Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study

In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH (1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism received subcutaneous injections of placebo or rhPTH(1-84) (50 mu g/day, titrated to 75 and then 100 mu g/day, to permit reductions in oral calcium and active vitamin D doses while maintaining serum calcium within 2.0-2.2 mmol/L). Predefined endpoints related to phosphate homeostasis and vitamin D metabolism were analyzed. Serum phosphate levels decreased rapidly from the upper normal range and remained lower with rhPTH(1-84) (P < 0.001 vs. placebo). At week 24, serum calcium-phosphate product was lower with rhPTH(1-84) vs. placebo (P < 0.001). rhPTH(1-84) treatment resulted in significant reductions in oral calcium dose compared with placebo (P < 0.001) while maintaining serum calcium. After pretreatment optimization, baseline serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH](2)D) levels were within the normal range in both groups. After 24 weeks, 1,25(OH)(2)D levels were unchanged in both treatment groups, despite significantly greater reductions in active vitamin D dose in the rhPTH(1-84) group. In hypoparathyroidism, rhPTH (1-84) reduces serum phosphate levels, improves calcium-phosphate product, and maintains 1,25(OH)(2)D and serum calcium in the normal range while allowing significant reductions in active vitamin D and oral calcium doses.