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Vitamin D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish. After hydroxylation in the liver into 25-hydroxyvitamin D (25(OH)D) and kidney into 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite can enter the cell, bind to the vitamin D-receptor and subsequently to a responsive gene such as that of calcium binding protein. After transcription and translation the protein is formed, e.g. osteocalcin or calcium binding protein. The calcium binding protein mediates calcium absorption from the gut. The production of 1,25(OH)2D is stimulated by parathyroid hormone (PTH) and decreased by calcium. Risk factors for vitamin D deficiency are premature birth, skin pigmentation, low sunshine exposure, obesity, malabsorption and advanced age. Risk groups are immigrants and the elderly. Vitamin D status is dependent upon sunshine exposure but within Europe, serum 25(OH)D levels are higher in Northern than in Southern European countries. Severe vitamin D deficiency causes rickets or osteomalacia, where the new bone, the osteoid, is not mineralized. Less severe vitamin D deficiency causes an increase of serum PTH leading to bone resorption, osteoporosis and fractures. A negative relationship exists between serum 25(OH)D and serum PTH. The threshold of serum 25(OH)D, where serum PTH starts to rise is about 75nmol/l according to most surveys. Vitamin D supplementation to vitamin D-deficient elderly suppresses serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents. The effects of 1,25(OH)2D and the vitamin D receptor have been investigated in patients with genetic defects of vitamin D metabolism and in knock-out mouse models. These experiments have demonstrated that for active calcium absorption, longitudinal bone growth and the activity of osteoblasts and osteoclasts both 1,25(OH)2D and the vitamin D receptor are essential. On the other side, bone mineralization can occur by high ambient calcium concentration, so by high doses of oral calcium or calcium infusion. The active metabolite 1,25(OH)2D has its effects through the vitamin D receptor leading to gene expression, e.g. the calcium binding protein or osteocalcin or through a plasma membrane receptor and second messengers such as cyclic AMP. The latter responses are very rapid and include the effects on the pancreas, vascular smooth muscle and monocytes. Muscle cells contain vitamin D receptor and several studies have demonstrated that serum 25(OH)D is related to physical performance. The active metabolite 1,25(OH)2D has an antiproliferative effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. Active calcium absorption from the gut depends on adequate formation of 1,25(OH)2D and an intact vitamin D receptor. Bone mineralization mainly depends on ambient calcium concentration. Vitamin D metabolites may play a role in the prevention of auto-immune disease and cancer.
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PMID:Vitamin D physiology. 1656 71

The sun is our most important source of vitamin D. Exposure to solaria, in sub-erythemogenic doses, also gives large amounts of this vitamin. The ultraviolet radiation in these sources converts 7-dihydrocholesterol to previtamin D3 in the skin. Furthermore, heat isomerization to vitamin D3 takes place, then transport to the liver and hydroxylation to calcidiol, which is transported to the kidneys and hydroxylated to the active hormone calcitriol. The vitamin D3 status of the body is supposed to be reliably imaged by calcidiol measurements. Calcidiol levels above 12.5 nmol/l prevent rickets and osteomalacia, but optimal levels are probably higher, in the range 100-250 nmol/l. A daily food intake of 100-200 microg vitamin D3 (50-100 g cod-liver oil), or a weekly exposure to two minimal erythemal doses of ultraviolet radiation (20 to 40 minutes whole body exposure to midday midsummer sun in Oslo, Norway), will give this level. An adequate supply of vitamin D3 seems to reduce the incidence rates or improve the prognosis of several cancer forms, including prostate, breast and colon cancer, as well as of lymphomas. Several other diseases are related to a low vitamin D3 status: heart diseases, multiple sclerosis, diabetes, and arthritis. The action mechanisms of vitamin D are thought to be mainly related to its known cell-differentiating and immuno-modulating effects. Even though most of the 250 annual death cases from skin cancer in Norway are caused by sun exposure, we should, in view of the health effects of ultraviolet radiation, consider modifying our restrictive attitude towards sun exposure and use of solaria.
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PMID:[The photobiology of vitamin D--a topic of renewed focus]. 1677 Mar 83

Vitamin D functions to regulate calcium homeostasis in intestine, kidney, and bone. Vitamin D deficiency during bone development causes rickets and in adults vitamin D deficiency, which has been shown to be common in the elderly population, can cause secondary hyperparathyroidism that can result in osteomalacia and increased risk of fracture. Recent evidence has suggested that vitamin D can have numerous other physiological functions including protection against certain autoimmune diseases, such as diabetes and multiple sclerosis and inhibition of proliferation of a number of malignant cells including breast and prostate cancer cells. Exactly how vitamin D affects numerous different systems is a subject of continuing investigation. This article will review new developments related to the function and regulation of vitamin D target proteins in classic vitamin D target tissues that have provided novel insight into the mechanism of vitamin D action.
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PMID:New insights into the mechanisms involved in the pleiotropic actions of 1,25dihydroxyvitamin D3. 1683 19

It is well-established that prolonged and severe vitamin D deficiency leads to rickets in children and osteomalacia in adults. More marginal vitamin D deficiency is likely to be a significant contributing factor to osteoporosis risk. However, recent emerging data from studies of adults suggest that low vitamin D status (serum 25-hydroxyvitamin D levels <50 nmol/l) may be contributing to the development of various chronic diseases, including cardiovascular disease, hypertension, diabetes mellitus, some inflammatory and autoimmune diseases, and certain cancers. Adequacy of vitamin D status in children and adolescents has been the focus of a number of recent investigations, and these studies have shown a high prevalence of low vitamin D status during the winter (especially in adolescents), with lower prevalence during the summer. Therefore, consideration of potential corrective strategies to allow children and adolescents to maintain adequate vitamin D status throughout the year, even in the absence of adequate summer sun exposure, is warranted.
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PMID:Vitamin D in childhood and adolescence. 1740 48

Stress fractures could be classified as fatigue fractures and insufficiency fractures (IF). Fatigue fractures occur when abnormal mechanical stress is applied to a normal bone, on the other hand insufficiency fractures occur when normal to moderate pressure is applied to a bone that has decreased resistance (Daffner and Pavlov in Am J Radiol 159:242-245, 1992). IF have been observed mainly in patients with postmenopausal osteoporosis, and are becoming more common with the increase of elderly population (Daffner and Pavlov in Am J Radiol 159:242-245, 1992). Other systemic and metabolic conditions that can result in osteopenia and IF include osteomalacia, hyperparathyroidism, hyperthyroidism, rheumatoid arthritis, fluoride treatment, diabetes mellitus, fibrous dysplasia, Paget's disease, irradiation and mechanical factors (Daffner and Pavlov in Am J Radiol 159:242-245, 1992; Soubrier et al. in Joint Bone Spine 70:209-218, 2003; Epps et al. in Am J Orthop 33:457-460, 2004; Austin and Chrissos in Orthopedics 28:795-797, 2005). In this case report, the authors present an osteoporotic woman who developed bilateral insufficiency fracture of the femoral shaft after longstanding steroid, thyroxine replacement and alendronate therapy due to partial empty sella syndrome and osteoporosis, resulting in the treatment of the fracture by inflatable intramedullary nailing.
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PMID:Bilateral femoral insuffiency fractures treated with inflatable intramedullary nails: a case report. 1757 2

Dietary reference intakes (DRIs) for Vitamin D (VitD) have been traditionally established based on plasma 25-OHD concentration sufficient to prevent rickets and osteomalacia. While nutritional rickets is still prevalent in developing countries, hypovitaminosis D is becoming widespread around the world regardless the latitude. Emerging evidence has unravelled the physiological roles of VitD beyond calcium homeostasis. Hypovitaminosis D has been linked to cancers, diabetes, CVD, periodontal diseases and influenza. Hypovitaminosis D is multifactorial and is related to VitD scarcity in foods, latitude, solar-irradiation, atmospheric-pollution, skin-pigmentation, clothing, sunscreen-use and indoor activities, etc. Plasma 25-OHD concentration range from 25-138 nmol/L. A higher plasma 25-OHD concentration is linked to higher bone-mass in adolescents, pre- and post-menopausal women. Plasma 25-OHD > or =75 nmol/L has been shown to enhance calcium absorption, suppress PTH elevation, reduce the risks of bone loss and fractures, and certain extra-skeletal diseases. VitD supplementation with 10 microg/d is insufficient to lower fracture risks. Combined VitD and calcium supplementation in higher doses has been found superior to VitD alone to increase bone-mass in adolescents and to reduce non-vertebral fractures in postmenopausal women. In future, DRIs for VitD are likely to be established beyond its skeletal roles to include multiple health outcomes. However, the desirable level of VitD has yet to be defined. Furthermore, redefining the upper-tolerable-level of VitD intake is necessary to prevent hypercalcemia and toxicity. There is also a urgent need to harmonize laboratory methods in VitD assay in different laboratories.
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PMID:The resurgence of the importance of vitamin D in bone health. 1829 22

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) (2) vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency.
Exp Clin Endocrinol Diabetes 2009 Feb
PMID:Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications. 1852 28

The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and gastrointestinal symptoms occurred among persons using Cd-containing polishing agent. The first experimental toxicological studies are from 1919. Bone effects and proteinuria in humans were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from Cd-pollution were issued in the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a quantitative assessment of these effects in humans is still subject to considerable uncertainty. The World Health Organization in its International Program on Chemical Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134, IPCS. WHO, Geneva, 1-280.) identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's and 2000 several epidemiological studies have reported adverse health effects, sometimes at low environmental exposures to Cd, in population groups in Japan, China, Europe and USA (reviewed in other contributions to the present volume). The early identification of an important role of metallothionein in cadmium toxicology formed the basis for recent studies using biomarkers of susceptibility to development of Cd-related renal dysfunction such as gene expression of metallothionein in peripheral lymphocytes and autoantibodies against metallothionein in blood plasma. Findings in these studies indicate that very low exposure levels to cadmium may give rise to renal dysfunction among sensitive subgroups of human populations such as persons with diabetes.
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PMID:Historical perspectives on cadmium toxicology. 1934 54

The natural selection hypothesis suggests that lighter skin colour evolved to optimise vitamin D production. Some authors question if vitamin D deficiency leads to sufficient health problems to act as a selection pressure. This paper reviews the numerous effects of vitamin D deficiency on human health and argues that vitamin D deficiency is sufficient to pose as a potent selection pressure for lighter skin colour. Vitamin D deficiency manifesting as rickets and osteomalacia are sufficient to impair reproductive success, but additionally, animal studies and some clinical observations suggest that vitamin D may have more direct impact on human fertility. Vitamin D deficiency may lead to a whole host of clinical conditions which impair health and increase mortality rates: increase susceptibility to bacterial and viral infections; rickets, osteomalacia and osteoporosis, with increased risk of falls and fractures; increased risk of cancers; hypertension and cardiovascular disease; maturity onset diabetes; autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and Type 1 diabetes; and gum disease. We submit that at higher latitudes, lighter skin colour evolved to facilitate vitamin D production under conditions of low ultra-violet B radiation in order to avoid a plethora of ill health, reproductive difficulties and early mortality.
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PMID:Vitamin D: in the evolution of human skin colour. 1971 44

Alcohol-induced chronic pancreatitis is associated with bone loss, but bone histomorphometric data describing the mechanism of cortical (Ct) and trabecular (Tb) bone loss are scarce. In this case-control study, we investigated 13 black male patients aged 41.2 +/- 8.9 years with alcohol-induced chronic pancreatitis by routine iliac crest cortical and trabecular histomorphometry and by biochemistry relevant to bone, liver function, and iron overload. Patients showed lower values for Ct thickness (P = 0.018), endocortical (Ec) wall thickness (P = 0.0002), Tb bone volume (0.019), Tb thickness (0.001), Tb wall thickness (P < 0.0001), Ec osteoid thickness (P = 0.001), Ec mineral apposition rate (P = 0.011), and Ec bone formation rate (P = 0.035). Ec eroded surface (P = 0.004) was elevated compared to controls. Tb osteoid thickness (P = 0.14) and Tb mineral apposition rate (P = 0.195) tended to be lower than in controls. Levels of 25-hydroxyvitamin D (P < 0.005), serum magnesium (P = 0.02), and ascorbic acid (P = 0.049) were lower and urine calcium/creatinine ratios higher than in controls. Alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) were negatively correlated but iron markers were positively correlated with bone structural and formation variables. The histomorphometric data were found to be consistent with alcohol bone disease. Osteomalacia was not a feature. Secondary pathogenetic factors were liver disease, hypovitaminosis D and C, diabetes mellitus, and possibly chronic pancreatitis.
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PMID:Cortical and trabecular bone microarchitecture and turnover in alcohol-induced chronic pancreatitis: a histomorphometric study. 2010 23


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