Dose Response to Vitamin D Supplementation in Postmenopausal Women

{{

Dose Response to Dose Response to Vitamin D Vitamin D Supplementation in Supplementation in Postmenopausal WomenPostmenopausal Women

Annals of Internal Med. 2012; 156:425-437Annals of Internal Med. 2012; 156:425-437

Jayme Bristow

To determine the effect of increasing To determine the effect of increasing oral doses of Vitamin D3 on serum 25-oral doses of Vitamin D3 on serum 25-[OH]D and serum parathryoid hormone [OH]D and serum parathryoid hormone (PTH) levels in postmenopausal white (PTH) levels in postmenopausal white women with Vitamin D sufficiency with women with Vitamin D sufficiency with sufficient calcium intakesufficient calcium intake

ObjectivesObjectives

The Institute of Medicine (IOM) developed The Institute of Medicine (IOM) developed a system known as Dietary Reference a system known as Dietary Reference IntakesIntakes

The IOM attempted to determine the RDA The IOM attempted to determine the RDA for vitamin D for vitamin D

They found no comprehensive studies on:They found no comprehensive studies on: the relationship between doses of Vitamin D the relationship between doses of Vitamin D

on serum 25-[OH]Don serum 25-[OH]D An RDA for 25-[OH]D linked to clinical An RDA for 25-[OH]D linked to clinical

outcomesoutcomes They also found that most studies combined They also found that most studies combined

the evaluation of Ca and Vitamin Dthe evaluation of Ca and Vitamin D

BackgroundBackground

RDA for Vitamin D is also hard to RDA for Vitamin D is also hard to determine because its supply depends on determine because its supply depends on many factors such as sun exposure, BMI, many factors such as sun exposure, BMI, and skin colorand skin color

Vitamin D insufficiency is defined as a Vitamin D insufficiency is defined as a 25-[OH]D level ≤ 50 nmol/L25-[OH]D level ≤ 50 nmol/L

Vitamin D is known to act on bone Vitamin D is known to act on bone metabolishm and calcium hemostasismetabolishm and calcium hemostasis

Also theorized that it plays an important Also theorized that it plays an important role in cellular proliferation and role in cellular proliferation and differentiation and survival of cells in differentiation and survival of cells in disorders of immunity and cancerdisorders of immunity and cancer

BackgroundBackground

1 year, randomized, prospective, 1 year, randomized, prospective, placebo-controlled trial placebo-controlled trial

Study was conducted at Creighton Study was conducted at Creighton University Medical Center (Omaha, University Medical Center (Omaha, Nebraska)Nebraska)

Study DesignStudy Design

{{ {{Inclusion CriteriaInclusion Criteria

WomenWomen 7 years post-7 years post-

menopausalmenopausal WhiteWhite Age 57-90Age 57-90 Vitamin D Vitamin D

insufficiencyinsufficiency

Exclusion CriteriaExclusion Criteria

Comorbid conditionsComorbid conditions Hx of cancer w/in 10 Hx of cancer w/in 10

yearsyears Terminal illnessTerminal illness Hip fractureHip fracture BMI < 45 kg/m2BMI < 45 kg/m2 High CaHigh Ca Low bone densityLow bone density Current use of Current use of

bisphosphonatesbisphosphonates


Patients were randomly assigned to 1 of Patients were randomly assigned to 1 of 7 Vitamin D3 doses or placebo for 1 year7 Vitamin D3 doses or placebo for 1 year 400 IU/d400 IU/d 800 IU/d800 IU/d 1600 IU/d1600 IU/d 2400 IU/d2400 IU/d 3200 IU/d3200 IU/d 4000 IU/d4000 IU/d 4800 IU/d4800 IU/d



Primary:Primary: 25-[OH]D and PTH levels after 6 months and 1 25-[OH]D and PTH levels after 6 months and 1

yearyear Secondary:Secondary:

Levels of serum 1,25-dihydroxyvitamin D3Levels of serum 1,25-dihydroxyvitamin D3 Serum Ca and creatinineSerum Ca and creatinine Urine bone markersUrine bone markers Bone mineral densityBone mineral density Calcium absorptionCalcium absorption Incidence of fallsIncidence of falls FEV1FEV1 Physical performance testsPhysical performance tests Blood pressureBlood pressure Cellular studiesCellular studies

OutcomesOutcomes

It was determined that every dosage It was determined that every dosage group needed 20 participants to achieve group needed 20 participants to achieve a 90% power to detect a difference a 90% power to detect a difference between dose groups in a 1 way analysis between dose groups in a 1 way analysis of variance modelof variance model

Provides a statistical test of whether or not the means of several groups are all equal, and therefore generalizes t-test to more than two groups

StatisticsStatistics

Mixed-effects models were used to Mixed-effects models were used to estimate dose-response curves for serum estimate dose-response curves for serum 25-[OH]D and PTH25-[OH]D and PTH

Mixed models are applied where multiple correlated measurements are made on each unit of interest or repeated measurements are made on the same statistical units, or where measurements are made on clusters of related statistical units.


Interactions between dose and time were Interactions between dose and time were also exploredalso explored

Covariance structures were compared by Covariance structures were compared by using the Akaike information criterionusing the Akaike information criterion

The compound symmetry structure had The compound symmetry structure had similar Akaike information criterion similar Akaike information criterion values, so it was chosenvalues, so it was chosen


Vitamin D dose–response curve.Baseline, 6-mo, and final serum 25-(OH)D levels are presented according to dosage of vitamin D or placebo.

Gallagher J C et al. Ann Intern Med 2012;156:425-437

Serum 25-(OH)D levels according to vitamin D dosage. Levels are shown with a fitted line by using the mixed-effects model, with 95% bootstrapped limits at 12 mo. 25-

(OH)D = 25-hydroxyvitamin D.


Effect of BMI and vitamin D dose on levels of serum 25-(OH)D at 12 months.BMI <25 kg/m2, n = 31; BMI 25.0–29.9 kg/m2, n = 56; and BMI ≥30.0 kg/m2, n = 76. 25-(OH)D = hydroxyvitamin

D; BMI = body mass index.


Safety and ADRsSafety and ADRs

The increased levels of 25-[OH]D were not The increased levels of 25-[OH]D were not linear but followed a quadratic curve linear but followed a quadratic curve suggestive of a rate-limiting mechanismsuggestive of a rate-limiting mechanism

BMI has a significant effect on serum 25-BMI has a significant effect on serum 25-[OH]D levels as well as on the dose of [OH]D levels as well as on the dose of Vitamin D3Vitamin D3

At 12 months there was a significant At 12 months there was a significant decrease in serum PTH levels associated decrease in serum PTH levels associated with increasing Vitamin D3 doseswith increasing Vitamin D3 doses

The effects of Vitamin D in other diseases The effects of Vitamin D in other diseases have not been establishedhave not been established

DiscussionDiscussion

{{ {{StrengthsStrengths

Double-blind, Double-blind, placebo controlplacebo control

Adequate powerAdequate power Multiple doses Multiple doses

were studiedwere studied Length of studyLength of study

LimitationsLimitations

Sample size was Sample size was smallsmall

Healthy, Healthy, postmenopausal postmenopausal white women onlywhite women only

DiscussionDiscussion

Gallagher J, Sai A, Templin T, Smith L. Dose response to vitamin d supplementation in postmenopausal women: a randomized trial.Annals Of Internal Medicine [serial online]. March 20, 2012;156(6):425-437. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed March 29, 2012.

Analysis of Variance. Analysis of Variance. Wikipedia. Wikipedia. Accessed 20 Accessed 20 March 2012. March 2012. http://en.wikipedia.org/wiki/Analysis_of_variance

Mixed Model. Mixed Model. Wikipedia. Wikipedia. Accessed 20 March Accessed 20 March 2012. 2012. http://en.wikipedia.org/wiki/Mixed_model

Akaike Information Criterion. Akaike Information Criterion. Wikipedia. Wikipedia. Accessed 20 March 2012. Accessed 20 March 2012. http://en.wikipedia.org/wiki/Akaike_informationhttp://en.wikipedia.org/wiki/Akaike_information_criterion_criterion

ReferencesReferences

Serum PTH levels, according to vitamin D dosage at 12 months.PTH = parathyroid hormone.


Documents

Dose Response to Vitamin D Supplementation in Postmenopausal Women