Monday, June 11, 2012

A 5-Tiered Approach for Medical Treatment of Hypercalcemia in Dogs

The definitive treatment of hypercalcemia involves treating or removing the underlying cause (see my post on the Top 10 Differentials for Hypercalcemia. Unfortunately, the etiology may not be readily apparent, and if the hypercalcemia is severe, it may be life-threatening. In those dogs, supportive medical measures should be used to help decrease the serum calcium concentration (1-3).

A mild degree of hypercalcemia may not be immediately dangerous and provides time to establish a definitive diagnosis before starting any treatment. However, in dogs with severe hypercalcemia, diagnostic and therapeutic efforts may need to proceed concurrently. Most dogs with a total calcium concentration >15.0 mg/dl will show systemic signs, and those with a calcium concentrations >18.0 mg/dl are critically ill.

Fluid Therapy and Diuresis: The First Tier of Medical Treatment
Fluid therapy with sodium chloride (saline) infusion is the first step in treating moderate to severe hypercalcemia. Sodium and calcium share the same renal reabsorptive system, so providing additional sodium to renal tubules will diminish calcium reabsorption, and increase calciuresis (1-4).

Diuretics can be administered following rehydration and fluid volume expansion for treatment of persistent and severe hypercalcemia that is not associated with renal failure. Loop diuretics such as furosemide (2-4 mg/kg, IV or SQ, every 8-12 hours) will increase calcium excretion by the kidneys.

In contrast to the loop diuretics, thiazide diuretics are contraindicated in hypercalcemia because these agents will decrease calcium excretion by the kidneys and therefore cause worsening of the hypercalcemia.

Gluococorticoids: The Second Tier of Medical Treatment
Glucocorticosteroids provide a second tier of treatment for hypercalcemic cases that do not respond adequately to IV fluids and furosemide. Glucocorticoids, such as prednisone (1-2 mg/kg, IM, every 12 hours) or dexamethasone (0.1-0.2 mg, IV or IM, every 12 hours), reduce bone resorption of calcium, reduce intestinal calcium absorption, and increase renal calcium excretion (1-3).

In addition, glucocorticoids are cytotoxic to malignant lymphocytes, leading to substantial reduction in serum calcium concentration in dogs with hypercalcemia secondary to lymphoma or myeloma, hypervitaminosis D, granulomatous disease, and hypoadrenocorticism. However, use of glucocorticoids may make definitive diagnosis of the underlying cause of the hypercalcemia difficult. This is especially true with lymphosarcoma because steroids are lymphocytolytic and may alter lymph node architecture and patterns of lymphocyte infiltration in bone marrow.

Calcitonin: The Third Tier of Medical Treatment
If hypercalcemia is severe, use of calcitonin as a third tier of treatment may be a valuable adjunctive therapy when fluid deficit replacement, saline diuresis, furosemide, and prednisone have failed to lower the serum calcium concentration (3,4). This drug has a rapid calcium-lowering effect, evident within 2 hours of administration, due to inhibitory effects on osteoclastic activity and renal tubular reabsorption of calcium.

The response to calcitonin, while rapid in onset, is usually short lived. Therefore, the drug (calcitonin-salmon for injection; 200 IU/ml; Miacalcin, Novartis) is generally administered at the dosage of 4 IU/kg IV, followed by 4–8 IU/kg, SC, every 12-24 hours as needed to control hypercalcemia.

Bisphosphonates: The Fourth Tier of Medical Treatment
The fourth tier of treatment is to add a bisphosphonate for the more prolonged control of hypercalcemia (2,5,6). Bisphosphonates act to lower serum calcium by reducing the number and action of osteoclasts. However, because these drugs do not act to rapidly lower the serum calcium, they are not as helpful in the acute management of life-threatening hypercalcemia. That said, because parenteral bisphosphonates are so effective in controlling hypercalcemia, many internists would use these agents even before salmon calcitonin is administered.

Pamidronate is the most commonly used parenteral bisphosphonate in dogs; the recommended dosage is 1.0-2.0 mg/kg administered in 0.9% saline as an slow infusion given over 4 hours (5,6). Adequate hydration is essential when treating with bisphosphonates since these drugs may cause nephrotoxicity, especially at higher doses. Pamidronate is now available as a generic preparation (e.g., from Florida Infusion), making it very cost effective.  The pamidronate insfusion can be repeated at 3-4 week intervals as needed to maintain normocalcemia.

Oral bisphosphonates, such as alendronate (Fosamax, Merck), are more convenient to use and can be administered once weekly at the dose of 2-4 mg/kg, PO (2). However, oral alendronate does not work as well to lower the serum calcium concentration as IV pamidronate. In addition, alendronate is more expensive and can cause esophagitits.

Calcimimetics: The Fifth Tier of Medical Treatment
Calcimimetics are the newest class of drugs, which act to mimics the action of calcium on tissues (i.e, they are calcium-sensing receptor agonists). The mostly commonly used drug of this class is cinacalcet (Sensipar; Amgen), available as 30 mg tablets.

These drugs, by interacting with the calcium-sensing receptors in the parathyroid glands to reduce the secretion of PTH, can effectively suppress circulating PTH in all forms of hyperparathyroidism (7). They have become a major therapy for secondary hyperparathyroidism associated with renal failure (7) as well as for treatment of certain patients with primary hyperparathyroidism (8,9). These drugs would be of no benefit for dogs with hypercalcemia of malignancy or vitamin D toxicosis.

Administration of cinacalcet will not cure hyperparathyroidism. It can only decrease parathyroid hormone secretion to a certain extent. In human patients with primary hyperparathyroidism, the drug  decreases mean serum calcium concentrations only by about 1 mg/dl.

In dogs, the dose is empirical, with a recommended starting dose being 7.5 to 3 0 mg per dog once daily. Cinacalcet is very expensive, with the cost of each 30-mg tablet of being over $10! Becasue of it's limited effectiveness and expense, cinacalcet is generally used as the "last resort" for medical treatment.

  1. Schenck PA, Chew DJ, Nagode LA, et al. Disorders of calcium: hypercalcemia and hypocalcemia. In: Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, ed. DiBartola SP, 3rd ed., pp. 122–194. Saunders Elsevier, St. Louis, MO, 2006. 
  2. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 4th ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233. 
  3. Nelson RW, Delany SJ. Elliott DE. Metabolic and electrolyte disorders. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine, 4th Ed. St. Louis, Mosby: 2008. 
  4. Ralson SH. Medical management of hypercalcemia. British Journal of Clinical Pharacology 1992; 34:11-20. 
  5. Fan TM. The role of bisphosphonates in the management of patients that have cancer. Veterinary Clinics of North America Small Animal Practice 2007;37:1091-110. 
  6. Hostutler RA, Chew DJ, Jaeger JQ, et al. Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia. Journal of Veterinary Internal Medicine 2005;19:29-33.
  7. Wuthrich RP, Martin D, Bilezikian JP. The role of calcimimetics in the treatment of hyperparathyroidism. European Journal of Clinical Investigation 2007; 37:915-922. 
  8. Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism 2005; 90:135-141. 
  9. Rothe HM, Liangos O, Biggar P, et al. Cinacalcet treatment of primary hyperparathyroidism. International Journal of Endocrinology 2011;2011:415719. Epub 2011 Mar 6.

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