Depression in Anorexia Nervosa: A Risk Factor for Osteoporosis

Context: Both anorexia nervosa (AN) and depression are associated with osteoporosis. We hypothesized that adolescent girls with AN and depression will have lower bone mineral density (BMD) than anorexic girls without depression. Objective: The
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  Depression in Anorexia Nervosa: A Risk Factorfor Osteoporosis Jerzy Konstantynowicz, Halina Kadziela-Olech, Maciej Kaczmarski, Roger M. D. Zebaze,Sandra Iuliano-Burns, Janina Piotrowska-Jastrzebska, and Ego Seeman  Department of Pediatrics and Auxology (J.K., H.K.-O., J.P.-J.) and Third Department of Pediatrics (M.K.), MedicalUniversity of Bialystok, University Children’s Hospital “Dr. Ludwik Zamenhof,” 15-274 Bialystok, Poland; and Departmentof Endocrinology and Medicine (J.K., R.M.D.Z., S.I.-B., E.S.), University of Melbourne, Repatriation Campus, 3081 Heidelberg West, Victoria, Australia Context:  Both anorexia nervosa (AN) and depression are associatedwithosteoporosis.WehypothesizedthatadolescentgirlswithANanddepressionwillhavelowerbonemineraldensity(BMD)thananorexicgirls without depression. Objective:  The objective of this study was to investigate whetherdepression is an independent risk factor for osteoporosis in anorexicadolescent girls. Design:  This study was cross-sectional. Setting: This study was conducted at the University Children’s Hos-pital(Bialystok,Poland)fromOctober2002throughSeptember2003. Participants:  Forty-five Caucasian anorexic girls aged 13–23 yr,matched by age, Tanner stage, weight, height, calcium intake, andduration of AN, were studied, including 14 with comorbid depression(based on Hamilton Depression Rating Scale and Montgomery-As-berg Depression Rating Scale) and 31 anorexic girls withoutdepression. MainOutcomeMeasures: Total body and lumbar spine (LS) BMD,fat mass, and lean mass assessed using dual-energy x-ray absorpti-ometry were compared between AN girls with and withoutdepression. Results: BMDwasreducedinbothgroups,relativetoreferencedata,butgirlswithANanddepressionhadlowerBMDthanthosewithANalone(LSZ-scores,  2.6  0.3 vs.  1.7  0.3;  P  0.02)(mean  SEM ).Quantitativeassessmentofdepressioncorrelatedindependentlywithtotal body BMD (r    0.4;  P    0.05) and LS BMD (r    0.6;  P   0.001). Conclusion:  Anorexic girls with depression are at higher risk of osteoporosisthanthosewithoutdepression.Themechanismsrespon-sible for decreased BMD in depression are not known. Independenttreatment of the depressive disorder in AN may partly alleviate thebone fragility.  (  J Clin Endocrinol Metab  90: 5382–5385, 2005) P OOR NUTRITION, CHRONIC caloric restrictions, low body weight, and hypogonadism frequently lead todeficits in bone mineral density (BMD) in anorexia nervosa(AN) due to both reduced accrual of peak bone mass andprematureboneloss(1–4).Deficitsinbonemassorbonesizein patients with AN may not be entirely reversible and in-crease fracture risk (4–8).Depression is associated with weight loss, bone loss, andosteoporosis in adults (9–12). Depression is reported in 36%of adolescent girls with AN (13). Although it is not a coreelement in anorexic disorder, it may exacerbate the courseand severity of AN (14–16). Both conditions occur duringgrowth and puberty, but no published data exist regardingBMD and depression in anorexic adolescent girls.The aim of the study was to investigate whether there isa link between depressive symptoms and low BMD in ad-olescent girls with AN. We hypothesized that adolescentgirlswithANanddepressionhavelowerBMDthananorexicgirls without depression. Patients and Methods The study was conducted between October 2002 and September 2003in the Outpatient Psychosomatic Clinic and the Pediatric Departmentsin the University Children’s Hospital “Dr. L. Zamenhof” at the MedicalUniversity of Bialystok (Bialystok, Poland). Girls suffering from AN forat least 6 months, being treated either as inpatients (96%) or outpatients,were recruited for this study. Written consent was obtained from par-ticipants and their parents or legal guardians. The study was approved by the Ethical Committee at the Medical University in Bialystok.Forty-nine Caucasian adolescent females aged 12.8–23.1 yr (mean16.6  1.8yr)whowerediagnosedwithANaccordingtobothDiagnosticand Statistical Manual of Mental Disorders IV American PsychiatricAssociation (17) and International Classification of Diseases (ICD-10)(18)criteria,wereenrolledintothestudy.Allgirlswereundernourished(BMI below the third percentile of the reference range), presented with bodyimagedistortionbasedonpsychiatricassessment(17,18),andhadeither primary amenorrhoea or secondary amenorrhoea for more than6 months during the study. Duration of AN ranged between 0.6 and 5.6yr.Beforeinclusiontothestudy,patientswerescreenedforthefollowingconditions: primary kidney and liver diseases, juvenile rheumatoid ar-thritis and other connective tissue diseases, scoliosis, hyperthyroidism,malabsorption, celiac disease, and schizophrenia. Of the 49 patientsscreened,fourwereexcludedbecausetheyfailedtomeetthecriteria;twohad schizophrenia, one had hyperthyroidism, and one had chronic hep-atitis B. None of the girls had ever received hormone therapy, glucocor-ticosteroids, neuroleptics, or parenteral nutrition, and none had hadspinal surgery. First Published Online June 7, 2005 Abbreviations: AN, Anorexia nervosa; BMC, bone mineral content;BMD, bone mineral density; BMI, body mass index; FM, fat mass;HAM-D, Hamilton Depression Rating Scale; LM, lean mass; LS, lumbarspine; MADRS, Montgomery-Asberg Depression Rating Scale; TB, total body.  JCEM is published monthly by The Endocrine Society (, the foremost professional society serving the en-docrine community. 0021-972X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(9):5382–5385  Printed in U.S.A.  Copyright © 2005 by The Endocrine Societydoi: 10.1210/jc.2005-0026 5382  Medical history and questionnaire were used to assess age of men-arche, gynecological age (measured as a number of years since firstmenstruation),historyoffractures,andcurrentandpastmedicationuse.Dietary calcium intake was assessed by an interview-based 24-h recall(19,20).Allpatientsunderwentclinicalexaminationandanthropometricmeasurements.Weightwasmeasuredonanelectronicscale(Seca,Ham- burg, Germany) and height using a Martin anthropometer. The bodymass index (BMI) was derived from the formula: BMI  weight (kilo-grams)/height 2 (square meters). Pubertal status was based on Tannerstaging of breast development and ascertained by a physician (21).Totalbody(TB)bonemineralcontent(BMC;grams),TBBMD(gramsper centimeter squared), lumbar spine (LS) BMD (grams per centimetersquared), fat mass (FM; grams and percentage), and lean mass (LM;grams) were determined using dual-energy x-ray absorptiometry(DPX-L, Lunar Radiation Corp., Madison, WI; versions 1.3z and 1.5 h).LS BMD was compared with age-matched reference ranges and ex-pressed as a Z-score. The estimated reproducibility error  in vivo  (coef-ficient of variation) was 1.14%, based on duplicate LS dual-energy x-rayabsorptiometry examination performed within 3 d in 32 subjects.All participants were examined by a psychiatrist and screened fordepressive symptoms. Anorexic subjects were divided into those witha depressive disorder and those without, based on the Hamilton De-pression Rating Scale (HAM-D) and the Montgomery-Asberg Depres-sion Rating Scale (MADRS), which are used to indicate the intensity of depression(22,23).ThecriteriaforthepresenceofdepressioninHAM-Dis more than or equal to eight scores, whereas the cut-off score fordepression in MADRS is more than or equal to 13. These two methodshavebeenvalidatedasscreeningtoolsfordepressioninadolescents(23).Weusedcut-offscores(HAM-D  13andMADRS  20)toconfirmthatthe girls had at least moderate depression.Datawereexpressedasmeans  sem .Two-tailedStudent’s t testwasused to examine the differences between depressed and nondepressedAN girls. The relationships among BMD, body composition, and de-pressionscoreswereassessedusingthePearsoncorrelationcoefficients.Using multiple regression analyses, BMD was adjusted for body com-positiontoaccountfordifferencesinBMI,LM,andFMbetweenthetwogroups.  P  0.05 was considered statistically significant. Additionally,Bonferroni corrections were performed. The data were analyzed usingStatView program (Abacus Concepts, Inc., Berkeley, CA). Results Fourteen of the 45 anorexic girls had moderate to severedepression (HAM-D  13 and MADRS  20) (Table 1). Nodifferences were observed in age, Tanner stage, menarche,gynecological age, duration of AN, calcium intake, bodyweight, height, and FM between the two groups. Of the sixgirls with primary amenorrhoea, five occurred in those withAN and depression. Two girls with AN and depression re-portedfractures(wristandankle),whereasnofractureswerereported in those without depression. There was a tendencytoward decreased BMI in depressed AN girls. Depressedanorexic girls had lower total and LS BMD and LM thannondepressed girls (Fig. 1). Depression scores were nega-tivelyassociatedwithallboneparameters,BMI,andLM,butnot FM (Table 2 and Fig. 2). After Bonferroni corrections, thesignificant differences between the depressed and nonde-pressed groups remained for all variables. After adjustmentfor LM and BMI, the association between depression and LSBMDremainedsignificant( P  0.05).However,TBBMDwasno longer associated with depression after adjustment forBMI ( P  0.34) and LM ( P  0.26). The five depressed ANgirls with primary amenorrhoea had significantly lowerspineBMDthanthosewithdepressionwhohadmenstruated(Z-score,   3.6    0.04  vs.   2.1    0.3;  P    0.02). However,whengirlswithprimaryamenorrheawereexcludedfromtheanalysis, there was a tendency for BMD to be lower in de-pressed (n   9) compared with nondepressed (n   30) an-orexic girls. Discussion Inthiscross-sectionalstudy,anorexicadolescentgirlswithdepression had greater deficits in BMD than those withoutdepression. A negative relationship was observed betweenBMD and the depression score. LM and BMI were also neg-atively associated with depression score. Girls with depres-sion and primary amenorrhoea had an additional reductionin BMD compared with those who had menstruated. Weconfirmed low BMD is common in girls with AN (1, 4, 5, 8)and extend this observation by reporting that depression inthisconditionisassociatedwithmoreseveredeficitsinBMD.A coincidence of depression and AN has been reported inadolescent girls and women (13, 16). Ivarsson  et al.  (24) re-ported that depression was a common comorbid problem inanorexic females, and AN may trigger the first episode of  TABLE 1.  Comparison of two groups of adolescent girls with ANin relation to depressive disorders Depressed(n  14)Nondepressed(n  31)  P HAM-D score 21.3  1.1 3.9  0.6 0.0001MADRS score 34.4  1.7 5.5  0.8 0.0001 Age (yr) 17.0  0.6 16.5  0.3 0.44Menarche (yr) 13.3  0.3 12.6  0.2 0.43Gynecological age (yr) 3.8  1.0 4.0  0.4 0.85Primary amenorrhoea (n) 5 1Tanner stage 3.9  0.3 3.9  0.1 0.93Weight (kg) 41.1  2.3 44.0  1.1 0.19Height (cm) 163.4  1.5 162.5  1.0 0.62BMI (kg/m 2 ) 15.3  0.4 16.7  0.3 0.08Duration of AN (yr) 1.4  0.8 1.6  1.3 0.52Calcium intake (mg/d) 512.8  75.3 551.8  38.6 0.61Fractures (no.) 2 0Fat mass (g) 6,000  1,295 6,514  602 0.68Fat (%) 13.4  2.4 14.4  1.1 0.67Lean mass (g) 30,428  2,276 35,058  517 0.009Total body BMC (g) 1,869  65 2,018  51 0.1Total body BMD (g/cm 2 ) 0.987  0.07 1.028  0.06 0.01LS BMD (g/cm 2 ) 0.906  0.04 1.015  0.02 0.003Z-score for spine BMD   2.6  0.3   1.71  0.3 0.02Data represent mean  SEM .F IG . 1. LS BMD expressed as Z-scores in anorexic girls with (n  14)and without (n    31) depression.  Bold line , Median;  box , valuesbetween the 25th and 75th percentiles;  lower  and  upper horizontalbars , values between 10th and 90th percentiles. Konstantynowicz  et al.  • Reduced BMD in Depressed Anorexic Girls J Clin Endocrinol Metab, September 2005, 90(9):5382–5385  5383  depression in adolescents. Bizeul  et al.  (16) reported that theseverity of depression influenced the eating disorder’s in-ventory in young anorexic women. Depression concomitantwith adolescent AN has been considered mainly secondaryto the features of AN, but the underlying relationships re-main unclear (25).To our knowledge, this is the first demonstration of aquantitative association between BMD and depression inanorexicadolescentgirls.Depressionmaymodifythecourseof AN and is associated with the severity of the disease inadolescence (26, 27). In this study, more severe deficits inBMD and LM occurred in depressed girls, whereas othervariables,includingFM,didnotdiffer.Yazici et al. (28)founddecreased BMD in women with major depressive disorder but did not confirm an association between BMD and theseverity of depression.Depression may be an independent risk factor for osteo-porosis in AN, although the causal pathway for lower BMDin depressed anorexic girls is unclear. An association be-tween depression and reduced bone mass in middle-aged orolderpopulationhasbeenfoundinseveralstudies(9,11,12).Osteoporosis has been considered a consequence of depres-sioninadults(29,30),althoughresultsvariedbysexandage.Depressivedisordershavebeenreportedtoincreaseariskof osteoporosis in men (31–34) and women (11, 28). Depressionis associated with fragility fractures in older women (35). Ahigher prevalence of depression has also been reported insomebutnotallstudiesofpatientswithosteoporosis(36–38).MADRS is as sensitive an instrument as HAM-D for detect-ing antidepressant efficacy in clinical trials. Thus, bothMADRS and HAM-D may be desirable tools for diagnosingdepression in adolescents (23).The mechanisms that may contribute to the developmentof osteoporosis in depressive disorders include increasedlevels of endogenous steroids (9, 11, 39), hyperprolactinemia(33), and hypogonadism (30, 33). Our study shows that pri-mary amenorrhoea in AN girls with a comorbid depressionmay also be associated with the decrease in BMD. Suchhormonal disturbances reported in depression may be pre-disposing factors for reduced accrual of bone or bone loss.Rapid bone loss and high remodeling are reported in short-term depression or during the first episode of major depres-sive disorder in adults (28, 39). Depression-induced neu-roendocrine alterations may contribute to low BMD inconjunction with caloric deficiency, inadequate dietary cal-cium intake, and malnutrition in anorexic girls. BMI and bodycomposition,reflectingnutritionalstatus,correlatepos-itivelywithBMD;thus,thedeficitsinBMDmaypartlyresultfrom malnutrition, reduced LM, and mechanical implica-tions associated therewith. It is also possible that depressedindividualsinthisstudyhadlowerBMI,LM,andlowerBMDindependentoftheAN.Furthermore,across-sectionalstudyis not able to reveal if reduced BMD occurred before thedevelopment of depression. However, this does not detractfrom the likelihood that the risk of fracture is higher in thesepatients than in girls with AN alone.Insight into the differing associations may offer alterna-tivestotreatment.Thus,antidepressantsmaybeapartofthemanagement of anorexic girls with depression. 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