Treating paraneoplastic hypercalcemia in dogs and cats
Cancer accounts for about 50% of all deaths in companion animals more than 10 years of age.1 Cancer-related morbidity and mortality can result not only from neoplastic invasion of vital organs such as the pulmonary parenchyma or liver but also from neoplasm-associated alterations in bodily structure or function that occur distant to the primary tumor and any metastatic lesions. These alterations are classically referred to as paraneoplastic syndromes. Hypercalcemia is a common paraneoplastic syndrome in people and companion animals that frequently contributes to morbidity.2-6 Various tumor-related factors may lead to paraneoplastic hypercalcemia, including the release of humoral peptides, the abnormal expression of membrane-bound ligands, and dysregulated enzymatic pathways responsible for calcium homeostasis.7-9The most common cause of hypercalcemia in companion animals is cancer, with about 45% to 65% of hypercalcemic dogs and 10% to 30% of hypercalcemic cats having underlying neoplasia.7,10-13 The cancers that most frequently lead to paraneoplastic hypercalcemia are T-cell lymphoma and apocrine gland anal sac adenocarcinoma in dogs and lymphoma, bronchogenic carcinoma, and squamous cell carcinoma in cats.7,10,14 Given the prevalence of cancer in geriatric pets and the morbidity associated with hypercalcemia, this review focuses on the diagnosis and treatment of paraneoplastic hypercalcemia in dogs and cats.
These mediators exert their biologic activities on three target organs: the kidneys, intestines, and bone matrix. If serum calcium concentrations are decreased, the parathyroid glands secrete PTH to act on 1) the distal renal tubules, causing calcium reabsorption and phosphorus excretion from the kidney; 2) the intestines indirectly through the conversion of calcidiol to highly active calcitriol in the proximal renal tubules, which will increase intestinal absorption of calcium and phosphate; and 3) the bones, either by stimulating the activity of existing bone cells (early effect) or by increasing the number of osteoclasts and their bone resorption activities (late effect) via PTH's effect on osteoblasts.
Conversely, if serum calcium concentrations are elevated, PTH secretion is down-regulated, leading to 1) a net calcium loss through the distal tubules, 2) a reduction in intestinal calcium absorption, and 3) diminished osteoclastic bone resorption. Both PTH and calcitriol promote calcium retention within the body, while calcitonin reduces calcium mobilization from the skeleton chiefly by inhibiting osteoclastic bone resorption.9,15 While PTH has a positive feedback effect on calcitriol synthesis, the main negative feedback mechanisms on calcitriol production are calcitriol itself, as well as hypercalcemia and high phosphorus concentrations.16 Calcitriol also provides a negative feedback effect on PTH secretion.