Consumption of vitamin D-and calcium-fortified soft white cheese lowers the biochemical marker of bone resorption TRAP 5b in postmenopausal women at moderate risk of osteoporosis fracture. Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women. Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women. Are Hill's criteria for causality satisfied for vitamin D and periodontal disease? Effects of Combined Calcium and Vitamin D Supplementation on Insulin Secretion, Insulin Sensitivity and β-Cell Function in Multi-Ethnic Vitamin D-Deficient Adults at Risk for Type 2 Diabetes: A Pilot Randomized, Placebo-Controlled Trial Effect of calcium and vitamin D supplementation on bone mineral density in women aged 65–71 years: a 3-year randomized population-based trial (OSTPRE-FPS) Long-term effects of calcium-vitamin-D3-fortified milk on bone geometry and strength in older men. Effect of vitamin D, calcium and multiple micronutrient supplementation on vitamin D and bone status in Bangladeshi premenopausal garment factory workers with hypovitaminosis D: a double-blinded, randomised, placebo-controlled 1-year intervention. Independent and combined effects of calcium-vitamin D3 and exercise on bone structure and strength in older men: an 18-month factorial design randomized controlled trial. Skeletal site-dependent response of bone mineral density and quantitative ultrasound parameters following a 12-month dietary intervention using dairy products fortified with calcium and vitamin D: the Postmenopausal Health Study. Calcium-vitamin D cosupplementation influences circulating inflammatory biomarkers and adipocytokines in vitamin D-insufficient diabetics: a randomized controlled clinical trial. Influence of Vitamin D & Calcium Supplementation in the Management of Periodontitis. Calcium plus vitamin D3 supplementation facilitated Fat loss in overweight and obese college students with very-low calcium consumption: a randomized controlled trial Vitamin D and Calcium Attenuate Bone Loss With Antiretroviral Therapy Initiation Does 24R,25(OH)2-vitamin D3 prevent postmenopausal bone loss? Increased Bone Resorption in the Proximal Femur in Patients with Hemiplegia Vitamin D Is a Major Determinant of Bone Mineral Density at School Age
The prevention of increased bone remodeling in postmenopausal women at low 10-y risk of osteoporotic fractures essentially relies on reinforcement of environmental factors known to positively influence bone health , among which nutrition plays an important role . In institutionalized women in their mid-eighties , we previously found that consumption of fortified soft plain cheese increased vitamin D , calcium , and protein intakes , reduced bone resorption biochemical markers , particularly the serum bone specific acid phosphatase tartrate resistant acid phosphatase , isoform 5b ( TRAP 5b ) that reflects osteoclast activity , and stimulated the serum bone anabolic factor insulin-like growth factor-I ( IGF-I ) . Whether these effects occur in much younger women was tested in a prospect i ve control study . Seventy-one healthy postmenopausal women aged 56.6 ± 3.9 y ( mean ± SD ) with low spontaneous supply of both Ca and vitamin D were r and omized to consume daily ( treated , n = 36 ) or not ( controls , n = 35 ) two servings ( 2 × 100 g ) of skimmed-milk , soft plain cheese for 6 wk . The vitamin D and Ca-fortified dairy product provided daily : 661 kJ , 2.5 μg vitamin D , 400 mg calcium , and 13.8 g protein . At the end of the intervention , the decrease in TRAP 5b and the increase in IGF-I were greater in the treated than in the control group ( P < 0.02 ) . The changes in serum carboxy terminal crosslinked telopeptide of type I collagen did not differ significantly between the two groups . In conclusion , like in elderly women , consumption by healthy postmenopausal women of a vitamin D and calcium-fortified dairy product that also increases the protein intake , reduces the serum concentration of the bone resorption biomarker TRAP 5b . This response , combined with the increase in serum IGF-I , is compatible with a nutrition-induced reduction in postmenopausal bone loss rate OBJECTIVES To investigate the therapeutic effect of combined use of vitamin K(2 ) and D(3 ) on vertebral bone mineral density in postmenopausal women with osteopenia and osteoporosis . SUBJECTS AND METHODS We enrolled 172 women with vertebral bone mineral density < 0.98 g/cm(2 ) ( osteopenia and osteoporosis ) as measured by dual-energy X-ray absorptiometry . In this study , we employed the criteria for diagnosis of osteopenia and osteoporosis using dual energy X-ray absorptiometry proposed by the Japan Society of Bone Metabolism in 1996 . Subjects were r and omized into four groups ( each having 43 subjects in vitamin K(2 ) therapy group , vitamin D(3 ) therapy group , vitamin K(2 ) and D(3 ) combined therapy group , or a control group receiving dietary therapy alone ) and treated with respective agents for 2 years , with bone mineral density was measured prior to therapy and after 6 , 12 , 18 , and 24 months of treatment . The bone metabolism markers analyzed were serum type 1 collagen carboxyterminal propeptide ( P1CP ) , serum intact osteocalcin , and urinary pyridinoline . Tests of blood coagulation function consisted of measurement of activated partial thromboplastin time ( APTT ) and analysis of concentrations of antithrombin III ( AT III ) , fibrinogen , and plasminogen . RESULTS Combined therapy with vitamin K(2 ) and D(3 ) for 24 months markedly increased bone mineral density ( 4.92 + /- 7.89 % ) , while vitamin K(2 ) alone increased it only 0.135 + /- 5.44 % . The bone markers measured , revealed stimulation of both bone formation and resorption activity . We observed an increase in coagulation and fibrinolytic activity that was within the normal range , suggesting that balance was maintained in the fibrinolysis-coagulation system . CONCLUSIONS Continuous combination therapy with vitamin K(2 ) and D(3 ) may be useful for increasing vertebral bone mass in postmenopausal women . Furthermore , the increase in coagulation function observed during this therapy was within the physiological range , and no adverse reactions were observed BACKGROUND Adequate intakes of calcium and vitamin D reduce bone loss and fracture risk in the elderly . Other nutrients also affect bone health , and adequate intakes may influence bone turnover and balance . OBJECTIVE We compared the long-term effects on bone turnover markers and calciotropic hormones of a multinutrient supplement , a calcium and vitamin D supplement , and dietary instruction aim ed at increasing calcium intake through foods . DESIGN Ninety-nine healthy postmenopausal women participated in a 3-y , r and omized trial , receiving either 1 ) supplemental calcium ( 1450 mg/d ) and vitamin D [ 10 microg ( 400 IU)/d ] , 2 ) calcium , vitamin D , and other nutrients ( multinutrient supplement ) , or 3 ) dietary instruction ( dietary control group ) . Data are from 83 subjects who completed the trial . RESULTS Increases over baseline in calcium intakes and serum 25-hydroxyvitamin D concentrations were sustained over 3 y in all treatment groups . Circulating parathyroid hormone concentrations were reduced at year 1 in all treatment groups but trended toward baseline thereafter . Bone turnover markers followed a similar pattern , and none of the changes in biochemical concentrations differed significantly between groups . CONCLUSIONS All 3 interventions offer long-term feasibility for increasing calcium intake and serum 25-hydroxyvitamin D concentrations . The dietary addition of micronutrients implicated in skeletal physiology confers no obvious bone-sparing effect in healthy postmenopausal women beyond that of calcium and vitamin D alone . The attenuation over time in suppression of parathyroid hormone and bone turnover might help explain why nutrient intervention tends to have less of a bone-sparing effect than do skeletally active medications such as estrogen or bisphosphonates There is mounting evidence that periodontal disease ( PD ) is linked to low serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations in addition to recognized risk factors like diet and smoking . This paper review s this evidence using Hill 's criteria for causality in a biological system . Evidence for strength of association , consistency , cohesion and ' dose-effects ' [ biological ' gradients ' ] include strong inverse correlations between serum 25(OH ) and both PD cross-sectionally and that PD is consistently more prevalent in darker vs. lighter skinned people and increases at higher latitudes with analogy for gingivitis and for disorders associated with PD whose risks increase with hypovitaminosis D. Evidence for plausibility includes that vitamin D increases calcium absorption and protects bone strength ; induces formation of cathelicidin and other defensins that combat bacterial infection ; reduces tissue production of destructive matrix metalloproteinases actively associated with PD and that prevalence of PD varies with common vitamin D receptor polymorphisms . Experimental evidence from limited supplementation studies [ using calcium and vitamin D ] shows that supplementation reduces tooth loss . Thus , existing evidence for hypovitaminosis D as a risk factor for PD to date meets Hill 's criteria for causality in a biological system . Further experimental evidence for effectiveness and temporality , preferably from r and omized controlled trials of vitamin D supplementation [ adjusting for other PD risk factors including diet and smoking to reduce confounding ] are necessary to confirm causality . If confirmed , dentists and periodontists could perform a valuable service to their patients by discussing the importance of adequate vitamin D status and on how to avoid deficiency Objectives To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity , insulin secretion , β-cell function , inflammation and metabolic markers . Design 6-month r and omized , placebo-controlled trial . Participants Ninety-five adults with serum 25-hydroxyvitamin D [ 25(OH)D ] ≤55 nmol/L at risk of type 2 diabetes ( with prediabetes or an AUSDRISK score ≥15 ) were r and omized . Analyses included participants who completed the baseline and final visits ( treatment n = 35 ; placebo n = 45 ) . Intervention Daily calcium carbonate ( 1,200 mg ) and cholecalciferol [ 2,000–6,000 IU to target 25(OH)D > 75 nmol/L ] or matching placebos for 6 months .  Measurements Insulin sensitivity ( HOMA2%S , Matsuda index ) , insulin secretion ( insulinogenic index , area under the curve ( AUC ) for C-peptide ) and β-cell function ( Matsuda index x AUC for C-peptide ) derived from a 75 g 2-h OGTT ; anthropometry ; blood pressure ; lipid profile ; hs-CRP ; TNF-α ; IL-6 ; adiponectin ; total and undercarboxylated osteocalcin . Results Participants were middle-aged adults ( mean age 54 years ; 69 % Europid ) at risk of type 2 diabetes ( 48 % with prediabetes ) . Compliance was > 80 % for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group ( 91 % achieved > 75 nmol/L ) , but remained unchanged in controls . There were no significant changes in insulin sensitivity , insulin secretion and β-cell function , or in inflammatory and metabolic markers between or within the groups , before or after adjustment for potential confounders including waist circumference and season of recruitment . In a post hoc analysis restricted to participants with prediabetes , a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity ( HOMA%S and Matsuda ) was observed . Conclusions Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity , insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes . However , in participants with prediabetes , supplementation with vitamin D and calcium may improve insulin sensitivity . Trial Registration Australian New Zeal and Clinical Trials Registry Summary The Osteoporosis Risk Factor and Prevention-Fracture Prevention Study ( OSTPRE-FPS ) was a r and omized population -based open trial ( n = 593 ) . The supplementation group ( n = 287 ) received daily cholecalciferol 800 IU + calcium 1,000 mg for 3 years while the control group ( n = 306 ) received neither supplementation nor placebo . Daily vitamin D and calcium supplementation have a positive effect on the skeleton in ambulatory postmenopausal women . Introduction Vitamin D deficiency is common in the elderly , and vitamin D levels are associated with low bone mineral density ( BMD ) . The working hypothesis was that vitamin D and calcium supplementation could prevent bone loss in ambulatory postmenopausal women . Methods The OSTPRE-FPS was a r and omized population -based open trial with a 3-year follow-up in 3,432 women ( aged 66 to 71 years ) . A r and omly selected sub sample of 593 subjects underwent BMD measurements . The supplementation group ( n = 287 ) received daily cholecalciferol 800 IU + calcium 1,000 mg for 3 years while the control group ( n = 306 ) received neither supplementation nor placebo . Results In the intention-to-treat analysis , total body BMD ( n = 362 ) increased significantly more in the intervention group than in the control group ( 0.84 % vs. 0.19 % , p = 0.011 ) . The BMD change differences at the lumbar spine ( p = 0.372 ) , femoral neck ( p = 0.188 ) , trochanter ( p = 0.085 ) , and total proximal femur ( p = 0.070 ) were statistically nonsignificant . Analyses in compliant women ( ≥80 % of use ) result ed in stronger and statistically significant effects at the total body and femoral regions . Conclusion Daily vitamin D and calcium supplementation have a positive effect on the skeleton in ambulatory postmenopausal women with adequate nutritional calcium intake The long-term effects of calcium and vitamin D supplementation on bone material and structural properties in older men are not known . The aim of this study was to examine the effects of high calcium ( 1000 mg/day)- and vitamin-D(3 ) ( 800 IU/day)-fortified milk on cortical and trabecular volumetric BMD ( vBMD ) and bone geometry at the axial and appendicular skeleton in men aged over 50 years . One hundred and eleven men who were part of a larger 2-year r and omized controlled trial had QCT scans  of the mid-femur and lumbar spine ( L(1)-L(3 ) ) to assess vBMD , bone geometry and indices of bone strength [ polar moment of inertia ( I(polar ) ) ] . After 2 years , there were no significant differences between the milk supplementation and control group for the change in any mid-femur or L(1)-L(3 ) bone parameters for all men aged over 50 years . However , the mid-femur skeletal responses to the fortified milk varied according to age , with a split of < or=62 versus > 62 years being the most significant for discriminating the changes between the two groups . Subsequent analysis revealed that , in the older men ( > 62 years ) , the expansion in mid-femur medullary area was 2.8 % ( P < 0.01 ) less in the milk supplementation compared to control group , which helped to preserve cortical area in the milk supplementation group ( between group difference 1.1 % , P < 0.01 ) . Similarly , for mid-femur cortical vBMD and I(polar ) , the net loss was 2.3 and 2.8 % less in the milk supplementation compared to control group ( P < 0.01 and < 0.001 , respectively ) . In conclusion , calcium-vitamin-D(3)-fortified milk may represent an effective strategy to maintain bone strength by preventing endocortical bone loss and slowing the loss in cortical vBMD in elderly men Due to little outdoor activity and low dietary intake of vitamin D ( VD ) , Bangladeshi low-income women are at risk for osteoporosis at an early age . The present study assessed the effect of VD , Ca and multiple micronutrient supplementation on VD and bone status in Bangladeshi young female garment factory workers . This placebo-controlled 1-year intervention r and omly assigned 200 apparently healthy subjects ( aged 16 - 36 years ) to four groups : VD group , daily 10 microg VD ; VD and Ca ( VD-Ca ) group , daily 10 microg VD+600 mg Ca ; multiple micronutrient and Ca ( MMN-Ca ) group , 10 microg VD and other micronutrients+600 mg Ca ; a placebo group .  Serum 25-hydroxyvitamin D ( S-25OHD ) , intact parathyroid hormone ( S-iPTH ) , Ca , phosphate and alkaline phosphatase were measured . Bone mineral density and bone mineral content were measured by dual-energy X-ray absorptiometry . All measurements were made at baseline and at 12 months . Significantly ( P < 0.001 ) higher S-25OHD concentrations were observed in the supplemented groups than in the placebo group after the intervention . Supplementation had an effect ( P < 0.001 ) on S-iPTH in the VD-Ca and MMN-Ca groups compared with the placebo group . Bone mineral augmentation increased at the femur in the supplemented groups . Supplementation with VD-Ca should be recommended as a strategic option to reduce the risk of osteomalacia and osteoporosis in these subjects . MMN-Ca may have analogous positive health implication s with additional non-skeletal benefits CONTEXT Exercise and calcium-vitamin D are independently recognized as important strategies to prevent osteoporosis , but their combined effects on bone strength and its determinants remain uncertain . OBJECTIVE To assess whether calcium-vitamin D(3 ) fortified milk could enhance the effects of exercise on bone strength , structure , and mineral density in middle-aged and older men . DESIGN , SETTING , PARTICIPANTS An 18-month factorial design r and omized controlled trial in which 180 men aged 50 - 79 years were r and omized to the following : exercise + fortified milk ; exercise ; fortified milk ; or controls . Exercise consisted of progressive resistance training with weight-bearing impact activities performed 3 d/week . Men assigned to fortified milk consumed 400 ml/d of 1 % fat milk containing 1000 mg/d calcium and 800 IU/d vitamin D(3 ) . MAIN OUTCOME MEASURES Changes in bone mineral density ( BMD ) , bone structure , and strength at the lumbar spine ( LS ) , proximal femur , mid-femur , and mid-tibia measured by dual energy x-ray absorptiometry and /or quantitative computed tomography . RESULTS There were no exercise-by-fortified milk interactions at any skeletal site . Main effect analysis showed that exercise led to a 2.1 % ( 95 % confidence interval , 0.5 - 3.6 ) net gain in femoral neck section modulus , which was associated with an approximately 1.9 % gain in areal BMD and cross-sectional area .  Exercise also improved LS trabecular BMD [ net gain 2.2 % ( 95 % confidence interval , 0.2 - 4.1 ) ] , but had no effect on mid-femur or mid-tibia BMD , structure , or strength . There were no main effects of the fortified milk at any skeletal site . CONCLUSION A community-based multi-component exercise program successfully improved LS and femoral neck BMD and strength in healthy older men , but providing additional calcium-vitamin D(3 ) to these replete men did not enhance the osteogenic response The aim of the current study was to examine whether calcium supplementation could prevent bone loss in postmenopausal women or more favourable outcomes could be obtained via the consumption of dairy products fortified with calcium and vitamin D3 . For this purpose changes in bone mineral density ( BMD ) at different skeletal sites , assessed by dual-energy X-ray absorptiometry , as well as in quantitative ultrasound ( QUS ) parameters of the calcaneus over 12 months were estimated . A population of 101 postmenopausal women ( 55 - 65 years old ) was r and omized into a dairy group ( DG : n 39 ) , receiving approximately 1200 mg calcium/d and 7.5 microg vitamin D3/d through fortified dairy products ; a calcium-supplemented group ( CaG : n 26 ) provided with a calcium supplement of 600 mg/d ; and a control group ( CG : n 36 ) . Over the intervention period the DG was found to have more favourable changes in pelvis ( P=0.040 ) , total spine ( P<0.001 ) and total body BMD ( P<0.001 ) than the other groups . A significant increase was also observed for DG in lumbar spine BMD ( 2.0 % ; 95 % CI 0.5 , 3.5 ) although it did not differentiate significantly compared to the other groups . No significant differences were observed with respect to the changes in QUS parameters . The current study revealed that recommended intakes of vitamin D3 and calcium via fortified dairy products for 12 months can induce favourable changes in pelvis , total spine and total body BMD in postmenopausal women but not in QUS parameters . No such favourable changes were observed via supplementation of calcium alone CONTEXT To the best of our knowledge , no study has examined the effects of vitamin D-calcium cosupplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient type 2 diabetics . OBJECTIVE This study was performed to assess the effects of vitamin D and calcium supplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient people with type 2 diabetes . METHODS Totally , 118 diabetic patients were enrolled in this r and omized , placebo-controlled clinical trial . After matching for age , sex , body mass index , type and dose of hypoglycemic agents , and duration of diabetes , subjects were r and omly assigned into 4 groups receiving the following : 1 ) 50000 IU/wk vitamin D + calcium placebo ; 2 ) 1000 mg/d calcium + vitamin D placebo ; 3 ) 50 000 IU/wk vitamin D + 1000 mg/d calcium ; or 4 ) vitamin D placebo + calcium placebo for 8 weeks . Blood sampling was done for the quantification of inflammatory biomarkers and adipocytokines at the study baseline and after 8 weeks of intervention . RESULTS Calcium ( changes from baseline : -75 ± 19 ng/ml , P = .01 ) and vitamin D alone ( -56 ± 19 ng/mL , P = .01 ) and joint calcium-vitamin D supplementation ( -92 ± 19 ng/mL , P = .01 ) result ed in a significant reduction in serum leptin levels compared with placebo ( -9 ± 18 ng/mL ) . This was also the case for serum IL-6 , such that calcium ( -2 ± 1 pg/mL , P < .001 ) and vitamin D alone ( -4 ± 1 pg/mL , P < .001 ) and their combination ( -4 ± 1 pg/mL , P < .001 ) led to significant reductions compared with placebo ( 3 ± 1 pg/mL ) . After adjustment for potential confounders , individuals in the calcium ( -3.1 ± 1.3 , P < .05 ) , vitamin D ( -3.1 ± 1.3 , P < .05 ) , and joint calcium-vitamin D groups ( -3.4 ± 1.3 , P < .05 ) had greater reductions in serum TNF-α concentrations compared with placebo ( 0.1 ± 1.2 ) . Individuals who received joint calcium-vitamin D supplements tended to have a decrease in serum high-sensitivity C-reactive protein levels compared with placebo after controlling for baseline levels ( -1.14 ± 0.25 vs 0.02 ± 0.24 ng/mL , P = .09 ) . CONCLUSION Joint calcium-vitamin D supplementation might improve systemic inflammation through decreasing IL-6 and TNF-α concentrations in vitamin D-insufficient people with type 2 diabetes INTRODUCTION It has long been recognized that vitamin D is a hormone and were many studies reporting that patients in periodontal maintenance programs taking vitamin D and calcium supplementation had a trend for better periodontal health compared to patients not taking supplementation . AIM To evaluate the effect of vitamin D and calcium supplementation in reducing gingival inflammation , using clinical parameters like gingival index ( GI ) , oral hygiene index-simplified ( OHIS ) , probing pocket depth ( PPD ) , clinical attachment level ( CAL ) and bone density ( BD ) . Also , to assess whether calcium and vitamin D oral supplementation influences alveolar Bone Density ( BD ) . DESIGN AND SETTING S A nonr and omised clinical trial done in Amrita School of dentistry , Kochi , India . MATERIAL S AND METHODS Group A taking vitamin D ( 250IU/day ) and calcium ( 500 mg/day ) supplementation  , and Group B were not taking oral supplementation . All subjects had at least one or more teeth with chronic moderate periodontitis . Digital Orthopantomogram images were taken to assess bone density . Data were collected at baseline and three months . STATISTICAL ANALYSIS USED OHI-S , GI , PPD , CAL , and Bone Densities ( BD ) were calculated per group . Karl Pearson Coefficient of correlation was used to test correlation of bone density with GI and OHI -S. Intergroup comparison of parameters were done using Independent two Sample t-test . Intragroup comparison of parameters at recall interval was done using Paired sample t-test . The results were considered statistically significant when p-value was < 0.05 . RESULTS Both Groups showed significant change in the periodontal parameters and bone density after three months and intragroup comparison showed highly significant results for vitamin D group in relation to GI , OHI S and bone density . CONCLUSION Calcium and vitamin D supplementation has got a positive effect on periodontal health and it can be used as an adjunct to non surgical periodontal therapy Background Recent evidence suggests that higher calcium and /or vitamin D intake may be associated with lower body weight and better metabolic health . Due to contradictory findings from intervention trials , we investigated the effect of calcium plus vitamin D3 ( calcium+D ) supplementation on anthropometric and metabolic profiles during energy restriction in healthy , overweight and obese adults with very-low calcium consumption . Methods Fifty-three subjects were r and omly assigned in an open-label , r and omized controlled trial to receive either an energy-restricted diet ( −500 kcal/d ) supplemented with 600 mg elemental calcium and 125 IU vitamin D3 or energy restriction alone for 12 weeks . Repeated measurements of variance were performed to evaluate the differences between groups for changes in body weight , BMI , body composition , waist circumference , and blood pressures , as well as in plasma TG , TC , HDL , LDL , glucose and insulin concentrations . Results Eighty-one percent of participants completed the trial ( 85 % from the calcium + D group ; 78 % from the control group ) . A significantly greater decrease in fat mass loss was observed in the calcium + D group ( −2.8±1.3 vs.-1.8±1.3 kg ; P=0.02 ) than in the control group , although there was no significant difference in body weight change ( P>0.05 ) between groups . The calcium + D group also exhibited greater decrease in visceral fat mass and visceral fat area ( P<0.05 for both ) . No significant difference was detected for changes in metabolic variables ( P>0.05 ) . Conclusion Calcium plus vitamin D3 supplementation for 12 weeks augmented body fat and visceral fat loss in very-low calcium consumers during energy restriction . Trial registration Clinical Trials.gov ( NCT01447433 , http:// clinical trials.gov/ ) Context Patients with HIV who initiate antiretroviral therapy ( ART ) lose bone mineral density ( BMD ) . The role of supplementation with vitamin D and calcium in preventing such loss is unknown . Contribution In a r and omized clinical trial of patients with HIV who were initiating ART , BMD , 25-hydroxyvitamin D , parathyroid hormone , phosphate metabolism , and markers of bone turnover were measured at baseline . Patients who then received vitamin D3 plus calcium along with ART had smaller declines in BMD of the hip and spine than those who received placebo along with ART . Caution Nearly all of the patients were men . Implication Supplementation with vitamin D and calcium may prevent bone loss  in patients with HIV initiating ART .  Antiretroviral therapy ( ART ) has transformed HIV infection from a terminal disease to a manageable chronic illness . Although incidence of AIDS-defining conditions has decreased , it has increased for other comorbid conditions ( 1 ) , including osteoporosis and fragility fractures ( 27 ) . Both viral and host factorsHIV infection mediated by certain viral proteins , HIV-associated inflammation , lifestyle and behavioral factors , underlying genetic predisposition , comorbid conditions , and ARTprobably contribute to bone loss and fracture risk ( 814 ) . Studies of ART initiation have confirmed that 2 % to 6 % of hip and spine BMD is lost over the first 24 to 48 weeks after initiation , with subsequent stabilization ( 1518 ) . The magnitude of bone loss is similar to that seen with glucocorticoids or during the first year of menopausal transition ( 19 , 20 ) . Initial loss is marked by an increase in serum bone resorption markers followed by a delayed compensatory increase in bone formation markers ( 21 ) ; therefore , this catabolic window , a high bone turnover state with excess resorption , may be a central mechanism of bone loss with ART initiation . Tenofovir disoproxil fumarate ( TDF ) , a nucleotide analogue reverse transcriptase inhibitor , has been associated with greater bone loss than other reverse transcriptase inhibitors ( 15 , 16 ) . Use of TDF is associated with increased parathyroid hormone ( PTH ) , elevated vitamin D binding protein , and reduced free 1,25-dihydroxyvitamin D [ 1,25-(OH)2D3 ] levels ( 22 , 23 ) , suggesting that functional vitamin D deficiency with TDF use potentially contributes to excess bone loss . Initiation of efavirenz ( EFV ) , a nonnucleoside reverse transcriptase inhibitor , is associated with a 6.2- to 12.5-nmol/L decrease in 25-hydroxyvitamin D [ 25-(OH)D ] levels ( 24 , 25 ) . Efavirenz induces cytochrome P450 enzymes involved in vitamin D metabolism and may accelerate the catabolism of 25-(OH)D and 1,25-(OH)2D3 , the latter being the active vitamin D metabolite ( 26 ) . These ART agents are combined with emtricitabine ( FTC ) , a nucleoside analogue reverse transcriptase inhibitor , into a fixed-dose combination , once-a-day pill ( EFV/FTC/TDF ) that is highly effective for treating HIV ( 27 ) . Beyond effects on bone metabolism , vitamin D has immunomodulatory effects mediated through the vitamin D receptor present on cells in both the innate and the adaptive immune system ( 28 , 29 ) . Vitamin D increases monocyte expression of CD14 and cathelicidin , molecules involved in innate immune responses ( 30 , 31 ) ; down-regulates cytokine expression in activated T cells ; and suppresses T-cell proliferation and production of interferon- and interleukin (IL)-2 , thus reducing the net state of inflammation ( 32 , 33 ) . These pathways are particularly relevant in HIV infection , in which excess monocyte and T-cell activation are important drivers of morbidity and mortality ( 3437 ) . We hypothesized that high-dose vitamin D and calcium supplementation would attenuate bone loss associated with initiation of EFV/FTC/TDF . In addition , we evaluated immunomodulatory effects of vitamin D in the setting of HIV treatment . We report the results of the AIDS Clinical Trials Group A5280 trial , a multicenter , r and omized , double-blind , placebo-controlled study assessing the effect of daily oral doses of 4000 IU of vitamin D3 and 1000 mg of calcium carbonate in adults with HIV initiating their first ART regimen with EFV/FTC/TDF . Methods Patients with ART-naive HIV without evidence of resistance to the antiretrovirals in the regimen and with HIV-1 RNA levels greater than 1000 copies/mL were eligible if they met the following criteria : screening 25-(OH)D level between 25 and 188 nmol/L ; creatinine clearance of 60 mL/min/1.73 m2 or greater , estimated by the CockcroftGault formula ; and serum calcium level less than 2.6 mmol/L. We excluded patients with daily calcium supplementation greater than 500 mg , daily vitamin D supplementation greater than 800 IU , any bisphosphonate use , recent steroid or chemotherapy treatments , clinical ly active thyroid disease , active substance or alcohol abuse , history of fragility fracture , documented osteoporosis , nephrolithiasis , or weight greater than 136 kg ( limit of the dual-energy x-ray absorptiometry [ DXA ] scanner ) . Pregnant and breastfeeding women were also excluded . We did 3-day dietary recalls at entry to estimate vitamin D and calcium intake . Patients were r and omly assigned to 4000 IU of cholecalciferol ( vitamin D3 ) daily plus 500 mg of calcium carbonate twice daily or identically matching placebos ( Tishcon ) and were counseled to take with food to facilitate absorption . Some experts consider the current upper U.S. Dietary Reference Intake of 2000 IU to be below actual physiologic requirements ; therefore , we tested the highest supplementation without risk for toxicity ( 3840 ) . A dose of 4000 IU of vitamin D3 is the highest daily dose considered safe for adults by the Institute of Medicine ( 41 ) and has previously been evaluated in persons with HIV with excellent tolerability and safety data ( 42 ) . Patients were r and omly assigned in a 1:1 ratio using permuted blocks stratified by screening serum 25-(OH)D levels ( 50 and > 50 nmol/L ) . R and omization was done using Web-based access to a central computer system maintained by the Frontier Science & Technology Research Foundation ( Buffalo , New York ) . The institutional review boards of all participating sites approved the study , and all patients provided written informed consent . The primary end point was percentage of change in total hip BMD from baseline to 48 weeks . Secondary end points included percentage of change in lumbar spine BMD at 48 weeks , change in plasma 25-(OH)D and PTH levels , markers of bone turnover , soluble inflammatory biomarkers , and CD4 cell counts at 24 and 48 weeks . Incidence of hypercalcemia and nephrolithiasis was monitored . All DXA scans were read in a blinded fashion at the Body Composition Analysis Center at Tufts Medical Center ( Boston , Massachusetts ) using a st and ardized protocol . Biomarker Assays Screening was done at local laboratories certified by the Clinical Laboratory Improvement Amendments . Serum sample s were stored at 70C at the Irving Institute Biomarkers Core Laboratory at Columbia University Medical Center ( New York , New York ) and underwent batched analysis . We measured 25-(OH)D2 and 25-(OH)D3 by liquid chromatographymass spectrometry , intact PTH by a radioimmunoassay ( Scantibodies ) , procollagen-1 N-terminal peptide ( P1NP ) by a radioimmunoassay ( Immunodiagnostic Systems ) , C-terminal telopeptide of type 1 collagen ( CTX ) by an enzyme-linked immunosorbent assay [ ELISA ] ( Immunodiagnostic Systems ) , IL-6 by an ELISA ( R&D Systems ) , soluble tumor necrosis factor receptor ( sTNFR ) by an ELISA ( R&D Systems ) , and soluble CD14 by an ELISA ( R&D Systems ) . Inflammatory biomarkers were chosen based on association with relevant end points ( 4346 ) . All biomarkers , except for 25-(OH)D , were measured in duplicate , and values were averaged for analysis . Statistical Analysis To provide an intention-to-treat analysis , evaluations were done regardless of treatment change or discontinuation . Two patients who did not have the correct vitamin D test done at baseline were excluded from the efficacy analyses . Stratified Wilcoxon rank-sum tests were used to evaluate for distribution shifts between the treatment groups , which were stratified by screening vitamin D levels . Fisher exact tests and Wilcoxon rank-sum tests were used to evaluate for differences between groups for categorical and continuous secondary outcomes , respectively . Wilcoxon signed-rank tests were used to evaluate change within a treatment group . The 95 % CIs for median changes within a group were estimated using a distribution-free method via percentiles . For the BMD outcomes , modification of the treatment effect by screening vitamin D stratum was evaluated by means of linear regression . Analyses of the primary outcomes of change in hip and spine BMD from baseline to 48 weeks used a multiple-imputation approach to fill in missing data with a Markov-chain Monte Carlo method . A prespecified complete-case approach was used for analyses by stratum and to assess interactions . Five imputations were used , based on screening 25-(OH)D strata , age , sex , and race/ethnicity . All statistical tests were 2-sided and interpreted at the 5 % nominal level of significance without adjustment for multiple comparisons . Analyses were done using the FREQ , UNIVARIATE , REG , MI , and MIANALYZE procedures in SAS , version 9.2 ( SAS Institute ) , and STRATIFY and PAIRED procedures in Proc-StatXact , version 9 ( Cytel ) . Role of the Funding Source The National Institute of Allergy and Infectious Diseases funded the study . Industry sponsors ( Bristol-Myers Squibb , Gilead Science , and Tishcon ) provided antiretrovirals , vitamin D , calcium , and matching placebos , and additional funding was provided for completion of DXA scans and laboratory assays . The National Institute of Allergy and Infectious Diseases had no role in the design and conduct of the study ; collection , management , analysis , or interpretation of the data ; preparation , review , or approval of the manuscript ; or decision to su bmi t the manuscript for publication . The manuscript was review ed by Summary The effect of oral 24R,25(OH)2-vitamin D3 as a prophylactic for postmenopausal bone loss was examined . Fifty-eight healthy , early postmeno-pausal women entered a double blind therapeutic trial for 2 years . After an initial examination the women were r and omized to treatment with 10 μg 24R,25(OH)2D3 daily or placebo . Participants were thereafter examined every 3 months ( nine examinations in all ) . In both groups the forearm bone mineral ( measured by single photon absorptiometry ) , the lumbar spine mineral , and the total body mineral ( measured by dual photon absorptiometry ) fell significantly and the same magnitude . Further-more , serum calcium , serum alkaline phosphatase concentration , and fasting urinary hydroxyproline were unchanged , as were the 24-hour urinary calcium excretion and the intestinal radiocalcium absorption . Our findings demonstrate that 24R,25(OH)2D3 treatment has no prophylactic effect on postmenopausal bone loss and does not alter calcium metabolic variables Levendo&U01E7;lu F , U&U01E7;urlu H , Gürbilek M , Akkurt E , Karagözo&U01E7;lu E : Increased bone resorption in the proximal femur in patients with hemiplegia . Am J Phys Med Rehabil 2004;83:835–841 . Objectives : To investigate the relationship between the proximal femoral bone mineral density and bone resorption markers , determinants of calcium metabolism and vitamin D levels in elderly stroke patients . Design : A total of 80 patients and 20 controls were enrolled in the study .  Bone mineral density measurements were obtained at the proximal femur . In all subjects ,  25-hydroxyvitamin D , 1,25-dihydroxyvitamin D , intact parathyroid hormone , osteocalcin , deoxypyridinoline , and ionized calcium concentrations  were measured . Barthel Index and Motricity Index Leg Score were recorded all patients . Results : The serum concentrations of deoxypyridinoline , intact parathyroid hormone , and the mean serum ionized calcium levels were significantly higher in patients with stroke than that of the control subjects . The mean serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations in patients were significantly lower than those of the control group ( P < 0.05 ) . The bone mineral density of proximal femurs of paretic limbs was decreased significantly compared with those of the control group ( P < 0.05 ) . There were significant correlations between the Z score of the hemiplegic side and the patients ’ Barthel Index , Motricity Index Leg Score , 25-hydroxyvitamin D , 1,25-dihydroxyvitamin D , calcium , and deoxypyridinoline . Conclusions : This study provides clear evidence that decreased mobility , vitamin D status , and bone turnover variables in patients after stroke are important factors in the greater bone loss in the paretic leg Background Vitamin D insufficiency in children may have long-term skeletal consequences as vitamin D affects calcium absorption , bone mineralization and bone mass attainment . Methodology /Principal Findings This school-based study investigated vitamin D status and its association with vitamin D intake and bone health in 195 Finnish children and adolescents ( age range 7–19 years ) . Clinical characteristics , physical activity and dietary vitamin D intake were evaluated . Blood and urine sample s were collected for serum 25-hydroxyvitamin D ( 25-OHD ) and other parameters of calcium homeostasis . Bone mineral density ( BMD ) and body composition were measured with dual-energy X-ray absorptiometry ( DXA ) . Altogether 71 % of the subjects were vitamin D insufficient ( 25-OHD < 50 nmol/L ) . The median 25-OHD was 41 nmol/L for girls and 45 nmol/L for boys , and the respective median vitamin D intakes 9.1 µg/day and 10 µg/day . In regression analysis , after adjusting for relevant factors , 25-OHD concentration explained 5.6 % of the variance in lumbar BMD ; 25-OHD and exercise together explained 7.6 % of the variance in total hip BMD and 17 % of the variance in whole body BMD . S-25-OHD was an independent determinant of lumbar spine and whole body BMD and in magnitude surpassed the effects of physical activity . Conclusions / Significance Vitamin D insufficiency was common even when vitamin D intake exceeded the recommended daily intake . Vitamin D status was a key determinant of BMD . The findings suggest urgent need to increase vitamin D intake to optimize bone health in children
Conclusions Vitamin D supplementation did not improve EF .
The significant effect of vitamin D in diabetics and a tendency for an association with BMI may indicate a role of excess adiposity and insulin resistance in modulating the effects of vitamin D on vascular function .
Abstract Background In addition to regulating calcium homoeostasis and bone health , vitamin D influences vascular and metabolic processes including endothelial function ( EF ) and insulin signalling .