Two pathogenic mechanisms are involved in the generation of hypercalcemia: (1) focal osteolytic bone destruction secondary to bone metastases and (2) uncoupling of bone turnover secondary to tumor-secreted humoral factors. Focal bone destruction by metastases involves the paracrine secretion of various cytokines that stimulate local osteoclasts and inhibit osteoblasts. Although this mechanism certainly contributes to hypercalcemia, it appears that systemic factors play a more important role. Malignant hypercalcemia caused by the production of humoral factors is often referred to as humoral hypercalcemia of malignancy (HHM). The humoral factor most commonly associated with HHM, including that of RCC, is parathyroid hormone-related protein (PTHrP) (Burtis et al. 1990; Mundy 1990). PTHrP causes hypercalcemia through bone resorption, as well as through renal calcium reabsorption (Rosol and Capen 1992). Partial sequence homology between PTHrP and parathyroid hormone (PTH) helps to explain the mechanisms by which this occurs. Unlike primary hyperparathyroidism, PTH levels are often normal or suppressed in cases of HHM (Walther et al. 1997; Flombaum 2000). Interleukin-6 (IL-6) and prostaglandin (PG), both of which stimulate osteoclast activity, represent additional humoral factors involved in HHM (Papac and Poo-Hwu 1999).

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