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Journal of Bone and Mineral Metabolism Jan 2021Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fracture. Because bone is constantly remodeled, and bone mass and... (Review)
Review
Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fracture. Because bone is constantly remodeled, and bone mass and structure are determined by the balance between bone resorption and bone formation, it is important to maintain normal bone turnover. Therefore, therapies that reduce bone resorption have been the mainstream of osteoporosis treatment. Receptor activator of nuclear factor-kappa B ligand (RANKL)-RANK signaling was found to play a pivotal role in the regulation of osteoclastic bone resorption, and inhibition of RANKL-RANK system has become an important therapeutic target for the treatment of osteoporosis. Denosumab, a fully human monoclonal anti-RANKL neutralizing antibody, is developed as a drug for the treatment of osteoporosis. This review summarized pharmacokinetic and pharmacodynamic properties of denosumab, clinical studies including phase 2 dose-ranging and its extension study, phase 3 fracture prevention study (FREEDOM) with extension up to 10 years, studies on male osteoporosis (ADAMO study), and on glucocorticoid-induced osteoporosis, along with relevant clinical studies in Japan. In addition, mechanism of denosumab action that can explain its long-term sustained effects, combination and sequential treatment as well as the problems in discontinuation of denosumab, and finally safety of denosumab therapy is discussed.
Topics: Animals; Bone and Bones; Clinical Trials as Topic; Denosumab; Humans; Molecular Targeted Therapy; Osteoporosis; RANK Ligand
PubMed: 33057808
DOI: 10.1007/s00774-020-01153-7 -
Scientific Reports May 2023Denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand, reduces skeletal-related events (SREs) and is approved for solid tumors with bone...
Denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand, reduces skeletal-related events (SREs) and is approved for solid tumors with bone metastases. We studied long-term denosumab efficacy and safety because real-world data is scarce. This single-arm, single-center retrospective study included denosumab-treated breast cancer patients with bone metastases. Kaplan-Meier survival curves assessed exposure, SREs, osteonecrosis of the jaw (ONJ), and death. 132 patients were enrolled. The median denosumab exposure was 28.3 months (range 1.0-84.9). In the first year, 11.1% experienced SREs. This increased to 18.6% in the second, 21% in the third, and 35.1% in the fourth year and beyond. The median time to first on-study SRE has not been reached. 10 denosumab users (7.6%) developed ONJ. ONJ incidence was 0.9% in the first year, 6.2% in the second, 13.6% in the third, and 16.2% in subsequent years. The median time to first on-study ONJ has not been reached yet. Seven patients resumed denosumab after careful management of ONJ. Our data suggest that long-term treatment with denosumab may further prevent or postpone SREs at the cost of an increased risk of ONJ. The majority of patients who resumed denosumab did not experience a recurrence of ONJ.
Topics: Humans; Female; Denosumab; Retrospective Studies; Breast Neoplasms; Kaplan-Meier Estimate; Long-Term Care
PubMed: 37225727
DOI: 10.1038/s41598-023-35308-z -
Frontiers in Endocrinology 2023To assess the alterations in bone mineral density and bone turnover marker concentrations following the administration of denosumab and romosozumab therapies in patients... (Meta-Analysis)
Meta-Analysis
PURPOSE
To assess the alterations in bone mineral density and bone turnover marker concentrations following the administration of denosumab and romosozumab therapies in patients with osteoporosis.
METHODS
PubMed was searched for studies published until January 28, 2023, that investigated the clinical efficacy and bone turnover marker changes of denosumab and romosozumab in the treatment of osteoporosis, with a minimum follow-up of 3 months in each study. Studies were screened, and data on changes in bone mineral density (BMD), P1NP, and TRACP-5b levels after treatment were extracted and included in the analysis.
RESULTS
Six studies were analyzed. At 3 months after treatment, the romosozumab group showed greater changes in lumbar BMD and bone turnover markers. BMD of total hip and femoral neck was relatively delayed. Beginning at 6 to 12 months, romosozumab showed greater changes in bone mineral density and markers of bone turnover.
CONCLUSION
Both romosozumab and denosumab have antiosteoporotic effects, with greater effects on BMD and bone turnover markers observed within 12 months of romosozumab treatment.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier CRD42023395034.
Topics: Humans; Bone Density; Denosumab; Bone Density Conservation Agents; Osteoporosis
PubMed: 37529613
DOI: 10.3389/fendo.2023.1188969 -
Clinical and Experimental Medicine Nov 2023Giant cell tumors of the bone (GCTB) are considered moderately malignant bone tumors. Denosumab, as a neoadjuvant therapy, provides new possibilities for treating GCTB.... (Review)
Review
Giant cell tumors of the bone (GCTB) are considered moderately malignant bone tumors. Denosumab, as a neoadjuvant therapy, provides new possibilities for treating GCTB. However, even after multiple studies and long-term clinical trials, there are limitations in the treatment process. Research data and Medical Subject Headings terms related to denosumab and GCTB were collected from January 2010 to October 2022 using the Web of Science and MeSH ( https://meshb.nlm.nih.gov ) browsers. These data were imported into CiteSpace and VOSviewer softwares for bibliometric analysis. Overall, 445 publications on denosumab and GCTB were identified. Over the last 12 years, the growth rate of the total number of publications has remained relatively stable. The USA published the highest number of articles (83) and had the highest centrality (0.42). Amgen Inc. and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) First Ortoped Rizzoli were identified as the most influential institutions. Many authors have made outstanding contributions to this field. Lancet Oncology had the highest journal impact factor (54.433). Local recurrence and drug dosage are current research hotspots, and future development trends will mainly focus on prognostic markers of GCTB and the development of new therapies. Further research is required to analyze denosumab's safety and efficacy and understand its local recurrence of GCTB, to identify the optimal dose. Future progress in this field will likely focus on exploring new diagnostic and recurrence markers to monitor disease progression and examine new therapeutic targets and treatment strategies.
Topics: Humans; Denosumab; Bone Density Conservation Agents; Bone Neoplasms; Giant Cell Tumor of Bone; Bibliometrics
PubMed: 37103655
DOI: 10.1007/s10238-023-01079-0 -
La Clinica Terapeutica 2023Denosumab, an antiresorptive agent, has shown results in improving bone mineral density and reducing fractures in postmenopausal women. While bisphosphonates are... (Review)
Review
OBJECTIVE
Denosumab, an antiresorptive agent, has shown results in improving bone mineral density and reducing fractures in postmenopausal women. While bisphosphonates are commonly used as initial therapy for osteoporosis, some studies suggest that denosumab could be an alternative initial treatment for high-risk patients, particularly the elderly population. This narrative literature review aimed to assess the use of denosumab in elderly individuals with osteoporosis, excluding its oncology applications.
METHOD
Multiple online databases including Scopus, PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and PEDro were searched for relevant English-language trials.
RESULTS
Between about hundred identified, the review selected 21 articles full-meeting the inclusion criteria. These papers all reporting that Denosumab demonstrated significant efficacy in reducing vertebral and nonvertebral fractures in postmenopausal and senile osteoporosis.
CONCLUSION
Even if limited evidence exists regarding its long-term effectiveness in elderly patients, nevertheless denosumab may be considered a first-line treatment for high-risk elderly patients with senile osteoporosis, particularly for those unable to take bisphosphonates. It has shown superior outcomes in improving bone density and reducing fracture risk, even in frail elderly individuals. Long-term use of denosumab has been reported as safe and effective, enhancing treatment compliance and outcomes.
Topics: Humans; Aged; Female; Denosumab; Osteoporosis; Bone Density; Diphosphonates; Frail Elderly
PubMed: 38048119
DOI: 10.7417/CT.2023.5023 -
Bone Sep 2023Increased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Increased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates.
MATERIALS AND METHODS
We have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS).
RESULTS
13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (-4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good.
DISCUSSION
This study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS.
CONCLUSION
Denosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.
Topics: Animals; Female; Diphosphonates; Denosumab; Retrospective Studies; Fibrous Dysplasia of Bone; Fibrous Dysplasia, Polyostotic; Pain
PubMed: 37301527
DOI: 10.1016/j.bone.2023.116819 -
Best Practice & Research. Clinical... Mar 2022Over the last two decades there have been significant developments in the pharmacotherapy of osteoporosis. The therapeutic arsenal has expanded with monoclonal... (Review)
Review
Over the last two decades there have been significant developments in the pharmacotherapy of osteoporosis. The therapeutic arsenal has expanded with monoclonal antibodies which have been developed based on discoveries of the molecular mechanisms underlying bone resorption and bone formation. Denosumab, the antibody binding RANKL, inhibits bone resorption, and romosozumab, the antibody binding sclerostin, inhibits bone resorption and stimulates bone formation as well. Both antibodies have shown potent anti-fracture efficacy in randomized clinical trials and this review will discuss the preclinical and clinical studies focusing on the effects on bone mass. After discontinuation of these antibodies, bone mineral density quickly returns to baseline and in the case of denosumab, discontinuation can not only induce rebound bone loss, but also the occurrence of vertebral fractures. Therefore, sequential antiresorptive therapy to maintain bone mass gains and anti-fracture efficacy is of utmost importance and will also be discussed in this review.
Topics: Bone Density; Bone Density Conservation Agents; Bone Resorption; Denosumab; Fractures, Bone; Humans; Osteoporosis
PubMed: 35219602
DOI: 10.1016/j.beem.2022.101623 -
Archives of Endocrinology and Metabolism Nov 2022Denosumab (DMAb) is a human monoclonal antibody used as an antiresorptive drug in the treatment of osteoporosis. Approval at a dosage of 60 mg every 6 months was based... (Review)
Review
Denosumab (DMAb) is a human monoclonal antibody used as an antiresorptive drug in the treatment of osteoporosis. Approval at a dosage of 60 mg every 6 months was based on the results of the randomized, placebo-controlled trial (FREEDOM). The design of this 3-year study included an extension for up to 10 years. Those who were randomized to DMAb continued on drug, while those who were randomized to placebo transitioned to DMAb. The 10-year experience with DMAb provides data on efficacy of drug in terms of reduced fractures and continued increases in bone mineral density (BMD). The 10-year experience with denosumab also provides information about rare complications associated with the use of DMAb, such as osteonecrosis of the jaw (ONJ), and atypical femoral fractures (AFF). This experience provided new insights into the reversibility of effects upon discontinuation without follow-on therapy with another agent. This review focuses upon prolonged treatment with DMAb, with regard to beneficial effects on fracture reduction and safety. Additionally, its use in patients with impaired renal function, compare its results with those of bisphosphonates (BPs), the occurrence/frequency of complications, in addition to the use of different tools, from imaging techniques to histological findings, to evaluate its effects on bone tissue.
Topics: Humans; Female; Denosumab; Osteoporosis; Bone Density Conservation Agents; Diphosphonates; Bone Density; Osteoporosis, Postmenopausal; Randomized Controlled Trials as Topic
PubMed: 36382761
DOI: 10.20945/2359-3997000000560 -
Expert Opinion on Drug Safety May 2021
Topics: Bone Density Conservation Agents; Denosumab; Female; Humans; Osteoporosis, Postmenopausal; Postmenopause; Time Factors
PubMed: 33372551
DOI: 10.1080/14740338.2021.1867102 -
Current Opinion in Pediatrics Feb 2023Aneurysmal bone cysts are rare, locally aggressive bone tumors. Optimal treatment of ABCs is still matter of debate as therapies including sclerotherapy, selective... (Review)
Review
PURPOSE OF REVIEW
Aneurysmal bone cysts are rare, locally aggressive bone tumors. Optimal treatment of ABCs is still matter of debate as therapies including sclerotherapy, selective arterial embolization and systemic treatment with denosumab are increasingly utilized, in addition to or instead of traditional curettage. The purpose of this review is to discuss current concepts and difficulties in diagnosing and treating primary ABCs, based on latest available literature.
RECENT FINDINGS
In diagnostics, multiple new fusion partners of USP-6 have been described on next-generation sequencing specifically for primary ABCs. In a recent systematic review, failure rates of percutaneous injections and surgery were comparable. In a literature review, the use of denosumab seemed effective but resulted in multiple cases of severe hypercalcemia in children.
SUMMARY
Accurately diagnosing primary ABC is crucial for treatment decisions. Curettage remains a valid treatment option, especially with adjuvant burring, autogenous bone grafting and phenolization. Percutaneous sclerotherapy represents a solid alternative to surgery, with polidocanol showing good results in larger studies. Systematic therapy with denosumab exhibits favorable results but should be reserved in the pediatric population for unresectable lesions, as it may result in severe hypercalcemia in children. When selecting a treatment option, localization, stability and safety should be considered.
Topics: Humans; Child; Denosumab; Bone Cysts, Aneurysmal; Hypercalcemia; Neoplasm Recurrence, Local; Polidocanol; Treatment Outcome
PubMed: 36409159
DOI: 10.1097/MOP.0000000000001205