Supplemental Calcium in Overweight People

An estimated 97 million people in the United States are overweight or obese, and therefore
have an increased risk for a number of other obesity-related co-morbid conditions (such as
hypertension, dyslipidemia, and Type 2 Diabetes) as well as for all-cause mortality. The
total cost attributable to obesity amounted to $99.2 billion in the US in 1995 and this
figure, like the prevalence of increased body mass, is rising at an alarming rate. At the
same time calcium intake in the US adult population is far below the RDA (recommended daily
allowance) and much below the daily optimal calcium intake recommended by the 1994 NIH
consensus conference. An analysis of the NHANES III database suggests a strong inverse
association between relative risk of obesity and calcium intake. Further, both prospective
studies in animal models, and retrospective analyses of human studies suggest calcium
supplementation may play a role in minimizing yearly weight gain, and may possibly induce
small weight losses.

In order to test the relationship between calcium intake and body weight, we propose to
conduct a 2-year, randomized, double-blind, placebo-controlled trial of calcium
supplementation (1500 mg/day of supplementary calcium vs. placebo) in adults with a BMI
greater than or equal to 25 kg/m(2). We will study the effects of supplemental calcium on
body weight, body composition, and obesity-related comorbid conditions, such as insulin
sensitivity and lipids. The effects of such supplementation on blood pressure will also be
systematically evaluated. A control group of untreated, healthy, adults will also be enrolled
for comparisons to study subjects.

- INCLUSION CRITERIA: (Overweight Subjects)

Volunteers will qualify if they meet the following criteria:

1. Good general health. Individuals taking medication for obesity-related co-morbid
conditions will not be excluded.

2. Age greater than or equal to 18 years.

3. Body Mass Index greater than or equal to 25 kg/m(2).

4. For women with childbearing potential, a negative pregnancy test at the initial
evaluation.

5. Normal fasting serum Ca (2.05-2.55 mmol/L) and serum phosphorous levels (2.3 - 4.3
mg/dl).

INCLUSION CRITERIA: (Normal Weight Subjects)

Volunteers will qualify if the meet the following criteria

1. Good general health.

2. Age greater than or equal to 18 years.

3. Body Mass Index 1-24.99 kg/m(2)

4. For women with childbearing potential, a negative pregnancy test at the initial
evaluation. Since these subjects have to undergo DXA (dual Energy X-ray
Absorptiometry) scan screening in their second visit, for safety purposes, pregnant
women will be excluded from participation in the study.

5. Normal fasting serum Ca (2.05-2.55 mmol/L) and serum phosphorus levels (2.3-4.3
mg/dl).

EXCLUSION CRITERIA: (overweight subjects)

Volunteers will be excluded (and referred to non-experimental treatment programs as
needed) for the following reasons:

1. A presence of major illnesses: renal, hepatic (other than obesity-related
steatosis), gastrointestinal, most endocrinologic (e.g., Cushing syndrome, hyper-
or hypothyroidism), hematological problems or pulmonary disorders (other than
asthma not requiring continuous medication or sleep-apnea related disorders);

2. Women who are pregnant, or who are currently nursing an infant; or who are having
unprotected intercourse;

3. Individuals who have a current substance abuse or a psychiatric disorder or other
condition that in the opinion of the investigators would impede competence or
compliance or possibly hinder completion of the study;

4. Subjects who regularly use prescription medications unrelated to the
complications of obesity {e.g., calcium channel blockers, diuretics (including
thiazide diuretics), beta-blockers etc}. Oral contraceptive use will be
permitted, provided the contraceptive has been used for at least two months
before starting study medication. The use of over-the-counter medications will be
reviewed on a case-by -case basis;

5. Subjects who have a total calcium intake of more than 3.5 g/day on the screening
calcium intake questionnaire (SCQ) or more than 3 g/day of total calcium intake
on review of their 7-day food diaries;

6. Subjects who take supplement calcium in excess of 300 mg/day or vitamin D
supplements in excess of 400 IU/day;

7. Recent (3 months) use of anorexiant medications;

8. History of renal stones;

9. Intentional weight change of more than 3% of body weight in the past two months.

10. Post-menopausal women who are medically advised to take calcium supplementation.

11. Subjects with iPTH greater than 75 pg/ml (Normal range: 10-75 pg/ml) when
associated with a serum calcium level greater than 2.5 mmol/L. (normal range 2.05
to 2.55 mmol/L)

12. Subjects with a serum 25-(OH)-D level less than 10 ng/ml (Normal range: 10-68
ng/ml) when associated with a serum 1-225-(OH)(2)-D level of less than 22 pg/ml
(Normal Range: 22-67 pg/ml.

13. Subjects with a consistently (2 weeks apart) elevated systolic blood pressure of
greater than 160 mm Hg and/or a diastolic blood pressure greater than 95 mm Hg.

EXCLUSION CRITERIA: (Normal Weight Subjects)

Volunteers will be excluded (and referred to non-experimental treatment programs as
needed) for the following reasons:

1. Presence of major illnesses: renal (serum creatinine greater than 1.6), hepatic
(AST/ALT greater than 3 times upper limit of normal range used in Clinical Center
assays), gastrointestinal, most endocrinologic (e.g. Cushing syndrome, hyper- or
hyothyroidism), hematological problems or pulmonary disorders (other than asthma
not requiring continuous medication or sleep-apnea related disorders);

2. Women who are pregnant, or who are currently nursing an infant;

3. Individuals who have current substance abuse of a psychiatric disorder or other
condition that in the opinion of the investigators would impede competence or
compliance or possibly hinder completion of the study;

4. Subjects who regularly use prescription medications. Oral contraceptive use will
be permitted, provided the contraceptive has been used for at least two months
before starting study medication. Individuals taking medications for most
conditions will be excluded, but medication use will be considered on a
case-by-case basis.

5. Subjects who take supplemental calcium in excess of 300 mg/day or vitamin D
supplements in excess of 400 IU/day.

6. Recent (3 months) use of anorexiant medications;

7. Intentional weight change of more than 3% of body weight