Effect Of Denosumab Research Articles

P0699 Comparative Effectiveness and Safety of Denosumab Versus Bisphosphonates in Osteoporosis Management Among Patients with Inflammatory Bowel Disease: A U.S. Propensity Matched Cohort Study

Abstract Background Denosumab, a fully monoclonal antibody, is approved for the treatment of osteoporosis, including glucocorticoid-induced osteoporosis. Denosumab is an alternative to bisphosphonate therapy and has been shown to improve bone mineral density, and reduce the incidence of new fractures, however there is limited data in patients with inflammatory bowel disease (IBD). Through this study we evaluate the effectiveness of denosumab versus bisphosphonates in reducing osteoporosis-related fractures and safety related to IBD-specific outcomes. Methods We conducted a retrospective cohort study using a U.S. multi-institutional database (TriNetX), examining patients with IBD with osteoporosis who were initiated on denosumab or bisphosphonates from 2013 to 2022. The primary aim of the study was to assess the 1- and 2-year risk of de-novo fractures (spine and/or hip) in the denosumab cohort compared to bisphosphonate cohort. Cox proportional hazard model was used to identify predictors of denosumab failure. The secondary aim was to evaluate the 2-year risk of IBD-related outcomes which included corticosteroid use, advanced therapy initiation, and surgery. 1:1 propensity score matching (PSM) was performed for demographics, comorbid conditions, BMI, hemoglobin, albumin, calcium/vitamin D supplementation, IBD medications including steroid use. Results Among 2,423 patients with IBD and osteoporosis (mean age 62.8, female sex 67.3%, Crohn’s disease 48.5%), 520 received denosumab and 1,903 received bisphosphonates. After PSM, there was no difference in the 1-year (2.33% vs 3.49%, aOR 0.65, 95% CI 0.31-1.38) and 2-year risk (4.65% vs 6.78%, aOR 0.65, 95% CI 0.39-1.14) of fractures between the denosumab cohort compared to the bisphosphonates cohort. In terms of IBD-related outcomes, denosumab was associated with a lower risk of prednisone use (aOR 0.73, 95% CI 0.56–0.96) but no significant difference in the risk of de-novo advanced therapy use (aOR: 0.76, 95% CI 0.442–1.334), IV steroid use (aOR 1.13, 95% CI 0.78–1.64) and surgery (aOR 0.79, 95% CI 0.49-1.27) [Table 1]. After cox regression analysis, chronic steroid use (HR 1.99, 95% CI 1.26-3.1), prednisone use (HR 1.71, 95% CI: 1.07–2.72) and history of falls (HR 3.00, 95% CI 1.34-4.09) as significant predictors of treatment failure with denosumab [Figure 1]. Conclusion Our study highlights the comparable effectiveness of denosumab compared to bisphosphonates in reducing the risk of fractures in patients with IBD and osteoporosis. There were no IBD-related safety signals related to denosumab use compared to bisphosphonates. Further prospective studies are needed to optimize osteoporosis management in this high-risk population.

A Randomized, Double-Blind, Comparison of Denosumab versus Zoledronic Acid on Prolonging Bone Metastasis-Free Survival in Men with Hormone-Refractory Prostate Cancer

Bone metastases represent a critical factor contributing to illness and mortality among men diagnosed with prostate cancer. This study evaluates the therapeutic effectiveness of denosumab, a fully human monoclonal antibody targeting RANKL, in comparison to zoledronic acid for reducing the occurrence of such metastases or mortality in these patients. The investigation utilized a Cox proportional hazards model to assess bone-metastasis-free survival, factoring in variables such as chemotherapy use. Kaplan-Meier survival curves and hazard ratios (HRs) were employed to evaluate treatment differences. Results indicated that the antibody extended survival by a median of 29.97 months over its comparator. Moreover, it postponed the initial onset of metastases and improved survival outcomes. It outperformed the alternative treatment in minimizing skeletal complications and holds potential as an innovative option for men in this condition.

The Effect of Denosumab on Pain and Radiological Improvement in Giant Cell Tumours of the Spine in the Acute Setting.

Retrospective Cohort Study. The current recommended treatment for Giant Cell Tumour (GCT) of the spine is en bloc excision. Denosumab is a monoclonal antibody reducing osteoclast activity that shows promising results when used as a neo - adjuvant treatment. However, the current literature remains limited. The purpose of this study was to assess the effect of denosumab on tumour characteristics and symptom relief in the acute phase of treatment of spinal GCT. We performed a retrospective review of 16 patients treated with denosumab as neo-adjuvant and stand - alone treatment. MRI and PET tumour characteristics were taken before and after treatment and patients were interviewed for subjective pain responses. Following treatment, all patients showed improvement of pain, of which 68.7% of patients were pain free with 43.75% noting improvement within 48hours. Mean relative volumetric reduction in tumour volume was 37.3% (P < .001). Eight patients showed high grade of Bilsky classification (Epidural spinal cord compression scale - ESCC) with seven of them showing significant improvement to low grade of ESCC (P = .016). Median baseline PET Standardised Uptake Value (SUV)max was 14.57 and post treatment was 4.8 (P < .001). This study provides necessary insight to the limited literature on the use of denosumab for spinal GCT in the acute phase. The clinical and radiographic responses observed demonstrate the critical role that neo-adjuvant denosumab has by reducing the tumour burden around critical adjacent neurovascular structures before eventual resection, significant pain improvement even with presence of fractured vertebra.

Denosumab and clinical outcomes among men with osteoporosis: a retrospective cohort study.

Direct evidence for fracture risk reduction of medications used among men with osteoporosis is very limited. This study aims to evaluate the real-world effectiveness of denosumab in reducing fracture risk. This study included 13,797 men aged ≥ 50years with osteoporosis who had initiated denosumab in Taiwan. Taiwan's National Health Insurance Research Database includes all Taiwan residents' complete health claim data. We compared incidence rates of clinical fractures between patients on denosumab 60mg subcutaneously every 6months (on-treatment) and patients ending therapy after one administration (off-treatment). Propensity score (PS) analysis, adjusting for measured differences at baseline covariates, was used to estimate the adjusted hazard ratio using a Cox proportion hazards model. During follow-up, 248 hip fracture events occurred. The crude incidence rates of hip fracture were 1.13 events and 1.73 events per 100 person-years in on-treatment and off-treatment cohorts, respectively. After PS inverse probability of treatment weighting, the cohorts achieved balance in all 59 covariates. The hip fracture event rate was lower in on-treatment cohort versus off-treatment cohort by 36% (hazard ratio, 0.64 [95% CI 0.50-0.83]). A similar magnitude of risk reduction was observed in clinical vertebral and nonvertebral fractures. A series of sensitivity analysis, including a validation analysis using a-million individual health records, demonstrated that unmeasured confounders were not suggested to impact study result interpretation. In this large, real-world study evaluating denosumab treatment among men with osteoporosis, the observed fracture risk reductions were consistent with the available risk reductions demonstrated in clinical trials among women with postmenopausal osteoporosis.

Lung transplantation and bone health: A narrative review.

Bone health after lung transplantation has not been comprehensively reviewed in over two decades. This narrative review summarizes available literature on bone health in the context of lung transplantation, including epidemiology, presentation and post-operative management. Osteoporosis is reported in approximately 30-50% of lung transplant candidates, largely due to disease-related impact on bone and lifestyle, and corticosteroid-related effects during end-stage lung disease (interstitial lung diseases, chronic obstructive pulmonary disease, and historically cystic fibrosis). After lung transplantation, many patients experience steroid-induced bone loss, followed by stabilization or recovery to baseline levels with pharmacological management. Although evidence on fracture incidence is limited, fracture risk appears to increase in the year following transplantation, with common fracture sites including the vertebrae and the ribs. Vertebral and rib fractures restrict chest expansion and affect lung function, underscoring the importance of fracture prevention in lung transplant recipients. There is limited evidence on pharmacological management of osteoporosis after lung transplantation. Existing randomized controlled trials have focused on parenteral bisphosphonates and calcitriol, but have been underpowered to evaluate their effect on fracture outcomes. Resistance training, particularly in conjunction with antiresorptive therapy, has also been shown to improve bone health when initiated two months after transplantation. No studies to date have documented effectiveness of denosumab in lung transplant recipients; more studies on pharmacotherapy are warranted to elucidate optimal medical management. Considering high osteoporosis prevalence and high fracture risk in lung transplant populations, development of formal guidance is warranted to promote improved management after transplantation.

RANK/RANKL Signaling Pathway in Breast Development and Cancer.

RANK pathway has attracted increasing interest as a promising target in breast cancer, given the availability of denosumab, an anti-RANKL drug. RANK signaling mediates progesterone-driven regulation of mammary gland development and favors breast cancer initiation by controlling mammary cell proliferation and stem cell fate. RANK activation promotes luminal mammary epithelial cell senescence, acting as an initial barrier to tumorigenesis but ultimately facilitating tumor progression and metastasis. Comprehensive analyses have demonstrated that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and estrogen receptor-negative breast cancer patients. RANK pathway also has multiple roles in immunity and inflammation, regulating innate and adaptive responses. In the tumor microenvironment, RANK and RANKL are expressed by different immune cell populations and contribute to the regulation of tumor immune surveillance, mainly driving immunosuppressive effects.Herein, we discuss the preventive and therapeutic potential of targeting RANK signaling in breast cancer given its tumor cell intrinsic and extrinsic effects. RANKL inhibition has been shown to induce mammary tumor cell differentiation and an antitumor immune response. Moreover, loss of RANK signaling increases sensitivity of breast cancer cells to chemotherapy, targeted therapies such as HER2 and CDK4/6 inhibitors, and immunotherapy. Finally, we describe clinical trials of denosumab for breast cancer prevention, such as those ongoing in women with high risk of developing breast cancer, large phase III clinical trials where the impact of adjuvant denosumab on disease-free survival has been assessed, and window trials to evaluate the immunomodulatory effects of denosumab in breast cancer and other solid tumors.

The effect of denosumab on minimum 3-years BMD changes in patients with osteoporotic hip fractures: a propensity score matching analysis.

Denosumab, a potent antiresorptive agent, has been recognised to increase bone mineral density (BMD) and reduce fracture risk in vertebrae and hips. Despite its widespread use, no sequential follow-up studies have investigated its effects on BMD in patients with hip fractures. This study aimed to analyse the effect of denosumab on BMD gain in patients with hip fractures and investigate the incidence of subsequent hip fractures. This retrospective study analysed 371 patients treated with denosumab for at least 3years, including 122 patients with hip fractures. 1:1 propensity score matching was used to compare BMD changes in the lumbar spine, total hip, and femoral neck, as well as additional hip fracture incidence between the hip fracture and the other than hip fracture group. Ultimately, 122 patients in each group were compared. Subgroup analysis compared osteoporosis medication-naïve patients with those with prior medication use. The hip fracture and other than hip fracture group exhibited significant annual increases in lumbar spine and total hip BMD, with no significant differences between them after matching. The femoral neck BMD increased significantly only in the first year. The incidence of additional hip fractures did not differ significantly between the groups. Moreover, the effect of denosumab on BMD increase was more pronounced in patients without a previous medication history for anti-osteoporosis treatment than in those with such a history. Denosumab significantly increased lumbar spine and total hip BMD in patients with hip fractures, with comparable efficacy to that in other than hip fracture patients. Its effect was more pronounced in medication-naïve patients, suggesting its efficacy regardless of hip fracture status.

Association of Delayed Denosumab Dosing with Increased Risk of Fractures: A Population-Based Retrospective Study.

Inhibitory effects of denosumab on bone remodeling are reversible and disappear once treatment is discontinued. Herein, we examined whether and to what extent delayed denosumab administration is also associated with fracture risk using nation- wide data. The study cohort included women aged 45 to 89 years who were started on denosumab for osteoporosis between October 2017 and December 2019 using data from the Korean Health Insurance Review and Assessment service. Participants were stratified according to the time of their subsequent denosumab administration from the last denosumab administration, including those with within 30 days early dosing (ED30), within the planned time of 180-210 days (referent), within 30-90 days of delayed dosing (DD90), within 90-180 days of delayed dosing (DD180), and longer than 181 days of delayed dosing (DD181+). The primary outcome was the incidence of all clinical fractures. A total of 149,199 participants included and 2,323 all clinical fractures (including 1,223 vertebral fractures) occurred. The incidence of all fractures was significantly higher in the DD90 compared to reference group (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.4). The risk of all fracture was even higher in the longer delayed DD180 group (HR, 1.9; 95% CI, 1.6 to 2.3) and DD181+ group (HR, 1.8; 95% CI, 1.5 to 2.2). Increased risks of fractures with delayed dosing were consistently observed for vertebral fractures. Delayed denosumab dosing, even by 1 to 3 months, was significantly associated with increased fracture risk. Maintaining the correct dosing schedule should be emphasized when starting denosumab.

The Effect of Denosumab on Risk for Emergently Treated Hypocalcemia by Stage of Chronic Kidney Disease : A Target Trial Emulation.

There is a paucity of data on treatment of osteoporosis in patients with advanced chronic kidney disease (CKD). To assess the risk for emergently treated hypocalcemia with denosumab by stage of CKD and presence of CKD-mineral and bone disorder (CKD-MBD). Target trial emulation. Medicare fee-for-service data with prescription drug coverage, 2012 to 2020. Female patients aged 65 years or older initiating denosumab, oral bisphosphonates, or intravenous (IV) bisphosphonates for osteoporosis. Hospital and emergency department admissions (that is, emergent care) for hypocalcemia were assessed in the first 12 treatment weeks. Inverse probability of treatment weighted cumulative incidence and weighted risk differences (RDs) were calculated. A total of 361 453 patients treated with denosumab, 829 044 treated with oral bisphosphonates, and 160 413 treated with IV bisphosphonates were identified. Risk for emergently treated hypocalcemia with denosumab versus oral bisphosphonates increased with worsening CKD stage (P < 0.001), with greatest risk among dialysis-dependent (DD) patients (3.01% vs. 0.00%; RD, 3.01% [95% CI, 2.27% to 3.77%]) and non-dialysis-dependent (NDD) patients with CKD stages 4 and 5 (0.57% vs. 0.03%; RD, 0.54% [CI, 0.41% to 0.68%]). Among patients with stages 4 and 5 CKD (NDD + DD), denosumab had a greater risk for emergently treated hypocalcemia versus oral bisphosphonates in those with CKD-MBD (1.53% vs. 0.02%; RD, 1.51% [CI, 1.21% to 1.78%]) than in those without CKD-MBD (0.22% vs. 0.03%; RD, 0.19% [CI, 0.08% to 0.31%]). Denosumab also showed increased risk compared with IV bisphosphonates. Generalizability to men and non-Medicare populations. Risk for emergently treated hypocalcemia with denosumab increased with worsening CKD stage and was highest in DD patients and those with CKD-MBD. U.S. Food and Drug Administration.

Osteoporosis in Systemic Mastocytosis: A Scoping Review.

Background: Mastocytosis (MS) is a rare disease that can involve various organs, including the bone. Given the incidence of the disease in the global population, MS poses a challenge for physicians, and early therapeutic intervention in the initial stages could significantly impact the quality of life of affected patients. Objective: The aim of this scoping review was to provide an overview of secondary osteoporosis in systemic mastocytosis (SM), focusing on the heterogeneity of its manifestations, the benefits of early diagnosis, and appropriate pharmacological treatment. Design: A technical expert panel (TEP) consisting of 8 physicians with expertise in metabolic bone diseases conducted the review following the PRISMA-ScR model. A strength of this study is that it provides various therapeutic approaches for patients with bone involvement in SM, although the limited available literature on the topic constituted a limitation. The TEP sought evidence regarding the following diagnostic and therapeutic modalities in the management of SM: "bisphosphonate therapy", "zoledronic acid therapy", "denosumab therapy", "IFN-alpha therapy", and "IFN-alpha therapy in combination with pamidronate". Results: Clinical data showed a correlation between densitometric outcomes, serum tryptase levels, and mast cell infiltration in the bone marrow, between increased bone mineral density and the presence of osteosclerosis in cases of advanced SM, between the severity of osteoporosis and hypertryptasemia, and also provided results on the long-term effects of bisphosphonate therapy, the therapeutic efficacy of zoledronic acid administration, the positive effect of denosumab on the reduction of serum tryptase levels (even if is proved in a limited numbers of cases) and the prevention of new fractures, and the effect of IFN-alpha in more severe cases of SM, either alone or in combination with pamidronate. Conclusions: Studies have demonstrated the effectiveness of various treatments depending on the form of mastocytosis, whether indolent systemic or advanced systemic, in the prognosis of the disease. However, this role should be further investigated in additional clinical studies, considering the limited data on the use of these interventions.

The effects of denosumab on osteoclast precursors in postmenopausal women: a possible explanation for the overshoot phenomenon after discontinuation.

Upon denosumab discontinuation, an observed overshoot phenomenon in bone turnover may occur, potentially leading to a reduction in bone mineral density and the occurrence of vertebral fractures. Several theories have been proposed to explain this phenomenon, one of which is that osteoclast precursors might be accumulating during treatment. Our aim was to study the effects of denosumab on osteoclast precursors in postmenopausal women. This cross-sectional observational study included 30 postmenopausal women with osteopenia or osteoporosis, divided into two groups: 15 treated with denosumab (mean duration 4years, range 6months-9years) and 15 treatment-naïve controls. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and were stained for CD14, MCSFR, CD11b and TNFRII. Osteoclast precursors (CD14+/MCSFR+, CD14+/CD11b + OR CD14+/TNFRII+) were identified with fluorescent activated cell sorting (FACS). The proportion of osteoclasts was determined by calculating their percentage of the total cell population in each whole blood sample. To confirm the expected suppression of bone turnover in the subjects treated with denosumab, we measured serum PINP, CTX and TRACP5b. Denosumab-treated patients exhibited a significantly higher count of CD14+/CD11b + osteoclast precursors compared to controls (median 4% vs 0.75%, P=.011). There was no correlation with the duration of treatment. Bone turnover markers were significantly lower in the group treated with denosumab than controls. Our findings indicate an increase in osteoclast precursors, which could explain the overshoot phenomenon observed after discontinuing denosumab.

Dose-specific effects of denosumab on serum calcium levels in patients with osteoporosis and various renal functions.

Patients with osteoporosis and advanced chronic kidney disease (CKD) are at increased risk for hypocalcemia when initiating denosumab. It remains unclear if subsequent doses of denosumab pose similar hypocalcemia risk as the initial dose does. To study dose-specific hypocalcemia risks of denosumab. An observational study of 10,398 consecutive patients with varying renal function who received denosumab within Mass General Brigham healthcare system between 1/1/2016 and 2/29/2024. Dose-specific effects of denosumab on serum calcium levels and incidence of hypocalcemia (albumin-corrected serum calcium level < 8.5 mg/dl). In 159 patients with sufficient data for three consecutive doses of denosumab, the initial dose of denosumab reduced serum calcium levels by an average of 0.34, 0.52, and 1.12 mg/dl, in patients with GFR of ≥60 (n=89), 30-59 (n=46) and < 30 (n=24) ml/min/1.73m2, respectively (p<0.001). Among patients with GFR of < 30 ml/min/1.73m2, the initial, second, and third dose of denosumab reduced serum calcium levels by an average of 1.12, 0.72, and 0.60 mg/dl, respectively (p=0.014).In a cohort of 325 patients with sufficient data for two doses of denosumab, a Kaplan-Meier analysis revealed a trend of higher incidence of hypocalcemia following the initial dose compared to the second dose in patients with GFR of < 30 ml/min/1.73m2. The magnitude of serum calcium decrease following subsequent dose(s) was smaller than that following the initial dose of denosumab among patients with osteoporosis and advanced CKD.

8455 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study

Abstract Disclosure: V. Rouach: Consulting Fee; Self; Amgen Inc. H. Gortler: None. Y. Greenman: None. C. Gabriel: None. G. inbalL: None. Background: Anti-resorptive therapies are the mainstay of osteoporosis management, but evidence of their efficacy in the diabetic population is limited and comparison between treatments is lacking. A retrospective analysis, presented at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting, suggests that denosumab leads to greater reduction in fracture risk than zoledronic acid among treatment-naive postmenopausal women with osteoporosis. However, a comparative study recently published suggests higher mortality with denosumab versus oral bisphosphonates. Aim: To assess the association between zoledronic acid or denosumab and the risk of major osteoporotic fracture and mortality in osteoporotic patients with diabetes type 2. Methods: The study population was identified by electronic records of a diabetes registry cross-linked with an osteoporosis registry of a large provider healthcare organization in Israel. Index date was at osteoporosis registry entry. Demographics, Comorbidity Index (CCI), diabetes complications, bone mineral density (BMD) T-scores, hemoglobin A1c levels, eGFR, purchase of statins, and anti-resorptive agents were collected. Propensity score matching was performed. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 27503 diabetic osteoporotic patients were identified, 13343 (48%) patients initiated treatment; 12214 (91.5%) started an oral bisphosphonate, 627 (4.7%) zoledronic acid and 502 (3.7%) denosumab. The median follow-up was 8.9 years. The denosumab treated patients were older (75.7 vs 71.9, p&amp;lt;0.01), had longer diabetes duration (8.4 vs 7.2, p&amp;lt;0.01), were more frequently treated with insulin (29.7 vs 23.9, p=0.02) and had a lower eGFR (59.4 vs 75.3, p&amp;lt;0.01). Male/Female ratio, BMI, CCI, smoking status, alcohol consumption, Hip BMD, HbA1c levels, microvascular complications, hypoglycemic events and statins prescriptions were similar. After propensity weighting, we observed a significant reduced risk of death among the denosumab treated patients (RR=0.72 [0.58-0.91]) without a significant difference in the risk of fracture (RR=0.9 [0.82-1.12]). Conclusions: In this cohort of diabetic osteoporotic patients, denosumab was associated with a significantly reduced mortality compared to zoledronic acid, without a significant difference in the risk of fractures. The effect of denosumab on mortality is yet to be explored. Presentation: 6/1/2024

9236 Denosumab Is Associated With Decreased Mortality Compared To Zoledronic Acid In Diabetic Osteoporotic Patients: A Population-Based Cohort Study

Abstract Disclosure: V. Rouach: Consulting Fee; Self; Amgen Inc. H. Gortler: None. Y. Greenman: None. C. Gabriel: None. G. inbalL: None. Background: Anti-resorptive therapies are the mainstay of osteoporosis management, but evidence of their efficacy in the diabetic population is limited and comparison between treatments is lacking. A retrospective analysis, presented at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting, suggests that denosumab leads to greater reduction in fracture risk than zoledronic acid among treatment-naive postmenopausal women with osteoporosis. However, a comparative study recently published suggests higher mortality with denosumab versus oral bisphosphonates. Aim: To assess the association between zoledronic acid or denosumab and the risk of major osteoporotic fracture and mortality in osteoporotic patients with diabetes type 2. Methods: The study population was identified by electronic records of a diabetes registry cross-linked with an osteoporosis registry of a large provider healthcare organization in Israel. Index date was at osteoporosis registry entry. Demographics, Comorbidity Index (CCI), diabetes complications, bone mineral density (BMD) T-scores, hemoglobin A1c levels, eGFR, purchase of statins, and anti-resorptive agents were collected. Propensity score matching was performed. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 27503 diabetic osteoporotic patients were identified, 13343 (48%) patients initiated treatment; 12214 (91.5%) started an oral bisphosphonate, 627 (4.7%) zoledronic acid and 502 (3.7%) denosumab. The median follow-up was 8.9 years. The denosumab treated patients were older (75.7 vs 71.9, p&amp;lt;0.01), had longer diabetes duration (8.4 vs 7.2, p&amp;lt;0.01), were more frequently treated with insulin (29.7 vs 23.9, p=0.02) and had a lower eGFR (59.4 vs 75.3, p&amp;lt;0.01). Male/Female ratio, BMI, CCI, smoking status, alcohol consumption, Hip BMD, HbA1c levels, microvascular complications, hypoglycemic events and statins prescriptions were similar. After propensity weighting, we observed a significant reduced risk of death among the denosumab treated patients (RR=0.72 [0.58-0.91]) without a significant difference in the risk of fracture (RR=0.9 [0.82-1.12]). Conclusions: In this cohort of diabetic osteoporotic patients, denosumab was associated with a significantly reduced mortality compared to zoledronic acid, without a significant difference in the risk of fractures. The effect of denosumab on mortality is yet to be explored. Presentation: 6/1/2024

Effect of denosumab, an anti-osteoporosis drug, on vascular calcification: A meta-analysis.

Denosumab is an effective drug for the treatment of osteoporosis. This meta-analysis was conducted to evaluate efficacy of denosumab on the treatment of vascular calcification (VC). Databases including PubMed, EMbase, the Cochrane Library, CNKI, Wanfang database were searched from the inception to January 10th, 2024. Eligible studies comparing denosumab versus no denosumab treatment on VC were included. Data were analyzed using Review Manager Version 5.3. Five studies were included in this meta-analysis. Three were RCTs and 2 were non-randomized studies. As a whole, 961 patients were included in denosumab group and 890 patients were included in no denosumab group. The follow-up period was from 6 to 36 months. Compared with the no denosumab group, the denosumab group demonstrated a decrease on VC score or area in all enrolled patients (SMD -0.85, 95% CI -1.72-0.02, P = .05). In the subgroup of patients with non-CKD, there was no statistical difference between the denosumab and no denosumab group concerning the change of VC score (SMD -0.00, 95% CI -0.12-0.12, P = .98). In the subgroup of patients with CKD 3b-4, there was no significant difference between the denosumab and no denosumab group concerning the change of VC score (SMD 0.14, 95% CI -0.72-1.00, P = .75). In the subgroup of CKD patients undergoing dialysis, the denosumab group demonstrated a significant decrease on VC score or area compared with the no denosumab group (SMD -2.30, 95% CI -3.78-0.82, P = .002). Our meta-analysis revealed that denosumab did not show a very definite inhibitory effect on VC. However, denosumab showed the effective effect on inhibiting VC in CKD patients undergoing dialysis. More large RCTs are needed to verify these results.

Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial.

Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Effect of bisphosphonate and denosumab treatment on TBS in Japanese breast cancer patients with AIBL.

Bisphosphonates and denosumab increase bone mineral density (BMD) for osteoporosis treatment in patients with aromatase inhibitor-associated bone loss (AIBL). This study aimed to directly compare bisphosphonates with denosumab in treating patients with AIBL and to determine the effect of denosumab on the trabecular bone score (TBS). Thirty-nine patients with AIBL receiving osteoporosis treatment (21 in the bisphosphonates group and 18 in the denosumab group) were retrospectively evaluated for changes in lumbar spine and femoral BMD, lumbar spine bone quality (assessed by TBS), and blood bone metabolic markers. The Mann-Whitney and Wilcoxon tests were used for statistical evaluation. After 24months of treatment, the lumbar spine BMD change rate was 5.82 ± 1.10% with bisphosphonates and 10.49 ± 1.20% with denosumab, with the change rate of denosumab significantly increasing over that of bisphosphonates. The change rate in femoral BMD was 2.69 ± 1.16% with bisphosphonates and 2.95 ± 1.26% with denosumab, with no significant difference between the two groups. The rate of decrease in tartrate-resistant acid phosphatase isoform 5b was significantly higher in the denosumab group. The change rate in TBS at 24months of treatment was 0.53 ± 1.26% in the bisphosphonates group and 1.08 ± 1.33% in the denosumab group, with no significant difference between the two groups. After 24months, TBS remained stable. Both bisphosphonates and denosumab may increase BMD, improve bone metabolism, and inhibit bone quality loss in patients with AIBL.

Hypercalcemia in children induced by denosumab: a case report and an analysis of the FDA adverse event reporting system database

ABSTRACT Background The potential risks of denosumab on pediatric patients have raised concerns about its safety. This article aims to analyze the adverse effects of denosumab in minors, with a specific focus on hypercalcemia. Research design and methods A case study involving a child was analyzed. The OpenVigil 2.1 was utilized to extract adverse event data from the FAERS database, focusing on denosumab as the primary suspect drug in pediatric patients. The study also reviewed published cases of children developing hypercalcemia after discontinuing denosumab. Results The incidence of denosumab induced hypercalcemia in individuals under 18 years old is significantly higher than the overall incidence. The signal value for hypercalcemia was higher in the male group and was highest in the adolescent group. Hypercalcemia usually appeared approximately 4 months after denosumab discontinuation. Males had a higher peak blood calcium level. Patients aged 0–11 years had a higher average peak serum calcium compared to aged 12–17 years. Conclusions This study highlights the risk of hypercalcemia after discontinuation of denosumab in minors, with young age and male gender identified as potential high-risk factors. These findings offer valuable safety warnings and preventative measures for the secure administration of this drug in pediatric populations.

Analysis of adverse drug reactions of Denosumab (Prolia) in osteoporosis based on FDA adverse event reporting system (FAERS).

To comprehensively analyze the ADRs associated with Denosumab (Prolia) in the treatment of osteoporosis using data from the FAERS database, and gain a better understanding of the potential risks and side effects of Denosumab (Prolia) therapy. Data of Denosumab (Prolia) were collected from the FAERS database covering the period from first quarter of 2010 to the third quarter of 2023. Disproportionality analysis was performed by calculating the reporting odds ratios (ROR), proportional reporting ratio (PRR), and Bayesian analysis confidence propagation neural network (BCPNN) to detect positive signals. Totally, 17,985,365 reports were collected from the FAERS database, 1,97,807 reports of Denosumab (Prolia) were identified as the "primary suspected (PS)" ADRs. Denosumab (Prolia) induced ADRs occurred in 27 organ systems. 38 significant disproportionality PTs satisfying with the three algorithms were retained at the same time. Unexpected significant ADRs such as bone density abnormal and immobile also occur. The majority of the ADRs occurred within the first 30 days after Denosumab (Prolia) initiation. Based on the American FAERS database, the high frequency ADRs of Denosumab (Prolia) were hypocalcaemia, bone density abnormal, eczema, rebound effect, spinal deformity, etc. Clinical use of this drug should focus on this part of ADRs. Attention should also be paid to newly discovered ADRs, such as immobile, menopausal symptoms, etc., to avoid more serious consequences. Cohort studies, more detailed and comprehensive case information, and long-term clinical investigations are needed to confirm these results and to further understand the safety profile of Denosumab (Prolia).

Denosumab: A Useful Addition to the Armamentarium for the Management of Male Osteoporosis.

Bone is a dynamic tissue. It remodels, preserving serum calcium, repairing microdamage, and maintaining strength. Osteoporosis is caused by a decrease in bone strength, which manifests clinically as low-energy vertebral and non-vertebral fractures. Osteoporosis poses a significant public health challenge. While it's often portrayed as primarily impacting postmenopausal women, there's been growing recognition among researchers and clinicians regarding its prevalence in men. Major fracture in men has higher mortality rates than in women. Denosumab is a fully human monoclonal immunoglobulin G2 (IgG2) antibody that binds to RANKL, the principal regulator of osteoclastic bone resorption. Multiple studies suggest that denosumab is both effective and safe, exhibiting higher adherence rates and greater patient satisfaction. In this narrative review, we highlighted the effects of denosumab in men with osteoporosis, subsequent changes in bone mineral density, and bone turnover markers outlining the literature and guideline support.