Optimal treatment management considerations for hypoparathyroidism

Bart Clarke, MD, a professor of medicine and endocrinologist at Mayo Clinic in Rochester, Minnesota, spoke with Rare Disease 360 about

Question:

How does hypoparathyroidism affect patients? What systems or organs can be impacted by the condition?

Bart Clarke, MD:

Hypoparathyroidism is an uncommon condition, but more common than I think is popularly realized. It’s characterized by low blood calcium, usually upper normal or high blood phosphorus, and then undetectable or very low levels of parathyroid hormone. There’s some variation in that between patients because some patients are mildly affected, others more severely so. But these biochemical changes occur because of the absence of parathyroid hormone or inability to secrete adequately. Because of that, patients develop low calcium and high phosphorus. Most of the symptoms come from the low calcium; so muscle cramps, tingling around the fingertips, sometimes the lips or tongue tip, even occasionally the toes can occur and these are commonly reported by patients. High phosphorus itself doesn’t usually cause much in the way of symptoms, but certainly can contribute to kidney stone formation along with the calcium supplements that these patients are commonly given.

Because of that, the main organ systems affected by the changes in these biochemistries affects mainly the nerves, the muscles, but can affect kidney function, as well. Patients often tell us that they have a brain fog or disconnect between what they hear and think about and can talk about. Of course for many patients that’s a prominent symptom that is hard to understand, but we attribute it to the low calcium mostly because most of these symptoms improve with adequate calcium replacement.

Question:

Vitamin D and calcium are often used in the treatment of hypoparathyroidism. How do these treatments address the condition? Are there any unmet treatment needs for hypoparathyroidism?

Bart Clarke, MD:

This is a very good question because it’s pretty obvious based on the biochemistries that we can correct those, in large part, by giving adequate calcium and vitamin D supplementation. Each patient is different. Most patients will take a fair amount of calcium, and of course, in the early days before we had any other therapies that could be given in the form of parathyroid hormone replacement, sometimes the doses of calcium were very high and inconvenient because so many doses were required during the course of a day. On average, most patients would require calcium in the form of citrate because it absorbs better than carbonate, oftentimes giving 600 mg 3 or 4 times a day fairly commonly. Some get by with less, some take a lot more. With that, usually calcitriol is given because this is an active form of vitamin D that stimulates the absorption of calcium from the intestine or supplements or food.

This will get the blood calcium relatively easily into the range of about 8.5 to 9.5 mg/dL. In this range, people feel generally better and don’t notice the tingling around the fingertips or muscle cramps or tetany in the hands as a result. Calcitriol is important, but because calcitriol doesn’t meet all the vitamin D needs in the body, we generally also give vitamin D-3 commonly 1,000 units, sometimes more to titrate the blood level for 25 hydroxyvitamin D into the goal range for the assay being used. The combination of these 2 replacement therapies, in a sense, will meet most of the needs of the patients for symptoms. The challenge comes when very high doses are required because this also causes constipation and difficulty taking so many tablets at the same time. Occasionally, patients will take more and then of course sometimes the calcium goes higher than or lower than it should, and this is because the absent parathyroid hormone that normally regulates these values in the blood is missing.

We’re trying to, in a sense, by giving calcium and vitamin D mainly to replace the function of parathyroid hormone, and as you can imagine, that works variably sometimes not so well.

Question:

Other than the previously mentioned therapies, what can be done to treat and/or manage hypoparathyroidism? What are the monitoring needs that may be required for these patients?

Bart Clarke, MD:

For many of these patients, calcium and vitamin D supplementation with both calcitriol and vitamin D-3 is adequate to control symptoms and to control the blood calcium and keep the blood phosphorus close to the normal range. In patients where this works, there really isn’t more that has to be done, but some patients, of course, are magnesium deficient that sometimes requires a magnesium supplement. Some of these patients when they take supplements, especially in high doses, can get higher in calcium that leads to kidney stones. Some patients, where the dose is required to maintain normal calcium in the blood, might also, at the same time, cause high urine calcium. Sometimes we use thiazides type diuretics to limit the calcium excretion in the urine. Between these different agents, in most cases, this works reasonably well. However, as you can imagine, there’s a few patients, and maybe as many as perhaps a third of patients who don’t feel well controlled on these approaches.

Because of this, other treatments have been developed; you’re probably aware that there is parathyroid hormone analogs that have been developed by various sponsors to try to meet the need of controlling calcium better in the way that it can’t be done, where it’s not adequately controlled where without the drug. Injectable parathyroid hormone one time a day usually is adequate to do this. Because right now there’s only 1 product on the market that’s been FDA-approved, this is a product that’s been derived from parathyroid hormone. The generic term is called palopegteriparatide, and this is a version of parathyroid hormone that’s long-acting that will tend to keep blood calcium levels in the desired range of 8.5 to 9.5 mg/dL with daily injections. That is commonly being used these days in patients who do not feel well controlled on the calcium and vitamin D supplementation.

Beyond these things, there’s other products being developed, of course, other ideas have come about that might actually make this easier. Some thought has been given to transplanting parathyroid glands into patients who have hypoparathyroidism and of course that may work in some settings, doesn’t work so well in other settings. But that is also another way of perhaps treating this if patients are severely affected.

Question:

How does hypoparathyroidism impact patient quality of life? What routine monitoring or management needs are required for patients?

Bart Clarke, MD:

Hypoparathyroidism, as you can imagine given that calcium is an important anolyte in the blood that controls nerve function, muscle function, intestinal function, and affects renal function, as well, as well as brain function. Because of that, people who don’t meet adequate control of calcium in the blood, who get high phosphorus, who get low magnesium and perhaps have other issues, certainly quality of life is impaired. Most patients, by most of the surveys taken, show at least mild to moderate impairment, some more severely than that.

How to fix this, of course, is thought to be, as we’ve discussed, giving adequate calcium active vitamin D, vitamin D-3 as well, magnesium if needed, an thiazides type diuretics to try to prevent high urine calcium loss that would lead to kidney stones. In many cases, these approaches do seem to work fairly well in combination. Some people get by with just calcium and calcitriol, but other patients take more of this variety of approaches that can be used to try to optimize the quality of life. Of course, the patients who are given injectable parathyroid hormone analogs oftentimes report feeling better than they did with just the symptomatic replacement with calcium and vitamin D. These are the options that patients are given.

Control of this condition is a moving window, as you can imagine, because diet affects this lack of intake can affect it, and of course monitoring various parameters is very helpful in the management of these patients. Typically, we would measure serum calcium even if it’s well controlled, probably at least every 3 months to make sure it stays normal. If it’s poorly controlled and fluctuating both high and low fairly frequently, then of course more frequent monitoring is required. Because of this, patients usually will have to go into an urgent care center or doctor’s office or emergency department at night or on the weekends, which creates another layer of difficulties with their quality of life because of course they recognize that it’s expensive and the personnel that deal with them sometimes don’t believe them and they have to explain what they mean by low calcium causing changes.

These things are done, but generally, if things are well controlled, monitoring serum calcium at least every 3 months and more frequently than that, as needed, is important. With that, we generally would check vitamin D levels both for calcitriol and for vitamin D-3 in the blood similarly in the same timeframe, probably once every 1 to 3 months to make sure it’s working. There’s no way patients can monitor at home with a meter, yet, but there’s meters being developed that may eventually simplify that and make that a lot easier. Magnesium levels we would check less often unless they’re requiring magnesium replacement. Of course, 24-hour urine calcium and creatinine would normally be checked at least once a year, if not twice a year, depending on how things go. One thing that’s important to consider is that if dose changes have to be made because either it’s not working well, the calcium is too low or too high, then of course once the dose change is made, monitoring is usually required within a week or 2 after that to make sure that the new dose is working better.

With that, there’s other considerations that comes up with kidney stone formation, certainly measuring by imaging, by ultrasound, CT scan of the abdomen and pelvis is commonly done. Because of the costs and radiation exposure of the CT scans, these are done less frequently, but certainly once a year to every 2 years. Collecting 24-hour urine calcium is done at least once a year, if not twice a year. Those are the main issues. Then addressing other concerns that come up. As you may be aware, evaluation of populations of these patients do show other findings that may explain other symptoms, and of course some of these are still controversial. Cataracts can form in some of these patients and need cataract surgery eventually, at an earlier age than usual. Some patients have risk of infection, upper respiratory and bladder infection in particular, and there’s other findings and studies looking at populations of these patients, comparing them to normal healthy controls that shows other variation in symptoms and findings.

The way we, as endocrinologists, view this, it’s mainly a calcium and phosphorus and parathyroid hormone disorder, but as time has gone on, other findings are showing that this really is a systemic disease that affects other parts of the body in ways that we still don’t fully understand.