29th December 2024

Causes of malignant hypercalcaemia

Parathyroid hormone-related protein (PTHrP)

PTHrP production by cancer cells accounts for 80% of malignant hypercalcaemia. This is most commonly associated with squamous cell cancers (e.g. squamous cell lung cancer), renal, bladder, breast and ovarian cancers. The PTHrP stimulates osteoblasts to produce RANK-ligand, which then activates osteoclasts to resorb bone, resulting in hypercalcaemia. Of note, this ectopic production means that malignant hypercalcaemia may be present even in the absence of bony metastases.

Osteolytic bone metastases

Osteolytic bone metastases, commonly found in myeloma and breast cancer, account for 20% of malignant hypercalcaemia.

Other – calcitriol and PTH

Other causes of malignant hypercalcaemia make up less than 1% of cancer-related calcium release.

Ectopic 1,25-dihydroxyvitamin D (calcitriol) can be produced in ovarian and germ cell tumours that release 1-alpha hydroxylase or in lymphoma cells. Excess calcitriol release in either case will stimulate bone resorption.

PTH (parathyroid hormone) itself may be produced by tumours, in the case of parathyroid carcinoma, or through ectopic release by small cell lung cancers, lung adenocarcinomas and renal cell cancer.