title: Transient Increased Calcium and Calcitriol Requirements After Discontinuation of Human Synthetic Parathyroid Hormone 1-34 (hPTH 1-34) Replacement Therapy in Hypoparathyroidism.
abstract: Synthetic human PTH 1-34 (hPTH 1-34) replacement therapy in hypoparathyroidism maintains eucalcemia and converts quiescent bone to high-turnover bone. However, the skeletal and metabolic effects of drug discontinuation have not been reported. Nine subjects with hypoparathyroidism received subcutaneous injections of hPTH 1-34 two to three times daily for 19.8 to 61.3 months and then transitioned back to calcium and calcitriol. Biochemistries and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) were assessed at baseline, while on treatment, and at follow-up 3 to 12 months after drug discontinuation. Two subjects developed hypocalcemia when hPTH 1-34 was abruptly discontinued. Thus, to avoid hypocalcemia, subjects were slowly weaned from hPTH 1-34 over several weeks. When hPTH 1-34 was stopped, subjects were requiring two to three times pretreatment doses of calcitriol and calcium to maintain blood calcium levels. Doses were gradually reduced over many weeks until calcium levels were stable on doses similar to baseline. Bone-specific alkaline phosphatase (BSAP), N-telopeptide (NTX), and osteocalcin (OC) increased significantly with hPTH 1-34; at follow-up, BSAP and NTX had returned to baseline while OC was still slightly elevated. During treatment, BMD was unchanged at the hip and lateral spine but declined at the anterior-posterior (AP) spine, radius, and total body. During weaning, BMD increased, with the hip and lateral spine exceeding pre-hPTH 1-34 values and the whole body returning to baseline. AP spine was increased non-significantly compared to baseline at follow-up. hPTH 1-34 must be gradually weaned in hypoparathyroid patients with high doses of oral medications given to avoid hypocalcemia. The transient increased requirements accompanied by increased BMD after long-term hPTH 1-34 therapy suggest a reversal of the expanded remodeling space favoring bone formation as the skeleton returns to a low-turnover state, reminiscent of the hungry bone syndrome. Further study and close monitoring is required to ensure safe transition to conventional therapy and to elucidate the physiological mechanism of this phenomenon.
authors.affiliation: Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.affiliation: Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Lori C
authors.initials: LC
authors.lastname: Guthrie
authors.affiliation: Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Marilyn H
authors.initials: MH
authors.lastname: Kelly
authors.affiliation: Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Brillante
authors.affiliation: Department of Pediatrics, Kaiser Permanente, Springfield, VA, USA.
authors.forename: C Michele
authors.initials: CM
authors.lastname: Christie
authors.affiliation: Clinical Center (CC)/Nuclear Medicine Department (NMD), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Reynolds
authors.affiliation: Rho, Inc., Chapel Hill, NC, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Yovetich
authors.affiliation: Rho, Inc., Chapel Hill, NC, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: James
authors.affiliation: Skeletal Clinical Studies Unit (SCSU), Craniofacial and Skeletal Diseases Branch (CSDB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D024042:Collagen Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007011:Hypoparathyroidism / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015675:Osteocalcin / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019379:Teriparatide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D028761:Withholding Treatment
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin; D019379:Teriparatide; D000469:Alkaline Phosphatase; D002117:Calcitriol; D002118:Calcium
keywords: BIOCHEMICAL MARKERS OF BONE TURNOVER; DXA; HORMONE REPLACEMENT; PARATHYROID-RELATED DISORDERS; PTH