Clinical trial NCT01315366: Hypovitaminosis D : A Link Between Bone/Mineral and Fat/Fuel Metabolism
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypovitaminosis D
Insulin Resistance
Obesity
Osteoporosis
Keywords: Vitamin D
Elderly
Cardiovascular profile
Insulin resistance
Gene polymorphisms
Lead sponsor: American University of Beirut Medical Center
Sponsor class: OTHER
Collaborators: name: Hotel Dieu de France Hospital
name: Rafic Hariri University Hospital
First posted: 2011-03-15
Enrollment: 257
Sex: ALL
Minimum age (years): 65
Maximum age (years): 95
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The HOMA index of insulin resistance
timeFrame: 1 year
measure: Bone mineral density (BMD) at the spine,hip and total body measured by DXA and bone turnover markers (Osteocalcin and cross laps).
timeFrame: 1 year
Secondary outcomes:
measure: 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.
timeFrame: 1 year
measure: Body fat mass and body lean mass measured by DXA
timeFrame: 1 year
measure: Serum DLk1 levels
timeFrame: 1 year
measure: Adiponectin Receptor expression and Leptin from subcutaneous fat and muscle biopsies at baseline and follow-up.
timeFrame: 1 year
measure: 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)
timeFrame: 1 year
measure: 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).
timeFrame: 1 year
measure: 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).
timeFrame: 1 year
measure: Bone turnover markers by subgroups of patients divided by polymorphisms of genes affecting mineral metabolism (VDR, ER, CaSR, and CYP2R1 gene polymorphisms).
timeFrame: 1 year
measure: Bone mineral density (BMD) at the spine measured by DXA
timeFrame: 1 year
measure: Adiponectin Receptor expression from subcutaneous fat and muscle biopsies
timeFrame: 1 year
measure: 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
timeFrame: 1 year
Other outcomes:
Locations:
city: Beirut
country: Lebanon
facility: American University of Beirut
Study officials:
affiliation: American University of Beirut Medical Center
name: Ghada El Hajj Fuleihan, MD, MPH
role: PRINCIPAL_INVESTIGATOR
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