What underlies humoral hypercalcemia of malignancy?

• A. Tumors secrete PTH-related peptide (PTHrP) causing PTH-independent hypercalcemia.
• B. PTHrP-mediated hypercalcemia results from suppression of PTH.
• C. Tumors secrete calcitonin causing PTH-independent hypercalcemia.
• D. Vitamin D activation by tumors causes hypercalcemia.

Answer: (A)

Humoral hypercalcemia of malignancy is driven by a tumor-produced peptide that closely mimics PTH. The cancer cells secrete PTH-related peptide (PTHrP), which binds the same receptors as PTH on bone and kidney. In bone, this stimulates osteoclast activity and bone resorption, releasing calcium into the bloodstream. In the kidneys, it increases calcium reabsorption, further raising serum calcium. Because the calcium is high, the body's feedback system suppresses the real parathyroid hormone, so PTH levels are low or inappropriately normal despite the hypercalcemia. This combination—calcium elevation with suppressed PTH—is the hallmark of HHM and directly points to PTHrP as the underlying driver.

Other mechanisms aren’t the typical cause of HHM. Calcitonin production would tend to lower calcium, not raise it. Activation of vitamin D by tumors (more often seen in certain lymphomas) can cause hypercalcemia, but that’s a different pathway, not humoral PTHrP-driven.