What are the side effects of Jubbonti (denosumab)?

Side Effects of Jubbonti (Denosumab)

Denosumab causes common musculoskeletal symptoms in 10-14% of patients and carries serious risks including osteonecrosis of the jaw, atypical femoral fractures, hypocalcemia, and a critical rebound fracture risk if discontinued abruptly. 1

Common Side Effects (Occurring in ≥10% of Patients)

Musculoskeletal symptoms are the most frequent adverse effects:

• Arthralgia (joint pain) occurs in 13-14.3% of patients 1, 2
• Back pain affects 10.5-11.5% of patients 1, 2
• Extremity pain and muscle pain occur in 10-14% 1
• Pain in extremity occurs in 9.9% versus 7.7% with placebo 2

Upper respiratory and infectious symptoms:

• Nasopharyngitis and common cold symptoms are frequently reported 1
• Urinary tract infections occur with increased frequency 1

Gastrointestinal effects:

• Constipation and mild upper GI symptoms occur with an odds ratio of 1.74 (95% CI 1.29-2.38) 1

Other common effects:

• Headache is reported in clinical trials 1
• Rash/eczema occurs with an odds ratio of 1.96 (95% CI 1.46-2.66) 1

Serious Adverse Effects Requiring Immediate Attention

Hypocalcemia is a critical concern that must be monitored:

• Asymptomatic hypocalcemia occurs in 2.4% of patients in clinical trials 1, 2
• Severe symptomatic hypocalcemia can result in hospitalization, life-threatening events, and fatal cases 2
• Risk is substantially higher in patients with creatinine clearance <30 mL/min 1
• Hypocalcemia is an absolute contraindication and must be corrected before starting treatment 1

Osteonecrosis of the jaw (ONJ):

• Confirmed incidence of approximately 1-2% in osteoporosis patients 1
• Eight events confirmed through 8 years of therapy in the FREEDOM extension 1
• Risk increases to approximately 5% after three years of treatment 3
• Patients require oral examination before initiating therapy 4, 1
• Avoid invasive dental procedures during treatment when possible 4, 3

Atypical femoral fractures:

• Two events confirmed through 8 years in the FREEDOM extension 1
• Incidence of 3.2-50 cases per 100,000 person-years, potentially rising to 100 per 100,000 person-years with prolonged exposure 3
• Evaluate any new or unusual thigh, hip, or groin pain immediately 3

Infections:

• Moderate-quality evidence shows increased risk with relative risk of 1.26 (95% CI 1.01-1.57) 1
• Bacterial cellulitis has been reported 1
• Serious adverse events of infection occur more frequently than placebo 5
• Patients should report signs of serious infection immediately, including skin infections, fever, chills, severe abdominal pain, urinary symptoms, and respiratory symptoms 3

The Critical Rebound Phenomenon: A Unique and Dangerous Risk

Denosumab discontinuation causes rapid rebound bone turnover with a nearly 20% risk of multiple vertebral fractures—this is the most dangerous aspect of denosumab therapy. 6, 7

• Denosumab does not bind to bone matrix, so its effects reverse rapidly after the last injection 3, 6
• Rebound increase in bone turnover occurs within 7-19 months of discontinuation 3, 6
• Multiple vertebral fractures can occur as early as 7 months (average ≈19 months) after the final dose 3, 2
• Never discontinue denosumab without immediately planning transition to bisphosphonate therapy 3, 8
• If denosumab must be stopped, immediate transition to high-dose bisphosphonate (zoledronic acid 5 mg IV) is mandatory within 6-7 months of last dose 3, 7
• Do not apply bisphosphonate "drug holiday" concepts to denosumab—the pharmacology is fundamentally different 3

Special Population Considerations

Renal impairment patients:

• No dose adjustment needed, but hypocalcemia risk is substantially higher with CrCl <30 mL/min 1
• More frequent calcium monitoring is required in severe renal impairment 1
• Denosumab does not require monitoring of renal function unlike bisphosphonates 4
• Marked elevation in serum PTH can occur in patients with severe renal impairment or receiving dialysis 2

Cancer patients receiving hormonal therapy:

• Higher incidence of cataracts: 4.7% versus 1.2% placebo in men receiving androgen deprivation therapy 1, 2

Rare but Documented Postmarketing Adverse Reactions

The FDA label documents additional serious reactions reported after approval 2:

• Anaphylaxis, rash, urticaria, facial swelling, and erythema (drug-related hypersensitivity)
• Severe musculoskeletal pain requiring discontinuation
• Cutaneous and mucosal lichenoid drug eruptions (lichen planus-like reactions)
• Alopecia (hair loss)
• Vasculitis (ANCA positive vasculitis, leukocytoclastic vasculitis)
• Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

Essential Monitoring Requirements

Before starting treatment:

• Verify pregnancy status in females of reproductive potential 2
• Correct hypocalcemia before first dose 1
• Obtain comprehensive dental examination 4, 1, 3
• Check serum calcium and vitamin D levels 1

During treatment:

• Monitor serum calcium regularly, especially in first month and in patients with renal impairment 1, 3
• Ensure adequate calcium (≥1000 mg daily) and vitamin D (≥400-800 IU daily) supplementation 1, 3
• Annual dental examination to detect early signs of ONJ 3
• Query patients for new thigh, hip, or groin pain at each visit 3
• Watch for signs of infection, jaw pain, swelling, numbness, loose teeth, or non-healing sores 3
• Assess for severe bone, joint, or muscle pain that may require discontinuation 3

Critical Pitfalls to Avoid

• Never stop denosumab abruptly without transition therapy—this can result in catastrophic multiple vertebral fractures 3, 8, 6
• Do not start denosumab in patients with uncorrected hypocalcemia 1
• Do not allow patients to undergo invasive dental procedures without careful risk-benefit assessment during treatment 4, 3
• Do not fail to ensure adequate calcium and vitamin D supplementation before and during treatment 1, 3
• Do not ignore new thigh, hip, or groin pain—evaluate immediately for atypical femoral fracture 3