However, hypercalcemia may occur when the concentration of calcium present in the extracellular fluid overwhelms the kidneys' compensatory mechanisms. As a consequence of dehydration, renal blood flow and the glomerular filtration rate decrease and proximal tubular calcium and sodium reabsorption increase leading to further increases in serum calcium concentrations. Anorexia, nausea, and vomiting associated with circulating volume contraction exacerbate dehydration. The normal daily exchange between bone and extracellular fluid is quite small. The fundamental cause of cancer-induced hypercalcemia is increased bone resorption with calcium mobilization into the extracellular fluid and secondarily, inadequate renal calcium clearance.
Osteolytic hypercalcemia is due to direct bone destruction by primary or metastatic tumor.
Humoral hypercalcemia is mediated by circulating factors secreted by malignant cells without evidence of bony disease. PTHrP is a primitive protein that appears to have important roles in calcium transport and developmental biology. Dehydration, anorexia, nausea, and vomiting that exacerbate dehydration reduce renal calcium excretion. Thiazide diuretics increase renal calcium reabsorption and may precipitate or exacerbate hypercalcemia. Mundy GR, Ibbotson KJ, D'Souza SM, et al.