Generic Name

Zoledronic acid

Mechanism

• Zoledronic acid is a bisphosphonate that selectively binds to hydroxyapatite in bone, concentrating its effect at sites of active osteoclastic resorption.
• Once internalized by osteoclasts, it reacts with farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway, generating a non-hydrolyzable ATP analogue that irreversibly inhibits protein prenylation.
• Inhibition of prenylation disrupts osteoclast cytoskeletal organization and signaling, leading to apoptosis and a rapid decline in bone resorption.
• The result is a net decrease in serum calcium and stabilization (or reversal) of lytic bone lesions in malignancy and other high‑turnover conditions.

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Pharmacokinetics

• Administration: Intravenous infusion over 15–30 min; typically given in a monitored setting.
• Absorption & Bioavailability: Not orally absorbed; bioavailability with IV route is 100 %.
• Distribution: Highly bound to bone (≈ 98 %); distribution half‑life ~2 h, but long skeletal retention (half‑life in bone ~54 days).
• Metabolism: Not metabolized in the liver; chemical stability is high.
• Elimination: Predominantly renal (≈ 90 %) via glomerular filtration; unchanged drug in urine.
• Clearance & Half‑Life: Apparent total clearance ≈ 1.2 L/h; terminal elimination half‑life ≈ 4–5 h in circulation, but skeletal half‑life considerably longer.
• Renal consideration: Dose adjustment or avoidance required for CrCl <30 mL/min.

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Indications

• Bone metastases from solid tumors (breast, prostate, lung) – to prevent skeletal‑related events (SREs).
• Multiple myeloma – for SREs and hypercalcaemia of malignancy.
• Paget disease of bone – to normalize bone turnover.
• Glucocorticoid‑induced osteoporosis – when oral bisphosphonates are contraindicated or ineffective.
• Hypercalcaemia of malignancy – single‑dose rescue.
• Pre‑operative prophylaxis of SREs in patients with spinal cord compression or impending fractures.

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Contraindications

• Severe renal impairment (CrCl <30 mL/min).
• Hypocalcaemia – correct calcium levels before dosing.
• Active dental or jaw pathology – high risk for osteonecrosis of the jaw (ONJ).
• Pregnancy/Nursing – potential teratogenic/teratogenic concerns.
• Recent (≤ 24 h) major surgery or trauma – avoid peri‑operative exposure.
• Atypical femoral fractures – risk increases with cumulative exposure.

*Warnings*:
• Monitor renal function and calcium; adjust dose as needed.
• Use adequate hydration and calcium/vitamin D supplementation.
• Educate patients regarding dental hygiene and routine dental checks.

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Dosing

• Infusion: 15–30 min under monitoring; ensure patient remains seated; oxygen may be supplied in settings of severe reactions.
• Pre‑treatment labs: serum calcium, phosphate, creatinine, eGFR, uric acid, and vitamin D levels.
• Post‑infusion: re‑check calcium and serum creatinine 24 h later.

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Adverse Effects

Common (≥ 10 %)
• Flu‑like syndrome (fever, myalgia, arthralgia) – often within 24 h.
• Hypocalcaemia (often asymptomatic but can present with tetany).
• Nausea, dyspepsia, or shortness of breath.
• Hypersensitivity reaction (rash, pruritus).

Serious (≤ 1 %)
• Osteonecrosis of the jaw (ONJ) – presenting as pain, swelling, exposed bone, or infection.
• Atypical femur fractures – insidious pain in thigh or groin; may require orthopedic evaluation.
• Renal dysfunction – acute deterioration or need for dialysis.
• Severe hypocalcaemia – tetany, seizures, cardiac arrhythmias.

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Monitoring

• Renal function: serum creatinine and eGFR pre‑dose, at 24 h, and at each subsequent infusion.
• Serum calcium: pre‑dose, 24 h, and as clinically indicated.
• Uric acid: baseline and 24 h; consider allopurinol for high‑risk patients.
• Dental assessment: baseline dental exam; reinforce oral hygiene and avoid invasive dental procedures during therapy.
• Bone turnover markers (optional): serum C‑terminal telopeptide (CTX) or BALP to gauge response.
• Adverse‑effect surveillance: report ONJ or atypical fractures promptly.

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Clinical Pearls

1. Hydration & Calcium – Give a 1 L saline infusion before Zometa if possible; ensure calcium & vitamin D are maintained > 800 IU vitamin D and 500 mg calcium daily to mitigate hypocalcaemia.
2. Avoid Dental Trauma – Patients should receive a comprehensive dental clearance 4–6 weeks before starting therapy and refrain from extractions/implants thereafter.
3. Infusion Speed Matters – Slower infusion (30 min) reduces flu‑like reactions; large volumes (> 100 mL) are contraindicated; use a dedicated 1 L bag.
4. Repeat Dose Triggers – Re‑assess calcium and eGFR at every infusion; if eGFR <30 mL/min, consider switching to oral bisphosphonates or PTH analogues.
5. Pregnancy Planning – Encourage contraception for one year post‑therapy due to long skeletal retention; discuss risks with patients of childbearing potential.
6. RA/RA‑induced Skeletal Complications – Zoledronic acid can be a valuable adjunct in rheumatology when steroid‑induced bone loss is severe and patients cannot tolerate oral bisphosphonates.
7. Oncologic Collaboration – Coordinate with oncology to integrate Zometa dosing with chemotherapy schedules, especially in regimens that elevate uric acid or renal load.

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