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- Vitamin D, steroid hormones, and autoimmunity. [JOURNAL ARTICLE]
- Ann N Y Acad Sci 2014 Apr 16.
The endogenous serum metabolite of vitamin D (calcitriol, 1,25(OH)2 D3 ) is considered a true steroid hormone (D hormone), and like glucocorticoids (GCs) and gonadal hormones, may exert several immunomodulatory activities. Serum vitamin D deficiency (25(OH) D), and therefore reduced 1,25(OH)2 D3 availability, is considered a risk factor for several chronic/inflammatory or autoimmune conditions, including infectious diseases, type 1 diabetes, multiple sclerosis, and especially autoimmune rheumatic diseases (ARD). In ARD in particular, 1,25(OH)2 D3 regulates both innate and adaptive immunity, potentiating the innate response (antimicrobial activity) but reducing adaptive immunity (antigen presentation, T and B cell activities). Regarding a possible synergism between vitamin D and GCs, several studies show that 1,25(OH)2 D3 has significant additive effects on dexamethasone-mediated inhibition of human lymphocyte and monocyte proliferation. Conversely, vitamin D deficiency seems to play a role in increasing autoantibody production by B cells, and seasonal vitamin D declines may trigger flares in ARD, as recently shown. Finally, 1,25(OH)2 D3 seems to reduce aromatase activity and limit the negative effects related to increased peripheral estrogen metabolism (cell proliferation, B cell overactivity).
- Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism - lack of effect of cinacalcet. [JOURNAL ARTICLE]
- Bone 2014 Apr 12.
NSHPT is a life threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice.To describe a case of NSHPT unresponsive to cinacalcet.A 23-day-old girl was admitted with hypercalcaemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75mmol/l (N: 2.10-2.62), P: 0.83mmol/l (1.55-2.64), PTH: 1096pg/ml (9-52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10IU/kg x 4/day) and then two days later, pamidronate (0.5mg/kg) for 2days. Doses of cinacalcet were given daily from day 28 of life starting at 30mg/m(2) and increasing to 90mg/m(2) on day 43. On day 33, 6days after pamidronate, serum Ca levels had fallen to 2.5mmol/l, but thereafter rose to 5mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18days. At 3months, the girl was mildly hypercalcemic, with no supplementation, and at 6months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation.The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.
- Management of osteoporosis with calcitriol in elderly Chinese patients: a systematic review. [REVIEW]
- Clin Interv Aging 2014.:515-526.
Osteoporosis, a skeletal disorder characterized by a reduction in bone strength, is becoming a major public health problem in the People's Republic of China, with a rapid increase observed among the population. Chinese guidelines particularly recommend use of active vitamin D in managing osteoporosis. 1,25-(OH)2D3 (calcitriol) is an active vitamin D metabolite. It plays a role in many biological processes, especially in bone metabolism and muscle function, and is mediated by vitamin D receptors. Osteoporosis in elderly men and women is characterized by uncoupled bone remodeling, which is induced by sex hormone deficiencies, somatopause, vitamin D deficiency, reduced synthesis of D hormone, and lack of receptors or receptor affinity for D hormone in target organs. Reviewed here are six randomized controlled trials on calcitriol monotherapy and five on calcitriol therapy combined with other antiosteoporotic agents. Evidence from these trials shows that calcitriol monotherapy can improve bone mineral density in elderly osteoporotic Chinese patients but may be insufficient for long-term treatment. Calcitriol can also decrease bone turnover markers and bring about significant improvements in muscle strength. Further, calcitriol in combination with other therapeutic bone agents was shown to be well tolerated and capable of additional bone-preserving effects compared with use of calcitriol alone in areas including bone mineral density, bone turnover markers, bone pain improvement, and fracture incidence. Hypercalcemia and hypercalciuria, the most common side effects of calcitriol therapy, were not documented in the trials reviewed, and might have been the result of the low dosages used. One study showed that treatment with calcitriol can improve quality of life in patients with osteoporosis, although not to the same extent as bisphosphonates.
- Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. [JOURNAL ARTICLE]
- Cochrane Database Syst Rev 2014 Apr 14.:CD000227.
Vitamin D and related compounds have been used to prevent osteoporotic fractures in older people. This is the third update of a Cochrane review first published in 1996.To determine the effects of vitamin D or related compounds, with or without calcium, for preventing fractures in post-menopausal women and older men.We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to December 2012), the Cochrane Central Register of Controlled Trials (2012, Issue 12), MEDLINE (1966 to November Week 3 2012), EMBASE (1980 to 2012 Week 50), CINAHL (1982 to December 2012), BIOSIS (1985 to 3 January 2013), Current Controlled Trials (December 2012) and reference lists of articles.Randomised or quasi-randomised trials that compared vitamin D or related compounds, alone or with calcium, against placebo, no intervention or calcium alone, and that reported fracture outcomes in older people. The primary outcome was hip fracture.Two authors independently assessed trial risk of selection bias and aspects of methodological quality, and extracted data. Data were pooled, where possible, using the fixed-effect model, or the random-effects model when heterogeneity between studies appeared substantial.We included 53 trials with a total of 91,791 participants. Thirty-one trials, with sample sizes ranging from 70 to 36,282 participants, examined vitamin D (including 25-hydroxy vitamin D) with or without calcium in the prevention of fractures in community, nursing home or hospital inpatient populations. Twelve of these 31 trials had participants with a mean or median age of 80 years or over.Another group of 22 smaller trials examined calcitriol or alfacalcidol (1-alphahydroxyvitamin D3), mostly with participants who had established osteoporosis. These trials were carried out in the setting of institutional referral clinics or hospitals.In the assessment of risk of bias for random sequence generation, 21 trials (40%) were deemed to be at low risk, 28 trials (53%) at unclear risk and four trials at high risk (8%). For allocation concealment, 22 trials were at low risk (42%), 29 trials were at unclear risk (55%) and two trials were at high risk (4%).There is high quality evidence that vitamin D alone, in the formats and doses tested, is unlikely to be effective in preventing hip fracture (11 trials, 27,693 participants; risk ratio (RR) 1.12, 95% confidence intervals (CI) 0.98 to 1.29) or any new fracture (15 trials, 28,271 participants; RR 1.03, 95% CI 0.96 to 1.11).There is high quality evidence that vitamin D plus calcium results in a small reduction in hip fracture risk (nine trials, 49,853 participants; RR 0.84, 95% confidence interval (CI) 0.74 to 0.96; P value 0.01). In low-risk populations (residents in the community: with an estimated eight hip fractures per 1000 per year), this equates to one fewer hip fracture per 1000 older adults per year (95% CI 0 to 2). In high risk populations (residents in institutions: with an estimated 54 hip fractures per 1000 per year), this equates to nine fewer hip fractures per 1000 older adults per year (95% CI 2 to 14). There is high quality evidence that vitamin D plus calcium is associated with a statistically significant reduction in incidence of new non-vertebral fractures. However, there is only moderate quality evidence of an absence of a statistically significant preventive effect on clinical vertebral fractures. There is high quality evidence that vitamin D plus calcium reduces the risk of any type of fracture (10 trials, 49,976 participants; RR 0.95, 95% CI 0.90 to 0.99).In terms of the results for adverse effects: mortality was not adversely affected by either vitamin D or vitamin D plus calcium supplementation (29 trials, 71,032 participants, RR 0.97, 95% CI 0.93 to 1.01). Hypercalcaemia, which was usually mild (2.6 to 2.8 mmol/L), was more common in people receiving vitamin D or an analogue, with or without calcium (21 trials, 17,124 participants, RR 2.28, 95% CI 1.57 to 3.31), especially for calcitriol (four trials, 988 participants, RR 4.41, 95% CI 2.14 to 9.09), than in people receiving placebo or control. There was also a small increased risk of gastrointestinal symptoms (15 trials, 47,761 participants, RR 1.04, 95% CI 1.00 to 1.08), especially for calcium plus vitamin D (four trials, 40,524 participants, RR 1.05, 95% CI 1.01 to 1.09), and a significant increase in renal disease (11 trials, 46,548 participants, RR 1.16, 95% CI 1.02 to 1.33). Other systematic reviews have found an increased association of myocardial infarction with supplemental calcium; and evidence of increased myocardial infarction and stroke, but decreased cancer, with supplemental calcium plus vitamin D, without an overall effect on mortality.Vitamin D alone is unlikely to prevent fractures in the doses and formulations tested so far in older people. Supplements of vitamin D and calcium may prevent hip or any type of fracture. There was a small but significant increase in gastrointestinal symptoms and renal disease associated with vitamin D and calcium. This review found that there was no increased risk of death from taking calcium and vitamin D.
- The effect of calcium with or without calcitriol supplementation on renal function in patients with hypovitaminosis d and chronic kidney disease. [Journal Article]
- Nephrourol Mon 2014 Jan; 6(1):e13381.
Hypovitaminosis D (serum 25-OHD < 30 ng/mL) is common in patients with chronic kidney disease (CKD). Vitamin D is believed to involve in the regulation of renin-angiotensin system and may be renoprotective.To compare the effects of calcium with or without calcitriol on renal function in patients with CKD.A prospective randomized trial was performed involving patients with stages 2-4 CKD and hypovitaminosis D. Baseline demographics data were taken at baseline. Patients were randomized equally into oral calcitriol plus calcium carbonate (calcitriol group) or calcium carbonate alone (non-calcitriol group). Serum levels of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D3 (1,25-(OH)2D), creatinine, calcium and urine protein creatinine index (uPCI) were measured at 6 and 12 weeks.Fifty (21 Female: 29 Male) patients with CKD with a median age of 53 (22-65) years were recruited. Their median MDRD eGFR (modification of diet in renal disease, estimation of glomerular filtration rate) was 36.0 (15-89) mL/min/1.73 m(2) with the CKD stage 2 (n = 8, 16%), stage 3 (n = 29, 58%), and stage 4 (n = 13, 26%) respectively. In both study groups serum 25-OHD levels were increased at 12 weeks (P = 0.001), in contrast to serum 1,25-(OH)2D levels which remained unchanged (P > 0.05), serum creatinine and uPCI were also remained unchanged until the end of study (P > 0.05 each). Patients with diabetes had higher serum creatinine (P = 0.01) and lower serum 1,25-(OH)2D (P = 0.02) at baseline. Regardless of the diabetics status, the serum 25-OHD was increased, and 1,25-(OH)2D remained unchanged at 12 weeks in both study groups. At 12 weeks, serum creatinine was decreased in patients with diabetes in the noncalcitriol group (P = 0.03) compared to stabilization of creatinine in the calcitriol group (P > 0.05). Serum calcium was increased, though it was still within the normal range in the calcitriol group (P < 0.001); whereas, in the noncalcitriol group, there was an initial reduction but increased back to baseline (P = 0.007). Urine PCI remained unchanged in both groups.We have demonstrated that calcitriol supplementation did not offer any additional benefit to reduce 25-OHD and 1,25-(OH)2D levels over calcium carbonate alone in patients with CKD in this short term study. Overall renal function remained unchanged. However, we found that calcitriol at 0.5 mg daily plus calcium carbonate 500 mg daily could be reno-protective in diabetic nephropathy regardless of their serum 25-OHD levels.
- The role of vitamin D in reducing cancer risk and progression. [JOURNAL ARTICLE]
- Nat Rev Cancer 2014 Apr 4.
Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.
- Immunomodulatory mechanisms of action of calcitriol in psoriasis. [Journal Article]
- Indian J Dermatol 2014 Mar; 59(2):116-22.
Calcitriol is well known for its therapeutic efficacy in psoriasis, but its mechanism of action is still unclear. In this study, we tried to elucidate the precise mechanism of calcitriol for its therapeutic efficacy in psoriasis.Proliferation and apoptosis studies were done to determine the effect of calcitriol on normal human epidermal keratinocytes (NHEKs) and T lymphocytes. To elucidate the effect of Calcitriol on relevant chemokines and epidermal proteins of psoriasis, real-time polymerase chain reaction were done on the modified reconstructed human epidermis (RHE) an in vitro model of psoriasis. All experiments were done in triplicate. Results were expressed as mean ± standard error of mean.In vitro, Calcitriol showed significant inhibition of NHEKs and T lymphocyte proliferation by inducing apoptosis of these cells. Moreover, in an in vitro model of psoriasis (RHE), Calcitriol significantly inhibited relevant gene expression of chemokines (Interleukin-8, Regulated upon Activation Normal T-cell Expressed and Secreted [RANTES]) and psoriasin (S100A7). Here, we observed that Calcitriol inhibits critical pathological events associated with the inflammatory-proliferative cascades of psoriasis. Calcitriol induced apoptosis of NHEKs and T lymphocytes as well as inhibited gene expression of relevant chemokines and epidermal proteins in the in vitro model of psoriasis.
- Suppression of IL-10 production by calcitriol in patients with multiple sclerosis. [JOURNAL ARTICLE]
- J Neuroimmunol 2014 Mar 18.
We investigated whether calcitriol (1,25-dihydroxyvitamin D) differentially modulates cytokine production by peripheral blood mononuclear cells from multiple sclerosis (MS) patients compared with that from healthy controls. In response to phytohemagglutinin (PHA) or lipopolysaccharide (LPS), cytokine level in a calcitriol-added sample was normalized to that in a calcitriol-absent sample, and this relative unit was compared. The relative unit of IL-12/23(p40) in LPS-stimulation was higher in MS patients. Moreover, the relative unit of IL-10 in PHA-stimulation was lower in MS patients, and negatively correlated with the Expanded Disability Status Scale. The anti-inflammatory response to vitamin D may be reduced in MS.
- Calcitriol enhances fat synthesis factors and calpain activity in co-cultured cells. [JOURNAL ARTICLE]
- Cell Biol Int 2014 Mar 31.
We have conducted an in vitro experiment to determine whether calcitriol can act as a fat synthesizer and/or meat tenderizer when skeletal muscle cells, adipose tissue, and macrophages are co-cultured. When co-cultured, pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) expression increased, whereas decreased anti-inflammatory cytokine (IL-10 and IL-15) expression decreased in both C2C12 and 3T3-L1 cells. Calcitriol increased reactive oxygen species (ROS) production in the media. While adiponectin gene expression decreased, leptin, resistin, CCAAT-enhancer-binding protein-beta (C/EBP-β), and peroxisome proliferator-activated receptor gamma (PPAR-γ) gene expression was significantly (P < 0.047) increased with calcitriol in 3T3-L1 cells co-cultured with two different cell types. Inducible nitric oxide synthase (iNOS) protein levels were also stimulated in the C2C12 and 3T3-L1 cells, but arginase l was attenuated by calcitriol. Cacitriol highly amplified (P = 0.008) µ-calpain gene expression in co-cultured C2C12 cells. The results showed an overall increase in pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines of C2C12 and 3T3-L1 cells with calcitriol in co-culture systems. µ-Calpain protein was also augmented in differentiated C2C12 cells with calcitriol. These findings suggest that calcitriol can be used as not only fat synthesizer, but meat tenderizer, in meat-producing animals.
- Impact of Vitamin D3 Dietary Supplement Matrix on Clinical Response. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2014 Mar 31.:jc20133162.
Context: As a result of research suggesting increased health risk with low serum 25-hydroxycholecalciferol (25(OH)D), healthcare providers are measuring it frequently. Providers and patients are faced with treatment choices when low status is identified. Objective: To compare the safety and efficacy of three vitamin D3 dietary supplements with different delivery matrices. Design & Setting: 12-week, parallel group, single-masked, clinical trial conducted in Seattle, WA and Kailua Kona, HI. Participants & Intervention: 66 healthy adults with (25(OH)D) < 33 ng/ml were randomly assigned to take one of three D3 supplements, i.e., a chewable tablet (TAB), an oil-based drop (DROP) or an encapsulated powder (CAP), at a label-claimed dose of 10,000 IU/day. Actual D3 content was assessed by a third-party, and the results adjusted based on the actual D3 content administered. Main Outcome Measures: mean change in 25(OH)D/mcg D3 administered; difference in the proportion of D3 insufficient participants (i.e., 25(OH)D ≤30ng/ml) reachingsufficiency (i.e., 25(OH)D ≥30ng/ml); and mean change in serum 1, 25-dihydroxycholecalciferol. Results: In two of the three products tested, the measured vitamin D3 content varied considerably from the label-claimed dose. Differences in 25(OH)D/mcg D3 administered were significantly different between groups (p=0.04; n=55). Pairwise comparisons demonstrated DROP resulted in a greater increase than TAB (p<0.05) but not than CAP. TAB was not different from CAP. The proportions reaching sufficiency were: 100% (TAB and CAP) and 80% (DROP) (p=0.03 between groups, n=55). 1, 25-dihydroxycholecalciferol did not change significantly in any group. Conclusions: Oil-emulsified vitamin D3 supplements resulted in a greater mean change in serum 25(OH)D concentration, but fewer patients reaching vitamin D sufficiency, than chewable or encapsulated supplements.