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.

Nutritional Management of Idiopathic Hypercalcemia in Cats

Over the last 15 years, idiopathic hypercalcemia has emerged to become the most common cause of hypercalcemia in cats (1-8). Although the underlying cause of this syndrome remains unclear, it is very likely that the cats' diet may be involved, especially the feeding of acidifying, magnesium-restricted diets designed to minimize struvite crystalluria and urolithiasis (9,10). For more information, see my last post on What's Causing Idiopathic Hypercalcemia in Cats?

Before the introduction of high-carbohydrate, magnesium-restricted acidifying diets by the pet food industry, cats did not develop idiopathic hypercalcemia — at least it was never reported until 1999, (1) and I certainly did not see a cat until the mid-1990s.

Nutritional Therapy

I generally start with diet modification as a first-line treatment. If an acidifying diet is being fed, it should be discontinued. However, it may not always be clear that the cat food being fed is an acidifying diet — one should always closely examine the ingredient list to look for the presence of an added urinary acidifier, such as dl-methionine, phosphoric acid, and ammonium chloride.

Although feline urine is normally mildly acidic, feeding cats commercial diets containing high amounts of carbohydrate (e.g., starch and fiber) will result in an alkaline urine pH (11,12). Therefore, many commercial cat food diets contain added acidifiers in order to “counteract” the alkalizing effects of the high carbohydrate diet, even when it is not promoted as a urinary tract diet.

No matter what type of diet is chosen, it is best to feed a wet-only diet to promote urinary dilution and lessen the chance for calcium oxalate stones (13). To this end, we have a variety of different types of cat food diets that have been proposed to help lower calcium in cats with idiopathic hypercalcemia (3-8).

Diets Recommended in the Literature

High-fiber diets
High fiber diets (e.g., Purina OM Overweight Management, Iams Intestinal Plus Low-Residue, Hill’s w/d) will restore normocalcemia in some cats with idiopathic hypercalcemia and calcium oxalate urolithiasis (1,5). The effects of fiber on intestinal absorption are complex and depend on the type and amount of fiber, as well as the interactions with other nutrients in the diet. However, these “high fiber diets” are usually supplemented with extra calcium; therefore, calcium content does not explain why these diets are occasionally helpful in treating idiopathic hypercalcemia. Again, changing from an acidifying diet to any diet that is less acidifying (such as high fiber) would be expected to be beneficial.

Another option, of course, would be to feed a lower calcium diet and add fiber to the diet (e.g., psyllium for a mixed-fiber source or guar gum for an all-soluble source) (8). However, because high-fiber diets tend to be lower in protein, cats with idiopathic hypercalcemia chronically fed these diets can loose lean muscle mass to become muscle wasted (14,15). This is especially true if the cat’s appetite is poor, a sign present in some cats with this syndrome (1-8).

Overall, I do not find high-fiber diets to be helpful in the vast majority of cats with idiopathic hypercalcemia and no longer recommend these diets.

Renal diets
Prescription kidney diets (e.g., Purina NF Kidney Function, Royal Canin Renal LP Modified, Iams Renal Plus, Hill’s k/d) also may result in normocalcemia in some cats with idiopathic hypercalcemia (5,6). Although these renal diets appear less acidifying than most maintenance or high-fiber diets, many renal diets still contain added dl-methionine. Most renal diets are low in calcium, so its decreased consumption should lead to a decrease in the amount of calcium absorbed (4).

Remember, however, that renal diets are also restricted in phosphorus, which may lead to increased calcitriol (active vitamin D) synthesis by the kidney; the action of this increased serum calcitriol could offset the advantage of the decreased calcium absorption in cats with idiopathic hypercalcemia (5,16).

Overall, because these diets are lower in protein, renal diets are not my first choice — with time, cats with idiopathic hypercalcemia can become muscle wasted on these diets (14,15).

Diets for calcium oxalate urolithiasis
Canned diets developed to prevent calcium oxalate urolithiasis (e.g., Royal Canin Urinary SO, Purina UR Urinary St/Ox, Iams Urinary-O Plus Moderate pH/O, Hill’s c/d) may be beneficial in the treatment of cats with idiopathic hypercalcemia (5,6). These diets are restricted in calcium and tend to be less acidifying, resulting in a neutral urine pH in most cats. However, some still contain dl-methionine, which should definitely be avoided. Some of these diets are also restricted in oxalic acid, which may help prevent the calcium oxalate stones that develop in 10-15% of cats with idiopathic hypercalcemia.

However, I do not find any of these “calcium oxalate” diets to be very helpful in normalizing the high ionized calcium concentrations found in cats with idiopathic hypercalcemia. Therefore, I cannot strongly recommend these diets, especially if no calcium oxalate stones are present.

Diets That I Recommend

Canned commercial diets with a "natural" macronutrient composition
Feeding commercial canned diets with a composition similar to what cats would eat in the wild—i.e., 40-60% protein, 30-50% fat, and <15% carbohydrates (17-20)— will also be beneficial in lowering serum calcium concentrations in some cats, particularly those with mild forms of idiopathic hypercalcemia.

One can use the online “Protein/Fat/Carbs Chart” found at www.catinfo.org to select a canned cat food that will provide a nutritional composition similar to what cats would ingest in small prey (e.g., small rodents, birds, and insects). Although this diet composition will result in an acidic urine pH (normal for cats), a high-protein diet is preferable over added acidifiers for prevention of struvite crystal formation in cats (12,21) and is not associated with the same degree of metabolic acidosis.

In addition to the macronutrient composition, one should ensure that the canned food selected does not have any added acidifiers (e.g., dl-methionine, phosphoric acid, or ammonium chloride) and is not a magnesium-restricted diet. A diet with a relatively low vitamin D content (< 5 μg [< 200 IU]/1000 kcal) is recommended. Although feeding a low-calcium diet may be ideal, none of the available commercial cat foods are calcium-restricted.

Home-prepared diet restricted in both calcium and vitamin D
For more control over the exact macronutrient, mineral, and vitamin D content of the cats’ diet, feeding a specially formulated, home-prepared diet is recommended. Some cats, especially those with mild ionized hypercalcemia, will show a good response to a diet restricted in both calcium and Vitamin D (22). Such diets must be specially formulated, since none of the commercial cat food diets could be low in either calcium or vitamin D content and still meet AAFCO guidelines to be a “complete and balanced” diet (23).

Again, I recommend formulating this diet to have a macronutritional composition similar to what cats would eat in the wild (i.e., 40-60% protein, 30-50% fat, and < 10% carbohydrates). Products containing high concentrations of vitamin D, such as organ meats and fish oil, should be avoided (22). Calcium content should be kept restricted to 600 mg per 1000 kcal of diet (in contrast, the minimal adult maintenance requirement set by AAFCO is 1500 mg per 1000 kcal) (23). Magnesium should not be restricted, and acidifiers should never be added.

Ideally, this home-prepared diet is formulated under the guidance of a veterinary nutritionist to ensure that it is nutritionally adequate for the cat. If no response is detected after a month or two on this restricted calcium diet, alternative medical therapies (e.g., glucocorticoids, alendronate) should be considered.

My Bottom Line

In cats with idiopathic hypercalcemia, clinical signs and the associated degree of ionized hypercalcemia are usually mild, at least at diagnosis. In general, the severity of hypercalcemia in these cats tends to be slowly progressive.

Therefore, as the first step in management of these cats, I recommend changing their diet to a canned food that has a macronutrient composition closer to a cat’s carnivorous diet in the wild — in other words, high protein, moderate fat, very low carbs, not magnesium-restricted, and no added acidifiers (17-20). Remember that, at least as far as we know, cats eating this way for many hundreds of years did not develop idiopathic hypercalcemia, so I'm hoping that Mother Nature knows best when it comes down to what these cats should be fed.

One should monitor ionized calcium concentrations at 4 and 8 weeks during this initial dietary change. If hypercalcemia persists, the diet can be switched to a home-prepared, formulated calcium- and vitamin D-restricted diet (22). Again, I would still maintain a macronutrient composition that mimics a cat’s natural diet.

If nutritional management fails to normalized ionized calcium concentrations or hypercalcemia is severe, drug therapy with glucocorticoids (e.g., daily oral prednisolone) or bisphosphonates (e.g., weekly oral alendronate) can be initiated (5-8,24). However, both of these drugs can produce adverse side effects (i.e., diabetes mellitus and esophagitis, respectively), so I prefer to withhold drug therapy until absolutely needed (8,25).

Once drug therapy has been instituted, I would still maintain the feeding a low-carb, high-protein canned diet to these cats. The higher protein intake will help maintain lean body mass, whereas the lower carbohydrates may help mitigate the diabetic effects of the high doses of prednisolone that may be needed to control hypercalcemia.

But in some cats, we'll be lucky, and the hypercalcemia will resolve after a change in the cat's diet to one with a nutrient composition closer to the food they were designed to eat. And in a few of those cats, the ionized calcium concentrations will remain normal for months to years, without the need for drug therapy.

References

1. McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases. J Am Anim Hosp Assoc 1999;35:297-301.
2. Midkiff AM, Chew DJ, Randolph JF, et al. Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14: 619–626.
3. Savary KC, Price GS, Vaden S. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000; 14:184-189.
4. Schenck PA and Chew DJ: Idiopathic hypercalcemia in cats. Waltham Focus 2005; 15: 20-24.
5. Chew DJ, Schenck PA. Idiopathic feline hypercalcemia In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Philadelphia: Saunders Elsivier, 2009; 236-241.
6. de Brito Galvao JF, Schenck PA, Chew DJ. Hypercalcemia: Diagnosis and treatment options in dogs and cats. Veterinary Focus 2011;21:27-34.
7. 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.
8. Baral RM. Disorders of calcium metabolism In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012; 625-642.
9. Ching SV, Fettman MJ, Hamar DW, et al. The effect of chronic dietary acidification using ammonium chloride on acid-base and mineral metabolism in the adult cat. J Nutr 1989;119: 902-915.
10. Fettman MJ, Coble JM, Hamar DW, et al. Effect of dietary phosphoric acid supplementation on acid-base balance and mineral and bone metabolism in adult cats. Am J Vet Res 1992;53:2125-2135.
11. Funaba M, Uchiyama A, Takahashi K, et al. Evaluation of effects of dietary carbohydrate on formation of struvite crystals in urine and macromineral balance in clinically normal cats. Am J Vet Res 2004;65:138-142.
12. Funaba M, Yamate T, Hashida Y, et al. Effects of a high-protein diet versus dietary supplementation with ammonium chloride on struvite crystal formation in urine of clinically normal cats. Am J Vet Res 2003;64:1059-1064.
13. Buckley CM, Hawthorne A, Colyer A, et al. Effect of dietary water intake on urinary output, specific gravity and relative supersaturation for calcium oxalate and struvite in the cat. Brit J Nutr 2011;106 Suppl 1:S128-130.
14. Wolfe RR. Sarcopenia of aging: Implications of the age-related loss of lean body mass. Proceedings of the Nestlé Purina Companion Animal Nutrition Summit: Focus on Gerontology. St. Louis, MO. 2010, pp. 12-17.
15. Little SE. Evaluation of the senior cat with weight loss In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;1176-1181.
16. Chew DJ, DiBartola SP, Schenck PA. In: Canine and Feline Nephrology and Urology. Second Ed. St. Louis: Elsevier Saunders, 2011.
17. MacDonald ML, Rogers QR, Morris JG. Nutrition of the domestic cat, a mammalian carnivore. Annu Rev Nutr 1984;4:521-562.
18. Zoran DL. The carnivore connection to nutrition in cats. J Am Vet Med Assoc 2002;221:1559-1567.
19. Zoran DL. The unique nutritional needs of the cat In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed: Saunders Elsevier, 2010;652-659.
20. Eisert R. Hypercarnivory and the brain: protein requirements of cats reconsidered. J Comp Physiol B 2011;181:1-17.
21. Funaba M, Hashimoto M, Yamanaka C, et al. Effects of a high-protein diet on mineral metabolism and struvite activity product in clinically normal cats. Am J Vet Res 1996;57:1726-1732.
22. Fascetti AJ, Delaney SJ. Nutritional management of endocrine disease. In: Fascetti AJ, Delaney SJ, eds. Applied Veterinary Clinical Nutrition. West Sussex: Wiley-Blackwell; 2012:289-300.
23. AAFCO (Association of American Feed Control Officials). Official Publication, 2012.
24. Whitney JL, Barrs VR, Wilkinson MR, et al. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. J Fel Med Surg 2011;13:129-134.
25. Lowe AD, Graves TK, Campbell KL, et al. Apilot study comparing the diabetogenic effects of dexamethasone andprednisolone in cats. J Am Anim Hosp Assoc 2009;45:215-224.

What's Causing Idiopathic Hypercalcemia in Cats?

Over the last two decades, a syndrome of idiopathic hypercalcemia in cats has emerged and appears to be increasing in frequency (1-6). The term "idiopathic hypercalcemia" refers to a high serum ionized calcium concentration of unknown cause, even after extensive medical evaluation has been undertaken to rule out other known causes of hypercalcemia, such as primary hyperparathyroidism and neoplasia (7,8).

Multiple factors have been considered in relation to the underlying cause of idiopathic hypercalcemia. It is still unclear if increased intestinal calcium absorption, increased bone resorption, or decreased renal calcium excretion (or some combination thereof) is the key factor leading to the development of the ionized hypercalcemia in this syndrome.

Despite the fact that the underlying cause of idiopathic hypercalcemia remains elusive, this has clearly become the most common type of hypercalcemia in cats.

Is the Cat's Diet Responsible?

It has been suggested that the diet fed may predispose cats to development of idiopathic hypercalcemia, as well as formation of calcium oxalate calculi found in 10-15% of cats with this syndrome (8,9).

Acidifying diets
Many believe that feeding of acidifying, magnesium-restricted diets predisposes cats to idiopathic hypercalcemia (4,8). In support of this hypothesis is the fact that both calcium oxalate stones and hypercalcemia first became prevalent in the 1990's, shortly after the introduction of feline acidifying diets designed for prevention of struvite crystals (1-3). In addition, 3 of 5 cats in one series (1) and all 14 cats for which diet history was available in another report (2) had been fed acidifying diets designed to minimize struvite crystalluria and urolithiasis.

When fed to normal cats, such acidifying diets may lead to a state of mild systemic acidosis (10), which, in turn, promotes increased calcium resorption from bone and can produce a state of negative calcium balance. The calcium salts present in bone represent the largest store of alkaline base in the body and, therefore, act as a buffer in states of metabolic acidosis (11). Therefore, when human subjects are fed a diet that produces a net acid load, excessive calcium salt may be released from bone, resulting in increased urinary calcium excretion (11-13). In agreement with these human studies, the induction of metabolic acidosis in cats fed an acidifying diet may result in both mild ionized hypercalcemia and hypercalciuria (10).

Excessive Vitamin D
Another plausible hypothesis is that excessive dietary vitamin D content in some cat foods may contribute to this syndrome (5). Cats have a low requirement for vitamin D (1.4 μg [56 IU] cholecalciferol per 100 kcal diet) (14), at least when fed a diet with adequate concentrations (and a correct ratio) of calcium and phosphorus.

The vitamin D levels in commercial cat diets are not listed on the label and are not always included on product guides or company websites. However, if the label states that a cat diet is “complete and balanced,” the vitamin D levels must be between 3.1-62.5 μg [125-2,500 IU] per 1000 kcal to comply with AAFCO guidelines (15). Therefore, the amounts of vitamin D added to commercial cat foods could range from 2- to 50-fold higher than the minimal requirement recommended by the NRC (14). Most commercial cat foods likely contain relatively high amounts of vitamin D, which could result in hypervitaminosis D in some cats and contribute to ionized hypercalcemia in at least some of them (14,16).

The finding of “normal” serum concentrations of 25-hydroxyvitamin D and calcitriol in most cats with idiopathic hypercalcemia goes against this hypothesis that excessive dietary vitamin D levels in the diet contributes to this syndrome (2,9).  However, it is important to realize that reference range limits for 25-hydroxyvitamin D and calcitriol have all been established in clinically normal cats fed standard diets which again may be rather heavily supplemented with vitamin D.

Bottom Line

In almost all cats with idiopathic hypercalcemia, clinical signs are usually relatively mild, at least at diagnosis. In general, the severity of hypercalcemia in these cats tends to be slowly progressive. Therefore, most cats can be treated as outpatients with either dietary therapy, alone or in combination with drug therapy— i.e., glucocorticoids or bisphosphonates (4-8,17).

I generally start with diet modification as a first-line treatment. In my next post, I'll review the 5 dietary options that have been proposed for this syndrome and give you my recommendations about how to best manage these cats with dietary therapy.

References:

1. McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases. J Am Anim Hosp Assoc 1999;35:297-301.
2. Midkiff AM, Chew DJ, Randolph JF, et al: Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14: 619–626.
3. Savary KC, Price GS, Vaden S. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000;14:184-189.
4. Schenck PA and Chew DJ: Idiopathic hypercalcemia in cats. Waltham Focus 2005; 15:20–24.
5. Chew DJ, Schenck PA. Idiopathic feline hypercalcemia In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Philadelphia: Saunders Elsivier, 2009;236-241.
6. de Brito Galvao JF, Schenck PA, Chew DJ. Hypercalcemia: Diagnosis and treatment options in dogs and cats. Veterinary Focus 2011;21:27-34. 
7. 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.
8. Baral RM. Disorders of calcium metabolism In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;625-642.
9. Schenck PA, Chew DJ, Refsal K, et al: Calcium metabolic hormones in feline idiopathic hypercalcemia (abstract). J Vet Intern Med 2004;18:442.
10. Ching SV, Fettman MJ, Hamar DW, et al. The effect of chronic dietary acidification using ammonium chloride on acid-base and mineral metabolism in the adult cat. J Nutr 1989;119:902-915.
11. Arnett TR. Extracellular pH regulates bone cell function. J Nutr 2008;138:415S-418S. 
12. Jajoo R, Song L, Rasmussen H, et al. Dietary acid-base balance, bone resorption, and calcium excretion. J Am College Nutr 2006;25:224-230.
13. Vormann J, Remer T. Dietary, metabolic, physiologic, and disease-related aspects of acid-base balance. J Nutr 2008;138:413S-414S. 
14. National Research Council. Vitamins. In: Nutrient Requirements of Dogs and Cats. Washington, DC: National Academies Press. 2006:193-245.
15. AAFCO. (Association of American Feed Control Officials). Official Publication, 2007.
16. Morita T, Awakura T, Shimada A, et al. Vitamin D toxicosis in cats: natural outbreak and experimental study. J Vet Med Sci 1995;57:831-837.
17. 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.

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. 
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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. 
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