Osteoporosis is a disease characterized by low bone mineral

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1 Depression and Bone Mineral Density in Young Adults: Results From NHANES III MICHAEL E. MUSSOLINO, MA, BRUCE S. JONAS, SCM, PHD, AND ANNE C. LOOKER, PHD Objective: The purpose of this cross-sectional population-based study was to assess the association of major depressive episode (MDE) and dysthymia with bone mineral density (BMD) in young adults. Methods: Data are from a nationally representative sample of 5,171 people aged 20 to 39 years from the Third National Health and Nutrition Examination Survey. Total proximal femoral BMD was measured using dual energy x-ray absorptiometry. MDE and dysthymia were measured using the Diagnostic Interview Schedule. Results: MDE was associated with lower BMD in multivariate models in men (mean BMD vs g/cm 2 ; odds ratio (OR) per 1 SD decline in BMD 1.65, 95% confidence interval (CI) ; p 0.02) but not in women (mean BMD vs g/cm 2 ;OR 0.96, 95% CI ; p.79). The same divergence by gender was seen for dysthymia. Conclusion: The relationship between BMD and MDE or dysthymia in young adults varies by gender. Key words: bone mineral density; depression, dysthymia, representative sample, young adults. MDE major depressive episode; BMD bone mineral density; NHANES III Third National Health and Nutrition Examination Survey; DIS Diagnostic Interview Schedule. INTRODUCTION Osteoporosis is a disease characterized by low bone mineral density (BMD). BMD has been shown to be a risk factor for fracture (1). There are established risk factors for osteoporosis (2). Depression has been implicated as a possible risk factor for low BMD (3), but the results to date have not been consistent. Among women, some studies have reported an association between depression and low BMD (4,5) or osteoporotic fractures (6), although other studies found no such relationship (7,8). Other research suggests that the relationship may vary depending on gender or race. For example, Schweiger et al. (9) and Halbreich et al. (10) reported that the relationship was more pronounced in men than in women, whereas Robbins et al. (11) found that the relationship occurred in white women, but not in white men or blacks. Most of the previous studies examined the issue in middleaged or older adults, and in five of the studies the mean age was about 60 years or older (3,6,7,9,11). There are few data on the BMD and depression relationship in younger women, and to our knowledge, this relationship has not been examined in young men. There is currently great interest in identifying factors that are associated with BMD in younger individuals because these factors may be important for attainment of peak bone mass (12). The Third National Health and Nutrition Examination Survey (NHANES III), a large-scale national study, provides an opportunity to investigate whether major depressive episode (MDE) and dysthymia are associated with lower BMD in a representative sample of men and women aged 20 to 39 years. Unlike some previous studies that examined subjects in institutional settings, our study provides a wider variation in the level of depression among subjects who met the full criteria for MDE and dysthymia. Thus, our results From the Centers for Disease Control and Prevention, National Center for Health Statistics. Address correspondence to Michael E. Mussolino, Centers for Disease Control and Prevention, National Center for Health Statistics, 3311 Toledo Road, Room 6431, Hyattsville, MD MMussolino@cdc.gov Received for publication September 4, 2003; revision received March 29, DOI: /01.psy d may be more broadly generalizable than some of the previous studies. MATERIALS AND METHODS Data for these analyses were taken from NHANES III. NHANES III collected data from a national probability sample of the civilian noninstitutionalized US population from 1988 to 1994 (13). Because only subjects between the ages of 20 and 39 years received both the bone density scan and the Diagnostic Interview Schedule (DIS), the eligible sample was limited to the 5,624 non-hispanic white, non-hispanic black, and Mexican-American men and women in this age group. Persons of other race-ethnicity groups were omitted because of the small number of observations. Also excluded were 138 subjects with missing values for MDE or dysthymia and 315 subjects with unknown values for any of the other variables assessed in the study. A total of 2,528 men and 2,643 women were included in the final analytic sample. Bone Mineral Density Measurement BMD was measured by trained examiners in mobile examination centers. Total proximal femoral BMD expressed in grams of bone mineral content per area of square centimeters was measured by dual energy x-ray absorptiometry (Hologic QDR-1000; Hologic, Inc., Waltham, MA). This is the standard technique for measuring areal BMD. Scans were reviewed by consultants at the Mayo Clinic, Rochester, MN, for quality control (14). Mood Disorders The DIS (15) is a structured psychiatric interview schedule developed for use by trained lay interviewers with versions that employ the same Diagnostic and Statistical Manual of Mental Disorders Third Edition (DSM-III) and DSM Revised Edition (DSM-III-R) as used by clinicians (16,17). The DSM-III version of the DIS was used in the NHANES III. The DIS was administered by trained interviewers in the mobile examination centers, where privacy could be ensured. In the present study, data from the DIS were used to assess the prevalence of those who had ever experienced two mood disorders: MDE and dysthymia. The definitions of MDE and dysthymia used in our study were based on preset diagnostic criteria from the National Institute of Mental Health for these conditions that are incorporated into the DIS and that allow these diagnoses to closely follow DSM-III guidelines. MDE was defined as persistent depressed mood: ( In your lifetime, have you ever had 2 weeks or more during which you felt sad, blue, depressed, or when you lost all interest and pleasure in things that you cared about or enjoyed? ). In addition, at least four of the following eight symptom groups must be present: change in appetite or weight, sleep disturbance, changes in psychomotor activity, loss of ability to experience pleasure and interest, fatigue, feelings of worthlessness or guilt, difficulty in concentrating, and preoccupation with death or a wish to die. Dysthymia was defined as a chronic depressed mood: ( Have you had 2 years or more in your life when you felt depressed or sad almost all the time, even if you felt OK sometimes? ). In addition, at least three of seven symptom groups must be present (these groups are the same as the second through eighth symptom groups listed above for MDE). Thus, those with dysthymia had symptoms characteristic of MDE for a longer period of time, but these /04/ Copyright 2004 by the American Psychosomatic Society 533

2 M. E. MUSSOLINO et al. symptoms were not necessarily of sufficient severity and/or frequency to meet the criteria for MDE. Persons can be independently diagnosed with either MDE or dysthymia or can be diagnosed with both disorders. Diagnosis of one does not preclude diagnosis of the other (13,18). Additional analyses were also conducted with MDE or dysthymia categorized into symptom groups (range 0 9 groups). This variable was defined as the number of positive symptom groups listed for MDE plus an additional dysphoria symptom indicator. Dysphoria was defined as dysphoric mood or loss of interest or pleasure in all or almost all usual activities and pastimes. Further details regarding how the DIS was administered and the diagnosis of these mood disorders have been published elsewhere (13,15). Other Baseline Variables We controlled for relevant established risk factors related to BMD (2) in our main analyses. Information on smoking status (current, former, never), alcohol consumption (drinks per month), physical activity, self-assessed health status, food energy, calcium consumption, protein intake, weight history including maximum weight, and chronic conditions related to secondary osteoporosis were obtained by interview, and weight and height were measured at the medical examination. The nutritional variables were determined using a 24-hour recall. The chronic conditions variable was based on self-reported doctor s diagnoses of congestive heart failure, stroke, chronic bronchitis, asthma, arthritis, goiter, other thyroid disease, or diabetes. Statistical Analysis Statistical analyses were performed using linear regression procedures in SAS (19) and SUDAAN (20). Sample weights were used when calculating point estimates, so estimates are representative of the civilian, noninstitutionalized US population at the time of NHANES III. All numbers reported in the text and tables are weighted except for sample size, which was included to give the actual number of participants. The Kolmogorov D statistic indicated that BMD was not normally distributed (p.01). However, results were unchanged after we used a logarithmic transformation of BMD. Therefore, we report BMD results that have not been transformed, which is in accordance with presentation of results in the vast majority of previously published analyses of BMD. Weighted multivariate regression analyses were performed using BMD as a continuous variable. Odds ratios were also calculated by comparing people with BMD values at 1 SD below the mean to those with the mean BMD value. The interaction between gender and depression was significant (p.0148). Thus, all models were stratified by gender. All models were adjusted for age, race-ethnicity, and the established risk factors for low BMD listed earlier, unless otherwise indicated. RESULTS Overall, 5.8% of men and 12.6% of women were diagnosed with MDE, whereas 4.6% of men and 8.6% of women had dysthymia. Of the total number of persons with MDE, 42.5% also met the criteria for dysthymia. Of those with dysthymia, 59.0% also met the criteria for MDE. Thus, there is considerable overlap between the two conditions. Baseline characteristics of persons by MDE status (yes, no) are shown in Table 1. Men with MDE were typically of shorter stature and more likely to report current smoking and weight loss from maximum weight of 10% than those with no history of MDE. Men with MDE had mean proximal femoral BMD that was 5.1% lower than men without MDE. Women with MDE were more likely to report weight loss from maximum weight of 10% than those without MDE. No differences in BMD TABLE 1. Characteristics of 5,171 Men and Women Aged Years by Major Depressive Episode (MDE) Status: Third National Health and Nutrition Examination Survey a Men MDE Women MDE Yes No Yes No Variable N a Age at interview (y) Race ethnicity, % Non-Hispanic white * 78.6 Non-Hispanic black * 15.0 Mexican-American Weight (kg) Height (cm) 175.6* Total femur bone mineral density (g/cm 2 ) 1.004* Smoking status, % Current 54.4* Former Never 32.0* Alcohol (drinks/month) Any chronic conditions, % Weight loss from maximum 10%, % 35.2* * 20.3 Dietary variables Food energy (kcal/day) 3, , , ,935.0 Calcium (mg/day) 1, , Protein (g/day) Physical activity level, % Low Moderate High * p 0.05, t-test comparing MDE groups within gender. a All numbers reported in the text and tables are weighted except for sample size, which was included to give the actual number of participants. 534

3 DEPRESSION AND BONE MINERAL DENSITY were found for women regardless of MDE history. Findings were similar when persons were classified according to dysthymia status. Table 2 shows odds ratios (OR) and 95% CI for the MDE and dysthymia regression models. After adjusting for several potential confounding factors in the multivariate models, men with MDE still had significantly lower BMD than those without MDE (mean BMD vs g/cm 2,OR 1.65, 95% CI , p.02). For women, however, no relation between BMD and MDE was found in either the age- and race ethnicity adjusted or risk-adjusted models (mean BMD vs g/cm 2, OR 0.96, 95% CI , p.79). Similar results were observed when we examined the BMD dysthymia relationship: men with this condition had lower BMD than nondysthymic men, but BMD did not differ by dysthymia in women. We also looked at MDE and dysthymia combined (ie, subjects with both conditions) in regression models. Results were similar to those seen when the conditions were considered separately (not shown). When subjects with either MDE or dysthymia were compared with those free of both conditions, the results remained unchanged: BMD differed significantly in men, but not in women. When a self-assessed health status variable was added to the multivariate models, MDE and dysthymia remained statistically significant predictors of BMD in men. Finally, no significant interactions between race ethnicity and depression (p.7428) or race ethnicity and gender (p.1900) were observed. Additional Analyses The MDE/dysthymia and BMD association for men remained when MDE or dysthymia were categorized into symptom groups (range 0 9 groups) in the multivariate model. We found evidence of a threshold effect, ie, men with five to TABLE 2. Odds Ratios a and 95% CI for Bone Mineral Density Associated With Major Depressive Episode (MDE) and Dysthymia Among Men and Women Aged Years, NHANES III b Age and race ethnicity adjusted Odds Ratios (95% CI) Risk-adjusted c Odds Ratios (95% CI) Men MDE 2.27 ( )** 1.65 ( )* Dysthymia 2.94 ( )*** 1.84 ( )** Women MDE 0.94 ( ) 0.96 ( ) Dysthymia 1.03 ( ) 1.09 ( ) a Odds ratios and 95% CI are based on a decrease of 1 SD in bone mineral density. b All numbers reported in the text and tables are weighted except for sample size, which was included to give the actual number of participants. c Models were adjusted for age at interview, race ethnicity, weight, height, food energy, calcium consumption, protein intake, alcohol consumption, smoking status, physical activity, chronic conditions, and weight change. * p 0.05; ** p 0.01; *** p MDE, comparison groups, no history of MDE; Dysthymia, comparison groups, no history of dysthymia; NHANES III, Third National Health and Nutrition Examination Survey. nine positive symptom groups had significantly lower BMD (3.0% lower) than men with zero to four positive symptom groups (OR 1.68, 95% CI , p.02). However, these variables were not significantly related to BMD in women when multivariate models were used (OR 1.05, 95% CI , p.66). DISCUSSION Our results from this large nationally representative sample suggest that MDE and dysthymia are associated with lower proximal femoral BMD in young men, but not in young women. Odds ratios suggest that the relationship may be somewhat stronger for dysthymia than for MDE (OR 1.84 vs. OR 1.65, respectively). Given the slow time frame for BMD changes in young adulthood, it seems reasonable that the more chronic condition, dysthymia, would have a stronger relationship. We also found evidence of a threshold effect in men. Men with five or more positive symptom groups for MDE or dysthymia had significantly lower BMD than men with four or fewer symptoms. Adjustment for established BMD risk factors did not appreciably alter conclusions. Previous studies have focused more exclusively on middle-aged and older individuals, and on more severe forms of depression. We believe our study fills several gaps by a) providing information about young adults, b) providing an expanded selection of mood disorder diagnoses, and c) exploring the symptomatology gradient that does not rely on meeting full diagnostic criteria. There are several direct pathways through which depression or dysthymia could lower proximal femoral BMD. For example, persistently elevated plasma cortisol levels have been associated with clinical depression (4) and also with low BMD (21). Elevated plasma cortisol levels in depression have been associated with hypothalamic pituitary adrenocortical axis disturbances (22), diminished glucose tolerance (23), and increased adrenal gland volume (24). Thus, it can be hypothesized that persistently elevated plasma cortisol levels in depressed patients may be associated with enhanced bone metabolism, particularly in the presence of chronic hypercortisolemia (4). Other processes may include hyperprolactinemia, hypogonadism, increased interleukin activity, and calcium imbalance (25). Depression and dysthymia may also operate indirectly in that their presence may affect behaviors, which may in turn result in lower BMD. For example, depression has been found to be associated with increases in smoking and alcohol use and with decreases in physical activity (26 29). In addition, both depression and lowered BMD or osteoporosis have been linked to deficits of n-3 fatty acids, so that the relationship between BMD, osteoporosis, and depression could be jointly explained, at least in part, by reduced intake of these fatty acids (30,31). Our results indicate that there is a divergence in the relationship between decreased bone density and MDE or dysthymia by gender, but the reason for this divergence is not obvious. There are, however, several possible explanations. One such explanation concerns gender differences in the re- 535

4 M. E. MUSSOLINO et al. porting of mood disorders. We found that the prevalence rates for MDE and dysthymia were approximately twice as high for women compared with men. Similar findings were reported elsewhere (18,32). There is a body of literature that supports the idea of response bias in reports of mental illness (33 36). In specific, women may be more open to reporting such symptomatology, so that the higher prevalence rates of MDE and dysthymia seen in women in our study could reflect inclusion of women with a milder degree of these mood disorders. Conversely, men who report such symptomatology may represent a more concentrated set of true positives, ie, persons who are actually experiencing major depression. Although this is clearly speculative, it would offer one explanation for the differing pattern of results. Another possible explanation is that depression has more of an impact on physical activity or diet among men than women. Unlike a previous study (11), we did not observe a divergence between bone density and MDE by race ethnicity, suggesting that the effect is the same in all three race ethnicity groups. The discrepancy in results could be due to differences in the samples used in the two studies, eg, the present study focused on young adults, whereas the previous study focused on the elderly. Our study has the advantage of being based on a representative sample that included a relatively large number of subjects with a clinical diagnosis of MDE compared with other studies. Thus, our results may be more broadly generalizable than those of previous studies. Our study is the first to look at the BMD depression relationship in younger individuals and includes a wider selection of mood disorder outcomes than some previous studies that examined the issue in institutionalized patients. However, our study has several limitations. It is cross-sectional in nature, and as such, cannot provide definitive evidence that MDE or dysthymia caused the lower BMD levels observed in male subjects. The threshold effect that we observed between MDE and bone density in men is suggestive in this regard, but it is also possible that selfselection played a role, eg, those with MDE or dysthymia already had lower BMD before the depressive episode. However, results did not change when we included self-reported health status or presence of chronic conditions in the analysis, which suggests that the relationship between MDE and dysthymia in men is not due to differences in health status. We conclude that MDE and dysthymia are associated with significantly lower proximal femoral BMD in young men, but not in young women. The relationship was stronger with dysthymia, the more chronic mood disorder. The association in men remained when the total number of positive symptoms of MDE and dysthymia were treated as a continuous variable. 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