What is the mechanism of hypercalcemia in malignancy?
Hypercalcemia of malignancy is caused by two mechanisms:
1. Osteolytic release of calcium from bone due to direct invasion of the neoplasm, as seen in skeletal metastasis of solid tumors of breast, lung, kidneys, and multiple myeloma. The release of calcium from the bone is mediated by the receptor activator of nuclear factor kappa B (RANK) and receptor activator of nuclear factor kappa B ligand (RANK-L) interaction. The RANK-L is produced by the bone marrow stromal cells and osteoblasts. The binding of RANK present on osteoclast progenitor cells to its ligand results in osteoclast activation, proliferation, and bone resorption, resulting in the release of calcium. The neoplastic environment with activated T cells, inflammatory cytokines (IL-6, IL-1B0, tumor necrosis factor-alpha) all promote the RANK-L-driven bone resorption and disturb the RANK/RANK-L/osteoprotegerin balance.
2. Stimulation of osteoclast activity by the release of tumor-derived endocrine factors. In this PTHrP and 1,25-dihydroxyvitamin D play an important role. PTHrP is secreted by squamous cell cancer of the lung, head and neck, renal cell, ovarian, breast, and esophageal cancer. It causes stimulation of the osteoclasts, increases calcium absorption in the loop of Henle and the distal convoluted tubule. Activated vitamin D, in turn, is secreted by lymphomas, or tumor-associated macrophages that possess 1-alpha hydroxylase activity .
