What are the side effects of Prolia (denosumab)?

Prolia (Denosumab) Side Effects

Prolia causes several common side effects including musculoskeletal pain (10-14%), upper respiratory infections, and gastrointestinal symptoms, but the most critical risks requiring monitoring are severe hypocalcemia (especially in renal impairment), osteonecrosis of the jaw, atypical femoral fractures, serious infections, and rebound vertebral fractures after discontinuation. 1, 2

Common Side Effects

The most frequently reported adverse effects include:

• Musculoskeletal symptoms occur in 10-14% of patients, manifesting as arthralgia, back pain, extremity pain, and muscle pain 1, 2
• Upper respiratory infections including nasopharyngitis and common cold symptoms are commonly reported 1
• Gastrointestinal symptoms particularly constipation and mild upper GI symptoms (odds ratio 1.74,95% CI 1.29-2.38) 1
• Dermatologic reactions including rash and eczema occur with an odds ratio of 1.96 (95% CI 1.46-2.66) 1
• Urinary tract infections and headache are also reported 1

Critical Adverse Effects Requiring Immediate Attention

Hypocalcemia

Hypocalcemia represents the most dangerous metabolic complication and is an absolute contraindication if present before treatment. 1, 2

• Asymptomatic hypocalcemia occurs in 2.4% of patients in clinical trials 1
• Patients with severe renal impairment (CrCl <30 mL/min) face substantially higher risk and require more frequent calcium monitoring 1, 3
• Creatinine clearance below 50 mL/min is an independent risk factor (odds ratio 5.90) for denosumab-induced hypocalcemia 3
• Severe symptomatic hypocalcemia can result in hospitalization, life-threatening events, and fatal cases, particularly in patients with metastatic bone disease 2, 4
• Symptoms include muscle spasms, twitches, cramps, numbness or tingling in fingers/toes, or around the mouth 2
• All patients must receive adequate calcium (1000-1200 mg daily) and vitamin D (800-1000 IU daily) supplementation 1, 2

Osteonecrosis of the Jaw (ONJ)

• ONJ incidence is approximately 1-2% in osteoporosis patients 1
• Through 8 years of therapy in the FREEDOM extension, 8 confirmed events occurred 1
• Patients should undergo dental examination before starting Prolia and maintain good oral hygiene throughout treatment 2
• Notify dentist before any dental procedures that you are receiving Prolia 2
• Report persistent pain or slow healing of mouth/jaw after dental surgery immediately 2

Atypical Femoral Fractures

• Two confirmed events occurred through 8 years in the FREEDOM extension 1
• Patients must report any new or unusual thigh, hip, or groin pain immediately 2
• These fractures can occur with minimal or no trauma 2

Serious Infections

Denosumab increases infection risk, particularly in immunocompromised patients or those on concurrent immunosuppressive therapy. 1, 2

• Bacterial cellulitis and other serious infections have moderate-quality evidence for increased risk (relative risk 1.26,95% CI 1.01-1.57) 1
• Endocarditis due to infection may occur more frequently 2
• CKD patients on steroids >2.5 mg/day or multiple immunosuppressive medications face significantly increased infection risk 5
• In CKD patients with infections, 50% required hospitalization for moderate infections 5
• Seek immediate medical attention for signs of infection including cellulitis 2

Multiple Vertebral Fractures After Discontinuation

This represents one of the most critical risks: stopping Prolia abruptly dramatically increases the risk of multiple spine fractures. 1, 2

• Never interrupt Prolia therapy without consulting your physician 2
• If discontinuation is necessary, immediate transition to alternative antiresorptive therapy (such as high-dose bisphosphonate) is mandatory to prevent rebound vertebral fractures 6
• Risk is particularly elevated in patients with prior vertebral fractures 2

Serious Allergic Reactions

• Anaphylaxis, rash, urticaria, facial swelling, throat tightness, trouble breathing, and hypotension have been reported 2
• Patients with prior systemic hypersensitivity reactions to denosumab should never receive Prolia or Xgeva 2

Special Population Considerations

Renal Impairment

• No dose adjustment needed, but hypocalcemia risk is substantially higher with CrCl <30 mL/min 1
• More frequent calcium monitoring is essential in severe renal impairment 1
• Patients with chronic kidney disease-mineral bone disorder (CKD-MBD) require blood tests before starting treatment 2

Cancer Patients on Hormonal Therapy

• Patients receiving androgen deprivation therapy or aromatase inhibitors have higher cataract incidence (4.7% vs 1.2% placebo) 1

Pregnancy and Breastfeeding

• Prolia is absolutely contraindicated in pregnancy as it may cause fetal harm including increased fetal loss, stillbirths, absent lymph nodes, and abnormal bone growth 2
• Effective contraception required during treatment and for at least 5 months after last dose 2
• Do not breastfeed while taking Prolia 2

Additional Reported Adverse Effects

• Marked elevation in parathyroid hormone (PTH) in patients with severe renal impairment or on dialysis 2
• Cutaneous and mucosal lichenoid drug eruptions (lichen planus-like reactions) 2
• Alopecia 2
• Vasculitis (ANCA positive vasculitis, leukocytoclastic vasculitis) 2
• Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome 2

Critical Monitoring Requirements

• Correct hypocalcemia before initiating treatment 1, 2
• Monitor serum calcium, vitamin D levels, and dental health regularly 1
• Assess renal function for CKD-MBD before starting in kidney disease patients 1
• No routine bone density monitoring needed during treatment 1
• Ensure adequate calcium/vitamin D supplementation in all patients 1, 2

Important Drug Interaction

Prolia and Xgeva both contain denosumab—never take both medications simultaneously 2

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