Hypovitaminosis D : A Link Between Bone/Mineral and Fat/Fuel Metabolism
NCT ID: NCT01315366
Last Updated: 2015-11-20
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE3
Total Enrollment
257 participants
Study Classification
INTERVENTIONAL
Study Start Date
2011-01-31
Study Completion Date
2015-07-31
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:
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
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
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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.
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.
Conditions
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Hypovitaminosis D
Insulin Resistance
Obesity
Osteoporosis
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
PREVENTION
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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High dose vitamin D
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.
Group Type
ACTIVE_COMPARATOR
Euro D and Ci-CalD
Intervention Type
DIETARY_SUPPLEMENT
Ci-Cal D (1000mg/day) and vitamin D (500IU/day) daily, plus a supplement of vitamin D3 (20,000 IU/wk) for one year.
Low dose Vitamin D
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.
Group Type
PLACEBO_COMPARATOR
Euro D, Ci-CalD
Intervention Type
DIETARY_SUPPLEMENT
Ci-Cal D(1000mg/day) and vitamin D (500IU/day) Ci-CalD daily, plus a weekly placebo Euro D supplement for one year.
Interventions
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Euro D and Ci-CalD
Ci-Cal D (1000mg/day) and vitamin D (500IU/day) daily, plus a supplement of vitamin D3 (20,000 IU/wk) for one year.
Intervention Type
DIETARY_SUPPLEMENT
Euro D, Ci-CalD
Ci-Cal D(1000mg/day) and vitamin D (500IU/day) Ci-CalD daily, plus a weekly placebo Euro D supplement for one year.
Intervention Type
DIETARY_SUPPLEMENT
Other Intervention Names
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Europharm
EuroPharm
Eligibility Criteria
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Exclusion Criteria
* BMI ≥ 25Kg/meters squared
* 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.
* 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.
Minimum Eligible Age
65 Years
Maximum Eligible Age
95 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
Yes
Sponsors
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Hotel Dieu de France Hospital
OTHER
Sponsor Role
collaborator
Rafic Hariri University Hospital
OTHER
Sponsor Role
collaborator
American University of Beirut Medical Center
OTHER
Sponsor Role
lead
Responsible Party
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Dr. Ghada El-Hajj Fuleihan
Professor
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Ghada El Hajj Fuleihan, MD, MPH
Role: PRINCIPAL_INVESTIGATOR
American University of Beirut Medical Center
Locations
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American University of Beirut
Beirut, , Lebanon
Site Status
Countries
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Lebanon
References
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Fuleihan GE, Deeb M. Hypovitaminosis D in a sunny country. N Engl J Med. 1999 Jun 10;340(23):1840-1. doi: 10.1056/NEJM199906103402316. No abstract available.
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El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife H, Choucair M, Arabi A, Vieth R. Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab. 2006 Feb;91(2):405-12. doi: 10.1210/jc.2005-1436. Epub 2005 Nov 8.
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Arabi A, Zahed L, Mahfoud Z, El-Onsi L, Nabulsi M, Maalouf J, Fuleihan Gel-H. Vitamin D receptor gene polymorphisms modulate the skeletal response to vitamin D supplementation in healthy girls. Bone. 2009 Dec;45(6):1091-7. doi: 10.1016/j.bone.2009.07.074. Epub 2009 Jul 30.
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Arabi A, Baddoura R, Awada H, Salamoun M, Ayoub G, El-Hajj Fuleihan G. Hypovitaminosis D osteopathy: is it mediated through PTH, lean mass, or is it a direct effect? Bone. 2006 Aug;39(2):268-75. doi: 10.1016/j.bone.2006.01.140. Epub 2006 Feb 21.
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Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008 Jun 23;168(12):1340-9. doi: 10.1001/archinte.168.12.1340.
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Maalouf J, Nabulsi M, Vieth R, Kimball S, El-Rassi R, Mahfoud Z, El-Hajj Fuleihan G. Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children. J Clin Endocrinol Metab. 2008 Jul;93(7):2693-701. doi: 10.1210/jc.2007-2530. Epub 2008 Apr 29.
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BACKGROUND
Bacha DS, Rahme M, Al-Shaar L, Baddoura R, Halaby G, Singh RJ, Mahfoud ZR, Habib R, Arabi A, El-Hajj Fuleihan G. Vitamin D3 Dose Requirement That Raises 25-Hydroxyvitamin D to Desirable Level in Overweight and Obese Elderly. J Clin Endocrinol Metab. 2021 Aug 18;106(9):e3644-e3654. doi: 10.1210/clinem/dgab296.
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El Sabeh M, Ghanem P, Al-Shaar L, Rahme M, Baddoura R, Halaby G, Singh RJ, Vanderschueren D, Bouillon R, El-Hajj Fuleihan G. Total, Bioavailable, and Free 25(OH)D Relationship with Indices of Bone Health in Elderly: A Randomized Controlled Trial. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e990-e1001. doi: 10.1210/clinem/dgaa780.
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Bassatne A, Jafari A, Kassem M, Mantzoros C, Rahme M, El-Hajj Fuleihan G. Delta-like 1 (DLK1) is a possible mediator of vitamin D effects on bone and energy metabolism. Bone. 2020 Sep;138:115510. doi: 10.1016/j.bone.2020.115510. Epub 2020 Jul 1.
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DERIVED
Rahme M, Al-Shaar L, Singh R, Baddoura R, Halaby G, Arabi A, Habib RH, Daher R, Bassil D, El-Ferkh K, Hoteit M, El-Hajj Fuleihan G. Limitations of platform assays to measure serum 25OHD level impact on guidelines and practice decision making. Metabolism. 2018 Dec;89:1-7. doi: 10.1016/j.metabol.2018.09.003. Epub 2018 Sep 15.
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Arabi A, Khoueiry-Zgheib N, Awada Z, Mahfouz R, Al-Shaar L, Hoteit M, Rahme M, Baddoura R, Halabi G, Singh R, El Hajj Fuleihan G. CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation. Osteoporos Int. 2017 Jan;28(1):279-290. doi: 10.1007/s00198-016-3713-5. Epub 2016 Jul 30.
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DERIVED
El-Hajj Fuleihan G, Baddoura R, Habib RH, Halaby G, Arabi A, Rahme M, Singh RJ, Kassem M, Mahfoud Z, Hoteit M, Daher RT, Kassir MF. Effect of vitamin D replacement on indexes of insulin resistance in overweight elderly individuals: a randomized controlled trial. Am J Clin Nutr. 2016 Aug;104(2):315-23. doi: 10.3945/ajcn.116.132589. Epub 2016 Jul 13.
Reference Type
DERIVED
Other Identifiers
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AUBMC-IM-GE-HF-20
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
AUBMC-GE-HF-1
Identifier Type: -
Identifier Source: org_study_id