Zoledronic acid
Zoledronic acid
Generic Name
Zoledronic acid
Brand Names
*Zometa®, Histonav®*) is a potent nitrogen‑containing bisphosphonate used intravenously to treat bone‑related disorders.
Mechanism
- Inhibition of osteoclast activity
- Binds strongly to hydroxyapatite in bone, preferentially taken up by osteoclasts during resorption.
- Inhibits farnesyl diphosphate synthase in the mevalonate pathway → prevents protein prenylation required for osteoclast function and survival.
- Reduction of bone turnover
- Decreases serum markers of bone resorption (e.g., C‑terminal telopeptide) and attenuates bone loss.
- Immunomodulatory effects
- Can inhibit osteoclast‑derived cytokine production, reducing tumor‑induced bone resorption in metastatic disease.
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Pharmacokinetics
| Parameter | Key Points |
| Absorption | Only IV; negligible oral bioavailability. |
| Distribution | Roughly 0.67 % of a dose remains in plasma after assay; majority (~75 %) is rapidly bound to bone. |
| Metabolism | No hepatic metabolism; undergoes renal clearance via glomerular filtration. |
| Elimination | Half‑life ~3.3 h in plasma; bone residence >10 years. |
| Renal requirement | *GFR ≥30 mL/min* for safe dosing; contraindicated if GFR <30. |
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Indications
- Osteoporosis – once‑annual IV dose to reduce fractures in post‑menopausal women and men with low bone density.
- Paget’s disease of bone – 0.1 mg weekly or 0.5 mg monthly (max. 5 mg).
- Bone metastases / skeletal‑related events – 4 mg every 3–4 weeks for breast, prostate, HER2‑positive breast, multiple myeloma, and other solid tumors.
- Multiple myeloma – 4 mg IV every 28 days (max. 5 mg).
- Prophylaxis of osteoporotic fractures in patients requiring high‑dose corticosteroids.
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Contraindications
- Contraindications
- Severe renal impairment (GFR 3 years.
- Atypical femoral fractures: Rare, dose‑dependent; consider reduced frequency if risk factors present.
- General: Flu‑like illness, fever, myalgia can occur post‑infusion (sore throat, headache).
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Dosing
| Indication | Dose | Frequency | Administration Notes |
| Osteoporosis | 5 mg IV | Once yearly (24 h infusion) | Give in fasting state; pre‑medicate with NSAID to blunt acute phase reaction. |
| Paget’s disease | 0.1 mg IV | Weekly or 0.5 mg monthly | Reduce dose if GFR <70 mL/min. |
| Bone metastases / SRE | 4 mg IV | Every 3–4 weeks | Limit cumulative exposure to <25 mg over 2 years. |
| Multiple myeloma | 4 mg IV | Every 28 days | 최대 5 mg; adjust for renal function. |
*All infusions should be given over 5–15 min in a central or peripheral line with adequate hydration.*
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Adverse Effects
Common (≤ 10 %)
• Flu‑like symptoms: fever, chills, myalgias, arthralgias.
• Diarrhea, dysgeusia, or nausea.
• Hypocalcemia (especially in osteoporotic patients).
Serious (≤ 1 %)
• Renal tubular acidosis Type 2 and acute kidney injury.
• Osteonecrosis of the jaw (ONJ) – especially when dental extraction is performed.
• Atypical femur fractures (sub‑trochanteric or subtrochanteric).
• Hypersensitivity rash or urticaria (rare).
• Insulin‑dependent diabetes mellitus exacerbation via calcium‑induced insulin resistance (rare).
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Monitoring
| Parameter | Timing | Target / Action |
| Serum creatinine & GFR | Baseline; 1 wk; monthly during therapy | Stay > 30 mL/min; adjust if decline 15 % |
| Serum calcium, phosphate, magnesium, vitamin‑D | Baseline; 1 wk; quarterly | Correct hypocalcemia / hypophosphatemia before dose |
| Echocardiogram or cardiac enzymes | If coronary artery disease is present | Monitor for rare cardiac events |
| Bone turnover markers (CTX, P1NP) | Every 6 months | Verify efficacy if patient fracture risk remains high |
| Dental assessment | Before start and annually | Identify risk of ONJ |
| Symptom diary for acute phase reaction | During first infusion | Adjust pre‑medication as needed |
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Clinical Pearls
- Pre‑infusion hydration (1–2 L of saline 24 h before) markedly reduces renal toxicity, especially in patients with borderline renal function.
- Calcium‑Supplementation: Administer oral calcium ≥ 1,000 mg/day and cholecalciferol 800 IU/day to prevent post‑dose hypocalcemia; particularly important for osteoporosis patients.
- Acute-phase reaction: Use NSAID (ibuprofen 400 mg) 30‑60 min before infusion; a short infusion (5 min) with a 2‑hr taper does not increase toxicity and decreases flu‑like symptoms.
- Dental hygiene: Avoid invasive dental procedures within 12 months of last zoledronic dose; if necessary, postpone bisphosphonate therapy for at least 1 month after procedure.
- Renal function thresholds: If GFR falls below 30 mL/min, hold therapy and re‑evaluate; no dose adjustment is recommended for mild to moderate impairment.
- Fracture risk beyond one year: For patients with persistent high fracture risk, consider supplemental denosumab or repeat zoledronic acid after a 12‑month drug holiday, weighing cumulative bisphosphonate exposure.
- Atypical fractures: Counsel patients to report sudden thigh or groin pain; imaging of the femur may be warranted if suspicion arises.
- Drug–Drug Interactions: Avoid concomitant use of other nephrotoxic agents (NSAIDs, aminoglycosides) and remember that *zoledronic acid is not removed by dialysis*.
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