As an endocrine hormone, vitamin D plays an important role in bone health and calcium homeostasis. Over the past two decades, the non-calcemic effects of vitamin D were extensively examined. Although the effect of vitamin D on beta cell function were known for some time, the effect of vitamin D on glucose and fuel homeostasis has attracted new interest among researchers. Yet, to date, studies remain inconclusive and controversial, in part, due to a lack of understanding of the threshold effects of vitamin D. In this review, a critical examination of interventional trials of vitamin D in prevention of diabetes is provided. Like use of vitamin D for bone loss, the benefits of vitamin D supplementation in diabetes prevention were observed in vitamin D-deficient subjects with serum 25-hydroxyvitamin D < 50 nmol/L (20 ng/mL). The beneficial effect from vitamin D supplementation was not apparent in subjects with serum 25-hydroxyvitamin D > 75 nmol/L (30 ng/mL). Furthermore, no benefit was noted in subjects that achieved serum 25-hydroxyvitamin D > 100 nmol/L (40 ng/mL). Further studies are required to confirm these observations.

A predisposition for the efficiency of nutraceuticals is that the product contains a sufficient quantity of a vitamin. Several studies have highlighted different quality issues. Our objective was to investigate whether the contents of the vitamins in selected types of food supplements were in accordance with labeling. We focused on two types of food supplements where content-related quality issues could result in public health risks: food supplements for supplementation with (a) folic acid (as 5-methyltetrahydrofolate (5-MTHF)) in pregnancy and (b) with vitamin D in the general population. The study was done on supplements from the global supply that are typically used by Slovenian consumers. We sampled one production batch of 30 different food supplements-six and 24 samples with 5-MTHF and cholecalciferol, respectively. We found samples with vitamin contents outside the 80-150% tolerance interval in both sets. Particularly, 5-MTHF was found to be more problematic, probably due to its lower stability. This study shows the need for better quality control. Quality control is needed during both the manufacturing process and product shelf lifetimes. Content quality should be also subject to external controls by authorities. Voluntarily quality control schemes would also enable consumers to identify products of sufficient quality.

Vitamin D is essential for bone health and is known to be involved in immunomodulation and cell proliferation. Vitamin D status remains a significant health issue worldwide. However, there has been no clear consensus on vitamin D deficiency and its measurement in serum, and clinical practice of vitamin D deficiency treatment remains inconsistent. The major circulating metabolite of vitamin D, 25-hydroxyvitamin D (25(OH)D), is widely used as a biomarker of vitamin D status. Other metabolic pathways are recognised as important to vitamin D function and measurement of other metabolites may become important in the future. The utility of free 25(OH)D rather than total 25(OH)D needs further assessment. Data used to estimate the vitamin D intake required to achieve a serum 25(OH)D concentration were drawn from individual studies which reported dose-response data. The studies differ in their choice of subjects, dose of vitamin D, frequency of dosing regimen and methods used for the measurement of 25(OH)D concentration. Baseline 25(OH)D, body mass index, ethnicity, type of vitamin D (D₂ or D₃) and genetics affect the response of serum 25(OH)D to vitamin D supplementation. The diversity of opinions that exist on this topic are reflected in the guidelines. Government and scientific societies have published their recommendations for vitamin D intake which vary from 400-1000 IU/d (10-25 μg/d) for an average adult. It was not possible to establish a range of serum 25(OH)D concentrations associated with selected non-musculoskeletal health outcomes. To recommend treatment targets, future studies need to be on infants, children, pregnant and lactating women.

Bisphosphonates like risedronate inhibit osteoclast-mediated bone resorption and are therefore used in the prevention and treatment of osteoporosis. Also vitamin D₃ and calcium supplementation is commonly used in the prevention or treatment of osteoporosis. Combined therapy of risedronate with 1,25(OH)₂D₃, the active metabolite of vitamin D₃, may be advantageous over the use of either monotherapy, but bears a risk of causing hypercalcemia thereby decreasing the therapeutic window for osteoporosis treatment. In this study, we evaluated the effect on bone mass of the combination of risedronate with the 17-methyl 19-nor five-membered D-ring vitamin D₃ analog WY 1048 in a mouse ovariectomy model for postmenopausal osteoporosis. Ovariectomy-induced bone loss was restored by administration of risedronate or a combination of risedronate with 1,25(OH)₂D_3. However, the combination of WY 1048 with risedronate induced an even higher increase on total body and spine bone mineral density and on trabecular and cortical bone mass. Our data indicate that combination therapy of risedronate with WY 1048 was superior in restoring and improving bone mass over a combination of risedronate with 1,25(OH)₂D₃ with minimal calcemic side effects.

It is anticipated that an intake of vitamin D found acceptable by Endocrine Society Guidelines (10 000 IU/day) with co-administered calcium supplements may result in frequent hypercalciuria and hypercalcaemia. This combination may be associated with kidney stones. The objective of this study was to compare the episodes of hypercalciuria and hypercalcaemia from calcium supplements co-administered with 10 000 IU or 600 IU vitamin D daily. This design allows a comparison of the Institute of Medicine recommendation for the RDA of vitamin D along with the upper limit of calcium intake with the high intake of vitamin D suggested by the Endocrine Society.

Harms of currently recommended high intake of vitamin D have not been studied.

The design was a randomized controlled trial with 2 groups with evaluation every 3 months for one year: (a) CaCO₃ 1200 mg/day with 10 000 IU vitamin D₃ /day or (b) CaCO₃ 1200 mg/day with 600 IU vitamin D₃ /day.

This study was conducted in an ambulatory research centre in healthy, white postmenopausal women.

Serum and 24-hour urine calcium were measured.

Hypercalcaemia and hypercalciuria occurred in both groups. At the final visit, 19/48 in the high dose D group had hypercalciuria. The odds of developing hypercalciuria were 3.6 [OR = 3.6(1.39, 9.3)] times higher in the high dose D group. The odds of developing hypercalcaemia did not differ between groups.

The safe upper level of vitamin D recommended by the Endocrine Society when accompanied by calcium supplements results in frequent hypercalciuria. The risk of kidney stones at these levels should be investigated.

One hundred years ago, vitamin D was identified as the cause and cure of osteomalacia. This role remains firmly established. Vitamin D influences skeletal mineralization principally through the regulation of intestinal calcium absorption. It has been proposed that vitamin D has direct beneficial effects on bone (besides the prevention of osteomalacia), but these have been difficult to establish in clinical trials. Meta-analyses of vitamin D trials show no effects on bone density or fracture risk when the baseline 25-hydroxyvitamin D is >40 nmol/L. A daily dose of 400 to 800 IU vitamin D₃ is usually adequate to correct such deficiency.

Nuclear receptors are a family of transcription factors that can be activated by lipophilic ligands. They are fundamental regulators of development, reproduction, and energy metabolism. In bone, nuclear receptors enable bone cells, including osteoblasts, osteoclasts, and osteocytes, to sense their dynamic microenvironment and maintain normal bone development and remodeling. Our views of the molecular mechanisms in this process have advanced greatly in the past decade. Drugs targeting nuclear receptors are widely used in the clinic for treating patients with bone disorders such as osteoporosis by modulating bone formation and resorption rates. Deficiency in the natural ligands of certain nuclear receptors can cause bone loss; for example, estrogen loss in postmenopausal women leads to osteoporosis and increases bone fracture risk. In contrast, excessive ligands of other nuclear receptors, such as glucocorticoids, can also be detrimental to bone health. Nonetheless, the ligand-induced osteoprotective effects of many other nuclear receptors, e.g., vitamin D receptor, are still in debate and require further characterizations. This review summarizes previous studies on the roles of nuclear receptors in bone homeostasis and incorporates the most recent findings. The advancement of our understanding in this field will help researchers improve the applications of agonists, antagonists, and selective modulators of nuclear receptors for therapeutic purposes; in particular, determining optimal pharmacological drug doses, preventing side effects, and designing new drugs that are more potent and specific.

Hypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)₂D], and impaired degradation of 1,25(OH)₂D. The ingestion of excessive amounts of vitamin D₃ (or vitamin D₂) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)₂D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)₂D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)₂D is impaired as a result of mutations of the 1,25(OH)₂D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)₂D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)₂D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)₂D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

The physiological role of vitamin D depends on calcium supply and calcium balance. When the calcium balance is normal, the major target of vitamin D is intestine. Vitamin D stimulates mainly active intestinal calcium transport mechanism. During a negative calcium balance, bone effects of vitamin D become dominant. Thus, the role of vitamin D in maintaining normocalcemia appears to have priority over skeletal integrity in these situations.

Clinical studies indicate that the combination of vitamin D and dietary calcium supplementation is more effective for reducing fracture risk than either supplement alone. Our previous dietary studies demonstrated that an adequate serum 25-hydroxyvitamin D3 (25D) of 80nmol/L or more reduces bone RANKL expression, osteoclastogenesis and maintains the optimal levels of trabecular bone volume (BV/TV%) in young rats. The important clinical question of the interaction between vitamin D status, dietary calcium intake and age remains unclear. Hence, 9 month-old female Sprague-Dawley rats (n=5-6/group) were pair-fed a semi-synthetic diet containing varying levels of vitamin D (0, 2, 12 or 20IU/day) and dietary calcium (0.1% or 1%) for 6 months. At 15 months of age, animals were killed, for biochemical and skeletal analyses. While changes to serum 25D were determined by both dietary vitamin D and calcium levels, changes to serum 1,25-dihydroxyvitamin D3 (1,25D) were consistently raised in animals fed 0.1% Ca regardless of dietary vitamin D or vitamin D status. Importantly, serum cross-laps levels were significantly increased in animals fed 0.1% Ca only when combined with 0 or 2 IUD/day of vitamin D, suggesting a contribution of both dietary calcium and vitamin D in determining bone resorption activity. Serum 25(OH)D3 levels were positively correlated with both femoral mid-diaphyseal cortical bone volume (R(2)=0.24, P<0.01) and metaphyseal BV/TV% (R(2)=0.23, P<0.01, data not shown). In multiple linear regressions, serum 1,25(OH)2D3 levels were a negative determinant of CBV (R(2)=0.24, P<0.01) and were not a determinant of metaphyseal BV/TV% levels. These data support clinical data that reduced bone resorption and increased bone volume can only be achieved with adequate 25D levels in combination with high dietary calcium and low serum 1,25D levels. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Vitamin D deficiency has emerged as a significant public health problem throughout the world. Even in the Indian context,it has been reported to be present in majority of children in spite of wide availability of sunlight. Recent guidelines have defined vitamin D status as severe deficiency, deficiency, sufficiency and risk for toxicity as 25(OH)D levels <5, <15, >20 and >50ng/mL, respectively.The manifestations of deficiency may vary from hypocalcemic seizures, tetany in infancy and adolescence to florid rickets in toddlers. Treatment is necessary for all individuals with deficiency whether symptomatic or not and consists of vitamin D supplementation as Stoss therapy or daily or weekly oral regimens with equal efficacy and safety, combined with calcium supplements. Routine supplementation starting from newborn period is being increasingly endorsed by various international organizations. Prevention by sensible sunlight exposure, food fortification and routine supplementation are the currently available options for tackling this nutritional deficiency.

Treatment of vitamin D deficiency with vitamin D is a common procedure when taking care of elderly patients, calcium supplementation being added only when calcium dietary intake is insufficient. Here, we report the case of a 58-year-old female who was referred to our unit because of suspicion of Paget's disease of the skull, based on elevated serum alkaline phosphatase and high skull methylene diphosphonate-technetium uptake. She had been prescribed cholecalciferol (100,000 IU/month) and calcium salts for the past 7 months after discovery of severe vitamin D deficiency by her primary care physician. No specific skull bone lesions were observed on both X-ray and computerized tomography. Serum calcium, phosphate and 25(OH) vitamin D levels were normal, while serum C-terminal cross-linked telopeptide, bone alkaline phosphatase and calcitriol were high and daily urinary calcium excretion was low. We found that she had not been compliant with the calcium prescription while vitamin D had been thoroughly taken. We suspected osteomalacia due to calcium deficiency. Both skull uptake and biological abnormalities normalised in few months after adding calcium supplementation to the vitamin D treatment, and spine bone mineral density increased by 9.5 % after 14 months of full treatment. The present case illustrates the necessity for adequate calcium intake during vitamin D repletion to normalise bone mineralisation and turnover and maintain the skeletal integrity.

Vitamin D is the sunshine vitamin that has been produced on this earth for more than 500 million years. During exposure to sunlight 7-dehydrocholesterol in the skin absorbs UV B radiation and is converted to previtamin D3 which in turn isomerizes into vitamin D3. Previtamin D3 and vitamin D3 also absorb UV B radiation and are converted into a variety of photoproducts some of which have unique biologic properties. Sun induced vitamin D synthesis is greatly influenced by season, time of day, latitude, altitude, air pollution, skin pigmentation, sunscreen use, passing through glass and plastic, and aging. Vitamin D is metabolized sequentially in the liver and kidneys into 25-hydroxyvitamin D which is a major circulating form and 1,25-dihydroxyvitamin D which is the biologically active form respectively. 1,25-dihydroxyvitamin D plays an important role in regulating calcium and phosphate metabolism for maintenance of metabolic functions and for skeletal health. Most cells and organs in the body have a vitamin D receptor and many cells and organs are able to produce 1,25-dihydroxyvitamin D. As a result 1,25-dihydroxyvitamin D influences a large number of biologic pathways which may help explain association studies relating vitamin D deficiency and living at higher latitudes with increased risk for many chronic diseases including autoimmune diseases, some cancers, cardiovascular disease, infectious disease, schizophrenia and type 2 diabetes. A three-part strategy of increasing food fortification programs with vitamin D, sensible sun exposure recommendations and encouraging ingestion of a vitamin D supplement when needed should be implemented to prevent global vitamin D deficiency and its negative health consequences.

Vitamin D is a steroid molecule, mainly produced in the skin that regulates the expression of a large number of genes. Several meta-analyses of epidemiological studies support the evidence that low vitamin D serum level, which is highly prevalent worldwide, could be a 'new' risk factor for many chronic diseases including cancer, and for all-cause mortality. A meta-analysis in healthy subjects suggested that current doses of vitamin D supplements could be associated with decrease in total mortality rates. However, these associations are insufficient to establish causality between vitamin D and all-cause mortality. Furthermore, long-term health effects of high doses of vitamin D, that is, prolonged supplementation and association with different baseline vitamin D levels, remain to be investigated. Several trials are ongoing but population-based, placebo-controlled randomized trials with total mortality as the main endpoint should be planned to confirm a real beneficial effect of vitamin D for non-skeletal diseases and to prove causality.

Vitamin D status is determined by the serum concentration of one of its metabolites, 25-hydroxy-D. Defining vitamin D deficiency based on its classical roles in gut calcium absorption and bone mineralization is problematic in dialysis patients and, until recently, was ignored in the nephrology literature. The newly recognized nonclassical functions of vitamin D include effects on the immune system, cardiovascular disease, and cancer. The nonclassical effects are likely to be equally relevant in the dialysis population, but suffer from a lack of strong evidence on which to base therapeutic targets. Past medical opinion in the nondialysis population warned that higher dose vitamin D supplementation may be toxic and was unnecessary. This is because older supplementation recommendations were based on early twentieth century studies using cod-liver oil to treat rickets. The clinical resolution of rickets requires a relatively low dose of vitamin D. Current vitamin D guidelines generally target higher 25-hydroxy-D levels of 30 ng/ml, based on optimizing markers of bone health. This results in very high estimates of 50-100% for the prevalence of vitamin D deficiency in dialysis patients. This review examines the relevance of data on the classical and nonclassical effects of vitamin D in dialysis patients. An evidence-based dosing regimen for use in dialysis patients is suggested to safely and reliably achieve vitamin D sufficiency.

Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D [1,25(OH)(2)D], which can elicit calcium mobilization from bone when intestinal calcium absorption is decreased. The skeletal adaptations, however, are still poorly characterized. To gain insight into these issues, we analyzed the consequences of specific vitamin D receptor (Vdr) inactivation in the intestine and in mature osteoblasts on calcium and bone homeostasis. We report here that decreased intestinal calcium absorption in intestine-specific Vdr knockout mice resulted in severely reduced skeletal calcium levels so as to ensure normal levels of calcium in the serum. Furthermore, increased 1,25(OH)(2)D levels not only stimulated bone turnover, leading to osteopenia, but also suppressed bone matrix mineralization. This resulted in extensive hyperosteoidosis, also surrounding the osteocytes, and hypomineralization of the entire bone cortex, which may have contributed to the increase in bone fractures. Mechanistically, osteoblastic VDR signaling suppressed calcium incorporation in bone by directly stimulating the transcription of genes encoding mineralization inhibitors. Ablation of skeletal Vdr signaling precluded this calcium transfer from bone to serum, leading to better preservation of bone mass and mineralization. These findings indicate that in mice, maintaining normocalcemia has priority over skeletal integrity, and that to minimize skeletal calcium storage, 1,25(OH)(2)D not only increases calcium release from bone, but also inhibits calcium incorporation in bone.

Vitamin D, a secosteroid (pro)-hormone, has been traditionally considered as a key regulator of bone metabolism, and calcium and phosphorous homeostasis through a negative feedback with the parathyroid hormone. However, during the last 20 years, the role played by vitamin D has been largely revised by recognizing its pleiotropic action on a wide spectrum of systems, apparatuses and tissues. Thus, vitamin D has growingly been involved as a primary determinant of biological modifications and specific clinical conditions. The effect of vitamin D on skeletal muscle and related outcomes (including physical function decline and disability) is surely one of the most relevant to study in the context of global aging. In the present review, the subclinical and clinical consequences of vitamin D deficiency/insufficiency, extremely frequent conditions in older age, are described. Special focus is given to skeletal muscle and physical function. Limitations of available scientific evidence on the topic are also discussed.

Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of vitamin D(3). This study therefore aimed to assess the effect of this dose of vitamin D(3) in patients with bone metastases from breast cancer.

Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D(3) and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter.

Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity.

Daily doses of 10,000 IU vitamin D(3) for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption.

Vitamin D deficiency has been implicated in chronic pain. Immigrant and ethnic minority populations have been shown to have lower vitamin D levels than native Western populations and often to be vitamin D deficient. This systematic review investigates the relationship between vitamin D and chronic pain in immigrant and ethnic minority populations. Included were studies reporting on 25-OH vitamin D levels in immigrant/ethnic minority populations affected by chronic pain, and/or reporting on the treatment of chronic pain with vitamin D preparations in such populations. We found that 25-OH vitamin D levels were low and often deficient in immigrant/ethnic minority populations. Vitamin D levels depended on the latitude of the study location and hence sunlight exposure. There was insufficient evidence to reach a verdict on the value of treating chronic pain in immigrant/ethnic minority patients with vitamin D preparations because the studies were few, small, and of low quality.

Several epidemiological, pre-clinical and clinical studies support Vitamin D as a preventive and therapeutic cancer agent.

Vitamin D and cancer: calcitriol, the biologically active form of vitamin D (1,25(OH)D), exerts its effects mainly through binding to nuclear vitamin D receptor (VDR). Calcitriol has been shown to be an anti-proliferative, pro-differentiation, pro-apoptotic agent and an inhibitor of cell migration. Animal and human in vitro studies strongly indicate that vitamin D may have benefits for many forms of cancer. Inadequate levels of circulating 25-hydroxy-vitamin D (25(OH)D) are associated with an increased risk and poor prognosis of several types of cancer. Vitamin D and melanoma: cutaneous malignant melanoma (CMM) represents a major public health issue: rates in Italy have almost doubled in the last decade and CMM is frequent among young adults. For resected stage II melanoma no standard adjuvant treatment exists and five-year overall survival is about 70%. Cultured melanoma cells can synthesize calcitriol from 25(OH)D and express the VDR. Moreover, 1,25(OH)D has anti-proliferative and pro-differentiation effects in human melanoma cells. 1,25(OH)D has been shown to induce apoptosis in human melanoma cell lines and has an inhibitory effect on the spreading of melanoma cells in vitro. Preliminary results on vitamin D: epidemiological data indicate that vitamin D deficiency is relatively common in Europe. In an Italian study, we found that 85% of the participants had insufficient levels of 25(OH)D. We have shown through a meta-analysis of randomized trials that vitamin D supplementation is associated with a significant reduction (7%) in total mortality in healthy subjects and an association between VDR and 25(OH)D and CMM progression has also been demonstrated. We have also reported significant associations between VDR polymorphisms and incidence of skin cancer. In early supplementation trials, the lack of effect on cancer incidence has been attributed to insufficient vitamin D supplementation, stressing the need to better study vitamin D bioavailability. In fact, a recent IARC report highlighted the need for new randomized trials, based on results from our meta-analyses on 25(OH)D serum levels and cancer risk. Clinical trial and biomarkers studies: in order to assess whether vitamin D supplementation could improve prognosis of CMM, an Italian multi-centre trial in stage II resected melanoma patients was planned to monitor changes in 25(OH)D. The study will address two important questions regarding the relationship between the biology of VDR and (1) vitamin D metabolism, and (2) CMM prognosis. This will involve investigating the association between VDR polymorphisms and Breslow thickness, the most important prognostic factor of CMM, and between 25(OH)D serum level, vitamin D supplementation and VDR. We will also evaluate at baseline whether VDR polymorphisms are associated with Breslow thickness and whether we obtain significant increase in 25(OH)D serum levels during the first year of supplementation. We will quantify the percentages of patients who have desirable levels of 25(OH)D and, if they don't, the mean time to reach that level. The findings from this study will be of great interest because vitamin D could have anti-cancer benefits for a wide spectrum of cancers.

Osteoporosis is a systemic skeletal disease characterized by diminished bone mass and deterioration of bone microarchitecture, leading to increased fragility and subsequent increased fracture risk. Therapeutic measures therefore aim at reducing individual fracture risk. In Austria, the following drugs, all of which have been proven to reduce fracture risk, are currently registered for the treatment of postmenopausal osteoporosis: alendronate, risedronate, etidronate, ibandronate, raloxifene, teriparatide (1-34 PTH), 1-84 PTH, strontium ranelate and salmon calcitonin. Fluorides are still available, but their role in daily practice has become negligible. Currently, there is no evidence that a combination of two or more of these drugs could improve anti-fracture potency. However, treatment with PTH should be followed by the treatment with an anticatabolic drug such as bisphosphonates. Calcium and vitamin D constitute an important adjunct to any osteoporosis treatment.

Adequate exposure to sunlight and fortification of dairy products with vitamin D have eliminated vitamin D deficiency secondary to inadequate endogenous production or nutrition in the majority of countries. Insufficient vitamin D intake secondary to using unfortified foods and social customs (such as avoiding sun exposure), however, contribute to the development of disease. Poor diet, a lack of sun exposure, and the age related decline in the dermal synthesis of 7-dehydrocholesterol are among the factors that predispose to vitamin D deficiency and consequent bone disease. Here, we present a case of severe osteomalacia presenting with multiple vertebral fractures due to poor diet and a lack of exposure to sunlight.

Vitamin D is a fat-soluble, seco-steroid hormone. In man, the vitamin D receptor is expressed in almost all tissues, enabling effects in multiple systems of the human body. These effects can be endocrine, paracrine and autocrine. The present review summarises the effects of ageing on the vitamin D endocrine system and on Ca homeostasis. Furthermore, consequences for vitamin D supplementation are discussed.

Sunlight provides most humans with their vitamin D requirement. Adequate vitamin D(3) by synthesis in the skin or from dietary and supplemental sources is essential for bone health throughout life. Vitamin D deficiency is defined as a 25(OH)D concentration <20 ng/mL (50 nmol/L); vitamin D sufficiency as a 25(OH)D >30 ng/mL (75 nmol/L), and insufficiency as 21-29 ng/mL. Vitamin D deficiency and insufficiency has been linked to a wide variety of chronic diseases including common cancers, autoimmune, cardiovascular, and infectious diseases. Healthcare professionals need to be aware of the vitamin D deficiency pandemic. Guidelines for sensible sun exposure and supplemental vitamin D of 800-1000 IU/day are needed.

Vitamin D, the sunshine vitamin, is now recognized not only for its importance in promoting bone health in children and adults but also for other health benefits, including reducing the risk of chronic diseases such as autoimmune diseases, common cancer, and cardiovascular disease. Vitamin D made in the skin or ingested in the diet is biologically inert and requires 2 successive hydroxylations first in the liver on carbon 25 to form 25-hydroxyvitamin D [25(OH)D], and then in the kidney for a hydroxylation on carbon 1 to form the biologically active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. With the identification of 25(OH)D and 1,25(OH)(2)D, methods were developed to measure these metabolites in the circulation. Serum 25(OH)D is the barometer for vitamin D status. Serum 1,25(OH)(2)D provides no information about vitamin D status and is often normal or even increased as the result of secondary hyperparathyroidism associated with vitamin D deficiency. Most experts agree that 25(OH)D of <20 ng/mL is considered to be vitamin D deficiency, whereas a 25(OH)D of 21-29 ng/mL is considered to be insufficient. The goal should be to maintain both children and adults at a level >30 ng/mL to take full advantage of all the health benefits that vitamin D provides.

To review the current literature on the health effects of vitamin D, especially the effects on inhabitants living in the northern latitudes.

Literature review.

The scientific literature concerning health effects of vitamin D was reviewed and the current dietary recommendations for inhabitants living in northern latitudes were discussed.

Vitamin D is a steroid-structured hormone produced in the skin upon exposure to UVB-radiation or obtained from certain food products (for example, liver). Its production is mediated by the vitamin D receptor, which belongs to the nuclear receptor family, and exerts its function as a transcription factor regulating several target genes. Active metabolites of vitamin D play an important role in calcium and phosphate homeostasis. Deficiency of vitamin D results in diminished bone mineralization and an increased risk of fractures. In addition, vitamin D is connected to a variety of other diseases that include different cancer types, muscular weakness, hypertension, autoimmune diseases, multiple sclerosis, type 1 diabetes, schizophrenia and depression.

Vitamin D plays a fundamental role in calcium and phosphate homeostasis. A deficiency of vitamin D has been attributed to several diseases. Since its production in the skin depends on exposure to UVB-radiation via the sunlight, the level of vitamin D is of crucial importance for the health of inhabitants who live in the Nordic latitudes where there is diminished exposure to sunlight during the winter season. Therefore, fortification or supplementation of vitamin D is necessary for most of the people living in the northern latitudes during the winter season to maintain adequate levels of circulating 25(OH)D3 to maintain optimal body function and prevent diseases.

Sun exposure of the skin, independent of dietary sources, may provide sufficient vitamin D in healthy individuals. A recent study of patients with cutaneous lupus erythematosus concluded that over 70% of them restrict their sun exposure.

We recruited 52 patients with biopsy-proven cutaneous lupus erythematosus to establish whether they are deficient in 25-hydroxyvitamin D [25(OH)D]. We measured their serum 25(OH)D levels during summer months, investigated the effects of several variables on 25(OH)D levels and assessed the role of vitamin D supplementation.

An overall mean 25(OH)D level of 63.03 (+/-23.3) nmol/l was obtained. Significantly low values (<25 nmol/l) were recorded in two (3.8%) patients and concentrations below 75 nmol/l were found in 34 (65.4%) patients. 25(OH)D levels were significantly lower among sun avoiders and daily sunscreen users, while significantly higher values were found among those who took cholecalciferol (vitamin D3) supplements. Low values were recorded among those with renal disease despite supplementation with vitamin D3 in some cases.

We suggest that patients with cutaneous lupus erythematous have suboptimal 25(OH)D levels, which are significantly raised by the addition of at least 400 IU/day of cholecalciferol. We recommend supplementation with an active vitamin D analogue in collaboration with a consultant nephrologist, for the subgroup of patients with renal disease.

Vitamin D(3) (cholecalciferol) sufficiency is essential for maximising bone health. Vitamin D enhances intestinal absorption of calcium and phosphorus. The major source of vitamin D for both children and adults is exposure of the skin to sunlight. Season, latitude, skin pigmentation, sunscreen use, clothing and aging can dramatically influence the synthesis of vitamin D in the skin. Very few foods naturally contain vitamin D or are fortified with vitamin D. Serum 25-hydroxyvitamin D [25(OH)D; calcifediol] is the best measure of vitamin D status. Vitamin D deficiency [as defined by a serum 25(OH)D level of <50 nmol/L (<20 ng/mL)] is pandemic. This deficiency is very prevalent in osteoporotic patients. Vitamin D deficiency causes osteopenia, osteoporosis and osteomalacia, increasing the risk of fracture. Unlike osteoporosis, which is a painless disease, osteomalacia causes aching bone pain that is often misdiagnosed as fibromyalgia or chronic pain syndrome or is simply dismissed as depression. Vitamin D deficiency causes muscle weakness, increasing the risk of falls and fractures, and should be aggressively treated with pharmacological doses of vitamin D. Vitamin D sufficiency can be sustained by sensible sun exposure or ingesting at least 800-1000 IU of vitamin D(3) daily. Patients being treated for osteoporosis should be adequately supplemented with calcium and vitamin D to maximise the benefit of treatment.

The fat-soluble vitamin D prohormones, ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), are essential for the efficient intestinal absorption of calcium and phosphate and the subsequent mineralization of bone. Inadequate vitamin D leads to chronic secondary hyperparathyroidism and osteoporosis. The increasing prevalence of osteoporosis has paralleled a pandemic of vitamin D insufficiency. Based on observational and prospective trials with clinical end points, the standards for vitamin D sufficiency have been recently revised. All patients with osteopenia or osteoporosis should be monitored with a reliable assay to maintain serum 25-hydroxyvitamin D levels more than 32 ng/dL. Patients who are taking bisphosphonates and those with coexisting primary hyperparathyroidism are not exempt from taking supplemental vitamin D.

Aging is a complex biological process driven by a selective class of molecules and pathways that affect overall deterioration of physiological functions to increase the risk of age-related diseases. A role of vitamin D in mammalian aging is well documented. Since vitamin D has an essential role in bone formation and mineralization, its deficiency results in impaired bone mineralization, such as rickets in children, osteomalacia in adults and osteoporosis in the aged population. Vitamin D replacement therapy therefore is one of the most commonly prescribed treatments for the elderly. Recent studies using genetically altered mouse models, such as in Fgf-23(-/-) and klotho mutant mice, that exhibit altered mineral ion metabolism due to high vitamin D activities showed features of premature aging that include atherosclerosis, emphysema, osteopenia/osteoporosis, hypogonadism, soft tissue calcifications and generalized atrophy of organs; the pathologic effects of vitamin D in these mouse models are obvious, as diminution or genetic ablation of the vitamin D pathway ameliorated most of the above-mentioned phenotypes, by reversing mineral ion metabolism, and the resultant effect being prolonged survival of the mutant mice. These in vivo mouse studies, although subject to further molecular characterization, add new insights into the role of vitamin D in aging.

The regulation of phosphate homeostasis was thought to be passively mediated by the calciotrophic hormones parathyroid hormone and 1,25(OH)2D3. This article summarizes the emerging trends that show an active regulation of phosphate homeostasis by fibroblast growth factor 23 (FGF-23) - a process fairly independent of calcium homeostasis - and how altered mineral ion metabolism may affect the aging process.

A major breakthrough in FGF-23 biology has been achieved by the demonstration of strikingly similar physical/biochemical phenotypes of Fgf-23(-/-) and klotho hypomorph mice, which eventually led to the identification of klotho as a cofactor in FGF-23 and its receptor interactions. Furthermore, FGF-23 has emerged as a counter regulator of the renal 1alpha(OH)ase and sodium-phosphate cotransporter activities to modulate phosphate homeostasis. Finally, studies point towards a role of dentine matrix protein 1 in affecting phosphate homeostasis, in coordination with FGF-23.

Recent mouse genetic studies have broadened our understanding of biochemical/molecular pathways involved in phosphate homeostasis, and linked FGF-23 to such regulation. Understanding the molecular interactions of essential calcium and phosphate regulators will enhance our knowledge of the coordinated regulation of mineral ion metabolism, and will help to redefine the molecular pathology of age-associated lesions accompanied by abnormal mineral ion metabolism such as vascular calcifications and osteoporosis.

The dose of vitamin D that some researchers recommend as optimally therapeutic exceeds that officially recognized as safe by a factor of two; it is therefore important to determine the precise mechanism by which excessive doses of vitamin D exert toxicity so that physicians and other health care practitioners may understand how to use optimally therapeutic doses of this vitamin without the risk of adverse effects. Although the toxicity of vitamin D has conventionally been attributed to its induction of hypercalcemia, animal studies show that the toxic endpoints observed in response to hypervitaminosis D such as anorexia, lethargy, growth retardation, bone resorption, soft tissue calcification, and death can be dissociated from the hypercalcemia that usually accompanies them, demanding that an alternative explanation for the mechanism of vitamin D toxicity be developed. The hypothesis presented in this paper proposes the novel understanding that vitamin D exerts toxicity by inducing a deficiency of vitamin K. According to this model, vitamin D increases the expression of proteins whose activation depends on vitamin K-mediated carboxylation; as the demand for carboxylation increases, the pool of vitamin K is depleted. Since vitamin K is essential to the nervous system and plays important roles in protecting against bone loss and calcification of the peripheral soft tissues, its deficiency results in the symptoms associated with hypervitaminosis D. This hypothesis is circumstantially supported by the observation that animals deficient in vitamin K or vitamin K-dependent proteins exhibit remarkable similarities to animals fed toxic doses of vitamin D, and the observation that vitamin D and the vitamin K-inhibitor Warfarin have similar toxicity profiles and exert toxicity synergistically when combined. The hypothesis further proposes that vitamin A protects against the toxicity of vitamin D by decreasing the expression of vitamin K-dependent proteins and thereby exerting a vitamin K-sparing effect. If animal experiments can confirm this hypothesis, the models by which the maximum safe dose is determined would need to be revised. Physicians and other health care practitioners would be able to treat patients with doses of vitamin D that possess greater therapeutic value than those currently being used while avoiding the risk of adverse effects by administering vitamin D together with vitamins A and K.

Vitamin D is a hormone responsible for calcium homeostasis and essential for bone mineralization throughout the lifespan. Recent studies revealed a high prevalence of hypovitaminosis D among healthy adults and children, especially in the northern hemisphere, and a link between this condition and suboptimal bone health. Moreover, maintenance of what are today considered optimal vitamin D stores has not been achieved throughout the year with currently recommended daily intake for vitamin D. The prevalence of hypovitaminosis D is even higher among adults with inflammatory bowel disease (IBD), a situation that may be caused by malabsorption and gastrointestinal losses through an inflamed intestine, among other factors. In children with IBD, existing reports of vitamin D status are scarce. The relationship between vitamin D status and bone health, although well-established in healthy adults and children, has been controversial among adults and children with IBD, and the reasons for this have not been investigated to date. Studies in animal models of colitis and in vitro human studies support a role of vitamin D in the regulation of the immune system of the gut and the potential of vitamin D and its derivatives as therapeutic adjuncts in the treatment of IBD. This role of vitamin D has not been investigated with translational studies to date. Currently, there are no guidelines for monitoring vitamin D status, treating hypovitaminosis D, and maintaining optimal vitamin D stores in patients with IBD. These tasks may prove particularly difficult because of malabsorption and gastrointestinal losses that are associated with IBD.

UV radiation is a well-documented human carcinogen, indisputably linked to the current continued increased rate of skin cancer. UV radiation is also responsible for cutaneous synthesis of vitamin (vit) D3, a substance that is then sequentially hydroxylated in the liver and kidney to yield 1,25(OH)2 vit D, a hormone critical for calcium homeostasis and skeletal maintenance. Because the UV action spectra for DNA damage leading to skin cancer and for vit D photosynthesis are virtually identical, the harmful and beneficial effects of UV irradiation are inseparable. This has given rise to the argument that sun avoidance, with a goal of skin cancer prevention, may compromise vit D sufficiency. Public interest in this matter has been heightened in recent years by multiple studies correlating the level of 25-OH vit D, the readily measurable "storage" precursor form of the vit, with a variety of benefits separate from skeletal health. Although the studies are of variable quality and all alleged treatment benefits are based on dietary supplementation with vit D, not on increased sun exposure, they have been interpreted by some as support for advocating increased sun exposure of the public at large. The goal of this review is to provide a detailed, balanced, and referenced discussion of the complex literature underlying the current popular interest in vit D and sun exposure for the purpose of increasing vit D photosynthesis. We review the nomenclature, metabolism, and established functions of vit D; the evidence supporting the less well-established but purported vit D effects; the concept of vit D insufficiency; populations at risk for vit D deficiency; and finally the risk/benefit of obtaining vit D from cutaneous photosynthesis versus diet or supplementation.

Most humans depend on sun exposure to satisfy their requirements for vitamin D. Solar ultraviolet B photons are absorbed by 7-dehydrocholesterol in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3. Season, latitude, time of day, skin pigmentation, aging, sunscreen use, and glass all influence the cutaneous production of vitamin D3. Once formed, vitamin D3 is metabolized in the liver to 25-hydroxyvitamin D3 and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D3. Vitamin D deficiency is an unrecognized epidemic among both children and adults in the United States. Vitamin D deficiency not only causes rickets among children but also precipitates and exacerbates osteoporosis among adults and causes the painful bone disease osteomalacia. Vitamin D deficiency has been associated with increased risks of deadly cancers, cardiovascular disease, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Maintaining blood concentrations of 25-hydroxyvitamin D above 80 nmol/L (approximately 30 ng/mL) not only is important for maximizing intestinal calcium absorption but also may be important for providing the extrarenal 1alpha-hydroxylase that is present in most tissues to produce 1,25-dihydroxyvitamin D3. Although chronic excessive exposure to sunlight increases the risk of nonmelanoma skin cancer, the avoidance of all direct sun exposure increases the risk of vitamin D deficiency, which can have serious consequences. Monitoring serum 25-hydroxyvitamin D concentrations yearly should help reveal vitamin D deficiencies. Sensible sun exposure (usually 5-10 min of exposure of the arms and legs or the hands, arms, and face, 2 or 3 times per week) and increased dietary and supplemental vitamin D intakes are reasonable approaches to guarantee vitamin D sufficiency.

To determine the heritability of low bone mineral density (BMD) at the hip in Ashkenazi Jewish families.

BMD at hip was accessed by dual x-ray absorptiometry (DEXA) in 166 female subjects from 61 families. Variance component analysis was used to estimate genetic contributions.

We observed significant genetic contributions to age-adjusted BMD at the femoral neck as measured by heritability 0.67 (P < 0.0001).

There is significant genetic determination in decreased BMD at the femoral neck in an Ashkenazi Jewish female population. These results warrant further gene mapping studies in this population to identify osteoporosis susceptibility loci.

The purpose of this review is to put into perspective the many health benefits of vitamin D and the role of vitamin D deficiency in increasing the risk of many common and serious diseases, including some common cancers, type 1 diabetes, cardiovascular disease, and osteoporosis. Numerous epidemiologic studies suggest that exposure to sunlight, which enhances the production of vitamin D(3) in the skin, is important in preventing many chronic diseases. Because very few foods naturally contain vitamin D, sunlight supplies most of our vitamin D requirement. 25-Hydroxyvitamin D [25(OH)D] is the metabolite that should be measured in the blood to determine vitamin D status. Vitamin D deficiency is prevalent in infants who are solely breastfed and who do not receive vitamin D supplementation and in adults of all ages who have increased skin pigmentation or who always wear sun protection or limit their outdoor activities. Vitamin D deficiency is often misdiagnosed as fibromyalgia. A new dietary source of vitamin D is orange juice fortified with vitamin D. Studies in both human and animal models add strength to the hypothesis that the unrecognized epidemic of vitamin D deficiency worldwide is a contributing factor of many chronic debilitating diseases. Greater awareness of the insidious consequences of vitamin D deficiency is needed. Annual measurement of serum 25(OH)D is a reasonable approach to monitoring for vitamin D deficiency. The recommended adequate intakes for vitamin D are inadequate, and, in the absence of exposure to sunlight, a minimum of 1000 IU vitamin D/d is required to maintain a healthy concentration of 25(OH)D in the blood.

The cholecalciferol inputs required to achieve or maintain any given serum 25-hydroxycholecalciferol concentration are not known, particularly within ranges comparable to the probable physiologic supply of the vitamin.

The objectives were to establish the quantitative relation between steady state cholecalciferol input and the resulting serum 25-hydroxycholecalciferol concentration and to estimate the proportion of the daily requirement during winter that is met by cholecalciferol reserves in body tissue stores.

Cholecalciferol was administered daily in controlled oral doses labeled at 0, 25, 125, and 250 micro g cholecalciferol for approximately 20 wk during the winter to 67 men living in Omaha (41.2 degrees N latitude). The time course of serum 25-hydroxycholecalciferol concentration was measured at intervals over the course of treatment.

From a mean baseline value of 70.3 nmol/L, equilibrium concentrations of serum 25-hydroxycholecalciferol changed during the winter months in direct proportion to the dose, with a slope of approximately 0.70 nmol/L for each additional 1 micro g cholecalciferol input. The calculated oral input required to sustain the serum 25-hydroxycholecalciferol concentration present before the study (ie, in the autumn) was 12.5 micro g (500 IU)/d, whereas the total amount from all sources (supplement, food, tissue stores) needed to sustain the starting 25-hydroxycholecalciferol concentration was estimated at approximately 96 micro g (approximately 3800 IU)/d. By difference, the tissue stores provided approximately 78-82 micro g/d.

Healthy men seem to use 3000-5000 IU cholecalciferol/d, apparently meeting > 80% of their winter cholecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. Current recommended vitamin D inputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence of substantial cutaneous production of vitamin D.