PTH Replacement Therapy Linked to Mild Benefits; More Research Needed
Treatment helped reduce phosphate levels, need for supplements
Parathyroid hormone (PTH) replacement therapy is superior to conventional treatment at lowering blood phosphate levels and the need for calcium and vitamin D supplements in people with chronic hypoparathyroidism, according to a review of clinical trial data.
It appeared to be associated with higher-than-normal calcium levels (hypercalcemia) and had only a small benefit in health-related quality of life over standard treatment, however.
While these findings may support the use of PTH replacement therapy for this patient population, larger and longer studies are needed to assess its effects on important outcomes, such as quality of life, the researchers noted.
The review study, “Parathyroid hormone therapy for managing chronic hypoparathyroidism: a systematic review and meta-analysis,” was published by an international team of researchers in the Journal of Bone and Mineral Research.
Hypoparathyroidism is caused by a deficient PTH production, resulting in lower than normal calcium levels and higher than normal phosphate levels in the blood. Patients also have a deficiency in vitamin D, which helps the body absorb calcium.
The condition is most frequently caused by unintentional damage to the parathyroid glands, which produce PTH, during neck surgery. While most cases recover, about 25% develop chronic or permanent hypoparathyroidism. Long-term manifestations may include kidney impairment and failure, irregular heartbeat, heart disease, seizures, depression, infection, cataracts, and impaired quality of life.
Conventional therapy — calcium supplements and calcitriol (the active form of vitamin D) — aims to normalize blood calcium levels and reduce calcium deficiency symptoms. However, it fails to control phosphate, may result in hypercalcemia and associated complications, and doesn’t address the disease’s underlying cause.
“The optimal treatment strategies for patients with chronic hypoparathyroidism remain uncertain,” the researchers wrote.
Delivering a lab-made version of PTH to patients is another therapeutic option, but the ideal PTH replacement therapy has yet to be found. Currently, this approach is indicated only for patients who don’t respond well to conventional therapy.
Two versions of a lab-made PTH are currently used for hypoparathyroidism — Takeda Pharmaceutical’s Natpara, approved for this indication, and Eli Lilly’s Forteo (teriparatide), used off-label.
TransCon PTH, Ascendis Pharma’s experimental long-acting PTH therapy, has shown promise in Phase 3 trials of adults with hypoparathyroidism. Regulatory submissions for its approval are expected this year.
“The use of PTH therapy in chronic hypoparathyroidism patients should be based on evidence regarding potential benefit on patient-important outcomes,” the researchers wrote.
PTH therapy vs. conventional treatment
With this in mind, the researchers retrospectively analyzed published studies up to May 2022 that reported results from randomized controlled trials comparing PTH therapy’s effectiveness against conventional treatment in people with chronic hypoparathyroidism. The researchers intended to inform recommendations for updating international guidelines on the condition.
From 311 studies accessed for eligibility, 11 that reported results from six trials covering 304 patients were included in the analysis. Three studies tested Forteo, two Natpara, and one TransCon PTH (at the time, only Phase 2 trial results had been published).
The number of patients varied greatly between trials, ranging from 10 to 134, and only one study was conducted with children. Four studies had a short treatment duration (up to six months), while the other two tested the treatment for about three years.
Three studies were conducted in the U.S., two in North America and Europe, and one in Denmark.
The researchers determined patients’ important outcomes as major complications of hypoparathyroidism, a 50% or greater reduction in calcium and calcitriol dose, quality of life, side effects, and blood levels of calcium, vitamin D, and phosphate, among others.
Several of these major complications, such as kidney abnormalities, seizures, heart-related problems, cataracts, fractures, infection, and mortality, were not assessed by any study.
“This may have been due to the small sample size of the studies and their relatively short-term duration,” the researchers wrote.
The strongest evidence for PTH therapy’s superiority over conventional care was observed for Natpara and TransCon PTH on their ability to allow “more patients to reduce or stop taking calcium and active vitamin D,” the research team wrote. The Forteo trials didn’t report this outcome.
This suggests PTH replacement therapy may reduce “the pill burden of the disease, but because the quality of evidence is low, further study of this effect is needed,” the researchers wrote.
Data also suggested PTH replacement therapy may result in a small improvement in physical and mental quality of life, and showed it was associated with lower blood phosphate levels than conventional therapy.
Patients receiving PTH therapy had increased rates of hypercalcemia and lower than normal vitamin D levels compared with those on conventional therapy.
Based on available data from four studies, serious side effects were infrequent, being reported in 9% of patients on PTH therapy and 7% on conventional therapy. No significant group differences were detected for the frequency of side effects, serious side effects, and discontinuing treatment due to side effects. The exception was thirst, which was reported more frequently with Natpara than with conventional therapy.
“The findings may support the use of PTH therapy in patients with chronic hypoparathyroidism,” the researchers wrote, noting that evidence from randomized trials for PTH therapy was limited due to the small sample size and limited duration.
“More definitive evidence requires considerably longer and larger studies which may be challenging for clinical studies for a rare disease,” they said.