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Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.
J Bone Miner Res. 2021 05; 36(5):942-955.JB

Abstract

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Authors+Show Affiliations

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.Department of Pediatrics, University of Pennsylvania Perlman School of Medicine, Philadelphia, PA, USA. Division of Endocrinology and Diabetes and Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA.Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33465815

Citation

Ferreira, Carlos R., et al. "Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation And/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 36, no. 5, 2021, pp. 942-955.
Ferreira CR, Kavanagh D, Oheim R, et al. Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. J Bone Miner Res. 2021;36(5):942-955.
Ferreira, C. R., Kavanagh, D., Oheim, R., Zimmerman, K., Stürznickel, J., Li, X., Stabach, P., Rettig, R. L., Calderone, L., MacKichan, C., Wang, A., Hutchinson, H. A., Nelson, T., Tommasini, S. M., von Kroge, S., Fiedler, I. A., Lester, E. R., Moeckel, G. W., Busse, B., ... Braddock, D. T. (2021). Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 36(5), 942-955. https://doi.org/10.1002/jbmr.4254
Ferreira CR, et al. Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation And/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. J Bone Miner Res. 2021;36(5):942-955. PubMed PMID: 33465815.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. AU - Ferreira,Carlos R, AU - Kavanagh,Dillon, AU - Oheim,Ralf, AU - Zimmerman,Kristin, AU - Stürznickel,Julian, AU - Li,Xiaofeng, AU - Stabach,Paul, AU - Rettig,R Luke, AU - Calderone,Logan, AU - MacKichan,Colin, AU - Wang,Aaron, AU - Hutchinson,Hunter A, AU - Nelson,Tracy, AU - Tommasini,Steven M, AU - von Kroge,Simon, AU - Fiedler,Imke Ak, AU - Lester,Ethan R, AU - Moeckel,Gilbert W, AU - Busse,Björn, AU - Schinke,Thorsten, AU - Carpenter,Thomas O, AU - Levine,Michael A, AU - Horowitz,Mark C, AU - Braddock,Demetrios T, Y1 - 2021/02/18/ PY - 2021/01/11/revised PY - 2020/06/08/received PY - 2021/01/15/accepted PY - 2021/1/20/pubmed PY - 2021/8/10/medline PY - 2021/1/19/entrez KW - AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS (ARHR2) KW - ENPP1 MUTATION KW - NEPHROCALCINOSIS KW - OSTEOPOROSIS SP - 942 EP - 955 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 36 IS - 5 N2 - Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR). SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/33465815/Response_of_the_ENPP1_Deficient_Skeletal_Phenotype_to_Oral_Phosphate_Supplementation_and/or_Enzyme_Replacement_Therapy:_Comparative_Studies_in_Humans_and_Mice_ L2 - https://doi.org/10.1002/jbmr.4254 DB - PRIME DP - Unbound Medicine ER -