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Service of Bone Diseases (World Health Organization Collaborating Center for Osteoporosis Prevention), Department of Rehabilitation and Geriatrics (T.C., R.R., S.F., J.-P.B.), and Service of Nuclear Medicine, Department of Radiology (D.H.), University Hospitals, CH-1211 Geneva 14, Switzerland
Address all correspondence and requests for reprints to: Dr. Thierry Chevalley, Service of Bone Diseases [WHO Collaborating Center for Osteoporosis Prevention], Department of Rehabilitation and Geriatrics, University Hospitals, CH-1211 Geneva 14, Switzerland. E-mail: Thierry.Chevalley{at}hcuge.ch.
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Abstract |
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Introduction |
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Rising calcium intake during childhood and adolescence increases bone mass gain, possibly resulting in higher peak bone mass, as demonstrated in prospective randomized, double-blind, placebo-controlled intervention trials (5, 6, 7, 8, 9, 10, 11, 12, 13). Follow-up studies suggest that the benefit may (11, 14, 15) or may not (16, 17, 18) persist after discontinuation of Ca supplementation. The maintenance of the benefit may depend upon the age and/or pubertal stage at the time of the intervention, the level of the spontaneous calcium intake, or the type of calcium salt or could be related to environmental conditions, including other nutrients and physical activity. This issue is of importance because long-term adherence to high calcium intake may be inconstant during childhood and adolescence. Of note, the benefit of milk supplementation tested in a randomized trial (19) may persist after stopping the intervention (20). This lasting effect is in agreement with recent epidemiological data analyzing the relation between milk intake during childhood and adolescence in girls, adult bone density, and osteoporotic fractures (21). The persistent gain we observed 3.5 yr after discontinuation of calcium supplementation when girls were aged 12.5 yr was associated with a slight, although not significant, difference in pubertal maturation (14). Therefore, at this follow-up time it was not possible to rule out that calcium supplementation would have induced an acceleration of pubertal maturation, accounting, either partially or totally, for the lasting gain observed at 12.5 yr, i.e. during the peripubertal period.
In this report we present the results of a follow-up examination of the same cohort at a mean age of 16.4 yr, i.e. 7.5 yr after discontinuation of the calcium supplementation. All subjects were postmenarche. The results confirm the lasting effect of the intervention with an interaction of menarcheal age and calcium intake.
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Subjects and Methods |
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Participants
Healthy prepubertal Caucasian girls with a mean age ± SD of 7.9 ± 0.5 yr (range, 6.6–9.4 yr; n = 149) were recruited within the Geneva district over an 8-month period, from April to November 1993. The ethics committee of the Department of Pediatrics of University Hospitals of Geneva approved the protocol. Informed consent was obtained from parents and children. The exclusion criteria were ratio weight/height below the third or above the 97th percentile, physical signs of puberty, chronic disease, malabsorption, bone disease, or regular use of medication. In a randomized, double-blind, placebo-controlled design, 149 subjects were allocated to receive either calcium-enriched foods or a placebo for 48 wk. Of this initial cohort, 144 were examined at baseline and at the end of the intervention study, 48 wk later [intention to treat cohort (ITT)] (11). The active treatment cohort (ACT) included the subjects who consumed the study foods during 48 wk. One year after the end of intervention, 59 and 72 girls from the originally randomized placebo and calcium intervention groups were reexamined when aged 9.9 ± 0.5 yr (range, 8.6–11.4 yr) (11). In June 1997, i.e. 3.5 yr after the end of intervention, 144 subjects in the ITT were contacted, and 116 girls, aged 12.5 ± 0.5 yr (range, 11.1–13.8 yr), underwent an additional evaluation from November 1997 to June 1998 (14). Finally, from October 2001 to June 2002, 125 girls, 58 and 67 from the originally randomized placebo and calcium intervention groups, with a mean age of 16.4 ± 0.5 yr (range, 15.1–18.0 yr) agreed to be reexamined. The times elapsed from the end of the intervention were 7.41 yr (95% confidence interval, 7.24–7.53) and 7.45 yr (95% confidence interval, 7.26–7.58) in the placebo and Ca-suppl. groups, respectively. Table 1
indicates the number of subjects examined at the different phases of the study and their pubertal maturation.
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The supplement (Ca-suppl.) was a milk calcium-phosphate salt extract, which enriched several food products: cakes (two kinds), biscuits, fruit juices, powdered drinking chocolate, chocolate bars, and yoghurts. On the average, the intake of two calcium-enriched servings per day provided a calcium supplement of about 850 mg. Two similar food products with respect to energy, protein, lipid, and mineral content, but without added milk calcium-phosphate salt were consumed daily by the control (placebo) group. The mean nutrient contents of the milk calcium-phosphate salt foods and placebo were: calcium, 436 and 46 mg; phosphate, 236 and 54 mg; lipids, 6.6 and 6.6 g; carbohydrates, 22.9 and 22.4 g; proteins, 2.3 and 2.2 g; and energy, 160 and 158 Kcal, respectively (11).
Clinical assessment
Weight, stadiometer-derived standing height, and body mass index (kilograms per square meter) were measured in all subjects. At baseline and 48 wk later, a pediatrician determined pubertal status. All girls were prepubertal (stage P1) at the end of the intervention period. When evaluated 1.0, 3.5, and 7.5 yr after discontinuation of the intervention, pubertal status was determined by a self-assessment questionnaire, with drawings and written description of Tanner’s breast and pubic hair classification. One year after the end of intervention, at a mean age of 10.0 yr, there was a nonsignificantly greater percentage of girls with pubertal stage P2 in the Ca-suppl. group (42%) than in the placebo group (29%; Table 1
). Three and a half years after the end of intervention, at a mean age of 12.5 yr, this trend for an earlier pubertal maturation, although again not statistically significant (0.05 < P < 0.1), was also noticed; 37% in the Ca-suppl. group and 22% in the placebo group were at stage P4–P5 (Table 1). Menarcheal age (assessed by questionnaire) was determined in 122 of the 125 girls when reexamined at a mean age of 16.4 yr. In three girls, precise information on the time (year and month) of first menstruation could not be obtained. No occurrence of any disease affecting bone health was recorded.
Calcium intake
Spontaneous Ca intake during the intervention phase was estimated by frequency questionnaires at baseline, 6 months, and 12 months. Total Ca intake (spontaneous ± Ca-suppl., in grams per year) was calculated, taking into account the individual compliance in the Ca-suppl. group. Compliance was recorded by the parents and was verified through regular phone calls and interviews by the trained dietician of the team. Additional frequency questionnaires on spontaneous Ca intake were assessed at each follow-up visit, i.e. 1.0, 3.5, and 7.5 yr after the end of intervention.
Bone variables
Areal bone mineral density (aBMD; grams per square centimeter) was determined by dual energy x-ray absorptiometry (QDR-2000 instrument, Hologic, Waltham, MA). Six skeletal sites were assessed: distal metaphysis and diaphysis of the radius, femoral neck, trochanter, midfemoral diaphysis, and L2–L4 vertebrae in antero-posterior view, as previously reported (11). The coefficient of variation of repeated aBMD measurements at these sites, as determined in young healthy adults, varied between 1.0–1.6%. During the intervention phase, the mean yearly aBMD gains at these six sites were 21 and 27 mg/cm2 (P < 0.005) in the placebo (n = 67) and Ca-suppl. (n = 77) groups, respectively (ITT cohort) (11). One year after the end of intervention, the mean aBMD gain from baseline of the six skeletal sites tended to remain greater, although not significantly, in the Ca-suppl. (57 mg/cm2; n = 72) than in the placebo (52 mg/cm2; n = 59) group (11).
At the next examination, 3.5 yr after discontinuation of the intervention, the difference from baseline in mean aBMD of the six skeletal sites was highly significant: placebo (n = 54), +151 mg/cm2, vs. Ca-suppl. (n = 62), +179 mg/cm2 (P = 0.012) (14).
Expression of the results and statistical analysis
The various anthropometric and osteodensitometric variables are given as the mean ± SD. Gains in bone variables were determined separately for each skeletal site. In addition, the mean change in aBMD of the six scanned sites was calculated. The differences between placebo and Ca-suppl. groups for anthropometric and osteodensitometric variables, calcium intakes, and menarcheal ages were evaluated using a two-tailed t test for unpaired values. For the relationship between menarcheal age and total calcium intake during intervention, a multiple regression was used to control for the influence of baseline body weight and standing height. For the relationship between aBMD gain and menarcheal age and for the differences in gains of osteodensitometric variables, a multiple regression and an analysis of covariance were used, respectively, to take into account the gain in both body weight and standing height. The significance level for two-sided P values was 0.05 for all tests. The data were analyzed using STATA software (version 7.0) (Stata Corp., College Station, TX).
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Results |
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). The spontaneous Ca intake was not statistically different between the placebo and Ca-suppl. groups (916 ± 344 vs. 879 ± 316 mg/d, respectively). It remained quite constant when evaluated 1, 3.5, and 7.5 yr after the end of intervention, with no significant difference between the placebo and Ca-suppl. groups (data not shown). The mean menarcheal age (13.0 ± 1.1 (±SD) yr) recorded in our cohort is similar to that reported in a women’s health survey carried out in a "typical" sample from the Geneva population (22). Contrasting with the very close similarity in both height and weight (Table 2), a significant difference between the placebo and the Ca-suppl. group was found for menarcheal age (Fig. 1). In the ITT, the Ca-suppl. group experienced menarche 0.41 yr, i.e. 4.9 months, earlier than the placebo group (12.82 ± 1.13 vs. 13.23 ± 1.14; P = 0.048) (Fig. 1). In the ACT, the difference in menarcheal age was still greater; the Ca-suppl. group experienced menarche 0.45 yr, i.e. 5.4 months, earlier than the placebo group (P = 0.042; Fig. 1). A significant negative correlation was found between menarcheal age and total Ca intake during the intervention, even after adjustment for baseline body weight and standing height (Fig. 2). The gain in aBMD from age 7.9–16.4 yr at the six skeletal sites was inversely related to the age of menarche (r = –0.41 to –0.22; P < 0.001 to P = 0.016) even after adjustment for the gain in body weight and standing height (Table 3 and Fig. 3). The greater gain in aBMD in the Ca-suppl. than in the placebo group was maintained, at least at some of the six skeletal sites examined, 1 and 3.5 yr after the end of intervention (11, 14). At 16.4 yr, i.e. about 7.5 yr after the end of the intervention, the aBMD gain at all skeletal sites tended to be greater in the Ca-suppl. than in the placebo group (Table 4).
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). The differences between Ca-suppl. and placebo in bone mineral mass accrual in the early menarche subgroup remained significant after adjustment for the gain in both body weight and standing height (Table 4). In contrast, in the late menarche subgroup, no lasting effect of calcium supplementation was observed (Table 4 and Fig. 4) The increase in mean axial and appendicular aBMD gain from age 7.9 to 16.4 yr was significantly greater (P = 0.009) in girls with a relatively early menarcheal age [placebo, 286 ± 36 mg/cm2 (menarcheal age, 12.2 ± 0.5 yr); Ca-suppl., 317 ± 46 mg/cm2 (menarcheal age, 12.1 ± 0.5 yr)] even after adjustment for the gain in both body weight and standing height (P = 0.006). In contrast, no significant difference (P > 0.05) in favor of the Ca-suppl. group was found in girls with a relatively late menarcheal age [placebo, 284 ± 58 mg/cm2 (menarcheal age, 13.9 ± 0.5 yr); Ca-suppl., 276 ± 50 mg/cm2 (menarcheal age, 13.9 ± 0.5 yr)]. There was no difference in standing height gain and there was a nonsignificant trend for a higher gain in bone mineral content and, to a lesser extent, in bone scanned areas among the Ca-suppl. girls with a relatively early menarcheal age. Note that in girls with early menarche, in whom the long-lasting difference in aBMD in favor of Ca-suppl. was recorded at 16.4 yr (Table 4 and Fig. 4), the placebo and Ca-suppl. groups had virtually the same baseline aBMD at all skeletal sites when examined at 7.9 yr of age (Table 5). In agreement with this differential response to Ca-suppl. between early and late menarche groups, the absolute values of aBMD, as measured at 16.4 yr, tended to be greater at all appendicular sites in girls with early menarche, reaching statistical significance in both radial diaphysis and trochanter (Table 6). The mean lumbar spine aBMD value of the Ca-suppl. group was not greater than that of the placebo group in girls with early menarche. Again, in agreement with the aBMD gain data, in girls with relatively late menarcheal age, none of the absolute aBMD values was greater in the Ca-suppl. compared with the placebo group (Table 6). The corresponding t scores for sites used in the clinical setting of osteoporosis diagnosis (23) indicate in girls with early menarche differences of +0.13, +0.64, +0.39, and +0.70 in favor of the Ca-suppl. compared with the placebo group in radial metaphysis, radial diaphysis, femoral neck, and femoral trochanter, respectively (Table 6). The mean t score values suggest that peak bone mass was attained in some (femoral neck and, to a lesser extent, lumbar spine), but not in other (radial metaphysis and diaphysis) skeletal sites examined. This difference in peak bone mass attainment would be compatible with the age range of the studied cohort (15.1–18.0 yr).
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Discussion |
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Calcium intake and menarcheal age
Exposure to calcium supplements in prepubertal girls may accelerate the onset of pubertal maturation and significantly lower menarcheal age. Although still debated, a recent report from North America suggests that "the onset of puberty in girls occurs on average at 8 yr of age" (24). Our intervention trial started at a mean age of 7.9 yr, i.e. probably at a time close to the onset of pubertal maturation. The supplemented girls from age 8 to 9 yr consumed calcium-enriched foods that provided daily a supplement of 850 mg above their spontaneous calcium intake, which amounted to about 880 mg/d. Thus, compared with the placebo group, this supplement approximately has doubled their calcium intake (11). A slightly greater difference in menarcheal age between the placebo and Ca suppl. groups was recorded in the ACT (5.4 months) compared with the ITT (4.9 months). This observation could be interpreted as some kind of dose effect of the supplementation, thus corroborating the significant inverse relationship found between the age of menarche and the total calcium intake during the intervention year. In our study the supplementation was given in the form of milk-extracted calcium salt, with phosphate as the main anion (11). This form may not be specific, because calcium citrate malate could also induce an acceleration of the timing of menarche (25). Our 7.5-yr follow-up study indicates that 1 yr after the end of intervention, when girls were, on the average, 9.9 yr of age, there was a trend for earlier pubertal maturation in the Ca suppl. compared with the placebo group (11). Such a trend was also observed at the next follow-up visit made 3.5 yr after the end of intervention (14). Therefore, the significantly earlier menarcheal age recorded was probably associated with an earlier onset of pubertal maturation.
Nutrition and menarcheal age
In many countries across the five continents a secular trend for earlier onset of menarche has been reported over the past 120 yr. Very consistent reports have been published from North America (26, 27), South America (28), Africa (29, 30), Asia (31, 32), Australia (33), and Europe (34, 35). Menarche has been occurring earlier at an average of 3 or 4 months/decade (36). Although both the increase in statural height and the reduction in menarcheal age have come to a deceleration in some populations, the increases are continuing in others (37). The secular trend in menarcheal age has been ascribed to changes in environmental conditions, particularly to better health, modifications in socio-economic status, or nutrition (27, 38, 39). The influence of nutrition is suggested in a recent study indicating a secular trend of earlier onset of menarche with increasing obesity (40). Whether there is a direct causal relationship between increased fatness and earlier menarcheal age remains uncertain (41). Leptin is implicated in the human reproductive system, particularly in initiating puberty (42, 43, 44). The role of leptin in calcium and bone metabolism is still controversial (45) Whether calcium supplementation, given at the onset of pubertal maturation, could influence the hypothalamic-pituitary-gonadal axis by a leptin-dependent or -independent (46) pathway and thereby accelerate the occurrence of menarche deserves to be further investigated.
Menarcheal age and bone mass gain
aBMD gain between 7.9 and 16.4 yr of age was inversely related to menarcheal age at both the axial and appendicular skeletal sites. In agreement with this finding, the absolute values of aBMD measured at 16.4 yr are also significantly greater in girls with early compared with late menarche. The increased gains in mean statural height and bone scanned areas observed at 1 and 3.5 yr after the end of calcium intervention were not present at 16.4 yr. This suggests that an acceleration of pubertal maturation may account for the transient nature of these increased gains. Except for radial sites, the values measured at a mean age of 16.4 yr were at or very close to peak bone mass for the three scanned femoral sites as well as for the lumbar spine. Indeed, the slopes of either femoral or spinal aBMD vs. age were not statistically significant, in agreement with previous studies in adolescent girls from our community in the same age range, i.e. between 15–18 yr of age (47, 48). Our data do not allow us to draw conclusions about the influence of menarcheal age per se on peak bone mass in healthy subjects. Bone mineral mass gain is still substantial within the 2–3 yr following menarche (47, 48). In the foregoing study, the period elapsed between the age of first menstruation and the time of aBMD measurement was less than 2.5 yr for 25% of the subjects. Therefore, the actual influence of menarcheal age on peak bone mass could be overestimated in this adolescent cohort with age ranging from 15–18 yr.
Menarcheal age and lasting response to high calcium intake
The long-lasting effect of calcium supplementation may depend on factors that determine very early on the onset of pubertal maturation and, consequently, the occurrence of the first menstruation, inasmuch as these two phenomena are tightly related. It may imply that the positive effect of calcium, when given during the prepubertal period, might be either maintained or lost after discontinuation of the supplementation according to the factors that determine the setting and physiological tempo of pubertal maturation. Only prospective randomized intervention studies using reliable biochemical markers of the onset of pubertal maturation and with long-term follow-up could assess the validity of this intriguing possibility.
Limitations
From the initial ITT, 13.6 (nine of 67) and 13.0% (10 of 77) of the placebo and Ca-suppl. groups, respectively, did not respond to the invitation to be reexamined 7.5 yr after the end of the intervention. This percentage of participants who were lost to follow-up is relatively small, taking into account the possible psychological and social instability that may occur during adolescence. Furthermore, comparison of the baseline characteristics of the subjects reexamined at 16.4 yr of age showed no difference from those of the initial ITT. The fact that the follow-up observation was not strictly double-blinded can be considered another limitation. However, the initial assignment to the placebo or calcium-enriched foods was double-blinded as was monitoring of the spontaneous calcium intake during intervention. Furthermore, menarcheal age was recorded without any knowledge of the anthropometric and bone variables values on the part of either the investigators or the participants. Our study does not allow us to draw a firm conclusion about the influence of menarcheal age on the lasting effect of calcium supplementation on peak bone mass. In this regard, some inference could be drawn for the values recorded at the level of the proximal femur (femoral neck and trochanter), where the mean t scores of early and late menarche subjects were not different from zero. However, for other skeletal sites, particularly in the forearm, reexamination is required at an age when all subjects will be several years away from the time of menarche. Finally, the possibility that the reported differences in menarcheal age as well as in aBMD gains between the placebo and Ca-suppl. groups stems from some randomization misfortune cannot be obviously excluded. As in any randomized trial, the statistical analysis provides an estimate of the probability that the observed differences between the placebo and Cal-suppl. groups could be observed from chance alone. The fact that in another independent randomized study (25), calcium supplementation was also associated with an earlier onset of menarche strongly suggests that our observation is not merely due to some randomization misfortune.
In conclusion, this 7.5-yr follow-up study in healthy girls from prepuberty to postmenarche suggests an interaction among calcium intake, the determinants of menarcheal age, and bone mineral mass accrual. Increasing the calcium intake in prepubertal girls may accelerate the onset of maturation. Reciprocally, the data suggest that the factors that determine the timing of pubertal maturation influence the lasting response to calcium supplementation. This interaction may pertain to the role of nutrition in the determination of menarcheal age. It can possibly also be relevant to the widely accepted epidemiological idea that late menarche is associated with an increased risk of osteoporosis in adulthood.
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Acknowledgments |
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Footnotes |
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First Published Online October 26, 2004
Abbreviations: aBMD, Areal bone mineral density; ACT, active treatment cohort; Ca-suppl., Ca supplement; ITT, intention to treat cohort.
Received June 2, 2004.
Accepted October 14, 2004.
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