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Evaluation of a Role for 1,25-Dihydroxyvitamin D3 in the Pathogenesis and Treatment of X-linked Hypophosphatemic Rickets and Osteomalacia

Marc K. Drezner, Kenneth W. Lyles, Mark R. Haussler and John M. Harrelson

Department of Medicine, Veterans Administration Hospital and Duke University Medical Center, Durham, North Carolina 27710Department of Pathology, Veterans Administration Hospital and Duke University Medical Center, Durham, North Carolina 27710Department of Orthopaedic Surgery, Veterans Administration Hospital and Duke University Medical Center, Durham, North Carolina 27710Department of Biochemistry, University of Arizona Medical College, Tucson, Arizona 85721

Published November 1980

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 characteristic of this disease. Thus, in the present study, we 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, ages 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 phenotypic expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the long-term 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. We, 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 phenotypic expression of this disease.

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