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Original Studies |
Department of Radiology (M.L.L., V.G.) and Division of Endocrinology and Metabolism (T.F.R., F.R.K.), Children’s Hospital Los Angeles, Los Angeles, California 90027; Department of Biostatistics (J.S.), University of California–Los Angeles, School of Medicine, Los Angeles, California 90027; and Department of Preventive Medicine (M.I.G.), University of Southern California, Los Angeles, California 90033
Address correspondence and requests for reprints to: Vicente Gilsanz, M.D., Ph.D., Children’s Hospital Los Angeles, Department of Radiology, MS #81, 4650 Sunset Boulevard, Los Angeles, California 90027. E-mail: gilsanz{at}hsc.usc.edu
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Abstract |
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Introduction |
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Puberty is the time of life when the greatest acquisition of bone occurs (6, 9). Regardless of gender, bone mass more than doubles during puberty (10). In this study, we used computed tomography (CT) to longitudinally measure the densities of cancellous and cortical bone and the cross-sectional dimensions of bone in the axial and appendicular skeletons of children at each Tanner stage of sexual development from early puberty to sexual maturity. Our aims were to examine whether measures for quantitative phenotypic traits, which contribute to bone mass and bone strength, at sexual maturity can be predicted from values in early puberty and to assess the constancy of a child’s expected measures relative to population percentiles. This knowledge may aid in the early identification of those children who are at risk for osteoporosis and fragility fractures later in life.
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Subjects and Methods |
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The study subjects were healthy white children who were recruited from schools of Los Angeles County. The investigational protocol was approved by the institutional review board for clinical investigations at Children’s Hospital Los Angeles, and informed consent was obtained from all subjects and their parents.
The children and their parents were asked about their medical history. Candidates were excluded if they had been given a diagnosis of chronic illness, had been ill for longer than 2 weeks during the previous 6 months, had taken any medications regularly within the previous 6 months, or had been hospitalized at any time since birth. Eligible candidates underwent a physical examination by a pediatric endocrinologist to determine their stage of sexual development. The grading system of Tanner was used, which includes assessments of the pattern of development of pubic hair in all children and of breast development in girls and penile and testicular size in boys (11). If discrepancies existed among criteria, greater emphasis was placed on the degree of breast development in girls and on testicular and penile size in boys, for determinations of Tanner stage. Only children in early puberty (Tanner stage 2) were enrolled in this study. Measurements of height, weight, and sitting height were obtained, and thereafter body surface area and body mass indices were calculated (12). Skeletal maturation was assessed on the basis of roentgenograms of the left hand and wrist according to the method of Greulich and Pyle (13), and those in whom skeletal age differed from chronological age by more than 1 yr were excluded from further evaluation. On the same day, measurements of bone size and bone density were obtained by CT. Subsequently, participants were given instructions to record their dietary intake over a 3-day period. Using this approach, a total of 50 healthy children (25 girls and 25 boys) were enrolled in this study.
All participants were asked to return every 6 months for a physical examination, and CT bone measurements were repeated at each change in Tanner stage from baseline (Tanner 2) to sexual maturity (Tanner 5). During the course of the study, 10 children were withdrawn [5 due to residence relocation (2 girls and 3 boys), 2 began taking birth control pills, 1 became pregnant, 1 boy was severely injured in an automobile accident, and another was randomly excluded at completion of the study to facilitate stratification of the results into quartiles]. Thus, we longitudinally studied the changes in bone density and bone size in the axial and appendicular skeletons of 20 girls and 20 boys from the beginning of puberty to sexual maturity.
Techniques and definitions of CT measurements
All CT measurements were done with the same scanner (CT-T 9800; General Electric Co., Milwaukee, WI), mineral reference phantom (CT-T bone densitometry package; General Electric Co.), and specially designed software. For determinations in the axial skeleton, the apparent density of cancellous bone and the cross-sectional area were measured at the lumbar vertebrae, and, in the appendicular skeleton, the cross-sectional area, the cortical bone area, and the material density of cortical bone were measured at the midshaft of both femurs, as described previously (14, 15). For this study, the density of cancellous bone was defined as the mean value of the CT unit of measurement (mg/cm3) at the midportion of the first three lumbar vertebral bodies. Because of the relatively small size of the trabeculae when compared with the pixel, CT values for apparent cancellous bone density reflect not only the amount of mineralized bone and osteoid, but also the amount of marrow per pixel (16). These measurements are analogous to in vitro determinations of the volumetric density of trabecular bone, which are obtained by washing the marrow from the pores of a specimen of cancellous bone, weighing it, and dividing the weight by the volume of the specimen, including the pores (17). The density of cortical bone was defined as the amount of bone per pixel (mg/cm3) at the midshaft of the femur. Because of the thickness and the relative lack of porosity of cortical bone in the femur, CT values reflect the material or true density of the bone (the amount of collagen and mineral in a given volume of bone) (14). These measurements are analogous to in vitro determinations of the intrinsic mineral density of bone, which are commonly expressed as the ash weight per unit volume of bone (18).
The coefficients of variation for repeated CT measurements of vertebral
cross-sectional area, cancellous bone density, femoral
cross-sectional area, cortical bone area and cortical bone density
were calculated to be between 0.6% and 2.0% (14, 15). The time
required for the procedure was 
10 min, and the radiation exposure
was 100–200 mrem (1.5 mSv) localized to the midportions of the
first three lumbar vertebrae and the femurs; the effective radiation
dose was 8 mrem (19, 20).
Nutritional analysis
Nutritional information was obtained every 6 months from all subjects until they achieved sexual maturity using written, 3-day records of dietary intake. Each participant and their parent(s) received instructions from a dietetic technician on how to record their food intake. The mean of the three daily determinations was calculated for each nutritional component in all subjects, and the information was entered into a database.
Statistical analysis
Statistical analysis was carried out using SPSS, Inc. for windows (version 7.5; SPSS, Inc., Chicago,
IL) and BMDP (version 7.0; BMDP Statistical Software, Cork, Ireland)
statistical programs. All results are expressed as mean ±
SD. The data were analyzed by ANOVA and multiple linear
regression analysis (21, 22). Differences among quartiles were assessed
by linear trend analysis using a repeated measures model with
unstructured covariance matrix (22, 23). An 
level of 0.05 was
accepted for significance in all statistical procedures.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. As expected, these parameters
increased with advancing sexual development in all children. There were
significant gender differences in the duration of puberty and, on
average, girls took 2.7 ± 0.54 yr whereas boys took 3.2 ±
0.71 yr to reach sexual maturity from Tanner stage 2 (P
= 0.007). Moreover, girls were slightly younger than boys at all Tanner
stages of sexual development.
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and 3 show the mean values for the 3-day
dietary intake records of the children. No significant changes in
nutritional intake were observed with advancing Tanner stage in girls
or boys. Calcium intake was higher in boys than in girls throughout the
study; on average, 966 ± 379 mg/day vs. 710 ±
238 mg/day, respectively. These gender differences were significant at
Tanner 4 (P = 0.017) and when dietary calcium at all
Tanner stages was used as a vector of observation; Hotelling’s
T2 test (P < 0.003). No
significant correlations were found between caloric intake and CT
values for any of the bone traits. Additionally, there were no
correlations between calcium intake and increases in CT values of the
cross-sectional dimensions of the vertebrae or the femurs, the density
of cancellous bone in the vertebrae, or the density of cortical bone in
the femurs in either boys or girls; all correlation coefficients
are between -0.18 and 0.14.
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Significant increases in values for all skeletal phenotypes were
observed with each advancing Tanner stage of sexual development in all
children. There was, however, no association between the timing (the
age at Tanner 2) or the duration (the difference in age between Tanner
5 and Tanner 2) of puberty and peak values for any of the CT bone
measurements.
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Overall, values for the vertebral cross-sectional area in all children were positively correlated with the area of cortical bone and the cross-sectional area of the femurs; this was true when all Tanner stages were considered together or when each Tanner stage was evaluated separately (all correlation coefficients were between 0.52 and 0.68). However, no correlation was found between the material density of cortical bone in the femurs and the apparent density of cancellous bone in the vertebral bodies. Values for cortical bone density were eight times higher than those for cancellous bone density, a finding consistent with histomorphometric studies, indicating an equivalent difference in the porosity of these two types of bone (24).
Although there were no gender differences in values for cancellous or cortical bone density, there were substantial differences in cross-sectional bone growth between boys and girls. Moreover, gender had a differential effect on cross-sectional bone growth in the axial and appendicular skeletons. At commencement of the study, boys had significantly greater vertebral cross-sectional area than girls (23%; P = 0.001), but not significantly greater femoral cross-sectional or cortical bone area. At completion, gender differences in the appendicular skeleton had increased and boys had significantly greater femoral cross-sectional dimensions than girls (18% and 17% for the cross-sectional and cortical bone areas, respectively; both, P < 0.0001). However, multiple regression analysis indicated that the greater increases in the cross-sectional growth of the femurs in boys were related to simultaneous greater gains in height and body weight. In contrast, gender differences in vertebral cross-sectional area persisted even after accounting for the confounding effects of body size.
Figures 1-4, panel a, shows values for
vertebral cross-sectional area, vertebral cancellous bone density,
femoral cross-sectional area, and femoral cortical bone area of each
boy and girl at the different Tanner stages. There were strong
correlations between the values for each bone trait at the different
Tanner stages in all subjects, and measurements in early puberty
accounted for 62–92% of the variations seen at sexual maturity (Table 5). Based on the initial CT measurements
in both boys and girls, values for vertebral and femoral
cross-sectional area, femoral cortical area, and the density of
cancellous bone were independently stratified into quartiles; each
quartile represented the mean value for five measurements. Linear trend
analyses using a repeated measures model with unstructured covariance
matrix revealed a linear regression across the Tanner stages at each
baseline quartile for each of these traits. Moreover, regardless of
gender, the regression lines across Tanner stages for each phenotype
differed among quartiles and did not overlap (
Figs. 1–4,
panel b). In contrast, values for femoral cortical bone density at the
beginning of puberty did not predict those at sexual maturity and the
linear regressions for the different quartiles intersected and were not
parallel (Fig. 5).
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Discussion |
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In contrast to the other bone phenotypes studied, there was no correlation between CT values for the material density of bone at early puberty and values at sexual maturity in either boys or girls. We found, however, small, but significant, increases in the density of cortical bone at the midshaft of the femur in both boys and girls from Tanner stage 2 to Tanner stage 5, on average, by about 3%. Unfortunately, it remains unclear whether the gains in bone density were due to an increase in mineralization or a decrease in porosity, because the limited resolution of CT scanners cannot correct for inaccuracies related to the number and diameter of the Haversian canals. It should be noted that the findings in the present study conflict with our previously published reports, suggesting that the material density of cortical bone remains constant throughout childhood and is not influenced by puberty (14, 25). This discrepancy is likely the reflection of the cross-sectional nature of the previous investigations and the rather small gains in CT values for cortical bone density that occur during puberty.
Several investigators have proposed that during puberty there is a physiologic and temporary decrease in the material density of bone. The contention is that during puberty there is either an increase in unmineralized osteoid as bone formation outstrips mineral deposition or an increase in bone porosity associated with the greater bone remodeling rate of the growing skeleton (26, 27). This notion of a transient growth-related reduction in bone density is commonly used to explain the large number of fractures sustained during adolescence (26, 27). However, our results do not support this hypothesis because the material density of bone increases, rather than decreases, during puberty. On the other hand, our findings are in accordance with a previous longitudinal study using dual-energy x-ray absorptiometry that showed parallel increases in standing height and bone mass at the midshaft of the femur in girls during puberty (28).
In the axial skeleton, cancellous bone density in the vertebrae increased during puberty, a finding that corroborates previous cross-sectional data (4, 29). Regardless of gender, CT values for cancellous bone density increased with Tanner stage of sexual development, and values at sexual maturity were, overall, 18% higher than at the beginning of puberty. We found no relation between the ages of the subjects at commencement of the study or the duration of puberty and CT values for cancellous bone density at sexual maturity. Due to technical limitations, we were unable to define whether the increases in CT values for cancellous bone density during puberty were a reflection of an increase in the degree of mineralization of the trabeculae, the number of trabeculae, or, as several investigators have suggested, the thickness of the trabeculae (16, 30).
Our findings complement existing evidence indicating that girls and boys have identical cancellous and cortical bone density, emphasizing that gender differences in bone mass in children are due to variations in bone size (15, 31, 32, 33). In the axial skeleton, gender differences in vertebral cross-sectional area were present at baseline, increased throughout puberty, and persisted even after accounting for differences in body mass. In contrast, there were no significant differences in femoral cross-sectional dimensions between boys and girls at baseline, but gender differences became apparent and increased during puberty. Multiple regression analysis revealed that the greater gains in femoral cross-sectional growth of boys were related to simultaneous greater gains in height and body weight. The results of the current study corroborate previous studies indicating that, although femoral cross-sectional bone acquisition is primarily driven by mechanical load related to increasing body mass, vertebral cross-sectional growth is not only associated with increasing body mass, but is also strongly influenced by gender (34, 35).
Nutritional analyses revealed that dietary calcium intake did not correlate with baseline values or changes in any of the skeletal phenotypes in girls, in boys, or when all children were considered together. However, the relatively small number of subjects studied and the inherent limitations associated with food questionnaires make comparisons among studies relating nutrition to bone accretion during growth prone to inaccuracy. Previous studies have yielded conflicting results. Whereas some found that persons who consume large quantities of calcium early in life have greater bone mass later in adulthood (36), others show no beneficial effect of dietary calcium supplementation on bone accretion during puberty (10, 37).
Because of difficulties in longitudinally studying subjects from childhood to an elderly age, the contention that senile osteoporosis is the result of inadequate bone acquisition during growth remains unproven. This notion is supported, however, by recent data showing that there is a strong resemblance between mother-daughter bone traits and that this resemblance is present even before the daughters have begun puberty (1, 38). Additional support for this concept comes from the knowledge that genes associated with the normal variations in bone mass in elderly women are also related to variations in bone density in children (2, 3, 39). If bone loss was the exclusive determinant of late life bone mass, one would not expect such a strong resemblance in bone traits between girls and their mothers or an association between candidate genes and bone mass to be depicted in childhood. Our results, and data from other investigations showing strong correlations between yearly bone mass measurements in prepubertal girls, suggest that bone traits can be tracked during growth (1). Thus, the genetic control of bone phenotypes associated with fragility fractures in the elderly is expressed very early in life and is tightly maintained throughout childhood and adolescence.
In conclusion, the findings of this study indicate that values for the apparent density of cancellous bone and the cross-sectional dimensions of bone in the axial and appendicular skeletons at early puberty predict values at sexual maturity. Whereas our results suggest that the genetic susceptibility for osteoporosis is present very early in life, they do not preclude the notion that tracking for bone traits can be altered by changing environmental factors. Rather, they suggest that osteoporosis prevention trials should start in early childhood and should be geared toward those children who have the highest risk for developing osteoporosis and fragility fractures later in life. Additional studies are needed to establish whether tracking for quantitative bone traits associated with weaker bones can be altered and/or whether baseline values in early puberty will change percentiles by sexual maturity as a result of simple nutritional, mechanical, or pharmocological intervention.
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Acknowledgments |
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Footnotes |
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Received March 2, 2000.
Revised June 27, 2000.
Accepted July 11, 2000.
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