A New Paradigm for Vitamin D Sufficiency

The specific aims of this study are as follows:

1. To establish that free 25(OH)D and VMR are similar in black and white populations.

2. To characterize the relationships between free 25(OH)D and VMR and two measures of bone
health (PTH and BMD) in black and white women.

3. To evaluate whether the relationship of free 25(OH)D (and in parallel analyses, VMR) and
bone health are stronger than those based on total 25(OH)D.

4. To evaluate whether free 25(OH)D and VMR respond to vitamin D intake (dose-response) in
a similar manner to total 25(OH)D.

The study population is postmenopausal Caucasian women age 60 and older. This six month study
includes four visits. These results will be compared to those from a study in AA women which
the investigators are also completing.

There are two study groups. One group will receive vitamin D supplementation, the other a
placebo. Subjects will be asked to refrain from taking outside Vitamin D supplements for the
duration of the study. If the subject is eligible based on the results from the first two
visits, the subject will be randomized into one of these two groups. Randomized subjects will
be taking the vitamin D or placebo for a period of 6 months and will have one visit at the 3
month mark and a final visit at the 6 month mark.

At the 3-month visit, the following procedures will be conducted: obtain interim medical and
travel history, vital signs, weight, and height measured by the Harpenden Stadiometer, record
adverse events and concomitant medications, Fasting blood collection: total 25(OH)D (by
Diasorin), PTH, serum calcium and creatinine, Fasting urine collection for calcium and
creatinine, and questionnaires: calcium food frequency questionnaire, quality of life
questionnaire, falls and flu questionnaires. Subjects will be instructed on how to collect a
24-hour urine sample (for final visit) and collection container will be dispensed. Unused
study supplements will be collected and counted, and study supplements will be dispensed
based on serum 25(OH)D level algorithm.

At the 6-month visit, in addition to what is completed at the 3-month visit, the following
procedures will also be conducted:24-hour urine calcium, sodium, oxalate and creatinine;
mini-mental health examination; physical performance examination (SPPB); and a physical
activity questionnaire. Unused study supplements will be collected and counted. No further
supplementation will be provided.

Inclusion Criteria:

1. Ambulatory women older than 60 years of age. Women who are ambulatory with an
assistive device such as cane or walker may be included. LMP must be > 5 years ago.

2. Self declared as white.

3. 20 nmol/L < Serum 25(OH)D level < 65 nmol/L.

4. Willingness to take study drug and participate for 6 months in the trial.

5. Willingness to refrain from the use of self-administered Vitamin D and Calcium
supplements during the trial.

Exclusion Criteria:

1. Serum 25(OH)D levels ≤ 20 nmol/L or ≥ 65 nmol/L.

2. BMD total hip below -2.5 standard deviation (using NHANES III adult young white men
and women as the point of reference) or history of osteoporotic fracture.

3. Moderate to severe fracture in one or more vertebrae by Instant Vertebral Assessment
on DXA.

4. Treatment with HRT, SERMs, calcitonin, PTH, strontium ranelate, androgens,
bisphosphonates, Denosumab or anabolic steroids during 6 months prior to entry.

5. Use of systemic corticosteroids (oral or IV) within the last year at an average dose
of greater than 5 mg per day of oral prednisone or equivalent for a period of three
months or more prior to screening.

6. Mini-Mental State Exam score below 21

7. Hypercalcemia (serum calcium > 10.6 mg/dl) or history of primary hyperparathyroidism.

8. History of hypercalciuria, kidney stones, or 24hr urine calcium >261 mg/day on
screening.

9. History of chronic liver disease, chronic renal insufficiency (GFR<30), Parkinson's,
metabolic bone disease (Hyperparathyroidism, Hypoparathyroidism, Paget's disease,
Fibrous osteodystrophy, Rickets, Osteomalacia, Osteosclerosis), hematologic tumors,
rheumatologic disease requiring steroids, conditions that influence vitamin D
absorption like celiac disease and irritable bowel disease, malabsorption or new
diagnosis or active treatment of cancer 12 months prior to inclusion.

10. Use of medications that influence bone metabolism (e.g. anticonvulsants).

11. Significant deviation from normal in either: history, physical examination or
laboratory tests as evaluated by the Principle Investigator. Participants with a
history of uncontrolled hypertension, uncontrolled diabetes, hypercalciuria,
nephrolithiasis and active sarcoidosis or tuberculosis will also be excluded.

12. Participation in another investigational trial 30 days prior to screening.

13. Spinal disease that affects interpretation of bone densitometry like scoliosis with a
Cobb angle greater than 15o, history of surgery at lumbosacral spine.

14. Bilateral hip replacement.

15. Currently smoking more than 10 cigarettes daily.

16. Currently consuming more than 2 units of alcohol daily. (One unit is equivalent to a
standard glass of beer (285ml), a single measure of spirits (30ml), a medium-sized
glass of wine (120ml), or 1 measure of an aperitif (60ml)

17. Unable to perform DXA due to excessive body girth/width. Body width on DXA > 25 cm.

18. Patients who are deemed unsafe to perform muscular function testing as evaluated by
the investigator.

19. Class III obesity.