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Denosumab

Denosumab is a fully IgG2 that specifically binds to receptor activator of nuclear factor kappa-B ligand (), a key mediator of , activation, and survival. By inhibiting the RANKL-RANK interaction, denosumab potently suppresses -mediated , thereby increasing density and reducing risk. Developed by Inc., it was first approved by the U.S. (FDA) in 2010 and is administered via subcutaneous injection. Denosumab is marketed under two brand names with distinct indications and dosing regimens. As Prolia (60 mg every 6 months), it is indicated for the of postmenopausal in women at high risk for , in men at high risk for , glucocorticoid-induced in men and women at high risk for , to increase bone mass in men receiving for nonmetastatic , and to increase bone mass in women receiving adjuvant aromatase inhibitor therapy for . As Xgeva (120 mg every 4 weeks), it is approved for the prevention of skeletal-related events in patients with and bone metastases from solid tumors, of adults and skeletally mature adolescents with unresectable or those for whom surgical resection would cause severe morbidity, and of hypercalcemia of malignancy refractory to therapy. These formulations share the same but differ in concentration and scheduling to address versus oncology-related bone pathology. Clinical use of denosumab requires careful monitoring due to potential adverse effects, including severe (particularly in patients with ), , atypical subtrochanteric and diaphyseal femoral fractures, and increased risk of multiple vertebral fractures upon discontinuation. Patients must receive adequate calcium and supplementation, and dental evaluations are recommended prior to initiation to mitigate jaw-related risks. With a of approximately 61% and a of about 32 days, denosumab provides sustained inhibition of bone turnover. Biosimilars, such as Jubbonti and Wyost (denosumab-bbdz) approved by the FDA in 2024, and additional ones including Enoby/Xtrenbo (denosumab-qbde), Osvyrti/Jubereq (denosumab-desu), Conexxence/Bomyntra, and Stoboclo/Osenvelt (denosumab-bmwo) approved in 2025, are interchangeable alternatives for both Prolia and Xgeva indications.

Medical uses

Osteoporosis

Denosumab, marketed as Prolia, is approved for the treatment of in postmenopausal women at high risk for , defined as those with a history of osteoporotic or multiple risk factors for . It is also indicated to increase bone mass in men with at high risk for . Additionally, denosumab is approved for the treatment of glucocorticoid-induced in men and women at high risk for receiving systemic glucocorticoid therapy (daily dosage equivalent to 7.5 mg or greater of ) for chronic conditions expected to last at least 6 months. It is further indicated to increase bone mass in men at high risk for receiving for nonmetastatic , and to increase bone mass in women at high risk for receiving adjuvant therapy for . The recommended dosing regimen for denosumab in is 60 mg administered as a subcutaneous injection every 6 months. This formulation is specifically designed for management and differs from the higher-dose regimen used in other indications. Denosumab is indicated for individuals at high risk for and may be particularly useful in those intolerant to other therapies or with contraindications, such as renal impairment precluding use. Efficacy in reducing fracture risk was demonstrated in the pivotal FREEDOM trial, a 3-year randomized, placebo-controlled study involving postmenopausal women with , where denosumab reduced the risk of new vertebral fractures by 68% (2.3% vs. 7.2% incidence; , 0.32; 95% CI, 0.26-0.41), hip fractures by 40% (0.7% vs. 1.2% incidence; , 0.60; 95% CI, 0.37-0.97), and nonvertebral fractures by 20% (6.5% vs. 8.0% incidence; , 0.80; 95% CI, 0.67-0.95). Long-term data from the 10-year FREEDOM extension trial showed sustained efficacy, with continued increases in bone mineral density (BMD) reaching 21.7% at the lumbar spine and 9.2% at the total hip compared to baseline, alongside persistently low fracture rates. By inhibiting , denosumab reduces activity and , thereby enhancing BMD and fracture protection in these populations.

Cancer-related bone conditions

Denosumab, marketed as Xgeva, is approved for the prevention of skeletal-related events (SREs) in patients with metastases from solid tumors and in those with . It is also indicated for the treatment of hypercalcemia of malignancy that is refractory to therapy. SREs include pathologic fractures, radiation or to , and , which significantly impact in advanced cancer patients. In clinical practice, denosumab targets the pathway to inhibit activity, thereby reducing and the incidence of these events in settings. Phase III randomized controlled trials have demonstrated denosumab's superiority over in preventing SREs across various solid tumors. In a pooled analysis of three trials involving patients with bone metastases from , , and other solid tumors, denosumab reduced the risk of first on-study SRE by 17% ( 0.83; 95% CI 0.76-0.90) and delayed the median time to first SRE by 8.21 months compared to . For instance, in patients, the median time to first SRE was 32.4 months with denosumab versus 27.4 months with . Similar benefits were observed in , where denosumab delayed time to first SRE (median 20.7 months versus 17.1 months) and reduced multiple SREs by 18%. These outcomes highlight denosumab's role in extending the interval between SREs, particularly in patients undergoing for , where loss is exacerbated. The recommended dosing for SRE prevention is 120 mg administered as a subcutaneous injection every 4 weeks, typically in the , , or . For hypercalcemia of , the regimen includes 120 mg every 4 weeks, with additional 120 mg doses on days 8 and 15 of the first month. All patients should receive calcium and supplementation as necessary to mitigate risk, alongside monitoring of serum calcium levels. Denosumab's offers convenience over intravenous bisphosphonates, with demonstrated efficacy in , , and other solid tumors, including a 23% reduction in subsequent SREs in cohorts.

Giant cell tumor of bone

Denosumab is approved for the treatment of adults and skeletally mature adolescents with unresectable (GCTB) or when surgical resection would likely result in severe morbidity. This indication targets the locally aggressive, benign nature of GCTB, where denosumab inhibits to suppress osteoclast-like giant cell activity essential for tumor-driven bone destruction. In a pivotal open-label phase 2 involving 282 patients with advanced GCTB, denosumab demonstrated with 74% of patients achieving stable disease or better after 6 months of , and an objective response rate of 25% (all partial responses) by modified RECIST criteria. Histopathologic analyses from biopsies showed near-complete elimination of osteoclast-like giant cells in 100% of evaluable patients, accompanied by reduced proliferative stromal cells and increased fibro-osseous matrix formation, confirming the drug's impact on tumor biology. These responses often allowed deferral of morbid , with only 30% of patients undergoing procedures during the study period. The recommended dosing regimen is 120 mg administered subcutaneously every 4 weeks, with additional loading doses of 120 mg on days 8 and 15 during the first month of . Patients require radiographic evaluations, such as or MRI, every 3 months to assess tumor response and determine if surgical intervention has become feasible. Treatment continuation is advised as long as clinical benefit persists without disease progression.

Pharmacology

Mechanism of action

Denosumab is a fully human monoclonal immunoglobulin G2 (IgG2) that specifically binds to receptor activator of nuclear factor kappa-B ligand () with high affinity, characterized by a (Kd) of approximately 3 × 10^{-12} M. This binding prevents RANKL from interacting with its receptor on the surface of osteoclast precursors and mature . By blocking this key signaling pathway, denosumab inhibits the , maturation, , and of osteoclasts, the primary cells responsible for . The suppression of osteoclast activity leads to a rapid and profound decrease in bone resorption, as evidenced by reductions in serum markers such as of (CTX) by approximately 85% within three days and up to 88% by one month, and urinary N-terminal telopeptide (NTX) by over 80% within one week. These effects manifest within weeks of , reflecting potent target engagement and downstream inhibition of bone breakdown processes. Physiologically, denosumab reduces overall bone turnover by markedly suppressing resorption while having minimal direct impact on bone formation, resulting in a net increase in through secondary mineralization and coupling effects. Unlike anabolic agents, it exerts no direct stimulatory effect on osteoblasts or bone-forming pathways. In contrast to bisphosphonates, which inhibit osteoclast function intracellularly by targeting farnesyl pyrophosphate synthase in the , denosumab acts extracellularly by neutralizing soluble and membrane-bound , offering a distinct that avoids intracellular accumulation.

Pharmacokinetics

Denosumab is administered subcutaneously and exhibits a of approximately 62% following this route. After a single 60 mg dose, the median time to maximum concentration (Tmax) is 10 days, with a range of 3 to 21 days, and the mean maximum concentration (Cmax) is 6.75 mcg/mL. The volume of distribution for denosumab is approximately 5.2 L, reflecting its distribution primarily within the vascular compartment as a , with binding to receptor activator of nuclear factor kappa-B ligand () occurring in both and . Denosumab undergoes catabolism via proteolytic degradation, similar to other antibodies, without involvement of hepatic enzymes. Its terminal is 25 to 30 days, with concentrations declining over 4 to 5 months post-dose. Clearance is nonlinear and decreases at higher doses due to target-mediated drug disposition, resulting in approximately dose-proportional exposure at therapeutic doses above 60 mg, while are nonlinear at lower doses. At the standard osteoporosis treatment regimen of 60 mg every 6 months, denosumab does not accumulate, and pharmacokinetics remain consistent with repeated dosing. Pharmacokinetics of denosumab are similar across men, postmenopausal women, and patients with bone metastases from solid tumors, with no notable differences based on age (28 to 87 years), race, or body weight (36 to 140 kg). No dose adjustment is required for renal impairment, as the degree of impairment does not affect pharmacokinetics; hepatic impairment studies have not been conducted, but adjustment is not anticipated given the drug's elimination pathway.

Contraindications and interactions

Contraindications

Denosumab is contraindicated in patients with pre-existing that has not been corrected prior to initiating therapy, as the drug can exacerbate this condition and lead to severe symptomatic , including a for potentially fatal cases in patients with advanced (eGFR <30 mL/min/1.73 m²), particularly those on . It is also contraindicated in individuals with a history of systemic reactions to denosumab or any of its excipients, including cases of , , dyspnea, throat tightness, facial and upper airway , lip swelling, , pruritus, and urticaria. For the indication (Prolia formulation), denosumab is contraindicated during due to the risk of fetal harm; women of reproductive potential should undergo pregnancy testing prior to initiation and use effective contraception during treatment and for at least 5 months after the last dose. Relative contraindications include unhealed lesions in the or planned invasive dental procedures, particularly in patients receiving the formulation (Xgeva), due to the elevated risk of ; a complete dental examination and appropriate preventive are recommended before starting in such cases. Severe renal (creatinine clearance <30 mL/min or receiving ) is a relative without close monitoring, as these patients face a higher risk of severe following administration, though no dose adjustment is required. A history of atypical femoral fractures may warrant caution, as denosumab has been associated with such events, and therapy should be evaluated carefully in at-risk individuals. Prior to initiating denosumab, must be corrected to levels above the lower limit of normal, with supplementation of calcium, , and magnesium as needed; serum calcium should be monitored closely, especially in the first weeks of therapy. For oncology patients, a dental is essential to assess and mitigate risks of . Denosumab is not recommended in pediatric patients with open growth plates due to potential impairment of bone growth and abnormal growth plate histology observed in animal studies; it is not approved for pediatric use in the osteoporosis indication and is limited to skeletally mature adolescents (aged 12 years and older) for giant cell tumor of bone.

Drug interactions

Denosumab exhibits minimal pharmacokinetic interactions with other medications due to its lack of involvement with (CYP450) enzymes. Clinical studies have shown no significant alterations in the of , a substrate, when co-administered with denosumab in postmenopausal women with , indicating that denosumab does not affect the of drugs primarily cleared via pathways. Similarly, no clinically meaningful changes in etanercept were observed following a single subcutaneous dose of denosumab in postmenopausal women with and low bone mineral density, suggesting limited impact on other biologic agents. In patients receiving anticancer therapies, such as or , or those with prior intravenous exposure, denosumab systemic exposure and pharmacodynamic effects (e.g., reductions in urinary N-telopeptide/) remained consistent, with no evidence of interference. Pharmacodynamic interactions with denosumab primarily involve additive effects on calcium . Concomitant use with agents that lower serum calcium levels or other calcium-lowering drugs can exacerbate risk due to enhanced suppression of and increased urinary calcium excretion. , in particular, have been associated with a higher incidence of denosumab-induced in patients with , as demonstrated in analyses. Additionally, calcimimetics like , which lower and serum calcium, may worsen when combined with denosumab, especially in patients with advanced (eGFR <30 mL/min/1.73 m²). To mitigate hypocalcemia risks, co-administration of calcium (at least 1000 mg daily) and (at least 400 IU daily) is mandatory for all patients receiving denosumab, with supplementation assessed and optimized prior to initiation. Concomitant use with calcimimetics should be avoided if possible, or closely monitored in high-risk populations. In settings, denosumab increases the risk of (ONJ) when used alongside or antiangiogenic agents like , as these therapies compound vascular and bone remodeling disruptions; prior intravenous use is a noted for ONJ development. Monitoring recommendations emphasize calcium assessment before initiating denosumab and approximately two weeks after each dose in at-risk patients, such as those with renal impairment, receiving concomitant hypocalcemia-inducing therapies, or inadequate supplementation; more frequent (e.g., weekly initially) is advised for advanced patients. Pre-existing must be corrected prior to starting therapy to prevent severe complications.

Adverse effects

Common adverse effects

Denosumab is generally well-tolerated, with common adverse effects primarily involving the musculoskeletal system. In clinical trials for treatment, such as the FREEDOM trial involving postmenopausal women, was reported in approximately 35% of patients receiving denosumab, compared to a similar rate in the group. occurred in about 20% of patients, and pain in the extremities in 13%. These events were typically mild to moderate and did not differ significantly from placebo in terms of overall incidence or severity. General adverse effects are also frequent but comparable to . Nasopharyngitis affected around 10% of patients, 8%, and 5% in trials. Dermatologic reactions, including eczema and , each occurred in approximately 3% of patients, with eczema showing a slight increase over (3.0% vs. 1.7%). In patients with cancer-related bone conditions treated with denosumab (Xgeva formulation), musculoskeletal events are more prevalent, affecting about 50% of individuals, often due to underlying disease progression alongside treatment. Common events include (13%), (11%), and pain in extremity (11%), which are similar to comparator therapies like . These common adverse effects are managed symptomatically with analgesics, rest, or topical treatments as appropriate, and rarely require discontinuation of denosumab. may present as a common abnormality, particularly in patients with risk factors, and is typically addressed with calcium and supplementation.

Serious adverse effects

Denosumab, a that inhibits , carries several serious adverse effects, primarily related to its potent suppression of and immune modulation. These risks, though infrequent, can lead to significant morbidity and require careful monitoring and preventive measures. Hypocalcemia is a notable risk, occurring in approximately 2-10% of patients, with severe cases ( calcium <1.7 mmol/L) reported in up to 1% of treated individuals, particularly those with . The FDA issued a black box warning in January 2024 highlighting the increased risk of severe, symptomatic, or fatal in patients with advanced (stage 4 or 5), where incidence can reach 41% compared to 2% with oral bisphosphonates. with calcium and is essential, and calcium levels should be monitored closely, especially within two weeks of administration and in patients with creatinine clearance <30 mL/min. Osteonecrosis of the jaw (ONJ) develops in 0.04-2% of patients treated for and up to 2% in those with cancer, with cumulative incidence rising to 11.6% after prolonged denosumab exposure in settings. Risk factors include invasive dental procedures, poor , , and concomitant use, which can exacerbate the condition by impairing vascular supply and . Preventive strategies involve a baseline dental evaluation prior to initiation and avoidance of elective oral during ; if ONJ occurs, denosumab should be discontinued and pursued. Atypical femoral fractures, typically subtrochanteric or diaphyseal, occur in less than 1% of patients, with an estimated incidence of 0.8 per 10,000 patient-years, and are linked to prolonged use exceeding three years due to oversuppression of . These fractures often present with prodromal thigh or pain, and bilateral involvement is common; patients should be evaluated promptly for such symptoms, and reassessed if confirmed. Serious infections arise in 4-8% of patients, potentially stemming from RANKL's role in immune function, including T-cell and survival. Common manifestations include , urinary tract infections, and , with serious infections, including skin infections, reported more frequently than in groups (4.0% vs. 3.3%). Patients with compromised immunity should be monitored for signs of , and prompt treatment initiated to mitigate complications. Discontinuation of denosumab leads to a characterized by rapid bone turnover resurgence, resulting in accelerated bone loss and an elevated risk of multiple vertebral fractures (up to 15% within 18 months). This phenomenon, observed in 3-10% of cases post-cessation, underscores the need for sequential antiresorptive therapy, such as bisphosphonates, to bridge the gap and prevent fractures. Other rare serious effects include dermatologic reactions such as Stevens-Johnson syndrome, with incidence below 0.1% based on and case reports, often requiring immediate discontinuation. Denosumab is contraindicated in due to teratogenic effects observed in , including increased fetal loss, stillbirths, and developmental abnormalities; women of reproductive potential must use effective contraception during treatment and for at least five months thereafter.

Society and culture

Development and history

Denosumab, developed by as the first biologic targeting , originated from research into the -RANK-RANKL pathway in the early . scientists identified OPG through DNA sequencing of a fetal rat intestine , revealing its role as a decoy receptor that inhibits formation and activity. Preclinical studies during the demonstrated that RANKL inhibition reduced numbers and increased in animal models, including transgenic mice overexpressing OPG, paving the way for antibody-based therapies. The first human dose of denosumab (then AMG 162), a fully generated using XenoMouse technology, was administered in 2001. Pivotal clinical development advanced through phase III trials, including the study published in 2009, which evaluated denosumab's efficacy in postmenopausal women with over three years. In parallel, phase III oncology trials reported in 2010 demonstrated denosumab's superiority to in delaying skeletal-related events (SREs) in patients with bone metastases from solid tumors, including . Regulatory milestones began with U.S. (FDA) approval of denosumab as Prolia (60 mg every six months) on June 1, 2010, for postmenopausal at high fracture risk, followed by approval as Xgeva (120 mg every four weeks) on November 18, 2010, for SRE prevention in bone metastases. In the , the authorized Prolia on May 26, 2010, and Xgeva on July 13, 2011. Expanded indications included FDA approval for in June 2013 and European approval for glucocorticoid-induced in June 2018. Post-approval research included long-term extension studies of the FREEDOM trial, with data up to 10 years of continuous denosumab treatment presented in 2016, confirming sustained bone mineral density gains and low fracture rates. development has been accelerated by expirations, including key U.S. protections ending February 19, 2025, and earlier European expirations in 2022 for most markets. Amgen entered a collaboration with GlaxoSmithKline in July 2009 to co-commercialize denosumab for postmenopausal in and select other regions, while retaining full rights in the U.S., , and for indications. The partnership was terminated in 2014, with regaining full commercialization rights by 2015.

Brand names and formulations

Denosumab is commercially available under the primary brand names Prolia and Xgeva, both developed by . Prolia is supplied as a sterile, preservative-free, clear, colorless to slightly yellow containing 60 mg of denosumab in 1 mL volume, packaged in a single-use prefilled for , and is indicated for treatment. Xgeva is formulated as a similar sterile, preservative-free with 120 mg of denosumab in 1.7 mL (70 mg/mL), provided in a single-use for subcutaneous injection, targeting oncology-related conditions. The formulations of both Prolia and Xgeva include the active ingredient denosumab, a human IgG2 , along with excipients such as 4.7% (Prolia) or 4.6% (Xgeva), acetate buffer (17 mM for Prolia, 18 mM for Xgeva), 0.01% , , and to adjust to 5.2. These single-use presentations are designed for direct subcutaneous delivery without dilution, ensuring stability and ease of administration by healthcare providers. Biosimilars to denosumab have entered the market, offering equivalent formulations to the reference products. In 2024, received approval for Jubbonti (interchangeable with Prolia) and Wyost (interchangeable with Xgeva) in both the and , featuring identical solution compositions, strengths, and delivery devices as the originators. Additional approvals followed in 2025, including Ospomyv and Stoboclo in the for and uses, respectively, and Obodence and Xbryk in the , all maintaining the same profiles, , and single-use or formats without differences from the reference formulations. By late 2025, over 10 biosimilars were approved in the . All denosumab products, including originators and biosimilars, require storage under refrigeration at 2°C to 8°C (36°F to 46°F) in their original carton to protect from light, with instructions to avoid freezing and vigorous shaking. Once removed from refrigeration, they can be kept at controlled up to 25°C (77°F) for a maximum of 14 days prior to use, after which any unused portion must be discarded. Denosumab is accessible globally through these originator and options, though regional availability varies depending on local regulatory authorizations and market entry timelines.

Legal status

Denosumab, marketed as Prolia and Xgeva, received initial approval from the (FDA) in 2010, with Prolia authorized on June 1 for treatment and Xgeva on November 18 for bone metastasis-related events. In January 2024, the FDA added a warning to Prolia's labeling regarding the increased risk of severe in patients with advanced . The first denosumab , Jubbonti and Wyost, were approved by the FDA in March 2024 as interchangeable products for all reference indications. Additional followed in 2025, including Stoboclo and Osenvelt in February, Enoby in September, and others such as Bildyos and Bosaya later that year, expanding options for and cancer-related bone conditions. By late 2025, over 10 were approved in the . In the United States, denosumab requires a prescription and is covered under Part B for physician-administered doses or Part D for self-administration, subject to medical necessity criteria. In the , the () authorized Prolia in May 2010 for postmenopausal and Xgeva on July 13, 2011, for skeletal-related events in cancer patients, with centralized marketing authorization valid across member states. Biosimilars Jubbonti and Wyost received approval in May 2024, followed by approvals in 2025 for products including Obodence, Xbryk, Jubereq, and Osvyrti, all referencing the originator for similar indications. By September 2025, the had recommended over 20 denosumab biosimilars. Reimbursement varies by systems, with centralized approval facilitating but not guaranteeing uniform access. Health Canada approved denosumab in 2011 for and indications, with biosimilars Jubbonti and Wyost authorized in February 2024. Coverage is available under provincial public drug plans, typically requiring for eligible patients. Denosumab was approved in in March 2013 for under the brand Praria and in in 2011 by the for similar uses. Biosimilars are emerging in , including Henlius's HLX14, approved in the United States in September 2025 and advancing in regional markets. In , it is classified as a Schedule 4 prescription-only medicine. The originator's patent exclusivity for denosumab expired in major markets between 2024 and 2025, enabling over 10 biosimilars globally by late 2025, primarily targeting high-burden indications like and .