What is denosumab?

What is Denosumab?

Denosumab is a fully human monoclonal IgG2 antibody that specifically binds to and inhibits RANKL (receptor activator of nuclear factor kappa-B ligand), thereby preventing osteoclast formation, function, and survival, which reduces bone resorption and increases bone mass and strength. 1

Mechanism of Action

• Denosumab binds to RANKL, a transmembrane or soluble protein essential for osteoclast biology, preventing RANKL from activating its receptor (RANK) on osteoclast surfaces and their precursors 1
• This inhibition blocks osteoclast differentiation, activation, and survival, thereby decreasing bone resorption while increasing both cortical and trabecular bone mass and strength 1
• The drug has an approximate molecular weight of 147 kDa and is produced in genetically engineered Chinese hamster ovary cells 1

Pharmacodynamics and Clinical Effects

• Treatment with 60 mg denosumab reduces the bone resorption marker serum CTX by approximately 85% within 3 days, with maximal reductions at 1 month 1
• CTX levels fall below the limit of quantitation in 39-68% of patients 1-3 months after dosing 1
• The effects are reversible: at the end of each dosing interval, CTX reductions attenuate from ≥87% to ≥45% as serum denosumab levels diminish 1
• Bone formation markers (osteocalcin and P1NP) subsequently decrease starting 1 month after the first dose, reflecting the physiological coupling of bone formation and resorption 1

Clinical Indications

Giant Cell Tumor of Bone (GCTB)

• Denosumab is indicated where surgery is not possible or unacceptably morbid and in patients with metastases from GCTB 2
• In a phase II study of 35 patients with recurrent or unresectable GCTB, 86% had tumor response with near complete elimination of giant cells or radiological stabilization at 6 months 2
• 26 of 31 evaluable patients reported reduced pain or improved functional status, with nine demonstrating bone repair 2
• The FDA and EMA granted marketing authorization for denosumab in GCTB in July 2011 2
• Denosumab is also used preoperatively in selected cases to solidify the soft tissue component, facilitating surgical resection and reducing recurrence risk 2
• Complete resection is usually preferred after denosumab treatment because curettage after denosumab is difficult and associated with higher local recurrence risk 2

Bone Metastases from Solid Tumors

• Denosumab is approved for prevention of skeletal-related events in patients with bone metastases from solid tumors 2
• In breast cancer and prostate cancer studies, denosumab was superior to zoledronic acid in delaying time to first skeletal-related event 3, 4
• In other solid tumors (excluding breast and prostate cancer), denosumab was non-inferior but not superior to zoledronic acid 3

Cancer Treatment-Induced Bone Loss

• Denosumab significantly reduces clinical fracture risk by 50% in breast cancer patients and 62% in non-metastatic prostate cancer patients receiving hormonal therapy 3
• In men receiving androgen deprivation therapy for prostate cancer, denosumab increased BMD by 6.7% at lumbar spine and 4.8% at total hip over 36 months 5

Dosing and Administration

For GCTB

• Denosumab is given as a monthly subcutaneous injection after three loading doses at weekly intervals 2
• Patients with metastatic disease may require life-long treatment 2
• Retrospective studies suggest intervals can be extended from 4-weekly to 8-weekly in patients with stable disease after 2 years of treatment 2

For Osteoporosis

• The standard dose is 60 mg subcutaneously every 6 months 1
• Median time to maximum concentration is 10 days (range: 3-21 days) 1
• Mean half-life is 25.4 days with no accumulation observed with multiple dosing 1

Essential Supportive Care

• All patients require daily calcium and vitamin D supplements throughout treatment 2, 5
• Recommended daily intake is 1,000 mg calcium and 600 IU vitamin D 6
• Adequate supplementation is crucial to prevent hypocalcemia and support bone mineralization 5
• Patients must avoid pregnancy by using adequate contraception 2

Critical Safety Considerations

Hypocalcemia Risk

• Severe hypocalcemia resulting in hospitalization, life-threatening events, and fatal cases have been reported postmarketing 1
• Patients with advanced chronic kidney disease (eGFR < 30 mL/min/1.73 m²), including dialysis-dependent patients, are at greater risk 1
• The presence of chronic kidney disease-mineral bone disorder markedly increases hypocalcemia risk 1
• Concomitant use of calcimimetic drugs may worsen hypocalcemia risk 1

Rebound Effect Upon Discontinuation

• Discontinuation of denosumab without follow-up antiresorptive therapy leads to rapid bone loss and increased fracture risk 5
• After discontinuation, bone resorption markers increase to levels 40-60% above pretreatment values but return to baseline within 12 months 1
• The rebound effect is associated with marked increase in vertebral fracture risk and hypercalcemia 6
• Bisphosphonate treatment is recommended if denosumab is discontinued for more than 6 months to suppress rebound osteolysis 2

Dental Considerations

• Patients should have a dental evaluation and complete invasive dental treatments before initiating denosumab 2
• Osteonecrosis of the jaw is a potential side effect requiring monitoring 2

Pediatric and Adolescent Populations

• The American College of Rheumatology guidelines recommend against denosumab in children ages 4-17 years with glucocorticoid-induced osteoporosis; oral bisphosphonates are preferred 6
• Pediatric safety and efficacy data are extremely limited with very low-grade evidence 6
• Adolescent primates treated with denosumab at 10-50 times the human dose had abnormal growth plates 1
• Denosumab is contraindicated in organ transplant recipients on multiple immunosuppressive agents due to lack of adequate safety data on infections 6

Special Populations

• No dose adjustment is necessary in patients with renal impairment, but careful monitoring is required 1
• No overall differences in safety or efficacy were observed between elderly (≥65 years) and younger patients 1

Important Contraindications and Limitations

• Patients with malignant giant cell tumors of bone do not benefit from denosumab 2
• Denosumab is not indicated in patients with bone metastases who have increased baseline risk of osteosarcoma, such as those with Paget's disease, open epiphyses, or prior skeletal radiation 2
• The drug should not be used in patients with pre-existing hypocalcemia 1