title: 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study. Alfacalcidol reduces accelerated bone turnover in elderly women with osteoporosis Effect of Calcium and Vitamin D Supplementation on Blood Pressure: The Women's Health Initiative Randomized Trial Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. The skeletal benefits of calcium- and vitamin D3-fortified milk are sustained in older men after withdrawal of supplementation: an 18-mo follow-up study. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Effect of cholecalciferol supplementation during winter months in patients with hypertension: a randomized, placebo-controlled trial. Relation of androgen receptor gene polymorphism to bone mineral density and fracture risk in early postmenopausal women during a 5-year randomized hormone replacement therapy trial. Effects of Supplemental Vitamin D and Calcium on Oxidative DNA Damage Marker in Normal Colorectal Mucosa: A Randomized Clinical Trial Effect of oral cholecalciferol 2,000 versus 5,000 IU on serum vitamin D, PTH, bone and muscle strength in patients with vitamin D deficiency Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women. Long-term vitamin D3 supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months. Calcium plus vitamin D supplementation and the risk of breast cancer. Monitoring the randomized trials of the Women's Health Initiative: the experience of the Data and Safety Monitoring Board Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. The effect of various vitamin D supplementation regimens in breast cancer patients The protective effect of hormone-replacement therapy on fracture risk is modulated by estrogen receptor alpha genotype in early postmenopausal women. Vitamin D and HRT: No benefit additional to that of HRT alone in prevention of bone loss in early postmenopausal women. A 2.5-year randomized placebo-controlled study Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. Postmenopausal hormone replacement therapy and autoantibodies against oxidized LDL. Calcium Plus Vitamin D Supplementation Has Limited Effects on Femoral Geometric Strength in Older Postmenopausal Women: The Women’s Health Initiative Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. Calcitriol treatment is not effective in postmenopausal osteoporosis. Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers Serum vitamin D concentration and prostate cancer risk: a nested case-control study. Calcium/Vitamin D Supplementation and Cardiovascular Events Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial Trials and tribulations of recruiting 2,000 older women onto a clinical trial investigating falls and fractures: Vital D study Long-term vitamin D3 supplementation may have adverse effects on serum lipids during postmenopausal hormone replacement therapy. Identification of Early Postmenopausal Women with No Bone Response to HRT: Results of a Five-Year Clinical Trial Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. Calcium- and vitamin D3-fortified milk reduces bone loss at clinically relevant skeletal sites in older men: a 2-year randomized controlled trial. Calcium plus vitamin D supplementation and the risk of colorectal cancer. Muscle strength and mobility in vitamin D-insufficient female geriatric patients: a randomized controlled trial on vitamin D and calcium supplementation Methods for combining randomized clinical trials: strengths and limitations. Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (Calcitriol) in combination with dexamethasone for castration‐resistant prostate cancer Biochemical bone markers and bone mineral density during postmenopausal hormone replacement therapy with and without vitamin D3: a prospective, controlled, randomized study. Effect of hormone therapy and calcitriol on serum lipid profile in postmenopausal older women: association with estrogen receptor-&agr; genotypes Calcium plus vitamin D supplementation and the risk of fractures. Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension: the VitDISH randomized controlled trial. Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: a randomized controlled trial. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Vitamin D Status and Impact of Vitamin D3 and/or Calcium Supplementation in a Randomized Pilot Study in the Southeastern United States Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women's Health Initiative randomized trial. Does Vitamin D Strengthen the Increase in Femoral Neck BMD in Osteoporotic Women Treated with Estrogen? Relation of estrogen receptor-α gene polymorphism and hormone replacement therapy to fall risk and muscle strength in early postmenopausal women Early postmenopausal bone loss is associated with PvuII estrogen receptor gene polymorphism in Finnish women: effect of hormone replacement therapy. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial. Long-term effects of calcium-vitamin-D3-fortified milk on bone geometry and strength in older men. Differences in vitamin D3 dosing regimens in a geriatric community-dwelling population. Vitamin D(3) is more potent than vitamin D(2) in humans. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. Relation of aromatase gene polymorphism and hormone replacement therapy to serum estradiol levels, bone mineral density, and fracture risk in early postmenopausal women* A parallel group double-blind RCT of vitamin D3 assessing physical function: is the biochemical response to treatment affected by overweight and obesity? The effects of calcitriol on falls and fractures and physical performance tests A randomized controlled trial of calcium plus vitamin D supplementation and risk of benign proliferative breast disease Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). Efficacy and safety of high dose intramuscular or oral cholecalciferol in vitamin D deficient/insufficient elderly. [GRADE guidelines: 5. Rating the quality of evidence: publication bias]. Does vitamin D3 have negative effects on serum levels of lipids? A follow-up study with a sequential combination of estradiol valerate and cyproterone acetate and/or vitamin D3. Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial. The GRADE approach is reproducible in assessing the quality of evidence of quantitative evidence syntheses. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial. Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. The Effect of Calcium plus Vitamin D on Risk for Invasive Cancer: Results of the Women's Health Initiative (WHI) Calcium Plus Vitamin D Randomized Clinical Trial Calcium, vitamin D supplementation, and physical function in the Women's Health Initiative. Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial. The tolerability and biochemical effects of high‐dose bolus vitamin D2 and D3 supplementation in patients with vitamin D insufficiency Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: a 1-year double-blind RCT in postmenopausal women. Randomized controlled trial of the effects of calcium with or without vitamin D on bone structure and bone-related chemistry in elderly women with vitamin D insufficiency. Influence of Reported Study Design Characteristics on Intervention Effect Estimates From Randomized, Controlled Trials Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements.
abstract: An unexplained loss of muscle strength occurs with aging . Vitamin D deficiency can cause myopathy and administration of 1,25-dihydroxyvitamin D3 [ 1,25-(OH2)D3 ] to persons with low serum concentrations can improve strength . To test the hypothesis that the weakness associated with aging is in part due to inadequate serum concentrations of [ 1,25-(OH2)D3 ] , we conducted a r and omized , controlled , double blinded trial in 98 men and women volunteers over 69 yr old . Treatment consisted of 0.25 micrograms 1,25-(OH)2D3 , orally , twice per day or identical placebo for 6 months .  Leg muscle strength of the quadriceps was measured with an isokinetic dynamometer . There was no difference between the two groups at 1 week , 1 month , or 6 months of treatment in any of the measures of muscle strength . We conclude that oral administration of 0.5 micrograms 1,25-(OH)2D3/day does not improve muscle strength in older persons . Further research is needed to determine the etiology of the decline in muscle strength associated with aging The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers ( VDPP ) brought together 10 cohorts to conduct a prospect i ve study of the association between vitamin D status , measured as serum concentrations of 25-hydroxyvitamin D ( 25(OH)D ) , and the development of 7 rarer cancer sites : endometrial , esophageal , gastric , kidney , non-Hodgkin lymphoma , ovarian , and pancreatic cancers . The cohorts come from 3 continents , with participants from a wide range of latitude who are racially diverse . Across each cancer site , there was no evidence of a protective association between higher concentrations of 25-hydroxyvitamin D ( > 75 nmol/L ) and cancer outcome . An increased risk at very high levels ( ≥100 nmol/L ) was noted for pancreatic cancer , confirming previous reports . The articles included in this issue detail the overall design and governance of the project , correlates of vitamin D status , and results from the cancer site-specific investigations . The Vitamin D Pooling Project realizes a major goal of consortium efforts , namely , to rigorously test hypotheses for rarer cancer outcomes that may not be adequately addressed in any one prospect i ve cohort study . The results of this study have application for the planning and conduct of intervention trials , especially in determining potential risks Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol , are important factors in the pathogenesis of age-related bone loss . The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on  bone loss in elderly women . Four hundred eighty-nine elderly women with normal bone density for their age , aged 65 - 77 yr , were entered into a r and omized double blind , placebo-controlled trial . Women were r and omized to one of four groups : conjugated estrogens ( 0.625 mg , daily ) to women without a uterus ( estrogen replacement therapy ) plus medroxyprogesterone acetate ( 2.5 mg , daily ) to women with a uterus ( hormone replacement therapy ) , calcitriol ( 0.25 microg twice daily ) , a combination of hormone replacement therapy/estrogen replacement therapy plus calcitriol , or placebos for 3 yr . The primary outcome was the change in bone mineral density of the femoral neck and spine . In the intent to treat analysis , hormone therapy ( hormone replacement therapy/estrogen replacement therapy ) produced a mean ( + /-1 SD ) increase in bone mineral density of 2.98 % ( + /-5.45 % ) at the femoral neck ( P < 0.0001 ) and 4.36 % ( + /-6.42 % ) at the spine ( P < 0.0001 ) . There were parallel increases in total hip and trochanter bone mineral density . Calcitriol increased bone mineral density 0.10 % ( + /- 4.27 % ) at the femoral neck ( P = 0.57 ) and 1.65 % ( + /- 4.83 % ) at the spine ( P < 0.0124 ) . The combination of hormone replacement therapy/estrogen replacement therapy + calcitriol  increased bone mineral density 3.80 % ( + /-4.95 % ) at the femoral neck ( P < 0.001 ) , 4.91 % ( + /-6.0 % ) at the spine ( P < 0.0001 ) , and parallel changes at the total hip and trochanter . All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck , spine , total hip and trochanter . There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone on bone mineral density at any site in the intent to treat analysis . In a secondary analysis of the effect in women who were adherent to treatment , calcitriol had a more significant effect on spine ( P = 0.003 ) and total hip ( P = 0.004 ) . The increase in bone mineral density in the adherent groups of women was always higher compared with the intent to treat groups . Combination therapy compared with hormone replacement therapy/estrogen replacement therapy alone produced a significantly greater response in trochanter ( P = 0.007 ) and total hip bone mineral density ( P = 0.0017 ) . In summary , hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinical ly relevant sites in a group of elderly women , with normal bone density for their age . Calcitriol was effective in increasing spine bone mineral density . In the adherent women , combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone CONTEXT Observational studies show an association between low vitamin D status assessed by circulating 25-hydroxyvitamin D and cardiovascular events and mortality . Data from r and omized controlled trials are limited . OBJECTIVE The aim of this study was to test whether daily doses of vitamin D(3 ) at 400 or 1000 IU/d for 1 yr affected conventional markers of cardiovascular disease ( CVD ) risk . DESIGN We conducted a parallel-group , double-blind , placebo-controlled r and omized controlled trial . R and omization was computer generated . Participants and study investigators were blinded to intervention groupings throughout the trial . SETTING The study was conducted at the Clinical Research Facility , University of Aberdeen , United Kingdom . PARTICIPANTS A total of 305 healthy postmenopausal women aged 60 - 70 yr were recruited for the study . INTERVENTION Each woman received a daily capsule of 400 or 1000 IU vitamin D(3 ) or placebo r and omly allocated . MAIN OUTCOME MEASURES Primary outcomes were serum lipid profile [ total , high-density lipoprotein , and low-density lipoprotein cholesterol ; triglycerides ; and apolipoproteins A-1 and B100 ] , insulin resistance ( homeostatic model assessment ) , inflammatory biomarkers ( high-sensitivity C-reactive protein , IL-6 , soluble intracellular adhesion molecule-1 ) , and blood pressure . RESULTS A total of 265 ( 87 % ) participants completed all study visits . Small differences between groups for serum apolipoprotein B100 change [ repeated measures ANOVA , P=0.04 ; mean ( sd ) , -1.0 ( 10.0 ) mg/dl ( 400 IU ) ; -1.0 ( 10.0 ) mg/dl ( 1000 IU ) ; and + 0.02 ( 10.0 ) mg/dl ( placebo ) ] were not considered clinical ly significant . Other systemic markers for CVD risk remained unchanged . There was significant seasonal variation in systolic and diastolic blood pressure independent of vitamin D dose ( P<0.001 , linear mixed model ) . Mean ( sd ) reduction in systolic blood pressure from winter to summer was -6.6 ( 10.8 ) mm Hg . CONCLUSIONS Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors . Confounding of seasonality should be recognized and addressed in future studies of vitamin BACKGROUND There is a paucity of research evaluating the relation between  vitamin D  and recurrence of breast cancer after treatment . OBJECTIVE This study was design ed to evaluate the associations between circulating concentrations of  25-hydroxyvitamin D [ 25(OH)D ]  and dietary , supplemental , and total intake of vitamin D  and recurrent or new breast cancer events within the Women 's Healthy Eating and Living ( WHEL ) Study . DESIGN A prospect i ve cohort study design ( n = 3085 ) was used to evaluate the relation between dietary , supplemental , and total vitamin D intake and recurrent breast cancer , and a nested case-control study with 512 matched pairs was used for analysis of the association between 25(OH)D and breast cancer recurrence . RESULTS No relation between 25(OH)D and breast cancer recurrence was observed . Compared with women with serum concentrations of 25(OH)D ≥ 30 ng/mL , adjusted odds ratios ( 95 % CI ) for breast cancer recurrence were 1.14 ( 0.57 , 2.31 ) for those with concentrations < 10 ng/mL , 1.00 ( 0.68 - 1.48 ) for concentrations ≥ 10 and < 20 ng/mL , and 1.05 ( 0.76 , 1.47 ) for concentrations ≥ 20 and < 30 ng/mL. No significant associations were observed when analyses were stratified by pre- and postmenopausal status or for local , regional , or distant recurrence or death . Vitamin D intake was not related to breast cancer recurrence overall , although for premenopausal women there was a significant inverse association between dietary vitamin D intake and recurrence ( P for trend = 0.02 ) . CONCLUSION These results do not provide support for a relation between concentrations of 25(OH)D after treatment and the recurrence of breast cancer . This trial is registered at clinical trials.gov for the WHEL Study as NCT00003787 To evaluate the effects of alfacalcidol on bone turnover in elderly women with osteoporosis , an open-label , prospect i ve , calcium-controlled study was conducted . A total of 80 patients with osteoporosis were divided into two groups : the control group , group C ( mean age , 78.0 years ) , in which patients were given calcium , and group D ( mean age , 77.4 years ) , in which the patients were given alfacalcidol 1 µg/day together with calcium for 6 months . Calcium regulation , lumbar bone mineral density ( LBMD ) , and markers for bone turnover were assessed . A significant increase in urinary calcium/creatinine ratio ( 90 % increase from baseline at 3 months ; P = 0.0083 , and 60 % at 6 months ; P = 0.0091 ) and a significant decrease in serum parathyroid hormone ( 30 % decrease from baseline at 6 months ; P < 0.0001 ) was observed in group D compared with the corresponding changes in group C. Significant decreases of bone resorption markers ( deoxypyridinoline and N-telopeptide ) at 6 months ( about 15 % decrease from the baseline values ) were observed in group D compared with the corresponding changes in group C. The changes in bone formation markers ( bone-derived alkaline phosphatase and osteocalcin ) in group D were significantly different at 6 months ( −21.5 % ; P = 0.0047 and −13.4 % ; P = 0.0032 , respectively ) from the values in group C. The magnitudes of the decrease in bone turnover markers were highly correlated with the corresponding baseline values , suggesting that alfacalcidol treatment effectively reduces bone turnover in patients with high bone turnover rates . The LBMD in group D increased by 1.7 % and that in group C decreased by 1.6 % ( P = 0.0384 ) . The changes in calcium metabolism and LBMD were in good agreement with those in previous reports . Although the changes in bone turnover markers in group D were slight , significant reduction in bone turnover with alfacalcidol treatment , together with the change in calcium metabolism , may account for the effects of alfacalcidol on BMD and on fracture prevention reported previously . In conclusion , alfacalcidol reduces bone turnover  in elderly women with high-bone-turnover osteoporosis , and it may have beneficial effects on bone Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower  blood pressure . We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in postmenopausal women . The Women 's Health Initiative Calcium/Vitamin D Trial r and omly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion . Change in blood pressure and the incidence of hypertension were ascertained . Over a median follow-up time of 7 years , there was no significant difference in the mean change over time in systolic blood pressure ( 0.22 mm Hg ; 95 % CI : −0.05 to 0.49 mm Hg ) and diastolic blood pressure ( 0.11 mm Hg ; 95 % CI : −0.04 to 0.27 mm Hg ) between the active and placebo treatment groups . This null result was robust in analyses accounting for nonadherence to study pills and in baseline subgroups of interest , including black subjects and women with hypertension or high levels of blood pressure , with low intakes of calcium and vitamin D or low serum levels of vitamin D. In 17 122 nonhypertensive participants at baseline , the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 ( 95 % CI : 0.96 to 1.06 . ) In postmenopausal  women , calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up Objective : Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events . The relationship between calcium plus vitamin D ( calcium/D ) supplementation and coronary artery calcium ( CAC ) has not been previously assessed in a r and omized trial setting . We compared CAC scores after trial completion between women r and omized to calcium/vitamin D supplementation and women r and omized to placebo . Methods : In an ancillary sub study of women r and omized to calcium carbonate ( 1,000 mg of elemental calcium daily ) plus vitamin D3 ( 400 IU daily ) or placebo , nested within the Women 's Health Initiative trial of estrogen among women who underwent hysterectomy , we measured CAC with cardiac CT in 754 women aged 50 to 59 years at r and omization . Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment , and scans were read central ly . CAC scores were measured by a central reading center with masking to r and omization assignments . Results : Posttrial CAC measurements were similar in women r and omized to calcium/D supplementation and those receiving placebo . The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo ( rank test P value = 0.74 ) . After adjustment for coronary risk factors , multivariate odds ratios for increasing CAC score cutpoints ( CAC > 0 , ≥10 , and ≥100 ) for calcium/D versus placebo were 0.92 ( 95 % CI , 0.64 - 1.34 ) , 1.29 ( 0.88 - 1.87 ) , and 0.90 ( 0.56 - 1.44 ) , respectively . Corresponding odds ratios among women with a 50 % or higher adherence to study pills and for higher levels of CAC ( > 300 ) were similar . Conclusions : Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women . Whether higher or lower doses would affect this outcome remains uncertain BACKGROUND Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers . However , interventional studies to test this effect are lacking . OBJECTIVE The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk  of all types . DESIGN This was a 4-y , population -based , double-blind , r and omized placebo-controlled trial . The primary outcome was fracture incidence , and the principal secondary outcome was cancer incidence . The subjects were 1179 community-dwelling women r and omly selected from the population of healthy postmenopausal women aged > 55 y in a 9-county rural area of Nebraska centered at latitude 41.4 degrees N. Subjects were r and omly assigned to receive 1400 - 1500 mg supplemental calcium/d alone ( Ca-only ) , supplemental calcium plus 1100 IU vitamin D3/d ( Ca + D ) , or placebo . RESULTS When analyzed by intention to treat , cancer incidence was lower in the Ca + D women than in the placebo control subjects ( P < 0.03 ) . With the use of logistic regression , the unadjusted relative risks ( RR ) of incident cancer in the Ca + D and Ca-only groups were 0.402 ( P = 0.01 ) and 0.532 ( P = 0.06 ) , respectively . When analysis was confined to cancers diagnosed after the first 12 mo , RR for the Ca + D group fell to 0.232 ( CI : 0.09 , 0.60 ; P < 0.005 ) but did not change significantly for the Ca-only group . In multiple logistic regression models , both treatment and serum 25-hydroxyvitamin D concentrations were significant , independent predictors of cancer risk . CONCLUSIONS Improving calcium and vitamin D nutritional status substantially reduces  all-cancer risk in postmenopausal women . This trial was registered at clinical trials.gov as NCT00352170 BACKGROUND In a previous 2-y r and omized controlled trial , we showed that calcium- and vitamin D3-fortified milk stopped or slowed bone loss at several clinical ly relevant skeletal sites in older men . OBJECTIVE The present study aim ed to determine whether the skeletal benefits of the fortified milk were sustained after withdrawal of the supplementation . DESIGN One hundred nine men > 50 y old who had completed a 2-y fortified milk trial were followed for an additional 18 mo , during which no fortified milk was provided . Bone mineral density ( BMD ) of the total hip , femoral neck , lumbar spine , and forearm was measured by using dual-energy X-ray absorptiometry . RESULTS Comparison of the mean changes from baseline between the groups ( adjusted for baseline age , BMD , total calcium intake , and change in weight ) showed that the net beneficial effects of fortified milk on femoral neck and ultradistal radius BMD at the end of the intervention ( 1.8 % and 1.5 % , respectively ; P < 0.01 for both ) were sustained at 18-mo follow-up ( P < 0.05 for both ) . The nonsignificant between-group differences at the total hip ( 0.8 % ; P = 0.17 ) also persisted at follow-up ( 0.7 % ; P = 0.10 ) , but there were no lasting benefits at the lumbar spine . The average total dietary calcium intake in the milk supplementation group at follow-up approximated recommended amounts for Australian men > 50 y old ( 1000 mg/d ) but did not differ significantly from that in the control subjects ( 1021 versus 890 mg/d ) . CONCLUSION Supplementation with calcium- and vitamin D3-fortified milk for 2 y may provide some sustained benefits for BMD  in older men after withdrawal of supplementation In all species tested , except humans , biological differences between vitamins D2 and D3 are accepted as fact . To test the presumption of equivalence in humans , we compared the ability of equal molar quantities of vitamin D2 or D3 to increase serum 25-hydroxyvitamin D [ 25(OH)D ] , the measure of vitamin D nutrition .  Subjects took 260 nmol ( approximately 4000 IU ) vitamin D2  ( n=17 ) or vitamin D3  ( n=55 ) daily for 14 d. 25(OH)D was assayed with a method that detects both the vitamin D2 and D3 forms . With vitamin D3 , mean ( + /-SD ) serum 25(OH)D increased from 41.3+/-17.7 nmol/L before to 64.6+/-17.2 nmol/L after treatment . With vitamin D2 , the 25(OH)D concentration went from 43.7+/-17.7 nmol/L before to 57.4+/-13.0 nmol/L after . The increase in 25(OH)D with vitamin D3  was 23.3+/-15.7 nmol/L , or 1.7 times the increase obtained with vitamin D2 ( 13.7+/-11.4 nmol/L ; P=0.03 ) . There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration . The lowest 2 tertiles for basal 25(OH)D showed larger increases in 25(OH)D : 30.6 and 25.5 nmol/L , respectively , for the first and second tertiles . In the highest tertile [ 25(OH)D > 49 nmol/L ] the mean increase in 25(OH)D was 13.3 nmol/L ( P < 0.03 for comparison with each lower tertile ) . Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small , it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose . The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered BACKGROUND Epidemiological evidence supports a relationship between vitamin D and mental well-being , although evidence from large-scale placebo-controlled intervention trials is lacking . AIMS To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women ; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms ; and if there is an association between serum 25-hydroxyvitamin D levels and mental health . METHOD A double-blind , r and omised , placebo-controlled trial of women aged 70 or older ( the Vital D Study : IS RCT N83409867 and ACTR12605000658617 ) . Participants were r and omly assigned to receive 500 000 IU vitamin D(3 ) ( cholecalciferol ) orally or placebo every autumn/winter for 3 - 5 consecutive years . The tools utilised at various time points were the General Health Question naire , the 12-item Short Form Health Survey , the Patient Global Impression-Improvement scale and the WHO Well-Being Index . Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants . RESULTS In this non- clinical population , no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health . Serum 25-hydroxyvitamin D levels in the vitamin D group were 41 % higher than the placebo group 12 months following their annual dose . Despite this difference , scores from the question naires did not differ . Furthermore , there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups . CONCLUSIONS The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3 ) is a practical intervention to prevent depressive symptoms in older community-dwelling women The Women 's Health Initiative ( WHI ) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women , including cancer , cardiovascular disease , and osteoporotic fractures . The WHI was initiated in 1992 , with a planned completion date of 2007 . Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial ( CT ) that will include about 64,500 women or an observational study ( OS ) that will include about 100,000 women . The CT is design ed to allow r and omized controlled evaluation of three distinct interventions : a low-fat eating pattern , hypothesized to prevent breast cancer and colorectal cancer and , secondarily , coronary heart disease ; hormone replacement therapy , hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and , secondarily , to reduce the risk of hip and other fractures , with increased breast cancer risk as a possible adverse outcome ; and calcium and vitamin D supplementation , hypothesized to prevent hip fractures and , secondarily , other fractures and colorectal cancer . Overall benefit-versus-risk assessment is a central focus in each of the three CT components . Women are screened for participation in one or both of the components -- dietary modification ( DM ) or hormone replacement therapy (HRT)--of the CT , which will r and omize 48,000 and 27,500 women , respectively . Women who prove to be ineligible for , or who are unwilling to enroll in , these CT components are invited to enroll in the OS . At their 1-year anniversary of r and omization , CT women are invited to be further r and omized into the calcium and vitamin D ( CaD ) trial component , which is projected to include 45,000 women . The average follow-up for women in either CT or OS is approximately 9 years . Concerted efforts are made to enroll women of racial and ethnic minority groups , with a target of 20 % of overall enrollment in both the CT and OS . This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component . Some detail is provided on specific study design choices , including eligibility criteria , recruitment strategy , and sample size , with attention to the partial factorial design of the CT . Some aspects of the CT monitoring approach are also outlined . The scientific and logistic complexity of the WHI implies particular leadership and management challenges . The WHI organization and committee structure employed to respond to these challenges is also briefly described BACKGROUND Low 25-hydroxy-vitamin D ( 25(OH)D ) levels are inversely related to blood pressure ( BP ) and have been associated with incident hypertension . In people living at northern latitudes diminished cholecalciferol synthesis in the winter increases the risk of vitamin D deficiency . We wanted to test the hypothesis that daily cholecalciferol supplementation in the winter lowers BP in patients with hypertension . METHODS We investigated the effect of 75 µg ( 3,000 IU ) cholecalciferol per day in a r and omized , placebo-controlled , double-blind study in 130 hypertensive patients residing in Denmark ( 56º N ) . Ambulatory BP ( 24-h BP ) and arterial stiffness were measured before and after 20 weeks of treatment , that took place between October and March . RESULTS A total of 112 patients ( mean age 61 ± 10 ) with a baseline p-25(OH)D of 23 ± 10 ng/ml completed the study . Compared with placebo , a nonsignificant 3/1 mm Hg ( P = 0.26/0.18 ) reduction was found in 24-h BP . In patients with vitamin D insufficiency ( < 32 ng/ml ) at baseline ( n =  92 ) , 24-h BP decreased by 4/3 mm Hg ( P = 0.05/0.01 ) . Central BP ( CBP ) estimated by applanation tonometry and calibrated with a st and ardized office BP was reduced by 7/2 mm Hg ( P = 0.007/0.15 ) vs. placebo . No differences in carotid-femoral pulse wave velocity ( PWV ) or central augmentation index ( AIx ) were found between treatment arms . CONCLUSIONS Cholecalciferol supplementation , by a dose that effectively increased vitamin D levels , did not reduce 24-h BP , although central systolic BP decreased significantly . In a post-hoc subgroup analysis of 92 subjects with baseline p-25(OH)D levels < 32 ng/ml , significant decreases in 24-h systolic and diastolic BP occurred during cholecalciferol supplementation In women , the influence of and rogens on bone health is not clear . It has been suggested that the and rogen receptor ( AR ) genotype is associated with bone mineral density and serum and rogen levels in pre- and perimenopausal women , but the association between AR genotype , bone mineral density , and fracture risk has not been studied in postmenopausal women . Therefore , we studied whether AR polymorphism affects bone mineral density , bone mineral density change , or fracture risk in a 5-year r and omized hormone replacement therapy ( HRT ) trial on 331 early postmenopausal women ( mean baseline age , 52.7 + /- 2.3 years ) . The participants consisted of two treatment groups : the HRT group ( n = 151 ) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3 , 100 - 300 IU + 93 mg calcium as lactate/day , and the non-HRT group ( n = 180 ) received 93 mg calcium alone or in combination with vitamin D3 , 100 - 300 IU/day for 5 years .  Bone mineral density was measured from lumbar spine and proximal femur ( DXA ) before and after the 5-year trial . All new symptomatic , radiographically defined fractures were recorded during the follow-up . The length of CAG repeat in exon 1 of AR gene was evaluated after polymerase chain reaction ( PCR ) amplification . The subjects were divided into three repeat groups according to AR alleles . None of the baseline characteristics were associated with AR gene polymorphism and HRT treatment . The polymorphism did not influence the calculated annual changes of lumbar or femoral neck bone mineral density during the 5-year follow-up in the HRT ( p = 0.926 and 0.146 , respectively ) or non-HRT ( p = 0.818 and 0.917 , respectively ) groups . In all , 28 women sustained 33 fractures during the follow-up . Thus , the numbers of fractures were limited . The AR repeat length variation was not significantly associated with fracture risk in the HRT or non-HRT groups ( p = 0.632 and 0.459 , respectively ; Cox proportional hazards model ) . In conclusion , AR gene polymorphism was not associated with baseline bone mineral density , 5-year bone mineral density change , or fracture risk in early postmenopausal Finnish women The exact antineoplastic effects of calcium and vitamin D3 in the human colon are unclear . Animal and in vitro studies show that these two agents reduce oxidative stress ; however , these findings have never been investigated in humans . To address this , we conducted a pilot , r and omized , double-blind , placebo-controlled , 2 × 2 factorial clinical trial to test the effects of calcium and vitamin D3 on a marker of oxidative DNA damage , 8-hydroxy-2′-deoxyguanosine ( 8-OH-dG ) , in the normal colorectal mucosa . Patients ( N = 92 ) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and /or 800 IU/d vitamin D3 versus placebo over 6 months . Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by st and ardized automated immunohistochemistry and quantified by image analysis . After 6 months of treatment , 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22 % ( P = 0.15 ) and 25 % ( P = 0.10 ) in the calcium and vitamin D3 groups , respectively , but not in the calcium plus vitamin D3 group . The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression ( P = 0.05 ) . Overall , these preliminary results indicate that calcium and vitamin D3 may decrease oxidative DNA damage in the normal human colorectal mucosa , support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms , and provide support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms . Cancer Epidemiol Biomarkers Prev ; 19(1 ) ; Summary Treatment of vitamin D deficiency for 3 months with oral cholecalciferol 5,000 IU daily was more effective than 2,000 IU daily in achieving optimal serum 25-hydroxyvitamin D ( 25OHD ) concentrations . Optimal 25OHD serum level calculated to be 63.8 nmol/L. All parameters of muscle strength improved following administration of cholecalciferol for 3 months . Introduction The aim of this study was to determine the optimal dose of cholecalciferol required to achieve target serum 25OHD level ≥75 nmol/L and its relationship to both bone turnover and muscle strength . Methods Thirty deficient patients ( serum 25OHD ≤50 nmol/L ) were r and omly assigned into two groups — i.e . 2,000 and 5,000 IU/day . Data were collected at baseline , at 2 and 3 months post-therapy : ( a ) clinical demographics , ( b ) dietary calcium recall , ( c ) physical tests of muscle function and ( d ) biochemistry . Statistical analysis used paired student t test and analysis of variance . Regression analysis was used to determine relationship between serum 25OHD and parathyroid hormone ( PTH ) . Results Twenty-six ( 87 % ) patients completed 3 months of therapy . The percent increase in serum 25OHD ( compared to baseline ) was 82.7 % in 2,000-IU group and 219.5 % in 5,000-IU group . All participants ( 100 % ) achieved a serum 25OHD concentration > 50 nmol/L ; only 5 subjects ( 45.4 % ) in 2,000-IU group compared to 14 subjects ( 93.3 % ) in 5,000-IU group achieved final 25OHD concentration ≥75 nmol/L ( p < 0.01 ) . In the regression analysis , the reflexion point at which the PTH level increased above the normal range was calculated to be 63.8 nmol/L 25OHD . All parameters of muscle strength showed trends in improvements following the administration of both the 2,000 and 5,000 IU doses . No patient reported untoward side effects and no patient developed hypercalcaemia . Conclusion Treatment for 3 months with oral cholecalciferol 5,000 IU daily may be more effective than 2,000 IU daily in achieving optimal serum 25OHD concentrations in vitamin D-deficient patients BACKGROUND Ergocalciferol ( vitamin D(2 ) ) supplementation plays a role in fall prevention , but the effect in patients living in the community in sunny climates remains uncertain . We evaluated the effect of ergocalciferol and calcium citrate supplementation compared with calcium alone on the risk of falls in older women at high risk of falling . METHODS A 1-year population -based , double-blind , r and omized controlled trial of 302 community-dwelling ambulant older women aged 70 to 90 years living in Perth , Australia ( latitude , 32 degrees S ) , with a serum 25-hydroxyvitamin D concentration of less than 24.0 ng/mL and a history of falling in the previous year . Participants were r and omized to receive ergocalciferol , 1000 IU/d , or identical placebo ( hereinafter , ergocalciferol and control groups , respectively ) . Both groups received calcium citrate , 1000 mg/d . Fall data were collected every 6 weeks . RESULTS Ergocalciferol therapy reduced the risk of having at least 1 fall over 1 year after adjustment for baseline height , which was significantly different between the 2 groups ( ergocalciferol group , 53.0 % ; control group , 62.9 % ; odds ratio [ OR ] , 0.61 ; 95 % confidence interval [ CI ] , 0.37 - 0.99 ) . When those who fell were grouped by the season of first fall or the number of falls they had , ergocalciferol treatment reduced the risk of having the first fall in winter and spring ( ergocalciferol group , 25.2 % ; control group , 35.8 % ; OR , 0.55 ; 95 % CI , 0.32 - 0.96 ) but not in summer and autumn , and reduced the risk of having 1 fall ( ergocalciferol group , 21.2 % ; control group , 33.8 % ; OR , 0.50 ; 95 % CI , 0.28 - 0.88 ) but not multiple falls . CONCLUSION Patients with a history of falling and vitamin D insufficiency living in sunny climates benefit from ergocalciferol supplementation in addition to calcium , which is associated with a 19 % reduction in the relative risk of falling , mostly in winter Public health recommendations do not distinguish between vitamin D2 and vitamin D3 , yet disagreement exists on whether these two forms should be considered equivalent . The objective of the present study was to evaluate the effect of a daily physiological dose of vitamin D2 or vitamin D3 on 25-hydroxyvitamin D ( 25(OH)D ) status over the winter months in healthy adults living in Dunedin , New Zeal and ( latitude 46 ° S ) . Participants aged 18 - 50 years were r and omly assigned to 25 μg ( 1000 IU ) vitamin D3 ( n 32 ) , 25 μg ( 1000 IU ) vitamin D2 ( n 31 ) or placebo ( n 32 ) daily for 25 weeks beginning at the end of summer . A per- protocol approach , which included ≥ 90 % supplement compliance , was used for all analyses . Serum 25-hydroxyvitamin D3 ( 25(OH)D3 ) , 25-hydroxyvitamin D2 ( 25(OH)D2 ) and parathyroid hormone ( PTH ) were measured at baseline and at 4 , 8 , 13 and 25 weeks . Geometric mean total serum 25(OH)D concentrations ( sum of 25(OH)D2 and 25(OH)D3 ) at baseline was 80 nmol/l . After 25 weeks , participants r and omised to D2 and placebo had a significant reduction in serum 25(OH)D3 concentrations over the winter months compared with vitamin D3-supplemented participants ( both P < 0.001 ) . Supplementation with vitamin D2  increased serum 25(OH)D2 but produced a 9 ( 95 % CI 1 , 17 ) nmol/l greater decline in the 25(OH)D3 metabolite compared with placebo ( P < 0.036 ) . Overall , total serum 25(OH)D concentrations were 21 ( 95 % CI 14 , 30 ) nmol/l lower in participants receiving vitamin D2 compared with those receiving D3 ( P < 0.001 ) , among whom total serum 25(OH)D concentrations remained unchanged . No intervention-related changes in PTH were observed . Daily supplementation of vitamin D3 was more effective than D2 ; however , the functional consequence of the differing metabolic response warrants further investigation BACKGROUND Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk , no r and omized trial has evaluated these relationships . METHODS Postmenopausal women ( N = 36 282 ) who were enrolled in a Women 's Health Initiative clinical trial were r and omly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3 ) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture . Mammograms and breast exams were serially conducted . Invasive breast cancer was a secondary outcome . Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects . A Cox proportional hazards model was used to estimate the risk of breast cancer associated with r and om assignment to calcium with vitamin D(3 ) . Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake , body mass index ( BMI ) , recreational physical activity , and breast cancer risks were evaluated using logistic regression models . Statistical tests were two-sided . RESULTS Invasive breast cancer incidence was similar in the two groups ( 528 supplement vs 546 placebo ; hazard ratio = 0.96 ; 95 % confidence interval = 0.85 to 1.09 ) . In the nested case-control study , no effect of supplement group assignment on breast cancer risk was seen . Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake ( diet and supplements ) ( r = 0.19 , P < .001 ) and were higher among women with lower BMI and higher recreational physical activity ( both P < .001 ) . Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity ( P(trend ) = .20 ) . CONCLUSIONS Calcium and vitamin D supplementation did not reduce invasive breast  cancer incidence in postmenopausal women . In addition , 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk . These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk Data Safety Monitoring Committees ( DSMB ) for large , long-term r and omized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects . The DSMB for the Women 's Health Initiative Clinical Trials , on observing early indication of a surprising  adverse cardiovascular effect of post-menopausal hormones , spent several years deliberating what recommendations it should make . This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence . The paper concludes with some recommendations for other DSMBs BACKGROUND Some evidence suggests that vitamin D may reduce  breast cancer risk . Despite the biological interaction between vitamin D and calcium , few studies have evaluated their joint effects on breast cancer risk . OBJECTIVE The objective was to evaluate the associations and potential interaction between vitamin D and calcium ( from food and supplements ) and breast cancer risk in a population -based case-control study . DESIGN Breast cancer cases aged 25 - 74 y ( diagnosed 2002 - 2003 ) were identified through the Ontario Cancer Registry . Controls were identified by using r and om digit dialing ; 3101 cases and 3471 controls completed epidemiologic and food-frequency question naires . Adjusted odds ratios ( ORs ) and 95 % CIs were estimated by using multivariate logistic regression . RESULTS Vitamin D and calcium intakes from food only and total combined intakes ( food and supplements ) were not associated with breast cancer risk , although the mean intake of vitamin D was low . Vitamin D supplement intake > 10 microg/d ( 400 IU/d ) compared with no intake was associated with a reduced risk of breast cancer ( adjusted OR : 0.76 ; 95 % CI : 0.59 , 0.98 ) . No categories of calcium supplement intake were significantly associated with reduced breast cancer risk , but a significant inverse trend was observed ( P = 0.04 ) . There were no significant interactions involving vitamin D , calcium , or menopausal status . CONCLUSIONS No associations were found between overall vitamin D or calcium intake and breast cancer risk .  Vitamin D from supplements was independently associated with reduced breast cancer risk . Further research is needed to investigate the effects of higher doses of vitamin D and calcium supplements In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias Sun exposure is associated with lower death rates for pancreatic cancer in some ecological studies . Skin exposure to UVB light induces cutaneous production of precursors to 25-hydroxyvitamin D [ 25(OH)D ] . Pancreatic islet and duct cells express 25(OH)D(3)-1alpha-hydroxylase that generates the biologically active 1,25(OH)(2 ) vitamin D form . Thus , 25(OH)D concentrations could affect pancreatic function and possibly pancreatic cancer etiology . We conducted a prospect i ve nested case-control study in the Alpha-Tocopherol , Beta-Carotene Cancer Prevention cohort of male Finnish smokers , ages 50 to 69 years at baseline , to test whether more adequate vitamin D status , as determined by prediagnostic serum 25(OH)D concentrations , was associated with lower pancreatic cancer risk . Two hundred incident exocrine pancreatic cancer cases that occurred between 1985 and 2001 ( up to 16.7 years of follow-up ) were matched by age and date of blood draw to 400 controls who were alive and free of cancer at the time the case was diagnosed .  Odds ratios ( OR ) and 95 % confidence intervals ( 95 % CI ) were calculated using conditional logistic regression . Higher vitamin D concentrations were associated with a 3-fold increased risk for pancreatic cancer ( highest versus lowest quintile , > 65.5 versus < 32.0 nmol/L : OR , 2.92 ; 95 % CI , 1.56 - 5.48 , P(trend ) = 0.001 ) that remained after excluding cases diagnosed early during follow-up . Contrary to expectations , subjects with higher prediagnostic vitamin D status had an increased pancreatic cancer risk compared with those with lower status . Our findings need to be replicated in other population s and caution is warranted in their interpretation and implication . Our results are intriguing and may provide clues that further the underst and ing of the etiology of this highly fatal cancer Vitamin D deficiency in the patients treated for breast cancer is associated with numerous adverse effects ( bone loss , arthralgia , and falls ) . The first aim of this study was to assess vitamin D status , determined by 25-OH vitamin D levels , among women diagnosed with breast cancer according to demographic/ clinical variables and bone mineral density ( BMD ) . The second aim of this study was to evaluate the effect of daily low-dose and weekly high-dose vitamin D supplementation on 25-OH vitamin D levels . This retrospective study included 224 women diagnosed with stage 0–III breast cancer who received treatment at the James P. Wilmot Cancer Center at the University of Rochester Medical Center . Total 25-OH vitamin D levels ( D2 + D3 ) were determined at baseline for all participants . Vitamin D deficiency was defined as a 25-OH vitamin D level < 20 ng/ml , insufficiency as 20–31 ng/ml , and sufficiency as ≥32 ng/ml . BMD was assessed during the period between 3 months before and 6 months following the baseline vitamin D assessment . Based on the participants ’ baseline levels , they received either no supplementation , low-dose supplementation ( 1,000 IU/day ) , or high-dose supplementation ( ≥50,000 IU/week ) , and 25-OH vitamin D was reassessed in the following 8–16 weeks . Approximately 66.5 % had deficient/insufficient vitamin D levels at baseline . Deficiency/insufficiency was more common among non-Caucasians , women with later-stage disease , and those who had previously received radiation therapy ( P < 0.05 ) . Breast cancer patients with deficient/insufficient 25-OH vitamin D levels had significantly lower lumbar BMD ( P = 0.03 ) . Compared to the no-supplementation group , weekly high-dose supplementation significantly increased 25-OH vitamin D levels , while daily low-dose supplementation did not significantly increase levels . Vitamin D deficiency and insufficiency were common among women with breast cancer and associated with reduced BMD in the spine . Clinicians should carefully consider vitamin D supplementation regimens when treating vitamin D deficiency/insufficiency in breast cancer patients Genetic factors regulate bone mineral density ( BMD ) and possibly development of osteoporosis . It has been suggested that estrogen receptor alpha ( ERalpha ) genotype is associated with BMD , but the association between ERalpha genotype , fracture risk , and postmenopausal hormone replacement therapy ( HRT ) has not been studied . Therefore , we evaluated whether ERalpha polymorphism is associated with fracture risk in a 5-year trial with HRT  in a population -based , r and omized group of 331 early postmenopausal women . The participants consisted of two treatment groups : the HRT group ( n = 151 ) received a sequential combination of 2 mg of estradiol valerate ( E2Val ) and 1 mg of cyproterone acetate with or without vitamin D3 , 100 - 300 IU + 93 mg calcium as lactate per day ; and the non-HRT group ( n = 180 ) received 93 mg of calcium alone or in combination with vitamin D3 , 100 - 300 IU/day . All new symptomatic , radiographically defined fractures were recorded . Pvu II restriction fragment length polymorphism of the ERalpha was determined using polymerase chain reaction ( PCR ) . In all , 28 women sustained 33 fractures  during the approximately 5.1-year follow-up . In the HRT group , the ERalpha genotype ( PP , Pp , and pp ) was not significantly associated with fracture risk ( p = 0.138 ; Cox proportional hazards model ) . When the genotype was dichotomized ( PP + Pp vs. pp ) , the incidence of new fractures in the HRT group was significantly reduced in women with the P allele ( p = 0.046 ) with the relative risk ( HR ) of 0.25 ( 95 % CI , 0.07 - 0.98 ) , in comparison with the non-P allele group . After adjustment for time since menopause and previous fracture , the association between the dichotomous genotype and fracture risk persisted with HR of 0.24 ( 95 % CI , 0.06 - 0.95;p = 0.042 ) . In the  non-HRT group , the ERalpha genotype was not significantly associated with fracture risk . During HRT , women with the pp genotype have a greater fracture risk than those with the P allele . The results suggest that the pp genotype is a relatively hormone-insensitive genotype , and it appears that women with the P allele may benefit more from the protective effect of HRT on fracture risk than women with the pp genotype The study was design ed to examine the effect of hormone replacement therapy ( HRT ) and low-dose vitamin D ( Vit D ) supplementation on the prevention of bone loss in non-osteoporotic early postmenopausal women and to determine whether Vit D supplementation can give additional benefit to an already optimized estrogen regimen . The effects of HRT and Vit D on bone mineral density ( BMD ) were studied in postmenopausal women in a 2.5-year r and omized placebo-controlled study . The study population was a subgroup of the Kuopio Osteoporosis Risk Factor and Prevention Study ( OSTPRE ) ( n=13100 ) . A total of 464 early postmenopausal women were r and omized to four groups : ( 1 ) HRT ( a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ( E2Val/CPA ) ; ( 2 ) vitamin D3 ( cholecalciferol , 300 IU/day ) ; ( 3 ) HRT+Vit D ; and ( 4 ) placebo ( calcium lactate ; 93 mg Ca2+/day ) . Lumbar ( L1–4 ) and femoral neck BMD were determined by dual-energy X-ray absorptiometry before and after 2.5 years of treatment . After 2.5 years , lumbar BMD had increased by 1.8 % in the HRT group ( p<0.001 ) and by 1.4 % in the HRT+Vit D group ( p=0.002 ) , whereas lumbar BMD had decreased by 3.5 % ( p<0.001 ) in the Vit D group and by 3.7 % ( p<0.001 ) in the placebo group . The loss of femoral neck BMD was lower in the HRT ( −0.3 % ) and the HRT+Vit D ( −0.9 % ) groups compared with the Vit D ( −2.4 % ) and the placebo groups ( −3.7 % ) . This study confirms the beneficial effect of HRT on BMD . It also shows that low-dose vitamin D supplementation has only a minor effect in the prevention of osteoporosis in non-osteoporotic early postmenopausal women and does not give any benefit additional to that of HRT alone CONTEXT Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures ; however , adherence to daily supplementation is typically poor . OBJECTIVE To determine whether a single annual dose of 500,000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture . DESIGN , SETTING , AND PARTICIPANTS A double-blind , placebo-controlled trial of 2256 community-dwelling women , aged 70 years or older , considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were r and omly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years . The study concluded in 2008 . INTERVENTION 500,000 IU of cholecalciferol or placebo . MAIN OUTCOME MEASURES Falls and fractures were ascertained using monthly calendars ; details were confirmed by telephone interview . Fractures were radiologically confirmed . In a sub study , 137 r and omly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels . RESULTS Women in the cholecalciferol ( vitamin D ) group had 171 fractures vs 135 in the placebo group ; 837 women in the vitamin D group fell 2892 times ( rate , 83.4 per 100 person-years ) while 769 women in the placebo group fell 2512 times ( rate , 72.7 per 100 person-years ; incidence rate ratio [ RR ] , 1.15 ; 95 % confidence interval [ CI ] , 1.02 - 1.30 ; P = .03 ) . The incidence RR for fracture in the vitamin D group was 1.26 ( 95 % CI , 1.00 - 1.59 ; P = .047 ) vs the placebo group ( rates per 100 person-years , 4.9 vitamin D vs 3.9 placebo ) . A temporal pattern was observed in a post hoc analysis of falls . The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months ( test for homogeneity ; P = .02 ) . In the sub study , the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3 % of the sub study participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group , 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L , were approximately 90 nmol/L at 3 months , and remained higher than the placebo group 12 months after dosing . CONCLUSION Among older community-dwelling women , annual oral administration of high-dose cholecalciferol result ed in an increased risk of falls and fractures . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12605000658617 ; is rct n.org Identifier : IS RCT N83409867 OBJECTIVES Oxidative modification of low-density lipoprotein ( oxLDL ) has been suggested to play an important role in the pathogenesis of atherosclerosis , and autoantibodies against oxLDL have recently found to reflect this process . The antioxidant effect and inhibition of LDL oxidation may be one of the cardioprotective mechanisms of postmenopausal estrogen therapy . METHODS The effects of postmenopausal hormone replacement therapy ( HRT ) on the concentrations of serum lipids and oxLDL autoantibodies were studied in a population -based prospect i ve 1-year study with 64 early postmenopausal women ( mean age 52.2 + /- 0.4 ( S.E.M. ) years ) . The participants were r and omized into two treatment groups : HRT-group : Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate alone or in combination with vitamin D3 , 300 IU/day + calcium lactate , 500 mg/day ( n = 31 ) and the non-HRT-group : Calcium lactate , 500 mg/day alone or in combination with vitamin D3 , 300 IU/day ( n = 33 ) . The groups were well matched regarding age , body mass index and baseline serum lipid concentrations . RESULTS The serum concentrations of total cholesterol and LDL-cholesterol decreased in the HRT-group ( 4.1 % , P = 0.05 and 6.4 % , P = 0.03 , respectively , paired t-test ) but did not change in the non-HRT-group . No changes in the serum concentrations of HDL-cholesterol or triglycerides were observed . Additionally , no changes in oxLDL autoantibody concentrations were observed in either group . CONCLUSIONS Although 1-year HRT lowered serum total- and LDL-cholesterol levels , it did not influence oxLDL antibody titers . On the basis of the present results we can not question the possibility of there being beneficial effects of HRT on the oxidative modification of LDL . However , this effect is not reflected in the levels of oxLDL autoantibodies Calcium plus vitamin D ( CaD ) supplementation has a modest but significant effect on slowing loss of femoral bone mass and reducing risk of hip fractures in adherent postmenopausal women . The goal of this study was to determine if CaD supplementation influences hip structural parameters that are associated with fracture risk . We studied 1,970 postmenopausal women enrolled in the Women ’s Health Initiative r and omized controlled trial of CaD at one of three bone mineral density ( BMD ) clinical centers . Hip structural analysis software measured BMD and strength parameters on DXA scans at three regions : femoral narrow neck , intertrochanter , and shaft . R and om effects models were used to test the average differences in hip BMD and geometry between intervention and placebo . There was greater preservation of hip BMD at the narrow neck with CaD relative to placebo across 6 years of intervention . CaD also altered the underlying cross-sectional geometry at the narrow neck in the direction of greater strength , with small increases in cross-sectional area and section modulus and a decrease in buckling ratio with CaD relative to placebo . While trends at both the intertrochanter and shaft regions were similar to those noted at the narrow neck , no significant intervention effects were evident . There was no significant interaction of  CaD and age or baseline calcium levels for hip structural properties . CaD supplementation is associated with modest beneficial effects on hip structural features at the narrow neck , which may explain some of the benefit of CaD in reducing hip fracture risk In a 5-yr r and omized prospect i ve study we examined the treatment effect of estrogen replacement therapy/hormone replacement therapy ( ERT/HRT ) , calcitriol , ERT/HRT and calcitriol , or placebo for 3 yr and the effect of discontinuation of therapy for 2 more yr on bone mineral density ( BMD ) , calciotropic hormones , markers of bone remodeling , and calcium absorption in 489 elderly women . The treatment phase of the study was double-blinded . After discontinuing therapy for 2 yr , there was rapid bone loss in all 3 treatment groups , and most of the decrease in BMD occurred in the first year . In the ERT/HRT group , spine BMD increased 5.5 % in yr 3 , decreased 3.2 % in yr 4 , and decreased 0.7 % in yr 5 ; femoral neck BMD increased 3.7 % in yr 3 , decreased 2.5 % in yr 4 , and decreased 0.4 % in yr 5 ; total body BMD increased 2.1 % in yr 3 , decreased 1.4 % in yr 4 , and decreased 0.6 % in yr 5 . In the combination group , spine BMD increased 7.1 % in yr 3 , decreased 4.3 % in yr 4 , and decreased 0.3 % in yr 5 ; femoral neck BMD increased 4.5 % in yr 3 , decreased 3.0 % in yr 4 , and decreased 0.01 % in yr 5 ; total body BMD increased 2.2 % in yr 3 , decreased 1.5 % in yr 4 , and decreased 0.6 % in yr 5 . In the calcitriol group , spine BMD increased 1.8 % in yr 3 , decreased 1.8 % in yr 4 , and showed no change in yr 5 ; femoral neck BMD increased 0.2 % in yr 3 , decreased 0.2 % in yr 4 , and decreased 0.6 % in yr 5 ; total body BMD decreased 0.4 % in yr 3 , decreased 0.6 % in yr 4 , and decreased 0.4 % in yr 5 . Compared with placebo , all treated groups at yr 5 had significantly higher total body BMD ; only the combination group had significantly higher spine BMD ( 3.4 % ; P < 0.001 ) and total hip BMD ( 2.4 % ; P < 0.01 . ) compared with the placebo group . Compared with baseline , only spine BMD in the combination group was significantly higher ( 2.6 % ; P < 0.001 ) at yr 5 . The increase in calcium absorption and the decrease in serum PTH levels in the calcitriol groups were reversed after discontinuation of treatment , and the decrease in bone markers was reversed in the hormone-treated groups . These results suggest that discontinuation of ERT/HRT and /or calcitriol therapy  in elderly women leads to a decrease in much of the BMD gained on treatment ; however , in the combination group there was a statistically significant residual effect on spine BMD STUDY OBJECTIVE To determine if calcitriol is an effective treatment in postmenopausal osteoporosis . DESIGN Double-blind , r and omized clinical trial of 2 years ' duration . SETTING University medical center with patients recruited by media announcements . PATIENTS Eighty-six postmenopausal women with vertebral compression fractures . INTERVENTIONS Patients were treated with calcitriol or placebo . Mean dose was 0.43 micrograms/d . Dietary calcium was 1000 mg/d ( 24.9 mmol/d ) . The medication dose and dietary calcium were adjusted for hypercalciuria or hypercalcemia . MEASUREMENTS AND MAIN RESULTS No significant differences between placebo and control groups were seen in the percent change in total body calcium ( 0.4 % + /- 1.0 compared with 0.0 % + /- 0.9 ) , single photon absorptiometry ( -0.5 % + /- 1.2 compared with -3.1 % + /- 0.9 ) or dual photon absorptiometry ( 0.0 % + /- 1.7 compared with -1.0 % + /- 2.2 ) . New fractures were seen in 16 % of the placebo group and 26 % of the calcitriol groups , so the difference in percent fractures was 10 % ( 95 % CI , -5.7 % to 25.7 % ) . Bone biopsies did not show changes in either group . The calcitriol group had significantly higher serum and urine calcium values , but renal function was not worse than in the placebo group . CONCLUSIONS Calcitriol is not an effective treatment for established postmenopausal osteoporosis We prospect ively examined the relation between pretrial serum vitamin D status and risk of oesophageal and gastric cancers among subjects who developed cancer over 5.25 years of follow-up , including 545 oesophageal squamous cell carcinomas ( ESCC ) , 353 gastric cardia adenocarcinomas , 81 gastric noncardia adenocarcinomas , and an age- and sex-stratified r and om sample of 1105 subjects . The distribution of  serum 25(OH)D  was calculated using the known sampling weights . For the cohort as a whole , the 25th , 50th , and 75th percentile concentrations of 25(OH)-vitamin D were 19.6 , 31.9 , and 48.7 nmol l−1 , respectively , and we found that higher serum 25(OH)D concentrations were associated with monotonically increasing risk of ESCC in men , but not in women . Comparing men in the fourth quartile of serum 25(OH)D concentrations to those in the first , we found a hazard ratio ( HR ) ( 95 % confidence interval ( CI ) ) of 1.77 ( 1.16–2.70 ) , P trend=0.0033 . The same comparison in women had a HR ( 95 % CI ) of 1.06 ( 0.71–1.59 ) , P trend=0.70 . We found no associations for gastric cardia or noncardia adenocarcinoma . Among subjects with low vitamin D status , higher serum 25(OH)D concentrations were associated with significantly increased risk of ESCC in men , but not in women . Further refinements of the analysis did not suggest any factors , which could explain this unexpected result BACKGROUND Epidemiological studies have yielded inconsistent associations between vitamin D status and prostate cancer risk , and few studies have evaluated whether the associations vary by disease aggressiveness . We investigated the association between  vitamin D status , as determined by serum 25-hydroxyvitamin D [ 25(OH)D ] level , and risk of prostate cancer in a case-control study nested within the Prostate , Lung , Colorectal , and Ovarian ( PLCO ) Cancer Screening Trial . METHODS The study included 749 case patients with incident prostate cancer who were diagnosed 1 - 8 years after blood draw and 781 control subjects who were frequency matched by age at cohort entry , time since initial screening , and calendar year of cohort entry . All study participants were selected from the trial screening arm ( which includes annual st and ardized prostate cancer screening ) . Conditional logistic regression was used to estimate adjusted odds ratios ( ORs ) with 95 % confidence intervals ( CIs ) by quintile of season-st and ardized serum 25(OH)D concentration . Statistical tests were two-sided . RESULTS No statistically significant trend in overall prostate cancer risk was observed with increasing season-st and ardized serum 25(OH)D level . However , serum 25(OH)D concentrations greater than the lowest quintile ( Q1 ) were associated with increased risk of aggressive ( Gleason sum > or = 7 or clinical stage III or IV ) disease ( in a model adjusting for matching factors , study center , and history of diabetes , ORs for Q2 vs Q1 = 1.20 , 95 % CI = 0.80 to 1.81 , for Q3 vs Q1 = 1.96 , 95 % CI = 1.34 to 2.87 , for Q4 vs Q1 = 1.61 , 95 % CI = 1.09 to 2.38 , and for Q5 vs Q1 = 1.37 , 95 % CI = 0.92 to 2.05 ; P(trend ) = .05 ) . The rates of aggressive prostate cancer for increasing quintiles of serum 25(OH)D were 406 , 479 , 780 , 633 , and 544 per 100 000 person-years . In exploratory analyses , these associations with aggressive disease were consistent across subgroups defined by age , family history of prostate cancer , diabetes , body mass index , vigorous physical activity , calcium intake , study center , season of blood collection , and assay batch . CONCLUSION The findings of this large prospect i ve study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer ; indeed , higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease Background — Individuals with vascular or valvular calcification are at increased risk for coronary events , but the relationship between calcium consumption and cardiovascular events is uncertain . We evaluated the risk of coronary and cerebrovascular events in the Women ’s Health Initiative r and omized trial of calcium plus vitamin D supplementation . Methods and Results — We r and omized 36 282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo .  Cardiovascular disease was a prespecified secondary efficacy outcome . During 7 years of follow-up , myocardial infa rct ion or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo ( hazard ratio , 1.04 ; 95 % confidence interval , 0.92 to 1.18 ) . Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo ( hazard ratio , 0.95 ; 95 % confidence interval , 0.82 to 1.10 ) . In subgroup analyses , women with higher total calcium intake ( diet plus supplements ) at baseline were not at higher risk for coronary events ( P=0.91 for interaction ) or stroke ( P=0.14 for interaction ) if assigned to active calcium/vitamin D. Conclusions — Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period Abstract Objective : To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community . Design : R and omised double blind controlled trial of 100 000 IU oral vitamin D3 ( cholecalciferol ) supplementation or matching placebo every four months over five years . Setting and participants : 2686 people ( 2037 men and 649 women ) aged 65 - 85 years living in the general community , recruited from the British doctors register and a general practice register in Suffolk . Main outcome measures : Fracture incidence and total mortality by cause . Results : After five years 268 men and women had incident fractures , of whom 147 had fractures in common osteoporotic sites ( hip , wrist or forearm , or vertebrae ) . Relative risks in the vitamin D group compared with the placebo group were 0.78 ( 95 % confidence interval 0.61 to 0.99 , P=0.04 ) for any first fracture and 0.67 ( 0.48 to 0.93 , P=0.02 ) for first hip , wrist or forearm , or vertebral fracture . 471 participants died . The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 ( 0.74 to 1.06 , P=0.18 ) . Findings were consistent in men and women and in doctors and the general practice population . Conclusion : Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community . What is already known in this topic Vitamin D and calcium supplements are effective in preventing fractures in elderly women Whether isolated vitamin D supplementation prevents fractures is not clear What this paper adds Four monthly oral supplementation with 100 000 IU vitamin D reduces fractures in men and women aged over 65 living in the general community  Total fracture incidence was reduced by 22 % and fractures in major osteoporotic sites by 33 Background R and omised , placebo-controlled trials are needed to provide evidence demonstrating safe , effective interventions that reduce falls and fractures in the elderly . The quality of a clinical trial is dependent on successful recruitment of the target participant group . This paper documents the successes and failures of recruiting over 2,000 women aged at least 70 years and at higher risk of falls or fractures onto a placebo-controlled trial of six years duration . The characteristics of study participants at baseline are also described for this study . Methods The Vital D Study recruited older women identified at high risk of fracture through the use of an eligibility algorithm , adapted from identified risk factors for hip fracture . Participants were r and omised to orally receive either 500,000 IU vitamin D3 ( cholecalciferol ) or placebo every autumn for five consecutive years . A variety of recruitment strategies were employed to attract potential participants . Results Of the 2,317 participants r and omised onto the study , 74 % ( n = 1716/2317 ) were consented onto the study in the last five months of recruiting . This was largely due to the success of a targeted mail-out . Prior to this only 541 women were consented in the 18 months of recruiting . A total of 70 % of all participants were recruited as a result of targeted mail-out . The response rate from the letters increased from 2 to 7 % following revision of the material by a public relations company . Participant demographic or risk factor profile did not differ between those recruited by targeted mail-outs compared with other methods . Conclusion The most successful recruitment strategy was the targeted mail-out and the response rate was no higher in the local region where the study had extensive exposure through other recruiting strategies . The strategies that were labour-intensive and did not result in successful recruitment include the activities directed towards the GP medical centres . Comprehensive recruitment programs employ overlapping strategies simultaneously with ongoing assessment of recruitment rates . In our experience , and others direct mail-outs work best although rights to privacy must be respected . Trial registration IS RCT N83409867 and ACTR12605000658617 OBJECTIVE The positive short-term effects of postmenopausal hormone replacement therapy ( HRT ) on serum lipids are well known , but it has been suggested that they vanish with time . Cholecalciferol ( vitamin D3 ) is widely used to prevent postmenopausal osteoporosis but the influence of vitamin D3 on serum lipids is poorly known . The long-term effects of HRT and vitamin D3 on the concentrations of serum lipids were studied in a population -based prospect i ve 3-year study . DESIGN AND METHODS 464 women were r and omized into four treatment groups : ( i ) HRT ( sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ) , ( ii ) Vit D3 ( vitamin D3 300 IU/day ) , ( iii ) HRT+Vit D3 ( both as above ) , ( iv ) placebo ( calcium lactate 500 mg/day ) . RESULTS 320 women completed the study . After three years of treatment , serum concentrations of low density lipoprotein ( LDL ) cholesterol decreased in the HRT group ( 10.1 % , P<0.001 ) and the HRT+Vit D3 group ( 5.9 % , P=0.005 ) , increased in the Vit D3 group ( 4.1 % , P=0.035 ) but remained unchanged in the placebo group . The concentrations of total cholesterol decreased by 5.8 % in the HRT group ( P<0.001 ) and by 3.3 % in the HRT+Vit D3 group ( P=0.023 ) , but did not change in the other two groups . Serum concentrations of high density lipoprotein ( HDL ) cholesterol decreased in the Vit D3 group ( 5.2 % , P=0.001 ) , HRT+Vit D3 group ( 3.7 % , P=0.046 ) , and the placebo group ( 4.5 % , P=0.006 ) but did not change significantly in the HRT group . The HDL/LDL ratio increased in the HRT group ( 10.5 % , P=0.006 ) and decreased in the Vit D3 group ( 10.5 % , P<0.001 ) whereas no changes occurred in the other two groups . In addition , serum triglycerides increased similarly in all groups ( 14.0 - 18.8 % , P<0.05 - 0.001 ) . CONCLUSIONS Our results confirm the positive long-term effect of HRT with sequential estradiol valerate and cyproterone acetate on serum lipid concentrations . In addition , the results suggest that vitamin D3 supplementation may have unfavorable effects on lipids in postmenopausal women .  Pure vitamin D3 treatment was associated with increased serum LDL cholesterol . Furthermore , the beneficial effects of HRT on serum LDL cholesterol content were reduced when estradiol valerate was combined with vitamin D3 . However , the relevance of these associations to cardiovascular morbidity remains to be established Abstract : Hormone replacement therapy ( HRT ) prevents postmenopausal bone loss and fractures . However , the occurrence of women with no bone response to HRT  has not been widely examined . We identified the densitometric nonresponders to long-term HRT and investigated some characteristics and biochemical variables as possible predictors of densitometric nonresponse in postmenopausal women . The study population was a sub sample of the Kuopio Osteoporosis Study ( n= 14.220 ) . A total of 464 early postmenopausal women were r and omized into four treatment groups : ( 1 ) HRT ( sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ) ; ( 2 ) vitamin D3 ; ( 3 ) HRT + Vitamin D3 combined ; and ( 4 ) placebo . In this study , the data from HRT and placebo groups were analyzed . Lumbar ( L2–4 ) and femoral neck bone mineral density ( BMD ) were determined by dual-energy X-ray absorptiometry ( DXA ) at baseline and after 5 years of treatment . A densitometric nonresponder was defined as a woman whose 5-year BMD change was similar to the mean BMD change ( + 95 % CI ) of the placebo group or worse . Altogether , 74 women in the HRT group and 104 women in the placebo group complied with the treatment . According to spinal BMD analysis , 11 % of the women were classified as densitometric nonresponders ; the corresponding proportion for femoral BMD analysis was 26 % . Both smoking ( p= 0.003 ) and low body weight ( p= 0.028 ) were significant risk factors for densitometric nonresponse to HRT . After 6 months of treatment the densitometric nonresponders ( hip ) had a significantly higher mean serum follicle stimulating hormone ( FSH ) level ( p= 0.038 ) and lower increases in serum estradiol levels ( p= 0.006 ) than the densitometric responders . The mean changes in serum FSH and alkaline phosphatase levels were significantly lower among the densitometric nonresponders ( spine ) than responders ( p= 0.043 and 0.017 , respectively ) . In conclusion , this prospect i ve study shows that especially current smokers and women with low body weight are at increased risk of poor bone response to HRT .  Repeated serum FSH , estradiol and alkaline phosphatase measurements during the first months of long-term HRT may be helpful in identifying the women with no bone response to HRT UNLABELLED Dietary supplementation with vitamin K(1 ) , with vitamin D(3 ) and calcium or their combination , was examined in healthy older women during a 2-year , double-blind , placebo-controlled trial . Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius . INTRODUCTION The putative beneficial role of high dietary vitamin K(1 ) ( phylloquinone ) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind , placebo-controlled trial in healthy Scottish women > or = 60 years of age . MATERIAL S AND METHODS Healthy , nonosteoporotic women ( n = 244 ) were r and omized to receive either ( 1 ) placebo , ( 2 ) 200 microg/day vitamin K(1 ) , ( 3 ) 10 microg ( 400 IU ) vitamin D(3 ) plus 1000 mg calcium/day , or ( 4 ) combined vitamins K(1 ) and D(3 ) plus calcium . Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist , markers of bone turnover , and vitamin status . Supplementation effects were tested using multivariate general linear modeling , with full adjustment for baseline and potential confounding variables . RESULTS Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups . However , women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius . Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years , serum vitamin K(1 ) increased by 157 % ( p < 0.001 ) , the percentage of undercarboxylated osteocalcin ( % GluOC ) decreased by 51 % ( p < 0.001 ) , serum 25-hydroxyvitamin D [ 25(OH)D ] increased by 17 % ( p < 0.001 ) , and PTH decreased by 11 % ( p = 0.049 ) . CONCLUSIONS These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1 ) together with supplements of calcium plus moderate vitamin D(3 ) to enhance BMC at the ultradistal radius , a site consisting of principally trabecular bone . The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation UNLABELLED In this 2-year r and omized controlled study of 167 men > 50 years of age , supplementation with calcium-vitamin D3-fortified milk providing an additional 1000 mg of calcium and 800 IU of vitamin D3 per day was effective for suppressing PTH and stopping or slowing bone loss at several clinical ly important skeletal sites at risk for fracture . INTRODUCTION Low dietary calcium and inadequate vitamin D stores have long been implicated in age-related bone loss and osteoporosis . The aim of this study was to assess the effects of calcium and vitamin D3 fortified milk on BMD in community living men > 50 years of age . MATERIAL S AND METHODS This was a 2-year r and omized controlled study in which 167 men ( mean age + /- SD , 61.9 + /- 7.7 years ) were assigned to receive either 400 ml/day of reduced fat ( approximately 1 % ) ultra-high temperature ( UHT ) milk containing 1000 mg of calcium plus 800 IU of vitamin D3 or to a control group receiving no additional milk . Primary endpoints were changes in BMD , serum 25(OH)D , and PTH . RESULTS One hundred forty-nine men completed the study . Baseline characteristics between the groups were not different ; mean dietary calcium and serum 25(OH)D levels were 941 + /- 387 mg/day and 77 + /- 23 nM , respectively . After 2 years , the mean percent change in BMD was 0.9 - 1.6 % less in the milk supplementation compared with control group at the femoral neck , total hip , and ultradistal radius ( range , p < 0.08 to p < 0.001 after adjusting for covariates ) . There was a greater increase in lumbar spine BMD in the milk supplementation group after 12 and 18 months ( 0.8 - 1.0 % , p < or = 0.05 ) , but the between-group difference was not significant after 2 years ( 0.7 % ; 95 % CI , -0.3 , 1.7 ) . Serum 25(OH)D increased and PTH decreased in the milk supplementation relative to control group after the first year ( 31 % and -18 % , respectively ; both p < 0.001 ) , and these differences remained after 2 years . Body weight remained unchanged in both groups at the completion of the study . CONCLUSIONS Supplementing the diet of men > 50 years of age with reduced-fat calcium- and vitamin D3-enriched milk may represent a simple , nutritionally sound and cost-effective strategy to reduce  age-related bone loss  at several skeletal sites at risk for fracture in the elderly BACKGROUND Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials . However , r and omized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking . METHODS We conducted a r and omized , double-blind , placebo-controlled trial involving 36,282 postmenopausal women from 40 Women 's Health Initiative centers : 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [ corrected ] twice daily ( 1000 mg of elemental calcium and 400 IU of vitamin D3 ) and 18,106 received a matching placebo for an average of 7.0 years . The incidence of pathologically confirmed colorectal cancer was the design ated secondary outcome . Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study . RESULTS The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo ( 168 and 154 cases ; hazard ratio , 1.08 ; 95 percent confidence interval , 0.86 to 1.34 ; P=0.51 ) , and the tumor characteristics were similar in the two groups . The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups . There were no significant treatment interactions with baseline characteristics . CONCLUSIONS Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer  among postmenopausal women . The long latency associated with the development of colorectal cancer , along with the seven-year duration of the trial , may have contributed to this null finding . Ongoing follow-up will assess the longer-term effect of this intervention . ( Clinical Trials.gov number , NCT00000611 . ) Background and aims : Insufficient vitamin D status , commonly found in older people , has been associated with muscle weakness which , in old age , impairs mobility and is a risk factor for falling . In a r and omized , double-blind placebo-controlled trial , we tested the hypothesis that vitamin D + calcium supplementation improves muscle strength and mobility , compared with calcium mono-therapy in vitamin D-insufficient female geriatric patients . Methods : Seventy female geriatric patients > 65 years of age with serum 25-hydroxyvitamin D3 ( 25OHD ) concentrations between 20 and 50 nmol/L , visiting an outpatient geriatric department , were included . Participants received either cholecalciferol 400 IU/day + calcium 500 mg/day ( D/Cal group ) or a placebo + calcium 500 mg/day ( Plac/Cal group ) for 6 months . At baseline and 6 months , muscle strength , power and functional mobility were tested . Results : At baseline , 25OHD was significantly ( p<0.05 ) associated with knee extension strength ( r=0.42 ) , h and grip strength ( r=0.28 ) , leg extension power ( r=0.34 ) , Timed Get Up and Go ( r=−0.31 ) and Modified Cooper test ( r=0.44 ) . At 6 months , a significant difference in 25OHD ( 77.2 vs 41.6 nmol/L , p<0.001 ) and 1,25OHD was found between the two groups . Significantly improving vitamin D status in the D/Cal group compared with the Plac/Cal group did not result in a significant difference in strength or functional mobility between the two groups . Conclusions : Daily 400IU vitamin D + 500 mg calcium supplementation is not enough to significantly improve strength or mobility in vitamin D-insufficient female geriatric patients Methods for combining data from several studies exist and appear to be quite useful . None satisfactorily addresses the question of what studies should be combined . This issue is the most serious method ological limitation . Even studies with statistically significant interaction might still be combined if the effect were in the same direction . Thus , substantial scientific input is required as to what criteria must be met by each potential study . Much can be learned from combining or pooling data but it must be done cautiously . Pooling exercises do not replace well design ed prospect i ve clinical trials . Efforts for establishing basic design criteria to allow for multicentre and multicountry trials to be more easily combined might be useful . Pre clinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone . On the basis of these data , the authors conducted a phase 2 trial of intravenous ( iv ) calcitriol at a dose of 74 μg weekly ( based on a recent phase 1 trial ) and dexamethasone in patients with castration‐resistant prostate cancer ( CRPC ) The effects of  postmenopausal hormone replacement therapy ( HRT ) and vitamin D on the serum concentrations of three bone biochemical markers and their associations with bone mineral density ( BMD ) were studied in a population -based 1-yr follow-up study . A total of 72 healthy postmenopausal women were r and omized into 4 treatment groups : HRT group ( sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ) , D group ( vitamin D3 , 300 IU/day ) , HRT+D group ( both of the above ) , and placebo group ( calcium lactate , 500 mg/day ) . Serum concentrations of osteocalcin ( OC ) and bone-specific alkaline phosphatase ( BAP ) were measured as biochemical markers of bone formation , and serum type I collagen carboxy-terminal telopeptide was measured as a marker of bone resorption at baseline and after 6 and 12 months of treatment . To investigate the associations of these markers with BMD , lumbar ( L2-L4 ) and femoral neck BMDs were determined by dual x-ray absorptiometry at baseline and after 2.5 yr of treatment . In both hormone groups , the serum concentrations of the three bone metabolic markers had decreased after 12 months . Those of OC decreased by 29.2 % ( P = 0.017 ) in the HRT group and by 37.3 % ( P = 0.004 ) in the HRT+D group , and BAP concentrations decreased by 34.4 % ( P < 0.001 ) in the HRT group and by 36.2 % ( P < 0.001 ) in the HRT+D group . Serum type I collagen carboxy-terminal telopeptide concentrations had decreased by 21.6 % ( P = 0.012 ) in HRT group and by 14.1 % ( P = 0.011 ) in the HRT+D group . In the D group , the serum concentrations of BAP had decreased by 11.7 % ( P = 0.040 ) after 12 months , but the other two markers showed no change . The only change seen in the placebo group was a 19.2 % increase in OC concentrations ( P = 0.041 ) after 6 months , but at 12 months , the mean OC level was similar to that at baseline . After 2.5 yr , both lumbar and femoral BMD had decreased in the D group [ 2.1 % ( P = 0.022 ) and 3.6 % ( P = 0.019 ) , respectively ] and in the placebo group [ 3.3 % ( P = 0.009 ) and 2.7 % ( P = 0.010 ) , respectively ] , whereas no significant changes occurred in the hormone groups . There were significant inverse correlations between the changes in lumbar and femoral BMDs and changes in all three biochemical markers ( r = -0.240 through -0.336 ; P = 0.005 - 0.064 ) . Our results suggest that HRT counteracts the biochemical changes caused by increased bone turnover associated with menopause . Importantly , the changes in bone markers correlate with long term changes in BMDs of lumbar spine and femoral neck .  Low dose vitamin D treatment , however , seems to have only marginal effects on bone metabolism in early postmenopausal healthy women Objective : The aim of this study was to examine the effect of conjugated equine estrogens alone ( ET ) , conjugated equine estrogens + medroxyprogesterone ( EPT ) , calcitriol alone , calcitriol + EPT/ET , or placebo on serum lipid profile and analyze the interaction with estrogen receptor-&agr ; gene single nucleotide polymorphisms ( ESR-&agr ; SNPs ) on the response to therapy . Methods : A total of 489 postmenopausal women older than 65 years were enrolled into a 3-year double-blind , placebo-controlled clinical trial . Results : In both intent-to-treat and complier ( > 80 % adherent ) analysis , there was a significant increase in serum high-density lipoproteins and a significant decrease in serum low-density lipoproteins ( LDLs ) and the LDL/high-density lipoprotein ratio in all hormone treatment groups compared with placebo ( P < 0.05 ) . However , serum triglycerides and very low-density lipoproteins increased in the EPT and ET + calcitriol groups versus placebo ( P < 0.05 ) . ESR-&agr ; SNPs PvuII and XbaI seemed to have a significant effect on the response to treatment . Genotypes containing the p allele showed a significantly greater decrease in serum cholesterol and very low-density lipoprotein than those having the P allele in the ET + calcitriol group ( P < 0.05 ) , and those with the x allele had a significantly greater decrease in serum cholesterol in the hormone therapy + calcitriol group at the end of 3 years versus the X allele , and a greater decrease in serum LDL in alleles x versus the X in the ET + calcitriol group ( P < 0.05 ) . Conclusions : ET with or without progesterone had a favorable effect on lipid profile  in postmenopausal older women , and this was dependent on estrogen receptor SNPs-PvuII and XbaI. However , this interaction with ESR-&agr ; SNPs needs to be confirmed in larger studies BACKGROUND The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal . METHODS We recruited 36,282 postmenopausal women , 50 to 79 years of age , who were already enrolled in a Women 's Health Initiative ( WHI ) clinical trial . We r and omly assigned participants to receive 1000 mg of elemental [ corrected ] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo .  Fractures were ascertained for an average follow-up period of 7.0 years . Bone density was measured at three WHI centers . RESULTS Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group ( P<0.01 ) . Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture ( 95 percent confidence interval , 0.72 to 1.08 ) , 0.90 for clinical spine fracture ( 0.74 to 1.10 ) , and 0.96 for total fractures ( 0.91 to 1.02 ) . The risk of renal calculi increased with calcium plus vitamin D ( hazard ratio , 1.17 ; 95 percent confidence interval , 1.02 to 1.34 ) . Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 ( 95 percent confidence interval , 0.52 to 0.97 ) . Effects did not vary significantly according to prer and omization serum vitamin D levels . CONCLUSIONS Among healthy postmenopausal women , calcium with vitamin D supplementation result ed in a small but significant improvement in hip bone density , did not significantly reduce hip fracture , and increased the risk of kidney stones . ( Clinical Trials.gov number , NCT00000611 . ) IMPORTANCE Observational data link low 25-hydroxyvitamin D levels to both prevalent blood pressure and incident hypertension . No clinical trial has yet examined the effect of vitamin D supplementation in isolated systolic hypertension , the most common pattern of hypertension in older people . OBJECTIVE To test whether high-dose , intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension . DESIGN Parallel group , double-blind , placebo-controlled  r and omized trial . SETTING Primary care clinics and hospital clinics . PARTICIPANTS Patients 70 years and older with isolated systolic hypertension ( supine systolic blood pressure > 140 mm Hg and supine diastolic blood pressure < 90 mm Hg ) and baseline 25-hydroxyvitamin D levels less than 30 ng/mL were r and omized into the trial from June 1 , 2009 , through May 31 , 2011 . INTERVENTIONS A total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year . MAIN OUTCOMES AND MEASURES Difference in office blood pressure , 24-hour blood pressure , arterial stiffness , endothelial function , cholesterol level , insulin resistance , and b-type natriuretic peptide level during 12 months . RESULTS A total of 159 participants were r and omized ( mean age , 77 years ) .  Mean baseline office systolic blood pressure was 163/78 mm Hg . Mean baseline 25-hydroxyvitamin D level was 18 ng/mL. 25-Hydroxyvitamin D levels increased in the treatment group compared with the placebo group ( + 8 ng/mL at 1 year , P < .001 ) . No significant treatment effect was seen for mean ( 95 % CI ) office blood pressure ( −1 [ −6 to 4]/−2 [ −4 to 1 ] mm Hg at 3 months and 1 [ −2 to 4]/0 [ −2 to 2 ] mm Hg overall treatment effect ) . No significant treatment effect was evident for any of the secondary outcomes ( 24-hour blood pressure , arterial stiffness , endothelial function , cholesterol level , glucose level , and walking distance ) . There was no excess of adverse events in the treatment group , and the total number of falls was nonsignificantly lower in the group receiving vitamin D ( 36 vs 46 , P = .24 ) . CONCLUSIONS AND RELEVANCE Vitamin D supplementation did not improve blood pressure or markers of vascular health in older patients with isolated systolic hypertension . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N92186858 Daily vitamin D in addition to calcium supplementation reduces falls and fractures in older women . However , poor adherence to therapy is a common clinical problem . To examine the effects of supervised oral 3-monthly vitamin D therapy on falls , muscle strength , and mobility , we conducted a 9-month r and omized , double-blind , placebo-controlled trial in 686 community-dwelling ambulant women aged over 70 years . Participants received either oral cholecalciferol 150,000 IU every 3 months ( n = 353 ) or an identical placebo ( n = 333 ) . All participants were advised to increase dietary calcium intake . Falls data were collected 3-monthly . At baseline , 3 , 6 , and 9 months , muscle strength was measured by a h and held dynamometer and mobility by the Timed Up and Go ( TUG ) test . Serum 25 hydroxyvitamin D ( 25OHD ) was measured in a subgroup of 40 subjects . Mean age at baseline was 76.7 ± 4.1 years . The average serum 25OHD value at baseline was 65.8 ± 22.7 nmol/L. By 3 , 6 , and 9 months after supplementation , 25OHD levels of the vitamin D group were approximately 15 nmol/L higher than the placebo group . Calcium intake did not change significantly between baseline ( 864 ± 412 mg/day ) and 9 months ( 855 ± 357 mg/day ) . Faller rates in the two groups did not differ : vitamin D group , 102 of 353 ( 29 % ) ; placebo group , 89 of 333 ( 27 % ) . At 9 months , compared to placebo or baseline , muscle strength , and TUG were not altered by vitamin D. In conclusion , oral cholecalciferol 150,000 IU therapy administered 3-monthly had neither beneficial nor adverse effects on falls or physical function . These data together with previous findings confirm that intermittent large doses of vitamin D are ineffective or have a deleterious effect on falls . Thus despite adherence issues with daily vitamin D replacement , an intermittent , high-dose vitamin D regimen can not be supported as a strategy to reduce falls and fractures CONTEXT Observational studies have reported an inverse association between serum 25-hydroxyvitamin D ( 25-OHD ) levels and incidence of upper respiratory tract infections ( URTIs ) . However , results of clinical trials of vitamin D supplementation have been inconclusive . OBJECTIVE To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch , New Zeal and . INTERVENTION Participants were r and omly assigned to receive an initial dose of 200,000 IU oral vitamin D3 , then 200,000 IU 1 month later , then 100,000 IU monthly ( n = 161 ) , or placebo administered in an identical dosing regimen ( n = 161 ) , for a total of 18 months . MAIN OUTCOME MEASURES The primary end point was number of URTI episodes . Secondary end points were duration of URTI episodes , severity of URTI episodes , and number of days of missed work due to URTI episodes . RESULTS The mean baseline 25-OHD level of participants was 29 ( SD , 9 ) ng/mL. Vitamin D supplementation result ed in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study . There were 593 URTI episodes in the vitamin D group and 611 in the placebo group , with no statistically significant differences in the number of URTIs per participant ( mean , 3.7 per person in the vitamin D group and 3.8 per person in the placebo group ; risk ratio , 0.97 ; 95 % CI , 0.85 - 1.11 ) , number of days of missed work as a result of URTIs ( mean , 0.76 days in each group ; risk ratio , 1.03 ; 95 % CI , 0.81 - 1.30 ) , duration of symptoms per episode ( mean , 12 days in each group ; risk ratio , 0.96 ; 95 % CI , 0.73 - 1.25 ) , or severity of URTI episodes . These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels . CONCLUSION In this trial , monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12609000486224 OBJECTIVES We investigated the incidence of new  non-vertebral fractures  during HRT or low-dose vitamin ( Vit ) D3 supplementation in a 5-year prospect i ve trial . METHODS A total of 464 early postmenopausal women , ( a subgroup of the Kuopio Osteoporosis Study , n = 13100 ) were r and omized to four groups : ( 1 ) HRT , a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ; ( 2 ) Vit D ( 300 IU/day and 100 IU/day during the fifth year ) ; ( 3 ) HRT + Vit D ; and ( 4 ) placebo .  Lumbar ( L2 - 4 ) and femoral neck bone mineral densities ( BMD ) were determined by dual X-ray absorptiometry ( DXA ) at baseline , after 2.5 and 5 years of treatment . All new symptomatic non-vertebral , radiographically defined fractures were recorded . RESULTS Altogether , 368 women ( 79 % ) completed the 5 year treatment . In all , 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up ( HRT 4 , Vit D 10 , HRT + Vit D 8 and placebo 17 ) . The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone ( P = 0.032 ) when adjusted by baseline BMD and previous fractures ; observed also with the intention-to-treat principle ( P = 0.048 ) . When the HRT groups were pooled , HRT showed a significantly lower incidence of new non-vertebral fractures ( P = 0.042 ) than women receiving placebo and also after adjusting as above ( P = 0.016 ) ; both in valid-case and in the intention-to-treat analysis . In the Vit D group , the fracture incidence was non-significantly decreased ( P = 0.229 ) in comparison with the placebo group . The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 ( 95 % CI , 0.10 - 0.90 ) and with Vit D 0.47 ( 95 % CI , 0.20 - 1.14 ) and with HRT + Vit D 0.44 ( 95 % CI , 0.17 - 1.15 ) , in comparison with the placebo group ( adjusted by femoral BMD and previous fractures ) . CONCLUSIONS This study is the first prospect i ve trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women . The effect of low-dose Vit D remains to be proved Objective : Vitamin D supplementation may be required for certain subgroups in the United States in whom status and intake are inadequate , but the impact of various doses , and whether calcium administration jointly or independently influences vitamin D metabolite levels , is unclear . Methods : In a pilot chemoprevention trial of biomarkers of risk for colorectal adenoma , we measured the impact of vitamin D supplementation and /or calcium supplementation on plasma vitamin D metabolite concentrations . Ninety-two adult men and women living in the southeastern United States were r and omized to 800 IU vitamin D3 , 2000 mg elemental calcium , both , or placebo daily for 6 months . We examined vitamin D status at baseline and postintervention and compared the change in plasma 25-hydroxyvitamin D ( 25(OH)D ) and 1,25(OH)2D levels by intervention group using general linear models . Results : Eighty-two percent of the study population had insufficient plasma 25(OH)D concentrations ( < 75 nmol/L ) at baseline , with the lowest levels observed among African American participants . Vitamin D supplements , with or without calcium supplementation , raised plasma 25(OH)D concentrations , on average , by 25 to 26 nmol/L. Half of the study participants were classified as having sufficient 25(OH)D status after 6 months of 800 IU of vitamin D3 daily . Calcium alone did not influence 25(OH)D concentrations . Conclusion : In this southeastern U.S. population , half of the study participants receiving 800 IU vitamin D3 daily had blood 25(OH)D concentrations of ≤75 nmol/L after a 6-month intervention period , supporting higher vitamin D dose requirements estimated by some groups . More research is needed to identify the optimal vitamin D dose to improve 25(OH)D status in various at-risk population Although calcium and vitamin-D intake were consistently shown to be inversely associated with  colorectal cancer risk  in several large prospect i ve studies and protective against adenoma and cancer in multiple r and omized trials , the Women 's Health Initiative ( WHI ) of calcium and low-dose vitamin-D supplementation trial found no overall effects on colorectal cancer . However , the previous report did not recognize an important biologic interaction with estrogen therapy . We investigated the treatment interaction of estrogen with calcium and vitamin-D on risk of colorectal cancer via a re analysis of primary data results from the WHI calcium and vitamin-D supplementation trial ( 1,000 mg elemental calcium , 400 IU of vitamin-D3 , or placebo ) , reanalyzing results from women concurrently r and omized to estrogen interventions  and placebo . Results indicate that concurrent estrogen therapy was a strong effect modifier of calcium and vitamin-D supplementation on colorectal cancer risk . While calcium plus vitamin-D supplementation among women concurrently assigned to estrogen therapies suggested increased risk ( Hazard Ratio = 1.50 , 95 % CI : 0.96 - 2.33 ) , among women concurrently assigned to placebos arms of the estrogen trials , calcium plus vitamin-D indicated suggestive benefits ( HR = 0.71 , 95 % CI : 0.46 - 1.09 ) ( p-for-estrogen-interaction = 0.018 ) . Consistent interaction was also found by reported estrogen use ( p interaction = 0.037 ) . Results indicate contrasting effects of calcium and vitamin-D by concurrent estrogen therapy on colorectal cancer risk . Although further clinical and mechanistic studies are warranted , the potential clinical implication s of the apparent interaction of estrogen therapy with calcium and vitamin-D supplementation should be recognized . Important biological mechanisms related to the key membrane receptor megalin and estrogen-dependent protein calbindin are discussed Abstract . The long-term effects on bone of estrogen therapy ( HRT ) combined with vitamin D3 supplementation were evaluated and compared with the effects of HRT without vitamin D3 supplementation in a 4-year prospect i ve , partly r and omized study among 60 osteoporotic women ( mean age 55.4 years ; range 49.7–59.4 years ) . The women studied were a subgroup of the population -based Kuopio Osteoporosis Risk Factor and Prevention Study ( OSTPRE ) ( n = 13100 ) . The bone mineral densities ( BMD ) of the lumbar spine and femoral neck were determined by dual-energy X-ray absorptiometry ( DXA ) in 3236 perimenopausal women . Those 106 women with baseline BMD more than 2 SDs less than the mean value in this population , either at the lumbar spine ( BMD < 0.826 g/cm2 ) and /or femoral neck ( BMD < 0.684 g/cm2 ) , were offered treatment for osteoporosis . After exclusions , 60 women were included in the analyses . Group allocation was : HRT ( estradiol valerate ( 2 mg ) plus cyproterone acetate , 1 mg , sequentially : ClimenR ) ( n = 21 ) ; HRT + Vit D : Climen + vitamin D3 ( cholecalciferol , 300 IU/day , no intake during June – August ) ( n = 23 ) ; controls :  16 women who refused all treatment served as a non-r and omized control group . In the HRT group , the highly significant increase in lumbar BMD was 5.4 % , 5.3 % , 4.7 % and 4.0 % after 1 , 2 , 3 and 4 years of treatment , respectively , all compared with the baseline values and with the control group . The increase in femoral neck BMD was statistically insignificant ( 1.4 % , 2.2 % , 1.9 % and 2.1 % , respectively ; p > 0.05 ) . In the HRT + Vit D group , the lumbar BMD increased by 3.7 % , 4.9 % , 4.9 % and 4.9 % ( p < 0.001 ) , whereas the 5.8 % increase in femoral neck BMD reached significance at 4 years ( p < 0.01 ) when compared with the control group as well as with the baseline values . However , there were no statistically significant differences in lumbar or femoral BMD changes between the two HRT groups . In conclusion , estrogen  can substantially increase lumbar bone mass in patients with postmenopausal osteoporosis . In addition , the combination of HRT and vitamin D3 may increase femoral neck BMD in osteoporotic women more than estrogen alone BACKGROUND . Several factors may increase fracture risk , among them reduced bone mineral density ( BMD ) , increased bone resorption , microarchitectural deterioration of bone , increased fall risk , and decreased muscle strength . We have previously reported that PvuII polymorphism of the estrogen receptor-α ( ER α ) gene is associated with bone loss rate , fracture risk , and response to hormone replacement therapy ( HRT ) in early postmenopausal Finnish women . METHOD . We studied the influence of the ERα genotype on fall risk and muscle strength in a 5-year r and omized  HRT trial of 331 early postmenopausal women ( subgroup of the population -based OSTPRE study , Kuopio , Finl and ) . A 5-year postal inquiry in May 1994 included questions on falls during the previous 12 months . Grip strength was measured with dynamometer . The ERα gene polymorphism was analysed using PCR and PvuII restriction enzyme digestion . RESULTS . In all , 97 out of the 331 women reported falls . Half of those ( 56 % ) were slip falls , mostly during the winter season . In  the HRT group , the ERα genotype was associated with fall risk ( P = 0.002 , logistic regression ) . The risk of falls ( RR ) was higher in women with the PP genotype than in those with the Pp ( RR = 5.26 , 95 % CI 1.98 - 13.94 , P = 0.001 ) or the pp ( RR = 3.84 , 95 % CI 1.46 - 10.12 , P = 0.007 ) genotype . When the falls were divided into slip ( environment-related ) and non-slip ( endogenous ) falls , the non-slip falls were associated with the genotype ( P = 0.004 ) , but the slip falls were not so clearly ( P = 0.061 ) . When all falls and non-slip falls were adjusted to the number of chronic health disorders and the variable time-since-menopause , the difference between the genotypes persisted ( P = 0.003 and P = 0.010 , respectively ) . In  the non-HRT group , the ERα genotype was not associated with fall risk . The baseline or the 5-year grip strength values were not influenced by the ERα genotype . In conclusion , ER α polymorphism is associated with fall risk , especially with non-slip falls , in early postmenopausal Finnish women during the HRT . We have previously reported that , during HRT , women with the P allele have decreased fracture risk and that they may preferentially derive benefit from the positive effect of HRT on BMD . This suggests that the influence of ERα polymorphism may depend on the target tissue ( bone versus the nervous system ) . CONCLUSIONS . In these early postmenopausal , non-osteoporotic and relatively healthy women , the increased fall risk associated with the PP genotype was not associated with increased fracture risk , possibly due to improved bone strength during the HRT although falls generally predispose to fractures Genetic factors regulate bone mineral density ( BMD ) and possibly the development of osteoporosis . An association between estrogen receptor ( ER ) polymorphism , BMD , and postmenopausal hormone replacement therapy ( HRT ) has not been established . Therefore , we studied the influence of the ER genotype on BMD before and after a 5-year HRT in a placebo-controlled , population -based , r and omized group of 322 early postmenopausal women . The participants were r and omized into two treatment groups : the  HRT group ( n = 145 ) received a sequential combination of 2 mg estradiol valerate and 1 mg CPA with or without vitamin D3 , 100 - 300 IU + 500 mg calcium lactate/day ( equal to 93 mg Ca2 + ) , and the  non-HRT group ( n = 177 ) received calcium lactate , 500 mg alone or in combination with vitamin D3 , 100 - 300 IU/day . PvuII restriction fragment length polymorphism ( RFLP ) of the ERalpha was determined using polymerase chain reaction ( PCR ) . BMDs of the lumbar spine ( L2 - 4 ) and proximal femur were measured by using dual-energy X-ray absorptiometry ( DXA ) . At the baseline , there were no significant differences in the lumbar or femoral neck BMDs between the three ER PvuII genotype groups ( PP , Pp , pp ) . After 5 years , the BMD of the femoral neck remained unaltered and that of the lumbar spine increased by 1.7 % in the HRT group , whereas both BMDs were decreased by 4 - 5 % in the non-HRT group . The ER genotype did not modulate the femoral neck BMD change during the follow-up . In contrast , in the  non-HRT-group  the lumbar spine BMD decreased more in subjects with the ER genotypes PP ( 6.4 % ) and Pp ( 5.2 % ) than in subjects with the pp genotype ( 2.9 % ) ( p = 0.002 ) . In the  HRT group , the relative changes of the lumbar spine BMD were similar in all three ER genotype groups . Thus without HRT , the pp genotype was associated with a smaller decrease in the lumbar spine BMD than the Pp and PP genotypes . Long-term HRT seemed to eliminate the ER genotype-related differences in the BMD . We conclude that subjects with the ER PvuII genotypes PP and Pp may have a greater risk of relatively fast bone loss after menopause than those with the pp genotype and that they may preferentially derive benefit from HRT PURPOSE Vitamin D has been linked to breast cancer risk , but prognostic effects are unknown . Such effects are biologically plausible given the presence of vitamin D receptors in breast cancer cells , which act as nuclear transcription factors to regulate gene activity . PATIENTS AND METHODS The study was conducted in a prospect i ve inception cohort of 512 women with early breast cancer diagnosed 1989 to 1996 .  Vitamin D levels were measured in stored blood . Clinical , pathologic , and dietary data were accessed to examine prognostic effects of vitamin D. RESULTS Mean age was 50.4 years , mean vitamin D was 58.1 + /- 23.4 nmol/L.  Vitamin D levels were deficient ( < 50 nmol/L ) in 37.5 % of patients , insufficient ( 50 to 72 nmol/L ) in 38.5 % of patients , and sufficient ( > 72 nmol/L ) in 24.0 % of patients . There was little variation in mean vitamin D levels between summer and winter months . Mean follow-up was 11.6 years ; 116 women had distant recurrences , and 106 women died . Women with deficient vitamin D levels had an increased risk of distant recurrence ( hazard ratio [ HR ] = 1.94 ; 95 % CI , 1.16 to 3.25 ) and death ( HR = 1.73 ; 95 % CI , 1.05 to 2.86 ) compared with those with sufficient levels . The association remained after individual adjustment for key tumor and treatment related factors but was attenuated in multivariate analyses ( HR = 1.71 ; 95 % CI , 1.02 to 2.86 for distant recurrence ; HR = 1.60 ; 95 % CI , 0.96 to 2.64 for death ) . CONCLUSION Vitamin D deficiency may be associated with poor outcomes in breast cancer The long term effects of hormone replacement therapy ( HRT ) and vitamin D3 ( Vit D ) on bone mineral density ( BMD ) were studied . A total of 464 nonosteoporotic early postmenopausal women from the Kuopio Osteoporosis Study ( n = 13100 ) were r and omized to four groups : 1 ) HRT ( sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate , 2 ) Vit D3 ( 300 and 100 IU/day during the fifth year ) , 3 ) HRT and Vit D combined , and 4 ) placebo .  Lumbar ( L2-L4 ) and femoral neck BMD were determined by dual x-ray absorptiometry ( DXA ) at baseline and after 2.5 and 5 yr of treatment . Intention to treat analysis ( n = 464 ) showed that after 5 yr , lumbar BMD remained unchanged in the HRT and HRT plus Vit D groups [ + 0.2 % ( P = 0.658 ) and + 0.9 % ( P = 0.117 ) , respectively ] , whereas lumbar BMD decreased by 4.6 % in the Vit D group and by 4.5 % in the placebo group ( P < 0.001 in both ) . The loss of femoral neck BMD was less in the HRT ( -1.4 % ; P = 0.005 ) and HRT plus Vit D ( -1.3 % ; P = 0.003 ) groups than in the Vit D and placebo groups ( -4.3 % ; P < 0.001 in both ) . Among those 370 women who complied with the 5-yr treatment , the effect was more pronounced : lumbar BMD had increased by 1.5 % in the HRT ( P = 0.009 ) and by 1.8 % in the HRT plus Vit D group ( P = 0.005 ) , with a plateau after 2.5 yr , whereas lumbar BMD had decreased in both the Vit D and placebo groups ( 4.6 % and 4.7 % ; P < 0.001 , respectively ) . Femoral neck BMD decreased again less in the HRT ( -0.4 % ) and HRT plus Vit D ( -0.6 % ) groups than in the Vit D and placebo groups ( -4.4 % in both ) . This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis . The data suggest that low dose vitamin D3 supplementation does not prevent  bone loss in healthy , nonosteoporotic , early postmenopausal women , and it confers no benefit additional to that of HRT alone 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 OBJECTIVE The adequate dose of vitamin D supplementation for community-dwelling elderly people has not been thoroughly investigated . This study aims to determine the efficacy of a low-dose and a higher dose of vitamin D3 in maintaining 25-hydroxyvitamin D [ 25(OH)D ] levels at or above 30 ng/mL. METHODS This was a single site , double-blind , r and omized exploratory clinical trial that enrolled adults 65 years of age and older . Within strata of baseline 25(OH)D levels ( < 30 versus ≥ 30 ng/mL ) subjects were r and omized in a 1:2 ratio to receive either 400 or 2,000 IU vitamin D3 daily for 6 months . The main outcome measures were changes in serum 25(OH)D levels according to baseline 25(OH)D levels and dose of vitamin D3 . RESULTS At baseline , 41 of 105 participants ( 39 % ) had low 25(OH)D levels ( < 30 ng/mL ) . After 6 months of vitamin D3 supplementation , 21 of 32 participants ( 66 % ) receiving 400 IU and 14 of 59 participants ( 24 % ) receiving 2,000 IU of vitamin D3 still had low 25(OH)D levels . The largest increases in serum 25(OH)D levels were observed in subjects with baseline levels < 30 ng/mL who received 2,000 IU of vitamin D daily . CONCLUSION Regardless of baseline 25(OH)D level , in persons 65 years of age and older , 6-month vitamin D3 supplementation with 400 IU daily result ed in low 25(OH)D in most individuals , while 2,000 IU daily maintained 25(OH)D levels within an acceptable range in most people on this regimen BACKGROUND Current unitage for the calciferols suggests that equimolar quantities of vitamins D(2 ) ( D2 ) and D(3 ) ( D3 ) are biologically equivalent . Published studies yield mixed results . OBJECTIVE The aim of the study was to compare the potencies of D2 and D3 . DESIGN The trial used a single-blind , r and omized design in 33 healthy adults .  Calciferols were dosed at 50,000 IU/wk for 12 wk . Principal outcome variables were area under the curve for incremental total 25-hydroxyvitamin D [ 25(OH)D ] and change in calciferol content of sc fat . RESULTS Incremental mean ( sd ) 25(OH)D area under the curve at 12 wk was 1366 ng · d/ml ( 516 ) for the D2-treated group and 2136 ( 606 ) for the D3 ( P < 0.001 ) . Mean ( sd ) steady-state 25(OH)D increments showed similar differences : 24 ng/ml for D2 ( 10.3 ) and 45 ng/ml ( 16.2 ) for D3 ( P < 0.001 ) . Subcutaneous fat content of D2 rose by 50 μg/kg in the D2-treated group , and D3 content rose by 104 μg/kg in the D3-treated group . Total calciferol in fat rose by only 33 ng/kg in the D2-treated , whereas it rose by 104 μg/kg in the D3-treated group . Extrapolating to total body fat D3 , storage amounted to just 17 % of the administered dose . CONCLUSION D3 is approximately 87 % more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of vitamin D than does equimolar D2 . For neither was there evidence of sequestration in fat , as had been postulated for doses in this range . Given its greater potency and lower cost , D3 should be the preferred treatment option when correcting vitamin D deficiency Data from laboratory studies , observational research , and /or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease ( CVD ) , but primary prevention trials with adequate dosing in general population s ( i.e. , unselected for disease risk ) are lacking . The ongoing VITamin D and OmegA-3 TriaL ( VITAL ) is a large r and omized , double-blind , placebo-controlled , 2 x 2 factorial trial of vitamin D ( in the form of vitamin D(3 ) [ cholecalciferol ] , 2000 IU/day ) and marine omega-3 fatty acid ( Omacor fish oil , eicosapentaenoic acid [EPA]+docosahexaenoic acid [ DHA ] , 1g/day ) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥ 50 and women aged ≥ 55 . The mean treatment period will be 5 years . Baseline blood sample s will be collected in at least 16,000 participants , with follow-up blood collection in about 6000 participants . Yearly follow-up question naires will assess treatment compliance ( plasma biomarker measures will also assess compliance in a r and om sample of participants ) , use of non- study drugs or supplements , occurrence of endpoints , and cancer and vascular risk factors . Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment , and deaths will be ascertained through national registries and other sources . Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance ; hypertension ; cognitive decline ; depression ; osteoporosis and fracture ; physical disability and falls ; asthma and other respiratory diseases ; infections ; and rheumatoid arthritis , systemic lupus erythematosus , thyroid diseases , and other autoimmune disorders CONTEXT Public health authorities around the world recommend widely variable supplementation strategies for adults , whereas several professional organizations , including The Endocrine Society , recommend higher supplementation . METHODS We analyzed published r and omized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health . CONCLUSIONS The extraskeletal effects of vitamin D are plausible as based on pre clinical data and observational studies . However , apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly , causality remains yet unproven in r and omized controlled trials ( RCTs ) . The greatest risk for cancer , infections , cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D ( 25OHD ) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis , estimated from serum 1,25-dihydroxyvitamin D and PTH , calcium absorption , or bone mass , can be normalized by 25OHD levels above 20 ng/mL. Moreover , vitamin D supplementation ( 800 IU/d ) in combination with calcium can reduce fracture incidence by about 20 % . Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women . Based on calculations of the metabolic clearance of 25OHD , a daily intake of 500 - 700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore , the recommendations for a daily intake of 1500 - 2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects , as suggested by The Endocrine Society Task Force , are premature . Fortunately , ongoing RCTs will help to guide us to solve this important public health question BACKGROUND . After the menopause , estrogen synthesis from and rogens and and rogen precursors by aromatase is the main source of circulating estrogens . AIM . To evaluate whether aromatase gene (CYP19)polymorphism affects circulating estradiol ( E[Formula : See Text])levels , bone mineral density ( BMD ) , BMD change or fracture risk . METHODS . A 5-year r and omized hormone replacement therapy ( HRT ) trial on 331 early postmenopausal women ( mean baseline age 52.7 ± 2.3 years ) . The participants consisted of two treatment groups : the HRT group ( n = 151 ) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D[Formula : See Text ] , 100 - 300 IU + 93 mg calcium as lactate/day , and the non-HRT group ( n = 180 ) received 93 mg calcium alone or in combination with vitamin D[Formula : See Text ] , 100 - 300 IU/day for 5 years . BMD was measured from lumbar spine and proximal femur ( DXA ) before and after the 5-year trial . All new symptomatic , radiographically defined fractures were recorded during the follow-up . The polymorphism ( intron 4 TTTA repeat ) of CYP19 was evaluated after PCR amplification of the polymorphic site . CYP19 polymorphism was divided into three repeat groups : short ( length of 7 or 8 in both alleles ; n = 135 ) , long ( length of 11 or higher in both alleles ; n = 47 ) , and medium ( rest of the values ; n = 149 ) . RESULTS . Of the baseline characteristics , only physical activity was associated with CYP19 polymorphism ( P = 0.04 ) and a borderline significance was observed with previous fractures ( P = 0.05 ) . In the HRT or non-HRT groups , the 5-year serum E[Formula : See Text ] change was not associated with CYP19 polymorphism ( P = 0.87 and 0.74 , respectively ) . Further , the polymorphism did not influence the calculated annual changes of lumbar or femoral neck BMD during the 5-year follow-up in the HRT ( P = 0.60 and 0.17 , respectively ) or non-HRT ( P = 0.92 and 0.80 , respectively ) groups . In all , 28 women sustained 33 fractures during the follow-up . The CYP19 polymorphism was not significantly associated with fracture risk ( P = 0.89 and 0.23 respectively ; Cox proportional hazards model ) in the HRT or non-HRT groups . CONCLUSIONS .CYP19 polymorphism was not associated with circulating E[Formula : See Text ] levels , BMD values , or fracture risk in these early postmenopausal Finnish women . If such an association exists in women , it may become apparent in older age groups Summary Vitamin D may affect skeletal muscle function . In a double-blind , r and omised , placebo-controlled trial , we found that vitamin D3 supplementation ( 400 or 1,000 I.U. vs. placebo daily for 1 year with bimonthly study visits ) does not improve grip strength or reduce falls . Introduction This study aim ed to test the supplementation effects of vitamin D3 on physical function and examine associations between overweight/obesity and the biochemical response to treatment . Methods In a parallel group double-blind RCT , healthy postmenopausal women from North East Scotl and ( latitude—57 ° N ) aged 60–70 years ( body mass index ( BMI ) , 18–45 kg/m2 ) were assigned ( computer r and omisation ) to daily vitamin D3 ( 400 I.U. ( n = 102)/1,000 I.U. ( n = 101 ) ) or matching placebo ( n = 102 ) ( 97 , 96 and 100 participants analysed for outcomes , respectively ) from identical coded containers for 1 year . Grip strength ( primary outcome ) , falls , diet , physical activity and ultraviolet B radiation exposure were measured bimonthly , as were serum 25(OH)D , adjusted calcium ( ACa ) and phosphate . Fat/lean mass ( dual energy X-ray absorptiometry ) , anthropometry , 1,25-dihydroxyvitamin D and parathyroid hormone were measured at baseline and 12 months . Participants and research ers were blinded throughout intervention and analysis . Results Treatment had no effect on grip strength ( mean change (SD)/year = −0.5 ( 2.5 ) , −0.9 ( 2.7 ) and −0.4 ( 3.3 ) kg force for 400/1,000 I.U. vitamin D3 and placebo groups , respectively ( P = .10 , ANOVA ) ) or falls ( P = .65 , chi-squared test ) . Biochemical responses were similar across BMI categories ( < 25.25–29.99 , ≥30 kg/m2 ) with the exception of a small change at 12-months in serum ACa in overweight compared to non-overweight participants ( P = .01 , ANOVA ; 1,000 I.U. group ) . In the  placebo group , 25(OH)D peak concentration change ( winter to summer ) was negatively associated with weight ( r = −.268 ) , BMI ( r = −.198 ) , total ( r = −.278 ) and trunk fat mass ( r = −.251 ) , with total and trunk fat mass predictive of winter to summer 25(OH)D change ( P = .01/.004 respectively , linear regression ) . Conclusion We found no evidence of an improvement in physical function following vitamin D3 supplementation for 1 year There is an increase in the incidence of falls with aging and about 10 % of falls lead to fractures . Nearly all hip fractures are due to falls and hip fractures are the most severe of the osteoporotic fractures because they lead to a 20 % mortality rate and a loss of independent living in 50 % of cases . Although there are multiple factors associated with falls , our interest is the role that vitamin D metabolism plays in the pathogenesis of falls . Recent clinical trials show that both vitamin D and the metabolite calcitriol reduce the number of falls by 30 - 40 % in elderly subjects . This should also reduce the number of fractures . In European studies , the decrease in falls could be attributed to an improvement in the muscle weakness that often accompanies vitamin D deficiency . However , in the studies using calcitriol there was no vitamin D deficiency , so the mechanism of its efficacy is less clear . It could be due to increased muscle strength , an improvement in the neurological control of balance or both . Underst and ing these mechanisms would allow us to search for analogs of vitamin D that act more selectively on muscle and on the central nervous system Experimental evidence provides strong support for anti-carcinogenic effects of calcium and vitamin D with respect to breast cancer . Observational epidemiologic data also provide some support for inverse associations with risk . We tested the effect of calcium plus vitamin D supplementation on risk of benign proliferative breast disease  , a condition which is associated with increased  risk of breast cancer . We used the Women ’s Health Initiative r and omized controlled trial . The 36,282 participants were r and omized either to 500 mg of elemental calcium as calcium carbonate plus 200 IU of vitamin D3 ( GlaxoSmithKline ) twice daily ( n = 18,176 ) or to placebo ( n = 18,106 ) . Regular mammograms and clinical breast exams were performed . We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to st and ardized review . After an average follow-up period of 6.8 years , 915 incident cases of benign proliferative breast disease had been ascertained , with 450 in the intervention group and 465 in the placebo group .  Calcium plus vitamin D supplementation was not associated with altered risk of benign proliferative breast disease overall ( hazard ratio = 0.99 , 95 % confidence interval = 0.86–1.13 ) , or by histologic subtype . Risk varied significantly by levels of age at baseline , but not by levels of other variables . Daily use of 1,000 mg of elemental calcium as calcium carbonate plus 400 IU of vitamin D3 for almost 7 years by postmenopausal women did not alter the overall risk of benign proliferative breast disease OBJECTIVE In contrast to age-matched men , endurance exercise training is not consistently associated with enhanced endothelial function in estrogen-deficient postmenopausal women . We determined whether endurance exercise training improves endothelial function in postmenopausal women treated with estrogen .  In a sub study , we determined if oxidative stress is mechanistically linked to endothelial function adaptations to endurance exercise training . PARTICIPANTS AND DESIGN Brachial artery flow-mediated dilation ( FMD ) was measured in 36 sedentary , estrogen-deficient postmenopausal women ( 45 - 65 y ) at study entry ( baseline ) , after 12 weeks of either placebo , oral ( 1 mg/d ) estradiol , or transdermal estradiol ( 0.05 mg/d ) ( r and omized ) , and after an additional 12 weeks of continued estradiol or placebo treatment with concurrent endurance exercise training . In subgroups of women , FMD also was measured during the infusion of ascorbic acid at baseline and following estradiol/placebo plus endurance exercise training , and in seven habitually endurance-trained estrogen-deficient controls . RESULTS FMD increased in the estrogen-treated groups ( both P < .01 ) after 12 weeks and remained unchanged in placebo .  FMD further increased following 12 weeks of endurance exercise training in estrogen-treated ( both P < .025 ) , but not placebo-treated women ( P = .55 ) . In the sub study , baseline FMD was similar between sedentary and endurance-trained controls . Ascorbic acid increased FMD at baseline in sedentary women and endurance-trained controls , and following endurance exercise training in placebo-treated , but not in estrogen-treated women . CONCLUSIONS Estrogen status appears to play an important modulatory role in improvements in endothelial function with endurance exercise training in postmenopausal women . The restored endurance exercise training adaptation in estrogen-treated postmenopausal women may be related to mitigation of oxidative stress CONTEXT Vitamin D or calcium supplementation may have effects on  vascular disease and cancer .  OBJECTIVE Our objective was to investigate whether vitamin D or calcium supplementation affects mortality , vascular disease , and cancer in older people . DESIGN AND SETTING The study included long-term follow-up of participants in a two by two factorial , r and omized controlled trial from 21 orthopedic centers in the United Kingdom . PARTICIPANTS Participants were 5292 people ( 85 % women ) aged at least 70 yr with previous low-trauma fracture . INTERVENTIONS Participants were r and omly allocated to daily vitamin D(3 ) ( 800 IU ) , calcium ( 1000 mg ) , both , or placebo for 24 - 62 months , with a follow-up of 3 yr after intervention . MAIN OUTCOME MEASURES All-cause mortality , vascular disease mortality , cancer mortality , and cancer incidence were evaluated . RESULTS In intention-to-treat analyses , mortality [ hazard ratio ( HR ) = 0.93 ; 95 % confidence interval ( CI ) = 0.85 - 1.02 ] , vascular disease mortality ( HR = 0.91 ; 95 % CI = 0.79 - 1.05 ) , cancer mortality ( HR = 0.85 ; 95 % CI = 0.68 - 1.06 ) , and cancer incidence ( HR = 1.07 ; 95 % CI = 0.92 - 1.25 ) did not differ significantly between participants allocated vitamin D and those not . All-cause mortality ( HR = 1.03 ; 95 % CI = 0.94 - 1.13 ) , vascular disease mortality ( HR = 1.07 ; 95 % CI = 0.92 - 1.24 ) , cancer mortality ( HR = 1.13 ; 95 % CI = 0.91 - 1.40 ) , and cancer incidence ( HR = 1.06 ; 95 % CI = 0.91 - 1.23 ) also did not differ significantly between participants allocated calcium and those not . In a post hoc statistical analysis adjusting for compliance , thus with fewer participants , trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated , although all results remain nonsignificant . CONCLUSIONS Daily vitamin D or calcium supplementation did not affect mortality , vascular disease , cancer mortality , or cancer incidence OBJECTIVES To evaluate and compare the effects and safety of high dose intramuscular ( IM ) or oral cholecalciferol on 25-hydroxyvitamin D [ 25(OH)D ] levels , muscle strength and physical performance in vitamin D deficient/insufficient elderly . STUDY DESIGN R and omized prospect i ve study . MAIN OUTCOME MEASURES 116 ambulatory individuals aged 65 years or older living in a nursing home were evaluated . Eligible patients with 25(OH)D levels < 30 ng/ml ( n=66 ) were r and omized to IM or Oral groups according to the administration route of 600,000 IU cholecalciferol . Demographic and descriptive data were collected . Biochemical response was measured at baseline , 6th and 12th weeks . Muscle strength was measured from quadriceps by using a h and -held dynamometer and physical performance was evaluated by short physical performance battery ( SPPB ) at the beginning and 12th week . RESULTS Among the screened ambulatory elderly only 5.2 % ( n=6 ) had adequate vitamin D levels . 37.1 % ( n=43 ) were vitamin D deficient and 57.7 % ( n=67 ) were insufficient . After administration of one megadose of vitamin D , mean serum 25(OH)D levels increased significantly at 6th week ( 32.72±9.0 ng/ml ) and at 12th week ( 52.34±14.2 ng/ml ) compared with baseline ( 11.76±7.6 ng/ml ) in IM group ( p<0.0001 ) . In Oral group levels were 47.57±12.7 ng/ml , 42.94±13.4 ng/ml and 14.87±6.9 ng/ml , respectively ( p<0.0001 ) . At 12th week the increase in IM group was significantly higher than Oral group ( p=0.003 ) . At the end of the study period , serum 25(OH)D levels were ≥30 ng/ml in all patients in IM group and in 83.3 % of the patients in the Oral group . Quadriceps muscle strength and SPPB total score increased significantly in both groups and SPPB balance subscale score increased only in IM group . Six patients ( 9.6 % ) developed hypercalciuria , no significant adverse events were observed . CONCLUSION In vitamin D deficient/insufficient elderly , a single megadose of cholecalciferol  increased vitamin D levels significantly and the majority of the patients reached optimal levels . Although both administration routes are effective and appear to be safe , IM application is more effective in increasing 25(OH)D levels and balance performance In the GRADE approach , r and omized trials are classified as high quality evidence and observational studies as low quality evidence but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted The effects of four different treatment schedules on serum lipid concentrations were studied for 1 year in 402 postmenopausal women in the Kuopio Osteoporosis Study . The women were r and omized to four treatment groups : A , Sequential combination of estradiol valerate and cyproterone acetate ( Climen ) ; B , Vitamin D3 , 300 IU/day ; C , Climen+Vitamin D3 , D , placebo . In group A , serum concentrations of total cholesterol ( Chol ) decreased by 4.8 % in 6 months and by 6.2 % in 12 months ( P < 0.001 ) , but in group C the decrease was only 2.9 % in 6 months ( P < 0.05 ) and 3.4 % in 12 months ( P < 0.01 ) . The decline of total-Chol in group A was accounted for by the 6.8 % to 7.5 % decrease in LDL-Chol levels ( P < 0.001 ) . The decrease of LDL-Chol in group C was statistically non-significant . Use of vitamin D3 ( group B ) , increased serum Chol by 2.7 % ( 6 months ) , P < 0.05 and by 2.1 % ( 12 months ) and the increases were the result of the 6.0 % to 6.2 % increase in LDL-Chol levels in 6 and 12 months , respectively ( P < 0.001 ) . Serum concentrations of HDL-Chol and TG remained relatively stable in all groups . No correlations were found between LDL-Chol , 25-OH-D3 and 1,25(OH)2-D3 levels in group B. Our results confirm the beneficial effect of estradiol valerate and cyproterone acetate on the lipid profile . In contrast , vitamin D3 had a negative influence on this profile by increasing serum concentrations of LDL-Chol . ( ABSTRACT TRUNCATED AT 250 WORDS PURPOSE In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer ( NMSC ) and melanoma , we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a r and omized placebo-controlled trial . METHODS Postmenopausal women age 50 to 79 years ( N = 36,282 ) enrolled onto the Women 's Health Initiative ( WHI ) calcium/vitamin D clinical trial were r and omly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 ( CaD ) daily or placebo for a mean follow-up period of 7.0 years . NMSC and melanoma skin cancers were ascertained by annual self-report ; melanoma skin cancers underwent physician adjudication . RESULTS Neither incident NMSC nor melanoma rates differed between treatment ( hazard ratio [ HR ] , 1.02 ; 95 % CI , 0.95 to 1.07 ) and placebo groups ( HR , 0.86 ; 95 % CI , 0.64 to 1.16 ) . In subgroup analyses , women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo ( HR , 0.43 ; 95 % CI , 0.21 to 0.90 ; P(interaction ) = .038 ) , which was not observed in women without history of NMSC . CONCLUSION Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma . However , in women with history of NMSC , CaD supplementation reduced melanoma risk , suggesting a potential role for calcium and vitamin D supplements in this high-risk group . Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation OBJECTIVE We evaluated the inter-rater reliability ( IRR ) of assessing the quality of evidence ( QoE ) using the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) approach . STUDY DESIGN AND SETTING On completing two training exercises , participants worked independently as individual raters to assess the QoE of 16 outcomes . After recording their initial impression using a global rating , raters grade d the QoE following the GRADE approach . Subsequently , r and omly paired raters su bmi tted a consensus rating . RESULTS The IRR without using the GRADE approach for two individual raters was 0.31 ( 95 % confidence interval [ 95 % CI ] = 0.21 - 0.42 ) among Health Research Methodology students ( n = 10 ) and 0.27 ( 95 % CI = 0.19 - 0.37 ) among the GRADE working group members ( n = 15 ) . The corresponding IRR of the GRADE approach  in assessing the QoE was significantly higher , that is , 0.66 ( 95 % CI = 0.56 - 0.75 ) and 0.72 ( 95 % CI = 0.61 - 0.79 ) , respectively . The IRR further increased for three ( 0.80 [ 95 % CI = 0.73 - 0.86 ] and 0.74 [ 95 % CI = 0.65 - 0.81 ] ) or four raters ( 0.84 [ 95 % CI = 0.78 - 0.89 ] and 0.79 [ 95 % CI = 0.71 - 0.85 ] ) . The IRR did not improve when QoE was assessed through a consensus rating . CONCLUSION Our findings suggest that trained individuals using the GRADE approach improves reliability in comparison to intuitive judgments about the QoE and that two individual raters can reliably assess the QoE using the GRADE system Osteoporosis is a major public health issue leading to significant morbidity , loss of independence and excess loss of life . It has been estimated that 13 to 17 million postmenopausal women have low bone mass or osteoporosis ( 1 , 2 ) . This is associated with almost 1.5 million fractures annually , including 300,000 hip fractures ( 2 , 3 ) . A review of the evidence by Cumming in 1990 ( 4 ) and subsequently published r and omized clinical trials have shown that calcium and /or vitamin D supplements may play a role in the prevention and treatment of osteoporosis by slowing the rates of bone loss in postmenopausal and elderly women ( 5–9 ) . However , there are a limited number of calcium and /or vitamin D trials ( 10–13 ) and observational studies [ review of evidence by Cumming and Nevitt ( 14 ) and Kanis ( 15 ) ] , to support a role for calcium and vitamin D supplementation in the reduction of hip and other fractures . It has also been suggested that calcium and vitamin D supplementation may play a role in the reduction of colorectal cancer incidence ( 16–21 ) . To address these major health concerns of postmenopausal women , the Calcium-Vitamin D ( CaD ) trial of the Women ’s Health Initiative ( WHI ) was design ed to test the primary hypothesis that women who are r and omized to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and secondarily , a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo . The objective of this paper is BACKGROUND Obesity in the United States has increased significantly during the past several decades . The role of calcium in the maintenance of a healthy body weight remains controversial . METHODS A r and omized , double-blinded , placebo-controlled trial was performed with 36 282 postmenopausal women , aged 50 to 79 years , who were already enrolled in the dietary modification and /or hormone therapy arms of the Women 's Health Initiative clinical trial . Women were r and omized at their first or second annual visit to receive a dose of 1000 mg of elemental calcium plus 400 IU of cholecalciferol ( vitamin D ) or placebo daily . Change in body weight was ascertained annually for an average of 7 years . RESULTS Women receiving calcium plus cholecalciferol supplements vs women receiving placebo had a minimal but consistent favorable difference in weight change ( mean difference , -0.13 kg ; 95 % confidence interval , -0.21 to -0.05 ; P = .001 ) . After 3 years of follow-up , women with daily calcium intakes less than 1200 mg at baseline who were r and omized to supplements were 11 % less likely to experience small weight gains ( 1 - 3 kg ) and 11 % less likely to gain more moderate amounts of weight ( > 3 kg ) ( P for interaction for baseline calcium intake = .008 ) . CONCLUSION Calcium plus cholecalciferol supplementation has a small effect on the prevention of weight gain , which was observed primarily in women who reported inadequate calcium intakes . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000611 BACKGROUND The bioequivalence of the different forms of vitamin D , ergocalciferol ( vitamin D2 ) and cholecalciferol ( vitamin D3 ) , has been question ed . Earlier studies have suggested that vitamin D2 is less biologically active than vitamin D3 . OBJECTIVE AND DESIGN In a parallel study , we tested the effects of supplementation with 50-μg/d doses of vitamin D2 or D3 or a placebo over a period of 8 weeks on 25(OH)D2 , 25(OH)D3 , their sum 25(OH)D ( primary outcome variables ) , and PTH in healthy volunteers applying a double-blind , r and omized study design . The study was conducted during the winter of 2012 in Halle ( Saale ) , Germany , at latitude 51 ° 47N , when UVB irradiation is virtually absent .  Blood sample s for the determinations of vitamin D status and PTH were collected at baseline and after 4 and 8 weeks of supplementation . RESULTS In the placebo  group ( n = 19 ) , 25(OH)D3 decreased from 39.4 ± 14.2 to 31.1 ± 12.4 nmol/L after 8 weeks ( P < .01 ) . In the vitamin D3 group ( n = 42 ) , the concentrations of 25(OH)D3 increased from 41.5 ± 22.8 nmol/L at baseline to 88.0 ± 22.1 nmol/L after 8 weeks ( P < .01 ) . In the group receiving vitamin D2 ( n = 46 ) , the 25(OH)D2 concentrations increased significantly , whereas the 25(OH)D3 concentration fell from 36.4 ± 13.3 nmol/L at baseline to 16.6 ± 6.3 nmol/L after 8 weeks ( P < .01 ) . The total 25(OH)D was not different between the groups at baseline but differed significantly between the groups after 4 and 8 weeks ( P < .001 ) . CONCLUSIONS Vitamin D3  increases the total 25(OH)D concentration more than vitamin D2 . Vitamin D2 supplementation was associated with a decrease in 25(OH)D3 , which can explain the different effect on total CONTEXT In humans , few studies have compared the potencies of ergocalciferol and cholecalciferol in improving and maintaining vitamin D status . OBJECTIVE Our objective was to evaluate the effects of a single very large dose of both calciferols on serum changes of 25-hydroxyvitamin D [ 25(OH)D ] , 1,25-dihydroxyvitamin D [ 1,25(OH)(2)D ] , ionized calcium , and parathyroid hormone ( PTH ) at baseline , and at 3 , 7 , 30 , and 60 d. DESIGN This was a prospect i ve r and omized intervention study . SETTING The study was performed in a nursing home residence . PARTICIPANTS A total of 32 elderly female patients ( age range 66 - 97 yr ) , with vitamin D deficiency was included in the study . INTERVENTION Participants were r and omized into four groups of eight to receive a single dose of 300,000 IU ergocalciferol or cholecalciferol by oral ( os ) or i m route . RESULTS 25(OH)D levels sharply increased at d 3 only when vitamins were given os . The 30-d basal difference in serum 25(OH)D was significantly greater after cholecalciferol os administration ( 47.8 + /- 7.3 ng/ml ) compared with other forms ( D(3 ) i m : 15.9 + /- 11.3 ; D(2 ) os : 17.3 + /- 4.7 ; D(2 ) i m : 5 + /- 4.4 ; all P < 0.001 ) . The area under the curve ( AUC ) of the serum 25(OH)D against time ( AUC(60 ) ) was : D(3 ) os , 3193 + /- 759 ng x d/ml vs. D(2 ) os , 1820 + /- 512 , P < 0.001 ; and D(3 ) i m , 1361 + /- 492 vs. D(2 ) i m , 728 + /- 195 , P < 0.01 . 25(OH)D significantly influences PTH levels at 3 ( P < 0.03 ) , 7 ( P < 0.01 ) , 30 ( P < 0.01 ) , and 60 d ( P < 0.05 ) . At 60 d , the form of vitamin ( cholecalciferol ) significantly lowers PTH levels ( P = 0.037 ) . CONCLUSIONS Cholecalciferol is almost twice as potent as ergocalciferol in increasing serum 25(OH)D , when administered either by mouth or i m . 25(OH)D plays a role in modulating serum PTH BACKGROUND Elderly people who have a fracture are at high risk of another . Vitamin D and calcium supplements are often recommended for fracture prevention . We aim ed to assess whether vitamin D3 and calcium , either alone or in combination , were effective in prevention of secondary fractures . METHODS In a factorial- design trial , 5292 people aged 70 years or older ( 4481 [ 85 % ] of whom were women ) who were mobile before developing a low-trauma fracture were r and omly assigned 800 IU daily oral vitamin D3 , 1000 mg calcium , oral vitamin D3 ( 800 IU per day ) combined with calcium ( 1000 mg per day ) , or placebo .  Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months . Analysis was by intention-to-treat and the primary outcome was new low-energy fractures . FINDINGS 698 ( 13 % ) of 5292 participants had a new low-trauma fracture , 183 ( 26 % ) of which were of the hip . The incidence of new , low-trauma fractures did not differ significantly between participants allocated calcium and those who were not ( 331 [ 12.6 % ] of 2617 vs 367 [ 13.7 % ] of 2675 ; hazard ratio ( HR ) 0.94 [ 95 % CI 0.81 - 1.09 ] ) ; between participants allocated vitamin D3 and those who were not ( 353 [ 13.3 % ] of 2649 vs 345 [ 13.1 % ] of 2643 ; 1.02 [ 0.88 - 1.19 ] ) ; or between those allocated combination treatment and those assigned placebo ( 165 [ 12.6 % ] of 1306 vs 179 [ 13.4 % ] of 1332 ; HR for interaction term 1.01 [ 0.75 - 1.36 ] ) . The groups did not differ in the incidence of all-new fractures , fractures confirmed by radiography , hip fractures , death , number of falls , or quality of life . By 24 months , 2886 ( 54.5 % ) of 5292 were still taking tablets , 451 ( 8.5 % ) had died , 58 ( 1.1 % ) had withdrawn , and 1897 ( 35.8 % ) had stopped taking tablets but were still providing data for at least the main outcomes . Compliance with tablets containing calcium was significantly lower ( difference : 9.4 % [ 95 % CI 6.6 - 12.2 ] ) , partly because of gastrointestinal symptoms . However , potentially serious adverse events were rare and did not differ between groups . INTERPRETATION The findings do not support routine oral supplementation with calcium and vitamin D3 , either alone or in combination , for the prevention of further fractures in previously mobile elderly people In the Women 's Health Initiative ( WHI ) trial of calcium plus vitamin D ( CaD ) , we examined the treatment effect on incidence and mortality for all invasive cancers . Postmenopausal women ( N = 36,282 ) were r and omized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo . Cox models estimated risk of cancer incidence and mortality . After 7.0 yr , 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [ hazard ratio ( HR ) = 0.98 ; CI = 0.90 , 1.05 , unweighted P = 0.54 ] . Mortality did not differ between supplement ( 315 , annualized% = .26 ) and placebo [ ( 347 , 0.28 % ; P = 0.17 ; HR = 0.90 ( 0.77 , 1.05 ) ] . Significant treatment interactions on incident cancer were found for family history of cancer , personal total intake of vitamin D , smoking , and WHI dietary trial r and omized group . Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality . Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer . The interactions are only suggestive given multiple testing considerations . The low vitamin D dose provided , limited adherence , and lack of serum 25(OH)D values should be considered when interpreting these findings OBJECTIVES The Women 's Health Initiative ( WHI ) r and omized trial of calcium/vitamin D supplementation found reduced bone loss with active treatment compared to placebo . Now we examine whether the treatment affected self-reported physical functioning and objective measures of physical functioning . DESIGN A r and omized , double-blind , placebo-controlled trial of 1,000 mg calcium carbonate plus 400 IU vitamin D(3 ) per day or matching placebo pills . SUBJECTS/ SETTING The study included 33,067 women ( 50 to 79 years old ) at 40 US study centers . MAIN OUTCOME MEASURES Physical functioning was assessed by question naire at enrollment in WHI , 1 year prior to calcium/vitamin D trial r and omization and at study close-out ( average follow-up 7.1 years ) . Objective physical performance and self-reported exercise measures were collected at WHI baseline ( 1 year prior to calcium/vitamin D enrollment ) and 2 years and 4 years after calcium/vitamin D trial enrollment in a sub sample ( n=3,137 ) . STATISTICAL ANALYSES PERFORMED Calcium/vitamin D effects were tested in unadjusted and interaction linear models for each of the physical function measures . Covariates were baseline total calcium intake , fracture risk score , treatment arm in the hormone therapy and dietary modification trials ( ie , active drug or placebo , low-fat diet intervention or usual diet , respectively ) and age . RESULTS Neither intention to treat nor high adherence analyses produced substantial effects of calcium/vitamin D  compared to placebo on physical functioning or performance . The interaction analyses also did not result in differences because of calcium/vitamin D. CONCLUSIONS As the first long-term r and omized trial to examine the effectiveness of calcium and vitamin D in protecting against decline of physical functioning in older women , the results did not support benefit BACKGROUND R and omized controlled trials testing the association between vitamin D status and upper respiratory tract infection ( URTI ) have given mixed results . During a multicenter , r and omized controlled trial of colorectal adenoma chemoprevention , we tested whether 1000 IU/day vitamin D(3 ) supplementation reduced winter episodes and duration of URTI and its composite syndromes , influenza-like illness ( ILI ; fever and ≥2 of sore throat , cough , muscle ache , or headache ) and colds ( no fever , and ≥2 of runny nose , nasal congestion , sneezing , sore throat , cough , swollen or tender neck gl and s ) . METHODS The 2259 trial participants were aged 45 - 75 , in good health , had a history of colorectal adenoma , and had a serum 25-hydroxyvitamin D level ≥12 ng/mL. They were r and omized to vitamin D(3 ) ( 1000 IU/day ) , calcium ( 1200 mg/day ) , both , or placebo . Of these , 759 participants completed daily symptom diaries . Secondary data included semiannual surveys of all participants . RESULTS Among those who completed symptom diaries , supplementation did not significantly reduce winter episodes of URTI ( rate ratio [ RR ] , 0.93 ; 95 % confidence interval [ CI ] , .79 - 1.09 ) including colds ( RR , 0.93 ; 95 % CI , .78 - 1.10 ) or ILI ( RR , 0.95 ; 95 % CI , .62 - 1.46 ) , nor did it reduce winter days of illness ( RR , 1.13 ; 95 % CI , .90 - 1.43 ) . There was no significant benefit according to adherence , influenza vaccination , body mass index , or baseline vitamin D status . Semiannual surveys of all participants ( N = 2228 ) identified no benefit of supplementation on ILI ( odds ratio [ OR ] , 1.14 ; 95 % CI , .84 - 1.54 ) or colds ( OR , 1.03 ; 95 % CI , .87 - 1.23 ) . CONCLUSIONS Supplementation with 1000 IU/day vitamin D(3 ) did not significantly reduce the incidence or duration of URTI in adults with a baseline serum 25-hydroxyvitamin D level ≥12 Objectives : To investigate the practicality and tolerability of high‐dose intramuscular ( i.m . ) vitamin D2 or oral vitamin D3 replacement in vitamin D‐insufficient patients , and to evaluate the biochemical efficacy of each formulation . Methods : Sixty‐nine patients with vitamin D insufficiency [ 25‐hydroxyvitamin D ( 25(OH)D ) < 40 nmol/L ] were recruited from the Rheumatology Outpatient Department of St George 's Hospital , London . In study 1 , 50 patients received 300 000 IU i.m . vitamin D2 ( ergocalciferol ) . In study 2 , 19 patients received 300 000 IU oral vitamin D3 ( cholecalciferol ) under observation . Biochemical response was measured at baseline , and at 12 and 24 weeks . Results : Bolus i.m . vitamin D2 or oral vitamin D3 was well tolerated . The change from baseline in serum 25(OH)D was significantly greater at 6 and 12 weeks in study 2 ( p<0.0001 and < 0.0001 , respectively ) . In study 1 , a modest increase in mean serum 25(OH)D at 6 , 12 , and 24 weeks was observed but no patients achieved a serum 25(OH)D concentration ⩾50 nmol/L. PTH remained elevated in 42 % of patients with secondary hyperparathyroidism at 12 weeks . In study 2 , 100 % and 89 % of patients had serum 25(OH)D>50 nmol/L at 6 and 12 weeks , respectively . All patients with elevated baseline PTH were fully suppressed at 12 weeks . No cases of hypercalcaemia were observed in either group . Conclusion : The 300 000‐IU bolus of vitamin D2 or D3 was practical , well tolerated , and safe . Vitamin D3 had greater potency than equimolar vitamin D2 , with a higher , sustained serum 25(OH)D response and efficacious PTH suppression . To adequately treat vitamin D insufficiency we would recommend administering 300 000 IU oral vitamin D3 approximately three times per year Few year-long vitamin D supplementation trials exist that match seasonal changes . The aim of this study was to determine whether daily oral vitamin D3 at 400 IU or 1000 IU compared with placebo affects annual bone mineral density ( BMD ) change in postmenopausal women in a 1-year double-blind placebo controlled trial in Scotl and . White women aged 60 to 70 years ( n = 305 ) were r and omized to one of two doses of vitamin D or placebo . All participants started simultaneously in January/February 2009 , attending visits at bimonthly intervals with 265 ( 87 % ) women attending the final visit and an additional visit 1 month after treatment cessation . BMD ( Lunar iDXA ) and 1,25-dihydroxyvitamin D[1,25(OH)2 D ] , N-terminal propeptide of type 1 collagen [ P1NP ] , C-terminal telopeptide of type I collagen [ CTX ] , and fibroblast growth factor-23 [ FGF23 ] were measured by immunoassay at the start and end of treatment . Circulating PTH , serum Ca , and total 25-hydroxyvitamin D [ 25(OH)D ] ( latter by t and em mass spectrometry ) were measured at each visit . Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group ( 0.05 % ± 1.46 % ) compared with the 400 IU vitamin D or placebo groups ( 0.57 % ± 1.33 % and 0.60 % ± 1.67 % , respectively ) ( p < 0.05 ) . Mean ( ± SD ) baseline 25(OH)D was 33.8 ± 14.6 nmol/L ; comparative 25(OH)D change for the placebo , 400 IU , and 1000 IU vitamin D groups was -4.1 ± 11.5 nmol/L , + 31.6 ± 19.8 nmol/L , and + 42.6 ± 18.9 nmol/L , respectively . Treatment did not change markers of bone metabolism , except for a small reduction in PTH and an increase in serum calcium ( latter with 1000 IU dose only ) . The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome , nor how much vitamin D is being stored There are few data on the relative effects of calcium supplementation with or without extra vitamin D on BMD in patients selected for low vitamin D status . The aim of this study is to evaluate the relative importance of vitamin D and calcium treatment on BMD and bone-related chemistry in elderly women with vitamin D insufficiency . Three hundred two elderly women ( age , 77.2 + /- 4.6 yr ) with serum 25(OH)D concentrations < 60 nM participated in a 1-yr r and omized , double-blind , placebo-controlled trial . All subjects received 1000 mg calcium citrate per day with either 1000 IU ergocalciferol ( vitamin D(2 ) ) or identical placebo ( control ) . The effects of time and time treatment interactions were evaluated by repeated- measures ANOVA . At baseline , calcium intake was 1100 mg/d , and 25(OH)D was 44.3 + /- 12.9 nM ; this increased in the vitamin D group by 34 % but not the control group after 1 year ( 59.8 + /- 13.8 versus 45.0 + /- 13.3 nM , p < 0.001 ) . Total hip and total body BMD increased significantly , and procollagen type I intact N-terminal propeptide ( PINP ) decreased during the study with no difference between the treatment groups ( hip BMD change :  vitamin D , + 0.5 % ; control , + 0.2 % ; total body BMD change : vitamin D , + 0.4 % ; control , + 0.4 % ; PINP change : vitamin D , -3.9 % ; placebo , -2.8 % ) . Although the fasting plasma and urine calcium increased in both groups equally , there was no detectable change in serum PTH . The increase in 25(OH)D achieved with vitamin D supplementation had no extra effect on active fractional intestinal calcium absorption , which fell equally in both groups ( vitamin D , -17.4 % ; control , -14.8 % ) . In patients with a baseline calcium intake of 1100 mg/d and vitamin D insufficiency , vitamin D(2 ) 1000 IU for 1 year has no extra beneficial effect on bone structure , bone formation markers , or intestinal calcium absorption over an additional 1000 mg of calcium . Vitamin D supplementation adds no extra short-term skeletal benefit to calcium citrate supplementation even in women with vitamin D insufficiency Published evidence suggests that aspects of trial design lead to biased intervention effect estimates , but findings from different studies are inconsistent . This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials . Outcome measures were classified as " mortality , " " other objective , " " or subjective , " and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity . Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear ( vs. adequate ) r and om-sequence generation ( ratio of odds ratios , 0.89 [ 95 % credible interval { CrI } , 0.82 to 0.96 ] ) and with inadequate or unclear ( vs. adequate ) allocation concealment ( ratio of odds ratios , 0.93 [ CrI , 0.87 to 0.99 ] ) . Lack of or unclear double-blinding ( vs. double-blinding ) was associated with an average of 13 % exaggeration of intervention effects ( ratio of odds ratios , 0.87 [ CrI , 0.79 to 0.96 ] ) , and between-trial heterogeneity was increased for such studies ( SD increase in heterogeneity , 0.14 [ CrI , 0.02 to 0.30 ] ) . For each characteristic , average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes , with little evidence of bias in trials with objective and mortality outcomes . This study is limited by incomplete trial reporting , and findings may be confounded by other study design characteristics . Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes BACKGROUND The Women 's Health Initiative ( WHI ) r and omized clinical trial ( RCT ) of calcium plus vitamin D ( CaD ) supplements found a 17 % excess in urinary tract stone incidence in the supplemented group . This study evaluated whether this risk is modified by participant characteristics . OBJECTIVE We examined the correlates of urinary tract stone occurrence in the CaD arm of the WHI trial . DESIGN We analyzed an RCT involving 36,282 postmenopausal women aged 50 - 79 y from 40 WHI centers : 18,176 women received 500 mg calcium carbonate plus 200 IU vitamin D(3 ) twice daily ( 1000 mg and 400 IU daily , respectively ) , and 18,106 women received a matching placebo for an average of 7.0 y. The incidence of urinary tract stones was determined . RESULTS The incidence of self-reported clinical ly diagnosed urinary tract stones was more common in the active CaD medication group than in the placebo group ( hazard ratio : 1.17 ; 95 % CI : 1.02 , 1.34 ) : 449 women in the CaD group and 381 women in the placebo group reported a stone during the trial . The rates of self-reported stones did not differ between various demographic , anthropomorphic , dietary , and other hypothesized risk factors according to r and omization assignment . Neither the total calcium intake nor the use of calcium supplements at baseline was associated with the risk of stones . In sensitivity analyses that censored participants who were below 80 % adherence , the findings were similar . CONCLUSIONS Daily supplementation with CaD for 7 y was associated with an increase in the number of self-reported urinary tract stones . These findings have implication s for CaD supplement use . This trial was registered with the WHI at clinical trials.gov as NCT00000611
target: There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women .
  Vitamin D₃ supplementation  decreased cancer mortality  and vitamin D supplementation  decreased all-cause mortality , but these estimates are at risk of type I errors due to the fact that too few participants were examined , and to risks of attrition bias originating from substantial dropout of participants .
  Combined vitamin D₃ and calcium supplements  increased nephrolithiasis , whereas it remains unclear from the included trials whether vitamin D₃ , calcium , or both were responsible for this effect .
background: BACKGROUND The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory .
  OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults .