Causes of ionized hypercalcemia

Possible causes for increased blood calcium includes fungal disease (granulomatous disease), osteolytic diseases, spurius, primary hyperparathyroidism, vitamin D toxicity, Addison's disease, chronic kidney disease, cancer, among others.

Primary hyperparathyroidism

Primary hyperparathyroidism is typically caused by a benign tumor of the parathyroid gland. Hyperplasia can also lead to hypercalcemia, but it typically affects more than one gland. The increased PTH secretion causes the calcium to be mobilized from the bone, increasing the blood calcium. This is also associated with increased urine calcium and the predisposition to calcium oxalate urinary calculi. 

Small parathyroid nodule
Large parathyroid nodule

Treatment

The treatment of choice for primary hyperparathyroidism is the surgical removal of the parathyroid nodule. Persistence of the hypercalcemia can occur if other (ectopic) parathyroid tissue were to be present. This is an uncommon scenario. Hypocalcemia is a possible consequence of parathyroid surgery. This is thought to occur because of the atrophy of the normal parathyroid gland, which will take some time to start producing parathyroid hormones over time. Therefore, monitoring this blood calcium after surgery is very important, especially during the first 72 hours. Alternatively, ethanol or heat ablation have been used to treat primary hyperparathyroidism, but they are not as effective. 

 

Percutaneous ethanol ablation

Parathyroid percutaneous ethanol ablation is another treatment option. Efficacy of ethanol ablation varies significantly, but it is estimated to be approximately 75% when compiling different studies. This is lower than surgical parathyroidectomy, which is estimated to have an efficacy of 94%. Reported complications of ethanol ablation includes transient bark change in 22%, coughing 11%, and bark change 6%. Dysphagia and hypersalivation have also been reported. Hypocalcemia occurs in 22% of cases and clinical hypocalcemia in 4% of cases. Resolution of the hypercalcemia in patients undergoing ethanol ablation varies from 12 hours to 3 weeks. In most cases, hypercalcemia resolves within 3 days. 

Medical treatment

Medical treatment includes administering bisphosphonate, which is a medication that prevents the body from releasing calcium from the bone into the systemic circulation. While the concept is interesting, in our experience, this medication has commonly failed to control hypercalcemia in dogs with primary hyperparathyroidism. Alendronate is the bisphosphonate most commonly used. It is given orally and typically administered 1-2 times per week. The bioavailability of this medication is very low and even lower when given with food. In this case, it is recommended to give the medication on an empty stomach after a 12-hour fast and wait an additional 2 hours to give any food. Therefore, this medication cannot be given with treats, peanut butter, or canned food. A pill gun can be used to aid administration. Esophagitis and esophageal strictures have been described in humans. So, we recommend placing a very small quantity of butter on the lips prior to administering the medication. It is important to give a very small amount, just enough to coat the esophagus. We also recommend following the pilling with water to help avoid having the pill become stuck in the esophagus. Another possible complication that has been described in cats is the potential for long bone fractures. This is thought to occur because when the medication prevents the calcium from being released into circulation, it tends to make the bone very brittle in the long term and this is thought to predispose to bone fractures. There have been very few cases described that raised suspicion for bone fractures secondary to alendronate. We suspect that the risks are higher in patients that require high doses for a prolonged period of time. Other possible complications include the development of hypocalcemia, thus the importance of monitoring the ionized calcium during treatment. We also recommend monitoring routine blood work to make sure that his other organs are tolerating the medication. 

Another more recent treatment option is the use of cinacalcet (Sensipar) to reduce the ionized calcium. This is a calcimimetic medication, which is a calcium-sensing receptor agonist. The calcium-sensing receptor senses extracellular levels of calcium ions in both the parathyroid glands and the renal tubules. Calcimimetic medications interact with the calcium-sensing receptors in the parathyroid glands to reduce the secretion of PTH. There is one study underway looking at dogs with primary hyperparathyroidism treated with cinacalcet. Anecdotally, this medication rarely helps and when it does, it tends to require high doses of cinacalcet.