Parathyroid hormone (PTH) replacement therapy is superior to conventional treatment for lowering blood phosphate levels and the need for calcium and vitamin D supplements in people with chronic hypoparathyroidism, according to a review of evidence from ‘clinical tests.
It appeared to be associated with higher than normal calcium levels (hypercalcaemia) and yet had only a slight benefit on health-related quality of life compared to standard treatment.
Although these results 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, noted the researchers.
The review study, “Parathyroid hormone therapy for the management of chronic hypoparathyroidism: a systematic review and meta-analysiswas published by an international team of researchers in the Journal of Bone and Mineral Research.
Hypoparathyroidism is caused by deficient production of PTH, resulting in lower than normal calcium levels and higher than normal phosphate levels in the blood. Patients also have a vitamin D deficiency, which helps the body absorb calcium.
The condition is most often caused by unintended 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 can include kidney failure 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 symptoms of calcium deficiency. However, it fails to control phosphate, can lead to hypercalcemia and associated complications, and does not address the underlying cause of the disease.
“The optimal treatment strategies for patients with chronic hypoparathyroidism remain unclear,” the researchers wrote.
Offering a lab-made version of PTH to patients is another treatment option, but the ideal replacement therapy for PTH has yet to be found. Currently, this approach is only indicated for patients who do not respond well to conventional therapy.
TransCon PTH, Ascendis PharmaceuticalsThe experimental long-acting PTH therapy has shown promise in phase 3 trials in adults with hypoparathyroidism. Regulatory submissions for its approval are expected this year.
“Use of PTH therapy in patients with chronic hypoparathyroidism should be based on evidence regarding potential benefits on important patient outcomes,” the researchers wrote.
PTH Therapy vs Conventional Treatment
With this in mind, the researchers retrospectively analyzed studies published up to May 2022 that reported the results of randomized controlled trials comparing the effectiveness of PTH therapy versus conventional therapy in people with chronic hypoparathyroidism. The researchers intended to inform recommendations for updating international guidelines on the condition.
Of 311 studies consulted for eligibility, 11 that reported the results of six trials involving 304 patients were included in the analysis. Three studies tested Forteo, two Natpara and one TransCon PTH (at the time, only results from phase 2 trials had been published).
The number of patients varied widely 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 around three years.
Three studies were conducted in the United States, two in North America and Europe, and one in Denmark.
Researchers determined that important patient outcomes were major complications of hypoparathyroidism, a 50% or greater reduction in calcium and calcitriol dose, quality of life, side effects, and blood calcium levels, vitamin D and phosphate, among others.
Many of these major complications, such as kidney abnormalities, seizures, heart problems, cataracts, fractures, infections, and mortality, have not been assessed by any study.
“This may be due to the small sample sizes of the studies and their relatively short duration,” the researchers wrote.
The strongest evidence for the superiority of PTH therapy over conventional care was seen for Natpara and TransCon PTH on their ability to enable “more patients to reduce or stop taking calcium and vitamin D active,” the research team wrote. The Forteo trials did not report this result.
This suggests that PTH replacement therapy may reduce “pill burden of disease, but as the quality of the evidence is low, further study of this effect is warranted,” the researchers wrote.
The data also suggests that PTH replacement therapy may lead to a small improvement in physical and mental quality of life, and has been shown to be 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 to those receiving conventional therapy.
Based on available data from four studies, serious side effects were uncommon, being reported in 9% of patients on PTH therapy and 7% on conventional therapy. No significant differences between the groups were detected for the frequency of side effects, serious side effects and discontinuation of treatment due to side effects. The exception was thirst, which was reported more frequently with Natpara than with conventional therapy.
“The results 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 small sample sizes. and of limited duration.
“More definitive evidence requires considerably longer and larger studies, which can be challenging for clinical studies of a rare disease,” they said.