Mmmhmm. We know. We’ve been there. (Image)

Steph’s Note: Let’s be honest. There’s that section of the nephrology module that we all kind of glossed over in school because it was complicated. It just seemed counter intuitive with negative feedback loops, and we kinda hated studying it. So we learned the minimal amount we had to and kept on going.

Sound familiar? What loop am I talking about?

The parathyroid hormone (PTH), calcium, phosphate, vitamin D system, that’s the one. Complete with kidneys, bone, intestines, and vasculature.

*shivers of dismay*

Really, it’s not as bad as it seems. (And this is coming from someone who didn’t reeeeeally learn it to understand it until her dad went on dialysis.) So let’s dive in and get it straight.

What is the Function of Parathyroid Hormone?

Where the PTH party at? The parathyroid glands. (Image)

It’s all about calcium homeostasis. The parathyroid gland secretes parathyroid hormone (PTH) whenever it detects low serum levels of calcium. Important note here. We’re talking about detecting low SERUM levels of calcium, not bone levels of calcium.

Why does the parathyroid gland care about low serum levels of calcium?

Calcium is pretty underrated as far as electrolytes go. We tend to always think about it in terms of the bones, but we forget that it’s needed in the blood for TONS of other bodily functions as well. Slightly important processes like…

Oh yeahhh, check out purple #2 there. That’s where the calcium influx is in the cardiac action potential. (Image)

Smooth muscle contraction (calcium channels in the sarcolemma)
Nerve impulse conduction (axonal signal propagation, neurotransmitter release)
Cardiac function (cardiac myocyte depolarization)
Blood clotting (phospholipid surface for coagulation)

And it’s all down to PTH to ensure that there’s sufficient levels of calcium in the blood to carry out these processes. Geez, talk about responsibility.

So once PTH is secreted from the parathyroid gland, what are the downstream effects?

There are 3 main targets for this hormone:

Bones
Kidneys
Intestines

In the bones, PTH stimulates bone resorption. This means it causes the bones to release calcium back into the blood, thereby helping to maintain the calcium-dependent processes mentioned above. Interestingly, while you would think PTH would work directly on osteoclasts (the cells that break down bone and are responsible for bone remodeling and resorption), those cells actually do not have receptors for PTH! So PTH actually works to modulate osteoblasts (the cells responsible for building bone), and, through a series of complex interplays, modulates osteoclast activity.

It’s like the ultimate natural checks and balances system. Can’t have PTH receptors on the osteoclasts because that’s just too much power. Gotta have them on the opposite cells to regulate. Regardless, bone resorption to increase serum calcium levels is helpful for cellular functions, but this unfortunately may be at the expense of bone integrity.

A lovely visual summary of the takeaways of PTH function. (Image)

In the kidneys, PTH serves 3 functions. First, it helps the kidney produce the enzyme necessary for converting inactive vitamin D (25-OH-D) to active vitamin D (1,25-OH2-D), aka calcitriol. Active vitamin D helps with calcium reabsorption in the distal convoluted tubule by a protein called calbindin-D. Second, PTH increases calcium reabsorption in the distal convoluted tubule and the collecting duct. Third, PTH lowers the amount of phosphate that is reabsorbed in the proximal convoluted tubule. (Phosphate loves to bind with calcium in the blood, which means less free and available calcium for bodily functions. So decreased phosphate in the blood = increased available calcium.)

The effects of PTH on calcium in the intestine are less direct but still essential. That active vitamin D it helped to make in the kidneys is also used in the small intestine to increase calcium absorption from food through both passive and active transport.

Now that we know what PTH normally does, let’s talk about what happens when things go wrong.

What is Secondary Hyperparathyroidism?

There are a few ways that PTH secretion can go wrong, but we’re going to focus on the most commonly encountered one here: secondary hyperparathyroidism. Let’s break that down really fast.

Obviously, hyperparathyroidism means the PTH level is high. “Secondary” refers to the fact that the PTH level is high as a result of another condition. Usually that other condition is chronic kidney disease (CKD) and/or vitamin D deficiency. To give you an idea of how many people are at risk for secondary hyperparathyroidism, take a look at these numbers:

CKD affects about 15% of the US population. That’s more than 1 in 7 adults! (So if you didn’t like that nephrology module in school…now’s the time to change that perspective. Speaking from experience here.)
Vitamin D deficiency affects up to 50% of the worldwide population!! (FYI, it’s implicated in many other disease states too, including multiple sclerosis.)

Why are these conditions associated with secondary hyperparathyroidism?

Vitamin D normally suppresses PTH secretion and regulates calcium and phosphate homeostasis. If there’s not enough vitamin D as in vitamin D deficiency and/or CKD, then PTH hormone steps in and ramps up.

In CKD, phosphorus isn’t sufficiently excreted, and hyperphosphatemia directly leads to increased PTH secretion. It also indirectly leads to PTH secretion by causing hypocalcemia (those phosphate-calcium binding complexes…).

What Does Secondary Hyperparathyroidism Look Like?

Clinically, signs of secondary hyperparathyroidism circle around bone loss and bone malformations (due to remodeling by osteoclasts). So patients may experience bone deformations, bone pain, and even fractures. Unfortunately, the calcium remodeling issues aren’t limited to just the bones…

Patients may also experience calcifications in the vasculature, viscera, the heart, skin tissue, and the eyes. Calcifications in the circulatory system, including the heart, may lead to ischemia and/or arrhythmias. Pruritis is common. It can also lead to calciphylaxis, which is when depositions in small arteries lead to skin tissue necrosis, which (as you might guess) is very painful and not overly responsive to usual pain management modalities. Calciphylaxis can also lead to infections and sepsis.

Take note of the secondary hyperparathyroidism row. It’s as we’ve described…high PTH, low (or compensated normal) calcium, low vitamin D, and variable phosphate. Phosphate is usually elevated if the etiology is CKD, but it is low if the etiology is vitamin D deficiency. (Image)

In terms of labs, evaluation should consist of the following:

PTH
Calcium
Albumin
Phosphorus
Vitamin D
Renal function panel

Of note, we often talk about using a “corrected” calcium level in patients with hypoalbuminemia. And in many patients, this is appropriate because calcium is highly albumin-bound. However, FYI, there is much debate about whether the traditional calculation for correcting calcium is an accurate estimation in those with more severe CKD or end-stage renal disease (ESRD). If resources allow, the most accurate assessment of calcium is an ionized calcium level, which gives you the biologically active portion of calcium in the serum.

How to Manage Secondary Hyperparathyroidism

Goals of Treatment for Secondary Hyperparathyroidism

The goal of treating secondary hyperparathyroidism is to drive lab values towards target ranges. The tricky part is this - not all of these lab values have known goal ranges for patients, especially those with CKD.

According to the 2017 KDOQI guidelines for CKD-Mineral and Bone Disease, here’s what we’re shooting for…

PTH: The goal range is unclear as each individual has his own homeostatic set point. To make things more complicated, PTH levels vary throughout a given day as well! There aren’t really specific thresholds for initiating or ceasing treatment. Rather, we’re supposed to check serial PTH levels to monitor trends. So the goal is really to induce a decrease in PTH, but as far as how much…?
For some frame of reference though, PTH levels greater than 600 pg/mL are associated with increased all-cause and cardiovascular mortality, as well as cardiovascular hospitalizations. On the other hand, PTH levels <100 pg/mL are considered hypoparathyroidism and are associated with increased risk of adynamic bone disease.
Phosphate: This lab should be maintained as close to the normal range as possible. However, KDOQI acknowledges that this is not exactly straightforward as the “normal” range varies from lab to lab AND there’s also variation (up to 1 mg/dL) in phosphate throughout the day. This means that results and treatment strategies could change depending on when a patient has labs drawn throughout the day! They do emphasize that sustained hyperphosphatemia should be the trigger for treatment and that medications to lower phosphate should not be started in patients with “normal” phosphate levels just to prevent hyperphosphatemia.
Calcium: Basically KDOQI states that we should treat and try to avoid hypercalcemia. Slight hypocalcemia may be tolerated in the setting of pharmacotherapy as long as patients are functionally ok. The rationale behind this is that hypercalcemia may contribute to vascular and valvular calcifications, so they’re airing on the side of avoidance here. But again, it’s difficult to exactly define what constitutes hyper- and hypocalcemia, especially in the setting of hypoalbuminemia (as previously mentioned).
Vitamin D: The goal here is to avoid deficiency or insufficiency, but an exact target goal hasn’t been established. Deficiency is defined as levels <20 ng/mL, and insufficiency is 21-29 ng/mL. So most clinicians prefer to keep levels at 30 ng/mL and above.
It’s realllllly hard to become toxic (or hypercalcemic) from too much vitamin D, so many clinicians will push that target even further. (There’s even been some evidence that we should push higher to suppress the PTH, like to 50 ng/mL.) So again, not super well-defined…but avoid low levels.

Pharmacotherapy for Secondary Hyperparathyroidism

There are 3 main classes of medications for achieving the above treatment goals (as wishy-washy as they may be!). They are phosphate binders, vitamin D and analogs, and calcimimetics. Let’s take a look at each of these.

Phosphate binders are exactly what they sound like - they bind dietary phosphate in the gut to prevent absorption, thereby lowering serum phosphate levels. The 3 types of phosphate binders are aluminum-containing, calcium-containing, and the newer (pricier) non-aluminum or calcium phosphate binders. All of these need to be taken with meals since they’re targeting dietary phosphate. Patients should also be counseled on ways to reduce dietary phosphate intake without compromising necessary protein, which can be a hard balancing act.

Here’s a handy chart of the pearls and pitfalls of these medications:

You can see how patients may come to hate these medications (and therefore not take them). They’re usually quite large pills, and patients have to take multiples of them at each meal, as well as with snacks if they’re substantial enough. Add to that the GI issues that accompany most of them (bloating, nausea, constipation, etc), and you have the perfect recipe for serious non-adherence. But it’s what we have available at this point if dietary restriction is not sufficient.

Next up are the vitamin D supplements - but first a disclaimer. There are no set guidelines for how to replete vitamin D…and there are a LOT of products from which to choose. So don’t be surprised if you see significant variability in products and doses between treatment sites or even from providers within the same healthcare system.

Let’s chat really quickly about the forms of vitamin D. There are generally 4 main forms of vitamin D and then lots of analogs. The 4 main forms are the following:

Cholecalciferol (vitamin D3): made from 7-dehydrocholesterol in the skin after exposure to UVB rays. Also in foods and supplements. Not biologically active.
Calcidiol (25-OH-D): made in the liver from cholecalciferol by 25-hydroxylation. Minimal biologic activity but major circulating form measured in lab assays.
Calcitriol (1,25-OH2-D): made in the kidneys from 25-OH-D by 1-alpha-hydroxylation. Biologically active and very potent form.
Ergocalciferol (vitamin D2): largely human made and added to foods or used as a prescription supplement. Must be converted to active form in the body. Has a shorter half-life than cholecalciferol.

Then there are the vitamin D analogs…

These are all analogs of active calcitriol. Calcitriol, paricalcitol, and doxercalciferol are the most commonly used in the US. (Image)

While it may seem like a bit of a free for all, most institutions have some sort of protocol in place to guide product selection and dosing based on lab values. Whatever is chosen, patients should continue to have serum vitamin D monitoring completed to ensure improvements are occurring, as well as serum calcium and phosphorus levels to ensure they are not developing hypercalcemia or hyperphosphatemia.

Now on to the 3rd class of medications for secondary hyperparathyroidism: calcimimetics.

As the drug class name implies, these drugs “mimic” calcium in the tissues. By doing this, they kinda trick the calcium sensing receptors (CaSR), specifically those on the parathyroid gland, into thinking there’s more calcium available than there actually is. As a result, the parathyroid gland decreases secretion of PTH, and the body lives on slightly less calcium than normal, which is why some patients experience slight hypocalcemia (usually asymptomatic) with these agents.

There are only 2 agents to worry about here - cinacalcet and etelcalcetide. Check out the summary chart below for more details:

Check out the head to head trial of these 2 agents here.

The tl;dr of Secondary Hyperparathyroidism

I think that about covers the gamut. Was that so bad? Hopefully not! I really think it’s just the negative feedback loop that messes with our brains on this one…

In summary, PTH is released in response to low calcium levels in the blood, and we need calcium for a wide variety of physiological functions, not just bone. When PTH is released, it works on its 3 targets - the bones, the kidneys, and the intestines - with the goal of increasing calcium levels.

Secondary hyperparathyroidism develops in response to CKD and/or vitamin D deficiency and can lead to long-term calcification complications. Treatment revolves around the use of phosphate binders, vitamin D and its analogs, and calcimimetics. The combination of agents required varies amongst patients, and management should be guided by serial PTH, calcium, phosphate, and vitamin D lab monitoring. While target levels haven’t necessarily been established for all of these parameters, using trends to ensure response is imperative.

More research is needed to determine optimal agents and dosing for all of these classes of medications. In the meantime, good luck with your judgment calls and recommendations! Monitor, monitor, monitor!

Understanding Secondary Hyperparathyroidism: The Pharmacist's Guide to PTH