What are the side effects of Prolia (denosumab)?

Prolia (Denosumab) Side Effects

Prolia is generally well-tolerated with most common side effects being mild musculoskeletal symptoms, but serious risks include severe hypocalcemia (especially in kidney disease), osteonecrosis of the jaw, atypical femoral fractures, and a critical rebound risk of multiple vertebral fractures if treatment is stopped abruptly.

Common Side Effects (Generally Mild)

The most frequently reported adverse effects in clinical trials include 1, 2:

• Musculoskeletal symptoms: Arthralgia, back pain, extremity pain, and muscle pain (reported in 10-14% of patients)
• Upper respiratory infections: Nasopharyngitis, common cold symptoms
• Gastrointestinal symptoms: Constipation (mild upper GI symptoms with OR 1.74,95% CI 1.29-2.38) 1
• Urinary tract infections
• Headache
• Rash/eczema (OR 1.96,95% CI 1.46-2.66) 1

Importantly, the overall rate of serious adverse events (23.8%) and discontinuation due to adverse events (2.4%) were nearly identical to placebo in the landmark FREEDOM trial 1.

Serious Adverse Effects Requiring Monitoring

Hypocalcemia (Most Critical Risk)

This is the most important safety concern, particularly in patients with kidney disease 2:

• Severe symptomatic hypocalcemia can result in hospitalization, life-threatening events, and fatal cases 2
• Patients with advanced chronic kidney disease (CrCl <30 mL/min or on dialysis) have markedly increased risk 2
• Asymptomatic hypocalcemia was reported in 2.4% of patients in clinical trials 1
• Symptoms include: muscle spasms, twitches, cramps, numbness/tingling in fingers/toes/around mouth 2

Critical management: All patients must have hypocalcemia corrected before starting Prolia and should receive adequate calcium (≥1000 mg daily) and vitamin D (≥400 IU daily) supplementation throughout treatment 1, 2.

Osteonecrosis of the Jaw (ONJ)

• Confirmed in 8 events through 8 years of therapy in the FREEDOM extension 1
• Incidence approximately 1-2% in osteoporosis patients 1
• Prevention requires: comprehensive dental examination before starting therapy, maintaining excellent oral hygiene, and avoiding invasive dental procedures during treatment 1, 2
• If invasive dental surgery is necessary, defer Prolia until complete healing is confirmed 1

Atypical Femoral Fractures

• Confirmed 2 events through 8 years in FREEDOM extension 1
• Patients should report new or unusual thigh, hip, or groin pain 2

Multiple Vertebral Fractures After Discontinuation (Rebound Effect)

This is a unique and critical risk with denosumab 2, 3, 4:

• Rapid bone loss and increased fracture risk occur after stopping treatment due to reversible mechanism of action 1, 3
• Risk of multiple vertebral fractures is particularly elevated in patients with prior vertebral fractures 2
• Denosumab should not be stopped abruptly 1
• Patients must transition to alternative therapy (typically bisphosphonates) if discontinuing denosumab 3, 4
• Bone turnover markers can become markedly elevated after discontinuation 5

Infections

• Moderate-quality evidence shows increased infection risk (RR 1.26,95% CI 1.01-1.57) 1
• Slight increase in bacterial cellulitis (1.3% vs 0.6% placebo), but no increase in serious infections overall 1
• Serious infections in skin, abdomen, bladder, or ear may occur 2
• Endocarditis risk may be increased 2

Other Serious Reactions

• Severe allergic reactions: anaphylaxis, rash, urticaria, facial swelling (seek immediate medical attention) 2
• Dermatologic reactions: epidermal and dermal adverse events including dermatitis, eczema, rashes (4-5% incidence) 2
• Severe musculoskeletal pain: though uncommon, can be severe enough to require discontinuation 2
• Hypophosphatemia: particularly in patients with pre-existing conditions like osteomalacia or Fanconi syndrome 6, 7

Special Population Considerations

Renal Impairment

• No dose adjustment needed (unlike bisphosphonates) 1, 2
• However, hypocalcemia risk is substantially higher in patients with CrCl <30 mL/min 2
• More frequent calcium monitoring required in severe renal impairment 1

Cancer Patients

In patients receiving androgen deprivation therapy or aromatase inhibitors 2:

• Higher incidence of cataracts in men on ADT (4.7% vs 1.2% placebo)
• Otherwise similar safety profile to general osteoporosis population

Contraindications

Absolute contraindications 2:

• Hypocalcemia (must be corrected before treatment)
• Pregnancy (may cause fetal harm including absent lymph nodes, abnormal bone growth)
• Known hypersensitivity to denosumab

Critical Monitoring Requirements

• Serum calcium: Regular monitoring, especially in first weeks of treatment 2
• Vitamin D levels: Intermittent evaluation 1
• Dental health: Before starting and during treatment 1, 2
• Renal function: Assess for CKD-MBD before starting in patients with kidney disease 2
• No routine bone density monitoring needed during treatment 1

Key Clinical Pitfalls to Avoid

1. Never stop denosumab abruptly without transitioning to alternative therapy 1, 2, 3
2. Never start in patients with uncorrected hypocalcemia or vitamin D deficiency 2, 6
3. Never use concurrently with Xgeva (contains same active ingredient) 2
4. Do not skip or delay doses as this increases vertebral fracture risk 2
5. Ensure adequate calcium/vitamin D supplementation in all patients 1, 2