Hypercalcemia Pharmacotherapy: A Review

Although there are several conditions that can lead to hypercalcemia, most (about 90%)¹ are caused by either hyperparathyroidism or malignancy (specifically lung cancer, breast cancer, and multiple myeloma).

With hyperparathyroidism, an overactive parathyroid gland secretes excessive amounts of parathyroid hormone (PTH), which in turn increases serum calcium levels. In the setting of malignancy, hypercalcemia is most frequently caused by cancerous cells metastasizing to the bone and causing resorption.

Other potential causes of hypercalcemia include sarcoidosis, oversupplementation, and dehydration.

Depending on your practice environment, you may not regularly encounter hypercalcemia. This article will serve as a quick review with a focus on the medications and medical interventions used to treat hypercalcemia.

Before covering the treatments, it's important to define hypercalcemia and discuss how calcium is measured in the blood. In most institutions, "total" serum calcium is measured. This accounts for all calcium in the bloodstream, including both protein bound and free/unionized calcium. A large portion of serum calcium is bound to albumin in the bloodstream, making it biologically inactive. Consequently, patients with low albumin may appear to have a "normal" plasma calcium, but their free/unionized calcium levels may actually be elevated._² Only free/unionized calcium can exert a biologic effect, so these patients may develop signs and symptoms of hypercalcemia.

The clinician can adjust for patients with low albumin by either (1) Measuring the free/unionized levels of calcium or (2) Using the corrected calcium formula. Measuring the free/unionized calcium level is generally more expensive than measuring total serum calcium, however, it is also thought to be more accurate; particularly in patients with critical illness. It is best to familiarize yourself with both methods for your clinical practice. For reference, the normal range of free/unionized serum calcium is usually between 4.6 and 5.5 mg/dL.

The albumin-adjusted corrected calcium can be calculated by using the following formula:

Corrected Ca = (0.8 x [4 - Albumin] + Serum Ca)

A normal range for total serum calcium level is between 8 and 10 mg/dL; with some slight variations between institutions. Hypercalcemia is defined as a total serum calcium of >10.5 mg/dL. It is further stratified into mild, moderate, or severe categories based on the following:

• Mild Hypercalcemia: Total Ca = 10.5 - 11.9 mg/dL

• Moderate Hypercalcemia: Total Ca = 12 - 13.9 mg/dL

• Severe Hypercalcemia: Total Ca = 14 mg/dL or greater

Now that we've reviewed the background, let's discuss the treatment of hypercalcemia.

Hypercalcemia Treatment

The treatment of hypercalcemia is often differentiated based on the presence or absence of symptoms. The typical symptoms of hypercalcemia include thirst, confusion, weakness, nausea/vomiting, and diarrhea. However, in severe cases, untreated hypercalcemia can lead to lethargy, coma, and death.

It's usually best not to aggressively treat asymptomatic hypercalcemia; particularly if the patient only has a mild-to-moderate elevation. In these cases, the first step is to not worsen the problem. If possible, avoid medications that can raise serum calcium (thiazide diuretics, calcium supplements, antacids, etc...). Additionally, hydration with normal saline may be used as a "gentle" way to reduce calcium. The saline will cause a relative dilution of serum calcium and help to facilitate calcium excretion through the urine.

For patients that are symptomatic, more aggressive therapies are used to reduce calcium levels. If the patient has a condition such as CHF where he/she may have fluid overload, then furosemide and other loop diuretics can be used instead of hydration to lower calcium. Be sure to assess renal function before administering loop diuretics, as they can contribute to and exacerbate acute renal failure.

Another option to lower calcium is to use IM or subcutaneous calcitonin. It will usually lower serum calcium by 1-2 mg/dL, and it works within 1 or 2 hours. This quick onset makes calcitonin a useful choice during symptomatic hypercalcemia. Unfortunately, tachyphylaxis (i.e. tolerance) to calcitonin rapidly develops and within about 48 hours calcitonin will often become ineffective.

The next step in therapy is to use IV bisphosphonates or denosumab. Most commonly, the IV bisphosphonates used for hypercalcemia are zoledronic acid and pamidronate. They are more effective than calcitonin at lowering serum calcium, and there isn't an association with tachyphylaxis. However, it takes IV bisphosphonates several days to reduce calcium levels, so they will need to be used in conjunction with something else for symptomatic patients. Bisphosphonates have a renal dose adjustment and are contraindicated in renal failure (CrCl < 30 ml/min).

The RANKL inhibitor denosumab is an option for treating hypercalcemia in patients with renal failure. Although data are sparse, there is no recommended dose adjustment. However, because it is a monoclonal antibody, there is a risk of infusion reactions. If you're interested in learning more about monoclonal antibodies, here is a previous article on the topic.

Here are a few additional clinical pearls for bisphosphonates and denosumab. Both IV bisphosphonates and denosumab have a significant risk of causing hypocalcemia, so it is important to closely monitor calcium levels. In addition to hypercalcemia of malignancy, both drug classes are also used to treat osteoporosis. They're also used to prevent skeletal-related events (SREs) in multiple myeloma and breast/lung cancers. It should also be noted that denosumab is only indicated for the prevention of SREs in solid tumors;, not multiple myeloma. Both IV bisphosphonates and denosumab do not have a specific indication for hyperparathyroidism-induced hypercalcemia, however, they may be used off-label in this setting.

The dosing and associated brand names are different depending on the indication, so here is a quick breakdown:

• Zoledronic acid

o Reclast³ - Osteoporosis. 5 mg IV once per year. There is no dose adjustment, but it is contraindicated at CrCl < 30 ml/min.

o Zometa⁴ - Oncology indications. 4 mg IV once every 1 - 3 months. There are various renal dose adjustments that start at CrCl of 60 ml/min. It is also contraindicated at CrCl < 30 ml/min.

• Denosumab

o Prolia⁵ - Osteoporosis. 60 mg SubQ once every 6 months. No renal adjustment.

o Xgeva⁶ - Oncology indications. 120 mg SubQ once monthly. No renal adjustment

Finally, while not technically a "drug therapy," hemodialysis can be used as a last resort to lower calcium levels.

Conclusion

Although relatively straightforward, there are many medications used for hypercalcemia that are not used often in other areas of clinical practice. It is worth our time as pharmacists to periodically review and be familiar with these medications.

References

1. Skugor, Mario; Milas, Mira. Hypercalcemia. Cleveland Clinic, 2009. Accessed from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/hypercalcemia/

2. Carroll, Mary; Schade, David. A Practical Approach to Hypercalcemia. Am Fam Physician. 2003 May 1;67(9):1959-1966. Accessed from: http://www.aafp.org/afp/2003/0501/p1959.html

3. Reclast. Prescribing Information. Accessed from: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/reclast.pdf

4. Zometa. Prescribing Information. Accessed from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021223s028lbl.pdf

5. Prolia. Prescribing Information. Accessed from: http://pi.amgen.com/united_states/prolia/prolia_pi.pdf

6. Xgeva. Prescribing Information. Accessed from: http://pi.amgen.com/united_states/xgeva/xgeva_pi.