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

Obesity Clinical Trial

— GEHF-VitD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01315366
• Other study ID #: AUBMC-GE-HF-1
• Secondary ID: AUBMC-IM-GE-HF-2
• Status: Completed
• Phase: Phase 3
• First received: February 2, 2011
• Last updated: November 19, 2015
• Start date: January 2011
• Est. completion date: July 2015

Study information

• Verified date: March 2015
• Source: American University of Beirut Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Lebanon: Institutional Review Board
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 257
• Est. completion date: July 2015
• Est. primary completion date: August 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 65 Years to 95 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Avitaminosis
• Hypovitaminosis D
• Insulin Resistance
• Obesity
• Osteoporosis
• Rickets
• Vitamin D Deficiency

Intervention

Dietary Supplement:
• 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.
• 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.

Locations

Country	Name	City	State
Lebanon	American University of Beirut	Beirut

Sponsors (3)

Lead Sponsor	Collaborator
American University of Beirut Medical Center	Hotel Dieu de France Hospital, Rafic Hariri University Hospital

Country where clinical trial is conducted

Lebanon, 

References & Publications (21)

Abdallah BM, Boissy P, Tan Q, Dahlgaard J, Traustadottir GA, Kupisiewicz K, Laborda J, Delaisse JM, Kassem M. dlk1/FA1 regulates the function of human bone marrow mesenchymal stem cells by modulating gene expression of pro-inflammatory cytokines and immune response-related factors. J Biol Chem. 2007 Mar 9;282(10):7339-51. Epub 2006 Dec 19. — View Citation

Abdallah BM, Jensen CH, Gutierrez G, Leslie RG, Jensen TG, Kassem M. Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1. J Bone Miner Res. 2004 May;19(5):841-52. Epub 2004 Jan 19. — View Citation

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. Epub 2006 Feb 21. — View Citation

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. — View Citation

Blüher M, Bullen JW Jr, Lee JH, Kralisch S, Fasshauer M, Klöting N, Niebauer J, Schön MR, Williams CJ, Mantzoros CS. Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: associations with metabolic parameters and insulin resistance and regulation by physical training. J Clin Endocrinol Metab. 2006 Jun;91(6):2310-6. Epub 2006 Mar 21. — View Citation

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. — View Citation

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. Epub 2005 Nov 8. — View Citation

Fay TN, Jacobs I, Teisner B, Poulsen O, Chapman MG, Stabile I, Bohn H, Westergaard JG, Grudzinskas JG. Two fetal antigens (FA-1 and FA-2) and endometrial proteins (PP12 and PP14) isolated from amniotic fluid; preliminary observations in fetal and maternal tissues. Eur J Obstet Gynecol Reprod Biol. 1988 Sep;29(1):73-85. — View Citation

Fliser D, Stefanski A, Franek E, Fode P, Gudarzi A, Ritz E. No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects. Eur J Clin Invest. 1997 Jul;27(7):629-33. — View Citation

Ford ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care. 2005 May;28(5):1228-30. — View Citation

Fuleihan GE, Deeb M. Hypovitaminosis D in a sunny country. N Engl J Med. 1999 Jun 10;340(23):1840-1. — View Citation

Gannagé-Yared MH, Azoury M, Mansour I, Baddoura R, Halaby G, Naaman R. Effects of a short-term calcium and vitamin D treatment on serum cytokines, bone markers, insulin and lipid concentrations in healthy post-menopausal women. J Endocrinol Invest. 2003 Aug;26(8):748-53. — View Citation

Lips P, Hosking D, Lippuner K, Norquist JM, Wehren L, Maalouf G, Ragi-Eis S, Chandler J. The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med. 2006 Sep;260(3):245-54. Erratum in: J Intern Med. 2007 Apr;261(4):408. — View Citation

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. — View Citation

Nagpal J, Pande JN, Bhartia A. A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men. Diabet Med. 2009 Jan;26(1):19-27. doi: 10.1111/j.1464-5491.2008.02636.x. — View Citation

Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ, Semega-Janneh M, Reynolds J, Yanovski JA. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 2004 Mar;89(3):1196-9. — View Citation

Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007 Apr;30(4):980-6. Epub 2007 Feb 2. — View Citation

Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007 Jun;92(6):2017-29. Epub 2007 Mar 27. Review. — View Citation

Richter V, Rassoul F, Purschwitz K, Hentschel B, Reuter W, Kuntze T. Circulating vascular cell adhesion molecules VCAM-1, ICAM-1, and E-selectin in dependence on aging. Gerontology. 2003 Sep-Oct;49(5):293-300. — View Citation

Snijder MB, van Dam RM, Visser M, Deeg DJ, Dekker JM, Bouter LM, Seidell JC, Lips P. Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab. 2005 Jul;90(7):4119-23. Epub 2005 Apr 26. — View Citation

Vieth R. Vitamin D toxicity, policy, and science. J Bone Miner Res. 2007 Dec;22 Suppl 2:V64-8. doi: 10.1359/jbmr.07s221. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	Body fat mass and body lean mass measured by DXA		1 year	No
Secondary	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	No
Secondary	Adiponectin Receptor expression and Leptin from subcutaneous fat and muscle biopsies at baseline and follow-up.		1 year	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Bone turnover markers by subgroups of patients divided by polymorphisms of genes affecting mineral metabolism (VDR, ER, CaSR, and CYP2R1 gene polymorphisms).		1 year	No
Secondary	Bone mineral density (BMD) at the spine measured by DXA		1 year	No
Secondary	Adiponectin Receptor expression from subcutaneous fat and muscle biopsies		1 year	No
Secondary	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	No

External Links

•   Calcium Metabolism and Osteoporosis Program, American University of Beirut