The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult-Onset Hypophosphatasia

Naoko Hidaka; Hiroaki Murata; Kanako Tachikawa; Keiichi Osaki; Takashi Sekiyama; Yuka Kinoshita; Hajime Kato; Yoshitomo Hoshino; Soichiro Kimura; Takashi Sunouchi; So Watanabe; Masaomi Nangaku; Noriko Makita; Toshimi Michigami; Nobuaki Ito

doi:10.1002/jbm4.10842

The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult-Onset Hypophosphatasia

JBMR Plus. 2023 Nov 20;7(12):e10842. doi: 10.1002/jbm4.10842. eCollection 2023 Dec.

Authors

Naoko Hidaka^{1

2}, Hiroaki Murata³, Kanako Tachikawa⁴, Keiichi Osaki⁵, Takashi Sekiyama⁵, Yuka Kinoshita^{1

2}, Hajime Kato^{1

2}, Yoshitomo Hoshino^{1

2}, Soichiro Kimura^{1

2}, Takashi Sunouchi^{1

2}, So Watanabe^{2

6}, Masaomi Nangaku¹, Noriko Makita^{1

2}, Toshimi Michigami⁴, Nobuaki Ito^{1

2}

Affiliations

¹ Division of Nephrology and Endocrinology The University of Tokyo Hospital Tokyo Japan.
² Osteoporosis Center The University of Tokyo Hospital Tokyo Japan.
³ Department of Orthopaedic Surgery, Panasonic Health Insurance Organization Matsushita Memorial Hospital Osaka Japan.
⁴ Department of Bone and Mineral Research, Research Institute Osaka Women's and Children's Hospital Osaka Japan.
⁵ Department of Rehabilitation, Panasonic Health Insurance Organization Matsushita Memorial Hospital Osaka Japan.
⁶ Department of Geriatric Medicine, Graduate School of Medicine The University of Tokyo Tokyo Japan.

Abstract

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue-nonspecific alkaline phosphatase. Adult-onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first-line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64-year-old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6-minute walk test (525 to 606 m). The EQ-5D-5L index was also improved (0.757 to 0.895). Within a follow-up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Keywords: DISORDERS OF CALCIUM/PHOSPHATE METABOLISM (OTHER); HUMAN ASSOCIATION STUDIES; INJURY/FRACTURE HEALING; OSTEOMALACIA AND RICKETS; THERAPEUTICS (OTHER).

Publication types

Case Reports