Hypovitaminosis D : A Link Between Bone/Mineral and Fat/Fuel Metabolism
Condition: Hypovitaminosis D; Insulin Resistance; Obesity; Osteoporosis
MeSH terms: Osteoporosis; Rickets; Insulin Resistance; Avitaminosis; Vitamin D Deficiency
Study type: Interventional
Phase: Phase 3

Summary: 
      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:

        1. 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.

        2. 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: 
      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.
    

Intervention name(s): Euro D and Ci-CalD; Euro D, Ci-CalD
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Ci-Cal D (1000mg/day) and vitamin D (500IU/day) daily, plus a supplement of vitamin D3 (20,000 IU/wk) for one year.; Ci-Cal D(1000mg/day) and vitamin D (500IU/day) Ci-CalD daily, plus a weekly placebo Euro D supplement for one year.
Other intervention name(s): Europharm; EuroPharm
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Vitamin D; Elderly; Cardiovascular profile; Insulin resistance; Gene polymorphisms