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Original Studies |
Departments of Radiology (V.G., A.K., M.L.L.), Orthopedics (D.L.S.), and Pediatrics (F.K.), Childrens Hospital Los Angeles, Los Angeles, California 90027; Departments of Endocrinology (S.G.K.) and Biostatistics (J.S.), University of California School of Medicine, Los Angeles, California 90024
Address all correspondence and requests for reprints to: Vicente Gilsanz, M.D., Ph.D., Childrens 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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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Various factors may account for the discrepancy between the results of previous studies, including technical limitations of measurement modalities and failure to appropriately match subjects. In children, bone measurements by absorptiometry methods are greatly influenced by the size of the growing skeleton, as they are unable to assess the size and the density of bone separately (14, 15). Moreover, previous comparisons of bone mass between black and white children did not take into account racial differences in upper and lower body segment lengths. Black children have longer legs and shorter trunks than white children, and failure to adjust for these differences may have led to inaccurate results (16, 17). Lastly, as puberty is a major determinant of bone gain during growth, the lack of precise matching of sexual maturation could explain significant differences between previous results.
Quantitative computed tomography (CT) allows for accurate measurements of the size and the density of bone in the axial and appendicular skeletons (14). In this study, we used quantitative CT to investigate whether there are differences in the size or the density of cancellous bone in the vertebrae and/or in the size or the density of cortical bone in the femur between black and white children at different stages of sexual development.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study subjects were healthy black and 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 this facility, and informed consent was obtained from all subjects and/or their parents. The subjects ranged in age from 8–18 yr.
The children and/or their parents were asked about their racial and ethnic backgrounds. Candidates were excluded if either of their parents or either set of grandparents was not of the same race. Candidates for the study were also excluded if they had been given a diagnosis of chronic illness; if they had been ill for longer than 2 weeks during the previous 6 months; if they had taken any medications, vitamin preparations, or calcium supplements regularly within the previous 6 months; or if they had been hospitalized at any time since birth. All subjects were appropriately physically active for their age.
Candidates underwent a physical examination by a pediatric endocrinologist to determine the 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, of breast development in girls, and of penile and testicular size in boys (16). If discrepancies existed among criteria, greater emphasis was placed on the degree of breast development and on testicular and penile size for determinations of Tanner stage.
Measurements of height, weight, and sitting height were obtained. Children in whom either height or weight was not within the 5th and 95th percentiles for the mean age-adjusted normal values for white children were excluded from further evaluation (18). Thereafter, body surface area and body mass index were calculated as previously described (19). Skeletal maturation was assessed on the basis of roentgenograms of the left hand and wrist according to the method of Greulich and Pyle (20). On the same day, measurements of bone size and bone density were obtained by CT.
Black and white children were matched by chronological age, gender, Tanner stage, height, and weight to control for these important determinants of bone mass. Because of the smaller number of black subjects available, white subjects were evaluated and enrolled in the study before their black counterparts. Thereafter, black subjects were identified, evaluated, and matched with white subjects who had been studied within the previous 3 months. For this analysis, the ages of each pair of subjects differed by less than 6 months, and neither height nor weight differed by more than 5%. Using this approach, we studied 80 unique matched pairs of children: 40 pairs of girls and 40 pairs of boys.
Determination of sample size was based on data from our previous studies demonstrating a mean difference in the vertebral bone density of 37 mg/cm3 with a SD of 20 mg/cm3 between black and white girls at the end of puberty (21). Using a paired t test and a 0.05 level of significance, a power of 0.99 was achieved for a sample size of eight subjects in each racial group.
Techniques and definitions of CT measurements
All CT measurements were made with the same scanner (CT-T 9800, General Electric Co., Milwaukee, WI) and mineral reference phantom (CT-T bone densitometry package, General Electric). 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 the femur, as previously described (22, 23).
For this study, the density of cancellous bone was defined as the mean value of the CT unit of measurement (milligrams per cm3) at the midportion of the first three lumbar vertebral bodies. Because of the relatively small size of the trabeculae 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 (14). 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 (24).
The density of cortical bone was defined as the amount of bone per pixel (milligrams per 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) (22). 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 (25).
In addition, to assess for possible differences in the lengths of the axial and appendicular skeletons, measurements of the heights of the vertebrae and the length of the femur were obtained. Vertebral height was calculated as the mean of the heights of the anterior, middle, and posterior portions of the first three lumbar vertebrae (centimeters), and the length of the femur was calculated as the distance between the acetabular roof and the distal lateral femoral condyle (centimeters).
The coefficients of variation for repeated CT measurements of vertebral cross-sectional area, cancellous bone density, femoral cross-sectional area, cortical bone area, cortical bone density, vertebral heights, and femoral lengths were between 0.6–2.5% (22, 23). The time required for the procedure was approximately 10 min, and the radiation exposure was approximately 100–200 mrem (1.5 mSv) localized to the midportions of the first three lumbar vertebrae and the femurs; the effective radiation dose was approximately 8 mrem (26, 27).
Biochemical assessment
After an overnight fast, blood was taken for determinations of calciotropic hormones, markers of bone turnover, and levels of GH and sex steroids. Levels of intact PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D (calcitriol), alkaline phosphatase, bone-specific alkaline phosphatase, calcitonin, insulin-like growth factor I, GH, and osteocalcin in the serum and the urinry excretion of pyridinoline and deoxypyridinoline were measured by Corning Nichols Institute (San Juan Capistrano, CA). Total testosterone, bioavailable testosterone, estradiol, dehydroepiandrosterone sulfate, sex hormone-binding globulin, and androstenedione were determined in the laboratory of Dr. S. Korenman, Division of Endocrinology, University of California-Los Angeles.
Nutritional analysis
Nutritional information was obtained from all subjects using written 3-day records of dietary intake. After receiving instructions from a dietetic technician, subjects recorded their food intake over a 3-day period. The mean of the three daily determinations was calculated for each nutritional component in all subjects, and the information was entered into a computerized database.
Statistical analysis
All results are expressed as the mean ± SD. The data were analyzed using Student’s t test for paired samples, ANOVA, and linear regression analysis (28, 29). A significance level of P < 0.05 was used for all comparisons. All tests were two-sided, and P < 0.05 indicated statistical significance for a power of 80%.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The anthropometric characteristics of the 160 children studied are
shown in Table 1
. By design, average
values for age, height, weight, body surface area, and body mass index
were similar for black and white children. Skeletal age also did not
differ between black and white children at any stage of sexual
development (Table 1). However, there were significant racial
differences in the lengths of the trunks and the legs. Sitting heights
were greater in white than in black children at all Tanner stages.
These differences were statistically significant when all subjects of
the same gender were considered together, (P < 0.01
and P < 0.001 for girls and boys, respectively) and at
Tanner stage I in girls (P = 0.01) and Tanner stage V
in boys (P = 0.03). Concordantly, the leg
length/sitting height ratio was significantly greater in black boys and
girls (Table 1).
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). Weak
positive correlations (r) were found between caloric intake and all
anthropometric variables, including CT measurements of vertebral and
femoral size (r = 0.11–0.34) in both girls and boys. There were,
however, no correlations between any of the nutritional variables and
the density of cancellous or cortical bone in girls, in boys, or when
all children were considered together.
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). When all children were considered
together, weak correlations were found between the cross-sectional
areas of the vertebrae and the cross-sectional and cortical bone areas
of the femurs and values for insulin-like growth factor I (r =
0.19–0.34). There was no significant relationship between any of the
biochemical measurements and CT measurements of cancellous or cortical
bone density.
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). Total testosterone, bioavailable
testosterone, dehydroepiandrosterone sulfate, androstenedione, and
estradiol levels increased with pubertal status, whereas sex
hormone-binding globulin levels decreased. These biochemical
indexes also correlated with age and anthropometric parameters,
including CT measurements of bone size in the axial and appendicular
skeletons. Variations in the material density of cortical bone were not
accounted for by differences in any of the sex steroids measured
(r = -0.09 to 0.19). After adjusting for Tanner stage, there were
also no correlations between apparent cancellous bone density and sex
hormone levels. CT measurements
Table 4 shows CT values for
vertebral heights and vertebral cross-sectional areas in black and
white children at different Tanner stages. The heights of the vertebral
bodies were significantly greater in white girls than in black girls at
Tanner stage II (P = 0.02), in white boys than in black
boys at Tanner stages II and IV (for both, P = 0.02),
and when all Tanner stages were considered together (P
= 0.003). There were, however, no significant differences in the
cross-sectional areas of the vertebral bodies of black and white
children at any Tanner stage or when all Tanner stages were considered
together.
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shows the mean values for
apparent cancellous bone density in black and white children at
different Tanner stages. Both pubertal status and race influenced
cancellous bone density in the vertebrae. The mean density of
cancellous bone did not differ among subjects in Tanner stage I, II, or
III in either racial group, but increased linearly in all children from
Tanner stages III-V. This increase during the final stages of puberty
was substantially greater in black than in white children. At Tanner
stage V, the mean vertebral bone density was 9.8% higher in black
girls and 11.7% higher in black boys than that in their matched white
counterparts. A linear fit over Tanner stages III, IV, and V yielded
significant differences (P = 0.004) between black
(101.83 + 18.66 x Tanner stage; standard error of the estimate =
22.14) and white (128.78 + 8.74 x Tanner stage; standard error of
the estimate = 19.79) children.
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). On
the average, the values for material cortical bone density were 8 times
higher than those for apparent cancellous bone density.
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shows the mean CT
values for femoral length and for the cross-sectional and cortical bone
areas at the midshaft of the femurs in black and white children at
different Tanner stages. There were significant racial differences in
the lengths of the femurs, regardless of gender. Overall, black
children had longer femurs than their matched white counterparts
(P = 0.002 and P = 0.0001 for girls and
boys, respectively). These racial differences were also present at
Tanner stage V in girls (P = 0.04) and at Tanner stages
I, III, and V in boys (P = 0.009–0.02).
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In contrast to the findings for femoral length and cross-sectional
area, CT values for cortical bone area at the midshaft of the femur
were similar in black and white children regardless of the level of
sexual development (Table 5). Body weight and height were the primary
determinants of the area of cortical bone at the midshaft of the femur
regardless of race or gender. A multiple regression model accounting
for chronological age, skeletal age, Tanner stage, sitting height,
surface area, and body mass index in addition to weight and height did
not substantially improve the predictive power of a model accounting
for weight and height alone.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our findings in the axial skeleton using quantitative CT compliment existing evidence showing that in girls, cancellous bone density in the vertebrae increases in the late stages of puberty, regardless of race, and that the magnitude of this increase is greater in black girls (21, 31). The results of this study also demonstrate similar patterns of increase in cancellous bone density in boys. Because of the limited resolution of CT scanners, we were unable to determine whether the differences in CT values in cancellous bone density during the later stages of puberty were a reflection of a greater increase in the number, the thickness, or the degree of mineralization of the trabeculae (14). Recent histomorphometric observations in adults would suggest however, that the structural basis for the higher cancellous bone density in blacks compared to whites is due to greater trabecular thickness (32).
In vitro studies indicate that the compressive strength of the vertebrae is mainly determined by the density of cancellous bone and its cross-sectional area (33, 34, 35). Although race influenced vertebral bone density, we found that values for cross-sectional area of the vertebral bodies were similar in black and white children at all stages of sexual development. Thus, our results suggest that racial differences in vertebral bone strength and the incidence of fractures in the axial skeleton of older subjects are a manifestation of early racial differences in the density of vertebral bone rather than in the size of the vertebrae.
In the appendicular skeleton, CT values for material density of cortical bone in black and white children were remarkably similar and constant. Neither race, pubertal status, age, gender, height, nor weight influenced these measurements. These data contradict the common belief that during the adolescent growth spurt, bone formation transiently outstrips mineral deposition, and there is a temporary decrease in bone density (36). It should be stressed that due to the thickness and the relative lack of porosity of the femoral cortex, CT values for cortical bone density reflect the true density of the bone and the amount of collagen and mineral in a given amount of bone (22). Values for cortical bone density in this study were 8 times higher than cancellous bone density values, a finding consistent with histomorphometric studies, indicating an equivalent difference in the porosities of these two forms of bone (37).
In contrast to the findings in the axial skeleton, race influenced the cross-sectional area of the bones in the appendicular skeleton. Although values for femoral cross-sectional area increased with height, weight, and other anthropometric parameters in all children, this measurement was substantially greater in black children. On the average, the cross-sectional area was 3% and 8.4% greater in black girls and boys, respectively. We were not able to define the exact time when these racial differences first appeared, as only small, nonsignificant differences were seen in prepubertal children. Studies with larger samples sizes will be needed to determine whether there are any racial differences in the cross-sectional area of the bones in the appendicular skeleton before puberty.
Although race had significant effects on femoral length and cross-sectional area, CT values for cortical bone area at the midshaft of the femur were similar in black and white children regardless of the level of sexual development. Previous comparative studies of cortical bone in the appendicular skeleton using radiogrammetry have yielded conflicting results. Although the long bones in black subjects were consistently shown to have greater diaphyseal width than those in white subjects, some investigators found their cortex to be thicker, whereas others reported it to be thinner (7, 38, 39). Using CT, we found greater cross-sectional area and similar cortical bone area in black children compared to white children, which would manifest as reduced cortical thickness in a two-dimensional representation. Because the same amount of cortical bone placed further from the center of the bone results in a bone of greater strength (40), the structural basis for the advantage of blacks in the appendicular skeleton is probably the consequence of the greater cross-sectional size of their long bones.
The mechanisms by which race has a differential effect on the size of the bones in the axial and appendicular skeletons are unknown. It should be stressed, however, that the growth of the femur and that of the vertebrae result from two different processes that are probably regulated by different means. In the femur, growth in bone length occurs by endochondral bone formation at the growth plates, whereas increases in bone width occur by apposition of subperiosteal bone. In the vertebrae, growth occurs by endochondral ossification, which commences in the central area of the cartilage anlage and expands toward the periphery in all directions. Previous observations during the treatment of children with hypopituitarism suggest that longitudinal growth in the axial skeleton, indicated by sitting height, is relatively more dependent on sex hormones, whereas growth in the appendicular skeleton, indicated by the difference between standing and sitting heights, is primarily under the control of GH (41). However, in this study, we found no significant differences in the serum levels of GH, growth factors, or sex steroids between black and white children that would explain the discrepant effect of race on vertebral and femoral size. Moreover, as racial differences in femoral length and vertebral height were present even in subjects with similar cross-sectional areas, it is unlikely that the length and the width of the bones are under the same controls.
The factors responsible for the rapid increase and racial differences in cancellous bone density that occur during puberty are also unknown. It should be noted that after adjusting for Tanner stage, there were no correlations between sex steroid levels and values for cancellous bone density. Regardless of the mechanisms, it is commonly thought that the greater accumulation of bone in black subjects is due to better renal calcium handling (shown by lower urinary calcium excretion in blacks) (42, 43, 44) and skeletal resistance to bone resorption by PTH (42, 45) (shown by lower serum levels of osteocalcin, bone-specific alkaline phosphatase, and urinary hydroxyproline). In addition, relatively higher PTH levels may promote optimal renal hydroxylation of 25-hydroxyvitamin D and, hence, maintain normal levels of 1,25-dihydroxyvitamin D and adequate intestinal calcium absorption. However, several studies in adults and the current study in children found no significant differences in the serum levels of calcium-regulating hormones and bone turnover markers between black and white subjects (46, 47).
In summary, the structural basis for the racial influences on bone growth differs in axial and appendicular skeletons. In the axial skeleton, these differences are based on greater cancellous bone density, whereas in the appendicular skeleton, they are founded on greater bone size. As skeletal mass in adulthood is the result at least in part of the amount of bone gained during growth, the skeletal advantages of black children described herein are likely to be important determinants of the greater skeletal resistance to fractures later in life.
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Acknowledgments |
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Footnotes |
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Received November 26, 1997.
Revised January 12, 1998.
Accepted January 15, 1998.
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References |
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, P = 0.007.