21st June 2023

Malignant hypercalcaemia

Aetiology

Malignant hypercalcaemia is a common electrolyte abnormality occurring in up to 30% of patients with cancer. There are several mechanisms which can lead to hypercalcaemia in the context of cancer:

• PTH-related protein (PTHrP) secretion – this is the most common cause. PTHrP is typically secreted by squamous cell carcinomas, breast, ovarian, kidney and bladder cancers. The protein shares homology with PTH and so binds to the PTH-1 receptor, resulting in bone resorption distal tubular calcium reabsorption.
• Osteolytic metastases – caused by the local breakdown of bone due to the presence of bony metastases, promoting osteoclast production. Most commonly associated with breast cancer and multiple myeloma.
• Ectopic PTH secretion – a rarer entity, seen associated with ovarian cancers, small cell and squamous cell cancers of the lung.

Management

Treatment depends on the severity of the hypercalcaemia and the patient’s symptomatology.

• Mild hypercalcaemia: <3.00mmol/L
• Moderate hypercalcaemia: 3-3.50mmol/L
• Severe hypercalcaemia: >3.50mmol/L or symptomatic

Treatment for malignant hypercalcaemia should firstly include conservative measures, targeting potential contributing factors, such as avoiding thiazide diuretics, calcium supplementation and dehydration. Initially, patients should be managed with intravenous fluid resuscitation as concurrent hypovolaemia is common and correcting this will promote renal excretion. Typically 2L of fluid is required every 24 hours for 48-72 hours. Following this, if renal function is permissive, zoledronic acid 4 mg IV should be administered, re-checking the calcium after 4-7 days. If GFR is 30-50 ml/min, administer a reduced dose of 3 mg.

If malignant hypercalcaemia is recurrent, especially in the context of malignancy with extensive bony metastases, denosumab may be administered prophylactically. This has the additional benefit of aiding with bony pain. It is important that prior to its administration, serum vitamin D levels are checked. Supplementation with calcium and vitamin D should be co-administered if denosumab is to be continued. Denosumab is licensed for the treatment of bony pain in all solid tumours with bony metastases except prostate cancer, where zoledronic acid should be employed.