Although relatively rare, hypoparathyroidism carries a disproportionately large burden of comorbidity among the approximately 58,700 people living with insufficient or absent levels of parathyroid hormone (PTH) in the U.S. In the recent “Understanding the Burden of Illness Associated with Hypoparathyroidism (PARADOX Study),” researchers led by Bart L. Clarke, MD, associate professor Mayo Clinic College of Medicine, Rochester, Minn., assessed patient self- reports of the symptoms they experienced. The 374 study participants were members of the Hypoparathyroidism Association who responded to an online questionnaire and who met inclusion criteria. Respondents averaged age 49 years and had lived with their condition for an average of 13 years. Most were female (85%) and had developed hypoparathyroidism postsurgically (78%).
The study findings startled researchers in terms of the magnitude of reported symptoms. “What we’re hearing from patients is that, in general, having this condition had a pretty significant impact on their quality of life,” Clarke says. “Basically, there was a lot more symptomatology than we have classically been taught that hypoparathyrodism can cause. In a global sense, that was the biggest surprise to me.” Symptoms clinicians would expect include what low calcium would cause, such as muscle cramps, tingling, and parasthesias. But what was reported went well beyond these classic symptoms, including what Clarke says his patients referred to as “brain fog,” which impacted their ability to focus, remember, learn and retain information, and hold a job.
Importantly, these unexpected but very commonly reported symptoms persist despite treatment. The current therapy (used for the last 50 years) involves replacing the calcium and vitamin D that
low/absent PTH causes. “Theoretically, at least, that should take care of their symptoms,” Clarke says. “But despite getting the best treatment that we have, these patients are telling us they are not very functional in their day-to-day life. It impacted relationships with family; it impacted intimacy with partners; it impacted their ability to exercise and any number of normal functions. Symptoms that we thought would get better with treatment did not.”
This might be because replacing calcium and vitamin D do not address the underlying cause of hypoparathyroidism. Although this treatment will prevent seizures and cardiac rhythm disturbances, some patients are more severely affected, or they might have other conditions complicating the picture. In the latter case, the interaction between the comorbid conditions and the hypoparathyroidism may aggravate certain symptoms, such as depression and anxiety. In the former case, patients are taken aback by how difficult managing their condition is. Clarke says his patients report dramatic quality-of-life differences, such as experiencing 16 or 17 symptoms a day for 13 hours a day, every day.
So-called “Empathy Gap”
“To some degree this is a problem of patients complaining of symptoms but not being heard,” Clarke says. Because some of the survey findings were not symptoms that endocrinologists would customarily attribute to low calcium, they might not think hypoparathyroidism is the cause and refer their patients elsewhere. As a result, patients walk away feeling that their care providers are unsympathetic. Some PARADOX researchers call this potential problem an “empathy gap.”
Others consider it more of a “failure of understanding the challenges of living with hypoparathy- roidism.” Tamara J. Vokes, MD, professor, University of Chicago Department of Medicine, and director, Osteoporosis and Metabolic Bone Disease Clinic, testified at the U.S. Food and Drug Administration hearing for approval of PTH1–84, a possible bioengineered replacement for the endogenous hormone that hypoparathyroid patients lack, on behalf of NPS Pharmaceuticals, Inc., the company that developed the drug. ￼“The more accurate portrayal of the problem here is that because hypoparathyroidism is a rare disease, most clinicians, including many endocrinologists, have no real direct experience caring for these patients. Although it is perceived as relatively easy to treat because it involves just oral supplements of calcium and active vitamin D, I think what physicians fail to understand is that this is not so easy,” Vokes says. Because the patient must constantly take the supplements to avoid the very unpleasant consequences of low calcium — what patients call “crashing” — this dependence can interfere with their lives. “And, I think even more than that, we’re asking these patients to stay at a calcium level that is at or just below the lower limit of normal. I don’t think any of us would be comfortable at that level. We’re asking them to be in a nonphysiologic range,” she says.
Although the PARADOX study has certain limitations, even within these limitations, it has underscored the need for new therapies to adequately treat hypoparathyroidism. One such limitation was the self-reported nature of data both because it cannot be verified and because it is neither objective nor necessarily balanced. “It asked patients to volunteer and express their symptoms, so you’re more likely to get the worst cases,” Vokes says. Another study limitation was the absence of a healthy, age-matched control group, which would help determine whether the incidence of a given symptom (e.g., depression) was higher in the hypoparathyroid group than in the control. “But, even though painting a dramatic picture clearly stands to benefit the [pharmaceutical] industry, the fact that these patient self-reports were not prompted by the industry, suggests that they are believable,” Clarke says.
Both researchers agree that current symptom control in hypoparathyroidism is far less than acceptable and that new therapies are therefore needed. According to Vokes, “The PTH replacement attempt has been going on so many years because of the hope that it will allow these patients to a) not depend on exogenous supplements — they could take an injection or two a day and then be able to go about their day just like a normal person would — and b) then perhaps we can allow them to have a little bit higher calcium without causing hypercalciuria and soft tissue calcifications.”
“We’re hoping that PTH1–84 will make a big difference for some of these patients,” Clarke says. In the three-year clinical trial (six-month initial period, then 30-month follow-up) of the drug, patients reported feeling 80% better on treatment than before treatment. “Having heard both sides — the conventionally treated and the experimental drug-treated — it sure seems to me that PTH does a lot of things we do not give it credit for,” Clarke continues. “Replacing the missing hormone is probably a good thing in general. If you don’t give it at all, you can bet that there’s going to be a lot of symptoms that are not fully dealt with or treated. We need a hormone replacement to help patients feel a lot better than they do now.”
The FDA ruling for approval of PTH1–84 was scheduled to take place in October 2014 but has been delayed until January 2015. Again, says Vokes, the problem is really failing to understand the challenge of the existing disease treatment. “Calcium supplementation does not allow these patients to go about their business normally,” she says. “Asking them to be in a nonphysiologic state fails to understand the discomfort they will experience as a result.” EN
— Horvath is a freelance writer based in Baltimore, Md. She wrote about erectile dysfunction in the December issue.