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

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

doi:10.1172/jci109930

Cited by 116 publications

(32 citation statements)

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“…The hypophosphatemia is caused by impaired proximal tubule phosphate reabsorption (1-6). The vitamin D deficiency is caused by decreased 25(OH)-vitamin D-1␣-hydroxylase activity (7)(8)(9)(10). Conventional therapy consists of oral administration of pharmacologic doses of vitamin D and phosphate, though hypercalciuria and nephrocalcinosis are frequent complications of such therapy (11)(12)(13)(14)(15).…”

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confidence: 99%

Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Baum

Loleh

Saini

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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X-linked hypophosphatemia is the most prevalent inherited form of rickets. In this disorder, rickets results from hyperphosphaturia and inappropriately normal levels of 1,25(OH) 2-vitamin D. Current therapy with oral phosphate and vitamin D improves the rickets, but has significant morbidity and does not significantly affect the short stature and hypophosphatemia. In the present study, we demonstrate that Hyp mice, which have a mutation homologous to that in patients with X-linked hypophosphatemia, have a 2-fold greater urinary prostaglandin E 2 (PGE2) excretion than C57͞B6 mice. To determine whether PGs were involved in the pathogenesis of this disorder, Hyp and C57͞B6 mice received i.p. injections with vehicle or indomethacin (1 mg͞kg of body weight twice daily for 4 days) and were studied Ϸ12 h after the last dose of indomethacin. In the Hyp mice, indomethacin treatment decreased the fractional excretion of phosphate from 13.0 ؎ 3.2% to 2.2 ؎ 1.1% (P < 0.05), and increased serum phosphate from 2.9 ؎ 0.2 mg͞dl to 4.1 ؎ 0.2 mg͞dl (P < 0.05). There was no effect of indomethacin in C57͞B6 mice. Indomethacin did not affect serum creatinine or inulin clearance, demonstrating that the normalization of urinary phosphate excretion was not caused by changes in glomerular filtration rate. Indomethacin treatment increased renal brush border membrane vesicle NaPi-2 protein abundance in Hyp mice to levels comparable to that of C57͞B6 mice, but had no effect in C57͞B6 mice. In vitro isolated perfused proximal tubule studies demonstrate directly that 10 ؊6 M bath indomethacin normalized the phosphate transport defect in Hyp mice but had no effect on C57͞B6 mice. In conclusion, there is dysregulation of renal PG metabolism in Hyp mice, and indomethacin treatment normalizes the urinary excretion of phosphate by a direct tubular effect.X-linked hypophosphatemia ͉ rickets ͉ sodium͞phosphate cotransporter NaPi-2

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confidence: 99%

Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Baum

Loleh

Saini

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Earlier calcitriol-alone treatment in patients with XLH resulted in a smaller increase in blood phosphate than is seen in mice treated with calcitriol. (35) In spite of these issues, the data presented by Liu and colleagues (19) are convincing and may have important clinical implications. If these findings prove promising in further preclinical studies with appropriate controls, and confirmed in well-controlled studies in subjects with XLH, it could bring about a major change in the way disorders of FGF23 excess are treated.…”

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confidence: 99%

“…What is often an issue in calcitriol-alone treatment though, as was seen in these early studies, is hypercalciuria. (35,39) In conventional combined phosphate and calcitriol treatment of XLH (and other FGF23 excess disorders), nephrocalcinosis is a worrisome complication of therapy.(24) However, data from studies analyzing risk factors for nephrocalcinosis in combined phosphate and calcitriol-treated XLH patients are conflicting. Vitamin D dose (40,41) and hypercalciuria (42) appear as major factors 926 OVEJERO ET AL.…”

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confidence: 99%

“…(35) Interpretation of these studies is difficult though due to both design flaws in the early clinical studies (lack of systematic treatment and control groups) and lack of modern reagents and assays. However, by histomorphometric analysis, it appeared that osteoid volume and width showed greater improvement with combined phosphate and calcitriol treatment that than with calcitriol alone.…”

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confidence: 99%

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1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

Ovejero

Gafni

Collins

2016

Journal of Bone and Mineral Research

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T he identification in the year 2000 of mutations in fibroblast growth factor 23 (FGF23) as the genetic cause of autosomal dominant hypophosphatemic rickets (ADHR) was a seminal discovery in the field of bone and mineral homeostasis.(1)Alterations in FGF23 levels were subsequently identified as the common abnormality in a number of phosphate homeostasis disorders, including X-linked hypophosphatemic rickets (XLH), (2) tumor-induced osteomalacia (TIO), (3) fibrous dysplasia of bone, (4) autosomal recessive hypophosphatemic rickets (ARHR), (5) cutaneous skeletal hypophosphatemia syndrome (CSHS), (6) familial tumoral calcinosis, (7) and others. The primary actions of FGF23 are to regulate blood phosphate and 1,25-dihydroxyvitamin D 3 (1,25-D) levels by its actions on renal sodium/phosphate cotransporters and 25-hydroxyvitamin D hydroxylation. (8) The fact that PTH, like FGF23, is also important in regulating phosphate and vitamin D homeostasis invokes the existence of an FGF23-Vitamin D-PTH axis that is key to many important aspects of bone and mineral biology. It is a complicated axis that involves the interaction of multiple receptors, a coreceptor, Klotho, (9) and multiple disparate but interacting signaling and enzymatic pathways. (10,11) Unraveling, in a hierarchical fashion, the roles of these complicated, intersecting, and overlapping pathways is important for both understanding mineral homeostasis physiology, and for the treatment of phosphate disorders. This has proved a significant challenge. Although a large number of very informative mouse models have been developed to understand and query this axis, at times the complexity of these models introduces potential confounders that are difficult to control for, and yield results inconsistent with observed human physiology. Thus, it is often difficult to understand and contextualize the findings and apply them to human mineral physiology and pathophysiology. The number of clinical studies conducted in this area is limited, and often focused on renal failure cohorts, the physiology of which differs significantly from those with normal renal function.Although a complete understanding of the FGF23-Vitamin D-PTH axis is lacking, there are a number of findings that are generally accepted to be true. These include: (1) FGF23 directly inhibits phosphate reabsorption and the generation of active vitamin D, 1,25-dihydroxyvitamin D 3 (1,25-D) at the level of the proximal renal tubule leading to a lowering of blood phosphate and 1,25-D levels (8) ; (2) in a classical feedback fashion, increases in blood phosphate and 1,25-D increase FGF23 levels (12,13) ; and (3) frank or relative FGF23-mediated reductions in serum 1,25-D lead to a compensatory increase in PTH, especially evident in the more severe forms of FGF23 excess such as TIO and renal failure. (14,15) The phosphaturic effects of increased PTH exacerbate the phosphate-lowering effects of FGF23 in patients with intact renal function such as TIO and XLH (reviewed in Blau and Collins (11) ). As for the hierarchic...

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Vitamin D Metabolism in Hypophosphatemic Rickets

Mason¹

1982

Arch Pediatr Adolesc Med

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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

Cited by 116 publications

References 44 publications

Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

Correction of proximal tubule phosphate transport defect inHypmicein vivoandin vitrowith indomethacin

1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

Vitamin D Metabolism in Hypophosphatemic Rickets

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