Elsevier

Bone

Volume 51, Issue 3, September 2012, Pages 474-479
Bone

Original Full Length Article
Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls

https://doi.org/10.1016/j.bone.2012.06.006Get rights and content

Abstract

Sclerostin, product of the SOST gene, is an important determinant of bone formation and resorption. Adolescents with anorexia nervosa (AN) have low bone density and decreased levels of bone turnover markers. However, sclerostin has not been examined in AN as a potential mediator of impaired bone metabolism. Our study objectives were to (i) assess associations of sclerostin with surrogate bone turnover markers in girls with AN and controls and (ii) examine effects of transdermal estradiol on sclerostin in AN. 69 girls (44 with AN and 25 normal-weight controls) 13–18 years old were studied at baseline. 22 AN girls were randomized to transdermal estradiol (plus cyclic medroxyprogesterone) or placebo in a double-blind study for 12 months. Sclerostin correlated positively with P1NP and CTX in controls (r = 0.67 and 0.53, p = 0.0002 and 0.005, respectively) but not in AN despite comparable levels at baseline. Changes in sclerostin over twelve months did not differ in girls randomized to estradiol or placebo. The relationship between sclerostin and bone turnover markers is disrupted in adolescent girls with AN. Despite an increase in BMD with estradiol administration in AN, estrogen does not impact sclerostin levels in this group.

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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