THERAPY
For any paraneoplastic syndrome, diagnosing and treating the underlying neoplastic disorder is mandatory to best manage the patient. However, pending definitive diagnosis of the primary disease, initial intervention for hypercalcemia should ideally consist of vigorous rehydration with isotonic saline solution (0.9% sodium chloride). Severe dehydration and hemoconcentration associated with hypercalcemia are common because of the anorexia, vomiting, and calcium-associated polyuria, despite the compensatory polydipsia. A decreased glomerular filtration rate leads to additional calcium retention as the kidneys attempt to conserve sodium. To reverse the established vicious cycle and increase calciuresis through an improved glomerular filtration rate, fluids devoid of calcium such as physiologic saline are usually recommended. In addition, the fluid of choice will have a high sodium concentration, since the sodium will compete with calcium for tubular reabsorption, resulting in enhanced calciuresis.15 However, the aggressive fluid therapy per se is more important than the actual type of fluid given, and lactated Ringers solution can be used if saline solution is not available.
After adequate hydration, a patients kidneys will first excrete sodium and then calcium, with clinical improvement usually seen within 24 hours of fluid therapy. Take the patients hydration, renal, and cardiovascular status into consideration when determining the fluid rate. Potassium supplementation may be required in some cases to avoid hypokalemia, especially if prolonged potassium-free intravenous fluid therapy is administered. Intravenous fluid therapy should aim to correct the dehydration over four to six hours after diagnosis in patients with moderate to severe hypercalcemia.
A loop diuretic, most commonly furosemide, may be added to the therapeutic regimen once the patient is adequately rehydrated. Furosemide inhibits the renal membrane sodium-potassium-dichloride cotransporter present in the thick ascending limb of Henles loop.45,46 The Handbook of Small Animal Therapeutics, edited by Lloyd E. Davis in 1985, is one of the first references recommending the use of furosemide for hypercalcemia treatment in dogs. The original recommended dosage was an initial bolus of 5 mg/kg followed by a constant-rate infusion (CRI) of 5 mg/kg/hr intravenously. This high dose of furosemide is based on human antihypercalcemic therapy and strictly requires a high rate of intravenous fluid administration (> three times maintenance fluid requirement) to avoid iatrogenic dehydration. We prefer using a lower dose of furosemide initially (2 to 4 mg/kg t.i.d. to q.i.d. intravenously, subcutaneously, or orally) to minimize the need for a high fluid rate.
In a recent study of six normocalcemic greyhounds, a 0.66-mg/kg loading dose of furosemide followed by a CRI of 0.66 mg/kg/hr (equivalent to 6 mg/kg over eight hours) was evaluated for its calciuretic efficacy compared with the same total dose of furosemide administered via two intravenous boluses of 3 mg/kg given four hours apart.47 Urine sodium and calcium loss as well as urine production and water intake were significantly larger in the CRI group compared with the intravenous bolus groups. The study concluded that the same total dose of furosemide over a given time frame resulted in more diuresis, natriuresis, and calciuresis, as well as less kaliuresis, compared with repeated intravenous boluses.47 Similar to the results obtained in normal greyhounds, it is our experience that the low-dose bolus followed by a CRI effectively reduces the degree of hypercalcemia.
Thiazide diuretics are absolutely contraindicated because of their hypercalcemic effect, as they cause tubular reabsorption of calcium rather than calciuresis.15,22
The use of glucocorticoids is controversial for treating hypercalcemia and is not a component of standard therapy in people because of glucocorticoids side effects and limited therapeutic value. The exact mechanisms of action of glucocorticoids in hypercalcemia are unknown, though it has been suggested that they increase renal calcium excretion, reduce bone resorption, and potentially decrease intestinal absorption.15,16,19 Glucocorticoids are most effective for hypercalcemia secondary to lymphoma, as they then also are part of the cytotoxic therapy aimed at the underlying cause. Prednisone at a dosage of 1 to 2.2 mg/kg given twice a day intravenously, subcutaneously, or orally or dexamethasone at a dosage of 0.1 to 0.22 mg/kg given twice a day intravenously, subcutaneously, or orally has been recommended.19,22 These high dosages should not be maintained indefinitely, and appropriate tapering is advised.
Glucocorticoids are included in most conventional lymphoma chemotherapy protocols, but their initial use should be avoided for two reasons. First, they may delay the definitive diagnosis and appropriate therapy of a malignant lymphoproliferative disease such as lymphoma. Additionally, their prolonged use may result in an increased risk of multidrug resistance (MDR phenotype), thereby negatively affecting the prognosis and chance of a long-lasting remission once appropriate multiagent cytotoxic therapy is instituted.48
Together with rehydration, potent injectable aminobisphosphonates, chiefly zoledronate and pamidronate, are currently the cornerstone of therapy for malignancy-associated hypercalcemia in people.9,49,50 They are considered the safest and most effective drugs for that purpose. Human malignant hypercalcemia most commonly results from multiple myeloma and solid carcinomas (e.g. breast, lung, prostate, renal) with bone metastases.9,15 Bisphosphonates are organic pyrophosphate analogues that possess high affinity for bone hydroxyapatite crystals and, thus, highly concentrate in sites of active bone turnover.
Bisphosphonates exert their main biologic effect by inducing osteoclast apoptosis.49 The inhibition of global osteoclastic activity decreases overall bone resorption and calcium release from the bone compartment.51-53 In people, bisphosphonates are usually initiated as soon as hypercalcemia is discovered since the response is not immediate. Blood calcium concentrations normalize within four to 10 days, and the effect lasts for about one to four weeks.52,53 Either pamidronate or zoledronate is acceptable; however, zoledronate is the most potent of the two formulations and is the current best choice in human medicine.9 Bisphosphonates that do not contain a nitrogen atom in their side chain, such as etidronate and clodronate, are not as potent as aminobisphosphonates in their antiresorptive activity and are generally not recommended for hypercalcemia of malignancy.51
While zoledronate administration also appears effective in dogs and cats, it remains cost-prohibitive in veterinary medicine. On the other hand, pamidronate is less expensive and is a good choice in hypercalcemic companion animals. Its use has been demonstrated in dogs at the recommended dosage of 1.3 to 2 mg/kg given once intravenously over 20 minutes or two hours in cases of experimental vitamin D toxicosis.54-56 An alternative safe dosage we are familiar with is 1 to 2 mg/kg given intravenously over two hours every 21 to 28 days in dogs.57 A dosage we are familiar with in cats is 1 to 1.5 mg/kg given intravenously over two hours every 21 to 28 days.
Because aminobisphosphonates act strictly at the bone level, a more pronounced effect on the hypercalcemia is obtained, both in human and veterinary patients, when their use is combined with therapies acting at the kidney level (saline diuresis, a loop diuretic) or in cases of hypercalcemia resulting from pure osteolytic processes rather than hypercalcemia secondary to increased quantities of calcitriol, PTH, or PTHrP.8
Other therapeutic agents have been recommended but have minor use in small-animal medicine because of their cost, side effects, or scheduling of administration. These agents include mithramycin, calcitonin, and gallium nitrate.
Mithramycin, also known as plicamycin, is an antitumor antibiotic with potent inhibitory effects on osteoclasts, leading to rapid inhibition of bone resorption. In a study of dogs with cancer-associated hypercalcemia, mithramycin was used as a single infusion of 0.1 mg/kg.58 Unfortunately, patients developed clinical signs of fever, vomiting, and diarrhea shortly after administration and suffered hepatocellular injury with subsequent hepatic necrosis. Other clinical consequences such as thrombocytopenia and renal necrosis have also been reported.59 Although unacceptable toxicosis is observed at 0.1 mg/kg, the use of mithramycin at a lower dosage (25 µg/kg infused over four hours) successfully controlled hypercalcemia for 24 to 72 hours.19
Similarly to the mechanism of mithramycin, calcitonin reduces osteoclastic activity and reduces hypercalcemia in small animals with vitamin D toxicosis.60,61 Reported dosages range from 4.5 to 8 IU/kg given subcutaneously every eight hours to 5 IU/kg given subcutaneously every 12 hours.61,62 For cats with rodenticide toxicosis, a dosage of 4 IU/kg given intramuscularly every 12 hours was effective and well-tolerated.63 Unlike calcitonins documented modest efficacy for the treatment of hypercalcemia secondary to vitamin D toxicosis, calcitonins utility in successfully managing hypercalcemia of malignancy in companion animals remains to be investigated. Calcitonin is used in people with Pagets disease and hypercalcemia of malignancy, but the effects of treatment can be quite variable.64-66 The main side effects of calcitonin are anorexia and vomiting. Its use is limited by cost and the fact that its effects are short-lived and because resistance frequently develops in a matter of days.15
Gallium nitrate is an antineoplastic that binds to the hydroxyapatite crystals in bone, thereby reducing their solubility.67,68 In some studies, gallium nitrate was demonstrated to be more effective than bisphosphonates at reducing calcium concentrations in people with hypercalcemia.69 However, despite this apparent efficacy, it is not considered a first-line treatment option for managing hypercalcemia given its potential for nephrotoxicity.
Novel therapies targeting the intercellular communication of osteoblasts and osteoclasts are under investigation. RANKL is expressed by osteoblasts and T lymphocytes and binds to its cognate receptor, receptor activator of nuclear factor kappa-B (RANK), present on the surface of osteoclast precursors and osteoclasts, leading to their proliferation, maturation, and activation. Promising antiresorptive molecules such as osteoprotegerin analogues, a soluble decoy RANKL receptor, or RANK nonfunctional constructs are being evaluated to decrease osteoclast activity and pathologic bone resorption.9,70
HYPERCALCEMIA OF MALIGNANCY: PATHOGENESIS
Hypercalcemia of malignancy may arise through three main mechanisms. First, tumor cells may produce and liberate soluble mediators capable of acting on bone and kidneys through endocrine and paracrine pathways, a mechanism referred to as humoral hypercalcemia of malignancy.3-5,7,8,15,19 Second, cancer cells may subvert the enzymatic activity of 1 alpha-hydroxylase, thereby causing the unregulated conversion of calcidiol to active calcitriol, which enhances intestinal absorption of calcium.8,22-26 This mechanism is poorly described with tumors in companion animals. Finally, certain tumor histologies such as leukemias, lymphomas, myeloma, and certain carcinomas may directly cause osteolysis when they invade or metastasize to bones, resulting in the dissolution of hydroxyapatite crystals through an agonist effect on osteoclasts during tumor progression.9,27
Humoral hypercalcemia of malignancy may involve the malignant secretion of PTHrP, a polypeptide structurally similar to intact PTH, as well as the liberation of cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor.3-5,7,8,15,19 The production and secretion of these humoral mediators lead to pathologic increases in osteoclastic resorption, often without visible radiographic bone lesions. The most common cancers associated with humoral hypercalcemia of malignancy in dogs are T-cell lymphoma (see boxed text titled “Canine T-cell lymphoma: The most common cause of hypercalcemia of malignancy in dogs”) and apocrine gland anal sac adenocarcinoma (see boxed text titled “Apocrine gland anal sac adenocarcinoma: The second most common cause of hypercalcemia of malignancy in dogs”)8 ; while in cats lymphoma, bronchogenic carcinoma, and squamous cell carcinoma are most commonly reported.7,10,28,29 Other tumors such as leukemias,30,31 thymoma,32,33 malignant melanoma,34 acanthomatous ameloblastoma,35 and various carcinomas have been sporadically reported to secrete PTHrP in dogs.36-40
Like its physiologic counterpart, PTHrP binds to PTH1 receptors on osteoblasts and renal tubular cells to exert its hypercalcemic effects.9,15,16,22 Some growth factors, such as epidermal growth factor and transforming growth factor-beta, increase PTHrP expression.15,22,41 Animals with hypercalcemia due to elevated PTHrP concentrations typically exhibit moderate to marked hypercalcemia, hypophosphatemia, and hypercalciuria with decreased fractional calcium excretion and increased fractional phosphorus excretion. For a supportive diagnosis of humoral hypercalcemia of malignancy, circulating PTHrP concentrations may be assessed by sending EDTA plasma samples to commercial laboratories.8
While it may seem at first that PTHrP is an abnormal hormone produced only by certain cancer cells, this hormone is produced by normal tissues in certain conditions and participates in calcium homeostasis and metabolism. For example, PTHrP is known to function in an endocrine manner in the fetus and is produced by the fetal parathyroid glands and the placenta, permitting ionized calcium uptake by the fetus.15 It is also produced by the mammary gland in lactating dams to facilitate calcium mobilization from maternal bones and may play a role in the transport of calcium into the milk.15 Finally, although the circulating blood concentrations are low in normal adults, PTHrP has been demonstrated in some epithelial tissues, endocrine glands, muscles, bone, brain, and lymphocytes.15
Metastatic carcinomas are commonly associated with malignant osteolysis in people and can lead to hypercalcemia both through humoral hypercalcemia of malignancy or direct osteolytic mechanisms. These tumors express osteotropism, or the affinity and ability to grow within bone; the exact mechanisms behind this phenomenon have yet to be fully characterized.
Tumor cells presence within the bone microenvironment can increase the number and activity of local osteoclasts through the paracrine release of factors such as interleukin-1, interleukin-6, tumor necrosis factor-alpha and tumor necrosis factor-beta, receptor activator of nuclear factor kappa-B ligand (RANKL), and prostaglandins, leading to localized bone resorption.15 Excessive focal bone resorption can cause bone pain, predispose patients to pathologic fracture, and induce hypercalcemia. These malignant clinical consequences occur most typically in companion animals with multiple myeloma and metastatic carcinomas of urinary bladder, prostate, and mammary gland origins and occasionally with lymphoma and leukemias.19,42-44 In cats, squamous cell carcinoma and osteosarcoma have been associated with hypercalcemia, possibly resulting from local osteolysis.10
The most common cause of a high calcium level is cancer. In about half of the cases of hypercalcemia in dogs the cause is lymphoma, a cancer of the lymphatic system. Lymphoma most often causes lymph nodes to swell, but it may localize in the liver, intestine, spleen, heart, brain, spinal cord, or kidneys. Tumors of the anal glands, and less frequently, other tumors, can also cause high calcium levels. Blood tests can determine if the calcium problem is due to cancer.
About one-third of Addison’s Disease cases have high calcium levels. Addison’s is a disease where too little cortisol is produced. These dogs usually act sick, with weakness, vomiting, and diarrhea often seen.
When examining a blood panel, a veterinarian may report to the owner that a pet has hypercalcemia, which is an elevated level of calcium in the blood. The owner often then wonders if there is too much calcium in the pet’s food or in the vitamins or supplements the pet is taking.
The prognosis for hypercalcemia depends on the severity of the underlying cause. Addison’s Disease can usually be well controlled. Lymphoma dogs respond to aggressive chemotherapy for an average of one to two years. If an anal gland tumor can be caught very early, surgery may be curative. Your veterinarian will investigate and determine the cause of the high calcium and discuss the prognosis and treatment plan with you.
Disease of one or more of the small parathyroid glands in the neck can cause hypercalcemia. A small benign tumor on a parathyroid gland can cause too much hormone to be produced, which then causes the calcium level to be too high. It is possible for a skilled professional to find these small masses on an ultrasound.
Hypercalcemia – Too Much Calcium, Animation
About 45% to 65% of hypercalcemic dogs and 10% to 30% of hypercalcemic cats have underlying neoplasia.