Hypercalcemia: An Overview for Pharmacists

Hypercalcemia: An Overview for Pharmacists

If you're like most pharmacists, electrolyte disorders is a subject that usually gets filed in the dreaded "learn and dump" part of your brain.

Where the information about electrolyte disorders lives in your brain (Image)

Where the information about electrolyte disorders lives in your brain (Image)

You know that place? Your own personal island of misfit toys where information goes to be forgotten. You'll learn an electrolyte disorder (and how to manage it). Then you'll get through the test (or the patient that you're working up), and the information is gone 3 days later.

Don't worry. I do it too...and this is a judgement free zone.

But one day soon, you'll come across the same electrolyte disorder again. And tl;dr pharmacy will have your back.

Today, let's focus on hypercalcemia, shall we?

Hypercalcemia Background and Pathophysiology

Hypercalcemia can be caused by a lot of things, but most cases (i.e. about 90%) are caused by one of 2 things:

  • Hyperparathyroidism
  • Malignancy 

Under the malignancy umbrella, it's most often lung cancer, breast cancer, and multiple myeloma that we're concerned about for hypercalcemia. 
 
With hyperparathyroidism, an overactive parathyroid gland secretes excessive amounts of parathyroid hormone (PTH), which in turn increases serum calcium levels. You remember some picture like this from physiology, right?

That's PTH doing it's thing. And PTH's 'thing' is to put calcium into your bloodstream. Kind of like how United's 'thing' is dragging people off of planes. PTH gets that calcium from anywhere it can. It increases dietary absorption, it increases renal reabsorption, and it increases bone resorption. 

That's a whole lot of "sorptions." Make sure you keep the terminology straight in your head:

  • Dietary absorption - This is where you initially get the substance (calcium in this case) into the body for the first time via the food you eat
  • Reabsorption - Initially as it goes through the nephron in your kidney, some calcium is excreted (i.e. it's set down a path that will have it exit your body through the urine). However, at a later part in the nephron, PTH can cause some of that excreted calcium to be taken up (i.e. reabsorbed) back into the blood stream 
  • Resorption - This is a special kind of reabsorption that involves cells or tissue. In the body, it is almost exclusively used for bones. So, bone resorption is the process of bone tissue getting broken down and absorbed into the blood stream

In the setting of malignancy, hypercalcemia is usually caused by cancerous cells metastasizing to the bone and causing resorption (thereby increasing serum calcium). Again, you'll see this most commonly with multiple myeloma, breast, and lung cancer. 
 
Other potential causes of hypercalcemia include sarcoidosis, over-supplementation, and dehydration (but again, these account for a combined 10% or less of all hypercalcemia cases). 

So, what exactly is hypercalcemia? And how do we measure it.

Obviously, hypercalcemia is a high calcium level. And remember that when you see the suffix "emia" on a word in medicine, it means we're talking about the blood stream (you may also see this referred to as serum or plasma). So hypercalcemia is having too much calcium in the blood stream. And now it should make sense why over secreting PTH (hyperparathyroidism) and increasing bone resorption via tumor metastasis will increase calcium levels. PTH's main job in the body is to increase serum calcium. And one of the main reasons your body undergoes bone resorption is to increase your serum calcium. When those processes go haywire, you can be left with overshooting the calcium goal.

We should also talk about how calcium is measured. In most institutions, "total" serum calcium is measured. This accounts for all calcium in the bloodstream, including both protein bound and free/unionized calcium.

No, that's not what I mean by "unionized." (Image)

No, that's not what I mean by "unionized." (Image)

As a quick reminder, 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" total calcium, but their free/unionized calcium levels may actually be elevated. 

Only free/unionized calcium can exert a biologic effect, so these patients may develop signs and symptoms of hypercalcemia.

You 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 the game of pharmacy school and life afterwards. So with that in mind...

The normal range of free/unionized serum calcium is between 4.6 and 5.5 mg/dL. And for total serum calcium, that range is between 8 and 10 mg/dL.

  • Free/unionized serum calcium: 4.6 - 5.5 mg/dL
  • Total serum calcium: 8 - 10 mg/dL

I mentioned the corrected calcium formula above. What's that? It's just a way for us to adjust the total calcium level for a patient with low albumin. That way we can estimate what their "effective" calcium level is. It's calculated by using the following formula:

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

So if our albumin is 2, and our calcium level is 9.5...

Corrected Ca = (0.8 x [4 - 2] + 9.5)
Corrected Ca = 11.1 mg/dL

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

Alright, we're past the background stuff. Let's move on to treatment.

 

Hypercalcemia Treatment

The treatment of hypercalcemia is usually differentiated based on the presence or absence of symptoms (symptoms which include thirst, confusion, weakness, nausea/vomiting, and diarrhea). In severe cases, untreated hypercalcemia can lead to lethargy, coma, and death.

In most scenarios, we won't aggressively treat asymptomatic hypercalcemia; particularly if we're dealing with a mild-to-moderate elevation. This can lead to us overshooting the problem and ending up with hypocalcemia.

For mild or asymptomatic hypercalcemia, the first step is not to make the problem worse. If possible, avoid medications that can raise serum calcium (I'm looking at you, 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.

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 (remember that loop diuretics increase the excretion of just about every electrolyte). Just be careful with loops because they can contribute to and exacerbate acute renal failure. Make sure your patient's kidneys are healthy.

For patients that are symptomatic, we need to get serious and pull out our big guns.

First, we might jump to IM or subcutaneous calcitonin. I didn't talk about it above, but your thyroid gland actually makes calcitonin...and it's basically "anti-PTH." So while PTH increases serum calcium, calcitonin lowers it.

The calcitonin we use in medicine is derived from salmon (so you have to avoid it in people with fish allergies). It will usually lower serum calcium by 1-2 mg/dL, and it works within 1 or 2 hours.

That's a pretty quick onset, and it makes calcitonin a useful choice during symptomatic hypercalcemia. Unfortunately, tachyphylaxis (i.e. tolerance) to calcitonin rapidly develops and within about 48 hours calcitonin becomes ineffective.

So what next?

Next we jump to our IV bisphosphonates or denosumab. The IV bisphosphonates normally 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. But there's a catch (isn't there always?).

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 (calcitonin is a totally legit option here). Zoledronic acid and pamidronate also have a renal dose adjustment and are contraindicated with a CrCl below 30 ml/min.

If our patient has severe hypercalcemia and renal failure (a pretty common scenario) what do we do? Say "Sorry, pal! I can't give you pamidronate!"?

Of course not. The RANKL inhibitor denosumab is our next option, and it can be used 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. 

Here are a few additional clinical pearls for bisphosphonates and denosumab...

  • Because they can take a while to work, you have to wait at least a few days before re-dosing bisphosphonates and denosumab (even if the patient's calcium level remains high).
  • 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. AND 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 are often used off-label in this setting.


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

  • Pamidronate [Aredia]
    • Not normally used for osteoporosis. It is used for Paget's disease, hypercalcemia of malignancy, and to reduce skeletal events in patients with multiple myeloma, breast, and lung cancer. For hypercalcemia, the dose is almost always 90 mg IV. 
  • Zoledronic acid
    • [Reclast] - Osteoporosis. 5 mg IV once per year. No dosage adjustment...it's either 5 mg or nothing (don't administer below CrCl of 30 ml/min).
    • [Zometa] - Hypercalcemia: 4 mg IV once. Minimum time to wait before giving another dose is 7 days. For skeletal events in oncology, the dose is 4 mg IV once per month. There is a range of dose adjustments starting at CrCl of 60. And again, you don't administer with CrCl < 30 ml/min. 
  • Denosumab
    • [Prolia] - Osteoporosis. 60 mg SubQ once every six months. No renal adjustment.
    • [Xgeva] - Oncology indications. 120 mg SubQ once per month. For hypercalcemia, you give doses on Day 1, Day 8, and Day 15 on the first month (so similar to Zometa, there is a recommended minimum of 7 days between doses). No renal adjustment.


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

Conclusion

So if I were to make a stepwise summary of all of the above treatments for hypercalcemia, it would look something like this:

  • Step 1: Don't make the problem worse
  • Step 2: Hydration and/or loop diuretic
  • Step 3: Calcitonin
  • Step 4: Bisphosphonate
  • Step 5: Denosumab
  • Step 6: Dialysis

Depending on where you practice, the order of those steps may be changed around. But that's a good starting point for a brief overview of what drug to turn to next. 

New FDA Approval: Ingrezza

New FDA Approval: Ingrezza

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