The Effect of Recombinant Human Parathyroid Hormone (rhPTH [1-84]) on Vitamin D Metabolism: Results from Phase III REPLACE and Phase I Clinical Studies

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 234-256-Bone & Calcium Metabolism: Clinical Trials & Case Series
Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-234
Dolores M Shoback*1, Michael Mannstadt2, Bart Lyman Clarke3, Tamara J Vokes4, Hjalmar Lagast5 and John P. Bilezikian6
1University of California - San Francisco VA Medical Center, San Francisco, CA, 2Massachusetts General Hospital and Harvard Medical School, Boston, MA, 3Mayo Clinic Rochester, Rochester, MN, 4University of Chicago, Chicago, IL, 5NPS Pharmaceuticals, Inc, Bedminster, NJ, 6College of Physicians & Surgeons, Columbia University, New York, NY
Patients with hypoparathyroidism are treated with calcitriol because they lack endogenous parathyroid hormone (PTH) to convert 25-hydroxyvitamin D (25[OH]D) to 1,25-dihydroxyvitamin D (1,25[OH]2D). We analyzed the effects of rhPTH(1-84) on vitamin D metabolism in patients with hypoparathyroidism in 2 clinical trials.

All patients enrolled were prescribed calcium and active vitamin D supplements (calcitriol or 1 alpha calcifediol). In the phase I study, patients received 2 subcutaneous injections of rhPTH(1-84) (50 and 100 μg), separated by a >=7-day washout period. In the REPLACE study, patients received (2:1 randomized) daily subcutaneous injections of rhPTH(1-84) 50 μg or placebo and vitamin D3(400 IU/day) for 24 weeks. Dose escalation to 75 µg and then to 100 µg was permitted if needed until active vitamin D could be eliminated and calcium reduced to <=500 mg/day.

In the phase I study, serum 1,25(OH)2D increased, after 8–16 hours, to a maximum baseline-adjusted level  (mean±SD) of 27.2±18.3 and 19.6±11.0 pg/mL with the 50-µg (n=6) and 100-µg (n=7) doses of rhPTH(1-84), respectively. 24-hour urine calcium excretion decreased by 13% and 23% with the 50- and 100-µg doses, respectively. Serum calcium levels showed maximum mean increases of approximately 0.7–0.9 mg/dL 12 hours after rhPTH(1-84) administration and remained above baseline levels after 24 hours with either dose.

In REPLACE, 36/84 (43%) patients treated with rhPTH(1-84) became independent of active vitamin D and reduced daily calcium to <=500 mg/day vs 2/37 (5%) patients in the placebo group by Week 24 (P<0.001). Active vitamin D doses were decreased by 79% in the rhPTH(1-84) group (n=90) and 30% in the placebo group (n=44) at Week 24 (P<0.001). Despite reductions in active vitamin D use by rhPTH(1-84)-treated patients, 1,25(OH)2D levels did not change (mean change from baseline at Week 24: +0.4 and 0 pg/mL for rhPTH(1-84) and placebo groups, respectively). In contrast, 25(OH)D showed a greater mean decrease at Week 24 in the rhPTH(1-84) (−11.2 ng/mL) vs the placebo (−1.4 ng/mL) group. At Week 24, mean urine calcium decreased by −74±190 mg/24 hours in the rhPTH(1-84) group and −84±169 mg/24 hours in the placebo group (P=0.06). In the placebo arm, reductions in urine calcium were mirrored by decreased total serum calcium levels. In contrast, total serum calcium remained above or near baseline levels in the rhPTH(1-84)-treated patients. Serum calcium levels were significantly higher in the rhPTH(1-84) vs placebo group at Weeks 1–16 (P<0.05), but not at Week 24.

Results indicate that rhPTH(1-84) treatment maintains serum 1,25(OH)2D in the normal range despite a significant reduction in active vitamin D requirements, while maintaining serum calcium at or near baseline, and reducing 24-hour urinary calcium in patients deficient in endogenous PTH secretion.

Disclosure: DMS: Investigator, NPS, Advisory Group Member, NPS. MM: Advisory Group Member, NPS. BLC: Advisory Group Member, NPS. TJV: Advisory Group Member, NPS. HL: Employee, NPS. JPB: Advisory Group Member, NPS, Principal Investigator, NPS.

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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