What are the considerations for using Denosumab (monoclonal antibody) in adolescents?

Denosumab Treatment in Adolescents

Primary Recommendation

Denosumab should generally be avoided in adolescents due to insufficient safety data and the serious risk of life-threatening rebound hypercalcemia after discontinuation, which occurs more frequently and severely in pediatric patients than adults. 1

Evidence Quality and Regulatory Status

• The FDA label explicitly states that safety and effectiveness of denosumab have not been established in pediatric patients 2
• Pediatric data on safety and efficacy are extremely limited with a very low grade of evidence 1
• Clinical studies in pediatric patients with osteogenesis imperfecta were terminated early due to life-threatening hypercalcemia events requiring hospitalization 2

Critical Safety Concerns Specific to Adolescents

Rebound Hypercalcemia (Most Serious Risk)

• Severe, life-threatening hypercalcemia occurs 5-7 months after denosumab cessation in adolescents, often requiring hospitalization and complicated by acute kidney injury 3, 4
• Hypercalcemic crisis occurred in 14.3% of pediatric patients in one prospective study 4
• Rebound hypercalcemia is unresponsive to hyperhydration alone and requires repeated doses of calcitonin or intravenous bisphosphonates 3, 5
• Hypercalcemia can recur within 4 weeks even after initial treatment 3
• The rebound effect is associated with marked increase in vertebral fracture risk in addition to hypercalcemia 1, 6

Growth and Development Risks

• Denosumab may impair long-bone growth in children with open growth plates and inhibit tooth eruption 2
• Animal studies show abnormal growth plates in adolescent primates at doses 10-50 times the human dose 2
• Neonatal animal studies demonstrated inhibition of bone growth and tooth eruption 2

Osteonecrosis of the Jaw

• ONJ has been reported in adolescents treated with denosumab, requiring surgical debridement 3
• This complication was previously thought not to occur in pediatric populations 1

Limited Indications Where Use May Be Considered

Giant Cell Tumor of Bone

• FDA-approved for "skeletally mature" adolescents with giant cell tumor of bone 3
• Fixed dosing is problematic—weight-adjusted dosing should be used in young people 3

Severe Osteoclast Bone Dysplasias

• Case reports show efficacy in central giant cell granuloma, aneurysmal bone cyst, and cherubism 5, 7
• Rapid clinical improvement occurs within 1 month, including pain reduction and sclerosis of lytic lesions 5

Severe Disuse Osteoporosis

• One case report showed 19% increase in BMD after single dose in spinal muscular atrophy 8

Contraindications in Adolescents

The 2017 American College of Rheumatology guidelines explicitly recommend against denosumab in specific pediatric populations:

• Children ages 4-17 years with glucocorticoid-induced osteoporosis should receive oral bisphosphonates, NOT denosumab 1
• Organ transplant recipients on multiple immunosuppressive agents should NOT receive denosumab due to lack of adequate safety data on infections 1

Management Protocol If Denosumab Must Be Used

Dosing Strategy

• Avoid fixed dosing—use weight-adjusted dosing in adolescents 3
• Consider progressive spacing of doses (lengthening intervals from 1 to 4 months) before cessation to prevent rebound hypercalcemia 5

Monitoring Requirements

• Monitor serum calcium, phosphorus, and magnesium closely during treatment 2
• Hypocalcemia (CTCAE grade 2) and hypophosphatemia occur within 1 month of initiating therapy 5
• Ensure adequate calcium (1,000 mg/day) and vitamin D (600 IU/day) supplementation 1, 2

Discontinuation Strategy

• Transition to bisphosphonate therapy before stopping denosumab to prevent rebound hypercalcemia 6, 4
• Zoledronic acid has been shown to alleviate rebound hypercalcemia when given after denosumab 4
• Monitor for hypercalcemia for at least 7 months after last dose 3

Preferred Alternative: Bisphosphonates

For adolescents requiring bone-targeted therapy, oral bisphosphonates are preferred over denosumab due to:

• Moderate-quality evidence of low harms in children 1
• Established safety profile in pediatric populations 1
• No rebound hypercalcemia risk 1

Intravenous bisphosphonates should be used if oral treatment is contraindicated 1

Key Clinical Pitfalls

• Do not use fixed adult dosing (60 mg every 6 months) in adolescents—this leads to excessive drug exposure relative to body weight 3
• Do not abruptly discontinue denosumab—this precipitates severe rebound hypercalcemia 3, 4, 5
• Do not assume safety data from adults applies to adolescents—bone turnover is higher in growing children, making complications more frequent and severe 7
• Do not use in children under 4 years of age—risk of impaired long-bone growth and dentition 2