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
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