Original Full Length ArticleSclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls
Highlights
► Serum sclerostin is positively associated with bone turnover markers in healthy adolescent girls. ► The relationship between sclerostin and bone turnover markers is disrupted in adolescent girls with anorexia nervosa. ► Transdermal estradiol replacement in adolescent girls with anorexia nervosa does not change sclerostin levels despite improving bone mass.
Introduction
Sclerostin is a member of the DAN (differential screening-selected gene aberrant in neuroblastoma) glycoprotein family and is secreted by osteocytes [1]. Sclerostin binds LRP5/6 to inhibit Wnt signaling in osteoblasts [2], [3]. In addition, sclerostin increases osteoclast formation and activity in vitro, mediated by RANKL [4]. The function of sclerostin on bone biology is illustrated by the abnormal skeletal features of sclerosteosis and van Buchem disease, two diseases characterized by sclerostin deficiency. These conditions are characterized by osteoblast hyperactivity and bone overgrowth, most notably in the mandible and skull. Sclerosteosis is a recessive disorder resulting from inactivating mutations in the SOST gene, which encodes sclerostin [5]. Van Buchem disease is caused by deletion of SOST transcription regulatory elements [6].
The SOST gene promoter has multiple estrogen-response elements [7], and several studies have shown that serum levels of sclerostin are negatively regulated by estradiol in adults. Sclerostin levels are higher in postmenopausal women as compared to premenopausal women [8], and treatment with transdermal estradiol [9], [10] or with raloxifene [11] significantly reduces sclerostin levels in this population. In elderly men, treatment with estradiol, but not testosterone, has been shown to reduce sclerostin levels [10]. Reductions in bone resorption markers were observed in parallel with the decrease in sclerostin [9], [10], [11].
Sclerostin levels have not previously been evaluated in anorexia nervosa (AN) or in children with disorders that alter bone metabolism. Individuals with AN have low levels of estrogen and the majority have decreased bone mineral density (BMD) [12], [13]. Although adolescents with AN are hypogonadal, they typically have low levels of both bone formation and bone resorption markers [12], [14], [15]. Multiple metabolic and hormonal abnormalities are present in patients with AN, including relative IGF-1 deficiency, hypercortisolism, and alterations in leptin and ghrelin [16], [17], [18], [19] which contribute to low levels of bone formation and resorption markers. It is not currently known whether changes in levels of bone turnover markers are also mediated by changes in sclerostin.
In this study we assessed associations of sclerostin with levels of surrogate markers of bone turnover in adolescent girls with AN and normal-weight controls. We have recently demonstrated in a randomized double-blind placebo-controlled study that physiologic estrogen replacement in adolescent girls with AN significantly improves BMD [20]. We utilized data from this study to examine the effects of 12 months of transdermal estradiol replacement or placebo on sclerostin levels in adolescent girls with AN. We hypothesized that at baseline, levels of sclerostin would be higher in estrogen deficient subjects with AN and would be inversely associated with a surrogate marker of bone formation (N-terminal propeptide of type 1 procollagen (P1NP)) and positively associated with a marker of bone resorption (CTX). We also hypothesized that sclerostin levels would decrease in subjects who received estradiol and predict changes in BMD.
Section snippets
Subjects and methods
The study was performed at the Clinical Research Center of Massachusetts General Hospital (MGH), Boston, MA, USA, and the Clinical Investigation Unit at the Hospital for Sick Children (SickKids), Toronto, ON, Canada. Written informed consent was obtained from all subjects prior to their participation. Parental consent was also obtained for subjects under the age of 18 years. The study was approved by the Institutional Review Board of Partners HealthCare, Boston, and the Research Ethics Board at
Baseline characteristics
Comparisons between normal-weight controls and subjects with AN are shown in Table 1. The two groups did not differ for bone age (as per study design), height, Tanner staging, and exercise activity. As expected, girls with AN had lower body mass index (BMI), lean mass, and fat mass. Consistent with our prior report, subjects with AN had significantly higher calcium and vitamin D intake than controls [22]. BMD at the lumbar spine and hip was significantly lower in subjects with AN than controls.
Discussion
Sclerostin levels have not been previously examined in adolescents with anorexia nervosa (AN). In this study, we showed that levels of sclerostin are associated with surrogate markers of bone turnover in normal-weight girls. In contrast, this relationship is not seen in adolescent girls with AN although levels of sclerostin do not differ in girls with AN compared with normal-weight adolescents. Additionally, although studies in adults have shown that estrogen decreases sclerostin levels,
Disclosure statement
The authors have nothing to declare.
Role of the funding source
This study was supported by NIH grants UL1 RR025758-01 and R01 DK062249.
NCT ID: NCT00088153.
Acknowledgments
We thank the staff at the Clinical Research Center of Massachusetts General Hospital and the Clinical Investigation Unit at SickKids for their nursing and bionutrition support.
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Anorexia nervosa and bone
2018, Current Opinion in Endocrine and Metabolic ResearchCitation Excerpt :Estrogen stimulates bone formation by inhibiting sclerostin secretion, a factor that inhibits osteoblast differentiation [54]. Consistent with these data, decreased ratios of OPG/RANKL [55] and increased sclerostin levels [56] have been reported in women but not adolescents with AN [57]. Numerous studies have reported that a longer duration of amenorrhea is associated with worse skeletal integrity [5,15,23]*, as is a history of amenorrhea in those who are currently eumenorrheic [8,58]**.
Bone metabolism in anorexia nervosa and hypothalamic amenorrhea
2018, Metabolism: Clinical and ExperimentalCitation Excerpt :Another study on girls with perhaps less severe AN (mean BMI 17.2 ± 0.21 versus 16.0 ± 1.6 in the former study) found no difference in sclerostin levels compared to controls [62]. In both studies, sclerostin levels correlated positively with bone turnover markers in the control groups but not in the AN females [19,62]. Furthermore, although estrogen has been shown to decrease sclerostin levels in postmenopausal women, there was no association between estradiol and sclerostin levels in adolescent girls with and without AN, and transdermal estradiol replacement in girls with AN did not affect sclerostin levels despite an increase in BMD [62,63].
Normal bone density and trabecular bone score, but high serum sclerostin in congenital generalized lipodystrophy
2017, BoneCitation Excerpt :The lower body weight of these patients could contribute to the higher values of serum sclerostin. Patients with anorexia nervosa also have low weight and low leptin, but sclerostin is normal [38]. Low BMI does not appear to be a determining factor in the elevation of sclerostin in patients with BSCL.
Hormonal and systemic regulation of sclerostin
2017, BoneCitation Excerpt :Perhaps in contrast to these results, however, is that observation that sclerostin levels were unchanged in adult women with anorexia nervosa who received PTH 1-34 treatment for six months [19]. Reasons for this noted difference are unclear, but may reflect underlying differences in skeletal biology and/or skeletal hormonal responses in anorexia nervosa subjects [20]. To determine whether the suppressive effect of PTH on sclerostin levels occurs in pathologic as compared to pharmacologic conditions, multiple investigators have now examined humans with parathyroid gland disorders.
Anorexia nervosa and bone metabolism
2014, BoneCitation Excerpt :In animal models, inhibition of sclerostin with a monoclonal antibody results in increased bone mass and bone strength [107] and recently, in a population of postmenopausal women, 12 months of treatment with a sclerostin monoclonal antibody significantly increased bone mineral density at the spine and hip [108]. Sclerostin levels have been shown to be significantly higher in young women with AN as compared to normal-weight controls [109], although serum sclerostin levels do not appear to mediate increases in BMD in girls and women with AN in response to treatment with transdermal, physiologic estrogen replacement [110] or teriparatide [111]. Whether sclerostin is an important contributor to the low bone mass in AN and whether treatment with a sclerostin monoclonal antibody will increase BMD in this population remain to be seen.