Bisphosphonates in bone metastases

Bone metastases are common in breast cancer (65–75%), prostate cancer (65–90%) and lung cancer (17–64%), and bone lesions occur in 70–95% of people with multiple myeloma.

Skeletal complications include bone pain, pathological fracture, spinal cord or nerve root compression and hypercalcaemia. Spinal cord compression and hypercalcaemia need emergency treatment.

Bone-modifying agents aim to prevent these skeletal-related events (SREs). The two main agents are bisphosphonates and denosumab.

They reduce osteoclast activity indirectly, through osteoblasts, and directly induce osteoclast apoptosis by inhibiting farnesyl pyrophosphate synthase.

Agents: zoledronic acid (intravenous) for bone metastases from solid tumours and myeloma; pamidronate (intravenous) for breast cancer and myeloma; ibandronate (intravenous or oral) for breast cancer; oral clodronate for osteolytic metastases.

Denosumab, a monoclonal antibody against RANKL, reduces osteoclast maturation and activity and is the main alternative.

Breast cancer: zoledronic acid, pamidronate and denosumab all reduce SREs. Start at the first presentation of bone metastases, even without symptoms. Denosumab reduced first SREs by 18% compared with zoledronic acid, but neither improved survival.

Prostate cancer: benefit is shown in castration-resistant disease (SREs 33% with zoledronic acid vs 44% with placebo). Hormone-sensitive disease carries a lower SRE risk, so bisphosphonates are reserved for castration-resistant disease.

Lung cancer: zoledronic acid and denosumab reduce SREs whether or not there are symptoms (39% vs 48% with placebo for zoledronic acid).

Multiple myeloma: bisphosphonates reduce vertebral fractures and SREs and improve pain; zoledronic acid improved survival compared with clodronate.

Other solid tumours: weaker evidence; consider bisphosphonates when skeletal complications develop.

Hypercalcaemia of malignancy: zoledronic acid is the most effective agent for lowering serum calcium.

Bone-modifying agents are commonly combined with radiotherapy for painful lesions.

Zoledronic acid is usually given every 3–4 weeks. A 12-weekly schedule was non-inferior in breast cancer, prostate cancer and myeloma, and can reduce adverse effects.

Adjust the zoledronic acid dose to creatinine clearance.

Denosumab is not nephrotoxic and can be used in kidney failure. It does not accumulate in bone, so stopping it may lose the effect, and there is no evidence to support less frequent dosing.

Osteonecrosis of the jaw: 1–10% with bisphosphonates and similar with denosumab, rising with duration (1.5% at 4–12 months, 7.7% at 27–48 months). Before starting: a dental examination and preventive dental treatment, with any extractions completed first; maintain good oral hygiene.

Kidney toxicity with zoledronic acid (4.9–44.5%, mostly mild and reversible). Risk factors are age over 65, NSAIDs or cisplatin, diabetes, myeloma and use for more than 2 years; acute kidney injury is more likely when creatinine clearance is below 60 mL/min.

Hypocalcaemia: 3–9% with zoledronic acid and 2–11% with denosumab, five to six times more frequent without calcium and vitamin D. With denosumab, give daily vitamin D (400 IU) and calcium (500 mg). Low baseline calcium and kidney impairment raise the risk; it usually appears within 10 days, so monitor early.

Flu-like reactions within 3 days (18–22% with zoledronic acid, 8–10% with denosumab); atypical femoral fractures are rare.

Older age is itself a risk factor for kidney toxicity, so check kidney function and adjust the dose.

Bone-modifying agents do not replace pain relief: use non-opioids and opioids, single-fraction radiotherapy (8 Gy) for painful uncomplicated metastases, and rehabilitation to maintain activities of daily living and quality of life.