Bisphosphonates

Bisphosphonates are pyrophosphate analogues that bind bone mineral and are taken up by osteoclasts. They are first-line therapy for osteoporosis, and are also used for Paget disease, hypercalcaemia of malignancy, skeletal metastases, myeloma and osteogenesis imperfecta.

Mechanism. Nitrogen-containing agents (alendronate, risedronate, ibandronate, zoledronic acid, pamidronate) inhibit farnesyl pyrophosphate synthase, disrupting osteoclast function and inducing apoptosis. Non-nitrogen agents (etidronate, clodronate) form toxic ATP analogues.

Pharmacokinetics. Oral bioavailability is under 1% and falls with food, calcium and iron. About half of the absorbed dose binds bone and the rest is excreted unchanged by the kidney. Skeletal half-life is years.

Differences. Intravenous agents avoid gastrointestinal effects and adherence problems. Ibandronate lacks proven hip fracture reduction. Zoledronic acid is the most potent. Etidronate and clodronate are little used.

• Oral administration: take fasting with 200 mL of plain water, at least 30 minutes before food, drink or other drugs (60 minutes for ibandronate), and stay upright for at least 30 minutes.
• Hypercalcaemia of malignancy: zoledronic acid 4 mg intravenously after rehydration; effect begins in 2 to 4 days; repeat after 7 days if needed.
• Skeletal metastases and myeloma: zoledronic acid 4 mg every 3 to 4 weeks, reduced to every 12 weeks after the first year in many patients.
• Paget disease: zoledronic acid 5 mg intravenously once.
• Before the first dose: check calcium and vitamin D, correct deficiency, and arrange dental assessment if risk factors are present.
• Drug holiday: after 5 years oral or 3 years intravenous therapy in lower-risk patients.

Special groups. Pregnancy: avoid, because the drug persists in bone and crosses the placenta. Breastfeeding: avoid. Children: osteogenesis imperfecta (pamidronate) under specialist care. Older adults: first-line, with attention to swallowing. Kidney impairment: avoid at eGFR under 35 mL/min for osteoporosis dosing; adjust oncology doses to creatinine clearance. Liver impairment: no adjustment. Regional: generic alendronate is inexpensive; once-yearly zoledronic acid helps where adherence to weekly dosing is poor.

Adverse effects. Oesophagitis and gastric irritation, acute phase reaction after the first intravenous dose (fever and myalgia for 24 to 72 hours, relieved by paracetamol), hypocalcaemia, acute kidney injury with rapid infusion, uveitis, osteonecrosis of the jaw (about 1 in 10,000 or less at osteoporosis doses, 1 to 2% at oncology doses), and atypical femoral fracture (thigh pain, rare, risk rises with duration).

Contraindications. Hypocalcaemia, oesophageal stricture or achalasia, inability to sit upright for 30 minutes (oral), renal impairment under the stated thresholds, and pregnancy.

Interactions. Calcium, antacids and iron reduce absorption. NSAIDs add gastric irritation. Aminoglycosides and loop diuretics add hypocalcaemia and nephrotoxicity.

Monitoring. Calcium and creatinine before each intravenous dose, vitamin D, dental health, thigh or groin pain, and bone density at 2 to 3 years.

Referral and escalation. Prodromal thigh pain (image both femora), jaw pain or exposed bone, dysphagia, and persistent hypocalcaemia.