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Parathyroid hormone replacement safe, effective in chronic hypoparathyroidism
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Adults with chronic hypoparathyroidism treated with recombinant human parathyroid hormone 1-84 for 5 years experienced sustained improvements in mineral homeostasis and modest increases in bone turnover markers, whereas serum calcium remained in the target range with reductions in oral calcium supplements, according to findings from a small, open-label extension study.
“Most studies on parathyroid hormone treatment for hypoparathyroidism published so far are relatively short term (6 months), but patients with this disease need lifelong treatment,” Michael Mannstadt, MD, chief of the endocrine unit at Massachusetts General Hospital and an associate professor at Harvard Medical School, told Endocrine Today. “Current questions in the field of hypoparathyroidism are about the long-term effects of treatment with parathyroid hormone. Is it safe? Does the efficacy change? Do bone turnover markers stay elevated? Does bone density change and, if so, in which direction?”
Mannstadt and colleagues analyzed data from 49 adults with chronic hypoparathyroidism from 12 U.S. centers who participated in REPLACE, a 24-week, randomized, double-blind, placebo-controlled trial assessing the safety and efficacy of recombinant human parathyroid hormone 1-84 and were eligible for RACE, an open-label extension study designed to assess long-term safety and efficacy (mean age, 48 years; 81.6% women). Patients self-administered the drug, once daily, in the morning, with dosage increased or decreased in stepwise increments of 25 µg up to a maximum dose of 100 µg per day, with the goal of achieving serum calcium levels in the target range of 8 mg/dL to 9 mg/dL. Primary outcomes measures were mean changes from baseline in albumin-corrected serum calcium, phosphorus and creatinine levels; estimated glomerular filtration rate; and urinary calcium excretion. The composite efficacy outcome was the proportion of patients who achieved a reduction in the use of oral calcium supplements and calcitriol while normalizing or maintaining albumin-corrected serum calcium levels compared with baseline.
As of May 2017, 40 patients completed 60 months of treatment.
Within the cohort, mean albumin-corrected serum calcium remained between 8.2 mg/dL and 8.7 mg/dL. Between baseline and month 60, urinary calcium decreased by a mean of 101.2 mg per 24 hours, serum phosphorus decreased by a mean of 1 mg/dL, and calcium-phosphorus product decreased by a mean of 8.5 mg²/dL². Serum creatinine and eGFR were unchanged, according to researchers.
The researchers observed treatment-emergent adverse events in 48 patients (98%); most were incident hypocalcemia (36.7%), muscle spasms (32.7%), paresthesia (30.6%) sinusitis (30.6%) and nausea (30.6%).
At 60 months, 28 of 40 patients achieved the composite efficacy outcome. Bone turnover markers increased, peaked at approximately 12 months, and then declined to values that remained above baseline, the researchers wrote.
“Long-term use of recombinant human parathyroid hormone 1-84 over 5 years was safe and effective for reducing oral calcium and calcitriol while maintaining serum calcium concentrations in the target range,” Mannstadt said. “Notably, urinary calcium excretion steadily declined over the 5 years without changes in serum calcium. Bone mineral density, which was higher than normal at baseline, decreased in the distal radius and remained stable at other sites.”
Mannstadt said the findings demonstrate that treatment with parathyroid hormone over 5 years has a safety profile similar to what was observed in the clinical trials and improves mineral homeostasis.
“Compared with short-term studies, parathyroid hormone had beneficial effects on urinary calcium, which steadily declined over 5 years; bone turnover markers reached a peak at about 1 year and then slowly drifted down to normal values,” he said.
Mannstadt said more long-term data are needed from larger cohorts of patients treated with parathyroid hormone.
“We don’t yet understand why it takes time for the urinary calcium to decrease,” Mannstadt said. “What would be the effect of alternate dosing frequency of parathyroid hormone injections on urinary calcium?” – by Regina Schaffer
For more information:
Michael Mannstadt, MD, can be reached at Partners Healthcare System, 50 Blossom St., Boston, MA 02114; email: mannstadt@mgh.harvard.edu.
Disclosures: Shire Human Genetic Therapies Inc. funded this trial. Mannstadt reports he has served as an advisory board member, consultant and site-investigator for Shire/Takeda.
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