Abstract
ContextConventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency.ObjectiveTo evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)].DesignOpen-label extension study; 5-year interim analysis.Setting12 US centers.PatientsAdults (N = 49) with chronic hypoparathyroidism.Intervention(s)rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum.Main Outcome Measure(s)Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal.ResultsForty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline.ConclusionTreatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.
Highlights
Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively
PTH plays a central role in mineral homeostasis by stimulating renal reabsorption of calcium, promoting renal phosphate excretion, and stimulating conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (1,25[OH]2D), the fully active form of vitamin D
Conventional therapy for hypoparathyroidism includes oral calcium and active vitamin D, as well as thiazide diuretics and magnesium supplementation as needed. This approach can correct the hypocalcemia associated with hypoparathyroidism, it does not replace other functions of PTH and can lead to or worsen hypercalciuria [2, 5]
Summary
RACE was an open-label extension conducted at 12 centers in the United States. The primary objective was to assess long-term safety and tolerability of rhPTH[1-84] in adult patients with hypoparathyroidism ( Fig. 1). Patients were eligible to participate in RACE if they completed the randomized, placebo-controlled, 24-week REPLACE Study and/or the 8-week open-label, dose-blind RELAY (Study of Safety and Efficacy of rhPTH[1-84] of Fixed Doses of 25 and 50 μg in Adults With Hypoparathyroidism) Study. A treatment interruption between the end of treatment in REPLACE or RELAY and enrollment in RACE was permitted. Patients were permitted to continue taking most baseline concomitant medications during the trial, including thiazide diuretics, hormone therapy (estrogen with or without progesterone), and antihypertensives. Other drugs known to affect bone or mineral metabolism were prohibited (e.g., calcitonin, cinacalcet, raloxifene, bisphosphonates, fluoride)
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