Hypercalcemia of malignancy (HCM) occurs through three main mechanisms: (1) Humoral hypercalcemia of malignancy (HHM, 80%): tumor secretion of PTHrP (parathyroid hormone-related peptide), which activates PTH/PTHrP receptors on osteoblasts, stimulating RANKL expression and osteoclast-mediated bone resorption, while also increasing renal calcium reabsorption — most common with squamous cell carcinomas (lung, head/neck), renal cell carcinoma, and breast cancer. (2) Local osteolytic hypercalcemia (20%): direct bone destruction by metastases releasing calcium — breast cancer, multiple myeloma, lymphoma; myeloma produces osteoclast-activating factors (RANKL, MIP-1α, IL-6). (3) Calcitriol-mediated (1%): lymphoma cells express 1-alpha-hydroxylase, converting 25-OH vitamin D to active 1,25-(OH)2 vitamin D (calcitriol), which increases intestinal calcium absorption. HCM is a poor prognostic indicator — median survival after diagnosis is 1-3 months for most solid tumors.