Hypercalcemia is condition in which the total calcium concentration in the circulation increases beyond 12.0mg/dL (3.0mmol/L) or the serum ionized calcium (biologically essential fraction of serum total calcium) increases above 6.0mg/dL (1.5mmol/L). True hypercalcemia is the increase in the concentration of iCa and not merely the increase of serum tCa. Hypercalcemia develops primarily when there is an increase in bone mobilization of calcium or a decrease in urinary calcium loss.
Calcium is an essential mineral and a vital cofactor of many enzymatic reactions which makes it a major controller of many cellular functions. It serves the principal functions in the form of insoluble calcium salts that are found in the skeleton and provide structural stability to the bones and soluble calcium ions which are required for various physiological intracellular and extracellular signaling pathways. These calcium ions are found in the cytosol and the extracellular fluid.
Total serum calcium is composed of three the fractions of protein bound calcium (mostly albumin), calcium complexes (with phosphate, lactate, bicarbonates, sulfate or citrate) and ionized calcium. The most biologically active form of calcium is ionized calcium and it comprises of the major part of serum total calcium (50%). It is also the fraction that is important for calcium regulation inside the body.
The mechanism of calcium regulation takes place through the action of PTH on kidneys and bones, action of calcitriol on bones and small intestines as well as the action of calcitonin on the small intestines.
PTH and vitamin D metabolites are secreted in response to lowering of serum calcium levels and are thus important for increasing the levels of serum calcium and Calcitonin is responsible for lowering it. Calcitonin mostly functions to regulate the post prandial serum calcium levels.
PTH is a polypeptide amino acid that is secreted by the chief cells in the parathyroid gland. PTH has a half-life of minutes and is thus responsible for the minute -to-minute regulation of calcium concentration in the circulation. Decreased serum calcium concentration stimulates the synthesis and secretion of PTH and inversely an increase in the serum calcium concentration inhibits its secretion. In the event of decreased serum calcium concentration PTH is secreted which facilitates the reabsorption of calcium from the renal tubules, increases the excretion of phosphorous, metabolisis of vitamin D and also leads to the mobilization of calcium from the bones.
Biologically active forms of vitamin D are produced in the skin due the action of the ultraviolet rays from the sun and some proportion of it is available in the diet of the animals as ergocalciferol or cholecalciferol. PTH stimulates the renal enzymes in the proximal tubular cells of the kidneys to synthesize 1,25-dihydroxyvitamin D also known as calcitriol, which plays a role in the daily regulation of serum calcium concentrations. Calcitriol is thus synthesized in response to low serum calcium levels and acts on the bones for the resorption of the mineral from them as well as acts on the small intestine stimulating the absorption on calcium from there in an attempt to balance the serum calcium concentration.
Calcitonin a polypeptide amino acid hormone is produced by the parafollicular or C cells of the thyroid gland in response to increased serum calcium concentrations. This hormone has the primary responsibility of limiting the postprandial hypercalcemia in normal mammals(Feldman, Nelson, Reusch, & Scott-Moncrieff, 2014; Schenck & Chew, 2013). Calcitonin regulates the calcium concentration by inhibiting resorption of calcium from the bones and has no effects on the kidney or the gut. Another possible pathway of regulating calcium in the circulation is that it acts on the satiety center ,reducing the appetite and in turn decreasing the dietary intake of calcium.(Feldman et al., 2014)
Disturbance in the synthesis or functioning of these hormones and the organs on which these hormones act upon, may lead to a disturbance in the regulation levels in the body and in turn may lead to hypercalcemia.
Through this assignment on Hypercalcemia I would like to develop a better understanding of the pathways through which hypercalcemia would occur in dogs and cats and also study the effects it has on the other organs of the body. I would like to learn about the current advancements in the field of veterinary internal medicine and the techniques that are being developed to diagnose and treat hypercalcemia in dogs and cats.
Causes /Types of Hypercalcemia
Primary hypercalcemia (Parathyroid dependent Hypercalcemia)
Abnormally functioning parathyroid gland continues secreting PTH in spite of a higher concentration of calcium in the serum. The parathyroid gland may be abnormally functioning due to hyperplasia or an adenoma or carcinoma. In this kind of parathyroid dependent hypercalcemia, the concentration of calcium is higher than normal along with that of PTH in the circulation. Increased synthesis of active vitamin D also aggravates the existing hypercalcemia. PTH receptors like PTH1R/PTHrP are responsible for the actions of PTH. PTH receptors are majorly found in the kidneys and the bones These receptor cells are also found throughout the body. Thus, the increased secretion of PTH leads to the resorption of calcium from the bones as well as decreased urinary excretion of calcium causing hypercalcemia.
Cancer associated hypercalcemia (malignant and benign)
Various studies have found malignant neoplasia to be the most common cause of hypercalcemia in dogs and cats(namely lymphoproliferative diseases like squamous cell carcinoma and multiple myeloma)(Messinger, Windham, & Ward, 2009; Savary, Price, & Vaden, 2000). Hypercalcemia of malignancy is an imbalance of the calcium concentration in the circulation due to an underlying neoplastic condition which can be due a humoral malignancy, solid tumors of the other organs metastasizing to the bones or neoplasia of the bone marrow. Metastasis of tumors to the bones and neoplastic conditions of the bones affect the bones locally causing hypercalcemia but humoral hypercalcemia of malignancy is a paraneoplastic syndrome which shows its effect at a site away from the tumor. A study shows that bone remodeling changes can be observed in hypercalcemia of malignancy and are not often those of hyperparathyroidism. This study indicated that the bone changes attributed to hypercalcemia of malignancy are due to the humoral calcemic factor which is distinctly different from that seen in hyperparathyroidism. Even though these clinical signs are not quite evident, they can be detected in histologically examining the bone(Norrdin & Powers, 1983).
Humoral Hypercalcemia of Malignancy(HHM) is most commonly associated with lymphosarcoma and the second most common tumor observed is the apocrine gland adenocarcinoma of the anal sac.(Messinger et al., 2009; Vasilopulos & Mackin, 2003). In cats the most common cause of HHM are lymphoproliferative disorders, squamous cell carcinomas and multiple myeloma (Vasilopulos & Mackin, 2003). The common factor associated with all of these conditions is Parathyroid Hormone related Protein (PTHrP). It has a chemical structure which is closely related to that of PTH and thus can act upon all the PTH receptors present in the body and replicate pathways of bone resorption and calcium reabsorption from the urinary tubules even in the absence of PTH. Tumors associated with humoral hypercalcemia of malignancy are known to secrete PTHrP along with interleukin-1 and prostaglandins which activate the mechanism of mobilization of calcium from the bones even in the absence of PTH in the circulation. PTHrP has its function in the fetuses where it is believed to be responsible for the ossification of the bones. In adults however, it isn’t present at detectable levels since its broken down into inactive forms and excreted through the urine rapidly. And it can only be detected in conditions associated with humoral hypercalcemia of malignancy, which is very helpful in the diagnosis of humoral hypercalcemia of malignancy. Some tumors are also known to secrete calcitriol in addition to PTHrP but PTHrP does not have the ability to stimulate the formation of calcitriol. In adenocarcinoma of the apocrine gland of the anal sacs, the amount of PTHrP in the circulation is directly proportional to the level of hypercalcemia.
Hematopoietic conditions affecting the bone marrow like multiple myeloma and lymphoma bring about osteolytic changes in the bones and are capable of causing hypercalcemia. T-cell lymphoma is the most common cause of hypercalcemia in dogs, accounting for almost 60% of dogs with hypercalcemia and almost 80%of dogs with hypercalcemia due to cancer (Messinger et al., 2009). These conditions are known to increase the osteoclastic activity in the bones thus causing the mobilization of calcium into the circulation. Lymphomas are capable of synthesizing vitamin D along with PTHrP since a majority of the lymphocytes have the capability to stimulate the synthesis of active forms of vitamin D, they also lead to excessive production of calcitriol which is a cause of hypercalcemia along with PTHrP. B-lymphocytes from a multiple myeloma tumor produce interleukin-1B which is known to stimulate osteoclastic activity which in turn causes resorption of calcium from the bones.
Solid tumors that metastasize to the bones rarely are the cause of hypercalcemia. Localized bone destruction is seen due to the metastasis of these solid tumors to the bones. Skeletal bones are generally involved in this type of hypercalcemia but rarely long bones like humerus and femur can show osteolytic changes too. Increase in the resorption surfaces of the bones and osteopenia can be seen which contribute to the increased concentration of serum calcium. Carcinomas of the mammary gland, prostate ,liver and lung most frequently metastasize to the bones in the dog and are associated with this type of hypercalcemia(Schenck & Chew, 2013).
Hypervitaminosis of vitamin D
The most common cause of hypervitaminosis D in dogs is rodenticide poisoning (most rodenticides contain cholecalciferol)(Mellanby, Mee, Berry, & Herrtage, 2005).Vitamin D toxicity can also occur due to excessive dietary supplementation of it, accidental consumption of human psoriasis cream (containing calcipotriene)or the accidental ingestion of plants (e.g. Day blooming jessamine). The minimal lethal dose of calcipotriene in dogs is 65microgram/kg body weight(Schenck & Chew, 2013). Since the skin of the dogs is known to not metabolize vitamin D to its active forms very well, the commercially available foods over overcompensate for this by supplementation of excessive vitamin D in the food. This overzealous supplementation can have adverse effects on the health of the animals. Hypercalcemia due to vitamin D toxicity can often be a life-threatening condition and may require treatment on an emergency basis. Increased absorption of calcium along with phosphorus from the small intestine are responsible for causing hypercalcemia. Resorption of calcium from the bones and decreased renal excretion of calcium are also contributing factors to the hypercalcemia. Soft tissue mineralization and nephrosis can occur due to acute toxicity of vitamin D. A serum total calcium concentration as high as up to 20mg/dL can be observed in acute conditions.
Hypoadrenocorticism is closely associated with hypercalcemia but the exact pathway due to which is causes hypercalcemia in animals is unknown.
Idiopathic hypercalcemia (in cats)
Most cats suffering from hypercalcemia independent of the parathyroid gland involvement are suffering from idiopathic hypercalcemia(Hardy et al., 2015). The exact pathogenesis of the development of this type of hypercalcemia is unknown. Increased concentration of vitamin D metabolites has not been detected in the circulation in cats suffering from idiopathic hypercalcemia. It is speculated that the receptors in cats may be sensitive to normal levels of vitamin D and its metabolites in such cats.
Ingestion of excessive calcium containing phosphate binders
Calcium containing phosphate binders are used to reduce the amount of dietary phosphorus available for absorption in the treatment of renal conditions. Excessive use of these calcium containing phosphate binders in animals makes excessive amount of calcium available for absorption from the intestines thus causing hypercalcemia.
A study proved that renal failure was the 2nd most common disorder associated with renal failure(Savary et al., 2000). Renal failure can be a cause of hypercalcemia and can also be an effect of hypercalcemia. In chronic kidney disease(CKD) the serum total calcium is elevated but this doesn’t imply that the ionized calcium concentration in the serum is elevated. The serum total calcium is generally elevated in CKD due to the other fractions and not ionized calcium in the serum. In some dogs and cats suffering from CKD, sometimes the set point of iCa in the blood has been reset to a higher limit. This leads to the elevation in the iCa concentration in the serum due to increased secretion of PTH. This causes hypercalcemia in such patients. The pathway for the synthesis of calcitriol may dysfunction leading to the decrease in the production of calcitriol which hampers the feedback mechanism for the synthesis of PTH also causing increased level of PTH in the circulation.
Transient non-pathological hypercalcemia
Hemoconcentration due to dehydration can cause transient hypercalcemia which can be corrected by correcting the dehydration level of the animal. Severe hypothermia can rarely but is capable of causing transient hypercalcemia.
Granulomatous diseases like schistosomiasis, blastomycosis, histoplasmosis and nocardia (in cats) have been known to cause persistent hypercalcemia which often is difficult to diagnose. This is due to the macrophages present in the granulomatous inflammation which are known to produce excessive calcitriol.
Signs and Symptoms
Dogs suffering from hypercalcemia may be asymptomatic. It is difficult to identify hypercalcemia just on the basis of the symptoms. It is generally routine in dogs and cats who have come for their annual or biannual routine screening or during blood tests prior to a surgical procedure. Dogs suffering from hypercalcemia may show symptoms of polyuria and compensatory polydipsia, anorexia and lethargy. Cardiac arrhythmias and muscle weakness duet excessive calcium can also be seen in some dogs and cats. Polyuria is seen as a result of calcium deposition in the renal tubules that inhibit the action of ADH on the tubules. Cats may or may not show milder forms of these symptoms. Since these symptoms too are not characteristic of hypercalcemia, they may go unnoticed by the owners. Presence of a visible mass due to neoplasia that is associated with hypercalcemia may help in the initial stages of the physical examination but is not a definitive symptom of hypercalcemia. Symptoms of hypercalcemia due to malignancy are associated with the primary tumor and the body systems being affected by the tumor.
Primary hypercalcemia due to hyperparathyroidism has been commonly observed in older dogs and older cats with breed specificity in dogs to the Keeshond breed. This type of hypercalcemia has not shown any sex predilection and thus can be observed equally in males as well as females.
Dogs or cats suffering from vitamin D toxicity may show symptoms of it 12-24 hours post consumption of the toxin. Aggressive signs of diarrhea, hematemesis and hematochezia along with lethargy, polyuria, polydipsia is observed in acute toxicosis which may not generally be seen in hypercalcemia due to other causes. Acute toxicity can also lead to renal failure with 24-48 hours of ingestion of the toxin which will reflect in the increased levels of BUN and serum creatinine.
Urolithiasis is a condition often associated with hypercalcemia in cats where renal calculi and uroliths made up of calcium oxalate are seen in such cats. Due to this urolithiasis, the cats can be seen showing signs of painful and frequent urination and sometimes, hematuria.
Initially the detection of increase in the levels of serum total calcium was considered as a sign of hypercalcemia. But this is not true hypercalcemia since the total calcium concentrations may or may not be due to the increase in the ionized serum calcium concentration. Application of correction formulae to calculate serum ionized calcium from total serum calcium may be inaccurate. Thus, specific assays developed for detecting levels of ionized calcium in the blood have to be used for the diagnosis of hypercalcemia. Serum total calcium is measured using colorimetry and serum ionized calcium can be measured using ion selective electrode analysis. In primary hypercalcemia due to hyperparathyroidism, the levels of PTH in the blood are elevated than normal along with the serum ionized calcium concentration. The PTH concentration is measured using two-site immunoradiometric assay which detects two ends of the intact PTH molecules names the carboxy-terminal and the amino-terminal. In a blood biochemistry assay, the presence of PTHrP is always indicative of a malignant condition to be the cause of the observed hypercalcemia. For this reason, PTHrP is also known as the tumor marker. PTHrP has a structure very similar to PTH but unlike PTH which is only found in the parathyroid gland, PTHrP can be found in tissues other than the parathyroid gland. Biochemistry of renal parameters along with the serum calcium levels can help detect renal causes of hypercalcemia. Measuring levels of vitamin D metabolites in the blood can help in the detection of vitamin D toxicity.
For the collection of blood samples for detecting the levels of total calcium and ionized calcium in the blood, EDTA vials should not be used as EDTA chelates calcium and this test will provide incorrect information. And processing of fresh samples will help get accurate results.
Radiographic imaging is an important tool for the detection of neoplasia that may be associated with hypercalcemia. Radiographs of the thoracic cavity are essential for the detection of abnormal lymph nodes in the thorax. Metastasis of tumors to the skeletal bones and ribs can be detected using these images too. Osteolytic changes of the vertebral column, ribs and the long bones can be indicative of neoplastic conditions that may be the cause of the hypercalcemia. Radiographic imaging will help detecting mediastinal masses which may be due to lymphoma associated with the hypercalcemia.
Histological examination of sites of osteolytic changes will help determine the bone changes occurring in the affected bones due to malignancy and thus help in the diagnosis of hypercalcemia. Aspirates of bone marrows should be tested to detect conditions like multiple myeloma which can also cause hypercalcemia.
Uroliths present in the kidney as well as cystic calculi can be seen on careful observation of the radiographs of the abdominal cavity. Ultrasonography of the cervical region will help in the detection of abnormal parathyroid tissue which only detectable in the case of primary hypercalcemia due to hyperparathyroidism, whereas in healthy dogs, it isn’t easily identifiable. These dogs show a solitary round or oval hypoechoic mass in close association with one thyroid lobe. Abnormal parathyroid nodules usually measure4to 6 mm, but they can be as large as 20mm in their greatest dimension(Pollard, Long, Nelson, Hornof, & Feldman, 2001).
Repeated per-rectal examination can help detect apocrine adenocarcinoma of the anal sac which will be in the form of a palpable mass at the location of the anal sacs and may occasionally be ulcerated. Tenesmus may also be observed a dog. These findings are almost always indicative of hypercalcemia due to this neoplastic condition.
In the case of parasites causing granulomatous inflammation which is responsible for persistent hypercalcemia, fecal examinations should be routinely done in addition to the blood biochemistry test in order to effectively diagnose the condition. In the absence of fecal tests in such cases, the worst is assumed, and a wrong line of treatment may be adopted. Which is shown in the case study of an 18-month-old spayed female who was showing signs of persistent hypercalcemia. After extensive evaluation, a tentative diagnosis of occult lymphosarcoma was made and the dog was euthanized. At necropsy an infection with Heterobilharzia americana was detected which went unnoticed since no fecal tests were conducted(Rohrer, Phillips, Ford, & Ginn, 2000).
Treatment of hypercalcemia is a two-step process and aims to resolve two issues namely, the increased serum calcium concentration and the underlying cause of hypercalcemia. The treatment of hypercalcemia involves three pathways of increasing the urinary calcium excretion, decreasing the absorption of calcium from the small intestines and inhibiting the mobilization of calcium from the bones. No one single treatment is prescribed for completely treating hypercalcemia, it has to be a combination of two or more approaches of treatment.
Fluid therapy is an important for treating mild hypercalcemia and hypercalcemia related to renal conditions. Hypercalcemia is known to cause osmotic diuresis due to the increased concentration of calcium in the circulation(Groman, 2012). This can lead to dehydration coupled with decreased intake of fluids by the animals. Hemoconcentration can also cause non-pathological hypercalcemia, thus keeping the animals hydrated can help resolve hemoconcentration. Physiologic saline (0.9% NaCl) is preferred over Lactated Ringer’s solution since it does not contain calcium. The intravenous route of infusion is preferred over the subcutaneous route since the fluid absorption through the subcutaneous layers is comparatively slow.
Diuresis is another important part of the treatment of hypercalcemia. Furosemide is used as the diuretic since it increases the urinary calcium excretion. But it should only be used after the animal has been well dehydrated using IV fluids otherwise this can lead to further dehydration.
The conventional method of treating Hypercalcemia due to primary hyperparathyroidism in dogs is the surgical excision of the parathyroid gland(parathyroidectomy). This treatment can be unsuccessful due to the failure to identify the abnormal tissue during the surgery and the subsequent failure to excise it.
Recently newer techniques have been developed for treating primary hypercalcemia and they are percutaneous ultrasound guided ethanol ablation and percutaneous ultrasound guided heat ablation. As a part of chemical ablation, ethanol is injected in the affected tissue to infiltrate it and cause tissue necrosis. The side effects of this technique are the necrosis of the surrounding structures thus affection the laryngeal cords of the animals.
As opposed to the percutaneous use of radiofrequency to supply the affected tissue with heat which leads to the thermal necrosis of the tissue. Radiofrequency energy is supplied at 10 to 20 W for 30 to 90 seconds until sonographically apparent tissue change is subjectively viewed(Pollard et al., 2001). Since no chemicals are used, this technique is comparatively safer than percutaneous chemical ablation. Parathyroidectomy is the most successful treatment option with the only postoperative complication of hypocalcemia. Percutaneous ultrasound guided heat ablation is a good alternative to chemical ablation since it’s a comparatively safer procedure.(Rasor, Pollard, & Feldman, 2007)
Hypocalcemia can be a post treatment complication of these surgical procedures thus appropriate supplementation of calcium should be provided to these dogs post surgery.
Nitrogen containing phosphate binders are used for treating hypercalcemia in cats. These phosphate binders inhibit the osteoclast activity in the bones by inhibition of the enzyme farnesyl diphosphate synthase(FPPS) in the HMG-CoA reductase (ie. Mevalonate) pathway(Hardy et al., 2015). In turn reducing the bone resorption which is known to be one of the major causes of hypercalcemia. The phosphate binders that are generally used are alendronate, pamidronate, ibandronate and risedronate. Pamidronate and clodronate have been used to treat hypercalcemia by IV infusion as orally consuming these biophosphonates caused irritation to the esophagus. But recent a study found out that once weekly alendronate treatment was successful in decreasing serum ionized calcium concentrations in most cats without clinically apparent adverse effects during a duration of 6 months of treatment. Bone accumulation of alendronate and decreased activity or number of osteoclasts is thought to be responsible for decreased serum ionized calcium concentration during this treatment.(Hardy et al., 2015)
Corticosteroids are used for treating the malignant as well as granulomatous conditions that are capable of causing hypercalcemia in dogs and cats. But these should be used with caution and should be withheld from animals suffering from Hypercalcemia which has an undiagnosed etiology. Excision of malignant tumors causing hypercalcemia also is effective in treating the resulting hypercalcemia. Corticosteroids also inhibit the calcium absorption from the intestines which is stimulated due to the action of vitamin D and are thus used in the treatment of hypervitaminosis D.
Vitamin D toxicity has to be aggressively treated initially till the animal is in a stable condition and not showing acute symptoms of hypervitaminosis. A maintenance treatment strategy has to be undertaken to make sure the hypercalcemia remains under control and that the toxicity has not caused damage to the other organs and a low calcium diet has to be provided to the animal. Calcitonin is used for the treatment of hypercalcemia specifically for hypercalcemia caused due to vitamin D toxicity since it inhibits the resorption of calcium from the bones. Calcitonin has a very short half-life and is known to have unwanted adverse effects. Thus, the role of calcitonin is limited in the treatment of hypercalcemia and cannot be used for prolonged durations of time. Soft tissue mineralization and nephrosis can occur due to acute toxicity of vitamin D.
Acidosis can add to the already existing hypercalcemia by decreasing the plasma protein binding affinity to calcium thus shifting more calcium to the ionized part of the total calcium in the circulation. Alkalizers like sodium bicarbonate are thus used in conjunction with other treatment strategies for treating hypercalcemia.
Fig. 2 is a table of the doses of drugs used for the treatment of hypercalcemia.
Hypercalcemia is a condition which may seem like a harmless, asymptomatic condition but the underlying causes of this condition may have harmful effects on the health of the animals if not detected on time. Thus, it is important to include calcium assays in routine blood testing for the timely detection of such conditons which is currently not being followed by majority of the veterinary clinics. There are numerous causes of hypercalcemia and measures to rule out every possible cause should be undertaken before chalking out a treatment strategy for treating a particular type of hypercalcemia.
|Total serum calcium concentration
|Ionized serum calcium concentration
|Parathyroid hormone related protein(PTHrP)
Fig.1 Normal reference intervals of serum concentrations of total calcium, ionized calcium, Parathyroid Hormone and Parathyroid Hormone related Protein (Feldman et al., 2014)
IV saline (0.9%)
|100-125mL/kg/day||Moderate to severe hypercalcemia||Contraindicated if congestive heart failure and /or hypertension present|
|1-4mg/kg q 8-12h IV, SQ, PO; constant rate infusion 0.2-1mg/kg/h||Moderate to severe hypercalcemia||Volume expansion is necessary prior to use of this drug|
|1-2.2mg/kg BID PO, SQ, IV
0.1-0.22 mg/kg BID IV, SQ
|Moderate to severe hypercalcemia||Use of these drugs prior to definitive diagnosis of the etiology may make it difficult to make a definitive diagnosis later|
|Inhibition of bone resorption
|4-6IU/kg SQ BID to TID||Hypervitaminosis D toxicity||Response may be short lived. Adverse effects like vomiting may be seen|
|1.3-2.0mg/kg in 150ml 0.9% saline in a 2h IV infusion, can repeat in 1-3 weeks
1-4mg/kg, q48-72 h PO; 10-30mg/cat once weekly followed by 6ml PO tap water and buttering of nose
Adjunctive therapy for malignancy associated hypercalcemia or primary hyperparathyroidism, feline idiopathic hypercalcemia
Fig. 2 Therapeutic drugs used for the treatment of hypercalcemia(Schenck & Chew, 2013)
Feldman, E. C., Nelson, R. W., Reusch, C. E., & Scott-Moncrieff, J. C. (2014). Canine and feline endocrinology: Elsevier Inc.
Groman, R. P. (2012). Acute Management of Calcium Disorders. Topics in companion animal medicine, 27(4), 167-171. doi:10.1053/j.tcam.2012.11.002
Hardy, B., Brito Galvao, J., Green, T., Braudaway, S., DiBartola, S. P., Lord, L., & Chew, D. (2015). Treatment of ionized hypercalcemia in 12 cats (2006–2008) using PO‐administered alendronate. Journal of veterinary internal medicine, 29(1), 200-206.
Mellanby, R., Mee, A., Berry, J., & Herrtage, M. (2005). Hypercalcaemia in two dogs caused by excessive dietary supplementation of vitamin D. Journal of small animal practice, 46(7), 334-338.
Messinger, J., Windham, W., & Ward, C. (2009). Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998–2003). Journal of veterinary internal medicine, 23(3), 514-519.
Norrdin, R. W., & Powers, B. E. (1983). BONE CHANGES IN HYPERCALCEMIA OF MALIGNANCY IN DOGS. Journal of the American Veterinary Medical Association, 183(4), 441-444.
Pollard, R. E., Long, C. D., Nelson, R. W., Hornof, W. J., & Feldman, E. C. (2001). Percutaneous ultrasonographically guided radiofrequency heat ablation for treatment of primary hyperparathyroidism in dogs. Journal of the American Veterinary Medical Association, 218(7), 1106-1110.
Rasor, L., Pollard, R., & Feldman, E. C. (2007). Retrospective evaluation of three treatment methods for primary hyperparathyroidism in dogs. Journal of the American Animal Hospital Association, 43(2), 70-77.
Rohrer, C., Phillips, L., Ford, S., & Ginn, P. (2000). Hypercalcemia in a dog: a challenging case. Journal of the American Animal Hospital Association, 36(1), 20-25.
Savary, K., Price, G. S., & Vaden, S. L. (2000). Hypercalcemia in cats: a retrospective study of 71 cases (1991–1997). Journal of veterinary internal medicine, 14(2), 184-189.
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Vasilopulos, R. J., & Mackin, A. (2003). Humoral hypercalcemia of malignancy: pathophysiology and clinical signs. COMPENDIUM ON CONTINUING EDUCATION FOR THE PRACTISING VETERINARIAN-NORTH AMERICAN EDITION-, 25(2), 122-128.
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