Parathyroid hormone-related peptide (PTHrP) exists in several isoforms, ranging in size from 60 to 173 amino acids, which are created by differential splicing and post-translational processing by prohormone convertases. PTHrP is produced in low concentrations by virtually all tissues. The N-terminus and the secondary structure of multiple isoforms of PTHrP resemble parathyroid hormone (PTH), allowing PTHrP to bind to the same receptor as PTH. The physiological role of PTHrP can be divided into 5 categories: 1) transepithelial calcium transport, particularly in the kidney and mammary gland; 2) smooth muscle relaxation in the uterus, bladder, gastrointestinal tract, and arterial wall; 3) regulation of cellular proliferation; 4) cellular differentiation and apoptosis of multiple tissues; and 5) as an indispensable component of successful pregnancy and fetal development (embryonic gene deletion is lethal in mammals).

Depending on the patient population, up to 80% of patients with malignant tumors and hypercalcemia will be suffering from humoral hypercalcemia of malignancy (HHM). Of these, 50% to 70% might have an elevated parathyroid hormone-related peptide (PTHrP) level. These patients will also usually show typical biochemical changes of excess parathyroid hormone (PTH)-receptor activation, namely, besides the hypercalcemia, they might have hypophosphatemia, hypercalcuria, hyperphosphaturia, and elevated serum alkaline phosphatase. Their PTH levels will typically be less than 30 pg/mL or undetectable.

In patients with biochemical findings that suggest, but do not prove, primary hyperparathyroidism (eg, hypercalcemia, but normal or near-normal serum phosphate, and a PTH level that is within the population reference range but above 30 pg/mL), HHM should be considered as a diagnostic possibility, particularly if the patient is elderly, has a history of malignancy, or risk factors for malignancy. An elevated PTHrP level in such a patient is highly suggestive of HHM as the cause for the hypercalcemia.