Hypovitaminosis D : A Link Between Bone/Mineral and Fat/Fuel Metabolism

Study Overview
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Brief Summary
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The optimal dose of vitamin D needed to optimize beneficial effects on musculoskeletal outcomes remains to be defined. Equally unclear is the impact of vitamin D on fuel metabolism and insulin sensitivity in human subjects. Thus, the overall objective of this proposal is to test the hypothesis that in ambulatory overweight elderly individuals, vitamin D administration at doses higher than currently recommended will: Have a salutary effect on parameters of glucose and fuel metabolism. It will thus decrease indices of insulin resistance, improve lipid profile, and decrease markers of cardiovascular disease including adipokines, inflammatory cytokines, and markers of cell adhesion. Have a superior effect on indices of mineral and musculoskeletal metabolism, including bone remodeling markers, lean mass, and bone mineral density. We will investigate whether this effect is modulated by entry status of vitaminD and PTH as detailed below

Detailed Description
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It has become increasingly recognized that low vitamin D levels are prevalent worldwide and to a more severe degree in the Middle East. Low vitamin D levels are associated with an increased risk of osteoporotic fractures, and of chronic conditions such as autoimmune disorders, diabetes, cancer, and the metabolic syndrome. Obese individuals are more likely to have low vitamin D levels, and in some studies obesity was a risk factor for fractures in both the young and elderly. Our group has investigated the impact of vitamin D therapy in the young, and preliminary data suggest that doses exceeding the currently updated recommended estimated average requirement (EAR) of 400IU for that age group may be more beneficial for bone health. The updated EAR recommendations by the IOM for any age group, although believed to cover the needs of all individuals in each age group, are limited by the lack of good evidence supporting such recommendations. Therefore, to-date, the optimal dose of vitamin D for both the young and elderly is unknown. Two hundred and fifty elderly (age≥65 years), overweight (BMI ≥25kg/m2) non-diabetic individuals, will be recruited through outpatient clinics that investigators may have access to at American University of Beirut-Medical Center (AUB-MC), Hotel Dieu de France (HDF) and Rafic Hariri University Hospital (RHUH), and will be randomized after a pre-screen, in a double-blinded fashion, to receive 500 IU or the equivalent of 3357 IU of vitamin D3 daily for one year. Clinical information, exercise questionnaires will be obtained at 0 and 12 months.In addition, subjects partaking in the original study will be offered the option to participate in the validity and reliability study of a food frequency questionnaire to assess dietary intakes of Ca, vitamins D and K, and to participate in the vascular study evaluating the relation of the above nutrients with vascular parameters. Information on educational level, insurance status, dietary, sunscreen use, sun exposure and skin pigmentation will be obtained at baseline. Information on falls, trauma, history of fractures and medications will be obtained at each visit (0, 3, 6 and 12 months). The measurement of height, weight, BMI, waist, hip, waist/hip ratio, mid arm circumference, mid-calf circumference and muscle strength of the subject, enrolled in the study, will be triplicated on each visit at 0,3,6 and 12 months. Blood pressure and heart rate will be measured at screening, baseline, 3 months, 6 months and 12 months. Blood will be drawn at baseline, 3, 6 and 12 months for measurement of serum creatinine, calcium, phosphorous, alkaline phosphatase, 25-OHD, 1,25(OH)2D, PTH, indices of bone remodeling (osteocalcin and crosslaps), and a second morning void urine specimen will be collected for Ca/Cr. Insulin resistance will be measured using the McAuley as well as HOMA and QUCKI indices. We will also measure serum levels of adipokines (adiponectin, leptin), DLK1-Pref1, inflammatory markers (CRP, IL-6) and adhesion molecules (sICAM, sVCAM). We will characterize polymorphisms of genes affecting mineral metabolism such as VDR, CaSR,ER and CYP2R1, and will measure adiponectin R expression from subcutaneous fat and muscle biopsies that will be obtained at 0 and 12 months.Bone density scans of Lumbar Spine, Femoral Neck, Total Hip, Total Body, Sub Total Body, body composition and hip structural analyses parameters as well as TBS variables for the spine will be obtained at the baseline and at 12 months of the study. A visit at 9 months will be scheduled to supply subjects with Ci-cal D and Euro D, and to ensure compliance. IRB approval and consent forms will be obtained. An independent Data and Safety Monitoring Board will be asked to review serious adverse events and if needed may be asked to review unblinded data at recruitment of 30%, 60% and 100% of study subjects and of serious adverse events forms throughout the study duration.Repeated measures analyses will be used to evaluate differences in outcomes of interest between the two treatment groups and time effect within each treatment arm.

Official Title
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Phase III Study on the Effect of Vitamin D Supplementation on Indices of Mineral and Musculoskeletal Metabolism and on Parameters of Glucose and Fuel Metabolism in Elderly Subjects

Conditions
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Hypovitaminosis D, Insulin Resistance, Obesity, Osteoporosis

Intervention / Treatment
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* Dietary Supplement: Euro D and Ci-CalD
* Dietary Supplement: Euro D, Ci-CalD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Elderly subjects (> or equal to 65 years old)without any disease mentioned in the exclusion criteria. BMI ≥ 25Kg/meters squared Exclusion Criteria: Exclusion criteria include: diabetes, subjects with impaired glucose tolerance on medication, presence of a chronic disease or major organ failure such as severe heart failure, kidney or liver failure, conditions or intake of medications known to affect bone metabolism, rickets or osteomalacia, history of kidney stones, a baseline vitamin D level of less than 10 ng/ml and history of fragility fractures or an overall fracture risk based on FRAX of >10% . Subjects with impaired glucose tolerance on no medications will not be excluded. The classification of individuals as diabetics or having impaired glucose tolerance will be based on the American Diabetes Association criteria for diagnosis.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High dose vitamin D<br>Ci-Cal D (1000mg/day) and vitamin D (500IU/day) Ci-Cal D daily, plus a supplement of vitamin D3 EuroD (20,000 IU/wk) for one year. | Dietary Supplement: Euro D and Ci-CalD<br>* Ci-Cal D (1000mg/day) and vitamin D (500IU/day) daily, plus a supplement of vitamin D3 (20,000 IU/wk) for one year.<br>* Other names: Europharm;|
| Placebo Comparator: Low dose Vitamin D<br>Ci-Cal D (1000mg/day) and vitamin D (500IU/day) Ci-Cal D daily, plus a weekly placebo (EURO D Placebo) supplement for one year. | Dietary Supplement: Euro D, Ci-CalD<br>* Ci-Cal D(1000mg/day) and vitamin D (500IU/day) Ci-CalD daily, plus a weekly placebo Euro D supplement for one year.<br>* Other names: EuroPharm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The HOMA index of insulin resistance | A full assessment of insulin resistance will be performed,using the HOMA, McAuley and QUICKI indices. The impact of vitamin D on all outcomes of interest will be assessed by treatment arms and then in sub-group analyses: by baseline levels of vit D-PTH at study entry: Vitamin D< 20 ng/ml-PTH>76pg/ml; vitamin D<20ng/ml and PTH<76 pg/ml, vitamin D>20ng by gender | 1 year | 
| Bone mineral density (BMD) at the spine,hip and total body measured by DXA and bone turnover markers (Osteocalcin and cross laps). | We will measure the bone mineral density at the spine, hip and total body. We will also test the bone turnover markers as osteocalcin and cross laps. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin, C- peptide, Fasting glucose, Chemistries, Vitamin D metabolites, Vitamin D binding protein, Urinary Ca/Cr ratio ,serum lipids,inflammatory markers(IL-6, CRP),adhesion molecules (sVCAM), GLA-OC and GLU-OC. | Gamma-Carboxyglutamatic Osteocalcin (GLA-OC) and Undercarboxylated Osteocalcin (GLU-OC). | 1 year | 
| Body fat mass and body lean mass measured by DXA |  | 1 year | 
| Serum DLk1 levels | Serum DLK1 levels Preadipocyte factor 1 (Pref-1), also known as delta like protein (Dlk1), is a molecule that belongs to the Notch Delta family of signaling molecules, epidermal growth factor (EGF)-like super family, and possesses several isoforms, some circulating, also termed Fetal antigen 1 (FA1). | 1 year | 
| Adiponectin Receptor expression and Leptin from subcutaneous fat and muscle biopsies at baseline and follow-up. |  | 1 year | 
| Morphologic bone assessment gathered defined by techniques incorporated into BMD acquisition scan image: Hip structural analyses parameters (Cortical thickness, Cross-sectional moment of inertia, section modulus) and trabecular bone structure (TBS) |  | 1 year | 
| Mc Auley Index of insulin resistance by subgroups of patients divided by polymorphisms of genes affecting mineral metabolism (VDR, ER, CaSR, and CYP2R1 gene polymorphisms). |  | 1 year | 
| BMD at the hip and body composition by subgroups of patients divided by polymorphisms of genes affecting mineral metabolism (VDR, ER, CaSR, and CYP2R1 gene polymorphisms). |  | 1 year | 
| Bone turnover markers by subgroups of patients divided by polymorphisms of genes affecting mineral metabolism (VDR, ER, CaSR, and CYP2R1 gene polymorphisms). |  | 1 year | 
| Bone mineral density (BMD) at the spine measured by DXA |  | 1 year | 
| Adiponectin Receptor expression from subcutaneous fat and muscle biopsies |  | 1 year | 
| Morphologic bone assessment gathered defined by techniques incorporated into BMD acquisition image:Hip structural analyses parameters and trabecular bone structure by subgroups of subjects divided by polymorphisms of genes affecting mineral metabolism | Genes affecting mineral metabolism are VDR, ER, CaSR, and CYP2R1 gene polymorphisms | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, Elderly, Cardiovascular profile, Insulin resistance, Gene polymorphisms