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

Side Effects of Prolia (Denosumab) Injection

Prolia causes common musculoskeletal symptoms and gastrointestinal effects in most patients, but serious risks include severe hypocalcemia (especially with kidney disease), osteonecrosis of the jaw, atypical femoral fractures, serious infections, and a critical risk of multiple vertebral fractures if treatment is stopped abruptly. 1

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

Musculoskeletal symptoms are the most frequently reported adverse effects:

• Back pain, arthralgia (joint pain), extremity pain, and muscle pain occur in 10-14% of patients 2, 1
• These symptoms typically manifest within the first 30 days after injection 3
• Severe and occasionally incapacitating bone, joint, and muscle pain has been reported in postmarketing surveillance, with onset ranging from one day to several months after starting treatment 1

Upper respiratory and infectious symptoms:

• Nasopharyngitis and common cold symptoms are frequently reported 2, 1
• Urinary tract infections (cystitis) occur commonly 2, 1

Gastrointestinal effects:

• Constipation and mild upper GI symptoms occur with an odds ratio of 1.74 (95% CI 1.29-2.38) 2

Dermatologic reactions:

• Rash, eczema, and dermatitis occur with an odds ratio of 1.96 (95% CI 1.46-2.66) 2, 3
• These are not typically specific to the injection site 1

Other common effects:

• Headache 2
• Hypercholesterolemia 1

Serious Adverse Effects Requiring Immediate Medical Attention

Severe hypocalcemia (critically important):

• Asymptomatic hypocalcemia occurs in 2.4% of patients in clinical trials 2
• Patients with advanced chronic kidney disease (CrCl <30 mL/min) face substantially higher risk and may experience life-threatening hypocalcemia requiring hospitalization 2, 1
• Symptoms include muscle spasms, twitches, cramps, numbness or tingling in fingers/toes/around mouth 1
• Hypocalcemia must be corrected before starting Prolia 1
• More frequent calcium monitoring is required in severe renal impairment 2

Osteonecrosis of the jaw (ONJ):

• Confirmed incidence of approximately 1-2% in osteoporosis patients 2
• Eight confirmed events occurred through 8 years of therapy in the FREEDOM extension trial 2
• Patients must maintain good oral hygiene and inform dentists before dental procedures 1
• Oral examination is required before initiating therapy 4, 1

Atypical femoral fractures:

• Two confirmed events through 8 years in the FREEDOM extension 2
• Patients should report new or unusual thigh, hip, or groin pain immediately 1
• Contralateral limb should be assessed if atypical fracture occurs 1

Multiple vertebral fractures after discontinuation (CRITICAL WARNING):

• This is the most dangerous risk: multiple vertebral fractures can occur as early as 7 months (average 19 months) after the last dose if Prolia is stopped abruptly 2, 1
• Prior vertebral fracture is a predictor of multiple fractures after discontinuation 1
• Patients must never stop, skip, or delay Prolia without discussing transition to alternative antiresorptive therapy with their physician 1

Serious infections:

• Moderate-quality evidence shows increased risk with relative risk of 1.26 (95% CI 1.01-1.57) 2
• Bacterial cellulitis, skin infections, abdominal infections, urinary tract infections, and ear infections occur more frequently 1
• Endocarditis has been reported more frequently in Prolia-treated patients 1
• Patients on immunosuppressants or with impaired immune systems face increased infection risk 1

Severe allergic reactions:

• Symptoms include low blood pressure, trouble breathing, throat tightness, facial/lip/tongue swelling, rash, itching, and hives 1
• Patients with prior hypersensitivity reactions should not receive denosumab 1

Special Population Warnings

Patients with kidney disease:

• No dose adjustment needed, but hypocalcemia risk is substantially elevated with CrCl <30 mL/min 2
• Assess for chronic kidney disease-mineral bone disorder (CKD-MBD) before starting treatment 2

Cancer patients on hormone therapy:

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

Pregnancy and contraception:

• Absolute contraindication in pregnancy 1
• Effective contraception required during treatment and for at least 5 months after last dose 1

Monitoring Requirements

Essential monitoring includes:

• Calcium and vitamin D levels before initial dose 2, 4
• Dental health assessment before starting therapy 2, 4
• Renal function assessment for CKD-MBD in patients with kidney disease 2
• All patients must take adequate calcium and vitamin D supplementation throughout treatment 2, 1

Critical Clinical Pitfalls to Avoid

Never discontinue Prolia abruptly - this is the single most dangerous error, as it leads to rebound bone turnover and multiple vertebral fractures 1. If discontinuation is necessary, immediate transition to high-dose bisphosphonate therapy is mandatory 4.

Do not confuse Prolia with Xgeva - both contain denosumab but are different products; patients should never receive both 1.

Do not start Prolia in patients with uncorrected hypocalcemia - this is an absolute contraindication 1.