ECE2014 Oral Communications Bone, calcium & vitamin D (5 abstracts)
The effect of recombinant human parathyroid hormone, rhPTH(1–84), on vitamin D metabolism and phosphate homeostasis: Results from phase III 24-Week REPLACE and phase I clinical studies
Maria Luisa Brandi 1 , Albert Beckers 2 , Tamara Vokes 3 , Michael Mannstadt 4 , John Bilezikian 5 , Bart Clarke 6 , Hjalmar Lagast 7 & Dolores Shoback 1
1University of Florence, Florence, Italy; 2University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium; 3University of Chicago, Chicago, Illinois, USA; 4Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 5College of Physicians and Surgeons, Columbia University, New York, USA; 6Mayo Clinic Rochester, Rochester, MN, USA; 7NPS Pharmaceuticals, Inc., Bedminster, New Jersey, USA.
PTH promotes conversion of 25-hydroxyvitamin D (25[OH]D) to 1,25-dihydroxyvitamin D (1,25[OH]2D), thus stimulating intestinal calcium and phosphate absorption. Because of low PTH levels in hypoparathyroidism, patients are prescribed calcitriol. Patients are predisposed to hyperphosphatemia owing to loss of PTH-stimulated phosphate excretion by the kidneys. Effects of rhPTH(1–84) on vitamin D metabolism and serum phosphate were studied.
In the phase I C09-002 study, patients received single 50-μg (n=6) and 100 μg (n=7) injections, separated by a ≥7-day washout. In REPLACE, patients were randomized to placebo (n=44) or rhPTH(1–84) (n=90) 50 μg/day (escalated to 75 and then 100 μg/day, if needed) while calcium or active vitamin D doses were reduced.1
In C09-002, mean±SD serum 1,25(OH)2D levels increased following rhPTH(1–84) by 27.2±18.3 pg/ml (50 μg) and 19.6±11.0 pg/ml (100 μg) at 8–16 h. In REPLACE, 53% of rhPTH(1–84)-treated patients achieved ≥50% reduction in calcium and active vitamin D while maintaining serum calcium (placebo, 2%; P<0.001).1 43% of rhPTH(1–84)-treated patients achieved active vitamin D independence and took ≤500 mg/day calcium by Week 24 (placebo, 5%; P<0.001). Although active vitamin D doses decreased by 78% (rhPTH(1–84)) and 30% (placebo; P<0.001), serum 1,25(OH)2D levels were maintained 24 h post-injection while 25(OH)D levels decreased by 11.2 ng/ml (rhPTH(1–84)) and 1.4 ng/ml (placebo).
In C09-002, rhPTH(1–84) decreased serum phosphate levels by 1.5 mg/dl at 5 h, increased 24-h urinary phosphate by 51% (50 μg) and 60% (100 μg), and decreased calcium-phosphate product by 11%–15% at 12 h. In REPLACE, lower serum phosphate levels following rhPTH(1–84) were maintained at Week 24 vs no change with placebo (P≤0.003). Decreases in calcium-phosphate product were greater with rhPTH(1–84) than placebo (P<0.001).
rhPTH(1–84) normalized serum calcium and maintained serum 1,25(OH)2D, despite reduced active vitamin D intake, and restored phosphate homeostasis in these hypoparathyroidism studies.
Reference
1. Mannstadt, et al. Lancet Diabetes Endocr. 2013;1:275-83.
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