Similarly to the mechanism of mithramycin, calcitonin reduces osteoclastic activity and reduces hypercalcemia in small animals with vitamin D toxicosis.^60,61 Reported dosages range from 4.5 to 8 IU/kg given subcutaneously every eight hours to 5 IU/kg given subcutaneously every 12 hours.^61,62 For cats with rodenticide toxicosis, a dosage of 4 IU/kg given intramuscularly every 12 hours was effective and well-tolerated.⁶³ Unlike calcitonin's documented modest efficacy for the treatment of hypercalcemia secondary to vitamin D toxicosis, calcitonin's utility in successfully managing hypercalcemia of malignancy in companion animals remains to be investigated. Calcitonin is used in people with Paget's disease and hypercalcemia of malignancy, but the effects of treatment can be quite variable.^64-66 The main side effects of calcitonin are anorexia and vomiting. Its use is limited by cost and the fact that its effects are short-lived and because resistance frequently develops in a matter of days.¹⁵

Gallium nitrate is an antineoplastic that binds to the hydroxyapatite crystals in bone, thereby reducing their solubility.^67,68 In some studies, gallium nitrate was demonstrated to be more effective than bisphosphonates at reducing calcium concentrations in people with hypercalcemia.⁶⁹ However, despite this apparent efficacy, it is not considered a first-line treatment option for managing hypercalcemia given its potential for nephrotoxicity.

Novel therapies targeting the intercellular communication of osteoblasts and osteoclasts are under investigation. RANKL is expressed by osteoblasts and T lymphocytes and binds to its cognate receptor, receptor activator of nuclear factor kappa-B (RANK), present on the surface of osteoclast precursors and osteoclasts, leading to their proliferation, maturation, and activation. Promising antiresorptive molecules such as osteoprotegerin analogues, a soluble decoy RANKL receptor, or RANK nonfunctional constructs are being evaluated to decrease osteoclast activity and pathologic bone resorption.^9,70

Paraneoplastic hypercalcemia is a common and serious complication observed in small-animal cancer patients. Various tumor types are capable of inducing hypercalcemia in cancer patients through multiple mechanisms that subvert or dysregulate calcium homeostasis. Canine T-cell lymphoma is the most common neoplasia associated with hypercalcemia, but other less frequent cancers and non-neoplastic diseases should be considered as important differential diagnoses in any patient with pathologic serum calcium elevations. Familiarity with clinical signs associated with hypercalcemia may allow for the early detection of underlying disease processes. The timely institution of definitive treatments and supportive management strategies will minimize the morbidity, and potential mortality, in companion animals suffering from hypercalcemia of malignancy.

Pamela Lucas, DVM
Hugues Lacoste, DVM, DACVIM (oncology)
Louis-Philippe de Lorimier, DVM, DACVIM (oncology)
Timothy M. Fan, DVM, PhD, DACVIM (oncology, internal medicine)
Department of Veterinary Clinical Medicine
College of Veterinary Medicine
University of Illinois
Urbana, IL 61802

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3. Rankin W, Grill V, Martin TJ. Parathyroid hormone-related protein and hypercalcemia. Cancer 1997;80(8 Suppl):1564-1571.

4. Weir EC, Norrdin RW, Matus RE, et al. Humoral hypercalcemia of malignancy in canine lymphosarcoma. Endocrinology 1988;122;602-608.

5. Weller RE. Paraneoplastic disorders in dogs with hematopoietic tumors. Vet Clin North Am Small Anim Pract 1985;15:805-816.

6. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995). J Am Vet Med Assoc 2003;223:825-831.