Treating Idiopathic Hypercalcemia in Cats with Alendronate

Use of Bisphosphonates to Treat Severe Idiopathic Hypercalcaemia in a Young Ragdoll Cat

J.L. Whitney, V.R.D. Barrs, M.R. Wilkinson, K.A. Briscoe, and J.A. Beatty

Journal of Feline Medicine and Surgery 2011;13:129-134.

Within the past 20 years, idiopathic hypercalcemia has emerged to become the most common type of hypercalcemia in cats (1-3). This condition is now widespread in the United States and has also been reported in many other parts of the world. Cats with idiopathic hypercalcemia range in age from very young to geriatric, and longhaired cats are over-represented (1-5). The diagnosis is based on the laboratory findings (high serum total and ionized calcium concentrations with low to low-normal PTH values) after exclusion of other less common causes of hypercalcemia (especially malignancies) (3-6).

Because the pathogenesis for idiopathic hypercalcemia remains unknown, treatment for this condition can be difficult. Response to dietary changes have produced mixed results, and most cats eventually require medical management, such as prednisolone, to control the hypercalcemia (4,7,8). When neither dietary modification nor treatment with prednisolone are successful in lowering the high circulating calcium concentrations, treatment with an oral bisphosphonate (i.e., alendronate; Fosamax) has been suggested as another option (4,7,8).

Despite the fact that protocols for alendronate have been published in numerous proceedings and book chapters (5,7,8), no case studies of cats with idiopathic hypercalcemia had been reported in a refereed scientific journal until this present report.

In this case report by Whitney et al. (9), the authors describe a cat with well-documented idiopathic hypercalcemia. This cat failed to respond completely to prednisolone but responded well to long-term treatment using alendronate, with resolution of all clinical and biochemical signs of hypercalcemia.

Case report
A 3-year-old Ragdoll cat was examined for investigation of polyuria, polydipsia, vomiting, weight loss, and hypercalcemia. Physical examination was unremarkable (body weight, 3.19 kg). Serum biochemical abnormalities included hypercalcemia (total calcium, 3.8 mmol/L [15.2 mg/dl]; reference range, 1.75-2.6 mmol/L) and hypophosphatemia (1.8 mmol/L; reference range, 2.1-2.8 mmol/L).

Repeat analysis confirmed total (3.74 mmol/L [15 mg/dl]) and ionized (1.8 mmol/L; reference range, 1.2-1.32 mmol/L) hypercalcemia. Urine specific gravity was 1.040 with normal concentrations of urea nitrogen and creatinine. On microscopic examination of the urine, occasional calcium oxalate crystals were identified.

Thoracic radiographs and abdominal ultrasound examination were unremarkable. Parathyroid glands could not be identified on cervical ultrasound examination. Serum intact parathyroid hormone (iPTH) was low, consistent with a parathyroid-independent process (iPTH < 12 pg/ml; reference range, 22-122 pg/ml). Idiopathic hypercalcemia was diagnosed and the cat was discharged on prednisolone (5 mg once daily, PO).

On day 14, the cat was reported to be lethargic and had lost weight (down to 3.06 kg). Persistent total hypercalcemia (3.7 mmol/L [14.8 mg/dl]) and ionized hypercalcemia (1.73 mmol/L) were detected. The frequency of prednisolone therapy was increased to 5 mg, BID. At one month, the owners reported ongoing lethargy and the cat had become anorectic. Serum total hypercalcemia (3.94 mmol/L [15.8 mg/dl]) and ionized hypercalcemia (1.87 mmol/L) persisted so the cat was switched to oral alendronate (Fosamax) 5 mg once weekly, PO.

At recheck, 1 month later, the cat was bright and eating well. No abnormalities were found on physical examination and she had gained weight. Total hypercalcemia was identified (3.85 mmol/L [15.4 mg/dl]). The dose of alendronate was increased to 10 mg once weekly, PO. One month later, the frequency of administration was subsequently increased to 10 mg every 3 days because of persistent hypercalcemia.

At assessment 5 months after initial presentation, the cat was bright with a good appetite and had gained 1.1 kg. No abnormalities were detected on physical examination, serum biochemistry or urinalysis. The serum total calcium (2.6 mmol/L [10.4 mg/dl]) and ionized calcium (1.6 mmol/L) were normal. The dose frequency of alendronate has been gradually reduced. At the time of writing, 18 months after initiating bisphosphonates, the cat is clinically and biochemically normal. The current dose of alendronate is 10 mg administered once weekly.

Bottom Line

This is the first reported case of the use of oral bisphosphonate, alendronate, in the successful long-term management of idiopathic hypercalcemia in a cat (9).

Pharmacology of the bisphosphonates

The bisphosphonates are a group of drugs that inhibit bone resorption and are the standard therapy for malignant humoral hypercalcemia in human patients (10). They act by inhibiting osteoclast apoptosis and sites of active bone turnover (11,12). When given by intravenous infusion, these drugs (e.g., pamidronate) have also been used in dogs for the treatment of primary and secondary bone cancer, cholecalciferol intoxication, and humoral hypercalcemia of malignancy (13-17).

There is a single reported case of the treatment of a cat with concurrent idiopathic hypercalcemia and chronic kidney disease with IV pamidronate (16). However, intravenous treatment with bisphosphonates is almost never needed in cats with idiopathic hypercalcemia, since the hypercalcemia is chronic and the cats are usually not in an acute crisis. Use of an oral bisphosphonates such as alendronate is preferred.

Dosing of alendronate in cats
The dosing regime in this cat (10 mg of alendronate once weekly without food) is similar to what others have reported for cats. If no decrease in serum calcium occurs after 1 month of therapy, the weekly dose can be gradually increased as high as 30 mg per week (5,7,8).

Food substantially reduces the bioavailability and absorption of oral alendronate, so it is recommended that it be administered on an empty stomach (generally after at least a 12-hour fast) (5,7,8). The oral bioavailability of alendronate in the fasted state is about 0.7% in humans, and less than 2% in all species studied (11,12).

Potential side effects of alendronate
Care must be taken when dosing cats with oral alendronate. In human patients oral alendronate administration has been associated with esophagitis and esophageal stricture in up to 15% of patients (18-22).  It is important to ensure that the medication does not stick in the esophagus, which could potentially lead to esophagitis. To minimize this risk, owners should immediately administer 5-6 ml of water orally to their cat after dosing to enhance the passage of the alendronate tablet into the stomach (5,7,8).

Effectiveness of alendronate
Overall, it appears that alendronate treatment is relative safe and effective for cats with idiopathic hypercalcemia, but further studies are needed. Oral bisphosphonates will likely replace prednisolone as the second choice for treatment of this disorder in cats.

Dietary therapy for idiopathic hypercalcemia?
However, I also believe that we need to reexamine the use of dietary therapy in these cats, since it is very likely that diet may play a role in the pathogenesis of idiopathic hypercalcemia. In my next post, I’ll discuss the role of diet, why high-fiber diets generally fail to lower calcium in these cats, and what diets may actually help some cats with mild hypercalcemia restore normocalcemia without the use of potentially toxic drugs.

References:

1. Savary KC, Price GS, Vaden SL. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000;14:184-189. 
2. Midkiff AM, Chew DJ, Randolph JF, et al. Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14:619-626. 
3. Schenck PA and Chew DJ: Idiopathic hypercalcemia in cats. Waltham Focus 2005; 15: 20-24.
4. Chew DJ, Schenck PA. Idiopathic feline hypercalcemia In: Bonagura JD,Twedt DC, eds. Kirk’s Current Veterinary Therapy XIV. St Louis: Sanders Elsevier, 2009; 236-241.
5. de Brito Galvao JF, Schenck PA, Chew DJ. Hypercalcemia: Diagnosis and treatment options in dogs and cats. Veterinary Focus 2011;21:27-34. 
6. Schenck PA, Chew DJ, Refsal K, et al: Calcium metabolic hormones in feline idiopathic hypercalcemia (abstract). J Vet Intern Med 2004;18:442.
7. Chew DJ, Schenck PA. Idiopathic hypercalcemia—what do I do? Proceeding of the North American Veterinary Conference 2007; 732-734.
8. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology, Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:221-233.
9. Whitney JL, Barrs VR, Wilkinson MR, et al. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. J Feline Med Surg 2011;13:129-134. 
10. Gnant M. Adjuvant bisphosphonates: a new standard of care? Curr Opin Oncol 2012; 24:635-642. 
11. Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18:75-85. 
12. Lin JH, Russell G, Gertz B. Pharmacokinetics of alendronate: an overview. Int J Clin Pract Suppl 1999;101:18-26. 
13. Rumbeiha WK, Fitzgerald SD, Kruger JM, et al. Use of pamidronate disodium to reduce cholecalciferol-induced toxicosis in dogs. Am J Vet Res 2000;61:9-13. 
14. Milner RJ, Farese J, Henry CJ, et al. Bisphosphonates and cancer. J Vet Intern Med 2004;18:597-604. 
15. Fan TM, de Lorimier LP, Charney SC, et al. Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement. J Vet Intern Med 2005;19:74-80. 
16. Hostutler RA, Chew DJ, Jaeger JQ, et al. Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia. J Vet Intern Med 2005;19:29-33. 
17. Fan TM. The role of bisphosphonates in the management of patients that have cancer. Vet Clin North Am Small Anim Pract 2007;37:1091-1110.
18. Lilley LL, Guanci R. Avoiding alendronate-related esophageal irritation. Am J Nurs 1997;97:12-14. 
19. Chase JL. Lowering the risk of esophagitis from alendronate therapy. Am J Health Syst Pharm 1998;55:892-893. 
20. Peter CP, Handt LK, Smith SM. Esophageal irritation due to alendronate sodium tablets: possible mechanisms. Dig Dis Sci 1998;43:1998-2002. 
21. Ribeiro A, DeVault KR, Wolfe JT, 3rd, et al. Alendronate-associated esophagitis: endoscopic and pathologic features. Gastrointest Endosc 1998;47:525-528. 
22. Abraham SC, Cruz-Correa M, Lee LA, et al. Alendronate-associated esophageal injury: pathologic and endoscopic features. Mod Pathol 1999;12:1152-1157. 

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.

References:

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.