What are the main side effects of Prolia (denosumab)?

Main Side Effects of Prolia (Denosumab)

The most common side effects of Prolia include musculoskeletal pain (back pain, joint pain, extremity pain in 10-14% of patients), upper respiratory infections, and gastrointestinal symptoms, while serious adverse effects requiring vigilant monitoring include hypocalcemia (particularly in patients with renal impairment), osteonecrosis of the jaw, atypical femoral fractures, and a critical risk of multiple vertebral fractures after discontinuation. 1, 2

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

Musculoskeletal Symptoms

• Back pain is the most frequently reported side effect across all treatment populations 1, 2
• Joint pain (arthralgia) occurs in 13-14.3% of patients receiving Prolia 1, 2
• Extremity pain and muscle pain affect 10-14% of patients 1, 2

Infectious Complications

• Upper respiratory tract infections, including nasopharyngitis and common cold symptoms, are commonly reported 1
• Urinary tract infections occur with notable frequency 1

Other Common Effects

• Gastrointestinal symptoms, particularly constipation, occur with an odds ratio of 1.74 (95% CI 1.29-2.38) 1
• Headache is reported across treatment populations 1, 2
• Rash and eczema occur with an odds ratio of 1.96 (95% CI 1.46-2.66) 1, 3
• High cholesterol is noted in postmenopausal women treated for osteoporosis 2

Serious Adverse Effects Requiring Immediate Medical Attention

Hypocalcemia (Most Critical Monitoring Priority)

• Asymptomatic hypocalcemia occurs in 2.4% of patients in clinical trials 1
• Severe symptomatic hypocalcemia can result in hospitalization, life-threatening events, and fatal cases, particularly in patients with advanced chronic kidney disease (CrCl <30 mL/min) 2
• Symptoms include muscle spasms, twitches, cramps, numbness or tingling in fingers/toes, or around the mouth 2
• Hypocalcemia is an absolute contraindication and must be corrected before initiating treatment 1, 4

Osteonecrosis of the Jaw (ONJ)

• Confirmed incidence of approximately 1-2% in osteoporosis patients, with 8 confirmed events through 8 years in the FREEDOM extension trial 1
• Mandatory baseline dental examination is required before starting therapy 1, 4, 5
• Patients should maintain good oral hygiene and inform dentists they are receiving Prolia before any dental procedures 2

Atypical Femoral Fractures

• Rare but serious complication with 2 confirmed events through 8 years in the FREEDOM extension 1
• Patients should report new or unusual thigh, hip, or groin pain immediately 2

Multiple Vertebral Fractures After Discontinuation (Critical Warning)

• Risk of nearly 20% for multiple vertebral fractures following Prolia discontinuation in postmenopausal women 6
• Patients should never stop, skip, or delay Prolia without consulting their physician 2, 6
• The rebound effect includes sharp increases in bone turnover markers and loss of bone density gained 6

Serious Infections

• Increased risk of bacterial cellulitis with relative risk of 1.26 (95% CI 1.01-1.57) based on moderate-quality evidence 1
• Serious infections in skin, abdomen, bladder, or ear may occur, potentially requiring hospitalization 2
• Endocarditis (inflammation of heart lining) may occur more frequently in Prolia users 2

Severe Allergic Reactions

• Anaphylaxis and serious hypersensitivity reactions have been reported, including rash, urticaria, facial swelling, throat tightness, trouble breathing, and hypotension 2, 3
• Patients with prior systemic hypersensitivity reactions should not receive denosumab 2

Special Population Considerations

Renal Impairment

• No dose adjustment needed, but hypocalcemia risk is substantially higher in patients with CrCl <30 mL/min or on dialysis 1, 2
• More frequent calcium monitoring is mandatory in severe renal impairment 1, 5

Cancer Patients on Hormonal Therapy

• Higher incidence of cataracts (4.7% vs 1.2% placebo) in patients receiving androgen deprivation therapy or aromatase inhibitors 1, 2

Less Common but Notable Adverse Effects

• Severe musculoskeletal pain requiring discontinuation has been reported postmarketing 2
• Marked elevation in parathyroid hormone (PTH) in patients with severe renal impairment 2
• Dermatologic reactions including drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, lichenoid drug eruptions, and alopecia 2
• Vasculitis (ANCA-positive vasculitis, leukocytoclastic vasculitis) 2

Essential Monitoring and Prevention Strategies

• Calcium supplementation (1000 mg daily) and vitamin D (at least 400 IU daily) are mandatory for all patients 1, 4, 5, 2
• Baseline serum calcium measurement must be performed and normalized before first dose 4, 5
• Regular calcium monitoring is necessary, especially after the first few doses 5
• Dental evaluation before initiation is mandatory to reduce ONJ risk 1, 4, 5
• Patients should practice good oral hygiene and avoid invasive dental procedures when possible during treatment 5, 2

Critical Clinical Pitfall to Avoid

The most dangerous error is abrupt discontinuation of Prolia, which triggers a severe rebound effect with rapid bone loss and high risk of multiple vertebral fractures. 2, 6 If discontinuation is necessary, transition to alternative therapy (typically high-dose bisphosphonates) is essential to mitigate this rebound effect. 6