Calcium supplementation and bone mineral accretion in adolescent girls: an 18-mo randomized controlled trial with 2-y follow-up 1 3

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1 Calcium supplementation and bone mineral accretion in adolescent girls: an 18-mo randomized controlled trial with 2-y follow-up 1 3 Helen L Lambert, Richard Eastell, Kavita Karnik, Jean M Russell, and Margo E Barker ABSTRACT Background: A recent meta-analysis raised doubt as to whether calcium supplementation in children benefits spine and hip bone mineral density (BMD). Objective: We used state-of-the-art measures of bone (fan-beam dual-energy X-ray absorptiometry and 4 bone turnover markers) to determine whether girls with low habitual calcium intake benefited from supplementation with a soluble form of calcium (calcium citrate malate dissolved in a fruit drink). Design: The trial was an 18-mo randomized trial of calcium supplementation (792 mg/d) with follow-up 2 y after supplement withdrawal. Subjects were 96 girls (mean age: 12 y) with low calcium intakes (mean: 636 mg/d). The main outcome measure was change in total-body, lumbar spine, and total hip bone mineral content (BMC) during supplementation and 2 y after supplement withdrawal. Changes in BMD and bone turnover markers were secondary outcome measures. Results: The mean additional calcium intake in the supplemented group was 555 mg/d. Compared with the control group, the supplemented group showed significantly (P 0.05) greater gains in BMC (except at the total hip site) over the 18-mo study. BMD change was significantly (P 0.05) greater for all skeletal sites, and concentrations of bone resorption markers and parathyroid hormone were significantly (P 0.01) lower in the supplemented group than in the control group after 18 mo. After 42 mo, gains in BMC and BMD and differences in bone resorption were no longer evident. Conclusions: Calcium supplementation enhances bone mineral accrual in teenage girls, but the effect is short-lived. The likely mechanism for the effect of the calcium is suppression of bone turnover, which is reversed upon supplement withdrawal. Am J Clin Nutr 2008;87: KEY WORDS Calcium supplementation, bone mineral content, growth, adolescence, bone turnover INTRODUCTION Osteoporosis may be prevented by increasing peak bone mass or decreasing the rate of bone loss with aging (1). Calcium supplementation of the diet could result in a greater peak bone mass and hence could reduce the risk of fracture in later life. It could also reduce fracture risk during childhood, because these fractures are related to low bone mineral density (BMD) (2, 3). A recent meta-analysis of 19 studies performed in 2859 children reported that calcium supplementation increased the bone density of the total body (and arms) in children treated with calcium supplements (4). However, these effects were small ( 2%) and were not present at the spine or hip, the sites relevant to the most important fractures in later life. The benefits of the supplements on the total-body BMD were reversible after supplementation was stopped. The analysis did not find any effect of sex, pubertal stage, ethnicity, calcium intake, or physical activity. Such a meta-analysis does have limitations. Fracture is the most important endpoint of such trials, but the trials were too small to study that factor. Bone turnover markers are at least as informative as BMD to an understanding of the effects of interventions on fracture risk, but they were not included in this meta-analysis. The authors of the meta-analysis pointed out that few studies were performed in children with low baseline calcium intakes (4). It is likely, however, that these children are the ones who would benefit the most. The mean baseline calcium intake among girls from Western countries varied between 716 and 1198 mg/d (although the analysis did include children with lower calcium intake from Gambia, China, and the Middle East). The statement concerning reversibility of effect on total-body bone density was based on a single trial (4). We can learn from studies in adults to help in designing studies in children. Thus, it would appear that soluble forms of calcium such as calcium citrate (5) or calcium citrate malate (6) may have greater effects on bone turnover markers and BMD than do insoluble forms of calcium. These forms were used in some (7 9) but not all of the clinical trials. The technology for studying bone has advanced over the period the meta-analysis covered. Thus, the authors included studies that used older physical methods such as single- and dualphoton absorptiometry (7) and earlier dual-energy X-ray absorptiometry devices that had lower resolution and software that was not adapted for studying children. When studying bone 1 From the Academic Unit of Bone Metabolism (HLL and RE) and the Human Nutrition Unit (KK and MEB), School of Medicine and Biomedical Sciences, and the Corporate Information and Computing Centre (JMR), University of Sheffield, Sheffield, United Kingdom. 2 Supported by the Osteoporosis Society, UK (studentship for Helen Lambert) Proctor and Gamble Food Division (project grant and provision of supplement and placebo). 3 Reprints not available. Address correspondence to M Barker, Human Nutrition Unit, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX United Kingdom. m.e.barker@sheffield.ac.uk. Received February 9, Accepted for publication September 20, Am J Clin Nutr 2008;87: Printed in USA American Society for Nutrition 455

2 456 LAMBERT ET AL FIGURE 1. The flow of participants through the stages of the study. turnover markers, we have come to understand the importance of using 1 (or 2) bone turnover markers to better detect effects; most of the studies so far have used 1 or 2 markers (7, 9). We designed the present study to address these limitations. The study was designed to include girls with low baseline calcium intakes, to use state-of-the-art devices (fan-beam dualenergy X-ray absorptiometry and 4 bone turnover markers), to use a soluble form of calcium as calcium citrate malate (CCM) dissolved in a fruit drink, and to include an offset period. SUBJECTS AND METHODS Study population and data collection The study was a single-blind, randomized, controlled supplementation trial, with investigators blinded to the treatment allocation. A total of 96 girls aged y were recruited from 22 schools in Sheffield, United Kingdom, between November 1996 and April 1997 (Figure 1). Initial screening was carried out in the schools with the use of a food-frequency questionnaire designed

3 CALCIUM SUPPLEMENTATION IN TEENAGE GIRLS 457 to assess calcium intake. Subjects were selected according to the following criteria: female, white, daily calcium intake 650 mg, no history of metabolic bone disease, and not taking medication known to affect bone metabolism. Treatment allocation was determined by stratified randomization according to tertiles of calcium intake from baseline weighed food diaries (completed after the first hospital visit) and the stage of puberty according to the Tanner stage for breast development (Tanner stage 1 and 2 and Tanner stages 3 5). Written informed consent was obtained from both the subjects and their parents. The North Sheffield Local Research Ethics Committee approved the research. The supplement was a calcium-fortified fruit drink (Punica Orange Refresh; Procter and Gamble, R& D Beverages STC, Newcastle, United Kingdom), and the placebo was a similar unfortified drink (Punica Orange). Both juices contained vitamin C added at a level of 20 mg/100 ml, and the supplement juice also contained 120 mg Ca/100 ml as CCM. The subjects were required to consume two 330-mL bottles of the drink each day for an 18-mo period; 1 bottle was drunk in the evening, because evening calcium supplementation has been shown to suppress the nocturnal increase in bone resorption (10). Thus the level of supplementation was 792 mg Ca/d. Subjects attended the Osteoporosis Centre, Northern General Hospital, for measurements at baseline and at 6, 12, 18, and 42 mo. Bone mineral content (BMC) and BMD were measured for the total body, lumbar spine, and total hip by dual-energy X-ray absorptiometry with the use of a fan-beam densitometer (Hologic QDR 4500A; Hologic Inc, Bedford, MA). Height was measured to the nearest 0.1 cm by using a wall-mounted stadiometer (Holtain Limited, Crymych, United Kingdom). Weight was measured to the nearest 10 g by using electronic scales (Hallamshire Scales Limited, Sheffield, United Kingdom). Pubertal stage was determined by using a self-administered questionnaire containing line drawings and written descriptions of the 5 Tanner stages (11). Date of menarche to the nearest month was also recorded when subjects returned for their follow-up visit at the 42-mo time point. Biochemical analysis Serum and urine samples were collected for the measurement of biochemical markers of bone turnover and hormonal status. Measurements were made from serum samples at 0, 6, 12, and 18 mo; urine samples were analyzed at all 5 time points. Nonfasting blood samples were obtained from subjects between 1130 and 1300 and collected into SST Vacutainer tubes (Becton Dickinson, Plymouth, United Kingdom) containing a clot activator. Blood was allowed to clot for 30 min and centrifuged (2000 g, 10 min, 4 C). Serum aliquots were frozen at 80 C within 1 h of drawing. Nonfasting, timed urine samples were collected between 1000 and 1300, aliquoted, and stored at 20 C. Urine samples were collected at 0, 6, 12, 18, and 42 mo. Cross-linked telopeptides from the N-terminal end of type I collagen (NTx) were measured in urine by using a competitiveinhibition enzyme-liked immunosorbent assay (ELISA) (Osteomark; Ostex International Inc, Seattle, WA); the intraassay CV was 3.8%. Free urinary deoxypyridinoline was also measured by ELISA (Pyrilinks-D; Metra Biosystems Inc, Mountain View, CA); the intraassay CV was 5.9%. Serum immunoreactive bone alkaline phosphatase (i bone ALP) was measured by ELISA (Alkphase-B; Metra Biosystems Inc); the intraassay CV was 2.0%. Serum osteocalcin was measured by using an immunoradiometric assay (ELSA-OSTEO; CIS Bio International, Gif-sur-Yvette, France); the intraassay CV was 2.6%. Serum concentrations of intact parathyroid hormone (PTH) were measured by using a 2-site immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA); the intraassay CV was 4.9%. Serum estradiol was measured by using an ELISA (Fertigenix-E 2 -Easia; Biosource Europe SA, Nivelles, Belgium); the intraassay CV was 9.6%. Serum insulin-like growth factor-1 (IGF-1) was measured by using a radioimmunoassay (Medgenix Diagnostics SA, Fleurus, Belgium); the intraassay CV was 9.7%. Urinary creatinine was measured using a 2-point rate dry slide technique (Vitros Chemistry Products, Ortho Clinical, Rochester, NY). All analytes were measured at 0, 6, 12, and 18 mo. In addition, urinary NTx was measured at 42 mo. Dietary measurements and physical activity Dietary intake was assessed by using 7-d weighed intake records at 0 and 18 mo and 4-d weighed records at 42 mo that were obtained with calibrated electronic weighing scales (Soehnle, Murrhardt, Germany). Four-day estimated records were completed at 6 and 12 mo; food portion sizes were estimated by using household measures (12). Weights of items consumed outside the home were also estimated. Nutrient intakes were calculated by using FOODBASE dietary software (version 1.2; Institute of Brain Chemistry and Human Nutrition, Queen Elizabeth Hospital, London, United Kingdom). Physical activity was assessed by using a validated 7-d recall questionnaire (13). Energy expenditure (kj d 1 kg body wt 1 ) was estimated from these physical activity data. Statistical analysis The power calculation for the study was made on the basis of detecting a 3% change in BMC with a significance level of 5%. With 96 subjects (48/group), the power of the study was 90%. The primary outcome measures were change in BMC (in g) from 0 to 18 mo and from 18 to 42 mo. Secondary measures were changes in BMD (in g/cm 2 ) and changes in biochemical markers of bone turnover. SPSS software (version 12.0; SPSS Inc, Chicago, IL) was used for all the analyses. Baseline characteristics of the supplemented and control groups were compared by using unpaired t tests for continuous variables and the chi-square test for categorical variables. Within group changes for nutrient intakes and physical activity measures were analyzed by using Wilcoxon s signed-ranks test, and differences between groups were compared with the Mann-Whitney U test. Agreement between food-frequency and weighed-intake methods for estimating calcium intake was assessed by using the kappa statistic. An intention-to-treat analysis was carried out on the 89 girls who attended baseline assessment and the 18-mo assessment. Between-group differences in outcome measures for the total intervention period were compared by repeated-measures analysis of covariance (simple ANCOVA) after adjustment for baseline values. Age at menarche and age at menarche visit interaction were used as covariates in further ANCOVA analyses. ANCOVA with adjustment for age at menarche was used to test whether bone gain in the 2 y after the intervention differed between the groups.

4 458 LAMBERT ET AL RESULTS The number of subjects at various stages of the study is shown in Figure 1. Of the 96 girls who underwent randomization, 12 withdrew before completing the study. Of these 12, 5 returned at 18 mo, so that measurements were obtained for 89 girls. This was the intention-to treat-cohort, comprising 45 girls from the supplemented group and 44 girls from the control group. Menarchal status information was provided by 78 of the 89 subjects in the intention-to-treat group. Of these 78 subjects, 5 missed one of the interim hospital visits, and we did not have complete information for all time points. Thus, the ANCOVA, which ascertained the effect of group and time on outcome after adjustment for pubertal development, was for 73 subjects 37 in the supplemented group and 36 in the placebo group. A total of 73 girls participated in the follow-up at 42 mo, and we obtained menarchal status information for 69 of those girls Analysis of the follow-up cohort therefore was for 69 subjects 35 from the original supplemented group and 34 from the original control group. There were no significant differences in treatment allocation, baseline bone measures, or sexual maturity between subjects who completed the study and those who did not. The baseline characteristics of the supplemented and control groups are shown in Table 1. There were no significant differences between treatment groups in age or anthropometric measurements, menarchal status, nutrient intake, physical activity, and concentrations of bone turnover markers and hormones. Although the groups were balanced across broad categories of Tanner stage (Tanner stages 1 and 2 compared with stages 3 and 4) as per the randomization procedure, the control group was weighted toward subjects in Tanner stage 1 (Table 1). The differences in the distribution of subjects was statistically significant (chi-square: , df: 3, P 0.002; P value is calculated by using Monte-Carlo techniques to allow for small expected values at Tanner stage). None of the other indicators of menarche were significantly different between the groups. Because of the effects of puberty on bone mineral accrual, it was essential to statistically adjust for these group differences in pubertal maturation. Age at menarche, a more precise measure of pubertal maturation than is Tanner stage, was used for statistical adjustment. The food-frequency questionnaire and the weighed-intake method of assessing calcium intake gave discrepant results ( 0.2). Therefore, with the the food-frequency questionnaire having been used for the initial screening process, all subsequent estimates of calcium intakes were based on weighed intakes. Mean SD baseline daily calcium intake in the intention-to-treat cohort was and mg/d for the control and supplemented groups, respectively. After 18 mo, the intake had increased to mg/d in the supplemented group (n 39), and it remained unchanged at mg/d in the control group (n 39). The additional intake from the supplement was 634, 594, and 436 mg/d at 6, 12, and 18 mo, respectively (mean: 555 mg/d). However, there was a significant (P 0.01) reduction in milk intake and a nonsignificant decrease in the consumption of dairy products in the supplemented group between baseline and 18 mo; these reductions together account for the lower-thanexpected overall increment in calcium intake. There was a fall in milk intake in the supplemented group at 18 mo, but protein intake remained unchanged from baseline (51 g/d at baseline and 52 g/d at 18 mo). TABLE 1 Baseline characteristics of supplemented and control groups of the intention-to-treat cohort 1 Control group (n 44) Supplemented group (n 45) Age (y) (0) (0) Height (cm) (0) (1) Weight (kg) (0) (1) Body fat (kg) (0) (0) (%) (0) Lean body mass (kg) (0) (0) BMI (kg/m 2 ) (0) (0) TBBMC (g) (0) (0) LSBMC (g) (0) (0) THBMC (g) (0) (0) TBBMD (g/cm 2 ) (0) (0) LSBMD (g/cm 2 ) (0) (0) THBMD (g/cm 2 ) (0) (0) Tanner stage 1 (n) 9 0 Tanner stage 2 (n) Tanner stage 3 (n) Tanner stage 4 (n) 2 5 Menarche Yes (n) 10 9 No (n) Energy expenditure (0) (0) (kj kg 1 d 1 ) Total activity (min/wk) (0) (0) Dietary energy (kj/d) (0) (0) Calcium intake (mg/d) (0) (0) Protein intake (g/d) (0) (0) NTx (nmol BCE/mmol (4) (2) creatinine) ifdpd (nmol/mmol (4) (2) creatinine) Osteocalcin (ng/ml) (19) (9) i bone ALP (U/L) (19) (10) IGF-1 (ng/ml) (16) (10) Estradiol (pg/ml) (16) (11) PTH (pg/ml) (15) (10) 1 TBBMC, total-body bone mineral content; LSBMC, lumbar spine BMC; THBMC, total hip BMC; TBBMD, total-body bone mineral density; LSBMD, lumbar spine BMD; THBMD, total hip BMD; NTx, N-teleopeptide; BCE, bone collagen equivalents; ifdpd, immunoreactive free urinary deoxypyridinoline; i bone ALP, immunoreactive bone alkaline phosphatase; IGF-1, insulin-like growth factor-1; PTH, parathyroid hormone. Unpaired t test for continuous variables and chi-square test for categorical variables showed no significant differences between the groups in age, anthropometric measurements, nutrient intake, physical activity, or bone mineral measurements. There were significant differences between the groups for Tanner stage: chi-square test , df 3, P None of the other indicators of menarche differed significantly between the groups. 2 x SD; no. of missing values in parentheses (all such values). Gains in height and weight did not differ significantly between the supplemented and placebo groups over the 18-mo intervention. Comparison in the intention-to-treat cohort showed that the mean SE final height at 18 mo was cm in the control group and cm in the supplemented group, a difference that was not significant (P 0.451, ANCOVA with adjustment for baseline height). Similarly, weight gain over the intervention period did not differ between the supplemented and

5 CALCIUM SUPPLEMENTATION IN TEENAGE GIRLS 459 TABLE 2 Bone mineral characteristics at 18 mo by group with adjustment for baseline values of the intention-to-treat cohort 1 Variable Control group (n 45) Supplemented group (n 44) P 2 TBBMC (g) LSBMC (g) THBMC (g) TBBMD (g/cm 2 ) LSBMD (g/cm 2 ) THBMD (g/cm 2 ) n 89. TBBMC, total-body bone mineral content; LSBMC, lumbar spine BMC; THBMC, total hip BMC; TBBMD, total-body bone mineral density; LSBMD, lumbar spine BMD; THBMD, total hip BMD. 2 For the difference between the groups (ANCOVA). 3 x SE (all such values). control groups (P 0.430, ANCOVA with adjustment for baseline weight). The mean weight of the supplemented group at 18 mo was kg, and that of the control group was kg. However, a chi-square test showed that the supplemented group progressed through puberty significantly (P 0.01) more rapidly than did the control group; 84% of the girls in the supplemented group (all but 8 of the group) reached menarche during the 18-mo study, whereas only 57% of the control group did so. Change in bone mineral variables and biochemical markers after 18 mo The bone mineral characteristics by group at the end of the 18-mo intervention after adjustment for baseline values are shown in Table 2. There was no difference between supplemented and control groups in measures of BMC and BMD at 18 mo, although there was a tendency for total-body BMD to be greater in the supplemented group (P 0.055). The absolute change in BMC and BMD after 18 mo in supplemented and control groups, after control for baseline values and age at menarche, is shown in Table 3. The gains in BMC at the total-body level and at the lumbar spine region were significantly greater (P for total-body BMC and P for lumbar spine BMC) in the calcium-supplemented group than in the control group. Compared with the control group, the supplemented group had acquired significantly greater total-body BMC at 6 (P 0.003) and 12 (P 0.007) mo; the effect was borderline at 18 mo (P 0.06). The supplemented group had significantly greater gains in lumbar spine BMC at 6(P 0.001), 12 (P 0.012), and 18 (P 0.019) mo than did the control group. The supplemented group also had greater gains in BMD and the difference in BMD gain between supplemented and control groups was significant at the total-body level (P 0.001) and the lumbar spine region (P 0.001). The supplemented group had significantly greater gains in total-body BMD at 6 (P 0.024), 12 (P 0.001), and 18 (P 0.005) mo than did the control group. The supplemented TABLE 3 Bone mineral measures at 6, 12, and 18 mo by group in the intention-to-treat cohort, with adjustment for baseline values, age at menarche, and age at menarche visit interaction Variable and group 0 mo 2 6mo 12mo 18mo P (group) 3 TBBMC (g) Control Supplemented P LSBMC (g) Control Supplemented P THBMC (g) Control Supplemented TBBMD (g/cm 2 ) Control Supplemented P LSBMD (g/cm 2 ) Control Supplemented P THBMD (g/cm 2 ) Control Supplemented P n 36 and 37 in the control and supplemented groups, respectively. TBBMC, total-body bone mineral content; LSBMC, lumbar spine BMC; THBMC, total hip BMC; TBBMD, total-body bone mineral density; LSBMD, lumbar spine BMD; THBMD, total hip BMD. 2 Data were adjusted for baseline, which had the effect of setting all values to the overall mean at time 0. 3 P values are combined values for group differences (ANCOVA). P values in other columns are for group differences at each time point. 4 x SE (all such values).

6 460 LAMBERT ET AL TABLE 4 Concentrations of biochemical markers of bone turnover and hormonal indexes at 6, 12, and 18 mo by group in the intention-to-treat cohort, with adjustment for baseline value, age at menarche, and age at menarche visit interaction 1 Variable and group 0 mo 2 6mo 12mo 18mo P 3 NTx (nmol BCE/mmol creatinine) Control (n 32) Supplemented (n 35) ifdpd (nmol/mmol creatinine) Control (n 32) Supplemented (n 35) Osteocalcin (ng/ml) Control (n 20) Supplemented (n 27) i bone ALP (IU/L) Control (n 22) Supplemented (n 26) IGF-1 (ng/ml) Control (n 21) Supplemented (n 25) Estradiol (pg/ml) Control (n 21) Supplemented (n 24) PTH (pg/ml) Control (n 20) Supplemented (n 25) BCE, bone collagen equivalents; NTx, N-teleopeptide; ifdpd, immunoreactive free urinary deoxypyridinoline; i bone ALP, immunoreactive bone alkaline phosphatase; IGF-1, insulin-like growth factor-1; PTH, parathyroid hormone. 2 The data were adjusted for baseline, which had the effect of setting all values to the overall mean at time 0. 3 P values were the combined value for group differences at each time point (ANCOVA). 4 x SE (all such values). group had significantly greater gains in lumbar spine BMD at 6(P 0.001) and 12 (P 0.011) mo than did the control group, but the effect was marginal at 18 mo (P 0.051). Biochemical markers and hormonal indexes for supplement and control groups over the 18-mo intervention period are shown in Table 4. The analysis relates to 73 subjects of the intention-to-treat cohort for whom there was age at menarche information and who attended all interim hospital visits. The biochemical analysis was incomplete for some analytes, and the number of missing values is given per analyte. The bone formation markers osteocalcin and i bone ALP and the bone resorption markers NTx and free urinary deoxypyridinoline fell over the 18-mo intervention. The difference in marker level between the supplemented and control groups throughout the intervention period was significant for osteocalcin (P 0.001), i bone ALP (P 0.033), and NTx (P 0.001). The supplemented group had significantly lower osteocalcin concentrations than did the control group at all 3 time points (P 0.004, 0.001, and at 6, 12, and 18 mo, respectively). The groups had significantly (P 0.03) different i bone ALP concentrations at 12 mo and significantly different NTx concentrations at 12 (P 0.001) and 18 (P 0.001) mo. There was a significantly (P 0.013) greater fall in PTH in the supplemented group than in the control group. The difference between the groups was significant at 12 (P 0.02) and 18 (P 0.02) mo. IGF-1 and estradiol did not differ significantly between the supplemented and control groups throughout the intervention period. Results after 42 mo The mean age at the follow-up visit was y. All subjects were postmenarchal at follow-up (mean age at menarche: y). There were no differences between the formerly supplemented group and the control group in nutrient intake (P 0.669, t test). The mean calcium intake was g/d (n 20) in the formerly supplemented group and g/d (n 24) in the control group. In the 2 y after withdrawal of the supplement, gains in BMC and BMD were significantly greater in the control group than in the formerly supplemented group (Table 5). During the follow-up period, the control group had significantly greater bone mineral acquisition at the total-body level (P for total-body BMC), the lumbar spine region (P for lumbar spine BMC), and the total hip region (P for total hip BMC, P for total hip BMD) than did the formerly supplemented group. Table 5 also shows that there was also a significantly (P 0.026) greater fall in NTx in the control group than in the formerly supplemented group. Changes in height and weight did not differ significantly between the 2 groups. The mean SE gain in height was cm in the formerly supplemented group and cm in the control group. This difference was not significant (P 0.090) when ANCOVA was used with adjustment for height at the end of the intervention (18-mo time point). The corresponding figures for gains in weight were kg for the formerly supplemented group and kg for the control group. This difference was not

7 CALCIUM SUPPLEMENTATION IN TEENAGE GIRLS 461 TABLE 5 Change in bone mineral characteristics and N-teleopeptide (NTx), concentrations between 18 and 42 mo by control and supplemented group of the intention-to-treat cohort with adjustment for age at menarche 1 Variable Control group Supplemented group P 2 TBBMC (g) LSBMC (g) THBMC (g) TBBMD (g/cm 2 ) LSBMD (g/cm 2 ) THBMD (g/cm 2 ) NTx (nmol BCE/mmol creatinine) n 34 and 35 in the control and supplemented groups, respectively. TBBMC, total-body bone mineral content; LSBMC, lumbar spine BMC; THBMC, total hip BMC; TBBMD, total-body bone mineral density; LSBMD, lumbar spine BMD; THBMD, total hip BMD; BCE, bone collagen equivalents. 2 P value after adjustment for age at menarche (ANCOVA). 3 x SE (all such values). significant (P 0.366, ANCOVA with adjustment for weight at 18 mo). DISCUSSION In this study, the effect of a nondairy dietary calcium supplement on bone mineralization was explored in a cohort of healthy adolescent girls with low baseline calcium intakes, and the mechanism for an effect was investigated. The results show that an increase in calcium intake averaging 555 mg/d, as CCM in a fruit drink, increased bone mineral gain in y-old girls with a low mean baseline calcium intake of 636 mg/d. Supplementation had most marked effects on rates of bone mass accretion during the first 6 12 mo. The increase in BMC and BMD was accompanied by a relative reduction in bone turnover markers, which was no longer present 2 y after withdrawal of the supplement. This study contradicts the conclusion of the meta-analysis (4) that calcium supplementation is ineffective in enhancing bone mineralization at the spine and hip during growth. It does agree with the conclusions that calcium supplementation is effective at the total body and that the effect is transitory. Our study may differ from the outcome of the meta-analysis in that we studied girls selected for their low baseline calcium intake, we used CCM in a form that was already solubilized, and we used state-of-theart measurements to study bone density and bone turnover. We also studied the mechanism by which calcium exerted its effects. In adults, calcium supplementation results in a decrease in bone remodeling by suppressing PTH secretion, and the increase in BMD is a consequence of the filling in of the remodeling space (14). The time course and magnitude of the suppression in bone turnover markers and PTH that we observed in this study would suggest that the mechanism is similar in children. In adults, the effect of calcium supplementation is most marked in the first year (15), and this would be predicted by our knowledge of the remodeling transient (14). This was true in our study and in those of others (7, 9, 16). If the filling in of the remodeling space were the main mechanism, then withdrawal of the supplement would be expected to result in an increase in PTH and a return of bone turnover to that found in unsupplemented persons; there would be an expansion in remodeling space. Thus, the effect would be expected to be reversible, as we observed here. Several studies have indicated that there may be offset of effect when the calcium supplement is stopped, as assessed by BMD (7, 17) and the bone turnover marker osteocalcin (7, 18), although the change in BMD was not reversible in the study from The Gambia (18). Is it possible that the effects of calcium supplementation could be irreversible? We observed that the girls in the supplemented group had a more rapid progression through puberty, but we do not have an explanation for this as yet. One group observed the same phenomenon in girls supplemented with a milk extract (19). It has been observed that an earlier menarche is associated with higher BMD and a lower risk of hip, spine, and wrist fractures after menopause (20). The other way in which the benefits could be irreversible would be through changes in bone size. Thus, the use of milk or milk extract may result in permanent benefits to bone. Bonjour et al (21) reported that, 3.5 y after the administration of milk extract was stopped, there was a persistent benefit of supplementation on the BMD of the lumbar spine, femur, and radius; at the lumbar spine, there also was a persistent benefit on bone area, mainly as a result of an increase in bone length. In a trial with a design similar to that of the present study, we explored the mechanism through which milk resulted in an increase in total BMC (22). We found that there was no decrease in bone turnover markers, but there was an increase in IGF-1. Thus, it may be that the protein content of milk (and its products) results in a long-term effect on bone by its stimulation of IGF-1 production (23). The increase in IGF-1 may have anabolic effects on bone (24). In conclusion, calcium supplementation of white girls with low calcium intake results in increases in the BMD of the lumbar spine, total hip, and total body. This effect appears to be mainly due to the suppression of PTH and, hence, to bone remodeling. There may be an effect of calcium supplementation on the timing of menarche, but that possibility requires further evaluation. We thank all of the Sheffield schools that participated in the study, especially the girls who took part, and their parents. We also acknowledge the work of Einas Behebani and Sarah O Brien, graduate students in human nutrition, who helped collect follow-up data. The authors responsibilities were as follows RE and MEB: conception and design of the study and interpretation of the data; HLL: conduct of the original study; KK: conduct of the follow-up study; JMR: statistical analysis; HLL, KK, RE, and MEB: the writing of the manuscript. RE receives research funding and consulting fees from Procter and Gamble, GlaxoSmithKline, and New Zealand Milk. None of the other authors had a personal or financial conflict of interest. REFERENCES 1. Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med 1998;338: Goulding A, Jones IE, Taylor RW, Williams SM, Manning PJ. Bone mineral density and body composition in boys with distal forearm fractures: a dual-energy x-ray absorptiometry study. J Pediatr 2001;139: Ma D, Jones G. The association between bone mineral density, metacarpal morphometry, and upper limb fractures in children: a populationbased case-control study. J Clin Endocrinol Metab 2003;88: Winzenberg TM, Shaw K, Fryer J, Jones G. Calcium supplementation for improving bone mineral density in children. Cochrane Database Syst Rev 2006;CD Kenny AM, Prestwood KM, Biskup B, et al. Comparison of the effects of calcium loading with calcium citrate or calcium carbonate on bone turnover in postmenopausal women. Osteoporos Int 2004;15:290 4.

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