Hipovitaminosis D: afectaciones no clásicas / Hypovitaminosis D: non-classical effects

El déficit de vitamina D es una situación prevalente a nivel mundial y afecta a personas de cualquier edad. El rol más importante de la vitamina D es la regulación de la absorción intestinal de calcio y el metabolismo de calcio y fósforo para mantener la homeostasis ósea y muscular. Las enfermedades clásicamente asociadas al déficit de esta hormona son el raquitismo en los niños. En los adultos, el espectro varía desde osteomalacia hasta hiperparatiroidismo secundario, con pérdida de masa ósea, aumento del riesgo de caídas e incremento del riesgo de fractura según el grado de deficiencia. Además de estas acciones clásicas, la vitamina D: regula el crecimiento y la diferenciación de células musculares lisas de los vasos sanguíneos, el sistema renina-angiotensina-aldosterona, favorece la liberación de insulina, regula el crecimiento y estimula la diferenciación de monocitos-macrófagos, células presentadoras de antígenos, células dendríticas y linfocitos. En los últimos años, numerosos autores han vinculado a la hipovitaminosis D con enfermedades autoinmunes, diabetes mellitus tipo 2, enfermedades cardiovasculares, cáncer, etc. Estas afecciones no asociadas clásicamente al déficit de vitamina D serán el objeto de esta revisión.

Vitamin D deficiency is prevalent worlwide and affects people of all ages. Calcium intestinal absorption regulation along with calcium, phosphorous and bone homeostasis are most important vitamin D roles. Raquitism is commonly associated with vitamin D deficiency in children. Vitamin D deficiency related diseases varies from osteomalacia to hyperparathyroidism (with bone loss and increased risks of falls and fractures) in adults. Besides this well known actions, vitamin D regulates the growth and differentiation of smooth muscle cells, regulates the renin-angiotensin-aldosterone system, promotes the release of insulin, regulates cell growth and stimulates the differentiation of monocytes-macrophages, antigen presenting cells, dendritic cells and lymphocytes. In recent years, many authors have linked to hypovitaminosis D with autoimmune diseases, Type2 diabetes mellitus, cardiovascular disease and cancer among others diseases. These not traditionally vitamin D deficiency associated conditions are going to be subjects for this review.

Hypophosphatemic rickets and osteomalacia / Raquitismo hipofosfatêmico e osteomalácia

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, 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-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.

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)2D3, com conseqüente desordem do metabolismo ósteo-mineral, resultando em raquitismo e osteomalácia 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 gene localizado no cromossomo X que codifica uma enzima proteolítica Zn-metaloendopeptidase reguladora do fosfato (PHEX), implicada na regulação do FGF-23, já foram identificadas, e sua participação reconhecida na gênese destes distúrbios. Os dados dos estudos genéticos nesta área convergem para a hipótese de que a homeostase do fósforo estaria vinculada a um complexo eixo metabólico ósteo-renal, cujos mecanismos de interação entre seus vários componentes têm sido aos poucos elucidados. Este artigo revisa o atual estado de conhecimento dos mecanismos fisiológicos envolvidos na regulação do metabolismo do fosfato, das bases fisiopatológicas dos raquitismos hipofosfatêmicos e analisa aspectos clínicos e de tratamento disponíveis para estas condições.

Bone mineral density and bone scintigraphy in adult Saudi female patients with osteomalacia

This prospective study was conducted to demonstrate the role of bone mineral density [BMD] and bone scan in the management of adult Saudi female patients with established diagnosis of osteomalacia. Bone scan using Tc99m methylene diphosphonate [MDP] and BMD of the lumbar spine and femoral neck using dual x-ray absorptiometry [DXA] were performed at the time of diagnosis 6 months and one year after therapy in 96 Saudi female patients attending the metabolic bone disease clinic at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia, between January 1997 through to June 1999, aged between 20 and 73-years [mean 42 years]. Alkaline phosphatase, calcium and inorganic phosphorus were measured for all patients before and after treatment. 25 Hydroxy Vitamin D was only measured with the first BMD measurements. The bone profile showed typical biochemical abnormalities of osteomalacia. The bone scan showed feature of "superscan" in all patients and "pseudofractures" in 43 patients. Bone mineral density measurements were compared with that of normal Saudi subjects matched for age and sex. The BMD was significantly low at diagnosis and showed significant improvement after therapy. The improvement of bone density in response to therapy was more evident in lumbar spine than in femoral neck bone. Our results showed that BMD in adult Saudi female patients with osteomalacia was markedly affected probably due to specific constitutional and environmental factors [inadequate exercise, lack of sun exposure and lack of intake of milk and dairy products]. In addition, lumbar BMD and serum calcium appeared to be better markers to monitor therapy. Bone scan helped in demonstrating disease activity, the presence of pseudofractures