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Original Article Hypophosphatemic Rickets and Osteomalacia

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Original Article Hypophosphatemic Rickets and Osteomalacia original article Hypophosphatemic Rickets and Osteomalacia Hamilton de Menezes Filho ABSTRACT Luiz Claudio G. de Castro The hypophosphatemic conditions that interfere in bone mineralization Durval Damiani comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reab- sorption by the renal tubuli. This process leads to chronic hyperphospha- turia 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, autosomal- dominant 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-met- aloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been Pediatric Endocrinology Unit, implicated in the pathogenesis of these disturbances. Genetic studies Instituto da Criança – Hospital tend to show that the phosphorus homeostasis depends on a complex das Clínicas, São Paulo University osteo-renal metabolic axis, whose mechanisms of interaction have been Medical School – USP (HCMF e poorly understood so far. This paper reviews the current knowledge status DD), São Paulo, SP; and concerning the pathophysiology of phosphate metabolism regulation Pediatric Endocrinology Unit, and the pathophysiologic basis of hypophosphatemic rickets. It also ana- lyzes the clinical picture and the therapeutic aspects of these conditions Department of Pediatrics, as well. (Arq Bras Endocrinol Metab 2006;50/4:802-813) Medicine College, Brasília University – UnB (LCGC), Keywords: Hypophosphatemic rickets; Osteomalacia; FGF-23; PHEX Brasília, DF, Brazil. gene; Phosphate metabolism RESUMO Raquitismo 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 hiper- fosfatúria e hipofosfatemia crônicas, associadas a níveis inapropriada- mente normais ou baixos de 1,25 (OH)2D3, 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 Received in 04/01/06 atribuído um papel central na fisiopatologia destes distúrbios. Várias Accepted in 05/08/06 mutações ativadoras do gene do FGF-23 e mutações inativadoras do 802 Arq Bras Endocrinol Metab vol 50 nº 4 Agosto 2006 Hypophosphatemic Rickets & Osteomalacia Menezes Filho, Castro & Damiani gene localizado no cromossomo X que codifica uma Rickets are metabolic bone diseases, character- enzima proteolítica Zn-metaloendopeptidase regu- ized by impaired mineralization of the osteoid matrix ladora do fosfato (PHEX), implicada na regulação during growth, affecting epiphyseal growth plate and do FGF-23, já foram identificadas, e sua partici- compromising both cortical and trabecular bone. pação reconhecida na gênese destes distúrbios. Os dados dos estudos genéticos nesta área convergem Osteomalacia, at the other hand, refers to a deficient para a hipótese de que a homeostase do fósforo mineralization of the osteoid matrix in modeling and estaria vinculada a um complexo eixo metabólico remodeling sites (4), injuring the corticoendosteal tis- ósteo-renal, cujos mecanismos de interação entre sue. In pediatric ages, rickets and osteomalacia may seus vários componentes têm sido aos poucos eluci- happen simultaneously, but after growth plate closure dados. Este artigo revisa o atual estado de conheci- only osteomalacia may occur. Rickets and osteomala- mento dos mecanismos fisiológicos envolvidos na cia can result from vitamin D deficiency (nutritional or regulação do metabolismo do fosfato, das bases fisiopatológicas dos raquitismos hipofosfatêmicos e metabolic disturbances), calcium and/or phosphorus analisa aspectos clínicos e de tratamento disponíveis deficiency and primary bone mineralization defects para estas condições. (Arq Bras Endocrinol Metab (hereditary hypophosphatasia) (5). 2006;50/4:802-813) Rickets and osteomalacia secondary to vitamin D deficiency and/or low calcium intake in the XXI Descritores: Raquitismo hipofosfatêmico; Osteomalá- century has been a delicate theme. Recently, local and cia; FGF-23; Gene PHEX; Metabolismo do fosfato regional studies have recorded higher than expected vitamin D deficiency prevalence, mainly in high lati- tude regions, due to insufficient ultraviolet light expo- HE BONE TISSUE IS A HIGHLY dynamic structure sure, but also in other countries, like France and Unit- throughout life. It has well known metabolic and T ed States, affecting urban healthy adolescents (6-8). mechanical functions, which are essential for the body This kind of rickets may also be related to specific sit- homeostasis. Bone-mineral metabolism is coordinated uations, such as whole body covering dressing (due to by an intricate physiological network and reflects a con- religious habits), people with dark pigmented skins tinuous interaction between genetics and environment, who live in temperate climate (due to melanin compe- with ontogenetic particularities in each development tition for ultraviolet rays), elderly people, vegetarians, stage. During fetal life, childhood and adolescence bone- restrictive diets and exclusive breastfeeding for long mineral metabolism moves toward bone formation and periods (9,10). modeling, promoting skeleton growth through changes In developed countries, hypophosphatemic in bone dimensions, geometry and density. Meanwhile, rickets (HR) are the main cause of inherited rickets bone-remodeling process occurs continuously through- (11). Initially, HR was seen as Vitamin D resistant out life and consists in substitution of old bone by new rickets, once the lack of response to therapy was one. This renewal process is elementary to maintain the thought to be a Vitamin D resistant state. Since than, bone resistance and quality and for the integrity of the many studies have been performed and they managed body physiology as well, since bone is an ion reservoir tis- to show that this disturb was consequence of a hyper- sue, mainly for calcium and phosphorus, critical elements phosphaturic disorder (12). Important advances in our for the systemic electrolytic equilibrium. current understanding of the molecular and biochem- Bone-mineral homeostasis is complex and some ical bases of HR have been brought after the develop- of its pathways have not been completely elucidated ment of new molecular techniques and improved yet. The parathyroid hormone (PTH)-calcitonin- genomic databases (2). 1,25(OH) Vitamin D (calcitriol) axis plays a funda- 2 3 HR comprises a set of disorders, inherited and mental role in this bone-mineral metabolism, but it acquired, that shares a common pathophysiology: could not respond alone for the whole dynamics of diminished phosphate reabsorption in renal tubules this equilibrium (1). The ascertainment of other (3,13-15). This process, established by an impaired involved regulatory biochemical-molecular mecha- phosphorus renal handling, leads to chronic hyper- nisms has been possible after studies of phosphate- phosphaturia and hypophosphatemia, which are asso- wasting bone diseases, such as hypophosphatemic rick- ciated to unsuitable normal or low levels of ets (2). Cumulated data from in vitro and in vivo 1,25(OH) VitaminD This phosphorus-wasting dis- researches, with human and animal models, converge 2 3. turbance affects bone metabolism, yielding rickets and toward the hypothesis of a bone-renal axis controlling osteomalacia in pediatric patients and osteomalacia in this homeostasis (1,3). adults. Arq Bras Endocrinol Metab vol 50 nº 4 Agosto 2006 803 Hypophosphatemic Rickets & Osteomalacia Menezes Filho, Castro & Damiani X-linked hypophosphatemic rickets (XHR), participate actively on this regulation. Amongst the autosomic dominant hypophosphatemic rickets most important contributing data to the knowledge of (ADHR) and tumor-induced osteomalacia (TIO) are phosphorus physiology, one can point out the elucida- the main syndromes that integrate the hypophos- tion of part of the role of sodium-dependent phos- phatemic rickets, being the XHR the most frequent phate co-transporter proteins (NaPiT-I, II and III) one (16,17). and the fibroblast growth factor 23. Although these diseases have different etiopath- NaPiT co-transporter system is present in many ogenies, biochemical and molecular evidences point to tissues.
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