Bone Mineral Density, Bone Turnover, and Osteoprotegerin in Depressed Women With and Without Borderline Personality Disorder KAI G. KAHL, MD, WIEBKE GREGGERSEN, MD, SEBASTIAN RUDOLF, MD, BEATE M. STOECKELHUBER, MD, CLAUDIA U. BERGMANN-KOESTER, MD, LEIF DIBBELT, MD, AND ULRICH SCHWEIGER, MD Objective: Low bone mineral density has repeatedly been reported in patients with major depressive disorder (MDD), and MDD has been discussed as a risk factor for the development of osteoporosis. MDD in young adults often occurs in the context of borderline personality disorder (BPD), and both MDD and BPD have been associated with a dysregulation of the hypothalamic– pituitary–adrenal system and subsequent hypercortisolemia. To date, it is unclear whether comorbid BPD in depressed patients modulates the extent of bone mass reduction. Therefore, we examined bone density, markers of bone turnover, and proinflammatory cytokines in depressed patients with and without BPD. Patients with BPD alone and healthy women served as comparison groups. Method: Twenty-four patients with MDD and 23 patients with comorbid MDD and BPD were included. Sixteen patients with BPD and 20 healthy women of similar body mass index served as the comparison group. BMD was assessed by means of dual-energy x-ray absorptiometry. Markers of bone turnover, endocrine and immune parameters were determined. For data analysis, the group of depressed patients without comorbid BPD was divided according to age into two groups (younger depressed patients with a mean age of 30 years and older patients with a mean age of 42.9 years). Results: BMD at the lumbar spine was significantly reduced in a) depressed women with comorbid BPD (mean age, 28.6 years) and in b) older depressed patients without BPD (mean age, 42.9 years). Osteocalcin, a marker of osteoblastic activity, and crosslaps, a marker of bone loss, were significantly different between the study groups. Tumor necrosis factor-␣ was increased in depressed patients when compared with healthy women. Furthermore, TNF-␣ was positively correlated with serum crosslaps, a marker for osteoclastic activity. Conclusion: Depression is associated with reduced bone mass, in particular in patients with comorbid BPD. Possible factors contributing to BMD reduction include endocrine and immune alterations associated with either MDD or BPD. We conclude from our data that a history of MDD with and without comorbid BPD should be considered as a risk factor in clinical assessment instruments for the identification of persons prone to osteoporosis. Key words: borderline personality disorder, osteoporosis, major depressive disorder, TNF-␣. BPD ⫽ borderline personality disorder; BMD ⫽ bone mineral density; AP ⫽ lumbar spine; RF ⫽ right femur; LF ⫽ left femur; FA ⫽ forearm; BMI ⫽ body mass index; HPAS ⫽ hypothalamic–pituitary–adrenal system; IGF-I ⫽ insulin-like growth factor-I; IL-6 ⫽ interleukin-6; MDD30 ⫽ patients with major depressive disorder and a mean age of 30 years; MDD43 ⫽ patients with major depressive disorder and a mean age of 43 years; MDD/BPD ⫽ patients with comorbid major depressive disorder and borderline personality disorder; OPG ⫽ osteoprotegerin; PTH ⫽ parathormone; TNF-␣ ⫽ tumor-necrosis factor-␣.
INTRODUCTION ow bone mass and osteoporosis are widely prevalent in developed countries, particularly among postmenopausal women. The World Health Organization considers osteoporosis to be second only to cardiovascular disease as a public health concern. Osteoporosis is characterized by low bone mineral density (BMD), and low BMD is an important risk factor for pathologic fractures. Morbidity from fractures is substantial, and mortality has been reported to be increased by approximately 20% after hip fracture (1,2). Osteoporosis is often a silent disease that might go undiagnosed for a long time. The cost-effective identification of clinical risk factors associated with the development of low
From the Department of Psychiatry and Psychotherapy (K.G.K., W.G., S.R., U.S.), the Institute of Radiology (B.M.S., C.U.B.-K.), and the Institute of Clinical Chemistry (L.D.), Medical University of Schleswig-Holstein, Lu¨beck, Germany. Address correspondence and reprint requests to Kai G. Kahl, MD, Klinik fu¨r Psychiatrie und Psychotherapie, Universita¨tsklinikum Schleswig-Holstein, Campus Lu¨beck, Ratzeburger Allee 160, 23538 Lu¨beck, Germany. E-mail: [email protected]
Recieived for publication March 21, 2005; revision received May 18, 2006. This study was supported by a grant of the Medical University of Schleswig-Holstein (FUL16/03). DOI: 10.1097/01.psy.0000237858.76880.3d Psychosomatic Medicine 68:669 – 674 (2006) 0033-3174/06/6805-0669 Copyright © 2006 by the American Psychosomatic Society
BMD may be crucial for identifying groups at risk, preventing further bone mineral reduction. Major depressive disorder (MDD) has been implicated as a possible risk factor for low BMD (3), but the results have been inconsistent. Some studies have reported an association between MDD and low BMD, whereas others have failed to report such an association. In addition, publication bias concerning negative results may play a role. Studies performed in psychiatric inpatients tended to report an association between severe MDD and low BMD in pre- and postmenopausal women (4 –7). This association was not replicated in one study with patients with mild MDD and in one study with women experiencing premenstrual dysphoric disorder (8,9). Five cross-sectional community- or population-based studies were performed, and three found an association between depressive symptomatology and reduced BMD in peri- and postmenopausal women (10 –12), whereas another study of 121 postmenopausal women found no association (13). Recently published data from the Third National Health and Nutrition Survey (NHANES III) reported reduced BMD in young adult men with depression, but not in depressed women (14). Of four prospective studies, three failed to support an association of depressive symptomatology with BMD in nonpsychiatric patients (15–17), whereas one prospective case– control study in depressed patients found greater BMD reduction after a 2-year follow up that was more pronounced in men (18). The majority of studies were performed in older subjects at a mean age ranging from 41 to 75 years (3). In these studies, stratification for comorbid personality disorders was not reported. However, comorbidity with personality disorders is common in adult and late-life depression (19,20). Approximately one third of major depressive episodes in young women occurs in the context of borderline personality disorder (BPD (21,22)). BPD is a severe and complex mental 669
K. G. KAHL et al. disorder characterized by a pervasive pattern of instability in the regulation of emotion, interpersonal relationships, selfimage, and impulse control. Several studies found increased symptom severity and increased chronicity in depressed patients with comorbid BPD (23,24). Both MDD and BPD have been reported to be associated with a dysregulation of the hypothalamic–pituitary–adrenal system (HPAS (25,26)). Furthermore, a dysbalance of pro- and antiinflammatory cytokines has been observed in MDD and in comorbid patients with MDD and BPD (27). Bone tissue is continuously rebuilt in a coordinated process of osteoclastic resorption and osteoblastic bone formation (28). Enhanced bone resorption has been associated with an inappropriate osteoclast activation (29,30). Several factors, including increased concentrations of glucocorticoids and proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6), have been shown to activate osteoclastic cells in vivo and in vitro, whereas osteoprotegerin (OPG) has been associated with prevention of bone loss (28). Therefore, we examined young depressed patients with and without comorbid BPD and determined hormonal and immunologic factors relevant to bone metabolism. MATERIALS AND METHODS Study Subjects The study was approved by the local ethics committee, and all subjects gave their informed written consent. Twenty-four premenopausal women with MDD (age range, 20 –51 years), 23 women with comorbid MDD and BPD (age range, 18 – 43 years), and 16 women with BPD (but without MDD; age range, 19 –34 years) were included. Diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and confirmed by means of a standardized interview (SCID I/II; German version). The frequency of comorbid psychiatric disorders is given in Table 1. Exclusion criteria were current or lifetime history of anorexia nervosa or underweight (adult body mass index [BMI] ⱕ18.5 kg/m2), schizophrenia, oligophrenia, pregnancy, an age of 17 years or younger, and medical illness. Subjects with high weight (BMI ⱖ30 kg/m2) were excluded to avoid confounding with the endocrine sequelae of obesity. Twenty healthy women (age range, 18 – 41 years) served as a further comparison group (CG). A standardized psychiatric interview gave no evidence of either an individual or family history of major psychiatric disorders in any subject in this group. None of the study subjects experienced an acute infectious or lifetime autoinflammatory disease, estrogen deficiency, or received nonpsychotropic medication (including hormones or steroids). Twenty of 24 women with MDD, 12 of 23 women comorbid with MDD and BPD, and 5 of 16 women with BPD received treatment with selective serotonin reuptake inhibitors (20 – 60 mg fluoxetine, 50 –200 mg sertraline), but no other psychotropic medication. For data analysis, the group of depressed women without borderline personality disorder was divided according to the age median of this group into younger (MDD30: mean age 30 years, n ⫽ 12) and older depressed TABLE 1.
patients (MDD43: mean age 42.9 years, n ⫽ 12). This categorization was done ex post because the group with depression only (but not the other groups) showed a significant negative correlation between age and bone density at the level of the spine (r ⫽ ⫺0.42; p ⫽ .046).
Bone Density Measurements Bone mineral density was measured in all patients by means of dualenergy x-ray absorptiometry (DEXA) at the lumbar spine, the neck of the right and left femur, and the forearm of the nondominant hand using a Lunar Prodigy Densitometer equipped with software containing reference data for an adult population (version 2.15.092; Lunar Corp., Wisconsin). These normative data were collected from a large sample of healthy probands enrolled in longitudinal studies of bone density and are specified for age, gender, BMI, and ethnic group (31). Individual BMD values were expressed as Z-scores for group comparisons within the patient subgroups (MDD30, MDD43, MDD/ BPD, BPD), and osteopenia was defined in accordance with the World Health Organization guidelines as a T-score ⱕ⫺1 (31). The staff involved in the determination of bone density was aware of the patient status of the subject but not of comorbid diagnosis. BMD was not measured in CG in compliance with government regulations restricting the use of radiation in healthy subjects.
Assays Serum was taken after an overnight fast at 8:00 AM and stored at ⫺40°C until analysis. Intact parathormone (PTH), 1,25-hydroxyvitamine D, and laboratory markers of bone turnover (intact osteocalcin and C-terminal degradation products of type I collagen, referred to as crosslaps) served as laboratory markers of bone turnover and were determined using commercial IRMA (Nichols Institute Diagnostics, Germany) and enzyme-linked immunosorbent assay (ELISA) kits (Osteometer Biotech A/S, Denmark), respectively. Cortisol was determined by RIA technique (DPC, Nauheim, Germany). Insulin-like growth factor I (IGF-I), leptin, and OPG were determined using available ELISA kits according to the manufacturer’s instructions (all from R&D Systems, Germany). High-sensitivity ELISA kits were used to determine TNF-␣ and IL-6 (Quantikinine; R&D Systems, Germany).
Statistical Analysis Data were analyzed using SPSS (version 13.0). We used a stepwise strategy to examine potential differences between the groups concerning the BMD, bone turnover markers, hormonal and immunologic parameters. We suspected age and weight as potential confounders. Weight was similar in all study groups, but age differed significantly between the groups. Therefore, analysis of covariance with age as a covariate was used to compare the study groups with respect to anthropometric, bone turnover, hormonal and immunologic data. The exception is the Z-scores of BMD. These scores are already corrected for age and weight. Group comparisons concerning Z-scores were therefore done using analysis of variance. We used the 2 test to compare the frequency of osteopenia between the groups. Pearson’s coefficients of correlation were calculated. A two-tailed p value below .05 was considered significant. All values are given as mean ⫾ standard deviation.
RESULTS Analysis of covariance with the covariate age revealed significant group differences for bone mineral density at the lumbar
Absolute Frequency of Comorbid Diagnoses in the Subgroups According to the Structured Clinical Interview (SCID)
MDD30 (n ⫽ 12) MDD43 (n ⫽ 12) BPD (n ⫽ 16) MDD/BPD (n ⫽ 23)
0 0 2 6
2 1 2 4
2 3 1 4
1 1 5 7
2 2 1 4
PTSD ⫽ posttraumatic stress disorder; MDD30 ⫽ patients with major depressive disorder and a mean age of 30 years; MDD43 ⫽ patients with major depressive disorder and a mean age of 43 years; BPD ⫽ borderline personality disorder; MDD/BPD ⫽ patients with comorbid major depressive disorder and borderline personality disorder. 670
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1/12 (8%) 3/12 (25%) 3/16 (19%) 5/23 (22%) 0.15 ⫾ 1.43 0.18 ⫾ 0.70 0.10 ⫾ 0.20 ⫺0.30 ⫾ 0.17 0.15 ⫾ 1.43 0.19 ⫾ 0.69 0.10 ⫾ 0.78 ⫺0.30 ⫾ 0.81 0.54 ⫾ 0.02 0.57 ⫾ 0.02 0.52 ⫾ 0.01 0.52 ⫾ 0.01c 0.54 ⫾ 0.07 0.53 ⫾ 0.03 0.53 ⫾ 0.04 0.52 ⫾ 0.05 2/12 (17%) 1/12 (8%) 2/16 (13%) 3/23 (13%) 1.05 ⫾ 0.04 1.05 ⫾ 0.05 1.04 ⫾ 0.03 1.00 ⫾ 0.02 1.06 ⫾ 0.13 1.01 ⫾ 0.12 1.06 ⫾ 0.11 1.01 ⫾ 0.12 MDD30 MDD43 BPD MDD/BPD
Data are given unadjusted and after adjustment for age (30.9 years) (⫾standard deviation). a p ⬍ .05 versus BPD. b p ⬍ .05 versus MDD30. c p ⬍ .05 versus MDD43. BPD ⫽ borderline personality disorder; BMD ⫽ bone mineral density; AP ⫽ lumbar spine; RF ⫽ right femur; MDD30 ⫽ patients with major depressive disorder and a mean age of 30 years; MDD43 ⫽ patients with major depressive disorder and a mean age of 43 years; MDD/BPD ⫽ patients with comorbid major depressive disorder and borderline personality disorder; LF ⫽ left femur; FA ⫽ forearm of the nondominant hand.
T-Score (LF) Adjusted Unadjusted
0.46 ⫾ 1.01 0.12 ⫾ 0.96 0.44 ⫾ 0.91 ⫺0.10 ⫾ 0.95
T-Score (FA) Z-Score (FA) Adjusted Osteopenia (LF)
BMD (g/cm2) (FA) BMD (g/cm2) (LF)
0.32 ⫾ 0.96 0.11 ⫾ 0.73 0.27 ⫾ 0.98 ⫺0.18 ⫾ 0.88
2/12 (17%) 1/12 (8%) 0/16 (0%) 3/23 (13%) 0.52 ⫾ 1.13 0.21 ⫾ 96 0.48 ⫾ 0.83 ⫺0.15 ⫾ 0.86 0.41 ⫾ 0.96 0.17 ⫾ 0.72 0.37 ⫾ 0.78 ⫺0.15 ⫾ 0.83 1.05 ⫾ 0.03 1.04 ⫾ 0.04 1.05 ⫾ 0.03 1.01 ⫾ 0.02 1.06 ⫾ 0.13 1.01 ⫾ 0.11 1.06 ⫾ 0.10 1.01 ⫾ 0.11 1/12 (8%) 4/12 (33%) 1/16 (6%) 2/23 (9%) 0.77 ⫾ 1.3 ⫺0.31 ⫾ 1.3 0.33 ⫾ 0.85 ⫺0.43 ⫾ 0.78 1.28 ⫾ 0.04 1.14 ⫾ 0.05b 1.25 ⫾ 0.03 1.17 ⫾ 0.03a,b MDD30 MDD43 BPD MDD/BPD
1.28 ⫾ 0.16 1.16 ⫾ 0.15 1.24 ⫾ 0.1 1.17 ⫾ 0.1
0.61 ⫾ 1.3 ⫺0.33 ⫾ 1.3a 0.20 ⫾ 0.84 ⫺0.52 ⫾ 0.78a,b
T-Score (RF) Z-Score (RF) Adjusted Unadjusted Adjusted
BMD (g/cm2) (AP)
BMD (g/cm2) (RF)
Bone Mineral Density and Osteopenia in Women With Depression and/or BPD
DISCUSSION Our data demonstrate low BMD in young depressed women comorbid with BPD and in older depressed women with MDD. These findings are in accordance with other studies examining psychiatric inpatients by using strict diagnostic criteria (5–7). Interestingly, BMD at the lumbar spine was significantly reduced in young depressed females with comorbid BPD (mean age, 28.6 ⫾ 7.2 years) when compared with patients of similar age with MDD (mean age, 30 ⫾ 4.6 years) or BPD (mean age, 25.9 ⫾ 5.1 years) alone. We interpret this result as suggesting that comorbidity with BPD may enhance the risk of bone loss in depressed patients. Low bone density in younger comorbid patients and in older patients with depression was only found at the level of the spine and not the hip. Bone density measurements at the level of the spine reflect a higher percentage of trabecular bone compared with measurements at the level of the hip. High bone turnover first affects trabecular bone, so this compartment is more sensitive to alterations of endocrine and metabolic factors.
spine (F ⫽ 2,9; df ⫽ 3,58; p ⫽ .029). Post hoc analysis yielded significantly lower BMD in comorbid patients when compared with younger depressed patients (p ⬍ .05) and patients with BPD alone (p ⬍ .05), and BMD was lower in older depressed women when compared with younger depressed women (p ⬍ .05) (Table 2). Furthermore, the patient groups differed significantly in Zscores (BMD values corrected for age, BMI, and ethnicity) at the lumbar spine (T ⫽ 3.8; df ⫽ 3,59; p ⫽ .015). Post hoc analysis revealed lower Z-scores in comorbid patients when compared with younger depressed patients (p ⬍ .05) and patients with BPD alone (p ⬍ .05), and lower Z-scores in older depressed women when compared with younger depressed women (p ⬍ .05) (Table 2). The rate of osteopenia as defined by a T-score ⱕ⫺1 standard deviation below that of a reference population at peak bone mass was not significantly different between the groups (Table 2). Analysis of covariance with the covariate age revealed significant differences between the study groups with regard to osteocalcin (F ⫽ 2.5; df ⫽ 4,77; p ⫽ .047), crosslaps (F ⫽ 4.2; df ⫽ 4,77; p ⫽ .004), TNF-␣ (F ⫽ 15.6; df ⫽ 4,77; p ⬍ .001), and osteoprotegerin (F ⫽ 4.2; df ⫽ 4,77; p ⫽ .004), and a trend toward different IL-6 concentrations (F ⫽ 2.2; df ⫽ 4,77; p ⫽ .075). The results of pairwise post hoc analyses are shown in Tables 3 and 4. Regression analysis revealed that TNF-␣ correlated positively with crosslaps (r ⫽ 0.216; p ⫽ .023). Logarithmic transformation of the values for serum crosslaps had no influence on the reported results (data not shown). No correlations were found between age, weight, BMI and any of the immunologic and hormonal parameters examined (data not shown). In particular, we found no influence of medication on the reported results (data not shown). White and red blood cell counts, serum electrolytes, and the concentrations of phosphate, magnesium, insulin, thyroid hormones, and prolactin were also similar among the groups (data not shown).
BONE DENSITY AND MAJOR DEPRESSIVE DISORDER
K. G. KAHL et al. TABLE 3.
Anthropometric and Hormonal Data of Women With Depression and/or BPD and a Comparison Group (ⴞstandard deviation)
Comparison group (n ⫽ 20) MDD30 (n ⫽ 12) MDD43 (n ⫽ 12) BPD (n ⫽ 16) MDD/BPD (n ⫽ 23)
Body Mass Index (kg/m2)
1,25-hydroxyvitamine D (ng/mL)
26.1 ⫾ 5.1 30.0 ⫾ 4.6 42.9 ⫾ 5.2 25.9 ⫾ 5.0 28.6 ⫾ 7.2
23.1 ⫾ 4.2 25.7 ⫾ 5.4 26.0 ⫾ 6.5 24.2 ⫾ 4.1 26.1 ⫾ 4.6
554 ⫾ 119 736 ⫾ 430 550 ⫾ 204 621 ⫾ 167 618 ⫾ 208
93 ⫾ 100 133 ⫾ 181 143 ⫾ 110 110 ⫾ 75 99 ⫾ 114
74 ⫾ 33 74 ⫾ 8 76 ⫾ 17 77 ⫾ 12 87 ⫾ 27
25 ⫾ 12 25 ⫾ 7 21 ⫾ 7 22 ⫾ 8 26 ⫾ 10
BPD ⫽ borderline personality disorder; MDD30 ⫽ patients with major depressive disorder and a mean age of 30 years; MDD43 ⫽ patients with major depressive disorder and a mean age of 43 years; MDD/BPD ⫽ patients with comorbid major depressive disorder and borderline personality disorder. TABLE 4.
Markers of Bone Turnover and Cytokines in Women With Depression and/or BPD and a Comparison Group
Comparison group (n ⫽ 20) MDD30 (n ⫽ 12) MDD43 (n ⫽ 12) BPD (n ⫽ 16) MDD/BPD (n ⫽ 23)
13.8 ⫾ 4.2 16.7 ⫾ 8.8 11.9 ⫾ 6.5 16.2 ⫾ 6.5 19.3 ⫾ 7.0a
2315 ⫾ 970 3325 ⫾ 1423a 3864 ⫾ 2437a,b 2723 ⫾ 1439 3860 ⫾ 1791a,b
2.0 ⫾ 0.5 4.3 ⫾ 0.8a,b,d 3.8 ⫾ 0.8a,b,d 2.0 ⫾ 0.7 2.7 ⫾ 1.4a,b
0.8 ⫾ 0.3 1.8 ⫾ 2.2a 0.9 ⫾ 0.4 1.2 ⫾ 0.8 1.6 ⫾ 1.4a
3.4 ⫾ 0.6 4.3 ⫾ 1.0a–d 3.5 ⫾ 0.7 3.4 ⫾ 0.8 3.4 ⫾ 0.7
11.6 ⫾ 7.1 8.4 ⫾ 8.7 22.6 ⫾ 33.5 21.8 ⫾ 18.3 20.4 ⫾ 14.3
The statistical results reflect pairwise post hoc analysis with analysis of covariance and the covariate age (⫾standard deviation). a p ⬍ .05 versus CG. b p ⬍ .05 versus BPD. c p ⬍ .05 versus MDD43. d p ⬍ .05 versus MDD/BPD. BPD ⫽ borderline personality disorder; TNF-␣ ⫽ tumor necrosis factor-␣; IL-6 ⫽ interleukin-6; OPG ⫽ osteoprotegerin; MDD30 ⫽ patients with major depressive disorder and a mean age of 30 years; MDD43 ⫽ patients with major depressive disorder and a mean age of 43 years; MDD/BPD ⫽ patients with comorbid major depressive disorder and borderline personality disorder; CG ⫽ comparison group.
In correspondence with the findings of bone reduction, we found elevated concentrations of serum crosslaps in all groups of depressed patients, indicating increased osteoclastic activity and bone resorption. Osteocalcin, a marker of osteoblastic activity, was enhanced in MDD/BPD. Our findings point to a high bone turnover in these patients. Other researchers also found higher concentrations of osteoclastic activity in depressed patients (7,32). Michelson and colleagues found reduced BMD associated with low bone turnover (5). They included women with a present or previous depressive episode, whereas in our study, only women with a present depressive episode were included. Both MDD and BPD have been associated with a dysregulation of the HPAS with increased cortisol secretion and lowered feedback sensitivity of the HPAS after stimulation with dexamethasone (25,26). Given the reports of osteoporosis in patients who are chronically treated with glucocorticoids or have Cushing syndrome, increased serum cortisol concentrations have been hypothesized to be one mechanism by which depression might induce bone loss (3). In our study, serum cortisol concentrations were slightly elevated in younger depressed and in comorbid patients, although this difference did not reach statistical significance. However, single measurements of morning cortisol do not precisely reflect a dysregulation of the HPAS, which is better detected by serum cortisol profiles or stimulation tests. As reported by other researchers (33–35), proinflammatory cytokines (TNF-␣, IL-6) were enhanced in depressed patients 672
compared with healthy women, although still within normal limits. Furthermore, TNF-␣ concentrations correlated with the osteoclastic marker serum crosslaps. Several studies have proposed a role for proinflammatory cytokines in the development of bone loss by modulating the balance between osteoclastic and osteoblastic activation (36). Bone tissue is continuously rebuilt in a coordinated process of osteoclastic resorption and osteoblastic bone mass increase. Enhanced bone resorption has been associated with an inappropriate osteoclast activation, and several factors, including increased concentrations of glucocorticoids and proinflammatory cytokines such as TNF-␣ and IL-6, have been shown to activate osteoclastic cells in vivo and in vitro (28,37). However, it has to be taken into account that alterations in serum cytokines do not necessarily reflect alterations of cytokine concentrations at the bone. Several studies examined the association of leptin with bone mass in premenopausal women. However, the results were divergent, demonstrating a positive, negative, or no association (38 – 40). In a recent study by Huang et al., the authors reported that the relationship between leptin and BMD is dependent on body weight (41). We found no group differences in leptin concentrations in our study and no association of leptin with bone mass, either with or without controlling for weight. Bone mineral density in younger depressed women (MDD30) was in the range of the reference population, although bone resorption was also enhanced in this group. Interestingly, we found the bone-protecting glycoprotein OPG elevated in this Psychosomatic Medicine 68:669 – 674 (2006)
BONE DENSITY AND MAJOR DEPRESSIVE DISORDER patient sample. OPG is a recently identified cytokine that belongs to the TNF-receptor superfamily. OPG acts as a decoy receptor for the osteoclast-stimulating receptor activator of nuclear factor B, thereby inhibiting osteoclastogenesis (42). Increased concentrations of OPG have been found in diseases associated with elevated cortisol or TNF-␣ concentrations such as Cushing syndrome and human immunodeficiency virus-infected patients (37). TNF-␣ has been described as a stimulator of OPG mRNA and protein in in vitro studies (43,44). These results led to the hypothesis that enhanced OPG concentrations may be a compensatory response to enhanced activity of osteoclasts or other members of the TNF family (42). In younger depressed patients (MDD30), proinflammatory cytokines and serum cortisol concentrations were also enhanced. Whether these alterations may have resulted in elevated OPG concentrations cannot be drawn from the data. Given the hypothesis of a compensatory upregulation of OPG in response to endocrine or immunologic factors, it remains an open question why OPG upregulation was not observed in MDD/BPD and in older depressed patients. It is a matter of debate whether depression simply magnifies the physiological bone loss that occurs after the age of 35 years or whether the disturbance of bone metabolism begins earlier and an adequate peak bone mass is not achieved. Our findings suggest that depression may rather enhance physiological bone loss, because younger patients with a mean age of 30 had no alterations in their BMD, whereas older premenopausal patients with MDD had considerable loss of BMD. However, patients with comorbid MDD and BPD displayed similar changes in bone mass as the group of older depressed patients. These results point to a role for BPD in modulating the onset and the extent of bone alterations. How may comorbidity with BPD influence bone metabolism? BPD in the absence of current major depressive episode has been associated with a dysregulation of the HPAS with subsequent elevated cortisol concentrations and lower suppression rates in the dexamethasone suppression test (26). These data indicate that BPD may be associated with chronic subtle hypercortisolism, which in turn may contribute to bone resorptive processes. Similarly, BMD in patients with incidentally discovered adrenal adenomas has been found reduced when compared with healthy probands, suggesting that subclinical hypercortisolism may adversely affect bone metabolism (45). Another hypothesis applies to the disease course of depression in comorbid patients. Comorbidity with BPD in MDD has been associated with more severe depressive episodes and chronicity (23,24). Therefore, the endocrine and immune alterations that accompany depressive episodes may be more chronic in comorbid patients. Perhaps a more parsimonious explanation of the effect of comorbidity with BPD on bone density is an increased chronicity of endocrine and immune alterations associated with MDD. Furthermore, several studies have consistently shown that the majority of patients with BPD had experienced adverse events early in life such as childhood abuse and neglect as well as parental loss (46). Findings from preclinical laboratory animal studies have provided evidence that maternal deprivaPsychosomatic Medicine 68:669 – 674 (2006)
tion and adverse rearing conditions in rodents are capable of inducing long-lived changes in endocrine and metabolic systems, including a dysregulation of the HPAS (47). This type of chronic stress may also lead to longlasting alterations of endocrine and immune systems and body composition (48). Other disease- and medication-related processes such as impaired fluid and electrolyte balance, dietary and vitamin D deficiency, decreased exercise, and exposure to sunshine could play a role in bone loss (32), but none of the available studies reports them as mediating factors in depression. Our data show similar concentrations of electrolytes, parahormone (PTH), estradiol, and 1,25-hydroxyvitamine D in all groups examined. These findings do not support the hypothesis that a deficiency of vitamin D or estradiol or alterations of the PTH metabolism may be the underlying cause of bone loss in our patients. More distal factors like low quality of nutrition and absence of encouragement to physical activity in childhood may be relevant in the MDD/BPD subgroup, which was particularly exposed to abuse and childhood neglect. There are several limitations to our study; the small number of patients in each group limits the interpretation of the negative results. This presently makes it difficult to differentiate whether the reported alteration of bone density is an effect of depression alone or the result of an interaction between depression and borderline personality disorder or its respective risk factors. Furthermore, smoking habits of the study subjects were not controlled for, and smoking has been described as a possible factor influencing BMD, particularly in postmenopausal women (49). In summary, comorbidity with BPD in depressed patients is associated with earlier and more severe bone loss compared with depressed patients without BPD. Possible pathophysiological mechanisms underlying increased bone resorption include a dysregulation of the HPAS and alterations in the balance of pro- and antiinflammatory cytokines. The data presented here suggest considering MDD as a risk factor for the development of osteoporosis, in particular in women comorbid with BPD. We propose to include MDD and MDD/ BPD in clinical risk assessment instruments for the identification of persons prone to osteoporosis. We thank M. Hu¨ppe and A. Katalinic for their helpful advice.
REFERENCES 1. Osteoporosis: review of the evidence for prevention, diagnosis, and treatment and cost-effectiveness analysis. Osteoporos Int 1998;8(suppl 4): S1– 88. 2. Cummings SR, Black DM, Nevitt MC, Browner WS, Cauley JY, Genant HK, Mascioli SR, Scott JC, Seeley DG, Steiger P, Vogt TM. Appendicular bone density and age predict hip fracture in women. JAMA 1990; 263:665– 8. 3. Cizza G, Ravn P, Chrousos GP, Gold PW. Depression: a major, unrecognized risk factor for osteoporosis. Trends Endocrinol Metab 2001;12: 198 –203. 4. Halbreich U, Palter S. Accelerated osteoporosis in psychiatric patients: possible pathophysiologic processes. Schizophr Bull 1996;22:447–54. 5. Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, Chrousos G, Gold P. Bone mineral density in women with depression. N Engl J Med 1996;335:1176 – 81. 6. Schweiger U, Deuschle M, Ko¨rner A, Lammers C-H, Schmider J, 673
K. G. KAHL et al.
7. 8. 9. 10. 11. 12.
13. 14. 15.
16. 17. 18. 19. 20.
21. 22. 23.
24. 25. 26. 27.
Gotthardt U, Holsboer F, Heuser I. Low lumbar bone mineral density in patients with major depressive disorder. Am J Psychiatry 1994;151: 1691–3. ¨ zc¸akar L. Bone mineral density in Yazici K, Akinci A, Su¨tc¸u¨ A, O premenopausal women with major depressive disorder. Psychiatry Res 2003;117:271–5. Halbreich U, Kahn L. Are women with premenstrual dysphoric disorder prone to osteoporosis? Psychosom Med 2001;63:361– 4. Kavuncu V, Kuloglu M, Kaya A, Sahin S, Atmaca M, Firidin B. Bone metabolism and bone mineral density in premenopausal women with mild depression. Yonsei Med J 2002;43:101– 8. Coelho R, Silva C, Maia A, Prata J, Barros H. Bone mineral density and depression: a community study in women. J Psychosom Res 1999;46: 29 –35. Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T. The association of bone mineral density and depression in an older population. J Am Geriatr Soc 2001;49:732– 6. Jacka FN, Pasco JA, Henry MJ, Kotowicz MA, Dodd S, Nicholson GC, Berk M. Depression and bone mineral density in a community sample of perimenopausal women: Geelong Osteoporosis Study. Menopause 2005; 12:88 –91. Reginster JY, Deroisy R, Paul I, Hansenne M, Ansseau M. Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women. Maturitas 1999;33:133–7. Mussolino ME, Jonas BS, Looker AC. Depression and bone mineral density in young adults: results from NHANES III. Psychosom Med 2004;66:533–7. Søgaard AJ, Joakimsen RM, Tverdal A, Fønnebø V, Magnus JH, Berntsen GKR. Long-term mental distress, bone mineral density and non-vertebral fractures. The Tromsø Study. Osteoporos Int 2004 (Epub ahead of print). Whooley MA, Kip KE, Cauley JA, Ensrud KE, Nevitt MC, Browner WS. Depression, falls and risk of fracture in older women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1999;159:484 –90. Whooley MA, Cauley JA, Zmuda JM, Haney EM, Glynn NW. Depressive symptoms and bone mineral density in older men. J Geriatr Psychiatry Neurol 2004;17:88 –92. Schweiger U, Weber B, Deuschle M, Heuser I. Lumbar bone mineral density in patients with major depression: evidence of increased bone loss at follow-up. Am J Psychiatry 2000;157:118 –20. Devenand DP. Comorbid psychiatric illness in late life depression. Biol Psychiatry 2002;52:236 – 42. Melartin TK, Rytsala HJ, Leskela US, Lestela-Mielonen PS, Sokero TP, Isometsa ET. Current comorbidity of psychiatric disorders among DSM-IV major depressive disorder patients in psychiatric care in the Vantaa Depression Study. J Clin Psychiatry 2002;63:126 –34. Corruble E, Ginestet D, Guelfi JD. Comorbidity of personality disorders and unipolar major depression: a review. J Affect Disord 1996;37: 157–70. Rossi A, Marinangeli MG, Butti G, Scinto A, Di Cicco L, Kalyvoka A, Petruzzi C. Personality disorders in bipolar and depressive disorders. J Affect Disord 2001;65:3– 8. Gunderson JG, Morey LC, Stout RL, Skodol AE, Shea MT, McGlashan TH, Zanarini MC, Grilo CM, Sanislow CA, Yen S, Daversa MT, Bender DS. Major depressive disorder and borderline personality disorder revisited: longitudinal interactions. J Clin Psychiatry 2004;65:1049 –56. Comtois KA, Cowley DS, Dunner DL, Roy-Byrne PP. Relationship between borderline personality disorder and axis I diagnosis in severity of depression and anxiety. J Clin Psychiatry 1999;60:752– 8. Heuser I. The hypothalamic–pituitary–adrenal axis in depression. Pharmacopsychiatry 1998;31:10 –3. Lieb K, Rexhausen JE, Kahl KG, Schweiger U, Philipsen A, Hellhammer DH, Bohus M. Increased diurnal salivary cortisol in women with borderline personality disorder. J Psychiatr Res 2004;38:559 – 65. Kahl KG, Bens S, Ziegler K, Rudolf S, Dibbelt L, Kordon A, Schweiger U. Cortisol, the cortisol– dehydroepiandrosterone ratio, and proinflammatory cytokines in patients with current major depressive disorder comorbid with borderline personality disorder. Biol Psychiatry (Epub ahead of print). Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear
29. 30. 31. 32. 33. 34. 35. 36. 37.
38. 39. 40.
factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer 2001;92: 460 –70. Orr FW, Lee J, Duivenvoorden WCM, Singh G. Pathophysiologic interactions in skeletal metastasis. Cancer 2000;88(suppl 1):2912– 8. Guise TA. Molecular mechanisms of osteolytic bone metastases. Cancer 2000;88(suppl 1):2892– 8. WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser 1994;843:1–129. Herra´n A, Amado JA, Garcı´a-Unzueta MT, Va´zquez-Barquero JL, Perera L, Gonza´lez-Macı´as J. Increased bone remodelling in first-episode major depressive disorder. Psychosom Med 2000;62:779 – 82. Van West D, Maes M. Activation of the inflammatory response system: a new look at the etiopathogenesis of major depression. Neuroendocrinol Lett 1999;20:11–7. Lanqillon S, Krieg J-C, Bening-Abu-Shach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 2000;22:370 –9. Dantzer R, Wollman E, Vitkovic L, Yirmiya R. Cytokines and depression: fortuitous or causative association? Mol Psychiatry 1999;4: 328 –32. Hofbauer LC, Khosla S, Lacey DL, Dunstan CR, Boyle WJ, Riggs BL. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000;15:2–12. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000;106:1481– 8. Blum M, Harris SS, Must A, Naumova EN, Phillips SM, Rand WM, Dawson-Hughes B. Leptin, body composition and bone mineral density in premenopausal women. Calcif Tissue Int 2003;73:27–32. Rauch F, Blum WF, Klein K, Allolio B, Schonau E. Does leptin have an effect on bone in adult women? Calcif Tissue Int 1998;63:453–5. Iwamoto I, Oouchi T, Kosha A, Murakami M, Fujino T, Nagata Y. Relationships between serum leptin level and regional bone mineral density, bone metabolic markers in healthy women. Acta Obstet Gynecol Scand 2000;79:1060 – 4. Huang K-C, Cheng W-C, Yen R-F, Tsai K-S, Tai T-Y, Yang W-S. Lack of independent relationship between plasma adiponectin, leptin levels and bone density in nondiabetic female adolescents. Clin Endocrinol 2004; 61:204 – 8. Ueland T, Bollerslev J, Godang K, Mu¨ller F, Frøland SS, Aukrut P. Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess—possible role in bone homeostasis. Eur J Endocrinol 2001;145:685–90. Hofbauer LC, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S. Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenic protein-2, and cytokines. Biochem Biophys Res Commun 1998;250:776 – 81. Brandstrom H, Johnsson KB, Vidal O, Ljunghall S, Ohlssaon C, Ljunggren O. Tumor necrosis factor-alpha and -beta upregulate the levels of osteoprotegerin mRNA in human osteosarcoma MG-63 cells. Biochem Biophys Res Commun 1998;248:454 –7. Hadjidakis D, Tsagarakis S, Roboti C, Sfakianakis M, Iconomidou V, Raptis SA, Thalassinos N. Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas? Clin Endocrinol (Oxf) 2003;58:72–7. Golier JA, Yehuda R, Bierer LM, Mitropoulou V, New AS, Schmeidler J, Silverman JM, Siever LJ. The relationship of borderline personality disorder to posttraumatic stress disorder and traumatic events. Am J Psychiatry 2003;160:2018 –24. Vickers MH, Reddy S, Ikenasio BA, Breier BH. Dysregulation of the adipoinsular axis—a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming. J Endocrinol 2001;170:323–32. Barker DJ. The fetal and infant origins of disease. Eur J Clin Investig 1995;25:457– 63. Hopper JL, Seeman E. The bone density of female twins discordant for tobacco use. N Engl J Med 1994;330:387–92.
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