Bisphosphonates 💊

Related Subjects: |Calcium Physiology |Hypercalcaemia |Hypophosphataemia |Hyperphosphataemia |Bisphosphonates |Osteoporosis |Osteonecrosis of the jaw

Important: Bisphosphonates work best (and are safest) when calcium and vitamin D are adequate. In UK practice, check adjusted calcium and correct vitamin D deficiency before starting; hypocalcaemia must be treated first. 💡 Many landmark fracture-reduction trials ensured participants were replete in calcium/vitamin D.

📖 About

• Bisphosphonates are first-line anti-resorptive agents for most people with osteoporosis, alongside exercise/strength & balance, falls risk assessment, smoking cessation, alcohol moderation, and calcium/vitamin D optimisation.
• They also have important roles in Paget’s disease and in oncology for malignancy-related hypercalcaemia and skeletal-related event reduction in metastatic bone disease/myeloma (specialist-led).
• Because they persist in bone, treatment is usually reviewed after 3–5 years to balance ongoing benefit against rare harms (e.g., atypical femoral fracture, osteonecrosis of the jaw).

🧩 Indications (UK practical)

• Osteoporosis with a fragility fracture: treat (vertebral, hip, wrist, humerus) unless contraindicated - fracture history often “trumps” DXA.
• High fracture risk without fracture: based on FRAX/QFracture ± DXA (e.g., T-score ≤ –2.5 or osteopenia with high calculated risk).
• Glucocorticoid-induced osteoporosis: people on prolonged systemic steroids (commonly ≥5 mg prednisolone daily for ≥3 months) especially with age ≥70, prior fragility fracture, or high risk on FRAX/QFracture.
• Men with osteoporosis: confirmed osteoporosis or fragility fracture/high calculated risk.
• Cancer treatment–induced bone loss / high-turnover secondary bone loss: e.g., aromatase inhibitors, androgen deprivation therapy (usually via oncology/endocrine pathways).
• Paget’s disease of bone: symptomatic disease (bone pain) or active disease with risk of complications.
• Hypercalcaemia of malignancy & metastatic bone disease: IV bisphosphonates (e.g., zoledronate/pamidronate) after rehydration to lower calcium and reduce skeletal events.

⚙️ Mode of Action

• Bisphosphonates bind strongly to hydroxyapatite and concentrate at sites of active bone resorption.
• Osteoclasts ingest them during resorption → impaired adhesion and survival → reduced bone resorption and stabilisation/increase in BMD.
• Nitrogen-containing agents (alendronate, risedronate, zoledronate) inhibit the mevalonate pathway (prenylation) → osteoclast dysfunction/apoptosis.

⏳ Duration of Therapy & Review

• Typical course: 3–5 years (oral) or 3 years (IV zoledronate) before formal review.
• At review, consider:
  • Lower risk: “drug holiday” with reassessment (new fracture risk, DXA interval as per local pathway).
  • Higher risk: continue therapy or switch (e.g., denosumab/teriparatide/romosozumab under specialist guidance).
• High risk features: hip/vertebral fracture, multiple fractures, very low T-score, ongoing steroids, or fractures on treatment.

💊 Common UK Choices

• First-line (most patients): alendronate weekly (or risedronate weekly) if able to follow administration rules and tolerate GI effects.
• If oral intolerance/poor adherence: ibandronate (monthly oral or IV) or zoledronic acid (yearly IV).
• Paget’s disease: IV zoledronic acid is commonly preferred for potency and convenience.
• Oncology indications: IV zoledronate or pamidronate (specialist protocols).

🚫 Contraindications & Key Cautions

• Hypocalcaemia: correct before treatment (risk of symptomatic hypocalcaemia, especially with IV therapy).
• Renal impairment: avoid/seek specialist advice in significant CKD (threshold depends on agent; IV zoledronate is particularly renal-sensitive).
• Oesophageal disorders / inability to sit upright: avoid oral bisphosphonates (risk of oesophagitis/ulceration).
• Vitamin D deficiency: treat first; check calcium after replacement where appropriate.
• Dental health / ONJ risk: highest with IV and cancer doses; aim for dental assessment and complete major dental work before starting where feasible.
• Atypical femoral fracture: rare; consider if new thigh/groin pain on long-term therapy (evaluate femur).
• Pregnancy: generally avoid.

💡 Administration Advice (Oral Bisphosphonates)

• Take first thing in the morning on an empty stomach with a full glass of water.
• Stay upright and avoid food/drink/other meds for at least 30 minutes (often 60 minutes for ibandronate).
• Separate from calcium/iron/magnesium supplements (they reduce absorption).