<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03783273</url>
  </required_header>
  <id_info>
    <org_study_id>1107213017</org_study_id>
    <nct_id>NCT03783273</nct_id>
  </id_info>
  <brief_title>The Influence of Food Matrix Delivery System on the Bioavailability of Vitamin D3</brief_title>
  <acronym>DFORT</acronym>
  <official_title>The Influence of Food Matrix Delivery System on the Bioavailability of Vitamin D3</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Aarhus</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study investigates the influence of different food matrices on the bioavailability of&#xD;
      vitamin D.&#xD;
&#xD;
      Although most vitamin D comes from skin synthesis in response to sun exposure, dietary intake&#xD;
      is also important - especially during winter time where there is no endogenous production of&#xD;
      vitamin D in Denmark. A way to maintain an adequate vitamin D status is to supplement either&#xD;
      as tablets/droplets or as fortified food. However, there seems to be an inter-individual&#xD;
      variation in response to supplementation.&#xD;
&#xD;
      This study aims to investigate whether this variation in absorption of vitamin D may depend&#xD;
      on delivery system.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND The current project is a part of the vitamin D fortification with enhanced&#xD;
      bioavailability study program (acronym: DFORT) which is an interdisciplinary project&#xD;
      including research groups from Denmark, Spain, and the Netherlands supported by the Danish&#xD;
      Innovation Foundation. The overall aim of DFORT is to develop more efficient strategies for&#xD;
      vitamin D fortification by studying the influence of the delivery matrix on the&#xD;
      bioavailability of vitamin D. DFORT is organized into four scientific work packages (WP).&#xD;
&#xD;
      The first two WPs have aimed to study whether complex formation (nano-encapsulation) of&#xD;
      vitamin D with different proteins may enhance the stability of vitamin D (WP 1 lead by prof.&#xD;
      Daniel Otzen, AU-iNANO) and the effect of complex formation in real food systems including&#xD;
      investigations on the stability during storage, light- and heat-exposure (WP 2 lead by&#xD;
      associate professor Trine Kastrup Dalsgaard, AU-FOOD). WP 1+2 have shown that vitamin D can&#xD;
      be stabilized by complex formation with whey protein and that the encapsulation may cause&#xD;
      less oxidative degradation thereby improving the stability of vitamin D in different food&#xD;
      systems.&#xD;
&#xD;
      In the current study (WP 3 lead by prof. Lars Rejnmark, AU-Health), the bioavailability of&#xD;
      vitamin D in different food matrices (including complex formation with whey protein) will be&#xD;
      studied in humans. Biological samples will be collected in WP 3 allowing for metabolomics&#xD;
      studies on possible associations between vitamin D supplementation through different food&#xD;
      matrices and metabolic phenotype (WP 4 lead by prof. Hanne C. Bertram, AU-FOOD).&#xD;
&#xD;
      Although most of the total body vitamin D is synthesized in the skin after exposure to UV&#xD;
      light (wavelength of 290-315 nm), most individuals require at least some dietary vitamin D to&#xD;
      maintain a replete vitamin D status. This is especially true during wintertime. With a&#xD;
      latitude of 56°N in Denmark, there is no endogenous synthesis of vitamin D in the months&#xD;
      extending from October to April, which means that the inhabitants have to rely on food&#xD;
      sources in order to maintain a replete vitamin D status. Cholecalciferol (vitamin D3 [D3]) is&#xD;
      the main dietary source of vitamin D, but it is only present in a limited number of food&#xD;
      items (such as fatty fish) making it difficult to achieve the recommended intake of 10 µg D3&#xD;
      per day.&#xD;
&#xD;
      Vitamin D status may be improved in response to an increased intake of vitamin D in terms of&#xD;
      either supplementation with tablets or food fortification. Numerous studies have shown&#xD;
      increased 25-hydroxy vitamin D (25OHD) levels in response to an increased intake of vitamin&#xD;
      D. It is generally assumed that mean 25OHD concentrations increase by 0.7 nmol/L in response&#xD;
      to an increased long-term intake of 1 µg vitamin D per day although the relative increase per&#xD;
      microgram supplemented may be higher if baseline levels are low. Despite this well-known&#xD;
      dose-response relationship in groups of people, several studies have documented that the&#xD;
      change in serum 25OHD levels in response to vitamin D supplementation varies widely.&#xD;
&#xD;
      Several reasons may account for the inter-individual variation in response to vitamin D&#xD;
      supplementation. In gross terms, the variation may be due to dosing inaccuracies&#xD;
      (inconsistencies between claimed and actual values of vitamin D) and variation in&#xD;
      bioavailability of vitamin D.&#xD;
&#xD;
      Inconsistencies between claimed and measured values of vitamin D content in vitamin D tablets&#xD;
      and food-fortified products may be due to inconsistencies in dose used for fortification or&#xD;
      to the instability of the vitamin per se. Discrepant results have been reported on the&#xD;
      stability of vitamin D in different food matrices and when exposed to different&#xD;
      physiochemical hazards. Some investigators have reported vitamin D to be unstable whereas&#xD;
      others have found it to be remarkable stable when exposed to oxidation, light, and to acid&#xD;
      and alkali.&#xD;
&#xD;
      Only few studies have searched for factors responsible for the inter-individual variation in&#xD;
      25OHD levels in response to vitamin D supplementation. These studies have suggested that body&#xD;
      composition (including fat mass content), genetic variants of the vitamin D binding protein&#xD;
      (VDBP), and the ratio of serum 24,25-dihydroxy vitamin D (24,25(OH)2D) to 25OHD may&#xD;
      contribute to variation in serum 25OHD levels. However, in a recent study only 47% of the&#xD;
      variations in the response to vitamin D supplementation could be explained by accounting for&#xD;
      factors of known importance to changes in 25OHD levels.&#xD;
&#xD;
      In addition to the above-mentioned indices, factors of importance to the intestinal&#xD;
      absorption of vitamin D as well as the food matrix by which vitamin D supplementation is&#xD;
      provided may contribute to inter-individual variations in 25OHD responses. However, only few&#xD;
      studies are available on the bioavailability of vitamin D from different food matrices and&#xD;
      the intestinal absorption of vitamin D, including the intraluminal fate, and molecular&#xD;
      mechanisms facilitating the absorption are still only partially understood.&#xD;
&#xD;
      As vitamin D is a fat-soluble molecule, it has generally been assumed that vitamin D is&#xD;
      absorbed in the small intestine by simple passive diffusion with vitamin D being incorporated&#xD;
      into the micelle and transported by chylomicrons via lymph veins to the liver. This is in&#xD;
      alignment with studies showing an increased risk of low 25OHD levels in patients with fat&#xD;
      malabsorption. Accordingly, it has been suggested that ingestion of vitamin D with a meal&#xD;
      rich in fat may increase the release of bile, allowing an increased incorporation of vitamin&#xD;
      D in the bile salt micelle thereby improving the bioavailability of vitamin D. However,&#xD;
      discrepant results have been reported, on whether the composition of the food matrices (and&#xD;
      its fat content) by which vitamin D is ingested influence its bioavailability.&#xD;
&#xD;
      In a randomized, controlled trial by Raimundo et al., the mean change in 25OHD levels two&#xD;
      weeks after the treatment with a single large oral dose of 50,000 IU D3 was larger, when the&#xD;
      meal had at least 15 g of fat compared to a fat-free meal. In contrast, the fat content of&#xD;
      the food matrices was not found to influence the time-concentration profile as measured by&#xD;
      vitamin D2 levels in plasma 2, 4, 8, 12, 48, and 72 h after ingestion of a single dose of&#xD;
      25,000 IU D2 added to either whole milk, skim milk or dissolved in 0.1 mL corn oil and&#xD;
      applied to toast. However, both of these studies are limited by the use of very high&#xD;
      (pharmacological) doses of vitamin D, which may override any physiological effects of the&#xD;
      composition of the food matrices.&#xD;
&#xD;
      A lack of an effect of the fat content of the food by which vitamin D is ingested is also&#xD;
      supported by studies on vitamin D fortification of orange juice. Comparing the&#xD;
      bioavailability of vitamin D added to orange juice or supplemented as capsules showed a&#xD;
      similar increase in 25OHD concentrations in response to 11 weeks of supplementation with 1000&#xD;
      IU vitamin D per day and the increase was significant compared to placebo. The fact that&#xD;
      vitamin D may be sufficiently absorbed following a fat-free meal (such as orange juice) may&#xD;
      be explained by recent findings on the mechanism by which vitamin D is absorbed. It seems&#xD;
      that vitamin D is not only absorbed by simple passive diffusion (by incorporation into the&#xD;
      micelle), as cholesterol membrane transporters, such as SR-BI, CD36, or NPC1L1, have been&#xD;
      shown to be involved in the absorption. Differences in expression levels and the existence of&#xD;
      functional polymorphisms in the genes encoding these proteins may also contribute to the&#xD;
      large inter-individual variation in postprandial responses to vitamin D.&#xD;
&#xD;
      Only very few studies are available on the time-plasma concentration profile of vitamin D&#xD;
      after intake of an oral dose. Denker et al. studied the pharmacokinetic profile of vitamin D3&#xD;
      after administration of a single D3 dose of either 2800 or 5600 IU, showing that plasma D3&#xD;
      levels increased steadily after the intake and peaked at 9±2.3 h with concentrations&#xD;
      returning to near baseline values by 72 h. It is unknown whether the food matrix (including&#xD;
      complex formation of vitamin D by encapsulation with whey proteins) affects the&#xD;
      bioavailability of vitamin D as assessed by the plasma-time concentration profiles and&#xD;
      whether this may influence the inter-individual variability in response to vitamin D&#xD;
      supplementation.&#xD;
&#xD;
      The importance of calcium intake, and especially calcium intake from milk products and&#xD;
      tablets (supplements) has been investigated in a number of studies, showing discrepant&#xD;
      results. A Cochrane meta-analysis has suggested an overall beneficial effect of increased&#xD;
      calcium intake from milk products and calcium supplements. However, a recent trial has&#xD;
      suggested an increase in blood pressure in the hours following intake of 1000 mg of calcium&#xD;
      citrate compared with placebo. It has so far not been investigated whether milk intake causes&#xD;
      similar effects on indices of cardiovascular health, including blood pressure and arterial&#xD;
      stiffness.&#xD;
&#xD;
      AIM The overall aim of the study is to investigate the influence of different food matrices&#xD;
      (including complex-formation with whey proteins) on the bioavailability of vitamin D, as&#xD;
      assessed by maximum concentration profiles (Cmax) and the time-concentration curve of D3 in&#xD;
      plasma and thereby whether the inter-individual variation in the absorption of vitamin D may&#xD;
      depend on delivery system.&#xD;
&#xD;
      Co-primary (null-) hypothesis:&#xD;
&#xD;
        -  The food matrix by which D3 is delivered does not affect Cmax of D3 as determined 10h&#xD;
           post-dosing.&#xD;
&#xD;
        -  The absorption profile (time-concentration curve in terms of Area Under the Curve from&#xD;
           0h to 12h [AUC0-12h]) does not differ according to the food matrix by which D3 is&#xD;
           delivered.&#xD;
&#xD;
      Secondary (null-)hypotheses&#xD;
&#xD;
        -  Compared with vitamin D provided as droplets, the absorption of D3 is not enhanced by&#xD;
           delivery through each of the tested food matrices (i.e., increased Cmax).&#xD;
&#xD;
        -  Compared with vitamin D added to juice, the absorption of D3 is not enhanced by whey&#xD;
           protein complex-bound D3 (i.e., increased Cmax).&#xD;
&#xD;
        -  Treatments do not affect plasma levels of parathyroid hormone (PTH) and ionized calcium.&#xD;
&#xD;
        -  The variability to vitamin D supplementation in terms of Cmax is lower if vitamin D is&#xD;
           complex-bound to whey proteins as compared to the other tested supplementation methods.&#xD;
&#xD;
        -  Arterial stiffness as assessed by tonometry is not affected by milk intake.&#xD;
&#xD;
      Explanatory hypotheses In order to allow for further investigations on indices of importance&#xD;
      to responses to vitamin D supplementation, data will be collected on body composition,&#xD;
      genetic polymorphisms, cholesterol status, and habitual dietary habits.&#xD;
&#xD;
      MATERIALS AND METHODS&#xD;
&#xD;
      STUDY DESIGN The study is performed as a multiple cross-over study using a balanced&#xD;
      latin-square design. This design allows for each participant to function as her own control&#xD;
      thereby counterbalancing risk of an adverse influence on results of the order of treatment or&#xD;
      other factors such as effect of period, as well as inter-individual variations attributable&#xD;
      to e.g., genetic variations, body weight etc. By randomization, each participant will be&#xD;
      allocated to receive all the five treatment regimes in a pre-specified order with a 10-21&#xD;
      days wash-out period in-between each of the treatment arms.&#xD;
&#xD;
      The treatment sequences are:&#xD;
&#xD;
      Treatment sequence 1: A B E C D&#xD;
&#xD;
      Treatment sequence 2: B C A D E&#xD;
&#xD;
      Treatment sequence 3: C D B E A&#xD;
&#xD;
      Treatment sequence 4: D E C A B&#xD;
&#xD;
      Treatment sequence 5: E A D B C&#xD;
&#xD;
      Treatment sequence 6: D C E B A&#xD;
&#xD;
      Treatment sequence 7: E D A C B&#xD;
&#xD;
      Treatment sequence 8: A E B D C&#xD;
&#xD;
      Treatment sequence 9: B A C E D&#xD;
&#xD;
      Treatment sequence 10: C B D A E&#xD;
&#xD;
      PROCEDURES FOR HANDLING VITAMIN D SUPPLEMENTATION The supplement will be acquired&#xD;
      commercially and stored at the Osteoporosis Clinic, Aarhus University Hospital and kept away&#xD;
      from other medication and supplementation. Sub-investigator is responsible for correct&#xD;
      handling and dispensing of vitamin D supplement, as well as securing that the supplement will&#xD;
      only be used as described in the protocol and that the participants are instructed to take it&#xD;
      correct.&#xD;
&#xD;
      PROCEDURES FOR RANDOMIZATION Randomization will be done using a computer generate list.&#xD;
      Treatments will not be blinded for the investigator. In terms of comparing juice with or&#xD;
      without whey proteins bound-complexes, a single-blind design will be applied, as participants&#xD;
      will not be told which of the treatments they are receiving. Each treatment sequence will be&#xD;
      allocated to the same number of patients - e.g. 3 participants will be in treatment sequence&#xD;
      1, 3 in treatment sequence 2 etc.&#xD;
&#xD;
      POPULATION Thirty participants will be recruited from the general background population by&#xD;
      direct mailing using a list of randomly selected individuals living in the area of Aarhus&#xD;
      generated by &quot;Research services&quot; at Statens Serum Institut. The study will be performed&#xD;
      during wintertime (November-April).&#xD;
&#xD;
      WITHDRAWAL AND DROPOUT Any participant can at any point drop out of the study without any&#xD;
      explanation and will not have to go through a final examination. The investigator can&#xD;
      withdraw a participant if this seems necessary for the participant's safety. Dropouts and&#xD;
      withdrawals will be noted and explained in the CRF.&#xD;
&#xD;
      Withdrawal will happen in case of one of the following criteria is fulfilled:&#xD;
&#xD;
        -  Change in vitamin D supplementation&#xD;
&#xD;
        -  Ionized calcium ≥1.40 mmol/L&#xD;
&#xD;
        -  Disease or new medication that will influence the study&#xD;
&#xD;
        -  Serious adverse effects/symptoms that is expected to be caused by vitamin D&#xD;
           supplementation Diseases that occur within 7 days of treatments can be a possible cause&#xD;
           of participation in the study. Sub-investigator can in this time frame be contacted in&#xD;
           order to investigate whether it is a cause of the vitamin D supplementation. In case it&#xD;
           is, the symptoms or disease will be followed until it is cured or have become chronic.&#xD;
&#xD;
      EXAMINATIONS Participants will be examined 5 times over a time period of 6 to 12 weeks. At&#xD;
      each visit, the participants will arrive fasting before 9am and will stay at the department&#xD;
      until blood sampling at 12 hours is taken. Hereafter, the participants is free to go home and&#xD;
      come back the following day for the 24 hours blood sampling and delivering the urine samples&#xD;
      or stay the night at the hospital. During the 12 hours at the department, the participants&#xD;
      will get standardized food.&#xD;
&#xD;
      Basic health information and questionnaires:&#xD;
&#xD;
      Participants will answer questionnaires regarding their general health as well as dietary&#xD;
      habits and sun exposure.&#xD;
&#xD;
      Biochemistry:&#xD;
&#xD;
      Blood samples will be collected at different time points (0, 2, 4, 6, 8, 10, 12, and 24&#xD;
      hours).&#xD;
&#xD;
      All measurements will be performed when all material from all 30 participants have been&#xD;
      collected in order to avoid variation in results. Blood samples will be stored in a biobank&#xD;
      for a maximum of 15 years after the end of the study.&#xD;
&#xD;
      Urine samples:&#xD;
&#xD;
      Urine will be collected in 3 batches at the first day of each dosing i.e., from 0-4 hours,&#xD;
      from 4-8 hours and from 8-24 hours.&#xD;
&#xD;
      All measurements will be performed when all material from all 30 participants have been&#xD;
      collected.&#xD;
&#xD;
      Bone scans:&#xD;
&#xD;
      Dual-Energy X-ray absorptiometry (DXA) and High-Resolution peripheral Quantitative Computed&#xD;
      Tomography (HRpQCT):&#xD;
&#xD;
      DXA scanning with the Hologic QDR Discovery scanner. Bone mineral density (BMD) will be&#xD;
      measured in lumbar spine (L1-L4), femoral neck, and the distal forearm. Furthermore, total&#xD;
      body composition will be determined, including fat- and lean-tissue mass.&#xD;
&#xD;
      A HRpQCT bone scan of the distal radius and tibia will be performed using an Xtreme&#xD;
      CT-scanner (SCANCO Medical AG, Switzerland). This will allow for assessment of volumetric BMD&#xD;
      for cortical and trabecular bone, bone structure and geometry (including cortical and&#xD;
      trabecular thickness, trabecular separation etc.) and bone strength.&#xD;
&#xD;
      Blood pressure measurements and tonometry:&#xD;
&#xD;
      Blood pressure and measurements of arterial stiffness (tonometry) are performed twice in each&#xD;
      participant in relation to treatment regimes &quot;C&quot; and &quot;D&quot;.&#xD;
&#xD;
      On both occasions, measurements are performed in the morning with the participant in the&#xD;
      fasting state. After the measurements are performed, the participant will be provided the&#xD;
      intervention together with a breakfast meal. After this, the participant will be fasting&#xD;
      until next measurement is performed four hours later.&#xD;
&#xD;
      Office blood pressure (BP) is measured in a sitting position after 5 minutes of rest on the&#xD;
      right upper arm using a digital automatic BP monitor. Three BP readings will be performed&#xD;
      with 2 minutes of rest in-between. The average of the last two measurements is recorded.&#xD;
&#xD;
      Arterial stiffness and pulse wave velocity (PWV) will be assessed by tonometry using the&#xD;
      SphygmoCor system (Xcel; AtCor Medical, Sydney, NSW, Australia). For measurements of&#xD;
      carotid-to-femoral PWV, an inflated femoral cuff placed on the right upper thigh combined&#xD;
      with carotid applanation tonometry will be used. Measurements are performed in a quiet room.&#xD;
      The participant will be resting for 10 minutes in a supine position prior to test start.&#xD;
      Brachial BP is measured on the right upper arm and two consecutive BP readings are performed.&#xD;
      If BP readings do not differ by &gt; 5 mmHg, the last one is recorded. If BP readings differ by&#xD;
      &gt; 5 mmHg, four BP readings are obtained. The average of the last two measurements is&#xD;
      recorded. AIx is assessed as the ratio of wave reflection amplitude to central pulse&#xD;
      pressure. The mean of two measurements are used in the analyses. Carotid-femoral PWV is&#xD;
      assessed as the distance travelled divided by the transit time using the direct&#xD;
      carotid-to-cuff distance as measured with a non-stretchable tape (infantometer). A minimum of&#xD;
      two measurements is performed. If measurements differs &lt; 0.5 m/s the average of the two&#xD;
      measurements is used for analyses. If PWV differs by &gt; 0.5 m/s a third measurement is&#xD;
      obtained and the median value is used for analyses. According to general recommendations, the&#xD;
      direct carotid-to-cuff distance mean PWV is multiple with 0.8.&#xD;
&#xD;
      PERSPECTIVES The study will provide insight into the bioavailability of vitamin D3&#xD;
      supplementation, including sources of variation. Since Denmark is a country with low latitude&#xD;
      and high prevalence of vitamin D insufficiency and fortification of food items is not common&#xD;
      or legislated, this study may lead to way to fortifying food items in Denmark.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 8, 2019</start_date>
  <completion_date type="Actual">May 26, 2020</completion_date>
  <primary_completion_date type="Actual">May 26, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>A multiple crossover study using a balanced latin square design. Each participant will receive all five treatments with a wash-out period of 10-21 days between each treatment.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Participants will not know if they receive juice with complex-bound vitamin D3 or not.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Cmax of vitamin D3</measure>
    <time_frame>10 hours</time_frame>
    <description>Maximum observed concentration of vitamin D3</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC of vitamin D3</measure>
    <time_frame>12 hours</time_frame>
    <description>Area under the curve for time-concentration relationships during the absorption phase</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Concentration of vitamin D metabolites</measure>
    <time_frame>24 hours</time_frame>
    <description>Plasma levels of vitamin D2+D3, 25OHD, 1,25(OH)2D, 24,25(OH)2D and VDBP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration of PTH</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in plasma PTH in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of ion-calcium</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in plasma ionized calcium in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine concentration of calcium</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in urine calcium in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine concentration of creatinine</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in urine creatinine in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine concentration of phosphate</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in urine phosphate in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine concentration of magnesium</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in urine magnesium in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine concentration of sodium</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in urine sodium in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine concentration of potassium</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in urine potassium in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine osmolality</measure>
    <time_frame>24 hours</time_frame>
    <description>Changes in urine osmolality in response to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic and diastolic blood pressure</measure>
    <time_frame>4 hours</time_frame>
    <description>Office blood pressure of the upper right arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse wave velocity</measure>
    <time_frame>4 hours</time_frame>
    <description>Assessed by tonometry using SphygmoCor system</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arterial stiffness</measure>
    <time_frame>4 hours</time_frame>
    <description>Assessed by tonometry using SphygmoCor system system (Xcel; AtCor Medical, Sydney, NSW, Australia)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Body composition</measure>
    <time_frame>Week 4</time_frame>
    <description>Assessed by DXA</description>
  </other_outcome>
  <other_outcome>
    <measure>Areal BMD</measure>
    <time_frame>Week 4</time_frame>
    <description>BMD at the lumbar spine, femoral neck and distal forearm assessed by DXA</description>
  </other_outcome>
  <other_outcome>
    <measure>Bone geometry</measure>
    <time_frame>Week 4</time_frame>
    <description>Assessed by HRpQCT of distal tibia and distal radius</description>
  </other_outcome>
  <other_outcome>
    <measure>Volumetric BMD</measure>
    <time_frame>Week 4</time_frame>
    <description>Assessed by HRpQCT of distal tibia and distal radius</description>
  </other_outcome>
  <other_outcome>
    <measure>Estimated bone strength</measure>
    <time_frame>Week 4</time_frame>
    <description>Assessed by HRpQCT of distal tibia and distal radius</description>
  </other_outcome>
  <other_outcome>
    <measure>Plasma concentrations of bone turnover markers</measure>
    <time_frame>Week 4</time_frame>
    <description>Plasma levels of bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide (P1NP), C-terminal telopeptide (CTX), sclerostin and fibroblast growth factor 23 (FGF-23)</description>
  </other_outcome>
  <other_outcome>
    <measure>Exome sequencing</measure>
    <time_frame>24 hours</time_frame>
    <description>Genetic variants of importance to vitamin D metabolism</description>
  </other_outcome>
  <other_outcome>
    <measure>Plasma concentrations of total cholesterol, triglycerides, LDL- and HDL-cholesterol</measure>
    <time_frame>24 hours</time_frame>
    <description>Cholesterol status</description>
  </other_outcome>
  <other_outcome>
    <measure>Plasma concentrations of metabolites</measure>
    <time_frame>24 hours</time_frame>
    <description>Metabolomics analyses: Blood samples for nuclear magnetic resonance and liquid chromatography mass spectrometry analyses</description>
  </other_outcome>
  <other_outcome>
    <measure>General health</measure>
    <time_frame>Week 1</time_frame>
    <description>Questionnaire</description>
  </other_outcome>
  <other_outcome>
    <measure>Dietary habits</measure>
    <time_frame>Week 1</time_frame>
    <description>Questionnaire</description>
  </other_outcome>
  <other_outcome>
    <measure>Sun exposure</measure>
    <time_frame>Week 1</time_frame>
    <description>Questionnaire</description>
  </other_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Vitamin D Deficiency</condition>
  <arm_group>
    <arm_group_label>Whey protein complex-bound D3 + juice</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>200 microgram vitamin D3 in a whey protein-complex added to 500 mL of juice.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>D3 + juice</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>200 microgram vitamin D3 added to 500 mL of juice.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>D3 + milk</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>200 microgram vitamin D3 added to 500 mL of skimmed-milk.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>D3 droplets</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>200 microgram vitamin D3 as droplets + 500 mL of water.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No vitamin D</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>500 mL of Water.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vitamin D3</intervention_name>
    <description>Single dose vitamin D3</description>
    <arm_group_label>D3 + juice</arm_group_label>
    <arm_group_label>D3 + milk</arm_group_label>
    <arm_group_label>D3 droplets</arm_group_label>
    <arm_group_label>Whey protein complex-bound D3 + juice</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Whey protein-complex</intervention_name>
    <description>Whey protein complex-bound vitamin D3</description>
    <arm_group_label>Whey protein complex-bound D3 + juice</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Water</intervention_name>
    <description>500 mL water</description>
    <arm_group_label>D3 droplets</arm_group_label>
    <arm_group_label>No vitamin D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Milk</intervention_name>
    <description>500 mL milk</description>
    <arm_group_label>D3 + milk</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Juice</intervention_name>
    <description>500 mL juice</description>
    <arm_group_label>D3 + juice</arm_group_label>
    <arm_group_label>Whey protein complex-bound D3 + juice</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Postmenopausal&#xD;
&#xD;
          -  Caucasian&#xD;
&#xD;
          -  Total plasma 25-hydroxy vitamin D &lt; 50 nmol/L&#xD;
&#xD;
          -  Understand oral and written Danish&#xD;
&#xD;
          -  Able to consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergic reaction/intolerance to Vitamin D supplementation / milk products /&#xD;
             juice&#xD;
&#xD;
          -  Known chronic kidney disease (creatinine &gt; 90 µmol/L), previous kidney transplantation&#xD;
             or known kidney artery stenosis&#xD;
&#xD;
          -  Known liver disease&#xD;
&#xD;
          -  Known gastrointestinal malabsorption&#xD;
&#xD;
          -  Current malignant disease&#xD;
&#xD;
          -  Hypercalcemia (ionised calcium ≥ 1.33 mmol/L)&#xD;
&#xD;
          -  Treatment with diuretics, lithium or current use of steroids&#xD;
&#xD;
          -  Current use of calcium and/or vitamin D supplementation&#xD;
&#xD;
          -  Planned travel during the intervention period to areas where sun exposure is expected&#xD;
&#xD;
          -  Use of solarium&#xD;
&#xD;
          -  Treatment with beta-blockers&#xD;
&#xD;
          -  Overt cardiovascular disease such as known severe heart failure (NYHA III-IV),&#xD;
             previous major heart surgery, pacemaker, arrhythmias (e.g. atrial fibrillations or&#xD;
             flutter, second- and third-degree atrioventricular block)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lars Rejnmark</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dept. of Endocrinology and Internal Medince, The Osteoporosis Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dept. of Endocrinology and Internal Medicine, The Osteoporosis Clinic</name>
      <address>
        <city>Aarhus N</city>
        <zip>8200</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Pedersen JN, Frislev HS, Pedersen JS, Otzen DE. Using protein-fatty acid complexes to improve vitamin D stability. J Dairy Sci. 2016 Oct;99(10):7755-7767. doi: 10.3168/jds.2016-11343. Epub 2016 Jul 27.</citation>
    <PMID>27474981</PMID>
  </reference>
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    <PMID>10197177</PMID>
  </reference>
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    <citation>Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003 Jan;77(1):204-10. doi: 10.1093/ajcn/77.1.204. Erratum In: Am J Clin Nutr. 2003 Nov;78(5):1047.</citation>
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    <PMID>23959785</PMID>
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    <citation>Blum M, Dallal GE, Dawson-Hughes B. Body size and serum 25 hydroxy vitamin D response to oral supplements in healthy older adults. J Am Coll Nutr. 2008 Apr;27(2):274-9. doi: 10.1080/07315724.2008.10719700.</citation>
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    <PMID>21605672</PMID>
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    <citation>Fu L, Yun F, Oczak M, Wong BY, Vieth R, Cole DE. Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation. Clin Biochem. 2009 Jul;42(10-11):1174-7. doi: 10.1016/j.clinbiochem.2009.03.008. Epub 2009 Mar 18.</citation>
    <PMID>19302999</PMID>
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    <citation>Zhao LJ, Zhou Y, Bu F, Travers-Gustafson D, Ye A, Xu X, Hamm L, Gorsage DM, Fang X, Deng HW, Recker RR, Lappe JM. Factors predicting vitamin D response variation in non-Hispanic white postmenopausal women. J Clin Endocrinol Metab. 2012 Aug;97(8):2699-705. doi: 10.1210/jc.2011-3401. Epub 2012 May 14.</citation>
    <PMID>22585090</PMID>
  </reference>
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    <citation>Borel P, Caillaud D, Cano NJ. Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr. 2015;55(9):1193-205. doi: 10.1080/10408398.2012.688897.</citation>
    <PMID>24915331</PMID>
  </reference>
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    <citation>Reboul E. Intestinal absorption of vitamin D: from the meal to the enterocyte. Food Funct. 2015 Feb;6(2):356-62. doi: 10.1039/c4fo00579a.</citation>
    <PMID>25367187</PMID>
  </reference>
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    <citation>Thompson GR, Lewis B, Booth CC. Absorption of vitamin D3-3H in control subjects and patients with intestinal malabsorption. J Clin Invest. 1966 Jan;45(1):94-102. doi: 10.1172/JCI105327. No abstract available.</citation>
    <PMID>4285212</PMID>
  </reference>
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    <citation>Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1183-94. doi: 10.1152/ajpendo.90899.2008. Epub 2009 Jan 21.</citation>
    <PMID>19158321</PMID>
  </reference>
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    <citation>Raimundo FV, Lang MA, Scopel L, Marcondes NA, Araujo MG, Faulhaber GA, Furlanetto TW. Effect of fat on serum 25-hydroxyvitamin D levels after a single oral dose of vitamin D in young healthy adults: a double-blind randomized placebo-controlled study. Eur J Nutr. 2015 Apr;54(3):391-6. doi: 10.1007/s00394-014-0718-8. Epub 2014 May 23.</citation>
    <PMID>24853643</PMID>
  </reference>
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    <citation>Tangpricha V, Koutkia P, Rieke SM, Chen TC, Perez AA, Holick MF. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. Am J Clin Nutr. 2003 Jun;77(6):1478-83. doi: 10.1093/ajcn/77.6.1478.</citation>
    <PMID>12791627</PMID>
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    <citation>Biancuzzo RM, Young A, Bibuld D, Cai MH, Winter MR, Klein EK, Ameri A, Reitz R, Salameh W, Chen TC, Holick MF. Fortification of orange juice with vitamin D(2) or vitamin D(3) is as effective as an oral supplement in maintaining vitamin D status in adults. Am J Clin Nutr. 2010 Jun;91(6):1621-6. doi: 10.3945/ajcn.2009.27972. Epub 2010 Apr 28.</citation>
    <PMID>20427729</PMID>
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    <citation>Reboul E, Goncalves A, Comera C, Bott R, Nowicki M, Landrier JF, Jourdheuil-Rahmani D, Dufour C, Collet X, Borel P. Vitamin D intestinal absorption is not a simple passive diffusion: evidences for involvement of cholesterol transporters. Mol Nutr Food Res. 2011 May;55(5):691-702. doi: 10.1002/mnfr.201000553. Epub 2011 Jan 31.</citation>
    <PMID>21280209</PMID>
  </reference>
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    <citation>Masson CJ, Plat J, Mensink RP, Namiot A, Kisielewski W, Namiot Z, Fullekrug J, Ehehalt R, Glatz JF, Pelsers MM. Fatty acid- and cholesterol transporter protein expression along the human intestinal tract. PLoS One. 2010 Apr 29;5(4):e10380. doi: 10.1371/journal.pone.0010380.</citation>
    <PMID>20454462</PMID>
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    <PMID>27798339</PMID>
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    <PMID>21148044</PMID>
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    <citation>Kazmi SA, Vieth R, Rousseau D. Vitamin D3 fortification and quantification in processed dairy products. International Dairy Journal 17:753-759, 2007</citation>
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    <citation>Cormick G, Ciapponi A, Cafferata ML, Belizan JM. Calcium supplementation for prevention of primary hypertension. Cochrane Database Syst Rev. 2015 Jun 30;2015(6):CD010037. doi: 10.1002/14651858.CD010037.pub2.</citation>
    <PMID>26126003</PMID>
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    <citation>Billington EO, Bristow SM, Gamble GD, de Kwant JA, Stewart A, Mihov BV, Horne AM, Reid IR. Acute effects of calcium supplements on blood pressure: randomised, crossover trial in postmenopausal women. Osteoporos Int. 2017 Jan;28(1):119-125. doi: 10.1007/s00198-016-3744-y. Epub 2016 Aug 20.</citation>
    <PMID>27543500</PMID>
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    <citation>Van Bortel LM, Laurent S, Boutouyrie P, Chowienczyk P, Cruickshank JK, De Backer T, Filipovsky J, Huybrechts S, Mattace-Raso FU, Protogerou AD, Schillaci G, Segers P, Vermeersch S, Weber T; Artery Society; European Society of Hypertension Working Group on Vascular Structure and Function; European Network for Noninvasive Investigation of Large Arteries. Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity. J Hypertens. 2012 Mar;30(3):445-8. doi: 10.1097/HJH.0b013e32834fa8b0.</citation>
    <PMID>22278144</PMID>
  </reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>December 7, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 21, 2018</study_first_posted>
  <last_update_submitted>May 28, 2020</last_update_submitted>
  <last_update_submitted_qc>May 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Vitamin D Insufficiency</keyword>
  <keyword>Vitamin D Supplementation</keyword>
  <keyword>Food Fortification</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D Deficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03783273
org study id: 1107213017
nct id: NCT03783273
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study investigates the influence of different food matrices on the bioavailability of
      vitamin D.

      Although most vitamin D comes from skin synthesis in response to sun exposure, dietary intake
      is also important - especially during winter time where there is no endogenous production of
      vitamin D in Denmark. A way to maintain an adequate vitamin D status is to supplement either
      as tablets/droplets or as fortified food. However, there seems to be an inter-individual
      variation in response to supplementation.

      This study aims to investigate whether this variation in absorption of vitamin D may depend
      on delivery system.
BACKGROUND The current project is a part of the vitamin D fortification with enhanced
      bioavailability study program (acronym: DFORT) which is an interdisciplinary project
      including research groups from Denmark, Spain, and the Netherlands supported by the Danish
      Innovation Foundation. The overall aim of DFORT is to develop more efficient strategies for
      vitamin D fortification by studying the influence of the delivery matrix on the
      bioavailability of vitamin D. DFORT is organized into four scientific work packages (WP).

      The first two WPs have aimed to study whether complex formation (nano-encapsulation) of
      vitamin D with different proteins may enhance the stability of vitamin D (WP 1 lead by prof.
      Daniel Otzen, AU-iNANO) and the effect of complex formation in real food systems including
      investigations on the stability during storage, light- and heat-exposure (WP 2 lead by
      associate professor Trine Kastrup Dalsgaard, AU-FOOD). WP 1+2 have shown that vitamin D can
      be stabilized by complex formation with whey protein and that the encapsulation may cause
      less oxidative degradation thereby improving the stability of vitamin D in different food
      systems.

      In the current study (WP 3 lead by prof. Lars Rejnmark, AU-Health), the bioavailability of
      vitamin D in different food matrices (including complex formation with whey protein) will be
      studied in humans. Biological samples will be collected in WP 3 allowing for metabolomics
      studies on possible associations between vitamin D supplementation through different food
      matrices and metabolic phenotype (WP 4 lead by prof. Hanne C. Bertram, AU-FOOD).

      Although most of the total body vitamin D is synthesized in the skin after exposure to UV
      light (wavelength of 290-315 nm), most individuals require at least some dietary vitamin D to
      maintain a replete vitamin D status. This is especially true during wintertime. With a
      latitude of 56°N in Denmark, there is no endogenous synthesis of vitamin D in the months
      extending from October to April, which means that the inhabitants have to rely on food
      sources in order to maintain a replete vitamin D status. Cholecalciferol (vitamin D3 [D3]) is
      the main dietary source of vitamin D, but it is only present in a limited number of food
      items (such as fatty fish) making it difficult to achieve the recommended intake of 10 µg D3
      per day.

      Vitamin D status may be improved in response to an increased intake of vitamin D in terms of
      either supplementation with tablets or food fortification. Numerous studies have shown
      increased 25-hydroxy vitamin D (25OHD) levels in response to an increased intake of vitamin
      D. It is generally assumed that mean 25OHD concentrations increase by 0.7 nmol/L in response
      to an increased long-term intake of 1 µg vitamin D per day although the relative increase per
      microgram supplemented may be higher if baseline levels are low. Despite this well-known
      dose-response relationship in groups of people, several studies have documented that the
      change in serum 25OHD levels in response to vitamin D supplementation varies widely.

      Several reasons may account for the inter-individual variation in response to vitamin D
      supplementation. In gross terms, the variation may be due to dosing inaccuracies
      (inconsistencies between claimed and actual values of vitamin D) and variation in
      bioavailability of vitamin D.

      Inconsistencies between claimed and measured values of vitamin D content in vitamin D tablets
      and food-fortified products may be due to inconsistencies in dose used for fortification or
      to the instability of the vitamin per se. Discrepant results have been reported on the
      stability of vitamin D in different food matrices and when exposed to different
      physiochemical hazards. Some investigators have reported vitamin D to be unstable whereas
      others have found it to be remarkable stable when exposed to oxidation, light, and to acid
      and alkali.

      Only few studies have searched for factors responsible for the inter-individual variation in
      25OHD levels in response to vitamin D supplementation. These studies have suggested that body
      composition (including fat mass content), genetic variants of the vitamin D binding protein
      (VDBP), and the ratio of serum 24,25-dihydroxy vitamin D (24,25(OH)2D) to 25OHD may
      contribute to variation in serum 25OHD levels. However, in a recent study only 47% of the
      variations in the response to vitamin D supplementation could be explained by accounting for
      factors of known importance to changes in 25OHD levels.

      In addition to the above-mentioned indices, factors of importance to the intestinal
      absorption of vitamin D as well as the food matrix by which vitamin D supplementation is
      provided may contribute to inter-individual variations in 25OHD responses. However, only few
      studies are available on the bioavailability of vitamin D from different food matrices and
      the intestinal absorption of vitamin D, including the intraluminal fate, and molecular
      mechanisms facilitating the absorption are still only partially understood.

      As vitamin D is a fat-soluble molecule, it has generally been assumed that vitamin D is
      absorbed in the small intestine by simple passive diffusion with vitamin D being incorporated
      into the micelle and transported by chylomicrons via lymph veins to the liver. This is in
      alignment with studies showing an increased risk of low 25OHD levels in patients with fat
      malabsorption. Accordingly, it has been suggested that ingestion of vitamin D with a meal
      rich in fat may increase the release of bile, allowing an increased incorporation of vitamin
      D in the bile salt micelle thereby improving the bioavailability of vitamin D. However,
      discrepant results have been reported, on whether the composition of the food matrices (and
      its fat content) by which vitamin D is ingested influence its bioavailability.

      In a randomized, controlled trial by Raimundo et al., the mean change in 25OHD levels two
      weeks after the treatment with a single large oral dose of 50,000 IU D3 was larger, when the
      meal had at least 15 g of fat compared to a fat-free meal. In contrast, the fat content of
      the food matrices was not found to influence the time-concentration profile as measured by
      vitamin D2 levels in plasma 2, 4, 8, 12, 48, and 72 h after ingestion of a single dose of
      25,000 IU D2 added to either whole milk, skim milk or dissolved in 0.1 mL corn oil and
      applied to toast. However, both of these studies are limited by the use of very high
      (pharmacological) doses of vitamin D, which may override any physiological effects of the
      composition of the food matrices.

      A lack of an effect of the fat content of the food by which vitamin D is ingested is also
      supported by studies on vitamin D fortification of orange juice. Comparing the
      bioavailability of vitamin D added to orange juice or supplemented as capsules showed a
      similar increase in 25OHD concentrations in response to 11 weeks of supplementation with 1000
      IU vitamin D per day and the increase was significant compared to placebo. The fact that
      vitamin D may be sufficiently absorbed following a fat-free meal (such as orange juice) may
      be explained by recent findings on the mechanism by which vitamin D is absorbed. It seems
      that vitamin D is not only absorbed by simple passive diffusion (by incorporation into the
      micelle), as cholesterol membrane transporters, such as SR-BI, CD36, or NPC1L1, have been
      shown to be involved in the absorption. Differences in expression levels and the existence of
      functional polymorphisms in the genes encoding these proteins may also contribute to the
      large inter-individual variation in postprandial responses to vitamin D.

      Only very few studies are available on the time-plasma concentration profile of vitamin D
      after intake of an oral dose. Denker et al. studied the pharmacokinetic profile of vitamin D3
      after administration of a single D3 dose of either 2800 or 5600 IU, showing that plasma D3
      levels increased steadily after the intake and peaked at 9±2.3 h with concentrations
      returning to near baseline values by 72 h. It is unknown whether the food matrix (including
      complex formation of vitamin D by encapsulation with whey proteins) affects the
      bioavailability of vitamin D as assessed by the plasma-time concentration profiles and
      whether this may influence the inter-individual variability in response to vitamin D
      supplementation.

      The importance of calcium intake, and especially calcium intake from milk products and
      tablets (supplements) has been investigated in a number of studies, showing discrepant
      results. A Cochrane meta-analysis has suggested an overall beneficial effect of increased
      calcium intake from milk products and calcium supplements. However, a recent trial has
      suggested an increase in blood pressure in the hours following intake of 1000 mg of calcium
      citrate compared with placebo. It has so far not been investigated whether milk intake causes
      similar effects on indices of cardiovascular health, including blood pressure and arterial
      stiffness.

      AIM The overall aim of the study is to investigate the influence of different food matrices
      (including complex-formation with whey proteins) on the bioavailability of vitamin D, as
      assessed by maximum concentration profiles (Cmax) and the time-concentration curve of D3 in
      plasma and thereby whether the inter-individual variation in the absorption of vitamin D may
      depend on delivery system.

      Co-primary (null-) hypothesis:

        -  The food matrix by which D3 is delivered does not affect Cmax of D3 as determined 10h
           post-dosing.

        -  The absorption profile (time-concentration curve in terms of Area Under the Curve from
           0h to 12h [AUC0-12h]) does not differ according to the food matrix by which D3 is
           delivered.

      Secondary (null-)hypotheses

        -  Compared with vitamin D provided as droplets, the absorption of D3 is not enhanced by
           delivery through each of the tested food matrices (i.e., increased Cmax).

        -  Compared with vitamin D added to juice, the absorption of D3 is not enhanced by whey
           protein complex-bound D3 (i.e., increased Cmax).

        -  Treatments do not affect plasma levels of parathyroid hormone (PTH) and ionized calcium.

        -  The variability to vitamin D supplementation in terms of Cmax is lower if vitamin D is
           complex-bound to whey proteins as compared to the other tested supplementation methods.

        -  Arterial stiffness as assessed by tonometry is not affected by milk intake.

      Explanatory hypotheses In order to allow for further investigations on indices of importance
      to responses to vitamin D supplementation, data will be collected on body composition,
      genetic polymorphisms, cholesterol status, and habitual dietary habits.

      MATERIALS AND METHODS

      STUDY DESIGN The study is performed as a multiple cross-over study using a balanced
      latin-square design. This design allows for each participant to function as her own control
      thereby counterbalancing risk of an adverse influence on results of the order of treatment or
      other factors such as effect of period, as well as inter-individual variations attributable
      to e.g., genetic variations, body weight etc. By randomization, each participant will be
      allocated to receive all the five treatment regimes in a pre-specified order with a 10-21
      days wash-out period in-between each of the treatment arms.

      The treatment sequences are:

      Treatment sequence 1: A B E C D

      Treatment sequence 2: B C A D E

      Treatment sequence 3: C D B E A

      Treatment sequence 4: D E C A B

      Treatment sequence 5: E A D B C

      Treatment sequence 6: D C E B A

      Treatment sequence 7: E D A C B

      Treatment sequence 8: A E B D C

      Treatment sequence 9: B A C E D

      Treatment sequence 10: C B D A E

      PROCEDURES FOR HANDLING VITAMIN D SUPPLEMENTATION The supplement will be acquired
      commercially and stored at the Osteoporosis Clinic, Aarhus University Hospital and kept away
      from other medication and supplementation. Sub-investigator is responsible for correct
      handling and dispensing of vitamin D supplement, as well as securing that the supplement will
      only be used as described in the protocol and that the participants are instructed to take it
      correct.

      PROCEDURES FOR RANDOMIZATION Randomization will be done using a computer generate list.
      Treatments will not be blinded for the investigator. In terms of comparing juice with or
      without whey proteins bound-complexes, a single-blind design will be applied, as participants
      will not be told which of the treatments they are receiving. Each treatment sequence will be
      allocated to the same number of patients - e.g. 3 participants will be in treatment sequence
      1, 3 in treatment sequence 2 etc.

      POPULATION Thirty participants will be recruited from the general background population by
      direct mailing using a list of randomly selected individuals living in the area of Aarhus
      generated by "Research services" at Statens Serum Institut. The study will be performed
      during wintertime (November-April).

      WITHDRAWAL AND DROPOUT Any participant can at any point drop out of the study without any
      explanation and will not have to go through a final examination. The investigator can
      withdraw a participant if this seems necessary for the participant's safety. Dropouts and
      withdrawals will be noted and explained in the CRF.

      Withdrawal will happen in case of one of the following criteria is fulfilled:

        -  Change in vitamin D supplementation

        -  Ionized calcium ≥1.40 mmol/L

        -  Disease or new medication that will influence the study

        -  Serious adverse effects/symptoms that is expected to be caused by vitamin D
           supplementation Diseases that occur within 7 days of treatments can be a possible cause
           of participation in the study. Sub-investigator can in this time frame be contacted in
           order to investigate whether it is a cause of the vitamin D supplementation. In case it
           is, the symptoms or disease will be followed until it is cured or have become chronic.

      EXAMINATIONS Participants will be examined 5 times over a time period of 6 to 12 weeks. At
      each visit, the participants will arrive fasting before 9am and will stay at the department
      until blood sampling at 12 hours is taken. Hereafter, the participants is free to go home and
      come back the following day for the 24 hours blood sampling and delivering the urine samples
      or stay the night at the hospital. During the 12 hours at the department, the participants
      will get standardized food.

      Basic health information and questionnaires:

      Participants will answer questionnaires regarding their general health as well as dietary
      habits and sun exposure.

      Biochemistry:

      Blood samples will be collected at different time points (0, 2, 4, 6, 8, 10, 12, and 24
      hours).

      All measurements will be performed when all material from all 30 participants have been
      collected in order to avoid variation in results. Blood samples will be stored in a biobank
      for a maximum of 15 years after the end of the study.

      Urine samples:

      Urine will be collected in 3 batches at the first day of each dosing i.e., from 0-4 hours,
      from 4-8 hours and from 8-24 hours.

      All measurements will be performed when all material from all 30 participants have been
      collected.

      Bone scans:

      Dual-Energy X-ray absorptiometry (DXA) and High-Resolution peripheral Quantitative Computed
      Tomography (HRpQCT):

      DXA scanning with the Hologic QDR Discovery scanner. Bone mineral density (BMD) will be
      measured in lumbar spine (L1-L4), femoral neck, and the distal forearm. Furthermore, total
      body composition will be determined, including fat- and lean-tissue mass.

      A HRpQCT bone scan of the distal radius and tibia will be performed using an Xtreme
      CT-scanner (SCANCO Medical AG, Switzerland). This will allow for assessment of volumetric BMD
      for cortical and trabecular bone, bone structure and geometry (including cortical and
      trabecular thickness, trabecular separation etc.) and bone strength.

      Blood pressure measurements and tonometry:

      Blood pressure and measurements of arterial stiffness (tonometry) are performed twice in each
      participant in relation to treatment regimes "C" and "D".

      On both occasions, measurements are performed in the morning with the participant in the
      fasting state. After the measurements are performed, the participant will be provided the
      intervention together with a breakfast meal. After this, the participant will be fasting
      until next measurement is performed four hours later.

      Office blood pressure (BP) is measured in a sitting position after 5 minutes of rest on the
      right upper arm using a digital automatic BP monitor. Three BP readings will be performed
      with 2 minutes of rest in-between. The average of the last two measurements is recorded.

      Arterial stiffness and pulse wave velocity (PWV) will be assessed by tonometry using the
      SphygmoCor system (Xcel; AtCor Medical, Sydney, NSW, Australia). For measurements of
      carotid-to-femoral PWV, an inflated femoral cuff placed on the right upper thigh combined
      with carotid applanation tonometry will be used. Measurements are performed in a quiet room.
      The participant will be resting for 10 minutes in a supine position prior to test start.
      Brachial BP is measured on the right upper arm and two consecutive BP readings are performed.
      If BP readings do not differ by > 5 mmHg, the last one is recorded. If BP readings differ by
      > 5 mmHg, four BP readings are obtained. The average of the last two measurements is
      recorded. AIx is assessed as the ratio of wave reflection amplitude to central pulse
      pressure. The mean of two measurements are used in the analyses. Carotid-femoral PWV is
      assessed as the distance travelled divided by the transit time using the direct
      carotid-to-cuff distance as measured with a non-stretchable tape (infantometer). A minimum of
      two measurements is performed. If measurements differs < 0.5 m/s the average of the two
      measurements is used for analyses. If PWV differs by > 0.5 m/s a third measurement is
      obtained and the median value is used for analyses. According to general recommendations, the
      direct carotid-to-cuff distance mean PWV is multiple with 0.8.

      PERSPECTIVES The study will provide insight into the bioavailability of vitamin D3
      supplementation, including sources of variation. Since Denmark is a country with low latitude
      and high prevalence of vitamin D insufficiency and fortification of food items is not common
      or legislated, this study may lead to way to fortifying food items in Denmark.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: A multiple crossover study using a balanced latin square design. Each participant will receive all five treatments with a wash-out period of 10-21 days between each treatment.
primary purpose: Treatment
masking: Single (Participant)
masking description: Participants will not know if they receive juice with complex-bound vitamin D3 or not.
measure: Cmax of vitamin D3
time frame: 10 hours
description: Maximum observed concentration of vitamin D3
measure: AUC of vitamin D3
time frame: 12 hours
description: Area under the curve for time-concentration relationships during the absorption phase
measure: Concentration of vitamin D metabolites
time frame: 24 hours
description: Plasma levels of vitamin D2+D3, 25OHD, 1,25(OH)2D, 24,25(OH)2D and VDBP
measure: Concentration of PTH
time frame: 24 hours
description: Changes in plasma PTH in response to treatment
measure: Plasma concentration of ion-calcium
time frame: 24 hours
description: Changes in plasma ionized calcium in response to treatment
measure: Urine concentration of calcium
time frame: 24 hours
description: Changes in urine calcium in response to treatment
measure: Urine concentration of creatinine
time frame: 24 hours
description: Changes in urine creatinine in response to treatment
measure: Urine concentration of phosphate
time frame: 24 hours
description: Changes in urine phosphate in response to treatment
measure: Urine concentration of magnesium
time frame: 24 hours
description: Changes in urine magnesium in response to treatment
measure: Urine concentration of sodium
time frame: 24 hours
description: Changes in urine sodium in response to treatment
measure: Urine concentration of potassium
time frame: 24 hours
description: Changes in urine potassium in response to treatment
measure: Urine osmolality
time frame: 24 hours
description: Changes in urine osmolality in response to treatment
measure: Systolic and diastolic blood pressure
time frame: 4 hours
description: Office blood pressure of the upper right arm
measure: Pulse wave velocity
time frame: 4 hours
description: Assessed by tonometry using SphygmoCor system
measure: Arterial stiffness
time frame: 4 hours
description: Assessed by tonometry using SphygmoCor system system (Xcel; AtCor Medical, Sydney, NSW, Australia)
measure: Body composition
time frame: Week 4
description: Assessed by DXA
measure: Areal BMD
time frame: Week 4
description: BMD at the lumbar spine, femoral neck and distal forearm assessed by DXA
measure: Bone geometry
time frame: Week 4
description: Assessed by HRpQCT of distal tibia and distal radius
measure: Volumetric BMD
time frame: Week 4
description: Assessed by HRpQCT of distal tibia and distal radius
measure: Estimated bone strength
time frame: Week 4
description: Assessed by HRpQCT of distal tibia and distal radius
measure: Plasma concentrations of bone turnover markers
time frame: Week 4
description: Plasma levels of bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide (P1NP), C-terminal telopeptide (CTX), sclerostin and fibroblast growth factor 23 (FGF-23)
measure: Exome sequencing
time frame: 24 hours
description: Genetic variants of importance to vitamin D metabolism
measure: Plasma concentrations of total cholesterol, triglycerides, LDL- and HDL-cholesterol
time frame: 24 hours
description: Cholesterol status
measure: Plasma concentrations of metabolites
time frame: 24 hours
description: Metabolomics analyses: Blood samples for nuclear magnetic resonance and liquid chromatography mass spectrometry analyses
measure: General health
time frame: Week 1
description: Questionnaire
measure: Dietary habits
time frame: Week 1
description: Questionnaire
measure: Sun exposure
time frame: Week 1
description: Questionnaire
arm group label: Whey protein complex-bound D3 + juice
arm group type: Experimental
description: 200 microgram vitamin D3 in a whey protein-complex added to 500 mL of juice.
arm group label: D3 + juice
arm group type: Active Comparator
description: 200 microgram vitamin D3 added to 500 mL of juice.
arm group label: D3 + milk
arm group type: Active Comparator
description: 200 microgram vitamin D3 added to 500 mL of skimmed-milk.
arm group label: D3 droplets
arm group type: Active Comparator
description: 200 microgram vitamin D3 as droplets + 500 mL of water.
arm group label: No vitamin D
arm group type: Placebo Comparator
description: 500 mL of Water.
intervention type: Dietary Supplement
intervention name: Vitamin D3
description: Single dose vitamin D3
arm group label: D3 + juice
arm group label: D3 + milk
arm group label: D3 droplets
arm group label: Whey protein complex-bound D3 + juice
intervention type: Combination Product
intervention name: Whey protein-complex
description: Whey protein complex-bound vitamin D3
arm group label: Whey protein complex-bound D3 + juice
intervention type: Other
intervention name: Water
description: 500 mL water
arm group label: D3 droplets
arm group label: No vitamin D
intervention type: Other
intervention name: Milk
description: 500 mL milk
arm group label: D3 + milk
intervention type: Other
intervention name: Juice
description: 500 mL juice
arm group label: D3 + juice
arm group label: Whey protein complex-bound D3 + juice
criteria: 
gender: Female
minimum age: 60 Years
maximum age: 80 Years
healthy volunteers: No
last name: Lars Rejnmark
role: Principal Investigator
affiliation: Dept. of Endocrinology and Internal Medince, The Osteoporosis Clinic
facility: 
country: Denmark
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responsible party type: Sponsor
mesh term: Vitamin D Deficiency
mesh term: Vitamin D
mesh term: Cholecalciferol