Makindo Medical Notes

🔗 Related Subjects: | Calcium Physiology | Hypercalcaemia | Bisphosphonates | Osteoporosis | Osteonecrosis of the Jaw

⚠️ Key Safety Points:
1️⃣ All cancer patients should have a dental review before or soon after starting bisphosphonates to prevent osteonecrosis of the jaw (ONJ).
2️⃣ Atypical femoral fractures may occur with long-term therapy (>5 years). Reassess need for continuation periodically.
3️⃣ Always ensure adequate calcium and vitamin D repletion before starting therapy.

💊 About

• Zoledronic acid is a potent bisphosphonate used to prevent and treat bone loss and malignancy-related skeletal complications.
• Always check the BNF entry for latest dosing and monitoring recommendations.

⚙️ Mechanism of Action

• Bisphosphonates are synthetic analogues of pyrophosphate, replacing the P–O–P bond with a non-hydrolysable P–C–P linkage.
• This allows strong binding to hydroxyapatite in bone, resisting enzymatic breakdown.
• They inhibit osteoclast-mediated bone resorption, stabilising bone mineral density and reducing fracture risk.
• Zoledronic acid also inhibits the mevalonate pathway in osteoclasts, disrupting cytoskeletal and resorptive function.
• Therapeutic decision is guided primarily by fracture risk (including fall risk and BMD) rather than BMD alone.

📋 Indications

• Osteoporosis — postmenopausal, male, and glucocorticoid-induced.
• Paget’s disease of bone.
• Hypercalcaemia of malignancy.
• Bone metastases and myeloma (prevention of skeletal events).

💉 Dosing (Ensure Hydration & Renal Assessment)

💡 Re-evaluation of Long-Term Therapy: The benefit–risk ratio should be reassessed after 5 years of continuous bisphosphonate therapy. Patients reporting hip, groin, or thigh pain should be evaluated for possible atypical femoral fracture, and discontinuation considered if confirmed.

🤝 Interactions

• Avoid or monitor with nephrotoxic agents such as NSAIDs, aminoglycosides, thalidomide, and radiographic contrast.
• Concurrent corticosteroids increase risk of osteonecrosis of the jaw.

🚫 Contraindications

• Hypocalcaemia (correct before starting).
• Severe renal impairment (eGFR < 30 mL/min/1.73 m²).
• Pregnancy and breastfeeding (safety not established).
• Active dental infection or planned major dental extraction — delay therapy until resolved.

⚠️ Side Effects

• 🩸 Hypocalcaemia and hypophosphataemia — monitor electrolytes post-infusion.
• 🦴 Osteonecrosis of the jaw (ONJ) — risk increased with poor oral hygiene or invasive dental work.
• 🦵 Atypical femoral fractures — thigh/groin pain may precede fracture.
• 💢 Acute-phase reaction after first infusion: fever, myalgia, flu-like symptoms.
• 🧠 Headache, dizziness, arthralgia, anaemia.
• 💧 Renal impairment — ensure adequate hydration before dosing.
• ❤️ Rarely: atrial fibrillation (observed in some osteoporosis trials).

🩺 Teaching Commentary

• Zoledronic acid provides potent anti-resorptive therapy in one short annual infusion — improving adherence compared with oral bisphosphonates.
• The key to safe prescribing is to ensure calcium/vitamin D correction and renal screening beforehand.
• Always document a dental status check before initiation, especially in oncology patients.
• In frailty medicine, consider a “drug holiday” after 5 years if fracture risk has fallen — per NICE NG226 (2022).

📚 References

• Zoledronic acid – BNF
• NICE NG226: Osteoporosis: Assessment and Management (2022)
• MHRA Drug Safety Update (2021): Bisphosphonates and Atypical Femoral Fracture
• Compston J. Bone Disease in Endocrine and Metabolic Disorders, 2023.