Hormone Tx Helps in Parathyroid Disorder

By Salynn Boyles, Contributing Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Treatment with the synthetic human hormone rhPTH(1-84) reduced the need for calcium and active vitamin D by at least 50% in more than half of patients with the rare endocrine disorder hypoparathyroidism, researchers reported.

In all, 53% of patients in the hormone replacement group achieved the primary endpoint of reducing their daily need for oral calcium and active vitamin D by half while maintaining adequate serum calcium concentrations. Just one patient (2%) in the placebo arm of the study met the endpoint (difference of 51.1%; 95% CI 39.9-62.3; P<0.0001), Michael Mannstadt, MD, of Massachusetts General Hospital in Boston, and colleagues, wrote in the online publication The Lancet Diabetes & Endocrinology.

Parathyroid hormone plays a key role in regulating calcium and phosphorus levels and without treatment patients with hypoparathyroidism have very low calcium levels and higher-than-normal levels of phosphorus. The condition is caused by deficient parathyroid hormone production and characterized by symptoms ranging from paresthesias and muscle cramps to painful muscle spasms and seizures.

The main treatment for the disorder is the prescription form of activate vitamin D (Calcitriol) and calcium, with the aim of forcing intestinal calcium absorption. Because there is no cure for the condition, this treatment is generally given for life.

The treatment increases serum calcium levels, but at a price. Long-term side effects often include calcium deposits in the kidneys, renal stones and chronic kidney disease, which are caused by the increased filtered load of calcium in the absence of parathyroid hormone-driven reabsorption.

"Physicians face a therapeutic challenge in managing chronic hypocalcemia without causing long-term damage, and therefore advise their patients to avoid trying to reach normal serum concentrations of calcium," endocrinologists Agnes Linglart, MD, PhD, and Anya Rothenbuhler, MD, PhD, of the Hospital Bicetre, near Paris, wrote in an editorial published with the study.

One recombinant parathyroid hormone -- teriparatide [rhPTH(1-34] -- has been approved for the treatment of osteoporosis, but it has a very short half-life of only about an hour unless administered by subcutaneous pump.

PTH(1-34) studies conducted over the last few years proved that replacing the parathyroid hormone is an effective treatment for hypoparathyroidism. But in one study patients needed two to three injections a day and in the other, a continuous insulin pump was used to deliver the treatment.

"These studies showed that you can treat hypoparathyroidism by replacing the hormone that is missing," Mannstadt told MedPage Today. "But the fact that PTH(1-34) is short-acting is a major drawback."

RhPTH(1-84) is identical in structure to the full-length endogenous hormone and is associated with a longer calcemic effect when injected into the thigh, Mannstadt added.

The recombinant therapy was developed by NPS Pharmaceuticals of Bedminster, NJ. It is approved in Europe for the treatment of osteoporosis, but has not been approved for any indication in the U.S.

The current study is the first phase III trial of rhPTH(1-84) for the treatment of hypoparathyroidism. Patients recruited for the 33-site trial were adults (18 to 85 years) with hypoparathyroidism of at least 18 months' duration.

The most common cause of hypoparathyroidism was postsurgical complication (74%), and close to four out of five (78%) of the participants were women. The primary endpoint was defined as meeting three criteria at week 24: 50% or greater reduction of oral calcium dose compared with baseline; 50% or greater reduction of active vitamin D dose compared with baseline; and maintenance of a stable albumin-corrected total serum calcium concentration greater than or equal to baseline concentration and less than or equal to the upper limit of normal, but ideally within the target range of 2.0 to 2.25 mmol/L.

After an optimization period, during which time calcium and active vitamin D doses were adjusted to achieve consistent serum calcium, patients were randomly assigned to 50 mcg per day of rhPTH(1-84) or placebo for 24 weeks.

Active vitamin D and calcium were progressively reduced, while rhPTH(1-84) could be titrated up from 50 mcg to 75 mcg and then to 100 mcg (weeks zero through five).

A total of 134 eligible patients were identified and randomly assigned to rhPTH(1-84) (n=90) or placebo (n=44) arms of the study. Six patients in the rhPTH(1-84) group and seven in the placebo group did not complete the study.

Among the findings:

A total of 48 (53%) patients in the rhPTH(1-84) group achieved the primary endpoint, compared with one (2%) patient in the placebo group.
The proportions of patients who had at least one adverse event were similar between groups (93% of patients in the rhPTH[1-84] group versus 100% of patients in the placebo group), with hypocalcemia, muscle spasm, paresthesias, headache, and nausea being the most common adverse events.
The proportions of patients with serious adverse events were also similar between the rhPTH(1-84) group (11%) and the placebo group (9%).
Of the rhPTH(1-84) patients who completed the study, 36 (43%) were able to stop taking the active vitamin D and were receiving 500 mg or less of oral calcium at week 24, compared with two (5%) of the 37 patients in the placebo group (P<0.0001).
During maintenance weeks 16 though 24, fewer rhPTH(1-84)-treated patients reported clinical symptoms associated with hypocalcemia (33% [95% CI 23.7-44.1] versus 41% [95% CI 26.3-56.8], P=0.39).
The researchers concluded that rhPTH(1-84) is an efficacious replacement for endogenous PTH in patients with hypoparathyroidism and that 50 mcg per day subcutaneously is an acceptable starting dose, with possible up-titration by increments of 25 mcg up to 100 mcg.

Linglart and Rothenbuhler wrote that the treatment may allow physicians to target normal calcium levels in their patients without fear of hypercalciuria.

"Replacing full-length PTH in patients with hypoparathyroidism seems, unsurprisingly, to be more appropriate than forcing absorption of calcium through the gut, and new indications and clinical development of this therapy are eagerly awaited by adult and pediatric endocrinologists," they concluded.

Action Points

  • This study was designed to test the effects of recombinant parathyroid hormone (rhPTH 1–84) in a randomized, placebo-controlled trial in adult patients with hypoparathyroidism.
  • RhPTH(1–84), administered subcutaneously in the outpatient setting, appears to be efficacious and well-tolerated as a PTH replacement therapy for patients with hypoparathyroidism over a 6-month period.

The study was funded by NPS Pharmaceuticals. Mannstadt and several co-authors reported links with the company, and two co-authors are company employees.

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