Effects of Calcium Supplementation on Body Weight and Adiposity in Overweight and Obese Adults

Context Some data suggest that body weight is inversely associated with calcium intake, increasing the possibility that supplemental calcium might facilitate weight loss or prevent weight gain. Contribution Researchers randomly assigned overweight and obese patients to supplemental calcium or placebo and found no between-group differences in measures of weight change. Caution Trial participants were almost all women. Implication Calcium supplementation is unlikely to prevent weight gain in persons who are overweight or obese. The Editors The high prevalence of overweight and obesity in the United States (1) has stimulated great interest in identifying approaches that may help to prevent weight gain or improve ability to lose weight. Increasing calcium intake is a potential means of weight management that has received much attention from both lay press (24) and the medical community (57). This interest has been stimulated by a series of cross-sectional studies (817) reporting that children and adults with low reported consumption of dietary (primarily dairy) calcium have greater body weight, a higher degree of adiposity, and greater risk for having components of the metabolic syndrome than those who report that they consume more calcium. Some (1824), although not all (2534), longitudinal investigations have also suggested that children and adults who consume a lower calcium diet tend to gain more weight than those with greater dietary or supplemental calcium intake. These data, together with some small clinical trials suggesting that weight loss during dieting may be augmented by supplemental (35) or dairy calcium (3538), have led to expectations that substantially augmenting calcium intake might diminish body weight by 0.5 kg or more each year (5, 18, 22, 39). Two possible mechanisms for an effect of dietary calcium on body weight have been suggested. First, calcium can combine with fatty acids in the intestine to form insoluble soaps that are therefore not absorbed (40, 41). Second, some researchers (4246) have proposed that low dietary calcium leads to increased adipocyte triglyceride deposition (4749). If calcium substantially affects fat accumulation, calcium supplementation could prevent additional weight and fat gain among people with high body weight. To test this hypothesis, we measured the effect of calcium carbonate supplementation for 2 years on the weight and body fat of overweight and obese adults. Methods Setting and Participants We recruited participants through advertisements posted in Bethesda, Maryland, and spontaneous reply to newspaper and radio advertising in the Washington, DC, metropolitan area seeking healthy adult volunteers for a project to study the health effects of calcium supplementation. Men and women age 18 to 80 years were eligible to enroll if they had a body mass index (BMI) of 25 kg/m2 or more and did not have cerebrovascular, cardiovascular, pulmonary, renal, hepatic, endocrinologic, or other substantial medical disease. Women were ineligible if they were pregnant, were breastfeeding, or had received a recommendation from a health care professional to take calcium supplements for any condition. We excluded persons who regularly used medications known to affect body weight, had a weight loss of 3% or more in the preceding 3 months, reported total calcium intake in excess of 3.5 g/d, used supplemental calcium in excess of 300 mg/d, used vitamin D supplements in excess of 400 IU/d, or had a history of renal stones. The institutional review board of the National Institute of Child Health and Human Development, National Institutes of Health, approved the research protocol. Each participant provided signed consent. We provided financial compensation for participants' time and inconvenience. Design Overview We conducted a single-center, randomized, double-blind, placebo-controlled trial from March 2002 to April 2006. After an outpatient visit to determine eligibility and obtain initial assessments, participants entered a 2-year, double-blind treatment period. Randomization and Interventions We randomly assigned participants, in a 1:1 ratio, to receive either elemental calcium, 1500 mg/d (calcium carbonate, purchased from Particle Dynamics, St. Louis, Missouri), or placebo, administered as 2 divided doses with meals. Investigators assigned consecutive code numbers to participants from prespecified lists stratified by race or ethnicity, sex, and BMI (25 to 26.99, 27 to 29.99, 30 to 34.99, and 35 kg/m2). The National Institutes of Health Clinical Center Pharmaceutical Development Section used permuted blocks with stratification to generate the allocations that translated code numbers into study group assignments by using a pseudo-random number program. The Pharmaceutical Development Section prepared placebo and calcium capsules to appear identical. Pharmacy personnel, not otherwise involved with the conduct of the study, dispensed study capsules with medication placed in containers that appeared identical and differed only by the individual participant code number. No participant, investigator, or other medical or nursing staff interacting with participants was aware of study group assignments for the duration of the trial. Initial Assessment At their prerandomization evaluation, participants reported after an overnight fast and were weighed in hospital gowns by using a digital scale (Life Measurement Instruments, Concord, California) that was calibrated with a known weight before each participant's measurement. We measured height by using a stadiometer calibrated before each measurement (Holtain, Crymych, United Kingdom). Research dietitians assessed abdominal and hip circumferences in triplicate to the nearest 0.1 cm, as recommended (50, 51), and measured triceps skinfold thickness to the nearest 0.5 mm by using Lange calipers (Cambridge Scientific Industries, Cambridge, Maryland). We measured blood pressure, obtained after a 5-minute rest period, 3 times at 5-minute intervals from seated participants by using an automated sphygmomanometer (Dinamap-Plus, Critikon, Tampa, Florida). We did whole-body dual-energy x-ray absorptiometry to estimate total body fat mass (Delphi A, software version 11.2, Hologic, Bedford, Massachusetts). We measured intact parathyroid hormone concentrations with 2-site immunochemiluminometric assays (52), and serum 25-hydroxy vitamin D levels by using a competitive binding assay (Nichols Advantage, Nichols Diagnostic, San Clemente, California) (53). We asked participants with substantial vitamin D deficiency (serum 25-hydroxy vitamin D level <25.0 nmol/L) to take vitamin D, 400 IU/d (ergocalciferol), in a multivitamin. We assessed baseline dietary calcium intake by using a 7-day food record that a registered dietitian reviewed with each participant to maximize accuracy and completeness, and analyzed for dietary calcium intake by using the Nutrition Data System for Research software, versions 4. 04_32 and 4. 05_33 (University of Minnesota, Minneapolis, Minnesota) (54). We measured calcium intake from multivitamins or calcium supplements with a validated calcium questionnaire (55) that was reviewed for completeness through an interview with a registered dietitian. We recorded the calcium content as it was listed on the label of each multivitamin or calcium supplement. We measured dietary and supplemental vitamin D intakes in the same manner. We estimated energy intake at baseline and at 2 years by using a food-frequency questionnaire that assessed total diet (5557). We measured socioeconomic status by using the Hollingshead score (58). Outcomes and Follow-up Primary efficacy end points were change in body weight and body fat mass at the end of 2 years of treatment. Secondary outcomes were fasting anthropometric measurements, body composition by dual-energy x-ray absorptiometry, and change in blood pressure, assessed yearly, along with questionnaire data on dietary and supplemental calcium intake (55). In addition, we contacted participants every 3 months to complete questionnaires about their adherence to the medication regimen; assess their general health; and obtain self-reports of mood, stress, physical activity, and hunger. Every 6 months, participants returned to the clinic to exchange their unused study medication for a new supply. We used the tally of returned capsules to assess adherence. To examine adequacy of the masking procedure, participants completed a questionnaire at the end of the study that requested they report their best guess about their study group assignment. Statistical Analysis All reported primary data analyses were prespecified. On the basis of our previous study of observed yearly changes in body weight over time (59), we needed a total sample size of 256 participants to detect a 0.35-kg difference per year in weight change (that is, 0.7 kg over 2 years) between groups with 80% power. Participant accrual was set at 340 participants to allow 25% loss to follow-up. We analyzed data by using SPSS for Windows, version 14.0 (SPSS, Chicago, Illinois). We assessed efficacy in the intention-to-treat sample of all randomly assigned participants. We did 2 efficacy analyses. The primary analysis used a multiple imputation model for missing data under a missing-at-random assumption (60). By using NORM, version 2.03 (The Pennsylvania State University, State College, Pennsylvania) (61, 62), we included all available baseline, 1-year, and 2-year outcome measures in an imputation model along with age, sex, race, baseline serum 25-hydroxy vitamin D concentration, baseline calcium intake, and study group. We then combined the coefficients from analyses of 20 imputed data sets into a single set of estimates according to Shafer (62) and the Rubin rules (63). To assess sensitivity of these results to the missing-at-random assumption, we conducted 3 additional analyses: assuming that all participants who withdrew from the study had major weight gain (2.2