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Institute of Endocrinology and Diabetes (W.H., B.M., S.G., P.W.L., C.T.C.) and Department of Nuclear Medicine (J.B.), The Children’s Hospital at Westmead, NSW 2145 Sydney, Australia; and Department of Pediatrics and Adolescent Medicine (W.H.), University of Innsbruck, 6020 Innsbruck, Austria
Address all correspondence and requests for reprints to: Wolfgang Högler, M.D., Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Sydney, Australia. E-mail: wolfgang.hoegler{at}uibk.ac.at.
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Abstract |
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Age z-scores for height, TB BMC, LTM, the BMC/LTM ratio, and LS volumetric bone mineral density (vBMD) decreased significantly (P < 0.001) with age in prepubertal subjects (n = 51) but were constant in the combined pubertal and postmenarchal group (n = 32). Osteopenia was found in 14.5% (TB), 15.8% (LS), and 28.4% (FN) of patients. In the longitudinal subgroup, TB BMC z-scores decreased by -0.28 (0.31) in subjects remaining prepubertal (n = 11) but increased by 0.71 (0.56) in subjects entering puberty (n = 6; P = 0.007). The z-scores for height and LTM increased in both groups.
Our results show a height-independent prepubertal decrease in bone mass accrual, which ceased with puberty. Optimizing bone mass in TS may require earlier induction of puberty than currently recommended. However, reduced FN volumetric bone mineral density and a dissociation of bone and muscle measures were age independent, suggesting an additional intrinsic bone defect.
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Introduction |
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The two-dimensional assessment of areal BMD (grams per centimeter squared) using dual-energy x-ray absorptiometry (DXA) can cause misclassification of individuals with short stature, as in TS, as osteopenic (16). In awareness of this technical limitation, most studies of children, adolescents, and young adults with TS did not detect significant osteopenia when (areal) total body (TB) BMD results were corrected for body size (8, 14, 17). Regional scans in young women with TS have shown normal vBMD (grams per centimeter cubed) at the phalanges using radiographic absorptiometry (12) and at the lumbar spine (LS) using DXA (18) and normal trabecular vBMD at the radius using peripheral quantitative computer tomography (pQCT) (19). In prepubertal girls with TS, however, trabecular LS vBMD was reduced using QCT (20).
Muscle mass and strength are significant contributors to bone strength and health (21, 22). Using pQCT, cortical size and bone mineral content (BMC) were reduced in relation to muscle size at the radius in 21 patients with TS (19). No study has investigated the muscle-bone relation in TS in a large sample, or longitudinally, so far.
The main purposes of the present study were 1) to identify the effect of puberty on bone and muscle mass in a cross-sectional and longitudinal cohort, 2) to examine TB and regional bone scans for the presence of osteopenia in children and adolescents with TS by applying size corrections to the areal DXA output, and 3) to examine the muscle-bone relation at the TB level.
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Subjects and Methods |
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The study population comprised 83 subjects with TS aged 4–24 yr with a mean (SD) age of 12.76 (4.4) yr. At the time of bone densitometry, subjects were prepubertal (n = 51), pubertal [pubertal stage 2 to menarche (n = 16)], or postmenarchal (n = 16). Ten patients of the pubertal group and three of the postmenarchal group had entered puberty spontaneously. In the postmenarchal subjects, bone densitometry was performed a mean (SD) 2.78 (3.18) yr after menarche, which had occurred at age 16.34 (2.24).
The common treatment regimen for pubertal induction in our hospital is either with ß-estradiol or conjugated estrogens, based on standard recommendations (23). This regimen is usually started at 14 yr of age but necessarily has to be individualized. At the time of measurement, 42 patients were on GH treatment with a standard dose of 9 mg/m2·wk to improve short stature. Seven of the 16 postmenarchal patients had never received GH. Eleven patients were additionally on treatment with Oxandrolone.
Karyotype was either 45 XO (n = 33) or showed a structurally abnormal X chromosome or various forms of mosaicism (n = 50), all with clear Turner phenotype. The chromosomal mosaic of five patients included 45XO/46XY cell lines without clinical signs of sexual ambiguity or virilization. All subjects were patients at The Children’s Hospital at Westmead.
A subgroup of 17 prepubertal patients starting GH treatment, aged 9.55 (3.12) yr, was studied longitudinally over a period of 2 yr. Their height z-score (SD score) was -2.74 (0.95), the weight z-score was -0.77 (1.18), and their bone age was 9.37 (2.2) yr. Bone densitometry, anthropometry, bone age, and pubertal stages were assessed before the commencement of GH (baseline) and after 6, 12, and 24 months of GH treatment at a dose of 7.83 (1.83) mg/m2·wk. This lower dose, in comparison with the higher doses currently recommended, was used as this longitudinal study was performed in the early 1990s, when no official guidelines were available. The patients were seen at 3-monthly intervals for clinical assessment. Adjustment of GH dose occurred every 6 months. Interestingly, five patients developed spontaneous puberty during the 2-yr study period, resulting in spontaneous menarche in all of them after the study ended. Puberty was induced in another 13-yr-old patient. One patient dropped out of the study after 18 months. The Institutional Ethics Committee approved both studies, and informed consent was obtained from all subjects and families.
Methods
Height was measured with a Harpenden stadiometer to the nearest 1 mm and weight with an electronic scale to the nearest 20 g on the day of the DXA scan. Height and weight z-scores (SD scores) were calculated according to sex and age (24). For subjects over 18 yr, height and weight z-scores were calculated as for an 18-yr-old. Sex-specific body mass index (BMI in kilograms per meter squared) z-scores for age were calculated from data derived from Cronk and Roche (25). Classification of subjects into normal weight, overweight, and obesity based on BMI was derived from Cole et al. (26). Pubertal stages were assessed according to Tanner (27).
A pencil beam DPX (Lunar Corp., Madison, WI) TB scanner with adult software (version 3.4) was used to perform DXA measurements on all subjects. Analysis was done with software version 4.7 by a single technician. The technique and measurement protocol, including quality-assurance testing, has been described previously (28, 29). In brief, the coefficients of variation for TB BMC, lean mass (LTM), and percent fat mass were 0.74, 0.82, and 1.59%, respectively. TB measurements were compared with our normative dataset of 249 healthy females aged 3–30 yr and analyzed according to a four-step procedure recently published (30). This procedure first involves comparison of z-scores for BMC and height to account for the strong body-size relation of DXA output and then examines the muscle-bone relation using z-scores for LTM and the BMC/LTM ratio. We slightly modified the procedure in this study by exclusively reporting age z-scores for DXA measures. Using height z-scores in subjects with short stature, particularly after puberty, can lead to undesired comparisons with much younger, prepubertal control subjects.
vBMD was derived from LS (L1-L4) and femoral neck (FN) scans performed on the same DPX. For comparison reasons, we used our normative database on females (3–30 yr) for the LS (n = 180) and the FN scans (n = 210), which is an expanded and updated version of the dataset previously published (29). Results for DXA variables are reported as age z-scores and as raw data.
Statistics
Data were analyzed using the Statistical Package for Social Sciences version 10.0 (SPSS Inc., Chicago, IL). Subject groups, corresponding to prepuberty, puberty, and post menarche were derived from the cross-sectional data set. Differences between the three groups were assessed by one-way ANOVA. Linear regression analysis was used to assess the age relationship of z-scores for the prepubertal group and the combined pubertal and postmenarchal group. We used t tests to assess differences between groups according to GH therapy and oxandrolone status, spontaneous vs. induced puberty, and between karyotypes 45XO and mosaicism. In the longitudinal subgroup, the change in anthropometric and densitometric variables over the 24-month study period was calculated. The difference in this change between subjects entering puberty and subjects remaining prepubertal was assessed by the Mann-Whitney U test. Data are presented as means (SD), and P < 0.05 were considered significant.
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Results |
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Population characteristics.
Table 1
shows the characteristics of the study population. There were no significant differences in z-scores for weight (P = 0.46), height (P = 0.17), or BMI (P = 0.16) between the prepuberal, pubertal, and postmenarchal groups. Percent fat increased significantly throughout the pubertal groups (P < 0.001). The percentage of subjects classified as overweight or obese was 27.5% in prepuberty, 37.5% in puberty, and 56% in the postmenarchal group (P = 0.11, Pearson 
2).
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shows the TB DXA results of prepubertal, pubertal, and postmenarchal subjects. BMC z-scores did not differ between pubertal groups, but LTM z-scores significantly decreased from the prepubertal to the pubertal period (P = 0.018). In prepubertal subjects, z-scores for BMC (r = -0.61), height (r = -0.44), LTM (r = -0.66), and the BMC/LTM ratio (r = -0.49) were inversely related to age (P < 0.001). After the onset of puberty, no significant relation with age was observed for any of these z-scores (Fig. 1, A–D). There was a strong relation between the z-scores for TB BMC and height (r = 0.66; P < 0.001), reflecting the dependence of DXA variables on body size. To adjust for body size, TB BMC z-scores predicted for height z-score were calculated based on our normative dataset. During the extended prepubertal period, BMC z-scores decreased compared with the predicted value for height z-score (r = -0.67; P < 0.001) but did not significantly change in the combined pubertal and postpubertal group (Fig. 2, regression line not shown). Osteopenia, defined as an observed TB BMC z-score >1.5 SD lower than predicted for height z-score was observed in 12 of 83 subjects (14.5%). These 12 subjects had a mean age of 14.60 (1.44) yr, and eight were prepubertal. Five subjects (6%) had values <–2 SD.
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). The prepubertal decrease in the BMC/LTM ratio z-score shows a gradual dissociation of the usually close relation between BMC and LTM.
Volumetric BMD.
Mean vBMD z-scores were not different between the three pubertal groups at the LS (P = 0.34) and the FN (P = 0.12) (Table 2). LS vBMD z-scores of prepubertal subjects decreased significantly with age (r = -0.61; P < 0.001) but were constant thereafter. This trend was not observed at the FN (Fig. 3). Osteopenia, defined as vBMD z-scores of <–1.5, was found in 12 of 76 subjects (15.8%) at the LS and in 21 of 74 subjects (28.4%) at the FN.
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Longitudinal study
Baseline characteristics of all prepubertal subjects and the 2-yr change in DXA variables are given in Table 3. Due to the quite unexpected development of spontaneous puberty in five subjects and the pubertal induction in another patient during the study period, we were able to study the effect of puberty. The increase in height over 2 yr was 13.93 (2.51) and 15.03 (3.20) cm in the prepubertal (n = 11) and the pubertal group (n = 6), respectively. Subjects entering puberty had a significantly greater increase in TB BMC (P = 0.007) and LTM (P = 0.022) compared with subjects remaining prepubertal (Table 3). The change in the z-scores for the TB DXA measures and height over 24 months for both groups is plotted in Fig. 4. Whereas all subjects increased their height z-scores during GH therapy, TB BMC z-scores decreased by -0.28 (0.31) in the group remaining prepubertal but increased by 0.71 (0.56) in pubertal subjects (P = 0.007). The corresponding change in LTM z-scores was 0.28 (0.49) and 1.07 (0.75); P = 0.031. Similar to our cross-sectional study, we calculated the individual difference between observed and predicted BMC z-scores. The mean change over 24 months for this difference was -0.70 (0.30) in the prepubertal group and -0.06 (0.45) in the pubertal group (P = 0.003). The decreasing z-score of the BMC/LTM ratio in prepubertal subjects shows the dissociation between muscle and bone mass. Changes in vBMD and corresponding z-scores were not significantly different between the two groups. LS vBMD z-score changed by -0.49 (0.89) in the prepubertal and -0.09 (0.62) in the pubertal group. The corresponding change in FN vBMD z-score was -0.39 (0.45) and -0.22 (1.07). Groups did not differ in GH dose or baseline bone age, nor was there any relation between GH dose and the change in z-scores of anthropometric and DXA measures.
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Discussion |
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The prepubertal decrease in TB BMC and LTM z-scores in our study mainly reflects the age-related decrease in height z-score due to the planar nature of DXA. The lack of a pubertal growth spurt in comparison with control subjects contributes to this decrease. However, TB BMC accrual was less than predicted for height z-score during the extended prepubertal period (Fig. 2), and most subjects classified osteopenic were in late prepuberty. The LS vBMD z-score also decreased prepubertally, which is consistent with results obtained from a study using QCT, where cancellous LS vBMD decreased significantly prepubertally (20).
Prepubertal estradiol levels are reduced in girls with TS compared with controls (31), which may lead to low bone mass, similar to that observed in aromatase deficiency (32). The fact that osteopenia in our study (except the FN) was mainly found in late prepuberty suggests a critical role of estrogen on BMC accretion at age 10–14 yr or a delayed skeletal response to the low prepubertal estrogen levels. In contrast to others (14), we suggest that the risk of rendering subjects osteopenic by delaying pubertal induction to the currently recommended age of 15 yr (23) is clinically relevant. There are concerns that estrogen accelerates skeletal maturity with a consequent reduction in final height. However, recent studies from the Dutch group suggest that final height is not compromised by early (12.7 yr) induction of puberty (33).
The role of estrogen is further supported by a study reporting greater BMD values in adult women with TS who had menstruated spontaneously compared with a TS group in whom puberty had been induced. The main difference between the groups was the exposure to prepubertal estrogen (34). Another study has reported comparable findings (35). Young women with TS on estrogen supplementation also have normal radial trabecular vBMD (19) and normal (18) or slightly reduced (3) LS vBMD. However, low size-corrected LS areal BMD in adults with TS was also reported (2). Insufficient estrogen treatment causes low vertebral bone mass (10), and the duration of treatment was positively correlated to BMD (3, 11). In addition, estrogen is reported to preserve bone at the endocortical surface (36, 37, 38). Therefore, the lack of estrogen may contribute to the decreased endocortical apposition at the upper extremities during puberty (19, 39) and to the increased bone remodeling (3, 10, 40) reported in TS.
There are, however, reasons to suggest an additional, intrinsic bone defect associated with the syndrome from our study. In contrast to other sites, there was a reduction in FN vBMD and a dissociation of bone and muscle measures throughout all age groups. The low FN vBMD found in our study may be of clinical relevance for two reasons. First, the weight-bearing femur is exposed to a frequently overweight child with TS (41). In contrast to adults, obesity is not protective of fractures in children (42). Second, fracture rate is increased in adults with TS at frequent fracture sites (2, 4, 6), including a 5-fold fracture risk at the FN (4). However, the 9% reduction compared with healthy controls found in the only study assessing FN vBMD in adult women so far, was not significant (3). Regional differences in bone mass have also been observed in other studies using a variety of bone imaging techniques. Generally, bone mass at cortical sites like the radius (1, 7, 8, 19) appears more affected than at the LS (8, 43). In accordance with these studies and a study in adults (3), our results suggest regional differences in bone mass in TS, which may have implications for future fracture risk. Future prospective studies will have to evaluate regional differences in bone mass, geometry, and particularly fracture risk in TS.
Despite the major role of muscle force and mass on bone strength (21, 22), the muscle-bone relation in TS has been addressed only in one study so far (19). Muscle size at the radius using pQCT was reported normal for age in 21 young women with TS, but BMC and cortical size were reduced for age. A similar dissociation of muscle and bone mass was found at all ages in our study (Table 2 and Fig. 1D). The major decrease in the z-score for the BMC/LTM ratio was observed prepubertally with a subsequent tendency toward improvement after the onset of puberty. TB (30, 44, 45) and forearm studies (46) document greater bone mass accretion for a given muscle mass in pubertal girls than boys, in line with the mechanostat view of estrogen action (36). The muscle-bone dissociation in TS indicates that estrogen deficiency has a more pronounced effect on bone than on muscle mass, an effect that can be seen in our longitudinal results (Fig. 4).
Correcting DXA output for bone or body size is essential as areal BMC or BMD z-scores of down to -5 could be misinterpreted as osteoporosis in children with short stature. In the absence of official guidelines in children, we defined osteopenia as a TB BMC score >1.5 SD lower than predicted for height z-score and as vBMD z-scores <–1.5 SD. Using -1.5 SD as a cutoff, 14.5% (TB), 15.8% (LS), and 28.5% (FN) of TS subjects were classified osteopenic, which is higher than the 6.7% expected for normal subjects. Many other studies found normal bone mass in children with TS when corrections for body size were made (8, 14, 17). Size-corrected values for the LS and the TB were even reported above the normal mean (14), which may be attributable to the bulky skeletal phenotype specific for TS. The finding of normal periosteal (but not endosteal) bone size for age at the radius (19) supports this interpretation.
Longitudinal studies in Turner girls are rare. Shaw et al. (17) measured LS areal BMD over 2.5 yr and found decreasing size-corrected values in nine of 14 patients. However, their subjects ranged widely in age and were on different treatment regimens. Other, smaller studies (7, 13, 47) showed inconclusive results. In the only longitudinal study that assessed the effect of puberty in 10 patients, the increase in LS and TB bone mass over a mean of 1.34 yr appeared to be greater in the estrogen-treated group (14). Our study confirms their findings but also found a marked dissociation between TB bone mass and both height and LTM between subjects remaining prepubertal and subjects entering puberty. Although both groups crossed height centiles upwards supported by GH, the lack of estrogen caused a decrease in BMC accrual and a lower increase in LTM in the prepubertal group. Our results are supported by the increase in calcium absorption and a decrease in bone turnover observed during puberty in TS (48, 49).
Several studies have suggested a positive role of GH on BMD in TS (12, 14, 15) but longitudinal studies are not convincing (12, 13, 17). It is unclear whether the gain in bone mass could exceed the GH-induced height gain. In our study, there was no difference in any of the DXA z-scores between the GH-treated and the untreated group, nor did we observe an increase in vBMD at the FN or the LS in the longitudinal study. In agreement with previous studies (2, 5, 11, 34, 35), karyotype and bone mass measures were not correlated.
In conclusion, osteopenia in late prepuberty is not uncommon in young women with TS, suggesting a potential role of prepubertal estrogen. Estrogen supplementation is essential to improve BMC accrual during growth in TS. In the timing of pubertal induction, the risk of rendering subjects osteopenic needs to be weighed up against a potential reduction in final height. The reduction of FN vBMD and the bone-muscle dissociation at all ages suggests an additional intrinsic bone defect.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMC, Bone mineral content; BMI, body mass index; DXA, dual-energy x-ray absorptiometry; FN, femoral neck; LS, lumbar spine; LTM, lean mass; pQCT, peripheral quantitative computer tomography; TB, total body; TS, Turner syndrome; vBMD, volumetric bone mineral density.
Received May 5, 2003.
Accepted September 17, 2003.
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