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Vitamin D is important for bone, for its essential role in promot­ing intestinal calcium absorption and mineralization of bone matrix. The major source of vitamin D is the skin, where it is produced by the action of ultraviolet light on steroid precursors. Vitamin D is also present in a limited number of foods, and the dietary sources of the vitamin can be important under circum­stances of decreased sunlight exposure. Dietary vitamin D is absorbed in the small intestine via the intestinal lymphatic sys­tem in the presence of bile acids. Vitamin D is derived from plant (vitamin D₂ or ergocalciferol) and animal sources (vitamin D₃ or cholecalciferol). The main dietary sources of vitamin D are fatty fish (salmon, sardines, tuna) and oils derived from them, some meat products (liver), eggs and wild mushrooms. Vitamin D (D₃ and D₂ collectively) is not a true vitamin, but a pro-steroid hormone that is biologically inert until metabolised. It is transported to the liver bound to a specific a-globulin (vita­min D binding protein), and to a small extent albumin and lipoproteins. In the liver, vitamin D is metabolised to 25(OH)D, which functions as the major storage form by virtue of its long half-life. In the kidney 25(OH)D (25-hydroxy-cholecalciferol) is further metabolised by a 1 a-hydroxylase enzyme to 1,25(OH)₂D (calcitriol), the hormone responsible for the biological effects of vitamin D. Metabolism of vitamin D may be even more com­plex, since recent studies demonstrated the existence of extrarenal 1 a-hydroxylases in many tissues, including bone and muscle. Locally produced 1,25(OH)₂D may therefore act as a paracrine/autocrine factor. The binding of calcitriol to the vitamin D receptor (VDR), a nuclear steroid hormone receptor, activates VDR to interact with retinoid X receptor (RXR) and form the VDR/RXR/co-factor complex, which binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription. These receptor are located in classical target tissues including bone, intestine, kidney and parathyroid glands as well as in many other tissues or cell types such as skin, muscle, and the immune system. Although the classical genomic pathway is responsible of most biological activity of vitamin D, some effects may be mediated by cell surface receptors through non-genomic pathways. Calcitriol is the major biologically active metabolite of vitamin D. The principal regulators of 1,25(OH)₂D production are PTH, 1,25(OH)₂D itself, dietary intake of calcium and phosphate. There are three primary target organs for circulating 1,25(OH)₂D: intestine, parathyroid gland and bone. In the intestine, calcitriol induces the expression of an epithelial calcium channel, calcium- binding protein (calbindin), and a variety of other proteins to help the transport of dietary calcium into the circulation. In the skeleton, calcitriol influences bone remodeling, mainly by acting on osteoblasts, in which it stimulates the production of osteocal­cin and different cytokines. VDRs have been identified in osteoblasts and in several osteoblastic cell lines while their pres­ence in osteoclasts is still under debate. In the parathyroid glands, 1,25(OH)₂D markedly decreases PTH gene transcription and parathyroid cell proliferation and induces parathyroid cell dif­ferentiation. Thus, the overall effects of 1,25(OH)2D on mineral metabolism may be summarized as: 1) increased intesti­nal calcium absorption, leading to increase in serum calcium; 2) decreased of serum PTH level (both through direct inhibition of PTH secretion from the parathyroid gland and indirect inhibition of PTH secretion by the raised serum calcium levels); 3) de­creased bone resorption (mainly due to a reduction in the PTH- mediated bone resorption); and 4) under certain conditions in­creased bone formation. Usually, under normal vitamin D status, the small intestine absorbs about 30% of dietary calcium. In the absence of calcitriol, intestinal calcium absorption is solely by the passive, extracellular route, which limits gross calcium ab­sorption to about 10-15% of intake.

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Introduction

Osteoporosis is the most prevalent metabolic bone disease among developed countries and it is defined as a skeletal disor­der characterized by compromised bone strength and increased risk of fracture. Its clinical significance lies in the occurrence of fractures, involving most commonly the forearm, the vertebral bodies and the hip, but fractures at other sites may be also asso­ciated with the disease. For Caucasians, the lifetime risk of an osteoporotic fracture at 50 years of age has estimated to be ap­proximately 40% for women and 13% for men. Each year more than 1.5 million people suffer hip, vertebral, and wrist frac­tures due to osteoporosis, a disease that can be prevented and treated. The occurrence of osteoporotic fractures leads to con­siderable mortality, morbidity, reduced mobility and decreased quality of life. Actually, the annual number of hip fractures in 15 countries of European Community (EC) has been estimated to be 500,000, with a total care cost of about 4.8 billion euros per year. This burden will increase in absolute terms because of the ageing of the population. Given the magnitude of the prob­lem, the prevention and treatment of osteoporosis is, therefore, of major importance for health organizations in all countries. The major determinant of bone strength and osteoporotic fracture risk is bone mineral density (BMD), as assessed by dual photon absorptiometry or dual energy x-ray absorptiometry. According to WHO criteria, osteoporosis is defined to exist when BMD values fall more than 2.5 standard deviations below the young adult ref­erence mean. Many studies indicated that the risk of fragility fractures increases progressively as BMD declines. It has been estimated that the risk of new vertebral fractures increases by a factor of 2.0-2.4 for each standard deviation decrease in BMD, irrespective of the site of bone density measurement. However, bone strength depends not only on BMD. Bone size as well as bone quality are other important components that interact with BMD in determining the risk of fracture. Skeletal bone mass is determined by a combination of endoge­nous (genetic, hormonal) and exogenous (nutritional, physical activity) factors. In adolescence to attain the optimal peak bone mass the main determinants are genetic, nutritional and behav­ioural (exercise). In adult and elderly populations the main deter­minants of age-related bone loss are represented by the gonadal status, by the influence of some nutrients and by the physical ac­tivity. Both a low peak bone mass and a high rate of bone loss represent risk factors for osteoporosis and osteoporotic frac­tures.

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Patients on long term hemodialysis caused by chronic renal failure commonly have accompanying renal bone disease, one of the major factors underlying this disease being secondary hyperparathyroidism. Parathyroid hyperplasia and high levels of immunoreactive PTH are present in the early stage of sec­ondary hyperparathyroidism. Clonal analysis has shown that in renal hyperparathyroidism the parathyroid glands initially grow diffusely and polyclonally, with successive development of foci of nodular hyperplasia and possibly of monoclonal neo- plasia. Somatic changes of specific genes have been suspect­ed of being responsible for parathyroid tumorigenesis in uremic hyperparathyroidism. However, the genetic loci responsible for tumor development remain to be identified and heterogeneous genetic abnormalities may contribute to the progression of sec­ondary parathyroid hyperplasia. The initial stimulus for PTH hy- persecretion is thought to be predominantly a chronic reduction of ionized calcium in the extracellular fluid, caused by the re­duced production of 1,25 (OH)₂ vitamin D and/or to phosphate retention. Although secondary hyperparathyroidism is some­times managed by calcium supplementation, by oral calcitriol therapy and by restriction of phosphate intake, many patients remain unresponsive to these conservative treatments. Lack of response to treatment may be due to alterations in the calcium sensing set-point and/or to an increased functional parathyroid gland mass. To date, there are conflicting data regarding the relative contribution of gland size and set-point abnormalities to non-suppressible PTH in hemodialysis pa­tients with secondary hyperparathyroidism. Many prior studies provided evidence for a calcium sensing abnormality in a subset of patients with severe hyperparathyroidism, but recent studies have failed to identify calcium set point abnor­malities in normocalcemic patients with secondary hyper- parathyroidism of different severity. Similarly, in spite of parathyroid gland enlargement, it has been difficult to conclu­sively show that gland size is responsible for impaired calcium- mediated PTH suppression in these patients. Whereas some studies have found a relationship between basal circulating PTH concentrations and parathyroid gland size, other in­vestigations have not.

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The frequency distribution of VDR and CaSR genotypes were in Hardy-Weinberg equilibrium. The distribution of Apa I a nd Taq I genotypes was very similar to what previously reported in Caucasian populations of European ancestry, while significant­ly differed from what observed in populations of Asiatic ances­try. The distribution of CaSR genotypes did not vary from that previously observed in Canadian population. Chi squared analysis revealed no significant difference in the distribution of any of the VDR or CaSR genotypes in subjects with secondary HPT compared to controls. When controls were subgrouped in osteoporotics and non osteoporotics, according to W.H.O. criteria, we observed a statistically significant in­creased prevalence of “AA”, “tt” and “ff’ VDR genotypes in os­teoporotics than in non osteoporotics (Tab. II), and of “ff’ VDR genotype in secondary HPT patients than in osteoporotics (Tab. III). Conversely, CaSR polymorphism distributions did not vary among secondary HPT, osteoporotic and non osteoporotic groups (Tab. IV). Secondary HPT patients were divided into two major groups according to serum PTH levels: group 1 in­cluding patients with higher PTH levels, unresponsive to med­ical treatment and thus requiring parathyroidectomy, and group 2 including subjects with serum PTH levels below 120 pg/ml. Interestingly, as shown in Table V, a trend for a two-fold in­creased prevalence of VDR genotype “aaTT” in group 1, with respect to group 2 was observed (P=0.07; Chi-squared test).

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Subjects

The study population comprised 100 patients affected with ure­mic secondary HPT and 200 age and sex matched controls. Patients had been recruited as part of a multicentric Italian study, including the Nephrology and Dyalisis Units of Bari, Cinisello Balsamo, Desio, Florence, Milan and Reggio Emilia. The inclusion criteria for the study were the following: age> 65 years, dyalitic age >2 years, mean Al levels <40 mg/l, serum in­tact PTH levels <120 pg/ml (Group 1) or >600 pg/ml (Group 2). The cause of renal failure was chronic glomerulonephritis in 43, nephroangiosclerosis in 14, tubulo-interstitial nephritis in 10, polycystic kidney disease in 10, diabetic glomerulosclerosis in 7, nephrotuberculosis in 1, and other causes in 15. Controls were selected from a cohort of 500 women and 200 men visited in Florence for osteoporotic risk evaluation which had previously participated to genetic association studies on VDR polymorphisms. Clinical characteristics of pa­tients and controls are given in Table I.

Clinical findings indicate that primary hypercalciuria predispos­es affected subjects to nephrolithiasis and nephrocalcinosis, even though its specific pathogenetic role has not been eluci­dated in both disorders. The effect of hypercalciuria is likely to depend on unusually high calcium concentrations in urine or tubular fluid of patients. When calcium concentrations exceed the threshold for precipitation, calcium salts may be deposited in renal interstitium or tubular lumen. Salt precipitation may be easier in kidney papilla, due to its particular architecture and physical-chemical characteristics of its fluids in tubules and interstitium. canadian-healthcare-shop we care about you health

The pathogenesis of nephrocalcinosis or nephrolithiasis may be similar in hypercalciuric subjects. This possibility is indicated by the presence of both defects in patients with tubular disor­ders and by the presence of nephrolithiasis in heterozygous relatives of homozygous patients with hypomagnesemia-hyper- calciuria-nephrocalcinosis syndrome or other tubular disorders. However, other factors in addition to hypercalciuria may be needed to cause the appearance of nephrocalcinosis or nephrolithiasis.

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