Introduction to Denosumab

Denosumab is a fully human monoclonal antibody that targets and inhibits RANKL (Receptor Activator of Nuclear Factor Kappa-B Ligand). It was first approved by the FDA in 2010 under the trade names Prolia and Xgeva.

• Class: RANKL inhibitor
• Type: IgG2 monoclonal antibody
• Half-life: Approximately 25-30 days
• Route of administration: Subcutaneous injection

In pediatrics, denosumab has emerging uses in treating rare bone disorders and certain oncological conditions, although its use remains off-label for many pediatric indications.

Mechanism of Action

Denosumab exerts its effects through the following mechanisms:

1. Binding to RANKL with high affinity and specificity
2. Preventing RANKL from activating its receptor, RANK, on the surface of osteoclasts and osteoclast precursors
3. Inhibiting osteoclast formation, function, and survival
4. Decreasing bone resorption and increasing bone mass and strength

This mechanism is crucial in conditions characterized by increased bone turnover, such as osteoporosis and certain bone metastases.

In the RANK-RANKL-OPG system:

• RANK: Receptor on osteoclasts
• RANKL: Ligand produced by osteoblasts and other cells
• OPG (Osteoprotegerin): Natural inhibitor of RANKL
• Denosumab acts as an artificial OPG, mimicking its effects

Indications

FDA-approved indications (primarily in adults):

• Treatment of postmenopausal women with osteoporosis at high risk for fracture
• Prevention of skeletal-related events in patients with bone metastases from solid tumors
• Treatment of giant cell tumor of bone
• Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy

Emerging pediatric uses (off-label):

• Osteogenesis imperfecta
• Fibrous dysplasia
• Aneurysmal bone cysts
• Juvenile Paget's disease
• Cherubism
• Giant cell tumor of bone in skeletally immature patients

The use of denosumab in pediatric populations is an area of ongoing research, with several clinical trials underway to establish its safety and efficacy in various bone disorders.

Dosage and Administration

Dosing in pediatrics is not well established and varies based on the condition being treated. The following are general guidelines based on limited studies and expert opinion:

Condition	Dosage	Frequency
Osteogenesis Imperfecta	1 mg/kg (max 60 mg)	Every 3 months
Giant Cell Tumor of Bone	120 mg	Every 4 weeks, with additional 120 mg doses on days 8 and 15 of the first month
Fibrous Dysplasia	1 mg/kg (max 60 mg)	Every 6 months

Administration:

• Given as a subcutaneous injection
• Common injection sites: upper arm, upper thigh, or abdomen
• Rotate injection sites to prevent lipoatrophy
• Supplementation with calcium and vitamin D is typically required

Adverse Effects

Common adverse effects (incidence ≥ 5%):

• Back pain
• Pain in extremity
• Musculoskeletal pain
• Hypercholesterolemia
• Cystitis

Serious adverse effects:

• Hypocalcemia: Can be severe and life-threatening, especially in patients with renal impairment
• Osteonecrosis of the jaw: Rare but serious, risk factors include poor oral hygiene and invasive dental procedures
• Atypical femoral fractures: Long-term use may increase risk
• Serious infections: Cellulitis reported more frequently in denosumab group in clinical trials
• Dermatologic reactions: Dermatitis, rashes, and eczema

Pediatric-specific concerns:

• Growth and development: Potential effects on skeletal maturation and dentition in growing children
• Rebound effect: Rapid bone loss and increased fracture risk upon discontinuation

Precautions and Contraindications

Contraindications:

• Hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating denosumab
• Known hypersensitivity to denosumab or any of its components

Precautions:

• Hypocalcemia: Monitor calcium levels, especially in patients with renal impairment
• Vitamin D deficiency: Correct before initiating therapy
• Osteonecrosis of the jaw: Assess for risk factors and consider dental examination prior to treatment
• Atypical femoral fractures: Monitor for new or unusual thigh, hip, or groin pain
• Serious infections: Use with caution in patients with immunosuppression
• Multiple vertebral fractures following discontinuation: May occur, especially in patients with a history of vertebral fracture
• Pregnancy: Limited human data; animal studies show fetal harm
• Lactation: No data on presence in human milk; consider developmental and health benefits of breastfeeding

Clinical Pearls

• Denosumab is not recommended for use in pediatric patients with growing skeletons due to the potential for interference with bone growth and development
• The effects of denosumab are rapidly reversible upon discontinuation, which can lead to a rebound increase in bone turnover and potential increased fracture risk
• Calcium and vitamin D supplementation is crucial during denosumab therapy to prevent hypocalcemia
• In pediatric patients with osteogenesis imperfecta, denosumab has shown promise in improving bone mineral density and reducing fracture rates
• The optimal duration of denosumab therapy in pediatric patients is not well established and requires careful consideration of risks and benefits
• Monitoring of bone turnover markers (e.g., serum CTX) can be helpful in assessing the response to therapy
• In giant cell tumor of bone, denosumab may be used as neoadjuvant therapy to reduce tumor size before surgery