropic area increased proportionally with higher BG content and smaller-sized BG particles.All putty samples showed more than 98%injectability through a 12G cannula,suggesting potential clinical suitability.However,injectability decreased with smaller cannulas,dropping to 34.7%-58.3%with a 19G cannula and further decreasing with a 23G cannula at higher BG contents.Incorporation of Denosumab preserved viscoelasticity and injectability but modified the flow behavior,shifting it from pseudo-plastic to more Newtonian with higher Denosumab content,while also reducing viscosity and thixotropic area values.Among all tested samples,putty containing a lower amount of Denosumab and smaller-sized BG exhibited the most suitable combination of injectability and rheological features.All putty samples were well described by both the Power law and Herschel-Bulkley rheological models(coeffi-cient of determination>0.95).This study highlights the influence of Denosumab on flowability and rheological relationships and sug-gests potential improvements in bioactivity through a dual synergistic effect of BG and Denosumab in minimally invasive bone graft sys-tems.
文摘BACKGROUND Aneurysmal bone cysts(ABCs)are usually treated with curettage or various minimally invasive percutaneous procedures.Patient refractory to these treatments,as well as those with locally advanced or unresectable tumors,present a challenge for orthopedic surgeons and require new treatment approaches.Antiresorptive drugs inhibit osteoclastic resorption and increase intralesional osteogenesis.Denosumab induces tumor ossification,but this effect may disappear after drug withdrawal due to limited impact on neoplastic cells.Bisphosphonates(BPs)may induce apoptosis of tumor cells and allow for long-term local control.We hypothesized that after denosumab treatment,BPs would better accumulate in the tumor and exert an irreversible antitumor effect.AIM To test the hypothesis that the sequential use of BPs after denosumab induction improves treatment outcomes in surgically unsalvageable ABCs.METHODS Using data from five electronic databases(Scopus,MEDLINE,EMBASE,PubMed,Web of Science),we aimed to identify all patients who received denosumab therapy(DT)for unresectable ABCs.Among published case reports and case series,we identified patients who discontinued denosumab for various reasons and divided them into two groups:Group 1 included 31 patients without further anti-resorptive therapy and Group 2 included 12 patients who received BPs in the context of rebound hypercalcemia.Local control rates in both groups were analyzed.RESULTS As of December 2024,43 patients have been reported in the literature who received DT for locally advanced/unresectable ABCs.There were 27 males and 16 females with a mean age of 15.8 years.At a median follow-up time of 15.5 months,there were 10 confirmed and two pathologically unconfirmed relapses after denosumab discontinuation.All 10 relapses occurred in patients in Group 1 at a median time of 13.5 months.Among patients in Group 2,with a median follow-up time of 12.5 months after completion of therapy,no local relapses were observed.The difference between local recurrence rates(32%vs 0%)is statistically significant(P value=0.02).Kaplan-Meier estimates show the same trend with marginal statistical significance(P value=0.085).Here we put forward a novel treatment algorithm.CONCLUSION BPs used in post-denosumab ossifying ABCs appear to improve treatment outcomes,presumably by targeting residual tumor cells.Prospective clinical studies are warranted to validate this promising two-stage conceptual strategy in difficult-to-treat ABC.
文摘BACKGROUND Giant cell tumor of bone(GCTB)is a rare,locally aggressive neoplasm that should be treated surgically,whenever possible.This treatment approach may be linked with greater morbidity besides functional impairment.Denosumab is a human monoclonal antibody.Its administration inhibits bone resorption and has become part of the therapeutic armamentarium against GCTB,as it allows local control with a view to downstaging for a more conservative surgical procedure.However,there is no consensus in the literature regarding the optimal denosumab regimen for GCTB.Therefore,a wide discussion of denosumab regimen is necessary.AIM To assess the effectiveness of various therapy protocols employing denosumab in individuals with GCTB.METHODS A broad and systematic literature search was carried out using the PRISMA guidelines.We analyzed studies that reported skeletally mature patients with GCTB regardless of sex or ethnicity treated with denosumab.Articles with fewer than five patients and in languages except Spanish,Portuguese and English were excluded.Statistical analysis with proportion meta-analysis was performed due to the dichotomous nature of the data.RESULTS 1005 articles were screened,of which 26 articles met the inclusion criteria and were selected,totaling 1742 patients,51.8%women and 48.2%men,with an average of 35 years of age.Treatment with denosumab was associated with high rates of clinical benefit(CB)and imaging response(IR),without changing local recurrence rates when compared to patients treated without denosumab,regardless of the therapeutic regimen adopted and the number of doses applied.The adverse events(AE)presented were mostly mild,with the exception of a malignant transformation to osteosarcoma.CONCLUSION Treatment of GCTB with denosumab is effective,showing high rates of CB and IR.The AE that occurred were mostly mild.We found no differences between the articles considering the researched outcomes regardless of the therapeutic regimen adopted.
文摘Objective:To evaluate the efficacy and safety of QL1206(a denosumab biosimilar to Xgeva■)in breast cancer patients with bone metastasis(BM)through subgroup analysis of a randomized,double-blind phaseⅢtrial(No.NCT04550949).Methods:This subgroup analysis included patients with BM from breast cancer enrolled in a phaseⅢtrial.Patients were randomized(1:1)to receive either three cycles of QL1206 or denosumab(120 mg subcutaneously every 4 weeks).Subsequently,they received 10 cycles of QL1206(120 mg)over 40 weeks,followed by a 20-week safety follow-up.The primary endpoint was the percentage changes from baseline to week 13 in urinary Ntelopeptide corrected for creatinine(u NTx/Cr).Results:The breast cancer cohort consisted of 311 patients.Vertebral involvement(66.4%)was the most prevalent BM site at enrollment,while 27.7%of patients presented with≥3 metastatic bone lesions.At week 13,QL1206 demonstrated a median u NTx/Cr reduction of-69.9%(range:-98.1%-568.0%)vs.-74.3%(range:-97.7%-386.3%)for denosumab.The analysis of covariance revealed comparable least-square means for log-transformed changes:-1.416[95%confidence interval(95%CI):-1.736 to-1.096]vs.-1.501(95%CI:-1.824 to-1.178),yielding an between-group difference of 0.085(90%CI:-0.062-0.232;P=0.343).After a 53-week treatment period,83.6%achieved bone density improvement/disease stabilization.Safety profiles were comparable between groups.Conclusions:QL1206 demonstrated similar efficacy and safety to the reference denosumab in patients with BM from breast cancer,supporting QL1206 as a new option for management of BM from breast cancer.
文摘BACKGROUND Denosumab inhibits the receptor activator of nuclear factor kappa-ligand.It markedly increases bone mineral density and has been proven to reduce the risk of fractures.However,numerous adverse effects,notably hypocalcemia,are prevalent in patients with end-stage renal disease(ESRD).AIM To analyze the incidence and predictors of hypocalcemia caused by denosumab compared to control in patients with ESRD.METHODS We conducted this study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.PubMed,Scopus,Cochrane Central,and EMBASE were systematically searched from inception through March 2024.All original studies investigating the effects of denosumab on patients with ESRD compared to control were extracted.The primary outcomes of our study were the incidence of mild,severe,and very severe hypocalcemia.Secondary outcomes included serum levels of intact parathyroid hormone,calcium,and phosphate.The results were pooled and analyzed using a random-effects model.RESULTS Seven articles comprising 3240 patients were included in our study.Patients treated with denosumab had a significantly increased incidence of mild hypocalcemia[risk ratio(RR):2.79;95%confidence interval(CI):0.99-7.91;P=0.05;I^(2)=37%]and of very severe hypocalcemia(RR:9.58;95%CI:1.58-57.98;P=0.01;I^(2)=49%).However,an increase in the occurrence of severe hypocalcemia was non-significant(RR:4.23;95%CI:0.47-38.34;P=0.20;I^(2)=96%).Alternatively,denosumab showed a significant decrease in serum intact parathyroid hormone[mean difference(MD):-433.20,95%CI:-775.12 to-91.28,I2=98%,P=0.01],while there was a non-significant decrease in phosphate(MD:-0.47,95%CI:-1.35 to 0.41,I^(2)=88%,P=0.30)and calcium levels(MD:-0.33,95%CI:-0.95 to 0.29,I^(2)=94%,P=0.29).CONCLUSION Our study demonstrated that denosumab is significantly associated with mild and very severe hypocalcemia in patients with ESRD making it necessary to detect and prevent this side effect of treatment.
文摘To evaluate the differences in outcomes of treatment with denosumab alone or denosumab combined with vitamin D and calcium supplementation in patients with primary osteoporosis. Patients were split into a denosumab monotherapy group （18 cases） or a denosumab plus vitamin D supplementation group （combination group; 23 cases）. We measured serum bone alkaline phosphatase （BAP）, tartrate-resistant acid phosphatase （TRACP）-5b and urinary N-terminal telopeptide of type-I collagen （NTX） at baseline, 1 week, as well as at I month and 2, 4, 8 and 12 months. We also measured bone mineral density （BMD） of L1-4 lumbar vertebrae （L）-BMD and bilateral hips （H）-BMD at baseline and at 4, 8 and 12 months. There was no significant difference in patient background. TRACP-5b and urinary NTX were significantly suppressed in both groups from I week to 12 months （except at 12 months for NTX）. In the combination group, TRACP-5b was significantly decreased compared with the denosumab monotherapy group at 2 and 4 months （P 〈 0.05）. BAP was significantly suppressed in both groups at 2-12 months. L-BMD significantly increased at 8 and 12 months （8.9%） in the combination group and at 4, 8 and 12 months （6.0%） in the denosumab monotherapy group, compared with those before treatment. H-BMD was significantly increased in the combination group （3.6%） compared with the denosumab group （1.2%） at 12 months （P 〈 0.05）. Compared with denosumab monotherapy, combination therapy of denosumab with vitamin D and calcium stopped the decrease in calcium caused by denosumab, inhibited bone metabolism to a greater extent, and increased BMD （especially at the hips）.
文摘BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease(CLD)patients.Denosumab has been shown to increase bone mineral density(BMD)and decrease the risk of osteoporotic fracture in the general population.However,there are few reports evaluating the efficacy of denosumab in CLD patients.AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo.The study period for evaluating efficacy and safety was 12 mo.Changes from baseline in BMD at the lumbar spine,femoral neck,and total hip were evaluated at 12 mo of denosumab treatment.Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b(bone resorption marker),serum total procollagen type I N-terminal propeptide(bone formation maker),and plasma pentosidine(bone quality marker).RESULTS Among the 405 CLD patients,138(34.1%)patients were diagnosed with osteoporosis;among these,78 patients met the exclusion criteria and thus 60 patients were finally included in the present study.The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine,femoral neck,and total hip were+4.44%,+3.71%,and+4.03%,respectively.Denosumab significantly improved BMD,regardless of sex,patient age,and presence of liver cirrhosis.Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment(P<0.001).Plasma pentosidine levels were also significantly lower at 12 mo of treatment(P=0.010).No patients experienced fractures and moderate-to-severe adverse events,except for transient hypocalcemia.CONCLUSION Denosumab treatment was safe and increased BMD,suppressed bone turnover,and improved bone quality marker levels in CLD patients with osteoporosis,irrespective of differences in baseline characteristics.
文摘This randomized prospective study aimed to evaluate the clinical outcome of denosumab treatment alone and in combination with teriparatide in treatment-naive postmenopausal Japanese female patients with osteoporosis. Thirty patients were randomly assigned to two groups:(1) denosumab group(denosumab alone, n=13); and(2) combination group(denosumab+teriparatide, n=17). Serum bone-specific alkaline phosphatase(BAP), serum tartrate-resistant acid phosphatase(TRACP)-5b, urinary cross-linked N-terminal telopeptides of type I collagen(NTX), and bone mineral density(BMD) of L1–4 lumbar vertebrae(L-BMD)and bilateral total hips(H-BMD) were determined at the first visit and at various time points up to 24 months post-treatment to determine percentage changes. Serum TRACP-5b and urinary NTX were equally suppressed in both groups and maintained at low levels, with slight increases at 12, 18 and 24 months. BAP was significantly decreased in both groups from 4 to 24 months, with significant differences between the groups at 4, 8 and 15 months(P<0.05). L-BMD was significantly increased at most time points in both groups, with a significant difference between the combination group and denosumab group at 24 months(17.2% increase versus 9.6% increase; P<0.05). There was no significant difference in H-BMD between the two groups, although the levels tended to be higher in the combination group than in the denosumab group(9.5% increase versus 5.6% increase). These findings suggest that denosumab+teriparatide combination therapy may represent an important treatment for primary osteoporotic patients at high risk of vertebral fracture.
文摘Background: Receptor activator of nuclear factor- κ B ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162)- binds RANKL with high affinity and specificity and inhibits RANKL action. Methods: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of- 1.8 to - 4.0 at the lumbar spine or- 1.8 to- 3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open- label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Results: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C- telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. Conclusions: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis.
文摘Target-mediated drug disposition (TMDD)model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK)ofmonoclonal antibodies.However,there are too many parameters in full TMDD model to be estimated based on limited clinical data,leading to instability of the final model.In the present study,we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS)model with the assumption that the total target concentration was a constant parameter during treatment with monoelonal antibody in clinical data modeling.Based on the parameters of a published TMDD model of denosumab,simulations were performed at population and individual levels.Then,a simplified TMDD model,QSS model, was used to examine the effects of hypotheses,in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation.Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses,the total receptor concentration had little influence on changes in drug concentration,and the model with constant total receptor concentration had the same predictive power.The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.
文摘Intrapelvic prosthetic migration prosthesis following hip arthroplasty can occur due to aseptic loosening, infection, injury and malposition of the cup with chronic instability. Revision surgery is the treatment option, but is often complex, is high risk owing to the co-morbidities of the patient, has higher complications and sometimes even patients refuse for the surgery. Osteoclast mediated bone resorption at the prosthetic bone interface is the main pathophysiology process involved in aseptic loosening associated intrapelvic migration. RANK/RANKL (Receptor Activated Nuclear factor κB Ligand) is the primary pathway responsible for the periprosthetic osteolysis, therefore, we have offered Denosumab which binds to RANKL and inhibits osteoclasts mediated bone resorption, to our two patients with intrapelvic prosthetic migration who have refused for the revision surgery. Here, we report the outcome of these two cases of Intrapelvic prosthetic migration following a hip arthroplasty that was treated using subcutaneous injection of 120 mg denosumab monthly for 3 months. Both the cases had good functional outcomes and radiographs showed good consolidation of bone around the prosthesis. These cases suggest denosumab can be repurposed to arrest further intrapelvic prosthetic migration due to its anti-resorptive and bone forming action and can avoid the need for a complex revision surgery.
