Hypophosphatemic rickets and osteomalacia

Abstract

The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomaldominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well. RESUMORaquitismo Hipofosfatêmico e Osteomalácia. Os distúrbios hipofosfatêmicos que comprometem a mineralização óssea englobam várias doenças, hereditárias e adquiridas, as quais compartilham um mesmo mecanismo fisiopatológico: a diminuição da reabsorção de fosfato nos túbulos renais. Este processo promove hiperfosfatúria e hipofosfatemia crônicas, associadas a níveis inapropriadamente normais ou baixos de 1,25 (OH) 2 D 3 , com conseqüente desordem do metabolismo ósteo-mineral, resultando em raquitismo e osteomalá-cia na faixa etária pediátrica e em osteomalácia nos adultos. O raquitismo hipofosfatêmico ligado ao X, o raquitismo hipofosfatêmico autossômico dominante e a osteomalácia induzida por tumor são as principais síndromes que constituem os raquitismos hipofosfatêmicos. Apesar de estas doenças apresentarem etiopatogenias distintas, as evidências bioquímico-moleculares indicam uma base fisiopatológica em comum: maior atividade de um agente fosfatúrico, sendo o fator de crescimento do fibroblasto 23 (FGF-23) o mais estudado e ao qual é atribuído um papel central na fisiopatologia destes distúrbios. Várias mutações ativadoras do gene do FGF-23 e mutações inativadoras do

Rare, genetically conditioned forms of rickets: Differential diagnosis and advances in diagnostics and treatment

“…10 Research on the pathogenesis of hypophosphatemic rickets and the role of a phosphaturic factor that was found to be FGF-23 made it possible to distinguish between FGF-23-dependent and FGF-23independent hypophosphatemic rickets. 10,14 The genetic background of hypophosphatemic rickets is shown in Table 1.…”

Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets

“…Hypophosphatemic rickets (HR) is a group of hereditary and acquired conditions characterized by renal phosphate wasting, leading to hypophosphatemia, associated with inappropriately normal to low vitamin D serum concentration, causing osteomalacia and/or rickets [1]. Although they share similar clinical and biochemical features, they have different genetic causes.…”

Risk factors affecting the development of nephrocalcinosis, the most common complication of hypophosphatemic rickets

“…Clinical treatment of hypophosphatemic rickets aims at minimizing the metabolic disturbances, reducing bone deformities, and improving growth velocity, although hyperphosphaturia persists, once the treatment does not alter the impaired tubular phosphate reabsorption (3). The treatment of children and adolescents with XHR includes phosphate administration (neutral salts of inorganic sodium and potassium phosphate) and calcitriol.…”