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Measurement of Volumetric Bone Mineral Density Accurately Determines Degree of Lumbar Undermineralization in Children with Growth Hormone Deficiency

Endocrine Unit, Department of Pediatrics, University of Pisa, Pisa, Italy

Address all correspondence and requests for reprints to: Giampiero I. Baroncelli, Endocrine Unit, Department of Pediatrics, University of Pisa, Via Roma 35, Pisa, Italy I-56125.

	Abstract

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The effect of anthropometric variables and bone size on bone mineral density (BMD) was examined in 22 children with GH deficiency (GHD) aged 6.1–8.0 yr at diagnosis and in 40 sex- and chronological age-matched controls. In all patients and controls, bone mineral content (BMC), BMD_area and BMD corrected for the apparent bone volume (BMD_volume) were measured by dual-energy x-ray absorptiometry in the lumbar spine at L2-L4 level. In patients, BMD_area was corrected for body height (BMD_height), body mass index (BMD_BMI), and bone age (BMD_BA). Patients showed significantly reduced (P < 0.0001) BMC (males 11.55 ± 0.71 g, females 10.13 ± 1.48 g) and BMD_area (males 0.502 ± 0.033 g/cm², females 0.515 ± 0.034 g/cm²) compared with controls (BMC: males 18.09 ± 1.23 g, females 15.58 ± 1.87 g; BMD_area: males 0.689 ± 0.065 g/cm², females 0.685 ± 0.059 g/cm²). In patients, BMD_height (males 0.537 ± 0.031 g/cm², females 0.548 ± 0.032 g/cm²) and BMD_BMI (males 0.641 ± 0.028 g/cm², females 0.624 ± 0.035 g/cm²) remained significantly lower (P < 0.02 to P < 0.0001) than BMD_area of controls. BMD_BA of patients was significantly reduced (-1.49 ± 0.51 Z score, P < 0.0001) in comparison with bone age-matched controls (n = 35). BMD_volume was significantly lower (P < 0.01 to P < 0.0005) in patients (males 0.268 ± 0.006 g/cm³, females 0.276 ± 0.010 g/cm³) compared with chronological age-matched controls (males 0.283 ± 0.013 g/cm³, females 0.293 ± 0.017 g/cm³). Mean bone volume of patients was affected to a greater extent than bone area (-2.36 ± 0.49 Z score and -1.56 ± 0.70 Z score, respectively). Bone area/bone volume ratio was significantly higher in patients than in chronological age-matched controls (0.53 ± 0.02 and 0.42 ± 0.08, P < 0.0001, respectively). Chronological age, body height, BMI, and bone age correlated significantly with BMD_area (r² = 0.389–0.450, P < 0.002 to P < 0.001) but not with BMD_volume (P = not significant). The results show that anthropometric variables and bone size affect lumbar BMC and BMD_area in children with GHD. Reduced lumbar BMD_volume indicates that apparent true bone density is decreased in children with GHD, suggesting a role of GH in bone mineralization.

	Introduction

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SOME studies demonstrated that children with GH deficiency (GHD) have reduced bone mineral density (BMD), partly because of delayed bone maturation (1, 2, 3, 4, 5). In growing children, BMD is closely related to age, bone maturation, and anthropometric variables (6, 7, 8, 9, 10). However, because BMD is an areal density (BMD_area) measurement, it is not a measure of true bone density (11, 12). True bone density is a function of bone mineral content (BMC) per volume of bone, that is the volumetric BMD. Volumetric BMD can be assessed only by quantitative computed tomography, but this technique involves high radiation exposure. In children, volumetric BMD is independent of age in lumbar trabecular bone (13) and distal radius (14), suggesting that in growing bones the increase in BMD_area is mainly caused by the increase in bone size. To adjust the values of BMD_area measured by dual-energy x-ray absorptiometry (DEXA) for bone size, mathematical models to calculate the apparent volumetric BMD (BMD_volume) have been proposed assuming the lumbar spine as a cylinder (7) or a cube (15). Lumbar BMD_volume remained significantly correlated with age and anthropometric variables but in a lesser degree than BMD_area (7, 16, 17). After adjustment for age, lumbar BMD_volume was not correlated with height, calcium intake, and physical activity (18).

In this study we assessed lumbar BMC and BMD_area by DEXA measurement in children with GHD at diagnosis and in sex- and age-matched controls. In patients, BMD_area was corrected for body height, body mass index (BMI), and bone age to examine the influence of these anthropometric variables on BMD_area. In addition, BMD_volume was calculated to evaluate the dependency of BMD_area on bone size.

	Materials and Methods

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Patients and controls

Twenty-two caucasian prepubertal children (13 males and 9 females) aged 6.1–8.0 yr with isolated GHD were examined at diagnosis before the start of GH replacement therapy. All patients fulfilled the clinical and diagnostic criteria for GHD: GH peaks less than 10 µg/L after two provocative pharmacological stimuli (levodopa and insulin tolerance test) and/or reduced spontaneous GH secretion for 24 h (mean GH concentrations <3 µg/L) (19). All patients had normal weight and length at birth, had normal renal and liver function, and did not take drugs known to affect bone or mineral metabolism. There was no history of any other chronic illness or bone disease. Karyotype, examined in all girls, was 46,XX. Three patients (2 males and 1 female) had taken part in a previous study investigating the effect of long-term recombinant human GH treatment on BMD_area (5).

Forty healthy caucasian prepubertal children (21 males and 19 females) aged 6.0–8.0 yr were enrolled as sex- and chronological age-matched controls. To have appropriate controls for bone age of patients, 35 healthy caucasian prepubertal children (18 males and 17 females) aged 3.0–6.0 yr were enrolled in the study as sex- and bone age-matched controls. The controls were friends or relatives of the patients, children or friends of hospital staff members, or siblings of patients who attended our hospital outpatient clinic. All controls were healthy with no known medical illness, and did not receive drugs known to affect bone or mineral metabolism.

Anthropometric data in patients and sex- and chronological age-matched controls are reported in Table 1. Dietary calcium intake and physical activity did not differ [P = not significant (NS)] between patients and controls (calcium intake: 871 ± 34 mg/day and 882 ± 37 mg/day, respectively; physical activity: no activity 86.3 ± 2.7% week h and 85.6 ± 2.5% week h, respectively; moderate activity 13.7 ± 2.6% week h and 14.4 ± 2.4% week h, respectively). No patient experienced a history of bone fractures or had vertebral deformities.

In all patients and sex- and chronological age-matched controls BMC, BMD_area, bone area, and bone dimensions (width and height) were detected in the lumbar spine at L2-L4 level. In all patients, BMD_area was corrected for body height (BMD_height) and BMI (BMD_BMI). In both patients and controls, bone volume and BMD_volume were calculated. The values of the parameters of bone mass (BMC, BMD_area, BMD_height, BMD_BMI, and BMD_volume), bone area, bone volume, and bone dimensions of patients were compared with those of controls. In addition, BMD_area of patients was corrected for their bone age (BMD_BA) comparing the BMD_area value with that of sex- and bone age-matched controls.

Informed consent to perform the study was obtained from the parents of each child. The study was approved by the ethics committee for human investigation of our department.

Assessment of anthropometric findings

Standing height was measured with a wall-mounted stadiometer by one of us. To allow a comparison between different ages and genders, height was expressed as Z score with respect to height SD according to the method of Tanner et al. (20) by using the formula: measured individual value-mean normal value for age and gender/SD of normal mean. Bone age was evaluated by using the Greulich and Pyle method (21). BMI was calculated using the formula wt (kg)/height (m²). Dietary calcium intake and physical activity rate were estimated by questionnaires as previously described (22). Physical activities were arbitrarily graded as no activity (e.g. sleeping, eating, studying, watching television, or listening to music) or moderate activity (e.g. walking, cycling, playing) (22). Vertebral deformities were excluded by conventional radiographs.

Assessment of lumbar bone mineral content, areal and volumetric bone mineral density, and bone size

Lumbar BMC (expressed as grams) and BMD_area [BMC corrected by the vertebral surface area scanned, expressed as grams per centimeter squared (g/cm²)] were measured by posteroanterior DEXA (Lunar DPX-L/PED, Lunar Radiation Corp., Madison, WI) in the lumbar spine at L2-L4 level, a site that provides a measure of integral (cortical plus trabecular) bone. In patients, BMD_height and BMD_BMI (expressed as g/cm²) were calculated by using the predicted equation describing the relationship between BMD_area (g/cm²) and body height (centimeters) or BMI in chronological age-matched controls, respectively. BMD_BA was obtained using bone age instead of chronological age to compute the Z score. BMD_volume (expressed as g/cm³) was calculated as BMC per bone volume. The estimation of L2-L4 volume was based on the method proposed by Kroger et al. (7); in this model the lumbar vertebral body was assumed to have a cylindrical shape. The validity of this model was assessed using in vivo volumetric data obtained from magnetic resonance imaging of lumbar vertebrae (23). The bone volume of each vertebral body was calculated as follows: volume = x (diameter/2)² x height, where diameter = width of vertebral body, and height = height of vertebral body. Width, height, and bone area were provided by the DEXA software program. The values of BMC, BMD_area, width, height, and bone area of each subject represented the means of two scans. The results were calculated as Z score by using the same formula we employed to calculate height Z score. The coefficient of precision in vivo was less than 1.0%.

Statistical analysis

The results are expressed as mean ± SD. Comparison of the data was determined with the nonparametric Wilcoxon’s (Mann-Whitney) rank-sum test. Simple and multiple regression analysis were carried out between parameters of bone mass and the anthropometric variables. For multiple regression analysis, independent variables included chronological age, body height, BMI, and bone age. A P < 0.05 was considered significant. All statistical analyses were carried out using the SPSS for Windows software program, version 5.0 (SPSS Inc., Chicago, IL).

	Results

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Anthropometric data in patients and controls

Statural age, height, and BMI of patients were significantly lower than those of chronological age-matched controls (Table 1). The mean value of statural age, bone age/chronological age ratio, and height Z score was similar between male and female patients.

Lumbar bone mineral content, areal and volumetric bone mineral density, and bone size in patients and controls

Mean values of BMC and vertebral width, height, bone area, and bone volume of both male and female patients were significantly lower than those of chronological age-matched controls (Table 2). Expressed as Z score, mean BMC was -3.31 ± 0.60 (-36.0%), mean width -1.30 ± 0.44 (-20%), mean height -2.90 ± 0.79 (-21%), mean bone area -1.56 ± 0.70 (-15%), and mean bone volume -2.36 ± 0.49 (-32%). Bone area/bone volume ratio was significantly higher (P < 0.0001) in patients (0.53 ± 0.02) than in chronological age-matched controls (0.42 ± 0.08), indicating that bone volume of patients was affected in a greater extent than their bone area.

View larger version (9K): [in this window] [in a new window]   Figure 1. Individual values, expressed as g/cm2, of lumbar BMDarea, BMDheight, and BMDBMI in patients (), and lumbar BMDarea in chronological age-matched controls (•). Males and females are represent in left and right panel, respectively. a, P < 0.0001 in comparison with mean BMDarea of controls; b,P < 0.01 in comparison with their mean BMDarea, and P < 0.0001 in comparison with mean BMDarea of controls; c, P < 0.05 in comparison with their mean BMDarea, and P < 0.0001 in comparison with mean BMDarea of controls; d, P < 0.0002 in comparison with their mean BMDarea, and P < 0.01 in comparison with mean BMDarea of controls; e, P < 0.0001 in comparison with their mean BMDarea, and P < 0.02 in comparison with mean BMDarea of controls.

View larger version (13K): [in this window] [in a new window]   Figure 2. Individual values, expressed as g/cm3, of lumbar BMDvolume in male and female patients () and chronological age-matched controls (•). a, P < 0.0005, and b, P < 0.01 in comparison with mean of controls.

Linear regressions between chronological age, body height, BMI, or bone age, and BMD_area or BMD_volume in patients are illustrated in Table 3. BMD_area correlated significantly with chronological age, body height, BMI, and bone age, whereas BMD_volume did not. In patients, BMD_area was significantly correlated with bone area (r² = 0.391, P < 0.005), whereas BMD_volume was neither correlated with bone area (r² = 0.090, P = NS), nor with bone volume (r² = 0.122, P = NS). To determine the relative contributions of the anthropometric variables to BMD_area and BMD_volume, multiple regression analysis was performed. The anthropometric variables were themselves highly intercorrelated (r² = 0.489–0.729, P < 0.0001). The composite interaction of all independent variables was predictive of BMD_area (r² = 0.534, P < 0.005) but not of BMD_volume (r² = 0.181, P = NS). As independent predictor of BMD_area and BMD_volume, no anthropometric variable reached significance.

	Discussion

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Our results confirm that children with GHD have reduced lumbar BMC and BMD_area at diagnosis, and that anthropometric variables and bone size influence BMD_area measurement in children with GHD. We also demonstrated that prepubertal children with GHD have decreased lumbar BMD_volume, suggesting that they have a reduction in apparent true bone density.

Our data indicate that BMD_area removes only in part its dependency on bone size, suggesting that it is not an appropriate parameter to assess bone density in children with growth disorders, because the size of the error may be clinically relevant. Indeed, previous data demonstrated that BMD_area underestimated the apparent true bone density in adolescents (5) and adults (24) with GHD.

Lumbar BMD_area of patients was significantly correlated with chronological and bone ages, body height, and BMI, demonstrating that these anthropometric variables influenced BMD_area in children with GHD as found in healthy children (6, 7, 8, 9, 10). However, none of the anthropometric variables we examined was an independent predictor of BMD_area. Lumbar BMD_height, BMD_BA, and BMD_BMI of patients remained significantly lower in comparison with controls, indicating that short stature, delayed bone maturation, and reduced BMI may account, only in part, for the reduced BMD_area. On the contrary, in healthy children (7, 16, 17), anthropometric variables did not correlate with BMD_volume in children with GHD, suggesting that BMD_volume is a more appropriate parameter to estimate true bone density than BMD_area in these patients. The patients showed a significant reduction in BMD_volume, even though the degree of such a reduction was less than that indicated by measurement of BMD_area. Indeed, as skeletal growth leads to a much greater change in bone volume than in bone area (15), it is possible that growth failure mainly affects bone volume than bone area. The patients showed a percent reduction in bone volume approximately twice that in bone area, and their bone area/bone volume ratio was significantly higher than that of controls. These findings suggest that prepubertal children with GHD have reduced apparent true bone density, and that small vertebral size is a main factor in decreasing lumbar BMD_area. Our results are in agreement with those recently reported by Boot et al. (25) showing reduced lumbar BMD_area and lumbar BMD_volume in children with GHD. On the contrary, Lu et al. (26) showed reduced BMD_area but normal BMD_volume at femoral neck and femoral shaft assuming both regions to have a cylindrical shape. This discrepancy between lumbar and femoral BMD_volume may be caused by the method used to approximate the bone shape to calculate the apparent bone volume of these skeletal sites. In addition, a different bone structure in lumbar spine vertebral body and in femoral neck or femoral shaft may also influence the DEXA-derived BMD_volume. Indeed, in healthy children no relation was found between BMD_volume of femoral shaft and BMD_volume of lumbar spine, and between BMD_volume of femoral neck and BMD_volume of femoral shaft, by DEXA measurement (17). Furthermore, Gilsanz et al. (27) showed no correlation between the density of trabecular bone in the vertebral body and that of cortical bone in the femur in prepubertal healthy children, by quantitative computed tomography.

Although DEXA-derived bone volume was a better parameter to correct BMC than bone area, the mathematical extrapolation of bone volume is a surrogate of the anatomical size, and the resulting values are not directly comparable with values measured with quantitative computed tomography. On the other hand, mathematical models may overestimate bone volume underestimating BMD_volume, because vertebral body has concave superior, inferior, anterior, posterior, and lateral surface (7, 15). In fact, lumbar spine vertebrae body is neither a cylinder (7) nor a cube (15). However, in prepubertal children the overestimation of bone volume is probably smaller than in adolescents and adults, because the concavity of vertebral body affecting the calculation of bone volume is less pronounced (28). Moreover, the volume ratio between intervertebral disc and vertebra affecting the height of lumbar spine vertebrae body may also influence the calculation of bone volume leading to underestimate BMD_volume (7). Anyway, even though DEXA-derived BMD_volume is not a synonymous with true bone density, it can be used for normalization of BMD values in subjects of different body sizes reducing the large biological variation reported in BMD_area measurements mainly caused by the confounding influence of age-related bone geometry changes (7, 15).

In conclusion, our study demonstrates that anthropometric variables influence lumbar BMC and BMD_area but not BMD_volume in prepubertal children with GHD. Decreased bone size is a main factor in reducing lumbar BMD_area. Reduced lumbar BMD_volume indicates that children with GHD have a decreased apparent true bone density supporting a role for GH in bone mineralization. Further studies are needed to define whether true bone density is affected in children with GHD.

Received December 11, 1997.

Revised May 15, 1998.

Accepted May 29, 1998.

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