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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2419
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 4 1292-1297
Copyright © 2008 by The Endocrine Society

Prognostic Indicators of Changes in Bone Density Measures in Adolescent Girls with Anorexia Nervosa-II

Madhusmita Misra, Rajani Prabhakaran, Karen K. Miller, Mark A. Goldstein, Diane Mickley, Laura Clauss, Patrice Lockhart, Jennalee Cord, David B. Herzog, Debra K. Katzman and Anne Klibanski

Neuroendocrine Unit (M.M., R.P., K.K.M., J.C., A.K.), Pediatric Endocrine Unit (M.M., R.P.), and Adolescent Medicine Unit (M.A.G.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Wilkins Center for Eating Disorders (D.M.), Greenwich, Connecticut 06831; Bedford Center for Eating Disorders (L.C.), Bedford, New Hampshire 03110; Eating Disorders Center (P.L.), Mercy Hospital, Portland, Maine 04101; Harris Center (D.B.H.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Division of Adolescent Medicine (D.K.K.), Department of Paediatrics, Hospital for Sick Kids, Toronto, Ontario, Canada M5G 1X8

Address all correspondence and requests for reprints to: Madhusmita Misra, M.D., MPH, BUL 457, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: mmisra{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Introduction: Adolescents with anorexia nervosa (AN) have low bone mineral density (BMD). Baseline predictors of temporal BMD changes ({Delta}BMD) in AN, including 1) gastrointestinal peptides regulating food intake and appetite that have been related to bone metabolism and 2) bone turnover markers, have not been well characterized. We hypothesized that baseline levels of nutritionally regulated hormones and of bone turnover markers would predict {Delta}BMD overall.

Methods: In a prospective observational study, lumbar and whole-body BMD was measured at 0, 6, and 12 months in 34 AN girls aged 12–18 yr and 33 controls. Baseline body mass index, lean mass, nutritionally regulated hormones [IGF-I, cortisol, ghrelin, leptin, and peptide YY (PYY)], bone formation, and resorption markers were examined to determine nutritional and hormonal predictors of bone density changes.

Results: In a regression model, baseline ghrelin and PYY predicted changes in spine bone measures; and baseline ghrelin, cortisol, and PYY predicted changes in whole-body bone measures independent of baseline nutritional status.

Conclusions: Neuroendocrine gastrointestinal-derived peptides regulating food intake are independent predictors of changes in bone mass in AN.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Adolescents with anorexia nervosa (AN) have low bone mineral density (BMD) (1, 2, 3, 4, 5, 6) associated with decreased bone turnover markers (3, 7), and BMD remains low despite short-term weight gain (3). Baseline predictors of subsequent BMD changes have not been comprehensively examined in adolescents with AN, and prognostic factors for bone mass accrual during the critical adolescent years are unclear. Because more than 90% of peak bone mass is achieved by the end of the second decade, an understanding of these factors is important.

Bone metabolism is affected by neuroendocrine modulators of food intake including peptide YY (PYY) (8), ghrelin (4, 9), and leptin (10); hormones such as estradiol (11), IGF-I (12, 13), and cortisol (14, 15, 16, 17, 18); and nutritional status, particularly lean mass (7, 12). Ghrelin, a novel orexigenic peptide secreted by the stomach (19), causes increased proliferation of osteoblasts in cultures, indicating a role in bone formation (20). PYY is an anorexigenic peptide secreted by the distal gut (21), and deletions of its receptor in mice are associated with increased bone formation (22), suggesting that PYY excess may lead to decreased bone formation. Leptin-deficient mice have increased bone mass (23), and inverse associations between leptin and bone have been reported in adults (24, 25). However, studies also indicate a positive association between leptin and bone density in humans (26, 27), and the relationship between leptin and bone remains under investigation.

In AN girls, specific alterations occur in peptides regulating food intake, such that PYY and ghrelin levels are elevated (8, 28, 29) and leptin is very low (3, 30). AN girls are also hypogonadal and hypercortisolemic (31, 32, 33). The predictive value of baseline nutritional status and nutritionally dependent hormones on subsequent BMD changes in AN have not been well characterized. Girls with AN have low levels of bone turnover markers (3), and it is not known whether baseline levels of these markers predict subsequent changes in BMD.

In this supplement to our accompanying paper (45) examining prospective changes in 1) bone density measures assessed using the Molgaard approach (34) and 2) height-adjusted bone density measures [bone mineral apparent density (BMAD) at the spine, and whole-body (WB) bone mineral content (BMC) adjusted for height] with weight gain and menstrual recovery, we report baseline nutritional and hormonal predictors of subsequent changes in bone density measures in girls with AN.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subject selection

Data from subjects reported in previously published studies by Soyka et al. (3) and Misra et al. (8, 28, 30, 35) were analyzed to determine baseline predictors of bone density changes over 1 yr in adolescent girls with AN and controls 12–18 yr old. Neither study had previously examined these baseline predictors of subsequent bone density changes. Inclusion and exclusion criteria and recruitment procedures are described in detail in our accompanying paper (45). The Institutional Review Board of Partners HealthCare approved the study, and informed assent and consent was obtained from all.

Experimental protocol

After a screening visit to determine eligibility, subjects were admitted to the General Clinical Research Center of Massachusetts General Hospital for the baseline visit. Body mass index (BMI) was calculated as the ratio of weight (in kilograms) to height (in meters) squared. Fasting labs were obtained for osteocalcin (OC), a marker of bone formation, and for IGF-I, estradiol, and leptin for all subjects. A second morning urine sample was obtained for N-telopeptide (NTX), a urinary marker of bone resorption, and for creatinine. A 24-h urine sample was obtained for urinary free cortisol (UFC). We have previously demonstrated that OC and NTX are sensitive to weight changes in AN (3) and therefore report these bone turnover markers. Other markers previously reported that are less sensitive to weight changes, such as bone-specific alkaline phosphatase and urinary deoxypyridinoline, are not reported here. In addition, 17 AN and 16 controls had fasting blood drawn for PYY and ghrelin and underwent frequent sampling for cortisol overnight between 2000 and 0800 h (cortisol area under the curve reported). This subset did not differ from the bigger group for baseline characteristics (data not reported). Bone density measures were measured at baseline and repeated at 6 and 12 months. A bone age was performed at baseline and read using methods of Greulich and Pyle (36). Duration since diagnosis did not differ between these groups.

Bone density and body composition measurement

Dual-energy x-ray absorptiometry (Hologic 4500A fan beam densitometer, software version 11.2; Hologic, Waltham, MA) was used to determine BMC and areal BMD at the spine and for the WB and fat and lean mass. Z-scores for the spine (L1–L4) were generated using the reference database available to Hologic (37). Low bone density reported by dual-energy x-ray absorptiometry may be the result of short bones (based on height Z-scores), thin bones [based on measures of bone area (BA) for height], or light bones (based on measures of BMC for BA) (34). To correct for body size, BMAD was calculated from lumbar BMC and BA (38). We used methods described by Ward et al. (38) to derive measures of lumbar and WB BMC for BA and BA for height Z-scores. The coefficients of variation (CV) for spine and WB BMD were 1.1 and 0.8% and for fat and lean mass 2.1 and 1.0%, respectively. Longitudinal measurements of bone density were performed on the same scanner for all subjects with the same software version.

Biochemical measurements

RIAs were used to measure cortisol (Diagnostic Products Corp., Los Angeles, CA; limit of sensitivity 1.0 µg/dl, CV 2.5–4.1%), leptin (Linco Diagnostics, Inc., St. Louis, MO; sensitivity 0.5 ng/ml, CV 3.4–8.3%), ghrelin (Phoenix Pharmaceuticals, Belmont, CA; sensitivity 2 pg/ml, CV 10%), total T3 (Diasorin, Stillwater, MN; sensitivity 9.0 ng/dl, CV 3.1–7.9%), and estradiol (Diagnostic Systems Laboratories, Inc., Webster, TX; limit of detection 2.2 pg/ml, CV 6.5–8.9%). Total PYY was measured using a human PYY (3–36) RIA (Phoenix Pharmaceuticals), with 100% cross-reactivity with the two biologically active forms of PYY (1–36 and 3–36 PYY) (intraassay CV 5.6%, lower limit of detection 2.8 pg/ml). An immunoradiometric assay was used to measure IGF-I (Nichols Institute Diagnostics, San Juan Capistrano, CA; detection limit 30 ng/ml, CV 3.1–4.6%) and OC (Nichols Institute Diagnostics; sensitivity 0.5 ng/ml, CV 3.2–5.2%). NTX was measured by ELISA (Ostex International, Inc., Seattle, WA; detection limit 20 nmol bone collagen equivalent; intraassay CV 5–19%). Urine creatinine was measured by the hospital laboratory (39). Samples were stored at –80 C until analysis and run in duplicate. Cortisol levels can be converted to SI units (nmol/liter) by dividing by 0.0363.

Statistical analysis

All data are presented as mean ± SD. Data were analyzed using the JMP program (version 4; SAS Institute Inc., Cary, NC). The Student’s t test was used to compare means. We used correlation analysis to determine predictors of changes in bone density measures. Stepwise regression modeling was performed to determine independent baseline predictors of changes in bone measures. When two variables that correlated with a particular bone measure strongly correlated with each other (r > 0.80), only one covariate was included in the stepwise regression model to avoid model instability.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics

Baseline biochemical characteristics have been reported previously (3, 8, 35) and are summarized in Table 1Go. Baseline bone density measures and changes in body composition and bone density measures over a 1 yr are reported in our accompanying manuscript (45) and are not included here. IGF-I, estradiol, and leptin were lower, and cortisol area under the curve, ghrelin, and PYY higher in AN than in healthy adolescents.


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  		TABLE 1. Baseline characteristics in 34 girls with AN and 33 controls

 
Predictors of change in bone density measures

On correlational analysis, changes in bone measures in AN were predicted by baseline levels of ghrelin, PYY, cortisol, IGF-I, and bone turnover markers (Table 2Go). When significant predictors were entered into a stepwise regression model (Table 3Go), for the lumbar spine, the most significant and independent baseline predictors of changes in lumbar bone density measures were BMI, lean mass, ghrelin, PYY, and OC. For the WB, significant predictors were baseline ghrelin, cortisol, PYY, IGF-I, and BMI.


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  		TABLE 2. Correlation coefficients between changes in bone density and baseline values of covariates in girls with AN

 

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  		TABLE 3. Stepwise regression modeling for predictors of change in lumbar bone density measures for girls with AN

 
Baseline ghrelin correlated inversely (r = –0.57; P = 0.02) and baseline cortisol positively with changes in BMI (r = 0.54; P = 0.03). We found no associations between baseline PYY or IGF-I with subsequent BMI changes. In an analysis of covariance model including baseline ghrelin, PYY, and recovery status, baseline ghrelin and PYY remained significant predictors of lumbar BMC, BMD, and BMAD changes after controlling for recovery status (details not reported). In an analysis of covariance model including baseline ghrelin, PYY, cortisol, and recovery status, baseline ghrelin and cortisol independently predicted changes in WB BMC and BMC/height, and PYY independently predicted WB BMD changes.


   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We demonstrate that baseline ghrelin, PYY, and cortisol are the most significant and independent predictors of subsequent changes in lumbar and WB bone density measures.

A major finding is that two important predictors of changes in bone density measures were the orexigenic and anorexigenic peptides ghrelin and PYY, respectively, independent of baseline nutritional and other hormonal markers. Both peptides play a major role in feeding behavior and may have direct and indirect effects on bone metabolism. The ghrelin receptor is expressed on osteoblasts, and ghrelin administration to osteoblast cultures is associated with increased osteoblastic activity (20, 40, 41). However, ghrelin inversely predicted changes in bone measures. Our previous studies have indicated that ghrelin may indirectly affect bone through effects on secretion of GH and cortisol (35). Ghrelin is a potent GH and ACTH secretagogue, and high cortisol in AN is associated with higher ghrelin levels and decreases in bone turnover markers (33). Increased cortisol has known deleterious effects on bone. Although GH is anabolic to bone, and AN girls have high GH concentrations, they also have a nutritionally acquired resistance to GH (42). It is possible that inverse associations observed between ghrelin and bone density measures are a consequence of ghrelin-stimulated increases in ACTH and therefore cortisol, with deleterious effects on bone, whereas ghrelin-stimulated increases in GH are not associated with bone anabolic effects because of GH resistance in AN. Conversely, inverse associations between baseline ghrelin and subsequent changes in BMI in our study may merely indicate that higher baseline ghrelin predicts girls less likely to recover, hence the inverse associations with bone density changes.

We have previously demonstrated that high PYY levels are associated with low levels of bone turnover markers (8). These data were consistent with Y2 receptor deletions in mice being associated with an increase in bone formation, the Y2 receptor being the putative receptor for PYY (22). We now demonstrate that PYY is an important baseline predictor of subsequent changes in bone density measures in AN, independent of baseline nutritional and other hormonal markers. Knowledge of the lowest weight in our subjects would have been useful to determine whether girls with lower ghrelin and PYY were the ones on the road to recovery although still very low weight and whether this could explain the inverse association between these peptides and changes in bone measures. Of note, although we observed an inverse association between baseline ghrelin and subsequent BMI changes, no such associations were observed for PYY.

For the WB, baseline cortisol was another important predictor of subsequent BA for height and BMC/height Z-score changes. Overall, the bone parameter best predicted from baseline values of the various predictors examined was WB BA. Given that WB BA was significantly lower in AN girls than in controls, an increase in this parameter over time likely represents a normalization of bone growth, which would be determined largely by nutritional status and the degree of recovery from AN. It is interesting that important baseline predictors of changes in WB BA for height were cortisol, ghrelin, and PYY. Contrary to expectation, we observed a positive association between cortisol and changes in WB BA for height. We have previously reported that baseline cortisol is an important predictor of recovery in AN, although the mechanism underlying this association is unclear (43). It may thus be that girls with higher cortisol and lower ghrelin and PYY levels are more likely to recover over time or, as discussed previously, that rapid changes occur in these parameters with initiation of nutritional intervention, even while body weight is still in the pathological range. Consistent with this, we observed a positive association between baseline cortisol and subsequent BMI changes. However, cortisol, ghrelin, and PYY remained significant predictors of bone changes even after adjusting for recovery status. Other baseline predictors of bone measures were IGF-I, a known bone trophic factor, and bone turnover markers.

Girls with higher baseline OC and NTX/creatinine had greater subsequent increases in lumbar BMC for BA and WB BA for height, respectively. Healthy adolescents have elevated levels of bone turnover markers (44), and this is associated with increased bone remodeling and subsequent increases in bone density measures. Girls with AN have low levels of bone turnover markers (3), and it is likely that girls with higher bone turnover markers have greater increases in bone remodeling, which should result in a subsequent increase in bone density.

Limitations of our study include the use of correlational analyses, which cannot determine causation. Another limitation is that duration since diagnosis was variable in our subjects, and duration of illness could not be determined with accuracy based upon history. It is also possible that some subjects were on the road to recovery when they were enrolled in the study, although all subjects met criteria for AN at enrollment. This could affect baseline neuropeptide levels and account for variability observed in these parameters within groups. In addition, baseline ghrelin, PYY, and cortisol were available only for a subset of subjects. This small sample size is a study limitation, and a study design that allows enrollment of a larger number of subjects at initial diagnosis may reduce the variability. Strong associations of these hormones with subsequent bone density changes, however, suggest that these associations are likely real. A larger study examining these parameters will be important to determine whether associations described in this manuscript hold up with a larger number of subjects.

Our data indicate that high baseline ghrelin and PYY and low levels of bone turnover markers and cortisol indicate a poor prognosis for subsequent increases in bone density. These data provide information regarding predictive factors that ultimately may be useful in developing interventional paradigms for children with this disorder. More studies are necessary to determine whether 1) baseline values of appetite-regulating peptides such as ghrelin and PYY and other hormones such as IGF-I and cortisol reflect the neuroendocrine state regulating feeding behavior in this disorder and indicate which girls are more likely to recover with nutritional intervention or 2) whether minor and early changes in nutritional status, for example in the early stages of nutritional intervention, are reflected in these hormones even before significant changes in weight become apparent.


   Footnotes
 
This work was supported by National Institutes of Health Grants R01 DK 062249, K23 RR018851, and M01-RR-01066.

Conflict of Interest: All authors have no conflict of interest to report.

First Published Online December 18, 2007

Abbreviations: AN, Anorexia nervosa; BA, bone area; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; CV, coefficient of variation; NTX, N-telopeptide; OC, osteocalcin; PYY, peptide YY; UFC, urinary free cortisol; WB, whole body.

Received October 31, 2007.

Accepted December 7, 2007.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals