Alendronate Dosing Protocol for Cats with Idiopathic Hypercalcemia

I have a quick question for you about the use of alendronate for treatment of cats with idiopathic hypercalcemia. First of all, I wanted to find out if you recommend this treatment, and what your experience is with the drug.

The protocol that I've been using is to start with an oral dose of 10 mg once weekly, and then increase the dose to 20 mg once weekly if needed. In a few cats, I've had to go as high as 30 mg per week to lower the total and ionized calcium concentrations.

Have you ever done twice weekly dosing? I was recently referred a hypercalcemic cat whose dose was changed from 20 mg once a week to 10 mg twice a week by the veterinarian in the hopes that twice weekly dosing would be more effective. I know it theoretically can be given twice weekly, but was wondering if you've found that twice weekly dosing was more effective.

Thank you for your help.

My Response:

As you know, treatment for idiopathic hypercalcemia in cat is currently empiric, since the cause of the disorder remains unknown. I generally start with a change in diet as a first step in treatment (1), since normocalcemia is sometimes restored after a change to a different diet. However, even in cats that show an initial response to dietary intervention, the duration of normocalcemia may be short-lived and the hypercalcemia can relapse. In these cats, I then turn to medical therapy (i.e., glucocorticoids or bisphosphonates) to help control the hypercalcemia.

Even though not extensively reported, I consider bisphosphonate therapy with alendronate (i.e, Fosamax, Merck; generic formulations also available) to be a better alternative than prednisolone for most cats with idiopathic hypercalcemia that fail dietary intervention (2-4). The complications I commonly see with chronic high-dose glucocorticoid treatment include muscle wasting and iatrogenic diabetes. Remember that steroids are catabolic for muscle tissue (5,6) and will produce insulin-resistance that can lead to hyperglycemia and overt diabetes mellitus (7).

Alendronate dosing protocol
Most cats with idiopathic hypercalcemia will respond to oral alendronate, at a dose range of 10-40 mg once weekly. Like you, I start with an initial oral dose of 10 mg per week, and then gradually increase the dose based on ionized calcium concentrations monitored at 4-6 week intervals (4).

This treatment protocol will restore normocalcemia in over two-thirds of the hypercalcemic cats treated with an average weekly dose of 15 mg (4). As with dietary therapy, many will eventually show relapse and will require an increase in alendronate dosage or the addition of glucocorticoid therapy. In a few cats, the serum ionized calcium will drop too far, and the dose can be decreased to 5 mg per week or 10 mg given every other week (2,4).

Alendronate is poorly absorbed from the GI tract
The oral bioavailability of alendronate in cats is poor. In one study, the percentage of the drug that was actually absorbed when administered to cats was found be only 3% (8). This percentage fell about 10-fold when alendronate was formulated in tuna juice.

To maximize intestinal absorption of this drug, we recommend that the cats be fasted overnight (12-18 hour fast) prior to the administration of the alendronate. The medication should then be given with 6-ml of plain water (to ensure passage of the tablet into the stomach), and the fast continued for at least 2-4 additional hours (4).  We do not recommend any kind of alendronate that has been formulated by compounding pharmacies in flavored solution or suspension because that will likely lead to a marked decrease in the intestinal absorption.

Twice weekly dosing of alendronate?
I don't see any problem with twice-weekly dosing of the alendronate. However, based on the pharmacokinetics of the drug, it's unlikely to be any more effective than once-weekly dosing. In humans, the original treatment protocols recommended a dosage of 10 mg once a day, but this was subsequently changed to 70 mg per week based on pharmacokinetic studies (9).

Remember, however, that the biggest issue with the use of this drug in cats is the need for prolonged fasting in order to even achieve 3% absorption. If the owners are giving the drug with food, less than 0.5% of the drug will be absorbed, if it's going to be absorbed at all.

Because of the issues associated with the prolonged fasting, I would not recommend twice-weekly dosing in my feline patients. We know that once-weekly dosing works in most cats, and the "stress" associated with twice-weekly prolonged fasting (as well tablet administration followed by a 6-ml flush of water) is just too much for the cat or the owner.

References:

1. Peterson ME. Nutritional management of endocrine disease in cats. Proceedings of the Royal Canin Feline Medicine Symposium 2013;23-28.
2. 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.
3. 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.
4. de Brito Galvao JF, Chew DJ, Parker VJ. Management of idiopathic hypercalcemia. In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, in press.
5. Horber FF, Scheidegger JR, Grunig BE, et al. Thigh muscle mass and function in patients treated with glucocorticoids. Eur J Clin Invest 1985;15:302-307. 
6. Menconi M, Fareed M, O'Neal P, et al. Role of glucocorticoids in the molecular regulation of muscle wasting. Crit Care Med 2007;35:S602-608. 
7. Lowe AD, Graves TK, Campbell KL, et al. A pilot study comparing the diabetogenic effects of dexamethasone and prednisolone in cats. J Am Anim Hosp Assoc 2009;45:215-224. 
8. Mohn KL, Jacks TM, Schleim KD, et al. Alendronate binds to tooth root surfaces and inhibits progression of feline tooth resorption: a pilot proof-of-concept study. J Vet Dent. 2009;26:74-81.
9. Fosamax (Alendronate sodium). Product insert. www.merck.com.

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.