RANK Ligand Inhibitors

RANK ligand inhibitors are monoclonal antibodies against RANKL; denosumab is the licensed agent. It is used for osteoporosis, bone loss during androgen deprivation or aromatase inhibitor therapy, skeletal metastases, myeloma, giant cell tumour of bone and refractory hypercalcaemia of malignancy.

Mechanism. Denosumab binds RANKL and prevents RANK activation on osteoclasts and precursors, reducing their formation, function and survival. Unlike bisphosphonates, it does not incorporate into bone, and its effect reverses within months.

Pharmacokinetics. Subcutaneous injection, half-life about 26 days, no renal clearance, so no dose adjustment in kidney disease. Biosimilar products are available.

Osteoporosis dose. 60 mg subcutaneously every 6 months.

Oncology dose. 120 mg subcutaneously every 4 weeks for skeletal-related events; for giant cell tumour of bone and refractory hypercalcaemia, 120 mg on days 1, 8 and 15 then every 4 weeks.

Versus bisphosphonates. Greater increases in bone density and an advantage in renal impairment, but a rebound after stopping and a need for continuous therapy.

• Osteoporosis: when oral bisphosphonates are not tolerated or absorbed, in eGFR under 35 mL/min, or for patients who prefer 6-monthly injections.
• Supplements: calcium 1000 mg and vitamin D 800 IU (20 micrograms) daily for all patients, with vitamin D deficiency corrected beforehand.
• Stopping: never stop abruptly. Rebound bone loss and multiple vertebral fractures can occur 7 to 19 months after the last dose. Give a follow-on antiresorptive (zoledronic acid 5 mg intravenously about 6 months after the last denosumab dose, with bone turnover marker follow-up).
• Late doses: give within 4 weeks of the due date if possible.

Special groups. Pregnancy: avoid; use contraception during and for 5 months after treatment. Breastfeeding: avoid. Children: specialist use only. Older adults: first-line when bisphosphonates fail. Kidney impairment: no dose change, but eGFR under 30 mL/min or dialysis carries severe hypocalcaemia risk, so check calcium in the 2 weeks after the first dose. Liver impairment: no adjustment. Regional: cost is the main barrier; vials stay stable for 14 days at room temperature if refrigeration lapses.

Adverse effects. Hypocalcaemia, skin infection (cellulitis), eczema, musculoskeletal pain, osteonecrosis of the jaw and atypical femoral fracture (rare), and multiple vertebral fractures after discontinuation.

Contraindications. Hypocalcaemia and pregnancy.

Interactions. Immunosuppressants add infection risk. Other calcium-lowering drugs add hypocalcaemia.

Monitoring. Calcium before each dose, vitamin D, creatinine, dental review, bone density yearly, and a plan for follow-on therapy at the time of the first dose.

Referral and escalation. Missed doses for more than 7 months, new vertebral fracture, severe hypocalcaemia in chronic kidney disease, or jaw pain.