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International Journal of Molecular... Apr 2023The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) is multifactorial and there is a substantial consensus on the role of antiresorptive drugs... (Review)
Review
The pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) is multifactorial and there is a substantial consensus on the role of antiresorptive drugs (ARDs), including bisphosphonates (BPs) and denosumab (Dmab), as one of the main determinants. The time exposure, cumulative dose and administration intensity of these drugs are critical parameters to be considered in the treatment of patients, as cancer patients show the highest incidence of MRONJ. BPs and Dmab have distinct mechanisms of action on bone, but they also exert different effects on immune subsets which interact with bone cells, thus contributing to the onset of MRONJ. Here, we summarized the main effects of ARDs on the different immune cell subsets, which consequently affect bone cells, particularly osteoclasts and osteoblasts. Data from animal models and MRONJ patients showed a deep interference of ARDs in modulating immune cells, even though a large part of the literature concerns the effects of BPs and there is a lack of data on Dmab, demonstrating the need to further studies.
Topics: Humans; Bisphosphonate-Associated Osteonecrosis of the Jaw; Denosumab; Bone Density Conservation Agents; Diphosphonates; Respiratory Distress Syndrome
PubMed: 37175652
DOI: 10.3390/ijms24097948 -
European Journal of Endocrinology Oct 2022Fractures occur in about half of older White women, and almost a third of older White men. However, 80% of the older individuals who have fractures do not meet the bone... (Review)
Review
Fractures occur in about half of older White women, and almost a third of older White men. However, 80% of the older individuals who have fractures do not meet the bone density definition of osteoporosis, suggesting that this definition is not an appropriate threshold for offering treatment. Fracture risk can be estimated based on clinical risk factors with or without bone density. A combination of calculated risk, fracture history, and bone density is used in treatment decisions. Medications available for reducing fracture risk act either to inhibit bone resorption or to promote bone formation. Romosozumab is unique in that it has both activities. Bisphosphonates are the most widely used interventions because of their efficacy, safety, and low cost. Continuous use of oral bisphosphonates for >5 years increases the risk of atypical femoral fractures, so is usually punctuated with drug holidays of 6-24 months. Denosumab is a further potent anti-resorptive agent given as 6-monthly s.c. injections. It is comparable to the bisphosphonates in efficacy and safety but has a rapid offset of effect after discontinuation so must be followed by an alternative drug, usually a bisphosphonate. Teriparatide stimulates both bone formation and resorption, substantially increases spine density, and reduces vertebral and non-vertebral fracture rates, though data for hip fractures are scant. Treatment is usually limited to 18-24 months, followed by the transition to an anti-resorptive. Romosozumab is given as monthly s.c. injections for 1 year, followed by an anti-resorptive. This sequence prevents more fractures than anti-resorptive therapy alone. Because of cost, anabolic drugs are usually reserved for those at very high fracture risk. 25-hydroxyvitamin D levels should be maintained above 30 nmol/L, using supplements if sunlight exposure is limited. Calcium intake has little effect on bone density and fracture risk but should be maintained above 500 mg/day using dietary sources.
Topics: Bone Density; Bone Density Conservation Agents; Denosumab; Diphosphonates; Female; Fractures, Bone; Humans; Male; Osteoporosis; Osteoporosis, Postmenopausal
PubMed: 35984345
DOI: 10.1530/EJE-22-0574 -
Clinical Medicine (London, England) Sep 2023Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease... (Meta-Analysis)
Meta-Analysis
Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease stage. HCM is associated with impaired quality of life, increased risk of hospitalisation and limited survival. Evidence-based guidelines for management of HCM have been lacking to date, despite its prevalence and detrimental impact. This concise guidance highlights key recommendations from the recent Endocrine Society Clinical Practice Guidelines on Treatment of Hypercalcaemia of Malignancy in Adults, published in December 2022. A systematic review and meta-analysis was commissioned to support the guideline development process. Key suggestions include the use of denosumab in preference to intravenous bisphosphonates as first-line treatment for HCM and the use of denosumab in cases of recurrent or refractory HCM in patients previously treated with intravenous bisphosphonates. The guideline also identifies priority areas for future research.
Topics: Humans; Adult; Hypercalcemia; Denosumab; Diphosphonates; Quality of Life; Neoplasms; Bone Density Conservation Agents
PubMed: 37775175
DOI: 10.7861/clinmed.2023-0227 -
Frontiers in Endocrinology 2023Denosumab demonstrates efficacy in reducing the incidence of hip, vertebral, and nonvertebral fractures in postmenopausal women with osteoporosis. We present a...
INTRODUCTION
Denosumab demonstrates efficacy in reducing the incidence of hip, vertebral, and nonvertebral fractures in postmenopausal women with osteoporosis. We present a population-based national cohort study to evaluate the infection risks in patients with osteoporosis after long-term denosumab therapy.
METHODS
We used the Taiwan National Health Insurance Research Database (NHIRD) to identify patients with osteoporosis. The case cohort comprised patients treated with denosumab. Propensity score (PS) matching was used to select denosumab nonusers for the control cohort. The study period was between August 2011 and December 2017. Our study comprised 30,106 pairs of case and control patients.
RESULTS
Patients receiving denosumab therapy had high risks of the following infections: pneumonia and influenza (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI]: 1.27 -1.39), urinary tract infection (aHR: 1.36; 95% CI:1.32 -1.40), tuberculosis (aHR: 1.60; 95% CI: 1.36 -1.87), fungal infection (aHR: 1.67; 95% CI:1.46 -1.90), candidiasis (aHR: 1.68; 95% CI: 1.47 -1.93), herpes zoster infection (aHR: 1.27; 95% CI: 1.19 -1.35), sepsis (aHR: 1.54; 95% CI:1.43 -1.66), and death (aHR: 1.26; 95% CI: 1.20 -1.32). However, the longer the duration of denosumab treatment, the lower the risk patients had of developing infections.
DISCUSSION
Denosumab therapy is associated with a higher infection risk at the early periods of treatment. Nevertheless, the risk attenuates significantly after the 2nd year of therapy. Clinicians should closely monitor infection status in patients with osteoporosis during the initial stages of denosumab therapy.
Topics: Humans; Female; Denosumab; Cohort Studies; Propensity Score; Osteoporosis; Fractures, Bone
PubMed: 37274347
DOI: 10.3389/fendo.2023.1182753 -
Calcified Tissue International Jan 2023There is limited evidence on the use of romosozumab (ROMO) in the treatment of osteoporosis in patients on hemodialysis (HD); thus, we aimed to investigate this topic.... (Observational Study)
Observational Study
There is limited evidence on the use of romosozumab (ROMO) in the treatment of osteoporosis in patients on hemodialysis (HD); thus, we aimed to investigate this topic. This prospective, observational, single-center cohort study included 13 prior osteoporosis treatment-naïve patients on HD with osteoporosis. They first received ROMO once monthly for 12 months (210 mg; subcutaneously once every month). Thereafter, they received denosumab (DENO) for an additional 12 months (60 mg; subcutaneously once every 6 months). We examined the incidence of new fractures; treatment safety; and temporal changes in the bone mineral density (BMD), bone metabolism markers, and vascular calcification. No new cases of fractures were noted. The median one-year percentage changes (from the baseline) in the BMDs at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were + 9.0%, + 2.5%, and + 4.7%, respectively. These changes were maintained for 24 months. The corresponding relative changes from the baseline to 24 months thereafter were + 14.9%, + 5.4%, and + 6.5%, respectively. The percentage changes in TH BMD and FN BMD were negatively correlated with baseline BMD. Coronary artery and thoracic aorta calcification scores increased slightly from baseline to 12 months thereafter. However, fatal events (cardiovascular disease-associated and all-cause deaths) did not occur during ROMO treatment. Effectiveness of ROMO was better in patients who had severe osteoporosis with low TH BMD, low FN BMD, and high tartrate-resistant acid phosphatase 5b level at ROMO initiation.
Topics: Humans; Female; Denosumab; Bone Density Conservation Agents; Prospective Studies; Cohort Studies; Osteoporosis; Bone Density; Fractures, Bone; Bone Diseases, Metabolic; Renal Dialysis; Osteoporosis, Postmenopausal
PubMed: 36287217
DOI: 10.1007/s00223-022-01031-6 -
Journal of Bone and Mineral Metabolism May 2023Zoledronic acid and denosumab are bone-modifying agents that are clinically important in multiple aspects of bone management for breast cancer patients. These aspects... (Review)
Review
Zoledronic acid and denosumab are bone-modifying agents that are clinically important in multiple aspects of bone management for breast cancer patients. These aspects include the prevention of osteoporosis induced by cancer-treatment bone loss, treatment and prevention of bone metastasis, and improvement of survival directly or indirectly by maintaining bone health. Interestingly, zoledronic acid and denosumab have different anticancer activities, and they may be associated with the improvement of survival of breast cancer patients under different mechanisms. Zoledronic acid is the most potent bisphosphonate. It provides significant benefits for improving breast cancer mortality in patients with suppressed estrogen level such as in postmenopausal or ovarian suppression condition. Although denosumab's anticancer activity has not been clearly proven compared with zoledronic acid's anticancer activity, denosumab is promising in preventing BRCA1 mutant breast cancer because RANKL is a targetable pathway in BRCA1-associated tumorigenesis. Further studies and more effective clinical use of these agents are anticipated to contribute to the improvement of the clinical outcome of breast cancer patients.
Topics: Humans; Female; Zoledronic Acid; Denosumab; Breast Neoplasms; Bone Density Conservation Agents; Imidazoles
PubMed: 36879056
DOI: 10.1007/s00774-023-01408-z -
Journal of Bone and Mineral Metabolism Jan 2024To describe the real-world use of romosozumab in Japan, we conducted a chart review of > 1000 Japanese patients with osteoporosis (OP) at high risk of fracture,...
INTRODUCTION
To describe the real-world use of romosozumab in Japan, we conducted a chart review of > 1000 Japanese patients with osteoporosis (OP) at high risk of fracture, across multiple medical institutions.
MATERIALS AND METHODS
Treatment-naïve and prior OP-treatment patients who received romosozumab for 12 months followed by ≥ 6 months of sequential OP treatment were included. The primary objective described the baseline demographics and clinical characteristics; secondary objectives evaluated changes in bone mineral density (BMD) and bone turnover markers in all patients and effectiveness of romosozumab in a sub-group of treatment-naïve patients using the fracture risk assessment tool (FRAX).
RESULTS
Of the 1027 patients (92.4% female), 45.0% were treatment-naïve. The mean ± SD age of treatment-naïve versus prior OP-treatment patients was 76.8 ± 8.5 and 77.1 ± 8.5 years. The most frequent prior OP treatment was bisphosphonates (45.0%). Romosozumab treatment for 12 months increased BMD at the lumbar spine in all groups; the median percent change from baseline in lumbar spine BMD was higher in the treatment-naïve (13.4%) versus prior OP-treatment group (bisphosphonates [9.2%], teriparatide [11.3%], denosumab [DMAb, 4.5%]). DMAb, bisphosphonates, or teriparatide after romosozumab maintained the BMD gains at all skeletal sites at month 18 in treatment-naïve patients. Most treatment-naïve patients were at high risk of fracture, BMD increased consistently with romosozumab regardless of the baseline fracture risk assessed by FRAX.
CONCLUSION
This large-scale, multicenter chart review provides clinically relevant insights into the profiles of patients initiating romosozumab, effectiveness of real-world romosozumab use, and sequential therapy in Japanese patients at high risk of fracture.
Topics: Humans; Female; Aged; Aged, 80 and over; Male; Teriparatide; Japan; Osteoporosis; Fractures, Bone; Bone Density; Bone Density Conservation Agents; Diphosphonates; Lumbar Vertebrae; Osteoporosis, Postmenopausal; Denosumab; Antibodies, Monoclonal
PubMed: 38086988
DOI: 10.1007/s00774-023-01477-0 -
Expert Opinion on Biological Therapy Mar 2022Fibrous dysplasia (FD) is a rare bone disease that is associated with various endocrine conditions, such as McCune Albright syndrome. It manifests as abnormal... (Review)
Review
INTRODUCTION
Fibrous dysplasia (FD) is a rare bone disease that is associated with various endocrine conditions, such as McCune Albright syndrome. It manifests as abnormal osteolysis, multiple fractures, or deformities that are reported during disease course. The receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) pathway is upregulated in FD and can be targeted with denosumab, a blocking monoclonal antibody.
AREAS COVERED
Preclinical and clinical data on the scientific rationale for using denosumab in FD and on the efficacy and safety of this therapy for this condition have been reviewed, in addition to other therapies.
EXPERT OPINION
Denosumab is a potential therapeutic agent against FD. A combined synergic approach involving theranostics might increase its therapeutic potential.
Topics: Antibodies, Monoclonal; Bone and Bones; Denosumab; Fibrous Dysplasia of Bone; Humans; Receptor Activator of Nuclear Factor-kappa B
PubMed: 34964677
DOI: 10.1080/14712598.2022.2022118 -
Osteoporosis International : a Journal... Apr 2022
Topics: Bone Density Conservation Agents; COVID-19; Denosumab; Female; Humans; Osteoporosis, Postmenopausal; Pandemics
PubMed: 35066593
DOI: 10.1007/s00198-021-06274-x -
Journal of Bone and Mineral Research :... Apr 2024Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III... (Comparative Study)
Comparative Study Randomized Controlled Trial
Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis.
Topics: Female; Humans; Biosimilar Pharmaceuticals; Bone Density; Bone Density Conservation Agents; Denosumab; Osteoporosis; Osteoporosis, Postmenopausal; Double-Blind Method
PubMed: 38477751
DOI: 10.1093/jbmr/zjae016