Mechanisms involved in the pathogenesis of malignant hypercalcaemia include increased bone resorption (osteolysis) and systemic release of humoral hypercalcaemic factors, with or without evidence of metastatic bone disease. Local osteolytic hypercalcaemia is attributed to tumour cell production of cytokines, particularly interleukins and tumour necrosis factors (TNF), prostaglandins, and growth factors, which stimulate prostaglandin function, while parathyroid hormone-related peptide (PTHrP) is the best characterized humoral mediator of hypercalcaemia.

In some tumours, such as squamous cell cancers, humoral mechanisms are dominant, while in others, for example multiple myeloma and lymphoma, osteolysis predominates. In breast cancer, both osteolysis and humoral mechanisms appear to be important. Dehydration is also an important contributory factor; calcium is a potent diuretic causing salt and water loss.

In myeloma, renal impairment may also develop from deposition of Bence-Jones proteins. Some lymphomas produce active metabolites of vitamin D that increases the intestinal absorption of calcium.

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