Denosumab - Drug Monograph

Introduction

Denosumab is a fully human monoclonal antibody that specifically targets receptor activator of nuclear factor kappa-B ligand (RANKL), a key mediator of osteoclast formation, function, and survival. Marketed under the brand names Prolia® and Xgeva®, denosumab represents a significant advancement in the treatment of bone-related disorders, offering a targeted approach to bone metabolism regulation.

Mechanism of Action

Denosumab binds with high affinity and specificity to RANKL, preventing its interaction with RANK (receptor activator of nuclear factor kappa-B) on osteoclasts and osteoclast precursors. This inhibition prevents osteoclast formation, function, and survival, thereby reducing bone resorption and increasing bone mass and strength. Unlike bisphosphonates, denosumab does not incorporate into bone matrix and its effects are reversible upon discontinuation.

Indications

• Treatment of postmenopausal women with osteoporosis at high risk for fracture (Prolia® 60 mg every 6 months)
• Treatment to increase bone mass in men with osteoporosis at high risk for fracture (Prolia®)
• Treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture (Prolia®)
• Prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva® 120 mg every 4 weeks)
• Treatment of giant cell tumor of bone in skeletally mature adults and adolescents (Xgeva®)
• Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy (Xgeva®)

Dosage and Administration

• 60 mg administered subcutaneously every 6 months
• Administer in the upper arm, abdomen, or thigh

• 120 mg administered subcutaneously every 4 weeks
• Administer in the upper arm, abdomen, or thigh

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: No dosage adjustment necessary
• Elderly: No dosage adjustment necessary

• Ensure adequate calcium and vitamin D supplementation
• Administer by healthcare professional
• Rotate injection sites

Pharmacokinetics

Contraindications

• Hypersensitivity to denosumab or any component of the formulation
• Pre-existing hypocalcemia (must be corrected prior to initiation)
• Pregnancy (category X)
• Dental procedures requiring invasive dental work (relative contraindication due to osteonecrosis of jaw risk)

Warnings and Precautions

• Hypocalcemia: Correct pre-existing hypocalcemia before initiation
• Osteonecrosis of the jaw: Reported incidence 1-2% in cancer patients
• Atypical femoral fractures: Rare but serious complications

• Serious infections: Increased risk of skin infections
• Dermatologic reactions: Including dermatitis, eczema, and rash
• Suppression of bone turnover: Monitor for oversuppression
• Multiple vertebral fractures after discontinuation: Implement transition therapy

Drug Interactions

• Immunosuppressants: Increased risk of serious infections
• Bisphosphonates: Avoid concomitant use (no clinical data)
• Calcium-lowering medications: Enhanced hypocalcemia risk
• Live vaccines: Avoid administration during treatment

Adverse Effects

• Arthralgia (15%)
• Back pain (12%)
• Pain in extremity (11%)
• Hypercholesterolemia (10%)
• Cystitis (10%)

• Hypocalcemia (1-3%)
• Serious infections (0.3-0.4%)
• Osteonecrosis of the jaw (0.7-1.9% in cancer patients)
• Atypical femoral fractures (<0.1%)
• Multiple vertebral fractures after discontinuation

Monitoring Parameters

• Serum calcium and vitamin D levels
• Renal function
• Dental examination
• Bone mineral density (if indicated)

• Serum calcium levels (within 2 weeks after initial dose)
• Vitamin D status (regular assessment)
• Signs/symptoms of hypocalcemia
• Dental health monitoring
• Bone turnover markers (if indicated)
• Signs of infection

• Bone mineral density (every 1-2 years)
• Renal function (annually)
• Adverse effect profile

Patient Education

• Importance of calcium and vitamin D supplementation
• Recognition of hypocalcemia symptoms (muscle spasms, numbness, seizures)
• Need for regular dental check-ups and good oral hygiene
• Report any thigh or groin pain (possible femoral fracture)
• Awareness of infection signs (fever, chills, skin redness)
• Understanding treatment duration and potential need for transition therapy
• Do not stop treatment without medical supervision
• Injection site care and rotation

• Regular weight-bearing exercise
• Smoking cessation
• Moderate alcohol consumption
• Fall prevention strategies

References

1. Cummings SR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765. 2. Smith MR, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer. N Engl J Med. 2012;367(13):1187-1197. 3. FDA Prescribing Information: Prolia® (denosumab) Injection. Amgen Inc. 2023. 4. FDA Prescribing Information: Xgeva® (denosumab) Injection. Amgen Inc. 2023. 5. Bone HG, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2017;102(5):1553-1561. 6. McClung MR, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821-831. 7. Saag KG, et al. Denosumab versus risedronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2018;379(11):1047-1057. 8. Lacey DL, et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11(5):401-419.