1. { Dose Response to Vitamin D Supplementation in Postmenopausal Women Annals of Internal Med. 2012; 156:425-437 Jayme Bristow

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

4. The Institute of Medicine (IOM) developed a system known as Dietary Reference Intakes The Institute of Medicine (IOM) developed a system known as Dietary Reference Intakes The IOM attempted to determine the RDA for vitamin D The IOM attempted to determine the RDA for vitamin D They found no comprehensive studies on: They found no comprehensive studies on: the relationship between doses of Vitamin D on serum 25-[OH]D the relationship between doses of Vitamin D on serum 25-[OH]D An RDA for 25-[OH]D linked to clinical outcomes An RDA for 25-[OH]D linked to clinical outcomes They also found that most studies combined the evaluation of Ca and Vitamin D They also found that most studies combined the evaluation of Ca and Vitamin D Background

5. RDA for Vitamin D is also hard to determine because its supply depends on many factors such as sun exposure, BMI, and skin color RDA for Vitamin D is also hard to determine because its supply depends on many factors such as sun exposure, BMI, and skin color Vitamin D insufficiency is defined as a 25- [OH]D level 50 nmol/L Vitamin D insufficiency is defined as a 25- [OH]D level 50 nmol/L Vitamin D is known to act on bone metabolishm and calcium hemostasis Vitamin D is known to act on bone metabolishm and calcium hemostasis Also theorized that it plays an important role in cellular proliferation and differentiation and survival of cells in disorders of immunity and cancer Also theorized that it plays an important role in cellular proliferation and differentiation and survival of cells in disorders of immunity and cancer Background

6. 1 year, randomized, prospective, placebo- controlled trial 1 year, randomized, prospective, placebo- controlled trial Study was conducted at Creighton University Medical Center (Omaha, Nebraska) Study was conducted at Creighton University Medical Center (Omaha, Nebraska) Study Design

7. {{ Inclusion Criteria Women 7 years post- menopausal White Age 57-90 Vitamin D insufficiency Exclusion Criteria Comorbid conditions Hx of cancer w/in 10 years Terminal illness Hip fracture BMI < 45 kg/m2 High Ca Low bone density Current use of bisphosphonates Study Design

8. Patients were randomly assigned to 1 of 7 Vitamin D3 doses or placebo for 1 year Patients were randomly assigned to 1 of 7 Vitamin D3 doses or placebo for 1 year 400 IU/d 400 IU/d 800 IU/d 800 IU/d 1600 IU/d 1600 IU/d 2400 IU/d 2400 IU/d 3200 IU/d 3200 IU/d 4000 IU/d 4000 IU/d 4800 IU/d 4800 IU/d Study Design

10. Primary: Primary: 25-[OH]D and PTH levels after 6 months and 1 year 25-[OH]D and PTH levels after 6 months and 1 year Secondary: Secondary: Levels of serum 1,25-dihydroxyvitamin D3 Levels of serum 1,25-dihydroxyvitamin D3 Serum Ca and creatinine Serum Ca and creatinine Urine bone markers Urine bone markers Bone mineral density Bone mineral density Calcium absorption Calcium absorption Incidence of falls Incidence of falls FEV1 FEV1 Physical performance tests Physical performance tests Blood pressure Blood pressure Cellular studies Cellular studies Outcomes

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

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

13. Interactions between dose and time were also explored Interactions between dose and time were also explored Covariance structures were compared by using the Akaike information criterion Covariance structures were compared by using the Akaike information criterion The compound symmetry structure had similar Akaike information criterion values, so it was chosen The compound symmetry structure had similar Akaike information criterion values, so it was chosen Statistics

14. 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

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

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

17. Safety and ADRs

18. The increased levels of 25-[OH]D were not linear but followed a quadratic curve suggestive of a rate-limiting mechanism The increased levels of 25-[OH]D were not linear but followed a quadratic curve suggestive of a rate-limiting mechanism BMI has a significant effect on serum 25-[OH]D levels as well as on the dose of Vitamin D3 BMI has a significant effect on serum 25-[OH]D levels as well as on the dose of Vitamin D3 At 12 months there was a significant decrease in serum PTH levels associated with increasing Vitamin D3 doses At 12 months there was a significant decrease in serum PTH levels associated with increasing Vitamin D3 doses The effects of Vitamin D in other diseases have not been established The effects of Vitamin D in other diseases have not been established Discussion

19. {{ Strengths Double-blind, placebo control Adequate power Multiple doses were studied Length of study Limitations Sample size was small Healthy, postmenopausal white women only Discussion

21. 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. Wikipedia. Accessed 20 March 2012. http://en.wikipedia.org/wiki/Analysis_of_variance Analysis of Variance. Wikipedia. Accessed 20 March 2012. http://en.wikipedia.org/wiki/Analysis_of_variance http://en.wikipedia.org/wiki/Analysis_of_variance Mixed Model. Wikipedia. Accessed 20 March 2012. http://en.wikipedia.org/wiki/Mixed_model Mixed Model. Wikipedia. Accessed 20 March 2012. http://en.wikipedia.org/wiki/Mixed_model http://en.wikipedia.org/wiki/Mixed_model Akaike Information Criterion. Wikipedia. Accessed 20 March 2012. http://en.wikipedia.org/wiki/Akaike_information_criter ion Akaike Information Criterion. Wikipedia. Accessed 20 March 2012. http://en.wikipedia.org/wiki/Akaike_information_criter ion http://en.wikipedia.org/wiki/Akaike_information_criter ion http://en.wikipedia.org/wiki/Akaike_information_criter ionReferences

22. Serum PTH levels, according to vitamin D dosage at 12 months.PTH = parathyroid hormone. Gallagher J C et al. Ann Intern Med 2012;156:425-437