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Crystalline Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Another interesting conceptual therapy to examine would be denosumab, a monoclonal antibody that mimics functional osteoprotegerin by binding and inhibiting OPG ligand (RANKL). While relatively safe in osteoporosis, denosumab has yet to be studied rigorously for CPPD. Osteoprotegerin serves as an alternative drug target; however, it likely plays a lesser role than ANK in CPPD.
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Denosumab is the first RANKL inhibitor to be approved by the FDA, and the first licensed antibody with an effect on bone remodelling, the process by which the body continuously removes old bone tissue and replaces it with new bone. This process is driven by various types of cells, including osteoclasts (which break down existing bone) and osteoblasts (which secrete new bone). Other cells known as osteocytes are also involved but their function is not well understood. The osteoclast precursor cells (known as “pre-osteoclasts”) express surface receptors known as RANK, an abbreviation for Receptor Activator of Nuclear Factor-Kappa B. The RANK receptor is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily and is activated by the RANK Ligand (known as RANKL) which exists as cell-surface markers on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts, and denosumab inhibits this maturation process by binding to and inhibiting RANKL. This process mimics the action of the endogenous RANKL inhibitor osteoprotegerin, which is found in decreasing concentrations and function in patients with osteoporosis. Thus, denosumab counters the declining levels of osteoprotegerin and protects bone from degradation, thus slowing the progression of bone loss.
Definition, risk factors, and epidemiology of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
The TNFRSF11B/OPG gene encoding a member of the TNF-receptor superfamily is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption and has been associated with osteoporosis (73). This protein specifically binds to its ligand, osteoprotegerin ligand, and both of these are key extracellular regulators of osteoclast development.
The pathophysiology and management of vascular calcification in chronic kidney disease patients
Published in Expert Review of Cardiovascular Therapy, 2023
Mehmet Kanbay, Sidar Copur, Cem Tanriover, Furkan Yavuz, Andrea Galassi, Paola Ciceri, Mario Cozzolino
Factors such as osteoprotegerin, osteopontin, bone morphogenic protein-7 (BMP-7), and fetuin-A are associated with VC [88]. One study investigating blood samples from 602 incident dialysis patients reported that higher osteoprotegerin and lower fetuin-A levels were related to higher mortality over up to 13 years of follow-up and that osteoprotegerin and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, however these molecules did not improve risk prediction [88]. The highest tertile of osteoprotegerin was significantly related to a greater mortality among patients without diabetes (HR 2.42, 95% CI 1.35 to 4.34), but not in those with diabetes (HR 1.26, 95% CI 0.82 to 1.93) and an elevated fetuin-A was associated with significantly decreased risk regarding cardiovascular mortality (HR 0.85 per 0.1 g/L, 95% CI 0.75 to 0.96) [88]. In addition, Bozic et al. showed that the combination of osteoprotegerin, osteopontin, and soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) increased the predictability of cardiovascular outcomes such that when CKD patients were grouped according to the number of biomarkers above (osteoprotegerin and osteopontin) or below (sTWEAK) their cut-off values, the combination of these biomarkers showed the highest risk for cardiovascular events [89].
Biosimilarity of HS-20090 to Denosumab in healthy Chinese subjects: a randomized, double-blinded, pharmacokinetics/pharmacodynamics study
Published in Expert Opinion on Investigational Drugs, 2022
Yaqi Lin, Heng Yang, Xiaoyan Yang, Can Guo, Shuang Yang, Guoping Yang, Qiong Wu, Chao Pan, Changan Sun, Chuan Li, Liangliang He, Jie Huang, Qi Pei
This randomized, double-blind, single-dose, two-parallel group study was conducted in healthy Chinese subjects to explore the bioequivalence of HS-20090 with Denosumab (Xgeva®) with respect to PK, PD, safety, and immunogenicity. A total of 154 eligible subjects were randomized (1:1) to receive 120 mg of either HS-20090 or Xgeva® in a single subcutaneous injection, with a follow-up period of 155 days. A healthy population was selected to avoid confounding factors, such as variability associated with a disease condition, comorbidities, and concomitant treatment. The inclusion criteria were as follows: 1) Healthy males aged between 18 and 50 years old, with total body weight of 58–68 kg and a body mass index (BMI) of 19–26 kg/m2; 2) Agreed to take effective actions to contraception for at least 6 months after the last dose of study medication; and 3) Normal laboratory test, vital signs, physical examination and electrocardiogram, or slight abnormality without clinical significance. The main exclusion criteria were as follows: 1) Subjects with a history or ongoing osteomyelitis or osteonecrosis of the jaw, dental disease, maxillary disease requiring oral surgery, a non-healed dental or oral surgery; 2) Previous or current known disease affecting bone metabolism; 3) Prior use of medications within 6 months before and during the study, which may affect bone metabolism; 4) Abnormal blood calcium level; and 5) Previous use of RANKL inhibitor or osteoprotegerin.
Effects of Creatine Supplementation on Properties of Muscle, Bone, and Brain Function in Older Adults: A Narrative Review
Published in Journal of Dietary Supplements, 2022
Scott C. Forbes, Darren G. Candow, Luis H. B. Ferreira, Tacito P. Souza-Junior
In regards to bone, an increase in muscle accretion from creatine supplementation may result in a greater muscle pull and mechanical stress on the bone, leading to bone accretion over time (i.e. muscle-bone interaction) (Forbes et al. 2018). Creatine may also directly affect the bone remodeling process. Bone cells rely on the creatine kinase reaction for the resynthesis of adenosine triphosphate (ATP) (Wallimann and Hemmer 1994). In cell culture models, creatine increased the activity and differentiation of osteoblast cells involved in bone formation (Gerber et al. 2005). Stimulating osteoblast cell activity may enhance the production of osteoprotegerin, a protein that inhibits osteoclast cell activity, which would subsequently decrease bone resorption (Yasuda et al. 1998). There is some evidence that creatine supplementation decreases the urinary excretion of cross-linked N-telopeptides of type I collagen (indicator of bone resorption) in older adults (Candow et al. 2008).