The complications of TS during adulthood also vary, with compromised bone health being one of the clinically evident complications [2,3,4,5,6]. Gravholt et al. previously reported the clinical characteristics of 594 subjects with TS in Denmark based on data from the Danish Cytogenetic Central Register and Danish National Registry of Patients, and reported an increased incidence of osteoporosis (RR 10.12 [95% CI 2.18–30.93]) and fractures (RR 2.16 [95% CI 1.50–3.00]) [6]. Multiple lines of evidence, including meta-analyses, indicate that estrogen insufficiency is a predominant risk factor for low bone mineral density (BMD) [7,8,9]. In addition, the early introduction of ERT to accrue better BMD during adulthood has been suggested [10,11,12,13,14,15]. As the acquisition of an adequate bone mass during adolescence and young adulthood is crucial for reducing the subsequent risk of osteoporosis, the appropriate introduction of ERT during adolescence is of clinical importance. Additionally, TS-associated comorbidities, including vitamin D deficiency, celiac disease, inflammatory bowel disease, and hyperthyroidism, are also risk factors for low BMD [1,16]. The genetic influence of haploinsufficiency of the short-stature homeobox (SHOX) gene on the skeletal characteristics in TS has also been reported [17]. Furthermore, the transcriptome analysis revealed a down-regulation of bone morphogenic protein 2 and insulin-like growth factor 2 expressions in human fibroblasts with 45, X karyotype compared with those with 46, XX karyotype [18], suggesting that the lack of one X chromosome may have a profound effect on bone metabolism beyond the effect of haploinsufficiency of the SHOX gene. 

Although BMD is an important surrogate marker for bone strength, other parameters of bone geometry also have significant impacts on bone strength; therefore, analyses of the bone geometry provide additional insights into the skeletal phenotype in children with TS. Cortical bones generally show age-dependent increases in the total cross-sectional area (CSA) and cortical thickness, and this is associated with increases in the strength−strain index (SSI) during puberty [25,30]. Pitukcheewanont et al. evaluated cortical bone geometry in 22 prepubertal TS with a mean (SD) age of 11.9 (3.3) years and found that the cortical bone CSA was similar to that of the controls after adjustments for weight, height, skeletal age, and pubertal stage [26]. Soucek et al. investigated 22 prepubertal girls with TS with a mean (SD) age of 10.3 (2.2) years and found a lower CSA Z-score in the TS group than in the controls, and this difference was not observed after adjustments for height. Therefore, the inclusion of prepubertal girls with delayed puberty may have affected the findings obtained. In a subpopulation of eight children younger than 10 years old, the cortical CSA was above the lower limit of the reference values in all of the subjects [21]. These findings indicate that cortical bone geometry, particularly cortical bone size, was unlikely affected during prepubertal ages in TS (Table 1) (Figure 1).

To obtain a more detailed understanding of the alterations in bone geometry in TS during the pubertal period, Soucek et al. performed a longitudinal analysis in TS in which ERT was initiated based on the current protocol, and found that the height-specific CSA Z-score was not altered in prepubertal girls, whereas age-dependent elevations were observed thereafter that were associated with increases in the SSI Z-score, suggesting that those with TS acquired larger bones during the pubertal period [24]. This characteristic of bone geometry may be explained by the unique effects of estrogen on the acquisition of cortical bone. Estrogen has been shown to inhibit periosteal apposition, whereas endocortical apposition is stimulated [30,31,32,33], which results in the acquisition of smaller bones with a narrower marrow cavity in girls than in boys; therefore, larger cortical bones in TS may be a reflection of the delayed administration of estrogen. In accordance with this notion, in a clinical setting of delayed puberty, the delayed increase in estrogen levels resulted in normal or larger cortical bones with a thinner cortex [30]. As larger cortical bones generally confer more strength to bones [34], the SSI Z-score is considered to be higher in the TS patients than in the controls during adolescence [24].

The larger CSA in TS indicates that bone strength is not impaired in children with TS; however, conflicting findings are available on this issue. Ross et al. examined the fracture incidence in 78 children with TS aged between 4 and 13 years old in 1991, and found that the annual incidence of fractures was similar in the TS patients and controls (19.9/1000 in TS vs. 27.8/1000 in controls), whereas the annual incidence of wrist fractures was higher in TS (9.1/1000 in TS vs. 3.5/1000 in controls) [19]. A recent longitudinal analysis of the fracture incidence in children with TS aged between 6 and 16 years demonstrated that the fracture rate of the limbs and spine was not higher in TS individuals [24]. The discrepancy between these two studies may be due to differences in the percentage of individuals receiving ERT. In the former study, 13 out of 78 subjects received ERT briefly for a mean duration of 6 months, whereas ERT was initiated in a defined protocol in the latter study, indicating that the former may have included more individuals for whom ERT was insufficiently performed; however, this difference may not have been a major factor that created a distinct result between two studies, because the age of the subjects in the former was younger than that in the later study, which may justify the increased percentage of subjects without ERT in the former study. Therefore, further accumulation of studies is clearly necessary to unravel whether the fracture risk is increased in children and adolescence with TS.

Growth hormone (GH) has been widely utilized to increase adult height in TS with successful outcomes [35,36,37,38,39]. In addition to its growth-promoting effects, GH has been shown to exert anabolic effects on the skeleton largely through its action to induce the expression of insulin-like growth factor 1, which was based on findings obtained from individuals with GH deficiency [40,41,42]. Additionally, a pharmacological dose of GH in short-statured children born with SGA increased the bone mass [43]. Although the effects of GH on BMD have been extensively examined in TS, conflicting findings have been obtained. Sas et al. investigated the effects of a 7-year treatment with GH on phalangeal vBMD and reported increases after adjustments for bone age [44]. In contrast, Ari et al. compared BMD between TS children treated with or without GH, and showed that after adjustments for bone size and bone age, the aBMD of LS and the radius did not significantly differ between the two groups [45]. Aycan et al. examined the effects of a 1-year GH treatment in prepubertal girls with TS with a mean age (SD) of 9.8 (2.5) years, and showed that GH treatment did not affect the vBMD of LS [46]. Similar findings were obtained on the effects of GH on BMD during childhood and adolescence [29,47,48]. These findings indicate that GH treatment in TS girls did not have a beneficial impact on BMD. However, as discussed earlier, bone strength is not affected by BMD only, bone geometry also plays important roles. Accordingly, Nour et al. recently investigated bone geometry using high-resolution pQCT and found that GH increased the bone size and the mechanical index of the polar moment of inertia, while DXA-based BMD was unaffected [49], which implies the beneficial effects of GH on bone strength, potentially resulting in reductions in the risk of fracture. Similar findings were reported on the effects of GH on decreases in the risk of fracture in age-related osteoporosis [50]. In addition to its effects on bone geometry, GH indirectly affected bone strength by improving muscle strength. Despite these benefits of GH on bone geometry and strength, limited information is currently available and, thus, further studies are needed to elucidate the effects of GH on fracture risk in adults with TS.

5. Effects of ERT during Adolescence on BMD in Young Adults with TS