Clinical Information

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 posttranslational 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

5) As an indispensable component of successful pregnancy and fetal development (embryonic gene deletion is lethal in mammals)

Humoral hypercalcemia of malignancy (HHM) is a common complication of cancer. Elevations of PTHrP are the most common cause of malignancy-associated hypercalcemia. PTHrP leads to hypercalcemia by stimulating calcium resorption from bone and reabsorption in the kidneys. It also plays a significant function in osteolysis in bony metastases, particularly in breast cancer, and has been postulated to play a role in malignancy-associated cachexia through induction of orexigenic peptides.

Various malignancies secrete PTHrP resulting in HHM. PTHrP production is most commonly seen in carcinomas of breast, lung (squamous), head and neck (squamous), kidney, bladder, cervix, uterus, and ovary. Neuroendocrine tumors may also occasionally produce PTHrP. Most other carcinomas, sarcomas, and hematolymphoid malignancies only sporadically produce PTHrP, with the exception of T-cell lymphomas and myeloma. In HHM, the typical laboratory presentation includes elevated calcium and PTHrP, decreased PTH, and suppressed serum 1,25 dihydroxyvitamin D3 levels. Patients with HHM may have increased PTHrP values before treatment. PTHrP level decreases and PTH level increases, accompanied by decreased serum calcium values, are observed with successful treatment.