β οΈ MHRA Safety Alert (Feb 2013): Long-term use of Denosumab has been linked to atypical femoral fractures and osteonecrosis of the jaw.
π Denosumab is a monoclonal antibody used in osteoporosis and metastatic bone disease.
It acts by inhibiting osteoclast formation and activity, thereby reducing bone resorption and increasing bone density.
Always correct hypocalcaemia before use and ensure adequate calcium and vitamin D supplementation.
Related Subjects:
| Calcium Physiology
| Hypercalcaemia
| Bisphosphonates
| Osteoporosis
π§ About
- Denosumab is a fully human monoclonal antibody (IgG2 subclass) that targets RANK ligand (RANKL), a key mediator of osteoclast differentiation and survival.
- By inhibiting RANKL, Denosumab prevents activation of osteoclasts β the cells responsible for bone breakdown β resulting in increased bone mass and reduced fracture risk.
- Used in both osteoporosis and malignant bone disease as an alternative to bisphosphonates, especially in renal impairment.
βοΈ Mechanism of Action
- RANKL (Receptor Activator of Nuclear Factor ΞΊB Ligand) normally binds to RANK on osteoclast precursors, promoting bone resorption.
- Denosumab binds to RANKL, preventing this interaction, reducing osteoclast formation, function, and survival.
- Result: decreased bone resorption and turnover, increased bone mineral density (BMD), and reduced fracture incidence.
π― Indications
- Osteoporosis in postmenopausal women and in men at increased fracture risk.
- Bone metastases from solid tumours (excluding most prostate cancers, where bisphosphonates remain preferred first-line).
- Giant cell tumour of bone (unresectable or metastatic).
- Glucocorticoid-induced osteoporosis (off-label).
π Dose
- Osteoporosis: Denosumab 60 mg subcutaneously (S/C) every 6 months into thigh, abdomen, or upper arm.
Supplement with calcium (β₯500 mg/day) and vitamin D (β₯400 IU/day).
- Bone metastases: Denosumab 120 mg S/C every 4 weeks, plus calcium and vitamin D supplementation unless hypercalcaemic.
- Giant cell tumour: 120 mg every 4 weeks with additional doses on days 8 and 15 during the first month.
Indication | Dose | Frequency | Route |
Osteoporosis | 60 mg | Every 6 months | Subcutaneous |
Bone metastases | 120 mg | Every 4 weeks | Subcutaneous |
Giant cell tumour of bone | 120 mg | Every 4 weeks + days 8 & 15 (1st month) | Subcutaneous |
β οΈ Cautions
- Correct hypocalcaemia prior to administration.
- All patients should receive calcium and vitamin D supplementation unless hypercalcaemic.
- Perform dental examination before initiating therapy, especially in cancer-related dosing (120 mg regimen).
- Avoid starting in patients with unhealed oral lesions or requiring dental surgery.
- Monitor serum calcium within 2 weeks after the first dose, particularly in renal impairment or malabsorption.
π« Contraindications
- Hypocalcaemia β must be corrected before treatment.
- Pregnancy and lactation β potential fetal harm (category X).
- Hypersensitivity to Denosumab or excipients.
π Side Effects
- Hypocalcaemia β monitor calcium, especially in renal impairment.
- Musculoskeletal pain, extremity pain, and fatigue.
- Skin infections (notably cellulitis), rashes.
- UTI, URTI, constipation, cataracts, sciatica.
- Osteonecrosis of the jaw (ONJ): risk increased with high-dose or cancer regimens.
- Rebound vertebral fractures can occur after discontinuation β plan transition to alternative antiresorptive therapy (e.g., bisphosphonate).
β οΈ Warning: Atypical Femoral Fractures
- Patients should report new or unusual thigh, hip, or groin pain β may indicate incomplete femoral fracture.
- Fractures can occur with minimal trauma, often bilaterally β always assess the contralateral femur.
- If suspected, pause Denosumab and evaluate benefits vs risks of continuing treatment.
π Interactions
- No major pharmacokinetic interactions identified.
- Concurrent use with corticosteroids or chemotherapy increases ONJ risk.
- See BNF for full list.
π¦· Dental Guidance
- Complete any invasive dental procedures before starting treatment.
- Maintain good oral hygiene and routine dental check-ups throughout therapy.
- Report jaw pain, loosening of teeth, or gum swelling promptly.
π§© Clinical Pearls
- Denosumab is not renally excreted β useful in patients with renal impairment where bisphosphonates are contraindicated.
- Monitor for rebound vertebral fractures after cessation β always plan alternative bone protection.
- ONJ risk: higher with 120 mg regimen for cancer vs 60 mg for osteoporosis.
- Duration of osteoporosis therapy: typically re-evaluate after 5 years of continuous use.
π‘ Teaching Tip
- Think of Denosumab as a βbiologic bisphosphonateβ β same end goal (osteoclast inhibition) via a completely different mechanism (RANKL blockade).
- Explain to learners that stopping Denosumab abruptly can cause a rebound surge in bone resorption β requiring transition to another antiresorptive drug.
- Mnemonic: DENOsumab DENOtes fewer osteoclasts.
π References
- BNF: Denosumab
- MHRA Drug Safety Update, Feb 2013: Atypical femoral fractures and ONJ
- NICE TA204 & TA265 β Denosumab for postmenopausal osteoporosis and bone metastases
- Cummings SR et al. NEJM 2009;361:756β765 β Denosumab and fracture prevention.