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 D(3)
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 D(3) concentration was 33.9+/-7.2 ng/ml and, despite
hypophosphatemia, the serum level of
1,25-dihydroxyvitamin D(3) 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 D(3)
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 D(3) 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 D(3) is
a factor in the pathogenesis of
X-linked hypophosphatemic rickets and
osteomalacia and may modulate the phenotypic expression of this disease.