A 2012 meta-analysis found that denosumab was better than placebo, zoledronic acid, and pamidronate, in reducing the risk of fractures in those with cancer.[13]
In those with postmenopausal osteoporosis denosumab decreases the risk of fractures but increases the risk of infection.[14] A 2013 review concluded that it is a reasonable treatment for postmenopausal osteoporosis.[15] A 2017 review did not find benefit in males.[16]
Bone remodeling is the process by which the body continuously removes old bone tissue and replaces it with new bone. It is driven by various types of cells, most notably osteoblasts (which secrete new bone) and osteoclasts (which break down bone); osteocytes are also present in bone.
Precursors to osteoclasts, called pre-osteoclasts, express surface receptors called RANK (receptor activator of nuclear factor-kappa B). RANK is a member of the tumor necrosis factor receptor (TNFR) superfamily. RANK is activated by RANKL (the RANK-Ligand), which exists as cell surface molecules on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. Denosumab mimics the natural action of osteoprotegerin, an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased effectiveness) in people with osteoporosis. This protects bone from degradation, and helps to counter the progression of the disease.[9]
It is contraindicated in people with hypocalcemia; sufficient calcium and vitamin D levels must be reached before starting on denosumab therapy.[17] Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions.[17]
Denosumab works by lowering the hormonal message that leads to excessive osteoclast-driven bone removal and is active in the body for only six months. Similarly to bisphosphonates, denosumab appears to be implicated in increasing the risk of osteonecrosis of the jaw (ONJ) following extraction of teeth or oral surgical procedures but, unlike bisphosphonate, the risk declines to zero approximately 6 months after injection.[18] Invasive dental procedures should be avoided during this time.
Use of Prolia can increase the risk of severe hypocalcemia among those with advanced kidney disease, especially those on dialysis.[22]
Discontinuation of denosumab is associated with a rebound increase in bone turnover. In rare cases this has led to severe hypercalcemia, but is common in children.[23] Vertebral compression fractures have also occurred in some people after discontinuing treatment.[23]
In August 2009, a meeting was held between Amgen and the Advisory Committee for Reproductive Health Drugs (ACRHD) of the U.S. Food and Drug Administration (FDA) to review the potential uses of denosumab.[24]
In October 2009, the FDA delayed approval of denosumab, stating that it needed more information.[25]
In June 2010, denosumab was approved by the FDA for use in postmenopausal women with risk of osteoporosis[26] under the brand name Prolia,[27] and in November 2010 as Xgeva for the prevention of skeleton-related events in people with bone metastases from solid tumors.[28] Denosumab is the first RANKL inhibitor to be approved by the FDA.[26]
In June 2013, the FDA approved denosumab for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where resection would result in significant morbidity.[29]
In January 2024, the FDA added a black box warning to Prolia because of the risk of severe hypocalcemia in those with advanced kidney disease. An FDA review found that Prolia had resulted in "hospitalization, life-threatening events, and death" in that population.[30]
In March 2024, the FDA approved applications from Sandoz for Jubbonti (denosumab-bbdz), a biosimilar to Prolia; and Wyost (denosumab-bbdz), a biosimilar to Xgeva.[31][32]
In March 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Jubbonti, intended for the treatment of osteoporosis in women who have been through menopause and in men at increased risk of fractures whose bone loss is linked to hormone ablation or long-term treatment with systemic glucocorticoid.[2][35] The applicant for this medicinal product is Sandoz GmbH.[2] In March 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Wyost, intended for the prevention of bone complications in adults with advanced cancer involving bone and for the treatment of adults and skeletally mature adolescents with giant cell tumour of bone.[36] The applicant for this medicinal product is Sandoz GmbH.[36] Denosumab, as Wyost,a biosimilar, was approved for medical use in the European Union in May 2024 for all indications of denosumab treated by Xgeva..[37] Denosumab, as Jubbonti, a biosimilar, was approved for medical use in the European Union in May 2024 for all indications of denosumab treated by Prolia.[37]
^ abcd"Jubbonti EPAR". European Medicines Agency. 21 March 2024. Archived from the original on 23 March 2024. Retrieved 23 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^"Denosumab". The American Society of Health-System Pharmacists. Archived from the original on 30 April 2021. Retrieved 16 March 2015.
^Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, et al. (November 2012). "Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials". European Journal of Cancer. 48 (16): 3082–92. doi:10.1016/j.ejca.2012.08.002. PMID22975218.
^Josse R, Khan A, Ngui D, Shapiro M (March 2013). "Denosumab, a new pharmacotherapy option for postmenopausal osteoporosis". Current Medical Research and Opinion. 29 (3): 205–16. doi:10.1185/03007995.2013.763779. PMID23297819. S2CID206967103.
^Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. (August 2009). "Denosumab for prevention of fractures in postmenopausal women with osteoporosis". The New England Journal of Medicine. 361 (8): 756–65. CiteSeerX10.1.1.472.3489. doi:10.1056/NEJMoa0809493. PMID19671655.
^EntrezGene8600 TNFSF11 tumor necrosis factor (ligand) superfamily, member 11; Homo sapiens
also known as RANKL. This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response.
^ ab"Wyost EPAR". European Medicines Agency. 21 March 2024. Archived from the original on 23 March 2024. Retrieved 23 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, et al. (May 2012). "Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab". Nature Reviews. Drug Discovery. 11 (5): 401–19. doi:10.1038/nrd3705. PMID22543469. S2CID7875371.
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