Bone-modifying agents (bisphosphonates, denosumab)
Zoledronic acid and denosumab reduce fractures, spinal cord compression and bone pain from bone metastases and myeloma, prevent treatment-induced bone loss, and in postmenopausal breast cancer modestly reduce recurrence in bone.
Pamidronate (1995, myeloma) and zoledronic acid (2002) reduce skeletal-related events by ~30-40%; denosumab (anti-RANKL, 2010) is superior to zoledronic acid for delaying SREs in solid tumours and non-inferior in myeloma, without renal dosing. Adjuvant bisphosphonates reduce bone recurrence and breast cancer mortality in postmenopausal women (EBCTCG 2015 meta-analysis: 3.3% absolute mortality reduction) and are guideline-recommended; denosumab did not improve disease outcomes adjuvantly (D-CARE). De-escalated dosing (12-weekly zoledronic acid, CALGB 70604) is standard. Osteonecrosis of the jaw (1-2%; dental review), hypocalcaemia, atypical femoral fractures and rebound vertebral fractures after stopping denosumab are the key harms. Also used for hypercalcaemia of malignancy and cancer-treatment-induced bone loss (aromatase inhibitors, ADT).
How it works
Inhibit osteoclast-mediated bone resorption (bisphosphonates via farnesyl pyrophosphate synthase in osteoclasts; denosumab by neutralising RANKL) to reduce the vicious cycle between tumour cells and bone turnover.
- Large reductions in fractures and cord compression
- Adjuvant survival benefit in postmenopausal breast cancer
- Generic zoledronic acid is cheap; 12-weekly dosing
- Osteonecrosis of the jaw
- Denosumab discontinuation rebound
- Optimal duration unknown
Latest papers
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