Denosumab (RANKL 억제제): 강력한 골흡수 억제제

변성은 ( Seong-eun Byun ) 대한골절학회 2021 대한골절학회지 Vol.34 No.4

RANKL의 인간 단일클론 항체인 denosumab은 골다공증 치료제로 사용되고 있다. Denosumab은 파골세포의 분화와 작용을 억제하여 골밀도를 증가시키고 척추, 고관절, 비척추 골절에 대한 예방효과를 나타낸다. FREEDOM 연구와 이를 10년까지 연장한 FREEDOM Extension 연구 등의 임상연구를 통하여 폐경 후 골다공증에 대한 denosumab 장기 투여의 효과와 안정성이 확인되었다. 또한 남성 골다공증 및 글루코코르티코이드 유발 골다공증에서도 denosumab의 효과와 안정성이 확인되었다. 따라서, 최근의 임상 가이드라인에서 denosumab을 골다공증에 대한 1차 치료제로 권고하고 있다. 이 종설에서는 denosumab의 작용기전, 약리적 특성, 유효성 및 안정성에 대해 살펴보았다. Denosumab, a fully human monoclonal antibody to the receptor activator of nuclear factor-kappa B ligand, was introduced and used as an anti-osteoporotic agent. Denosumab prevents bone resorption by inhibiting the differentiation and action of osteoclasts, resulting in an increase of bone mineral density and broad-spectrum anti-fracture efficacy. Clinical studies, including FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months) and its extension up to 10 years, FREEDOM Extension, demonstrated its long-term efficacy and safety in postmenopausal osteoporosis. In addition, the efficacy and safety of denosumab were confirmed in male osteoporosis and glucocorticoid- induced osteoporosis. Therefore, recent clinical guidelines recommend denosumab as an initial treatment. This review summarizes the mechanism of action, pharmacological characteristics, efficacy, and safety issue of denosumab.

Evaluation of Local Recurrence in Giant-Cell Tumor of Bone Treated by Neoadjuvant Denosumab

Pramod Shekarappa Chinder,Suraj Hindiskere,Srinath Doddarangappa,Utkarsh Pal 대한정형외과학회 2019 Clinics in Orthopedic Surgery Vol.11 No.3

Background: Giant-cell tumor of bone (GCTB) is a locally aggressive primary benign tumor presenting as an expansile osteolytic lesion affecting the epiphysis of long bones. Denosumab halts the osteolysis by giant cells thereby downstaging the tumor, helping in performing less morbid procedures to remove the tumor. Our aim was to report the incidence of local recurrence (LR) in patients operated following neoadjuvant denosumab, to investigate factors associated with LR following extended curettage for GCTB, and to compare the postoperative functional and oncological outcome of patients operated with and without neoadjuvant denosumab. Methods: A total of 123 patients with a mean age of 29.6 years undergoing extended curettage for GCTB were retrospectively divided into group 1 receiving neoadjuvant denosumab and group 2 operated without denosumab. The mean follow-up period was 35 months. The perioperative characteristics and outcome were compared between the two groups and the factors for LR of GCTB were analyzed. Results: The incidence of LR among patients operated after neoadjuvant denosumab therapy was 42.8% and was significantly high compared to that in patients without denosumab (p < 0.001). On multivariate logistic regression analysis, use of denosumab as a neoadjuvant was the only factor independently associated with LR following surgery (p = 0.002). Patients treated with denosumab had a lower LR-free survival rate (log-rank, p = 0.018). Conclusions: Denosumab was independently associated with increased LR following surgery for GCTB. Denosumab has to be used cautiously in patients in whom the burden of downstaging the disease outweighs the possible chance of LR.

Denosumab's Therapeutic Effect for Future Osteosarcopenia Therapy : A Systematic Review and Meta-Analysis

I Gusti Putu Suka Aryana,Sandra Surya Rini,Siti Setiati 대한노인병학회 2023 Annals of geriatric medicine and research Vol.27 No.1

Background: Osteosarcopenia, a combination of osteopenia/osteoporosis and sarcopenia, is a common condition among older adults. While numerous studies and meta-analyses have been conducted on the treatment of osteoporosis, the pharmacological treatment of osteosarcopenia still lacks evidence. Denosumab, a human monoclonal antibody, has shown encouraging results for the treatment of osteosarcopenia. Our systematic review and meta-analysis aimed to investigate the potential dual role of denosumab as an anti-resorptive agent and for other beneficial muscle-related effects in patients with osteosarcopenia, and to evaluate whether denosumab can be a treatment of choice compared to bisphosphonate. Methods: Relevant literature was collated from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Google Scholar databases. The primary outcome was denosumab’s effect on lumbar spine bone mineral density (LS BMD), handgrip strength, and gait speed change. The secondary outcome was the effect of denosumab on appendicular lean mass (ALM). The outcomes were presented as mean difference (MD). A random effects model was used in the analysis to represent the population. The risk of bias was assessed using funnel plots. Results: Out of the 3,074 studies found, four full-text studies met the inclusion criteria, including 264 and 244 participants in the intervention and control groups, respectively. Regarding a primary outcome, our meta-analysis showed that denosumab showed no significant differences in LS BMD and gait speed changes compared to other agents—MD=0.37, 95% confidence interval (CI), -0.35 to 0.79; p=0.09 and MD=0.11; 95% CI, -0.18 to 0.40; p=0.46, respectively. Denosumab had a significant effect on handgrip strength change compared to standard agents—MD=5.16; 95% CI, 1.38 to 18.94; p=0.007, based on the random effects model. Conclusions: Denosumab was better than bisphosphonate and placebo in improving muscle strength (handgrip strength). Therefore, denosumab may be favored in individuals with osteosarcopenia to improve muscular performance and reduce fall risk.

Effect of Denosumab on the Change of Osteoclast Precursors Compared to Zoledronate Treatment in Postmenopausal Women with Osteoporosis

Sung Hye Kong,김정희,Sang Wan Kim,정애진,Song-Hee Lee,Sang-Kyu Ye,Chan Soo Shin 대한골대사학회 2022 대한골대사학회지 Vol.29 No.2

Background: A rapid increase in bone turnover and bone loss has been observed in response to the discontinuation of denosumab. It led to an acute increase in the fracture risk, similar to that observed in the untreated patients. We aimed to investigate the effect of denosumab on osteoclast (OC) precursor cells compared to that of zoledronate. Methods: The study compared the effects of denosumab (60 mg/24-week) and zoledronate (5 mg/48-week) over 48 weeks in postmenopausal women with osteoporosis. From patients’ peripheral mononuclear cells, CD14+/CD11b+/vitronectin receptor (VNR)- and CD14+/CD11b+/VNR+ cells were isolated using fluorescent-activated cell sorting, representing early and late OC precursors, respectively. The primary endpoint was the changes in OC precursors after 48 weeks of treatment. Results: Among the 23 patients, 11 were assigned to the denosumab group and 12 to the zoledronate group (mean age, 69 years). After 48 weeks, the changes in OC precursors were similar between and within the groups. Serum C-terminal telopeptide of type I collagen levels were inversely correlated with OC precursor levels after denosumab treatment (r=-0.72, P<0.001). Lumbar spine, femur neck, and total hip bone mineral density (BMD) increased in both groups. Lumbar spine BMD increased more significantly in the denosumab group than in the zoledronate group. Conclusions: Denosumab and zoledronate treatments induced similar changes in OC precursors. During denosumab treatment, old age and suppressed bone turnover were associated with increased OC precursor cell populations. Further validation studies with prospective designs are required.

Update on Denosumab Treatment in Postmenopausal Women with Osteoporosis

민용기 대한내분비학회 2015 Endocrinology and metabolism Vol.30 No.1

Denosumab, a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), blocks binding of RANKL to the RANK receptor, found on the surface of osteoclasts and osteoclast precursors, resulting in decreased bone resorption. Subcutaneous denosumab administration once every 6 months increases bone mineral density at the lumbar spine, total hip, and/or femoral neck, and reduces markers of bone turnover significantly in postmenopausal women with osteoporosis. Relative to placebo, denosumab treatment reduces the risk of vertebral, nonvertebral, and hip fractures significantly. The benefits of denosumab treatment are generally obvious after the first dose and were continued for up to 8 years of treatment in an extension study. The tolerability profile of denosumab during this extension phase was consistent with that observed during the initial 3-year FREEDOM trial. Postmarketing safety surveillance has not shown any unexpected findings. Ongoing safety surveillance will more fully define the long-term safety of denosumab. The benefits of denosumab would seem to be greater than its risks. Denosumab is an important choice in the treatment of postmenopausal women with osteoporosis at increased risk of fractures, including older patients who have difficulty with oral bisphosphonate intake and patients who are intolerant of, or unresponsive to, other therapies.

Assessment of Denosumab in Korean Postmenopausal Women with Osteoporosis: Randomized, Double-Blind, Placebo-Controlled Trial with Open-Label Extension

고정민,정동진,정윤석,강무일,김인주,민용기,오한진,박일형,이일섭,Brian Waterhouse,Antonio Nino,Lorraine A. Fitzpatrick,Barbara Kravitz 연세대학교의과대학 2016 Yonsei medical journal Vol.57 No.4

Purpose: The efficacy and safety of denosumab was compared with placebo in Korean postmenopausal women with osteoporosisin this phase III study. Materials and Methods: Women aged 60 to 90 years with a T-score of <-2.5 and ≥-4.0 at the lumbar spine or total hip were randomizedto a single 60 mg subcutaneous dose of denosumab or placebo for the 6-month double-blind phase. Eligible subjects entered the 6-month open-label extension phase and received a single dose of denosumab 60 mg. Results: Baseline demographics were similar in the 62 denosumab- and 64 placebo-treated subjects who completed the double-blind phase. Treatment favored denosumab over placebo for the primary endpoint {mean percent change from baseline in lumbarspine bone mineral density (BMD) at Month 6 [3.2% (95% confidence interval 2.1%, 4.4%; p<0.0001)]}; and secondary endpoints(mean percent change from baseline in lumbar spine BMD at Month 1, total hip, femoral neck, and trochanter BMD at Months 1 and 6, and median percent change from baseline in bone turnover markers at Months 1, 3, and 6). Endpoint improvementswere sustained over 12 months in the open-label extension (n=119). There were no new or unexpected safety signals. Conclusion: Denosumab was well tolerated and effective in increasing BMD and decreasing bone turnover markers over a 12-month period in Korean postmenopausal women. The findings of this study demonstrate that denosumab has beneficial effectson the measures of osteoporosis in Korean postmenopausal women.

The Effect of Denosumab on Bone Mass in Super Elderly Patients

Chaiho Jeong,하정훈 대한골대사학회 2020 대한골대사학회지 Vol.27 No.2

Background: Denosumab is a potent antiresorptive drug leading to significant reduction in the risk of vertebral and non-vertebral fractures in postmenopausal osteoporosis. The effect of denosumab in super-elderly patients lacks data to date and few literature has proven the efficacy to this specific group. The purpose of this study was to determine the effectiveness and safety of denosumab in the super-elderly. Methods: We retrospectively evaluated 60 patients older than 80 with osteoporosis treated with denosumab. Patients were treated with denosumab every 6 months for 12 months 2017 to 2020. The primary endpoint was defined by the changes in bone mineral density (BMD) of 3 measurement sites: the lumbar spine, femoral neck, and total hip. Changes in bone turnover markers, serum calcium, serum phosphate, and 25-hydroxy-vitamin D were also observed. Results: All 60 patients were female, and the mean age was 83.9±3.1, from age 80 to 94. After 12 months of denosumab treatment, significant increases in BMD were observed; 3.02±2.74% for the lumbar spine (P=0.000), 3.10±6.90% for the femoral neck (P=0.005), and 2.89±5.80% for the total hip (P=0.002) The bone turnover marker C-terminal telopeptide of type I collagen and osteocalcin significantly declined after 12 months of treatment (-34.8±45.9%; P=0.002 and –35.5±38.9%; P=0.004 respectively). Symptomatic hypocalcemia and serious adverse drug reactions that required drug discontinuation were not observed during treatment. Conclusions: Denosumab is thought to be an anti-osteoporotic medication that is sufficiently effective and safe even for the super-elderly.

폐경기 골다공증 환자에서 데노수맙 사용에 대한 비용-효과 분석

배그린,권혜영,Bae, Green,Kwon, Hye-Young 한국임상약학회 2018 한국임상약학회지 Vol.28 No.2

Background: In South Korea, 22.3% of women ${\geq}50years$ of age and 37% of women ${\geq}70years$ of age visit the doctor to obtain treatment for osteoporosis. According to the analysis of the National Health Insurance Services claim data between 2008 and 2012, the number and incidence of hip and vertebral fractures increased during the same period. Denosumab, a newly marketed medicine in Korea, is the first RANK inhibitor. Methods: A cost-utility analysis was conducted from a societal perspective to prove the superiority of denosumab to alendronate. A Markov cohort model was used to investigate the cost-effectiveness of denosumab. A 6-month cycle length was used in the model, and all patients were individually followed up through the model, from their age at treatment initiation to their time of death or until 100 years of age. The model consisted of eight health states: well; hip fracture; vertebral fracture; wrist fracture; other osteoporotic fracture; post-hip fracture; post-vertebral fracture; and dead. All patients began in the well-health state. In this model, 5% discounted rate, two-year maximum offset time, and persistence were adopted. Results: The total lifetime costs for alendronate and denosumab were USD 5,587 and USD 6,534, respectively. The incremental cost-effectiveness ratio (ICER) for denosumab versus alendronate was USD 20,600/QALY. Given the ICER threshold in Korea, the results indicated that denosumab was remarkably superior to alendronate. Conclusion: Denosumab is a cost-effective alternative to the oral anti-osteoporotic treatment, alendronate, in South Korea.

Efficacy and safety of denosumab treatment for Korean patients with Stage 3b–4 chronic kidney disease and osteoporosis

Jin Taek Kim,You Mi Kim,Kyong Yeun Jung,Hoonsung Choi,So Young Lee,Hyo-Jeong Kim 대한내과학회 2024 The Korean Journal of Internal Medicine Vol.39 No.1

Background/Aims: We evaluated the efficacy and safety of denosumab treatment in severe chronic kidney disease (CKD) patients with osteoporosis. We also investigated whether the treatment affects the coronary artery calcifications. Methods: Twenty-seven postmenopausal women with Stage 3b–4 CKD and osteoporosis were enrolled. Twenty patients received denosumab plus calcium carbonate and vitamin D, and seven controls received calcium carbonate and vitamin D for 1 year. Dual-energy X-ray absorptiometry and coronary artery calcium (CAC) scoring computed tomography were performed before and after treatment. Hypocalcemic symptoms and serum calcium levels were evaluated. Results: After 1 year of treatment, the percent changes of femur neck (3.6 ± 3.2% vs. -0.7 ± 4.4%, p = 0.033) and total hip (3.4 ± 3.8% vs. -1.9 ± 2.1%, p = 0.001) bone mineral density (BMD) were significantly increased in the denosumab treated group compared to the control group. However, the percent change of lumbar spine BMD did not differ between two groups (5.6 ± 5.9% vs. 2.7 ± 3.9%, p = 0.273). The percent change of bone alkaline phosphatase was significantly different in the denosumab-treated group and control group (-31.1 ± 30.0% vs. 0.5 ± 32.0%, p = 0.027). CAC scores did not differ between groups. No hypocalcemic events occurred in both groups. Conclusions: If carefully monitored and supplemented with calcium and vitamin D, denosumab treatment for 1 year provides significant benefits in patients with Stage 3b–4 CKD and osteoporosis. However, denosumab treatment did not affect coronary artery calcifications in these patients.

Denosumab use in osteogenesis imperfecta: an update on therapeutic approaches

Majdoub Fatma,Ferjani Hanene Lassoued,Nessib Dorra Ben,Kaffel Dhia,Maatallah Kaouther,Hamdi Wafa 대한소아내분비학회 2023 Annals of Pediatirc Endocrinology & Metabolism Vol.28 No.2

Osteogenesis imperfecta (OI) is an inherited skeletal disorder that leads to bone fragility and multiple fractures. Given advances in the genetic understanding of existing phenotypes and newly discovered mutations, therapeutic management of OI has become challenging. Denosumab, a monoclonal antibody that inhibits the interaction between the receptor activator of nuclear factor kappa B ligand (RANKL) and its receptor RANK, has been approved to treat postmenopausal osteoporosis and emerged as an important therapy for malignancies and other skeletal disorders, including pediatric skeletal conditions such as OI. This review summarizes information about denosumab therapy in OI by exploring its mechanisms of action, main indications, and safety and efficacy. Several case reports and small series have been published about the short-term use of denosumab in children with OI. Denosumab was considered a strong drug candidate for OI patients with bone fragility and a high risk of fracture, particularly for patients with the bisphosphonate (BP)-unresponsive OI-VI subtype. The evidence for denosumab's effects in children with OI indicates that it effectively improves bone mineral density but not fracture rates. A decrease in bone resorption markers was observed after each treatment. Safety was assessed by tracking the effects on calcium homeostasis and reporting side effects. No severe adverse effects were reported. Hypercalciuria and moderate hypercalcemia were reported, suggesting that BPs be used to prevent the bone rebound effect. In other words, denosumab can be used as a targeted intervention in children with OI. The posology and administration protocol require more investigation to achieve secure efficiency.