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Current Osteoporosis Reports Dec 2022Inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) with denosumab is an effective treatment in a number of conditions including osteoporosis where... (Review)
Review
PURPOSE OF REVIEW
Inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) with denosumab is an effective treatment in a number of conditions including osteoporosis where suppression of bone resorption is desired. However, denosumab discontinuation is associated with rebound increase in bone resorption and subsequent loss in bone mass and a rapid return to baseline fracture risk. We review recent data on the rebound increase in bone resorption following denosumab discontinuation and the potential mechanisms behind this phenomenon.
RECENT FINDINGS
Osteoclasts have been considered to be highly specialised cells that undergo apoptosis after fulfilling their function of bone resorption. However, recent studies suggest that osteoclasts are longer lived cells which migrate through vasculature and are capable of undergoing fission into a novel cell type (the osteomorph) and re-fusion in a process termed osteoclast recycling. The life cycle of the osteoclast is more complex than previously appreciated. Osteoclast recycling provides a novel mechanistic framework to examine changes in osteoclast biology in response to treatment of bone diseases and provides an exciting new avenue towards personalised medicine.
Topics: Humans; Osteoclasts; Denosumab; RANK Ligand; Bone Resorption; Osteoporosis
PubMed: 36201122
DOI: 10.1007/s11914-022-00756-5 -
BioDrugs : Clinical Immunotherapeutics,... Mar 2023Denosumab has been approved for the treatment of bone metastases from solid tumors. QL1206 is the first denosumab biosimilar and needs to be compared with denosumab in a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Denosumab has been approved for the treatment of bone metastases from solid tumors. QL1206 is the first denosumab biosimilar and needs to be compared with denosumab in a phase III trial.
OBJECTIVE
This phase III trial aims to compare the efficacy, safety, and pharmacokinetics between QL1206 and denosumab in patients with bone metastases from solid tumors.
METHODS
This randomized, double-blind, phase III trial was conducted in 51 centers in China. Patients aged 18-80 years, with solid tumors and bone metastases, and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. This study was divided into a 13-week double-blind period, a 40-week open-label period, and a 20-week safety follow-up period. In the double-blind period, patients were randomly assigned (1:1) to receive three doses of QL1206 or denosumab (120 mg subcutaneously every 4 weeks, each). Randomization was stratified by tumor types, previous skeletal-related events, and current systemic anti-tumor therapy. In the open-label period, up to ten doses of QL1206 could be given in both groups. The primary endpoint was percentage change in urinary N-telopeptide/creatinine ratio (uNTX/uCr) from baseline to Week 13. Equivalence margins were ± 0.135. Secondary endpoints included percentage change in uNTX/uCr at Week 25 and 53, percentage change in serum bone-specific alkaline phosphatase at Week 13, 25, and 53, and time to on-study skeletal-related events. The safety profile was evaluated based on adverse events and immunogenicity.
RESULTS
From September 2019 to January 2021, in the full analysis set, 717 patients were randomly assigned to receive QL1206 (n = 357) or denosumab (n = 360). Median percentage changes in uNTX/uCr at Week 13 in two groups were - 75.2% and - 75.8%, respectively. Least-squares mean difference in the natural log-transformed ratio of uNTX/uCr at Week 13 to baseline between the two groups was 0.012 (90% confidence interval - 0.078 to 0.103), within the equivalence margins. There were no differences in the secondary endpoints between the two groups (all p > 0.05). Adverse events, immunogenicity, and pharmacokinetics were similar in the two groups.
CONCLUSIONS
Denosumab biosimilar QL1206 had promising efficacy, tolerable safety, and pharmacokinetics equivalent to denosumab and could benefit patients with bone metastases from solid tumors.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04550949, retrospectively registered on 16 September, 2020.
Topics: Humans; Denosumab; Biosimilar Pharmaceuticals; Bone Neoplasms; Double-Blind Method
PubMed: 36802320
DOI: 10.1007/s40259-023-00579-5 -
Hepatology (Baltimore, Md.) Jul 2020
Topics: Denosumab; Humans; Liver Diseases; Osteoporosis
PubMed: 31863598
DOI: 10.1002/hep.31084 -
Journal of Molecular Medicine (Berlin,... Mar 2024This study compiles the main hypotheses involved in the etiopathogenesis of medication-related osteonecrosis of the jaw (MRONJ). A narrative review of the literature was... (Review)
Review
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.
Topics: Humans; Bone Density Conservation Agents; Bisphosphonate-Associated Osteonecrosis of the Jaw; Denosumab; Diphosphonates; Jaw
PubMed: 38302741
DOI: 10.1007/s00109-024-02425-9 -
Medicine Jan 2023Denosumab is a human monoclonal antibody that targets nuclear factor-kappa B ligand and is highly effective in blocking bone resorption. Bibliometrics can intuitively... (Review)
Review
Denosumab is a human monoclonal antibody that targets nuclear factor-kappa B ligand and is highly effective in blocking bone resorption. Bibliometrics can intuitively show the research development process, research status, research hotspots and development trend of a certain topic for researchers. This study assessed the course of research and development for denosumab in terms of publications over the past 2 decades. Web of Science databases were searched to identify publications related to research on denosumab from January 1, 2005 to December 31, 2022. The VOS Viewer software (version 1.6.17) and Bibliometrix package in R (version 4.1.3) were used in this study. There were 5119 denosumab-related publications during this period. The total number of citations of denosumab-related publications reached 94917. The most articles were published in the field of Endocrinology Metabolism. As an international language, English remains the most popular language for writing papers. Five of the top ten institutions originated in the USA. Through the VOS Viewer analysis, we found that the relationships between Amgen Inc. with its collaborations were grouped into 4 clusters, the USA was the mainland for research and development on denosumab, closely collaborating with many other countries, such as Canada, Japan, England, and China. Wagman RB from USA was the most prolific author with 119 publications. The journal with the most publications was Osteoporosis International (481 publications). The most cited article was "Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis" with 2053 citations. The clinical trial comprised 6 of the 10 most frequently cited publications, and the rest consisted of reviews. The most frequent keywords for publications since January 1, 2014 were "prevention" and "management," indicating that a number of prevention and management measures have been developed to regulate the use of denosumab in treating osteoporosis. Our research provided a comprehensive review of denosumab-related publications, suggesting that the development of denosumab is a long process and numerous clinical trials have been conducted before applications in clinical settings.
Topics: Humans; Female; Denosumab; Bibliometrics; Osteoporosis; Publications; Antibodies, Monoclonal
PubMed: 36705356
DOI: 10.1097/MD.0000000000032784 -
Osteoporosis International : a Journal... May 2022This paper systematically reviewed and assessed all retrievable pharmacoeconomic studies on denosumab for the treatment of osteoporosis. Denosumab was more... (Review)
Review
UNLABELLED
This paper systematically reviewed and assessed all retrievable pharmacoeconomic studies on denosumab for the treatment of osteoporosis. Denosumab was more cost-effective in patients with older age, prior fracture experience, lower BMD T-scores, and more risk factors. ESCEO-IOF guidelines were more applicable to improve the quality of pharmacoeconomic studies in osteoporosis.
INTRODUCTION
There are many pharmacoeconomic studies on denosumab for osteoporosis. However, the corresponding reviews are outdated or incomplete and need to be updated and refined. This article aims to systematically review and evaluate all retrievable pharmacoeconomic studies of denosumab for osteoporosis.
METHODS
A systematic literature search was performed utilizing PubMed, EMBASE(Ovid), Proquest(EconLit), Chongqing VIP, WanFang Database, and Chinese National Knowledge Infrastructure to identify full-text articles published before September 2021. The quality of full-text articles was evaluated by the Consolidated Health Economic Evaluation Reporting Standards(CHEERS) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases International Osteoporosis Foundation guideline(ESCEO-IOF).
RESULTS
In total, 21 full-text articles were eligible for inclusion. Denosumab for postmenopausal osteoporosis was not dominant compared to zoledronate and teriparatide. However, denosumab was dominant compared with strontium ranelate, raloxifene, and ibandronate in patients over 65 years. The probabilities of denosumab being cost-effective or dominant were more than 85% compared with no treatment and risedronate in patients aged over 70 years. Compared to alendronate, the highest rate of denosumab dominance occurred in patients aged 65 to 75 years, at about 65%. Most of the articles had higher CHEERS scores than ESCEO-IOF scores (converted into percentages).
CONCLUSIONS
The cost-effectiveness of denosumab for the treatment of osteoporosis was influenced by multiple factors. Generally, denosumab was more cost-effective in patients with older age, prior fracture experience, lower BMD T-scores, and more risk factors. ESCEO-IOF guidelines were more applicable to improve the transparency, generalization, and quality of pharmacoeconomic studies in osteoporosis.
Topics: Bone Density Conservation Agents; Cost-Benefit Analysis; Denosumab; Female; Fractures, Bone; Humans; Osteoporosis; Osteoporosis, Postmenopausal
PubMed: 35059777
DOI: 10.1007/s00198-021-06268-9 -
Drug Design, Development and Therapy 2020Denosumab is a receptor activator of nuclear factor kappa-Β ligand inhibitor, which suppresses the bone resorption process to preserve bone mass. It is usually... (Review)
Review
Denosumab is a receptor activator of nuclear factor kappa-Β ligand inhibitor, which suppresses the bone resorption process to preserve bone mass. It is usually recommended to postmenopausal women and men with high fracture risk. With the recent publication of the results from FREEDOM study and its extension, the long-term effect of denosumab in preventing fragility fractures has been put forward. This review aims at summarising the evidence of denosumab in reducing fracture risk and its safety derived from clinical studies. Most of the evidence are derived from FREEDOM trials up to 10 years of exposure. Denosumab is reported to prevent vertebral and non-vertebral fractures. It is also proven effective in Japanese women, patients with chronic kidney diseases and breast cancer patients receiving antineoplastic therapy. Denosumab discontinuation leads to high remodeling, loss of bone mineral density and increased fracture risk. These negative effects might be preventable by bisphosphonate treatment. The safety profile of denosumab is consistent with increased years of exposure. In conclusion, denosumab is a safe and effective option for reducing fracture risk among patients with osteoporosis.
Topics: Bone Density; Bone Density Conservation Agents; Bone Remodeling; Denosumab; Humans; Osteoporosis
PubMed: 33061307
DOI: 10.2147/DDDT.S270829 -
Revue Medicale Suisse Jan 2021New recommendations from the Swiss Association against Osteoporosis (SVGO) concerning fracture risk stratification and treatment delineate two new risk categories :... (Review)
Review
New recommendations from the Swiss Association against Osteoporosis (SVGO) concerning fracture risk stratification and treatment delineate two new risk categories : very high risk (FRAX 10-years probability of fracture at least 20 % above the usual intervention threshold) and imminent risk (major osteoporotic fracture in the last 2 years). In these patients, parenteral therapies are recommended first. Among them, romosozumab is now available in Switzerland and is indicated for 1 year in absence of cardiovascular contra-indications, followed by an anti-resorptive. Regarding denosumab, several studies indicate that post-treatment bone loss may be, at least partially, prevented by zoledronate. Finally, monitoring BMD changes and the T-score reached on any therapy could be used as an indicator of anti-fracture efficacy.
Topics: Antibodies, Monoclonal; Bone Density; Denosumab; Drug Approval; Humans; Infusions, Parenteral; Osteoporosis; Osteoporotic Fractures; Switzerland; Zoledronic Acid
PubMed: 33443834
DOI: No ID Found -
Annals of Internal Medicine Oct 2020Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect.
BACKGROUND
Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect.
OBJECTIVE
To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time.
DESIGN
Population-based cohort study.
SETTING
The Health Improvement Network U.K. primary care database, 2010 to 2019.
PATIENTS
Persons aged 45 years or older who initiated denosumab therapy for osteoporosis.
MEASUREMENTS
Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date ("on time"), delay by 4 to 16 weeks ("short delay"), and delay by more than 16 weeks ("long delay"). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture.
RESULTS
Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) ( for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45).
LIMITATION
Dosing schedules were not randomly assigned.
CONCLUSION
Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay.
PRIMARY FUNDING SOURCE
National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.
Topics: Aged; Denosumab; Drug Administration Schedule; Female; Fractures, Bone; Humans; Male; Osteoporosis; Retrospective Studies; Risk Factors; Time-to-Treatment
PubMed: 32716706
DOI: 10.7326/M20-0882 -
The Journal of Hand Surgery Sep 2023Many hand surgeons treat benign bone tumors without referral to orthopedic oncologists. However, there have been considerable advances in medical therapy for some of... (Review)
Review
Many hand surgeons treat benign bone tumors without referral to orthopedic oncologists. However, there have been considerable advances in medical therapy for some of these tumors, with which hand surgeons may not be as familiar. This review focuses on the mechanism and uses of denosumab in the treatment of benign tumors of bone. Although the hand surgeon may not be directly prescribing this therapy, they are often the only physician treating the patient for these conditions. As such, awareness regarding the use of this therapy in reducing pain, decreasing tumor volume, and treatment of potential lung metastases is critical to those taking on these cases without the support of an orthopedic oncologist. This article aims to familiarize hand surgeons with denosumab to help promote knowledge of this therapeutic option and the potential role of this medication in the treatment of primary bone tumors in the hand.
Topics: Humans; Denosumab; Bone Density Conservation Agents; Giant Cell Tumor of Bone; Bone and Bones; Bone Neoplasms
PubMed: 37032292
DOI: 10.1016/j.jhsa.2023.02.013