Vitamin D: do we get enough? Treatment of osteoporosis with 1-alpha-hydroxycholecalciferol and calcium. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Impact of cholecalciferol treatment on biomarkers of inflammation and myocardial structure in hemodialysis patients without hyperparathyroidism. The Effect of Calcium and Vitamin D3 Supplementation on the Healing of the Proximal Humerus Fracture: A Randomized Placebo-Controlled Study Effects of high-dose cholecalciferol on serum markers of inflammation and immunity in patients with early chronic kidney disease Effect of a 300 000-IU loading dose of ergocalciferol (Vitamin D2) on circulating 1,25(OH)2-vitamin D and fibroblast growth factor-23 (FGF-23) in vitamin D insufficiency. Linear growth in relation to the circulating concentrations of insulin-like growth factor I, parathyroid hormone, and 25-hydroxy vitamin D in children with nutritional rickets before and after treatment: endocrine adaptation to vitamin D deficiency. Calcium homeostasis influences radiological fracture healing in postmenopausal women Effect of 25-OH-vitamin D on fracture healing in elderly rats. Comparative Efficacy of Oral and Intravenous Calcitriol Treatment in Haemodialysis Patients: Effects on Serum Biochemistry and Cytokine Levels Comparison of effects of calcitriol and calcium carbonate on secretion of interleukin-1 beta and tumour necrosis factor-alpha by uraemic peripheral blood mononuclear cells. Effects of single high-dose vitamin D3 on fracture healing Cytokine profile in patients with multiple sclerosis following vitamin D supplementation Comparative Effect of Oral Pulse and Intravenous Calcitriol Treatment in Hemodialysis Patients: The Effect on Serum IL-1 and IL-6 Levels and Bone Mineral Density Cefazolin-sodium has no adverse effect on fracture healing in an experimental rabbit model. Experimental osteoporosis induced by ovariectomy and vitamin D deficiency does not markedly affect fracture healing in rats Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects. Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation Comparison of effects of alfacalcidol and alendronate on mechanical properties and bone collagen cross-links of callus in the fracture repair rat model. Effects of a short-term calcium and vitamin D treatment on serum cytokines, bone markers, insulin and lipid concentrations in healthy post-menopausal women Effect of 1,25-dihydroxy vitamin D3 on fracture healing and bone remodeling in ovariectomized rat femora. Insulin-like growth factor I, growth hormone, and insulin sensitivity: the effects of a one-year cholecalciferol supplementation in middle-aged overweight and obese subjects Effect of 1 alpha-hydroxyvitamin D3 treatment on production of tumor necrosis factor-alpha by peripheral blood mononuclear cells and on serum concentrations of soluble tumor necrosis factor receptors in hemodialysis patients.
Summary On September 29 , 2011 , acknowledged experts in the field of vitamin D , mainly European , were brought together in order to discuss the recent scientific advances in relation to vitamin D : the current requirements and associations with various health outcomes . In this article , the discussion s result ing from the meeting are summarized . Introduction Several groups at risk for developing vitamin D insufficiency have been identified . Accordingly , review s indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l . In addition to the role of vitamin D in bone health , recent studies suggest that it may play a pivotal role in other systems , e.g. , the cardiovascular system , pancreas , muscle , immune system and brain . Most evidence , however , is obtained from observational studies and yet inconclusive . Methods To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes , a workshop entitled “ Vitamin D Expert Meeting : Do we get enough ? ” , was organized . Results Despite low vitamin D levels worldwide , consensus on the definition of deficiency is not yet reached . In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects , r and omized controlled trials in these fields are warranted . The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation , in most studies co-administered with calcium , reduces fracture risk in the senior population . Conclusion To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 μg ( 800 IU ) , which is best achieved with a supplement A double-blind comparative study of 1 alpha-OHD3 and placebo was performed on 37 patients with osteoporotic hip fracture without clinical osteomalacia .  1 alpha-OHD3 , in a dose of 1 microgram/day together with 2.5 g CaCO3 , did not heal osteoporosis as judged from determinations of bone mineral density and histomorphometric analyses during four months of treatment . However , 1 alpha-OHD3 seemed to have an effect on fracture healing as concluded from the posttreatment alkaline phosphatase level . Hypercalcemia was common , occurring in six out of 19 patients treated with 1 alpha-OHD3 . It is concluded that treatment of osteoporosis with 1 alpha-OHD3 and calcium is ineffective and potentially dangerous because it frequently causes hypercalcemia BACKGROUND Elevated circulating concentrations of proinflammatory cytokines may contribute to the pathogenesis of congestive heart failure ( CHF ) . In vitro studies suggest that vitamin D suppresses proinflammatory cytokines and increases antiinflammatory cytokines . OBJECTIVE We evaluated the effect of vitamin D supplementation on the survival rate and different biochemical variables in patients with CHF . DESIGN One hundred twenty-three patients r and omly received either 50 mug vitamin D(3)/d plus 500 mg Ca/d [ D(+ ) group ] or placebo plus 500 mg Ca/d [ D(- ) group ] for 9 mo . Biochemical variables were assessed at baseline and after 9 mo . The survival rate was calculated for a follow-up period of 15 mo . RESULTS Ninety-three patients completed the study . Significant treatment effects were observed on logarithmic-transformed serum concentrations of 25-hydroxyvitamin D ( P = 0.001 ) , parathyroid hormone ( P = 0.007 ) , tumor necrosis factor alpha ( P = 0.006 ) , and interleukin 10 ( P = 0.042 ) . 25-Hydroxyvitamin D increased by 26.8 ng/mL in the D(+ ) group but increased only by 3.6 ng/mL in the D(- ) group . Compared with baseline , parathyroid hormone was significantly lower and the antiinflammatory cytokine interleukin 10 was significantly higher in the D(+ ) group after 9 mo . The proinflammatory cytokine tumor necrosis factor alpha increased in the D(- ) group but remained constant in the D(+ ) group . The survival rate did not differ significantly between the study groups during the follow-up period . CONCLUSIONS Vitamin D(3 ) reduces the inflammatory milieu in CHF patients and might serve as a new antiinflammatory agent for the future treatment of the disease . Our data provide evidence for the involvement of an impaired vitamin D-parathyroid hormone axis in the progression of CHF INTRODUCTION Vitamin D ( 25-hydroxyvitamin D , 25(OH)D ) deficiency , hypovitaminosis D , is highly prevalent in chronic kidney disease patients and is potentially involved with complications in the hemodialysis ( HD ) population . The aim of this study was to evaluate the impact of cholecalciferol supplementation on biomarkers of mineral metabolism , inflammation , and cardiac function in a group of HD patients presenting with hypovitaminosis D and low intact parathyroid hormone ( iPTH ) levels . MATERIAL AND METHODS HD patients with iPTH levels of < 300 pg/mL , not receiving vitamin D therapy , and presenting with 25(OH)D levels of < 30 ng/mL were enrolled in this prospect i ve study . Oral cholecalciferol was prescribed once a week in the first 12 weeks ( 50,000 IU ) and in the last 12 weeks ( 20,000 IU ) of the study . High-sensitivity C-reactive protein , interleukin-6 , and serum albumin were used as inflammatory markers .  Echocardiograms were performed on a midweek interdialytic day at baseline and after 6 months of cholecalciferol supplementation . RESULTS In all , 30 patients were included in the final analysis . We observed a significant increase in serum 25(OH)D levels after 3 months ( 46.2 ± 14.4 ng/mL vs. 18.1 ± 6.6 ng/mL ; P < .001 ) and after 6 months ( 40.4 ± 10.4 ng/mL vs. 18.1 ± 6.6 ng/mL ; P < .001 ) of cholecalciferol supplementation . There were no significant changes in alkaline phosphatase , iPTH , phosphorus , and serum albumin levels , but there was a slight but significant increase in calcium levels after 6 months of cholecalciferol supplementation ( 9.4 ± 0.6 mg/dL vs. 9.0 ± 0.6 mg/dL ; P = .02 ) . Additionally , we observed a significant reduction in high-sensitivity C-reactive protein levels after 3 months ( median : 0.62 [ 0.05 to 29.6 ] mg/L vs. 0.32 [ 0.02 to 3.13 ] mg/L ; P = .02 ) and after 6 months ( median : 0.62 [ 0.05 to 29.6 ] mg/L vs. 0.50 [ 0.02 to 5.66 ] mg/L ; P = .04 ) of cholecalciferol supplementation , as well as a significant reduction in interleukin-6 levels ( median : 6.44 pg/mL vs. 3.83 pg/mL ; P = .018 ) after 6 months of supplementation . Left ventricular mass index was significantly reduced at the end of supplementation ( 159 ± 55 g/m(2 ) vs. 175 ± 63 g/m(2 ) ; P = .03 ) . CONCLUSIONS Cholecalciferol supplementation in HD patients was found to be safe and efficient to correct hypovitaminosis D and established little impact on mineral metabolism markers . Additionally , we observed a reduction in important surrogate markers of cardiovascular risk , namely systemic inflammation and left ventricular hypertrophy , suggesting an anti-inflammatory action and possibly an improvement of cardiac dysfunction The purpose of this study was to ( 1 ) quantify the healing process of the human osteoporotic proximal humerus fracture ( PHF ) expressed in terms of callus formation over the fracture region using BMD scanning , and ( 2 ) quantify the impact of medical intervention with vitamin D3 and calcium on the healing process of the human osteoporotic fracture . The conservatively treated PHF was chosen in order to follow the genuine fracture healing without influence of osteosynthetic material s or casts . Thirty women ( mean age = 78 years ; range = 58–88 ) with a PHF , osteoporosis or osteopenia ( based on a hip scan , WHO criteria ) , and not taking any drugs related to bone formation , including calcium or vitamin D supplementation  , were r and omly assigned to either oral 800 IU vitamin D3 plus 1 g calcium or placebo , in a double-blind prospect i ve study . We measured biochemical , radiographic , and bone mineral density effect parameters to evaluate the impact on the healing process . Scanning procedures of the fractured shoulder included use of a fixation device to obtain the highest possible precision . Double scans of the fractured shoulder revealed a coefficient of variation ( CV ) on BMD measurements that improved from 2.8 % immediately after fracture occurrence to 1.7 % at 12 weeks ( P = 0.003 ) approaching the 1.2 % levels observed over the healthy shoulder . BMD was similar in the two groups at baseline ( active 0.534 g/cm2 vs. placebo 0.518 g/cm2 ) , and both increased over the 12-week observation period , with peak levels in week 6 . By week 6 BMD levels were higher in the active group ( 0.623 g/cm2 ) compared with the placebo group ( 0.570 g/cm2 , P = 0.006 ) . Thirty seven percent of the patients presented with vitamin D levels below 30 nmol/l , indicative of mild vitamin D insufficiency . In conclusion , we have demonstrated that it is possible to quantify callus formation of the PHF with sufficiently high precision to demonstrate the positive influence of vitamin D3 and calcium over the first 6 weeks after fracture . Whether this results in more stable fractures , extends to other fracture types , or applies to other osteogenic bone agents such as bisphosphonates remains to be examined Background / objectives : Vitamin D has anti-inflammatory and immune-regulating properties . We aim ed to determine if high-dose cholecalciferol supplementation for 1 year in subjects with early chronic kidney disease ( CKD ) improved circulating markers of inflammation and immunity . Subjects/ methods : In this double-blind , r and omized , placebo-controlled trial , 46 subjects with early CKD ( stages 2 and 3 ) were supplemented with oral cholecalciferol ( 50 000 IU weekly for 12 weeks followed by 50 000 IU every other week for 40 weeks ) or a matching placebo for 1 year . Serum tumor necrosis factor-α , interleukin-6 , monocyte chemoattractant protein-1 ( MCP-1 ) , interferon gamma-induced protein-10 and neutrophil gelatinase-associated lipocalin were measured at baseline , 12 weeks and 1 year . Serum cathelicidin ( LL-37 ) was measured at baseline and 12 weeks . An in vitro experiment was performed to investigate the effect of 1,25-dihydroxyvitamin D3 ( 1,25(OH)2D3 ) treatment on MCP-1 secretion in THP-1 monocytes activated with lipopolysaccharide ( LPS ) and Pseudomonas aeruginosa . Results : By 12 weeks , serum MCP-1 decreased in the cholecalciferol group ( 66.2±2.5 to 60.8±2.6 pg/ml , group-by-time interaction P=0.02 ) but was not different from baseline at 1 year . Other markers of inflammation and immunity did not change . In vitro , LPS- and Pseudomonas-activated monocytes treated with 1,25(OH)2D3 had significantly less MCP-1 secretion compared with untreated cells . Conclusions : High-dose cholecalciferol  decreased serum MCP-1 concentrations by 12 weeks in patients with early CKD , although the decrease was not maintained for the remainder of the year . In vitro results confirm an MCP-1-lowering effect of vitamin D. Future studies should determine if vitamin D-mediated reductions in MCP-1 concentrations reflect improved clinical outcomes CONTEXT Several trials have reported an increased risk of fractures and falls after intermittent high-dose vitamin D. Treatment with loading doses of vitamin D may increase 1,25(OH)(2 ) vitamin D catabolism through changes in calcium/phosphate homeostasis and fibroblast growth factor-23 ( FGF-23 ) . OBJECTIVE The aim was to determine the effects of high-dose vitamin D on circulating concentrations of 1,25(OH)(2 ) vitamin D and FGF-23 in patients with osteoporosis and vitamin D insufficiency . DESIGN , SETTING , PATIENTS , AND INTERVENTION We carried out a prospect i ve study of 45 subjects with vitamin D deficiency/insufficiency treated with a bolus dose of 300 000 IU of vitamin D(2 ) i m . Blood sample s were obtained at baseline and 1 , 2 , and 3 months after treatment . OUTCOME MEASURES Changes in 1,25(OH)(2)-vitamin D and FGF-23 were measured . RESULTS Loading dose of vitamin D(2 ) increased 1,25(OH)(2)-vitamin D(2 ) at 3 months , with a mean [ SD ] of 41 [ 56 ] pmol/L at baseline and 162.3 [ 137.8 ] pmol/L at 3 months ( P < .001 ) . FGF-23 increased significantly at all time points with a peak at 3 months , with percent change from baseline ( mean [ SEM ] ) of 50 % [ 48 % ] at 3 months ( P < .01 ) . There was a positive correlation between FGF-23 and serum phosphate ( r = 0.36 , P = .024 ) and calcium ( r = 0.532 , P < .001 ) and a negative correlation between total 1,25(OH)(2)-vitamin D and FGF-23 ( r = -0.32 , P = .036 ) at 3 months . CONCLUSIONS High-dose vitamin D increases 1,25(OH)(2)-vitamin D and FGF-23 concentration . Further studies are required to determine whether adjusting vitamin D dose and frequency to minimize increases in FGF-23 may prevent the adverse outcomes associated with high-dose intermittent vitamin D supplementation The objective of the study was to determine the degree of linear growth retardation of patients with vitamin D deficiency rickets at presentation and the magnitude of catch-up growth in relation to their calcium ( Ca ) homeostasis and hormones affecting it before and after treatment . This prospect i ve study recorded the anthropometric data and measured the circulating 25-hydroxy vitamin D ( 25-OH-D ) , insulin-like growth factor I ( IGF-I ) , parathyroid hormone , Ca , phosphate , and alkaline phosphatase concentrations in 46 infants and children with nutritional ( vitamin D deficiency ) rickets before and 6 months or more after treatment with one intramuscular injection of vitamin D3 megadose ( 300000 IU ) . Forty normal age- and sex-matched children were included as controls for the auxological data . At presentation , patients ' mean age = 13.1 + /- 1.1 months , length st and ard deviation scores ( LSDS ) = -1.5 + /- 0.2 , and body mass index = 16.3 + /- 0.85 . They were significantly shorter and had markedly lower growth velocity st and ard deviation scores ( GVSDS ) compared with normal controls ( LSDS = 0.25 + /- 0.18 and 0.31 + /- 0.22 , respectively ) . Six months after treatment , the LSDS increased significantly in patients to -0.45 + /- 0.13 , with a significantly increased GVSDS ( 2.76 + /- 0.45 ) and body mass index ( 16.9 + /- 0.65 ) . They were still shorter but with significantly higher GVSDS compared with normal controls . Serum Ca and phosphate concentrations increased from 2.07 + /- 0.25 and 1.23 + /- 0.24 mmol/L , respectively , before treatment to 2.44 + /- 0.2 and 1.94 + /- 0.2 mmol/L , respectively , after treatment . Serum alkaline phosphatase and parathyroid hormone concentrations decreased from 1183 + /- 219 U/L and 294 + /- 87 pg/mL , respectively , before treatment to 334 + /- 75 U/L and 35.2 + /- 15.2 pg/mL , respectively , after treatment . The 25-OH-D level increased from 4.5 + /- 0.56 ng/mL before treatment to 44.5 + /- 3.7 ng/mL after treatment . Circulating concentrations of IGF-I increased significantly after treatment ( 52.2 + /- 18.9 ng/mL ) vs before treatment ( 26.6 + /- 12.8 ng/mL ) . The 25-OH-D concentrations were correlated significantly with the IGF-I levels before and after treatment ( r = 0.603 and r = 0.59 , respectively ; P < .001 ) . The GVSDS after treatment was correlated with the increase of IGF-I and 25-OH-D levels ( r = 0.325 and r= 0.314 , respectively ; P < .01 ) . These data denote that the accelerated linear growth after treatment of nutritional vitamin D deficiency is mediated through activation of the growth hormone/IGF-I system and suggests an important role of vitamin D as a link between the proliferating cartilage cells of the growth plate and growth hormone/IGF-I secretion . Three different sequential stages of vitamin D deficiency can be recognized according to the clinical /radiological , biochemical , and hormonal data of patients at presentation Introduction Recent studies suggest that calcium and 25-[OH]-cholecalciferol represent substantial co-factors in fracture healing . However , there still seems to be no sustainable consensus regarding the influence on fracture healing patterns . In this study , the influence of calcium and vitamin D levels on fracture callus formation was prospect ively analysed using pQCT scan . Methods 94 postmenopausal females with distal radius fractures and consecutive surgery were included .  Calcium , 25-[OH]-cholecalciferol , parathyroid hormone and bone-specific alkaline phosphatase levels were obtained prior surgical treatment and after 6 weeks . A pQCT scan was performed on both sites . Bone mineral density and fracture callus area were determined after detecting the outer border contour at a threshold of 280 mg/ccm . Patients received daily supplements of 1000 mg calcium and 880 IU 25-[OH]-cholecalciferol .  Results Mean 25-[OH]-cholecalciferol level was 19.61 ± 21.87 ng/ml , mean parathyroid hormone level was 52.6 ± 58.9 ng/l and mean Ca level was 2.23 ± 0.35 mmol/l . After 6 weeks of supplementation a significant increase of calcium ( p < 0.001 ) and 25-[OH]-cholecalciferol ( p < 0.001 ) , and a significant decrease of parathyroid hormone ( p < 0.001 ) levels were observed . Sixth week follow-up fracture callus area correlated significantly with postoperative normal range calcium levels on the fractured site ( p = 0.006 ) . Bone mineral density correlated with age ( p < 0.001 ) , but not with calcium and 25-[OH]-cholecalciferol levels after 6 weeks . All fractures presented timely adequate callus formation . Conclusion Calcium and parathyroid hormone serum levels influence fracture callus area interpreted as fracture callus formation patterns . Calcium levels within physiological range accounted for highest fracture callus area . Therefore , a balanced calcium homeostasis is required for appropriate callus formation To investigate the effect of 25-OH-vitamin D supplements ( calcidiol ) on fracture healing in the elderly , an experimental model with 15 18-month-old female Wistar rats was design ed . An experimental fracture in the middle third of both femora of each rat was made . Then the rats were r and omly assigned to two groups : one group was subcutaneously treated with 25-OH-vitamin D during all healing processes , and the other group ( the control group ) was not . After 5 weeks of healing , the animals were killed and both femora were extracted . Blood sample s were collected before fracture and at death to determine the levels of 25-OH-vitamin D.  All bones that were extracted were subjected to a torsion test to assess healing ; a significantly greater maximum shear force before failure was supported in the treated group ( p < 0.01 ) . Moreover , a positive correlation ( p < 0.01 ; r=0.55 ) was found between blood levels of 25-OH-vitamin D at death and the mechanical strength of the callus . Thus , the administration of 25-OH-vitamin D after the experimental fracture significantly improved the mechanical strength of the fractured bone . If similar results are found in the human , then treatment with 25-OH-vitamin D after the occurrence of a fracture would be a good way to improve  fracture healing  in the elderly This study compared the effects of oral and intravenous calcitriol on serum biochemistry parameters and levels of bone-resorptive cytokines in haemodialysis patients . Patients were r and omized to receive oral ( n = 18 ) or intravenous ( n = 16 ) calcitriol treatment for 6 months . Serum levels of total calcium , ionized calcium , intact parathyroid hormone ( iPTH ) , magnesium , alkaline phosphatase , tumour necrosis factor-α ( TNF-α ) , interleukin (IL)-1 and IL-6 were measured at baseline and after 3 and 6 months of treatment . After treatment , serum levels of iPTH , total calcium , ionized calcium , TNF-α , IL-1 and IL-6 were not significantly different from baseline . The intravenous calcitriol treatment group showed significant decreases in levels of iPTH , TNF-α , IL-1 and IL-6 and a significant increase in total calcium level after 3 and 6 months . There was no significant change in serum ionized calcium levels . Significantly decreased serum alkaline phosphatase and magnesium levels were found in both treatment groups after 3 and 6 months . In conclusion , intravenous calcitriol treatment has a significant depressive effect on iPTH and bone-resorptive cytokines in patients undergoing haemodialysis We studied 26 non-dialysed patients with chronic renal failure [ creatinine clearance ( CCr ) 32.6 + /- 12.7 ml/min ] . They were divided into three groups according to their CCr and serum intact parathyroid hormone ( PTH ) and were given 0.5 micrograms/day oral calcitriol ( calcitriol group , n = 8) , 3 g/day calcium carbonate ( CaCO3 group , n = 10 ) , or neither ( control uraemic group , n = 8) .  Serum intact PTH decreased from 154 + /- 75 to 90 + /- 43 pg/ml in the calcitriol group ( P < 0.01 ) and from 162 + /- 97 to 77 + /- 62 pg/ml in the CaCO3 group ( P < 0.001 ) . Calcium carbonate was also effective in suppressing serum tartrate-resistant acid phosphatase , alkaline phosphatase and intact osteocalcin levels , while calcitriol did not suppress serum osteocalcin . Secretion of interleukin-1 beta ( IL-1 beta ) and tumour necrosis factor-alpha ( TNF-alpha ) by phytohaemagglutinin A (PHA)-activated peripheral blood mononuclear cells ( P BMC ) was greater in uraemic patients than in age-matched healthy controls ( n = 8) . Calcitriol was effective in suppressing secretion of both cytokines , while calcium carbonate was capable of suppressing only TNF-alpha secretion . CCr decreased from 37.4 + /- 15.4 to 33.0 + /- 11.8 ml/min ( P < 0.05 ) in the CaCO3 group , while it did not decrease in either the calcitriol group or the control uraemic group during a 6 month period . These results suggest that supplementation with calcitriol is necessary to maintain bone formation and normalize IL-1 beta and TNF-alpha secretion by activated P BMC in uraemic patients The benefits of vitamin D3 on fracture healing have been commonly demonstrated in vitamin-D3-depleted animal models . The aim of this study was to examine the effects of a single high dose of vitamin D3 on fracture healing in a healthy animal model , which has not been previously reported . Twenty healthy young adult guinea pigs were r and omly divided into two groups as ‘ control ’ and ‘ vitamin D ’ , and their right tibias were fractured with digital manipulation . Guinea pigs in vitamin D group were injected intramuscularly with 50000 IU/kg of vitamin D3 . The animals were killed at 7 , 14 , 21 and 28 days following fracture . Ultrastructural analysis of the harvested tibias revealed that a single high dose of vitamin D3 stimulated fracture healing . The observed effects at the fracture zone in a healthy animal model included advancement of blood supply , acceleration of synthesis and organization of collagen fibres , acceleration of the proliferation and differentiation of osteoprogenitor cells , and activation of the mineralization of the matrix Multiple sclerosis ( MS ) patients were r and omized , in a double blind design , and placed into either a vitamin D supplemented group or a placebo control group . As expected , serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation ( 17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months ) . Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later . Placebo treatment had no effect on serum TGF-beta 1 levels . Tumor necrosis factor (TNF)-alpha , interferon (IFN)-gamma , and interleukin (IL)-13 were not different following vitamin D supplementation . IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance . Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1 Introduction : Increased serum levels of bone-resorptive cytokines such as interleukin-1β ( IL-1β ) and interleukin-6 ( IL-6 ) have been implicated for changes in bone remodeling in hemodialysis patients . In this prospect i ve r and omized study , we aim ed to compare the effect of oral and intravenous ( IV ) pulse calcitriol on serum levels of IL-1β and IL-6 . Patients and Methods : Twenty-eight hemodialysis patients were included and consecutively r and omized to receive either oral ( n = 14 , M/F = 7/7 , mean age 42 ± 15 years ) or IV pulse ( n = 14 , M/F = 6/8 , mean age 38 ± 14 years ) calcitriol treatment . No difference was found between groups for age , sex distribution , primary renal disease , mean time on hemodialysis and baseline biochemical parameters including serum levels of IL-1β and IL-6 . Results : The percent fall of intact parathyroid hormone ( iPTH ) was significantly less with oral compared to IV calcitriol between 0 and the 3rd month ( 32 ± 21 vs. 56 ± 28 % , p = 0.03 ) . However , the percent fall in iPTH at the 6th month of the therapy was not different in the oral group compared to the IV group ( 57 ± 22 vs. 73 ± 24 % , p = 0.12 ) . The increase in bone mineral densities was higher in the IV group than the oral group . Oral and IV calcitriol caused a significant fall in IL-1β ( p = 0.02 and p = 0.03 , respectively ) and IL-6 levels ( p = 0.02 and p < 0.001 , respectively ) at the 6th month of treatment . The percent fall in serum IL-6 levels at the 6th month was significantly greater in the IV compared to the oral group ( 61 ± 18 vs. 36 ± 33 % , p = 0.04 ) , while the percent changes in serum IL-1β levels were similar . Conclusion : IV calcitriol therapy has a greater suppression of PTH at the 3rd month of the therapy . Despite no difference in serum PTH levels at the 6th month , IV therapy has a greater increase in bone mineral densities and a greater decrease in serum IL-6 levels . These findings suggest IV calcitriol treatment has a superior effect on bone remodeling by influencing the levels of bone-resorptive cytokines as compared to the oral therapy group , beyond its suppressive effect on iPTH OBJECTIVES This study aims to investigate whether cefazolin-sodium has any adverse effect on fracture healing in an experimental rabbit model . MATERIAL S AND METHODS The study was performed on 50 male New-Zeal and white rabbits . Under general anesthesia , closed double fracture of middle one-third of the tibia-fibula of the left lower extremity of the subjects was produced by manual compression followed by closed reduction of fracture and long leg circular cast was applied . Subjects were divided r and omly into five groups including 10 rabbits in each group . The first and second group were administered ciprofloxacin 50 mg/kg SC bid and cefazolin-sodium 50 mg/kg IM on the seventh day of fracture . The third group was applied a single high-dose of vitamin D ( 50.000 IU/kg ) IM following fracture . The fourth group was applied daily vitamin E ( alpha tocopherol ) 20 mg/kg IM for five days from one hour before the production of fracture . Control group did not receive any treatment before and after fracture . Initial and control X-ray examinations were performed immediately and four weeks after production of fracture , respectively . At the end of the fourth week , animals were sacrificed and a histological examination of the fracture site was performed . RESULTS Histological evaluation showed that the histological grade of the fracture healing was significantly lower in the ciprofloxacin group , while it was significantly higher in the cefazolin-sodium , vitamin D and vitamin E groups , compared to control group ( p<0.005 ) . CONCLUSION Significantly improved histological grade of the fracture healing in subjects treated with cefazolin-sodium than controls suggest that it may be reasonable to choose cefazolin-sodium as an antibiotic therapy for the treatment of infection in patients with bone fractures Background The question of whether fracture healing and mechanical properties of the callus are influenced by osteoporosis ( OP ) is still not settled . We therefore studied this issue in vitamin D-depleted ovariectomized ( OVX ) rats , an OP model previously shown to induce weakening of the femoral neck , and thus thought to be closer to the human condition than the classic OVX rat model . Methods 72 female Wistar rats were r and omized into two groups : ovariectomy and vitamin D-deficient diet ( Ovx-D group ) or sham operation and normal rat chow ( Sham group ) . After 12 weeks , a closed tibial midshaft fracture was performed on the right side and fixed with an intramedullary nail . Bone loss and callus formation were monitored with DXA ; serum levels of estradiol and vitamin D3 were measured and histomorphometric analyses were performed . Mechanical properties of callus , tibia , femoral shaft , and femoral neck were examined in 3-point cantilever bending 6 weeks after fracture . Results The Ovx-D group showed reduced BMD in the spine and femoral neck , and reduced trabecular bone volume in the femoral head . There were no differences in BMD and mechanical properties of callus between the groups . Except for reduced stiffness of the right femoral neck in the Ovx-D group ( p = 0.02 ) , no differences in the mechanical strength of long bones were detected . Interpretation Our results suggest that the systemic effects of estrogen and vitamin D deficiency are not crucial for fracture healing or mechanical properties of the callus Insufficient vitamin D status has been linked to autoimmune diseases , cancer and metabolic disorders , like obesity and insulin resistance . In vitro and animal studies suggest that vitamin D may play a crucial role in immune activation and inflammation . The relation between vitamin D and pro-inflammatory cytokines is not completely established . Furthermore , it is not known if the effect of vitamin D on entities of metabolic syndrome is mediated through its effect on cytokines or other biomarkers . The objectives of this study were to investigate if there is a relationship between vitamin D status and such pro-inflammatory cytokines as tumor necrosis factor-alpha ( TNF-α ) , interleukin 6 ( IL-6 ) and high sensitive C-reactive protein ( hs-CRP ) in patients with overweigh and obesity . We also proposed that the intervention with high dose of cholecalciferol may have effect on the cytokine levels and result in corresponding changes in the measures of insulin resistance ( HOMA-IR and QUICKI ) . Serum levels of IL-6 , TNF-α and hs-CRP were measured in 332 overweight and obese subjects who completed a 1-year r and omised intervention with either 40,000 IU vitamin D ( cholecalciferol ) per week or 20,000 IU vitamin D per week  ,  or placebo .  We found significant associations between IL-6 , TNF-α , vitamin D and insulin resistance indices at baseline . One year intervention with vitamin D  decreased serum IL-6 levels ; however hs-CRP levels were significantly increased . Neither measures of insulin resistance , nor TNF-α were influenced by a 1-year vitamin D supplementation Patients with cystic fibrosis ( CF ) suffer from chronic lung infection and inflammation leading to respiratory failure . Vitamin D deficiency is common in patients with CF , and correction of vitamin D deficiency may improve innate immunity and reduce inflammation in patients with CF . We conducted a double-blinded , placebo-controlled , r and omized clinical trial of high-dose vitamin D to assess the impact of vitamin D therapy on antimicrobial peptide concentrations and markers of inflammation . We r and omized 30 adults with CF hospitalized with a pulmonary exacerbation to 250 000 IU of cholecalciferol or placebo  , and evaluated changes in plasma concentrations of inflammatory markers and the antimicrobial peptide LL-37 at baseline and 12 weeks post intervention . In the vitamin D group , there was a 50.4 % reduction in tumor necrosis factor-α ( TNF-α ) at 12 weeks ( P<0.01 ) , and there was a trend for a 64.5 % reduction in interleukin-6 ( IL-6 ) ( P=0.09 ) . There were no significant changes in IL-1β , IL-8 , IL-10 , IL-18BP and NGAL ( neutrophil gelatinase-associated lipocalin ) . We conclude that a large bolus dose of vitamin D is associated with reductions in two inflammatory cytokines , IL-6 and TNF-α . This study supports the concept that vitamin D may help regulate inflammation in CF , and that further research is needed to eluci date the potential mechanisms involved and the impact on clinical outcomes Both bone density and quality are important determinants of bone strength . Bone quality is prescribed by matrix characteristic including collagen cross-linking and bone structural characteristics and is important in reinforcement of bone strength . We investigated the effects of alfacalcidol ( ALF ) , a prodrug of calcitriol , and alendronate ( ALN ) , a bisphosphanate , on the mechanical properties and content of enzymatic cross-links in femoral bone using a fracture repair rat model . Forty 3-month-old female Wistar-Imamichi rats were r and omized into 4 groups : SHAM ( sham-operated+vehicle ) , OVX ( ovariectomy+vehicle ) , ALF ( ovariectomy+ALF , 0.1 microg/kg/d , p.o . ) and ALN ( ovariectomy+ALN , 10 microg/kg/d , s.c . ) . Treatment began immediately after SHAM or OVX surgery . Three weeks later , all animals underwent transverse osteotomies at the midshaft of the left femur . Treatment was continued and rats were sacrificed at 12 weeks post-fracture for evaluation by X-ray radiography , micro-CT , pQCT , biomechanical testing and bone histomorphometry . In the ALN group , no new cortical shell appeared and the callus diameter was significantly larger than in the OVX group ( p<0.05 ) . Stiffness of fractured callus in the ALF group , but not in the ALN group , was significantly higher than in the OVX group . Young 's modulus in the ALN group was significantly decreased compared to the OVX group . Moreover , micro-CT analysis showed that ALN treatment increased the lowly mineralized bone in the callus by , result ing in the highest content of woven bone area and lowest content of lamellar bone . The total amount of enzymatic cross-links in both the ALF and ALN groups was significantly higher than in the OVX control group . Of particular interest , the Pyr-to-Dpyr ratio was significantly decreased by ALF administration , suggesting that ALF but not ALN normalized the enzymatic cross-link patterns in fractured bone to the control level . In conclusion , ALN and ALF treatment increased bone strength via the distinctive effect on bone mass and quality .  ALN formed larger calluses and increased enzymatic cross-links despite delayed woven bone remodeling into lamellar bone , whereas ALF treatment induced lamellar bone formation coincided with increasing in the enzymatic cross-linking and normalizing the cross-link pattern in callus to native bone pattern In vitro studies have shown that 1,25 dihydroxyvitamin D3 [ 1,25(OH)2D3 ] decreases cytokine production by monocytes and lymphocytes . In addition , intravenous or oral pulse calcitriol treatment suppresses interleukin 6 ( IL6 ) and interleukin1ß ( IL1ß ) in hemodialysis patients . We studied the effect of a daily 12-week course of 1000 mg calcium and 800 U cholecalciferol on circulating 25 hydroxyvitamin D [ 25(OH)D ] , PTH , cytokines , osteoprotegerin ( OPG ) , C-reactive protein ( CRP ) , bone markers , lipid parameters and insulin levels in 47 healthy post-menopausal women . Thirty-nine women completed the study . A significant increase in 25(OH)D and a significant decrease in PTH were observed ( p=0.0043 and p<0.0001 , respectively ) . In addition , alkaline phosphatase , osteocalcin and , to a lesser extent , urinary free deoxypiridinoline ( DPD ) decreased significantly ( p<0.0001 , p=0.0002 and p=0.026 , respectively ) . No change in circulating IL6 , tumor necrosis factor a ( TNFa ) , CRP , OPG , triglycerides , LDL- and HDL-cholesterol , and insulin levels was observed . Correlation studies in the 47 women enrolled in the study revealed inverse significant correlations between OPG on one side and body mass index , LDL-cholesterol , IL6 , CRP and insulin levels on the other ( p=0.002 , p=0.002 , p=0.004 , p=0.023 and p=0.0001 ) . Also , IL6 was significantly correlated with insulin levels ( p=0.0005 ) . In a multivariate model , both insulin and LDL-cholesterol were independently associated with OPG , while only insulin was independently associated with IL6 . Our results showed no effect of a short-term calcium-vitamin D treatment on circulating cytokines , CRP , insulin levels and lipid parameters . This could be related to the low circulating cytokine concentrations in healthy subjects or to the short duration of treatment . The interesting association we found between OPG and some cardiovascular risk markers deserves further investigation Osteoporosis is a major health problem characterized by compromised bone strength that predisposes patients to an increased risk of fracture , more and more investigations are focusing on the treatment of osteoporotic fracture healing . However , there are few studies elucidating the efficacy of vitamin D , 1,25-dihydroxy vitamin D(3 ) ( 1,25(OH)(2)D(3 ) ) , on osteoporotic fracture healing . In the present study we have established an osteoporotic fracture rat model to evaluate the effects of 1,25(OH)(2)D(3 ) on fracture healing .  Female SD rats of six-month-old ( n=40 ) allocated r and omly into two groups were given ovariectomy . Bilateral midshaft femoral osteotomy was performed 12 weeks post-ovariectomy . Then treatment was begun at the second day after osteotomy and continued until sacrifice at 6 and 16 weeks post-fracture with middle chain triglyceride ( MCT ) vehicle and 1,25(OH)(2)D(3 ) at 0.1 microg/kg/day by oral gavage . Fracture callus was evaluated by soft X-ray radiography , micro-computed tomography ( micro-CT ) , biomechanical testing and histology . Soft X-ray radiography , at 6 weeks post-fracture , showed a less distinct fracture line in the 1,25(OH)(2)D(3 ) group compared with the MCT-vehicle group , however , the fracture line was invisible in both groups at 16 weeks post-fracture . Micro-CT based histomorphometric data , at 6 weeks post-fracture , showed that the total volume of callus ( TV ) was approximately 23 % higher in the 1,25(OH)(2)D(3 ) group than that in the MCT-vehicle group ( P<0.001 ) , and the new bone volume ( BV ) , BV/TV , the trabecular number ( Tb . N ) , and density of TV also showed the same trend . At 16 weeks post-fracture , the increment still existed as shown by Tb . Th and density of TV ( P<0.001 , vs control ) . Biomechanical testing data , at 6 weeks post-fracture , showed that the ultimate load at failure and energy absorption of the 1,25(OH)(2)D(3 ) group were nearly one fold higher than that of the MCT-vehicle group ( P<0.001 ) . At 16 weeks post-fracture , the ultimate load and energy absorption were also higher with the treatment of 1,25(OH)(2)D(3 ) ( P<0.01 vs control ) . Histology showed that the fracture callus in the 1,25(OH)(2)D(3 ) group was remodeled better compared to the control group . In conclusion , 1,25(OH)(2)D(3 ) could promote fracture healing by improving the histomorphometric parameters , mechanical strength and tendency to increase transformation of woven bone into lamellar bone in an ovariectomized rat model Both altered GH-IGF-I axis and low serum levels of 25-hydroxyvitamin D ( 25(OH)D ) are linked to measures of metabolic syndrome . Our hypothesis was that there is a relation between GH , IGF-I , and 25(OH)D ; and that vitamin D supplementation may have an effect on the levels of GH , IGF-I , and IGF-I/IGFBP-3 ratio . 318 overweight and obese subjects completed a one-year r and omized intervention with either 40,000 or 20,000 IU cholecalciferol per week or placebo .  GH , IGF-I , IGFBP-3 and measures of insulin resistance were evaluated at baseline and at the end of study . There was a significant relation between entities of GH-IGF-I axis and insulin resistance .  Subjects with severe obesity had significantly lower serum 25(OH)D and had a significant linear decline in IGF-I/IGFBP-3 ratio with increasing serum 25(OH)D quartiles . Vitamin D status was an independent predictor of GH-IGF-I axis and supplementation with vitamin D decreased IGF-I/IGFBP-3 ratio in subjects without severe obesity . No corresponding effect of vitamin D supplementation on BMI or insulin resistance was observed . Adverse effects of GH-IGF-I axis on glucose metabolism and the development of metabolic syndrome may be in part associated with the changes in vitamin D status The effect of 1,25-dihydroxyvitamin D3 [ 1,25-(OH)2D3 ] deficiency , as well as of replacement therapy with 1 alpha-hydroxyvitamin D3[1 alpha-(OH)D3 ] , on the production of tumor necrosis factor-alpha ( TNF-alpha ) by peripheral blood mononuclear cells ( P BMC ) and on the serum levels of soluble TNF receptors ( sTNFRs ) in hemodialysis ( HD ) patients was investigated . P BMC from HD patients without prior therapy with hydroxylated vitamin D3 analogs and from normal controls produced similar amounts of TNF-alpha , either spontaneously or after stimulation with lipopolysaccharide ( LPS ) . After oral administration of 1 alpha-(OH)D3 , a precursor of 1,25-(OH)2D3 , LPS-induced TNF-alpha production by P BMC of HD patients was significantly higher than that of HD patients prior to the treatment or of healthy controls . Such treatment did not , however , affect spontaneous TNF-alpha production by P BMC . Serum concentrations of both soluble TNF receptors [ sTNFR-A(p75 ) and sTNFR-B(p55 ) ] were significantly higher in HD patients than in controls . The ratio of sTNFR-A/sTNFR-B decreased significantly in HD patients following 1 alpha-(OH)D3 therapy . These results suggest that therapy with 1 alpha-hydroxylated vitamin D3 analogs normally given to HD patients for the management of renal osteodystrophy may also regulate the in vivo activity of TNF-alpha
INTRODUCTION Vitamin D is essential for bone mineralization and for the subsequent maintenance of bone quality .
Mineralization is part of hard callus formation and bone remodelling , processes , which are part of fracture healing .
We provide a comprehensive review of the literature to summarize and clarify if possible , the cellular effects of vitamin D and its clinical involvement in the process of fracture healing in human .
CONCLUSION Despite these results , and the presumed beneficial effect of vitamin D supplementation in deficient patients , clinical studies that address the effects of vitamin D deficiency or supplementation on fracture healing are scarce and remain inconclusive .