Generic Name

Xgeva

Mechanism

Xgeva interferes with the mevalonate pathway:
• Inhibits farnesyl pyrophosphate synthase (FPPS), blocking prenylation of small GTPases (e.g., Rho, Rac, Ras).
• Prevents osteoclast anchoring, resorptive activity, and survival, leading to osteoclast apoptosis.
• Decreases bone resorption and releases growth factors stored in hydroxyapatite, thereby reducing tumor‑mediated bone turnover.

Pharmacokinetics

• Molecular weight: 718.5 Da.
• Distribution: ~95 % bound to bone matrix; plasma half‑life 1–2 h, but bone residence >30 days.
• Metabolism: None; eliminated unchanged.
• Excretion: Renal (≈5 %) – requires careful dosing in renal impairment.
• Volume of distribution: Large due to bone affinity.
• Peak plasma concentration: Reached during the 15‑min infusion; no steady‑state accumulation with quarterly dosing.

Indications

• Metastatic bone disease: Prevention of SREs (pathologic fractures, spinal cord compression, hypercalcemia, etc.) in solid tumors (e.g., breast, prostate, lung).
• Multiple myeloma: Reduction of SREs.
• Osteogenesis imperfecta: Annual IV infusions (dose based on weight) for children <15 y to increase bone density and decrease fracture risk.

Contraindications

• Hypersensitivity to zoledronic acid or any excipient.
• Severe renal impairment (creatinine clearance <30 mL/min) – contraindicated.
• Uncontrolled interstitial lung disease.
• Hypocalcemia or conditions predisposing to hypocalcemia.
• Pregnancy: Category D – avoid due to teratogenic potential.
• Dental surgery: Strongly advised to see dentist ≥10 days prior to infusion.
• Fresh frozen plasma therapies: Avoid simultaneous use.

Warnings
• Osteonecrosis of the jaw (ONJ) – monitor dental health.
• Acute phase reactions (APRs) – fever, myalgias, arthralgias, especially within first week.
• Renal dysfunction – monitor serum creatinine; avoid if ≥30 mL/min.
• Hypocalcemia/ hypophosphatemia – supplement Ca²⁺/Vit‑D prior to infusion.

Dosing

• Pre‑infusion: 1–2 g calcium carbonate and 1000 IU vitamin D₃ orally to reduce hypocalcemia risk.
• Post‑infusion: Continue calcium + vitamin D for ≥30 days; advise patient to avoid bisphosphonate‑containing mouthwashes.
• Monitoring: Baseline renal panel, serum calcium/phosphorus; CBC and uric acid every 3–4 weeks.

Adverse Effects

• Common:
• Acute phase reaction (fever, chills, myalgias, arthralgias) – up to 40 %.
• Flu‑like symptoms, fatigue, headache.
• Elevated serum creatinine (transient).
• Serious:
• Osteonecrosis of the jaw (incidence < 0.5 % with prophylaxis).
• Severe hypocalcemia → seizures, tetany.
• Renal impairment/acute kidney injury (rare).
• Acute respiratory distress syndrome (rare).
• Rhabdomyolysis (very rare).

Monitoring

• Renal function: Serum creatinine & eGFR before each infusion; baseline and at every 3–4 week clinic visit.
• Calcium & Phosphorus: Pre‑infusion, 24 h post‑infusion, then monthly.
• Bone turnover markers: Optional (e.g., urinary N-telopeptide) for research use.
• Dental assessment: Baseline oral exam; avoid invasive dental procedures within 10 days before infusion.

Clinical Pearls

• Optimize prophylaxis: Calcium + vitamin D ± magnesium should be started at least 24 h before infusion.
• Targeted dialysis: If patient develops acute kidney injury, a single dialysis session can remove up to 20 % of circulating zoledronic acid; consider after 48 h.
• Dosing nuance: In patients weighing  38 °C often requires acetaminophen; it does NOT dampen efficacy.
• Avoid concomitant vitamin K antagonists: These may delay bruising resolution after infusion.
• Caution in pregnancy: Consider switching to denosumab if pregnancy occurs during therapy.
• Re‑infusion intervals: In advanced metastatic disease with prolonged survival, schedule every 4 weeks ± 2 days to accommodate outpatient visits.

--
• *Prepared for medical students and clinicians seeking a concise, evidence‑based reference on Xgeva.*