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Journal of Bone and Mineral Research :... Dec 2023Denosumab (Dmab) is increasingly prescribed worldwide. Unlike bisphosphonates (BPs), its effect on mortality has yet to be well explored. This study examined the...
Denosumab (Dmab) is increasingly prescribed worldwide. Unlike bisphosphonates (BPs), its effect on mortality has yet to be well explored. This study examined the association between Dmab and all-cause mortality compared with no treatment in subjects with a fracture and BPs in subjects without a fracture. The study population was from the Sax Institute's 45 and Up Study (n = 267,357), a prospective population-based cohort with questionnaire data linked to hospital admissions (Admitted Patients Data Collection [APDC] data were linked by the Centre for Health Record Linkage), medication records (Pharmaceutical Benefits Scheme [PBS] provided by Services Australia), and stored securely (secure data access was provided through the Sax Institute's Secure Unified Research Environment [SURE]). The new-user cohort design with propensity-score (PS) matching was implemented. In the fracture cohort, Dmab and oral BP users were matched 1:2 to no treatment (Dmab: 617 women, 154 men; oral BPs: 615 women, 266 men). In the no-fracture cohort, Dmab users were matched 1:1 with oral BPs and zoledronic acid (Zol) users (Dmab:oral BPs: 479 men, 1534 women; Dmab:Zol: 280 men, 625 women). Mortality risk was measured using sex-specific pairwise multivariable Cox models. In the fracture cohort, compared with no treatment, Dmab was associated with 48% lower mortality in women (hazard ratio [HR] = 0.52, 95% confidence interval [CI] 0.36-0.72) but not in men. Oral BPs were associated with 44% lower mortality in both sexes (women HR = 0.56, 95% CI 0.42-0.77; men HR = 0.56, 95% CI 0.40-0.78). In the no-fracture cohort, compared with BPs, Dmab was associated with 1.5- to 2.5-fold higher mortality than oral BPs (women HR = 1.49, 95% CI 1.13-1.98; men HR = 2.74; 95% CI 1.82-4.11) but similar mortality to Zol. Dmab in women and oral BPs were associated with lower post-fracture mortality than no treatment. However, Dmab users had generally higher mortality than oral BP users in those without fractures. © 2023 American Society for Bone and Mineral Research (ASBMR).
Topics: Male; Humans; Female; Bone Density Conservation Agents; Denosumab; Prospective Studies; Diphosphonates; Zoledronic Acid; Fractures, Bone
PubMed: 37915252
DOI: 10.1002/jbmr.4930 -
Clinical Oral Implants Research Sep 2023The aim of Working Group 3 was to address the influence of both material- and anti-resorptive drug- related factors on clinical and biological outcomes and complications... (Review)
Review
OBJECTIVES
The aim of Working Group 3 was to address the influence of both material- and anti-resorptive drug- related factors on clinical and biological outcomes and complications in implant dentistry. Focused questions were addressed on (a) implant materials other than titanium (alloy)s, (b) transmucosal abutment materials and (c) medications affecting bone metabolism were addressed.
MATERIALS AND METHODS
Three systematic reviews formed the basis for discussion in Group 3. Consensus statements and clinical recommendations were formulated by group consensus based on the findings of the systematic reviews. Patient perspectives and recommendations for future research were also conveyed. These were then presented and accepted following further discussion and modifications as required by the plenary.
RESULTS
Zirconia is a valid alternative to titanium as material for implant and transmucosal components, allowing soft and hard tissue integration with clinical outcomes-identified by implant survival, marginal bone loss and peri-implant probing depths-up to 5-years comparable to titatnium. However, most of the evidence for zirconia implants is based on 1-piece implants limiting the indication range. Furthermore, based on expert opinion, zirconia transmucosal components might be preferred in the esthetic zone. In patients receiving low-dose bisphosphonate therapy, the rate of early implant failure is not increased, while the long-term effects remain poorly studied. Although it has not been sufficiently addressed, similar outcomes can be expected with low-dose denosumab. A drug holiday is not recommended when considering implant placement in patients treated with low-dose ARD. However, the specific therapeutic window, the cumulative dose and the administration time should be considered. Access to peri-implant supportive care is mandatory to prevent peri-implantitis-related medication-related osteonecrosis of the jaw (MRONJ) or implant-related sequestra (IRS). In patients receiving low-dose anti-resorptive drugs (ARD) therapy, the risk of complications related to implant placement is high, and implant procedures in this specific population should be strictly treated in a comprehensive multidisciplinary center. Finally, healthy dental implants should not be removed before low or high-dose ARD.
CONCLUSIONS
Zirconia implants can be an alternative to titanium implants in selected indications. However, the current state of evidence remains limited, especially for 2-piece implant designs. Administration of low-dose ARD did not show any negative impact on early implant outcomes, but careful follow-up and supportive care is recommended in order to prevent peri-implant MRONJ and IRS. Implant placement in high-dose patients must be strictly considered in a comprehensive multidisciplinary center.
Topics: Humans; Bone Density Conservation Agents; Titanium; Dental Implants; Alloys
PubMed: 37750518
DOI: 10.1111/clr.14135 -
International Journal of Endocrinology 2023To summarize the characteristics of all reported patients with hypophosphatasia (HPP) who sustained atypical femoral fracture (AFF) and identify all available evidence...
OBJECTIVE
To summarize the characteristics of all reported patients with hypophosphatasia (HPP) who sustained atypical femoral fracture (AFF) and identify all available evidence to quantify the rate of coexistence between HPP and AFF.
METHODS
Potentially eligible articles were identified from the MEDLINE and EMBASE databases from its inception to September 2022, using a search strategy consisting of terms related to "Hypophosphatasia" and "Atypical femoral fracture." Eligible articles must report one of the following information: (1) individual data of patients diagnosed with HPP and AFF, (2) prevalence of HPP among patients with AFF, or (3) prevalence of AFF among patients of HPP. Characteristics of patients reported in each study were extracted.
RESULTS
A total of 148 articles were identified. After the systematic review, 24 articles met the eligibility criteria. A total of 28 patients with AFF and HPP were identified. The mean ± SD age of the reported patients was 53.8 ± 12.5 years, and 22 patients (78.6%) were female. Nine patients (32.1%) received antiresorptive medication (bisphosphonate and/or denosumab), and two patients (7.1%) received teriparatide prior to the development of AFF. Seven (25.0%) and eighteen (64.3%) patients sustained unilateral and bilateral AFF, respectively (laterality not reported in three cases). Thirteen patients (46.4%) had a history of fractures at other sites. Four (14.3%) and seven (25.0%) patients received asfotase alfa and teriparatide after sustaining AFF. Two studies reported the prevalence of AFF among patients with HPP of approximately 10%. One study reported one HPP patient in a cohort of 72 patients with AFF.
CONCLUSIONS
Based on the limited evidence, AFF occurred in up to 10% of patients with HPP. Based on the 28 case reports, about two-thirds did not receive antiresorptive treatment, suggesting that the HPP itself could potentially be a risk factor for AFF.
PubMed: 37731773
DOI: 10.1155/2023/5544148 -
JBMR Plus Jul 2024The coronavirus disease 2019 (COVID-19) pandemic triggered significant disruptions in health care systems around the world, with a particularly heavy impact on patients...
The coronavirus disease 2019 (COVID-19) pandemic triggered significant disruptions in health care systems around the world, with a particularly heavy impact on patients with chronic diseases. A number of studies have shown an immediate decrease in on-time denosumab therapy at the start of COVID-19 pandemic. However, independent of the "emergency" that occurred during the COVID-19 pandemic, there are other situations in which denosumab is discontinued. In such situations, it is important to have a programmed strategy to optimize care while limiting the risk for unwanted outcomes.
PubMed: 38827117
DOI: 10.1093/jbmrpl/ziae046 -
EFORT Open Reviews Dec 2023Denosumab is a fully humanised monoclonal antibody to RANK ligand, inhibiting the RANK-RANKL pathway. It promotes the apoptosis of osteoclast-like giant cells, a... (Review)
Review
Denosumab is a fully humanised monoclonal antibody to RANK ligand, inhibiting the RANK-RANKL pathway. It promotes the apoptosis of osteoclast-like giant cells, a secondary ossification and connective tissue formation. Given its high efficacy, denosumab is the standard treatment of unresectable or metastatic giant cell tumour of bone (GCTB) requiring morbid surgery. Neoadjuvant administration of denosumab may be justified to enable the resection of the tumour in certain cases; it should be considered, however, with caution for joint-saving surgery due to high local recurrence rates. In cases of unresectable or metastatic GCTB, however, denosumab treatment should be administered for years or even as a lifelong therapy. This poses many yet unanswered questions concerning the frequency of denosumab treatment as well as the ratio of the adverse events in the following years. Denosumab suppresses, not directly targets, the neoplastic stromal cells of GCTB. Ongoing in vitro studies suggest that other drugs alone or in combination (e.g. sunitinib) with denosumab may target both the neoplastic and the giant cells. Promising results have been reported regarding the off-label use of denosumab in other giant cell-rich tumours/tumour-like lesions, i.e. aneurysmal bone cysts and central giant cell granulomas. Data are derived, however, mostly from case reports and case series. Large prospective clinical trials are needed to evaluate the role and also the side effects of denosumab in the treatment of these rare diseases.
PubMed: 38038377
DOI: 10.1530/EOR-23-0138 -
Biomedicines Oct 2023Our objective was to overview the most recent data on primary hyperparathyroidism (PHP) in children and teenagers from a multidisciplinary perspective. Methods:... (Review)
Review
Our objective was to overview the most recent data on primary hyperparathyroidism (PHP) in children and teenagers from a multidisciplinary perspective. Methods: narrative review based on full-length, English-language papers (from PubMed, between January 2020 and July 2023). Results: 48 papers (14 studies of ≥10 subjects/study, and 34 case reports/series of <10 patients/study). Study-sample-based analysis: except for one case-control study, all of the studies were retrospective, representing both multicenter (n = 5) and single-center (n = 7) studies, and cohort sizes varied from small (N = 10 to 19), to medium-sized (N = 23 to 36) and large (N = 63 to 83); in total, the reviewed studies covered 493 individuals with PHP. Case reports/series (n = 34, N = 41): the mean ages studied varied from 10.2 to 14 years in case reports, and the mean age was 17 years in case series. No clear female predominance was identified, unlike that observed in the adult population. Concerning the assessments, there were four major types of endpoints: imaging data collection, such as ultrasound, 99mTc Sestamibi, or dual-phase computed tomography (CT); gene testing/familial syndrome identification; preoperative findings; and exposure to surgical outcome/preoperative drugs, like cinacalcet, over a 2.2-year median (plus two case reports of denosumab used as an off-label calcium-lowering agent). Single-gland cases (representing 85% of sporadic cases and 19% of genetic PHP cases) showed 100% sensitivity for neck ultrasounds, with 98% concordance with 99mTc Sestamibi, as well as a 91% sensitivity for dual-phase CT, with 25% of the lesions being ectopic parathyroids (mostly mediastinal intra-thymic). Case reports included another 9/41 patients with ectopic parathyroid adenomas, 3/41 with parathyroid carcinomas, and 8/41 subjects with brown tumors. Genetic PHP (which has a prevalence of 5-26.9%) mostly involved , followed by , , , and , as well as one case of . Symptomatic PHP: 70-100% of all cases. Asymptomatic PHP: 60% of genetic PHP cases. Renal involvement: 10.5% of a cohort with genetic PHP, 71% of sporadic PHP cases; 50% (in a cohort with a mean age of 16.7), 29% (in a cohort with a mean age of 15.2); 0% (in infancy) to 50-62% (in teenagers). Bone anomalies: 83% of the children in one study and 62% of those in two other studies. Gastrointestinal issues: 40% of one cohort, but the data are heterogeneous. Cure rate through parathyroidectomy: 97-98%. Recurrent PHP: 2% of sporadic PHP cases and 38% of familial PHP cases. Hungry bone syndrome: maximum rate of 34-40%. Case reports identified another 7/41 subjects with the same post-parathyroidectomy condition; a potential connection with ectopic presentation or brown tumors is suggested, but there are limited data. Minimally invasive thoracoscopic approaches for ectopic tumors seemed safe. The current level of statistical evidence on pediatric PHP qualifies our study- and case-sample-based analysis (n = 48, N = 534) as one of the largest of its kind. Awareness of PHP is the key factor to benefit our young patients.
PubMed: 37893182
DOI: 10.3390/biomedicines11102810 -
The Korean Journal of Internal Medicine Mar 2024Cancer treatment-induced bone loss (CTBL) is associated with anti-tumor treatments, including endocrine therapies, chemotherapeutic treatments, radiotherapy,...
Cancer treatment-induced bone loss (CTBL) is associated with anti-tumor treatments, including endocrine therapies, chemotherapeutic treatments, radiotherapy, glucocorticoids, and tyrosine kinase inhibitors. Osteoporosis, characterized by the loss of bone mass, can increase the risk of fractures, leading to mortality and long-term disability, even after cancer remission. Cancer and osteoporosis have marked clinical and pathogenetic similarities. Both have a multifactorial etiology, affect the geriatric population, and markedly influence quality of life. Lifestyle management, including calcium and vitamin D supplementation, is recommended but the supporting evidence is limited. Oral and injectable bisphosphonates are effective for osteoporosis and malignant bone disease. Bisphosphonates increase bone mineral density (BMD) in patients with CTBL. Denosumab is also used in the management of CTBL; in clinical trials, it improved BMD and reduced the risk of fracture. Currently, there are no bone anabolic therapies for patients with cancer. Appropriate therapies are necessary to maintain optimal bone health, particularly in patients at heightened risk.
PubMed: 38439172
DOI: 10.3904/kjim.2023.386 -
Nature Medicine Mar 2024Erosive hand osteoarthritis (OA) is a prevalent and disabling disease with limited treatment options. Here we present the results of a monocentric, placebo-controlled,... (Randomized Controlled Trial)
Randomized Controlled Trial
Erosive hand osteoarthritis (OA) is a prevalent and disabling disease with limited treatment options. Here we present the results of a monocentric, placebo-controlled, double-blind, randomized phase 2a clinical trial with denosumab, a receptor activator of nuclear factor-κB ligand inhibitor, evaluating the effects on structure modification in erosive hand OA. Patients were randomized to 48 weeks treatment with denosumab 60 mg every 3 months (n = 51, 41 females) or placebo (n = 49, 37 females). The primary (radiographic) endpoint was the change in the total Ghent University Scoring System (GUSS) at week 24, where positive changes correspond to remodeling and negative changes to erosive progression. Secondary endpoints were the change in the GUSS at week 48 and the number of new erosive joints at week 48 by the anatomical phase scoring system. Baseline mean GUSS (standard deviation) of target joints was 155.9 (69.3) in the denosumab group and 158.7 (46.8) in the placebo group. The primary endpoint was met with an estimated difference between groups of 8.9 (95% confidence interval (CI) 1.0 to 16.9; P = 0.024) at week 24. This effect was confirmed at week 48 (baseline adjusted GUSS (standard error of the mean) denosumab and placebo were 163.5 (2.9) and 149.2 (3.9), respectively; with an estimated difference between groups of 14.3 (95% CI 4.6 to 24.0; P = 0.003)). At patient level, more new erosive joints were developed in the placebo group compared with denosumab at week 48 (odds ratio 0.24 (95% CI 0.08 to 0.72); P = 0.009). More adverse events occurred in the placebo group (125 events in 44 patients (90%)) compared with the denosumab group (97 events in 41 patients (80%)). These results demonstrate that denosumab has structure modifying effects in erosive hand OA by inducing remodeling and preventing new erosive joints. EU Clinical Trials Register identifier 2015-003223-53 .
Topics: Female; Humans; Denosumab; Double-Blind Method; Osteoarthritis; RANK Ligand; Treatment Outcome; Male
PubMed: 38361122
DOI: 10.1038/s41591-024-02822-0 -
The Korean Journal of Internal Medicine Jan 2024We evaluated the efficacy and safety of denosumab treatment in severe chronic kidney disease (CKD) patients with osteoporosis. We also investigated whether the treatment...
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.
CONCLUSION
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.
Topics: Humans; Female; Denosumab; Bone Density Conservation Agents; Calcium; Osteoporosis; Bone Density; Vitamin D; Renal Insufficiency, Chronic; Calcium Carbonate; Republic of Korea; Osteoporosis, Postmenopausal
PubMed: 38145616
DOI: 10.3904/kjim.2023.292 -
JAMA Oncology Apr 2024The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy, Safety, and Population Pharmacokinetics of MW032 Compared With Denosumab for Solid Tumor-Related Bone Metastases: A Randomized, Double-Blind, Phase 3 Equivalence Trial.
IMPORTANCE
The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases.
OBJECTIVES
To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study.
DESIGN, SETTING, AND PARTICIPANTS
In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab.
INTERVENTIONS
Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49.
MAIN OUTCOMES AND MEASURES
The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr).
RESULTS
Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups.
CONCLUSIONS AND RELEVANCE
MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04812509.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; Denosumab; Biosimilar Pharmaceuticals; Antibodies, Monoclonal, Humanized; Bone Neoplasms; Creatinine; Double-Blind Method
PubMed: 38329745
DOI: 10.1001/jamaoncol.2023.6520