It has the advantage of convenience with subcutaneous administration and is not associated with acute phase reactions or renal toxicity. HHS Vulnerability Disclosure, Help Disclaimer, National Library of Medicine In the DEFEND (DEnosumab FortifiEs boNe Density) trial (n = 330), the overall incidence of infectious AEs were similar (60% denosumab, 61% placebo); however more serious infections were reported in the denosumab group (eight denosumab, one placebo). Denosumab is currently contraindicated for use in those with concurrent hypocalcemia, during pregnancy (category X), and in those with history of hypersensitivity reaction to denosumab [ 26 ]. a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have If you keep this medicine at home, store it in the original carton in a refrigerator. Furthermore, when treatment is started, adherence is often poor [8]. Musculoskeletal Pain: Severe and occasionally incapacitating bone, joint, and/or Bone metastases occur in more than 1.5 million patients with cancer worldwide[1] and are most commonly associated with cancers of the prostate, lung, and breast; with incidence rates as high as 75% of patients with metastatic disease. Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy. Serious Infections: In a clinical trial (N=7808) in women with postmenopausal The elimination half-life of denosumab is 32 days, and the terminal half-life is 5-10 days. A meta-analysis of 7 Phase I studies, 2 Phase II studies, and 2 Phase III studies (n = 1,564) determined the SC bioavailability of denosumab to be 64% with the first-order absorption rate constant ka = 0.00883 per hour, and the RANKL degradation rate was determined to be 0.00148 per hour. malignancies were reported in no patients in the placebo group and 4 (3.3%) patients in the New anti-resorptives and antibody mediated anti-resorptive therapy. consequences, including ONJ, atypical fractures, and delayed fracture healing. Take only the amount of calcium and vitamin D that your doctor has prescribed. Xgeva is meant to be taken long-term. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. Anaphylaxis was reported in five patients; there were no fatal outcomes from this complication [46]. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, et al. South Asian J Cancer. Burge R, Dawson-Hughes B, Solomon D, et al. Denosumab does not incorporate into bone. Cosman F, Eriksen E, Recknor C, et al. Background. osteoporosis, Prolia resulted in significant suppression of bone remodeling as Prolia (denosumab) prescribing information, Amgen. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. infections of the abdomen, urinary tract and ear were more frequent in patients treated with The manufacturer of denosumab recommends all patients using denosumab to receive calcium 1000 mg daily and at least 400 IU of vitamin D daily to avoid hypocalcemia complications. chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid Patients randomized to receive denosumab had a longer time to first SRE (20.7 vs 17.1 months; HR 00.82; P = 0.008). [43] However, the clinical data with denosumab is conflicting on this issue. This acts to inhibit osteoclast formation, function, and survival, thereby decreasing bone resorption. Further, questions remain on how to transition patients off of denosumab, without resulting in an increased in BTMs. Learn In postmenopausal women with low bone mineral density, it was found to lead to a 3.0% to 6.7% increase in bone mineral density of the lumbar spine. Same Active Ingredient: Prolia contains the same active ingredient (denosumab) found in XGEVA . The treatment was well-tolerated with no drug-related serious adverse events reported [27]. Similar sites. The 120 mg dose of denosumab administered subcutaneously (SC) once every 4 weeks (Q4W) was the minimal dose that maintained maximal suppression of bone turnover over the entire dosing interval in a high proportion of patients. incidence of opportunistic infections and the overall incidence of infections were similar [22] In addition, preclinical models of multiple myeloma bone disease have shown that inhibition of RANKL reduced osteolysis[23] and tumor burden while increasing survival. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Treatment of postmenopausal women with osteoporosis at high risk for fracture; Treatment to increase bone mass in men with osteoporosis at high risk of fracture; Suppression of bone resorption by binding to RANK ligand, preventing its binding to RANK and decreasing osteoclast formation, activity, and survival, Route of administrationChemical structure, Subcutaneous every 6 months(C6404 H9912 N1724 O2004 S50) consists of 2 heavy and 2 light chains; each light chain consists of 215 amino acids and each heavy chain consists of 448 amino acids with 4 intramolecular disulfides. Effect of denosumab versus zoledronic acid treatment in patients with breast cancer and bone metastases: Results from the extended blinded treatment phase. FOIA Another major safety concern is infection risk, given RANKL inhibition of non-skeletal immune cells, causing a theoretical immune suppression. postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab) [32]. Denosumab is an effective agent for minimizing bone loss associated with certain cancer treatments. [27] Administration of denosumab resulted in rapid reductions in biochemical markers of bone turnover, in a dose-dependent manner, which lasted up to 13 weeks. Croucher PI, Shipman CM, Lippitt J, Perry M, Asosingh K, Hijzen A, et al. In a Phase III trial comparing denosumab with zoledronic acid in multiple myeloma patients with at least 1 osteolytic lesion, denosumab did not reach superiority (though non-inferiority was achieved), and a post-hoc analysis showed less favorable survival in the denosumab group (HR 2.26, CI 1.13 4.50), though AEs were similar between groups [52]. Recent advances in bone biology provide insight into the pathogenesis of bone diseases. The FDA has approved two new indications for denosumab (Prolia, made by Amgen): (1) to increase bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitors for breast cancer; and (2) to increase bone mass in men at high risk for fracture receiving androgen-deprivation therapy for non-metastatic prostate cancer. For more information about Amgens privacy practices, please visit www.amgen.com/privacy. Bookshelf Adult Indications and Dosage FDA-Labeled Indications and Dosage (Adult) Recommended Dosage. Based upon monoclonal antibody pharmacokinetics, denosumab is most likely cleared by the reticuloendothelial system with minimal renal filtration and excretion. [24] Various studies have also evaluated the effect of RANKL inhibition in conjunction with chemotherapeutic agents. Over the 41-month study duration, the proportion of denosumab and zoledronic acid patients developing at least one SRE was 35.9 and 40.6%, respectively, for an absolute difference of 4.7% [Table 1]. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. XGEVA is not chemotherapy or other treatment for your cancer. Padhi D, Jang G, Stouch B, et al. Although anaphylaxis and allergic reactions are rare, it would be useful for the manufacturer to provide a test dose of this denosumab. if you cannot take daily calcium and vitamin D. Denosumab may cause bone loss (osteonecrosis) in the jaw. 2018 Mar;19(3):370-381. doi: 10.1016/S1470-2045(18)30072-X. [31] In the denosumab group, a significant delay in time to first on-study SRE was observed (hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.71-0.95; P < 0.001 noninferiority). Before evidenced by markers of bone turnover and bone histomorphometry. Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. A major benefit of denosumab over the standard therapy with bisphosphonates is a continuous BMD increase with use as opposed to a plateau effect seen with bisphosphonates, and the possibility of combination with teriparatide for further BMD gains. Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. This use is approved for the Xgeva brand of denosumab. Consider discontinuing muscle pain has been reported in patients taking Prolia. management plan of each patient. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: Integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. [19] Prostate cancer cells can also upregulate RANKL expression in osteoblasts.[20]. musculoskeletal pain, hypercholesterolemia, and cystitis. Extensive dental surgery to treat ONJ In the trial by Fizazi et al., which compared zoledronic acid to denosumab in prostate cancer, 1,901 patients meeting the eligibility criteria were randomized one to one to either denosumab 120 mg subcutaneous injection or to IV injection of zoledronic acid 4 mg adjusted for creatinine clearance. Orwoll E, Teglbjrg C, Langdahl B, et al. A dental examination with appropriate Do not share this medicine with another person, even if they have the same symptoms you have. Ellis GK, Bone HG, Chlebowski R, et al. findings and the effect of long-term treatment are unknown. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. September 16, 2011. S Zaheer has no conflict of interest. Copyright 1996-2022 Cerner Multum, Inc. We are experimenting with display styles that make it easier to read articles in PMC. Hip fracture reduction: 41%. Pamidronate and zoledronic acid were mainly used for tumor-related diseases, and their ROR values were 494.8 and 458.3, respectively. A possible effect on the immune system by denosumab was postulated based on preclinical data where RANKL was found to be a costimulatory cytokine for T-cell activation[42] and lymphocyte development. In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single SC administered denosumab dose of 60 mg, the mean maximum denosumab concentration (Cmax) was 6.75 mcg/ml (standard deviation [SD] = 1.89 mcg/ml), with a median time to maximum denosumab concentration (Tmax) was 10 days (range: 3 21 days), reflecting slow absorption by the SC route. Denosumab. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative randomized controlled trial. full Smith MR, Egerdie B, Hernaxndez Toriz N, Feldman R, Tammela TL, Saad F, et al. fda-approved indications include prevention of skeletal-related events (e.g., bone pain and fractures) secondary to multiple myeloma or bone metastases from solid tumors, giant cell tumor of the bone, hypercalcemia of malignancy, osteoporosis in postmenopausal women with osteoporosis at high risk for fracture as well as men with osteoporosis at After 12 months of therapy, denosumab showed greater BMD gains at total hip (2.0% denosumab, 0.5% risedronate), femoral neck (1.4% denosumab, 0% risedronate), and lumbar spine (3.4% denosumab, 1.1% risedronate), p < 0.0001 at all sites. A phase 1 study compared the safety, pharmacokinetics, and pharmacodynamics of denosumab in patients with multiple myeloma and bone lesions (n = 25) or breast cancer and bone metastases (n = 29) with intravenous (IV) pamidronate. Primary study endpoint was time to first on-study SRE (noninferiority); secondary endpoints consisted of time to first on-study SRE (superiority) and time to first and subsequent on-study SREs. More, Prolia is indicated for the treatment of glucocorticoid-induced osteoporosis Studies in prevention of skeletal-related events in multiple myeloma have yielded less favorable results, though data is limited [51]. This in turn decreases bone resorption and reduces cancer-induced bone destruction. [37] However, in the denosumab 147 study, where denosumab 120 mg was given every 4 weeks, ONJ occurred in 5% of the denosumab arm over the course of the study. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. Brush and floss your teeth regularly while receiving this medication. Hannan E, Magaziner J, Wang J, et al. Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association? vertebral, nonvertebral, and Site is running on IP address 54.71.195.151, host name ec2-54-71-195-151.us-west-2.compute.amazonaws.com (Boardman United States) ping response time 11ms Good ping.Current Global rank is 800,892, category rank is . Brown JM, Corey E, Lee ZD, True LD, Yun TJ, Tondravi M, et al. References: Denosumab should be administered by a healthcare professional. Corresponding author: E. Michael Lewiecki, MD, New Mexico Clinical Research & Osteoporosis Center, 300 Oak St. NE, Albuquerque, NM 87106, USA, Phone 505-938-2117, Fax 505-884-4006, The publisher's final edited version of this article is available at, denosumab, mAb, osteoporosis, receptor activator of nuclear factor kappa-B ligand, treatment, {"type":"clinical-trial","attrs":{"text":"NCT02166437","term_id":"NCT02166437"}}, {"type":"clinical-trial","attrs":{"text":"NCT01465568","term_id":"NCT01465568"}}, {"type":"clinical-trial","attrs":{"text":"NCT01732770","term_id":"NCT01732770"}}. Another major safety concern is infection risk, given RANKL inhibition in with! Immunity - implications for therapy, et al interest ( ) to readers as Prolia ( denosumab ) information. Jang G, Stouch B, et al Amgens privacy practices, please visit www.amgen.com/privacy copyright Cerner. F, et al Chlebowski R, et al croucher PI, Shipman CM, J. 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