Evaluation of a role of 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia

M. K. Drezner, K. W. Lyles, Mark R Haussler, J. M. Harrelson

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristics of this disease. Thus, in the present study, the authors investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D3 therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, aged 14-30 yr, had normocalcemia (9.22±0.06 mg/dl); hypophosphatemia (2.25±0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12±0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D3 concentration was 33.9±7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D3 was not increased, but was normal at 30.3±2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotype expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the longterm response to pharmacological amounts of 1,25-dihydroxyvitamin D3 therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D3 in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. The authors, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D3 is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotype expression of this disease.

Original languageEnglish (US)
Pages (from-to)1020-1032
Number of pages13
JournalJournal of Clinical Investigation
Volume66
Issue number5
StatePublished - 1980
Externally publishedYes

Fingerprint

Familial Hypophosphatemic Rickets
Osteomalacia
Calcitriol
Phosphates
Hypophosphatemia
Serum
Vitamin D
Kidney
Therapeutics
Phenotype
Biopsy
Calcifediol
Bone and Bones
Physiologic Calcification
Parathyroid Hormone
Homeostasis
Pharmacology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Evaluation of a role of 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia. / Drezner, M. K.; Lyles, K. W.; Haussler, Mark R; Harrelson, J. M.

In: Journal of Clinical Investigation, Vol. 66, No. 5, 1980, p. 1020-1032.

Research output: Contribution to journalArticle

@article{3ccb98873c6e474fac9079054d13a9c8,
title = "Evaluation of a role of 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia",
abstract = "Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristics of this disease. Thus, in the present study, the authors investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D3 therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, aged 14-30 yr, had normocalcemia (9.22±0.06 mg/dl); hypophosphatemia (2.25±0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12±0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D3 concentration was 33.9±7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D3 was not increased, but was normal at 30.3±2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotype expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the longterm response to pharmacological amounts of 1,25-dihydroxyvitamin D3 therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D3 in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. The authors, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D3 is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotype expression of this disease.",
author = "Drezner, {M. K.} and Lyles, {K. W.} and Haussler, {Mark R} and Harrelson, {J. M.}",
year = "1980",
language = "English (US)",
volume = "66",
pages = "1020--1032",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Evaluation of a role of 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia

AU - Drezner, M. K.

AU - Lyles, K. W.

AU - Haussler, Mark R

AU - Harrelson, J. M.

PY - 1980

Y1 - 1980

N2 - Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristics of this disease. Thus, in the present study, the authors investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D3 therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, aged 14-30 yr, had normocalcemia (9.22±0.06 mg/dl); hypophosphatemia (2.25±0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12±0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D3 concentration was 33.9±7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D3 was not increased, but was normal at 30.3±2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotype expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the longterm response to pharmacological amounts of 1,25-dihydroxyvitamin D3 therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D3 in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. The authors, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D3 is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotype expression of this disease.

AB - Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristics of this disease. Thus, in the present study, the authors investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D3 therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, aged 14-30 yr, had normocalcemia (9.22±0.06 mg/dl); hypophosphatemia (2.25±0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12±0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D3 concentration was 33.9±7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D3 was not increased, but was normal at 30.3±2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotype expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the longterm response to pharmacological amounts of 1,25-dihydroxyvitamin D3 therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D3 in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. The authors, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D3 is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotype expression of this disease.

UR - http://www.scopus.com/inward/record.url?scp=0019158921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0019158921&partnerID=8YFLogxK

M3 - Article

C2 - 6253520

AN - SCOPUS:0019158921

VL - 66

SP - 1020

EP - 1032

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -