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Bone May 2020Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated.
METHODS
Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated.
RESULTS
Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07-0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00-3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [1]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group.
CONCLUSION
Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed.
Topics: Aged; Bone Density; Bone Density Conservation Agents; Denosumab; Diabetes Mellitus; Female; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause
PubMed: 32058020
DOI: 10.1016/j.bone.2020.115268 -
Cancer Medicine Jun 2023Denosumab is recommended for advanced giant cell tumor of bone (GCTB) that is unresectable or resectable with unacceptable morbidity. But the effect of preoperative...
BACKGROUND AND OBJECTIVES
Denosumab is recommended for advanced giant cell tumor of bone (GCTB) that is unresectable or resectable with unacceptable morbidity. But the effect of preoperative denosumab treatment on the local control GCTB remains controversial.
METHODS
We conducted a study of 49 patients with GCTB in the limbs treated with denosumab before surgery and 125 patients without in our hospital from 2010 to 2017. Propensity-score matching (PSM) at a 1:1 ratio between the denosumab and control groups was performed to minimize possible selection bias, and compared the recurrence rate, limb function, and surgical degradation between the two groups.
RESULTS
The 3-year recurrence rates in the denosumab group and the control group were 20.4% and 22.9% after PSM, respectively (p = 0.702). In the denosumab group, 75.5% (n = 37/49) of patients experienced surgical downgrading. Limb joint preservation rates were 92.1% (35) for 38 patients treated with denosumab and 60.2% (71) for 118 control subjects. (p ≺ 0.001). Postoperative MSTS were higher in patients in the denosumab group than in the control group (24.1 vs. 22.6, p = 0.034).
CONCLUSIONS
Preoperative denosumab treatment did not result in an increased risk of local recurrence of GCTB. Patients with advanced GCTB may benefit from preoperative denosumab treatment for surgical downgrading and the preservation of the joint.
Topics: Humans; Denosumab; Bone Density Conservation Agents; Retrospective Studies; Bone Neoplasms; Giant Cell Tumor of Bone; Propensity Score; Giant Cells; Neoplasm Recurrence, Local
PubMed: 37212474
DOI: 10.1002/cam4.5870 -
The Journal of Clinical Endocrinology... Apr 2024Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations...
CONTEXT
Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents.
OBJECTIVE
This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders.
PARTICIPANTS
Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document.
EVIDENCE
Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available.
CONCLUSION
Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks.
Topics: Adolescent; Child; Humans; Bone and Bones; Bone Density Conservation Agents; Denosumab; Ligands; Minerals; RANK Ligand
PubMed: 38041865
DOI: 10.1210/clinem/dgad657 -
Cells Oct 2023This work investigated whether the anti-resorptive drugs (ARDs) zoledronic acid (Zol) and denosumab (Dmab) affect differently the levels of circulating immune cell...
This work investigated whether the anti-resorptive drugs (ARDs) zoledronic acid (Zol) and denosumab (Dmab) affect differently the levels of circulating immune cell subsets, possibly predicting the risk of developing medication-related ONJ (MRONJ) during the first 18 months of treatment. Blood samples were collected from 10 bone metastatic breast cancer patients receiving cyclin inhibitors at 0, 6, 12, and 18 months from the beginning of Dmab or Zol treatment. Eight breast cancer patients already diagnosed with MRONJ and treated with cyclin inhibitors and ARDs were in the control group. PBMCs were isolated; the trend of circulating immune subsets during the ARD treatment was monitored, and 12 pro-inflammatory cytokines were analyzed in sera using flow cytometry. In Dmab-treated patients, activated T cells were stable or increased, as were the levels of IL-12, TNF-α, GM-CSF, IL-5, and IL-10, sustaining them. In Zol-treated patients, CD8+T cells decreased, and the level of IFN-γ was undetectable. γδT cells were not altered in Dmab-treated patients, while they dramatically decreased in Zol-treated patients. In the MRONJ control group, Zol-ONJ patients showed a reduction in activated T cells and γδT cells compared to Dmab-ONJ patients. Dmab was less immunosuppressive than Zol, not affecting γδT cells and increasing activated T cells.
Topics: Humans; Female; Zoledronic Acid; Denosumab; Bone Neoplasms; Breast Neoplasms; Cyclins; Respiratory Distress Syndrome
PubMed: 37887274
DOI: 10.3390/cells12202430 -
Hua Xi Kou Qiang Yi Xue Za Zhi = Huaxi... Oct 2018Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of bisphosphonates (BPs) or other targeted agent therapies. MRONJ appears as exposed bone,... (Review)
Review
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of bisphosphonates (BPs) or other targeted agent therapies. MRONJ appears as exposed bone, pus, and swelling in the oral and maxillofacial regions. However, neither surgery nor conservative therapy can eliminate symptoms thoroughly. In addition to BPs, several antiresorptive and antiangiogenic agents, such as denosumab and bevacizumab, as well as targeted agents, such as sunitinib and temsirolimus, can cause osteonecrosis of the jaw according to the literature. This review aims to summarize the research progress on these new drugs.
Topics: Angiogenesis Inhibitors; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Denosumab; Diphosphonates; Humans
PubMed: 30465354
DOI: 10.7518/hxkq.2018.05.019 -
Skeletal Radiology Sep 2020Giant cell tumours of bone (GCTB) are benign giant cell-rich tumours typically occurring in the epi-metaphysis of skeletally mature patients. Despite their benign... (Review)
Review
Giant cell tumours of bone (GCTB) are benign giant cell-rich tumours typically occurring in the epi-metaphysis of skeletally mature patients. Despite their benign classification, GCTB may be locally aggressive with local recurrence as a challenging issue. Denosumab is a human monoclonal antibody that inhibits osteolysis via the RANK-RANK ligand pathway. There is currently no consensus on optimal treatment duration or imaging modality for monitoring patients on denosumab therapy. This review illustrates the radiological findings of GCTB on denosumab treatment seen on plain radiographs, CT, MRI, PET-CT and DEXA, with reference to the current literature. Recognizing imaging features indicative of a positive response to denosumab is important for therapeutic decision-making. Imaging findings with respect to duration of denosumab treatment, tumour upregulation during treatment, tumour recurrence and malignant transformation are discussed. The development of a sclerotic neocortex and varying degrees of matrix osteosclerosis are seen on plain radiographs. Reconstitution of subarticular bone and articular surface irregularity are optimally evaluated on CT which can also quantify tumour density. MRI demonstrates heterogeneous low signal matrix and is useful to assess decrease in size of cystic and/or soft tissue components of GCTB. A fat-suppressed fluid-sensitive MR sequence is important to detect tumour reactivation. Reduction in F-FDG-PET avidity represents an early sensitive sign of response to denosumab treatment. Regardless of imaging modality, close follow-up in a specialist centre and careful evaluation of nonresponders is necessary as local recurrence after cessation of denosumab treatment and malignant transformation of GCTB have been described.
Topics: Bone Density Conservation Agents; Bone Neoplasms; Denosumab; Giant Cell Tumor of Bone; Humans; Neoplasm Recurrence, Local; Positron Emission Tomography Computed Tomography
PubMed: 32335707
DOI: 10.1007/s00256-020-03449-1 -
The Bone & Joint Journal Feb 2016The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in... (Review)
Review
UNLABELLED
The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in the form of osteoporotic fractures and metastatic bone disease. In recent years there has been an increasing understanding of the pathways involved in bone metabolism relevant to osteoporosis and metastases in bone. Newer therapies may aid the management of these problems. One group of drugs, the antibody mediated anti-resorptive therapies (AMARTs) use antibodies to block bone resorption pathways. This review seeks to present a synopsis of the guidelines, pharmacology and potential pathophysiology of AMARTs and other new anti-resorptive drugs. We evaluate the literature relating to AMARTs and new anti-resorptives with special attention on those approved for use in clinical practice. Denosumab, a monoclonal antibody against Receptor Activator for Nuclear Factor Kappa-B Ligand. It is the first AMART approved by the National Institute for Health and Clinical Excellence and the US Food and Drug Administration. Other novel anti-resorptives awaiting approval for clinical use include Odanacatib. Denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases. Recent evidence suggests, however, that denosumab may have an adverse event profile similar to bisphosphonates, including atypical femoral fractures. It is, therefore, essential that orthopaedic surgeons are conversant with these medications and their safe usage.
TAKE HOME MESSAGE
Denosumab has important orthopaedic indications and has been shown to significantly reduce patient morbidity in osteoporosis and metastatic bone disease.
Topics: Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal, Humanized; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Bone Neoplasms; Bone Resorption; Cost-Benefit Analysis; Denosumab; Diphosphonates; Drug Approval; Femoral Fractures; Genetic Markers; Humans; Hypocalcemia; Osteoporosis; Osteoporotic Fractures; Practice Guidelines as Topic; Quality-Adjusted Life Years; RANK Ligand
PubMed: 26850419
DOI: 10.1302/0301-620X.98B2.36161 -
British Journal of Clinical Pharmacology Jun 2019Potent antiresorptive drugs (bisphosphonate and denosumab) are often used to protect bone health in postmenopausal breast cancer patients. In addition, clinical trials... (Review)
Review
Potent antiresorptive drugs (bisphosphonate and denosumab) are often used to protect bone health in postmenopausal breast cancer patients. In addition, clinical trials have shown that these drugs increase disease-free survival, though the mechanism of adjuvant benefit is largely unknown. Here we review the bone health and adjuvant data for both classes of antiresorptive drugs and highlight differences in their pharmacology. Inhibition of bone resorption is vitally important to protect against osteoporotic fractures, and may also contribute to adjuvant survival benefits by making the bone microenvironment less amenable to breast cancer metastasis. After a course of therapy, stoppage of bisphosphonates yields a persistent antiresorptive effect, whereas discontinuation of denosumab causes a rebound increase in bone resorption markers and a loss of bone mineral density to baseline levels. Whether the potential adjuvant benefits of denosumab are also rapidly lost after drug discontinuation deserves further investigation.
Topics: Aromatase Inhibitors; Bone Density; Bone Density Conservation Agents; Bone Neoplasms; Bone Resorption; Breast Neoplasms; Chemotherapy, Adjuvant; Denosumab; Diphosphonates; Disease-Free Survival; Female; Fractures, Bone; Humans; Postmenopause; Risk Assessment; Risk Factors
PubMed: 30536446
DOI: 10.1111/bcp.13834 -
Yonsei Medical Journal Sep 2022Giant cell tumors (GCTs) are common benign primary bone tumors and are well known for their locally aggressive performance and tendency to recur. The purpose of this... (Meta-Analysis)
Meta-Analysis
PURPOSE
Giant cell tumors (GCTs) are common benign primary bone tumors and are well known for their locally aggressive performance and tendency to recur. The purpose of this study was to analyze the effects of denosumab and risk factors for recurrent spinal GCTs.
MATERIALS AND METHODS
We searched PubMed, EMBASE, Web of Science, and Cochrane Library databases to identify differences between individuals treated with and without denosumab and risk factors for spinal GCT recurrence. Patient data, including age, sex, tumor resection range, location, denosumab use, Campanacci grade, and radiotherapy, were documented. Comparable factors were evaluated using odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs).
RESULTS
Sixteen studies were included. The overall incidence of spinal GCT recurrence was 29%. Campanacci grade III tumors showed better recurrence outcomes than grades I and II (OR, 16.36; 95% CI, 4.19-63.93; <0.001). Gross total resection (OR, 0.09; 95% CI, 0.04-0.19; <0.001), radiotherapy (OR, 0.27; 95% CI, 0.11-0.65; =0.004), and the use of denosumab during subtotal resection (OR, 2.95; 95% CI, 1.07-8.17; =0.04) were important factors for reducing recurrence.
CONCLUSION
Clinicians must consider the effects of gross total resection, radiotherapy use, and denosumab use in cases of subtotal resection during spinal GCT treatment. So far, many researchers have used denosumab in spinal GCT, but none have clearly suggested an endpoint. Most studies, however, recommend using it for more than 6 months.
Topics: Bone Neoplasms; Denosumab; Giant Cell Tumor of Bone; Humans; Neoplasm Recurrence, Local; Risk Factors
PubMed: 36031783
DOI: 10.3349/ymj.2022.63.9.834 -
Reumatismo May 2017Osteonecrosis of the jaw (ONJ) is a rare adverse event of antiresorptive drugs such as bisphosphonates (BP) and denosumab (DMAb). The diagnosis of ONJ is considered in... (Review)
Review
Osteonecrosis of the jaw (ONJ) is a rare adverse event of antiresorptive drugs such as bisphosphonates (BP) and denosumab (DMAb). The diagnosis of ONJ is considered in cases where exposed bone in the maxillofacial region does not heal within 8 weeks in a patient previously treated with an antiresorptive agent. In patients with osteoporosis, ONJ is reported as a very rare adverse event while in oncologic patients with bone metastases or malignant hypercalcemia the incidence is significantly higher (up to the 1-10% of the patients). The pathophysiology of ONJ is still not completely understood but it is multi-factorial. ONJ is a condition associated with poor oral health, oral surgery, and use of antiresorptive agents. Prevention is of paramount importance especially in cancer patients, in whom the large majority of cases of ONJ (>90%) are reported, but it should also be considered in osteoporotic patients, especially during dental surgical procedure. Some simple prevention procedures are effective in reducing the risk of its appearance. When ONJ unfortunately occurs, the large majority of patients can be managed conservatively. In conclusion, ONJ is a rare condition associated with antiresorptive drugs. Both osteoporotic and oncologic patients should be well informed about its low absolute risk and regarding the fact that the benefits of antiresorptive therapy far outweigh this potential risk of ONJ.
Topics: Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Denosumab; Diphosphonates; Humans; Incidence; Italy; Osteoporosis; Risk Factors; Severity of Illness Index
PubMed: 28535616
DOI: 10.4081/reumatismo.2017.983