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Major Depression Is a Risk Factor for Low Bone Mineral Density: A Meta-Analysis
Major Depression Is a Risk Factor for Low Bone Mineral Density: A Meta-Analysis Raz Yirmiya and Itai Bab Background: The role of depression as a risk factor for low bone mineral density (BMD) and osteoporosis is not fully acknowledged, mainly because the relevant literature is inconsistent and because information on the mechanisms mediating brain-to-bone signals is rather scanty. Methods: Searching databases and reviewing citations in relevant articles, we identified 23 studies that quantitatively address the relationship between depression and skeletal status, comparing 2327 depressed with 21,141 nondepressed individuals. We subjected these studies to meta-analysis, assessing the association between depression and BMD as well as between depression and bone turnover markers. Results: Overall, depressed individuals displayed lower BMD than nondepressed subjects, with a composite weighted mean effect size (d) of ⫺.23 (95% confidence interval: ⫺.33 to ⫺.13; p ⬍ .001). The association between depression and BMD was similar in the spine, hip, and forearm. It was stronger in women (d ⫽ ⫺.24) than men (d ⫽ ⫺.12) and in premenopausal (d ⫽ ⫺.31) than postmenopausal (d ⫽ ⫺.12) women. Only women individually diagnosed for major depression by a psychiatrist with DSM criteria displayed significantly low BMD (d ⫽ ⫺.36); women diagnosed by self-rating questionnaires did not (d ⫽ ⫺.06). Depressed subjects had increased urinary levels of bone resorption markers (d ⫽ .52). Conclusions: The present findings portray depression as a significant risk factor for low BMD. Premenopausal women who are psychiatrically diagnosed with major depression are particularly at high-risk for depression-associated low BMD. Hence, periodic BMD measurements and antiosteoporotic prophylactic and curative measures are strongly advocated for these patients. Key Words: Bone mineral density, major depression, meta-analysis, osteoporosis
O
steoporosis, the most common degenerative disease in developed countries (1), is characterized by low bone mass and deterioration of skeletal structure, causing bone fragility and increased fracture incidence. In the United States alone, approximately 10 million individuals over the age of 50 have osteoporosis. In addition, 33.6 million Americans in this age group have osteopenia (i.e., a decrease in bone mineral density [BMD] that precedes osteoporosis and its potential complications later in life). The estimated annual fracture rate due to an underlying bone disease is 1.5 million. These fractures lead to pain, skeletal mutilation, disability, loss of independence, and increased mortality (2). In its early stages, before the occurrence of fractures, osteoporosis is a symptom-free silent disease and hence most osteoporotic individuals are left undiagnosed. This situation is unfortunate in view of available effective antiosteoporotic preventive and curative treatment modalities, which can be initiated before the appearance of a first fracture. Moreover, it has been suggested that the bone loss that leads to osteoporosis might begin relatively early in life, at a time when treatment could potentially slow its course. Despite its inherent limitations, BMD determination is currently the main tool for diagnosing osteopenia and osteoporosis (2). Because it is
From the Department of Psychology (RY) and Bone Laboratory (IB), The Hebrew University of Jerusalem, Jerusalem, Israel. Address correspondence to Raz Yirmiya, Ph.D., Department of Psychology, The Hebrew University of Jerusalem Mount Scopus, Jerusalem 91905 Israel; E-mail: [email protected]. Received Dec 29, 2008; revised Feb 25, 2009; accepted Mar 13, 2009.
0006-3223/09/$36.00 doi:10.1016/j.biopsych.2009.03.016
impractical to perform frequent whole population screening for subjects with low BMD, knowledge of its risk factors is essential for identifying individuals in danger of developing osteoporosis, allowing a rational comprehensive assessment of these patients and the administration of preventive and therapeutic measures (3). Several risk factors have been implicated in the development of osteoporosis, including low peak bone mass, age, female gender, estrogen deficiency, calcium deficiency, low levels of physical activity, glucocorticoid therapy and other medications, and several medical conditions as well as smoking and drug abuse (2– 4). In the last 14 years, ample research implicated major depression in bone loss and osteoporosis (comprehensively reviewed in 5–7). Like osteoporosis, major depression is a prevalent disorder, considered the second leading global cause of years of life lived with disability (8). The number of patients experiencing a major depressive episode in the United States mounts to 10 –14 million annually (more than 5% of the population) (9). However, despite the high prevalence of both diseases, most official publications emanating from authorities such as the National Institutes of Health, the National Osteoporosis Foundation, the National Osteoporosis Society (United Kingdom), and Osteoporosis Canada do not fully acknowledge depression as a risk factor for low BMD and osteoporosis, apparently because the literature on the relationship between these conditions is insufficiently conclusive. Some studies report that patients with major depression present up to 15% lower BMD, whereas others, particularly large-scale population-based studies, show a weak or no relationship between the two conditions. We have recently demonstrated, in a mouse model, a causal relationship between depression and bone loss as well as the involvement of the sympathetic nervous system in this relationship (10). This study and the increasing number of publications in the field prompted us to examine the evidence in humans for a possible impact of depression on skeletal status. Indeed, with meta-analytical proBIOL PSYCHIATRY 2009;66:423– 432 © 2009 Society of Biological Psychiatry
424 BIOL PSYCHIATRY 2009;66:423– 432 cedures we portray major depression as a risk factor for low BMD, mainly in premenopausal women.
Methods and Materials Sample of Studies Studies were identified with the computerized databases MEDLINE, ISI Web of Science, BIOSIS Previews, Dissertation Abstracts, Health and Wellness Resource Center (Gale), and PsychoINFO, covering the period ending December 1, 2008. We used a combination of the keyword “depression” with keywords related to skeletal biology and pathology, including “bone”, “osteoporosis”, “osteopenia”, “osteoclast”, “osteoblast”, and “osteocalcin”. Relevant reports were also gathered from reference lists of published articles, including primary studies and several reviews (3–5,11–13). Inclusion criteria were: 1) full journal publication or dissertation, and 2) comparison of BMD and/or bone remodeling parameters between depressed individuals and matched control subjects. In total, 24 articles were identified that complied with these criteria (14 –37). Further abstract search yielded no additional publications with sufficient information for inclusion in the meta-analysis. Data Extraction Data were extracted independently by two examiners (R.Y. and I.B.), with standardized data-abstraction forms. Disagreements were resolved by discussion. The extracted information included year of publication, country where the study was conducted, gender, mean age, sample size, menopausal status, depression assessment tool, skeletal sites used for BMD determination, serum osteocalcin measurement, and levels of urinary bone resorption markers. Authors were contacted if further study details were needed. Appropriate quantitative data for inclusion in the meta-analysis could not be obtained for one study (32). In most studies, the depressed and nondepressed samples were matched on at least some variables, including age, body mass index (or body weight), race, marital and menopausal status, hormone therapy, calcium intake, physical activity, and alcohol consumption. Smoking rates were usually higher in depressed compared with nondepressed participants. For studies reporting adjusted results (e.g., for age, body mass index, estrogen usage, physical activity, alcohol consumption, smoking), we used the adjusted values. In addition, information on potential moderator variables related to the clinical manifestation of depression was extracted, including proportion of subjects taking antidepressant drugs, depression severity, illness duration, and lifetime number of depressive episodes. However, these data were absent in most reports and hence insufficient for inclusion in the meta-analysis. Statistical Analyses We carried out separate meta-analyses for BMD, serum levels of osteocalcin, and urinary levels of bone resorption markers, including deoxypyridinoline, telopeptide (with absolute values or values normalized for creatinine), and cross-laps, in depressed and nondepressed individuals. Due to the low number of studies that assessed the bone resorption markers and because most of these studies reported only one such marker, separate comparisons for each marker were unattainable. Therefore, the comparison was conducted across the three resorption markers. Analyses were performed with the Comprehensive Meta-Analysis (CMA) software (Englewood, New Jersey). In each meta-analysis, standardized effect sizes derived from the individual studies were combined to determine a composite mean weighted effect size (d) along with its 95% confidence interval (CI) and significance www.sobp.org/journal
R. Yirmiya and I. Bab level (i.e., the effect size is significant if the CI does not include a zero) (38). Greater weight is given to studies with larger samples; hence, this procedure corrects for biases associated with small sample sizes. Because the effects of depression on BMD and bone remodeling were studied in different settings (e.g., psychiatric inpatients and outpatients, community dwellers) and because participant demographic data differed greatly between studies, we assumed the presence of heterogeneity a priori, namely, that the effect of individual trials would vary more than expected by chance alone. Therefore, the variance and statistical significance of differences were assessed with randomeffect calculations in all analyses. To determine the validity of the meta-analyses, we employed funnel plots (i.e., plots of the standard difference in means [d] against the SEM) (39). This was followed by quantitative evaluation of the degree of asymmetry (39,40).
Results The 23 studies included in the analysis (14 –31,33–37) encompassed 2327 depressed and 21,141 nondepressed individuals (Table 1). The association between depression and BMD was addressed in 22 studies (with the exception of [19]). The effect of depression on serum osteocalcin and urinary bone resorption markers was assessed in 8 of these studies (14,17,19,21–24,36) and in an additional report that measured only osteocalcin and the resorption markers (19). Effect sizes, corresponding CIs for each study, and a forest plot summarizing the association between depression and BMD are presented in Figure 1. The effect sizes range from ⫺1.16 to .33, with 20 studies reporting either decreased or unchanged BMD and only 2 studies showing increased BMD in depressed versus nondepressed individuals. The composite weighted mean effect size, d, of ⫺.219, with its CI between ⫺.325 and ⫺.126, implies that overall BMD is significantly lower in depressed than in nondepressed individuals (p ⬍ .001). However, homogeneity in the overall analysis was rejected (p ⫽ .0001). Hence, we used categorical model fitting procedures to further explore whether potential moderator variables could account for this heterogeneity. Because of the well-established differences in osteoporosis prevalence between women and men, we initially analyzed gender as such a moderator variable. Both women and men with depression (n ⫽ 1870 and 457, respectively) displayed significantly lower BMD than their matched control subjects (n ⫽ 15,795 and n ⫽ 5346; p ⫽ .0001 and p ⫽ .003, respectively) (Figure 2). However, gender was found to be a significant moderator variable; in women the association of depression and BMD was significantly stronger than in men (p ⫽ .032). For men, homogeneity was not rejected (p ⫽ .36), indicating that no other moderator variables would further explain the association of depression and BMD in this gender. In contrast, in women homogeneity was rejected (p ⬍ .0001), and thus further categorical model fitting was continued only within this gender. The female skeletal site where bone density was measured was not found to be a significant moderating variable of the association between depression and BMD (p ⫽ .59) (Figure 1 in Supplement 1). Both spine and hip BMD was significantly lower in depressed than in nondepressed women (p ⫽ .002 and p ⫽ .003, respectively). Although in the forearm the association was statistically insignificant (p ⫽ .128), this result should be interpreted cautiously because forearm BMD was measured in only 5
Year
Country
Gender
Schweiger et al. (29)
1994
Germany
Michelson et al. (24) Amsterdam et al. (15)
1996 1998
US US
Reginster et al. (27) Wooley et al. (34) Herran et al. (19) Schweiger et al. (30)
1999 1999 2000 2000
Belgium US Spain Germany
Robbins et al. (28)
2001
US
Kavunco et al. (23) Yazici et al. (37) Mussolino et al. (25)
2002 2003 2004
Turkey Turkey US
Whooley et al. (33) Furlan et al. (18) Jacka et al. (20) Kahl et al. (22) Ozsoy et al. (26)
2004 2005 2005 2005 2005
US US Australia Germany Turkey
Sogaard et al. (31) Wong et al. (35)
2005 2005
53/27 27/30 24/24 4/3 2/2 12/12 461/6,895 19/19 8/7 10/14 145/758 85/561 42/42 25/15 297/2,346 127/2,401 16/497 9/10 14/64 10/16 21/12 21/11 343/1437 169/1830
Yazici et al. (36) Kahl et al. (21) Altindag et al. (14) Diem et al. (16) Eskandari et al. (17) Spangler et al. (32)e
2005 2006 2007 2007 2007 2008
Norway Hong Kong Turkey Germany Turkey US US US
Women Men Women Women Men Women Women Women Womenc Menc Women Men Women Women Women Men Men Women Women Womend Women Men Women Men Women Womend Women Women Women US
35/30 23/16 36/41 200/3,977 89/44 e
Bone Sitea spine spine, hip, forearm spine spine, hip spine, hip
Menopausal Status
60.7 60.6 41.0 39.6
post
DSM
BMD
preb preb
DSM DSM
BMD, osteocalcin, osteoclastic markers BMD
post post preb post
SR (GHQ-28) SR (GDS) DSM (SCAN) DSM
BMD BMD osteocalcin, osteoclastic markers BMD
post
SR (CES-D)
BMD
pre pre pre
DSM DSM SR (DIS)
BMD, osteocalcin, osteoclastic markers BMD BMD
post post pre pre
SR (GDS) DSM SR (DSM-based) DSM DSM
BMD BMD BMD BMD, osteocalcin, osteoclastic markers BMD
post
SR (custom) SR (GDS)
BMD BMD
post pre pre post pre post
DSM DSM DSM SR (GDS) DSM SR (CES-D)
BMD, osteocalcin, osteoclastic markers BMD, osteocalcin, osteoclastic markers BMD, osteocalcin, osteoclastic markers BMD BMD, osteocalcin, osteoclastic markers BMD
forearm spine, hip
63.4 73.4 44.1 61.9 61.7 74.0 74.8 36.1 30.1 30.1 29.6 66.6 64.2 52.9 25.2 36.2 36.2 50.6 72.4
spine, hip spine, hip, forearm spine, hip hip spine, hip, forearm spine, hip
45.4 27.5 41.4 75.7 35.0 63.8
spine hip spine, hip spine, hip hip spine, hip spine, hip spine, hip spine, hip, forearm spine, hip
Depression Assessment Toola
Mean Age
Outcome
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BMD, bone mineral density; SR, self-rating; GHQ-28, General Health Questionnaire-28; GDS, Geriatric Depression Scale; SCAN, Schedule for Clinical Assessment in Neuropsychiatry; CES-D, Center for Epidemiologic Studies Depression Scale; DIS, Diagnostic Interview Schedule. a Measurements of hip BMD were reported either for the “total hip” or for specific parts of the hip (including the femoral neck, trochanter, intertrochanter, and Ward’s triangle). In the latter case, the data of the femoral neck (which is more sensitive to bone loss due to various causes) were used in the analysis. b This study included both pre- and postmenopausal women in the analysis. However the study was coded as premenopausal, because the subjects were relatively young (⬍44.7 years on average) and the proportion of postmenopausal women was not high (⬍one-third). c In this longitudinal study, BMD was measured both at the beginning of the study and at follow-up; only the follow-up data were used in the analysis. d In this study, depression-associated BMD differences were measured in the context of borderline personality disorder (BPD) (which by itself had no effect on BMD). Thus, the experimental group comprised women with comorbid major depressive disorder and BPD, whereas the control group comprised women with BPD only. e The results of this study were not included in the meta-analysis, because appropriate quantitative data could not be obtained. The total number of participants in this study was 4539, but no information on the number of depressed versus nondepressed control subjects could be obtained.
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Study Name
Depressive/ Control Subjects (n)
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Table 1. Characteristics of All Studies That Quantitatively Addressed the Relationship Between Depression and Skeletal Status
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Figure 1. Estimates of the effect sizes in all studies that quantitatively examined the association between depression and bone mineral density (BMD). For each study, the square in the forest plot denotes the value of the effect size (d), and the horizontal lines extending to the right and left of the square indicate the widths of the 95% confidence intervals (CIs)—also presented numerically in the second column from the left. The size of the square represents the relative weight of the particular study in the overall meta-analysis, which is also presented numerically in the right column. The circle at the bottom of the graph represents the overall estimate of the association between depression and BMD.
studies. Moreover, one of these studies (31), which had been performed in a large sample and therefore had a high weight in the meta-analysis, was methodologically problematic. It was conducted longitudinally, and some of the women had a depressive episode many years before the BMD measurement. Furthermore, in that study, depression was assessed quite crudely with a 1-item evaluation, namely, “Have you felt unhappy and depressed during the past couple of weeks?” Excluding this study from the meta-analysis led to a significant association between depression and BMD in the forearm too (p ⫽ .011). Examination of the moderating effect of menopausal status revealed that both pre- and postmenopausal women displayed a significant association between depression and decreased BMD (p ⫽ .0001 and p ⫽ .01, respectively) (Figure 2 in Supplement 1). The association was stronger in pre- than in postmenopausal subjects, but the difference did not reach statistical significance (p ⫽ .124). This difference could be rendered significant (p ⫽ .047) by excluding one report (36). Surprisingly, in contrast with almost all other studies, including a previous report by the same group (37), this report suggests that BMD is increased in women with “mild to moderate depression.” Analyzing the effect of the depression assessment procedure used in the various studies revealed a significantly stronger association between depression and BMD in women diagnosed individually by a psychiatrist according to the DSM (41) criteria, compared with subjects assessed with self-rating (SR) questionnaires (p ⫽ .002) (Figure 3). Specifically, BMD was significantly lower in depressed women who had been formally diagnosed as suffering from major depression according to DSM criteria (p ⫽ .0001), whereas in women diagnosed by SR questionnaires the effects of depression on BMD did not reach statistical significance (p ⫽ .079). www.sobp.org/journal
Collectively, the studies addressing the relationship between depression and bone turnover markers compared 256 depressed with 232 nondepressed individuals (Figure 3A in Supplement 1). The effect sizes of the association between depression and serum osteocalcin levels ranged from ⫺.676 to 1.047, with two studies showing reduced levels, two studies reporting no effect, and four studies reporting increased osteocalcin levels in depressed compared with nondepressed women. The composite weighted mean effect size (d ⫽ .153) with its CI (⫺.049 to .356) implies that, overall, individuals with depression did not display a significant alteration in osteocalcin levels (p ⫽ .14). Homogeneity was rejected (p ⫽ .0001), but due to the small number of studies, further categorical model fitting was unattainable. Five studies assessed the association between depression and urinary levels of one bone resorption marker, and two additional studies reported associations with two markers (Figure 3B in Supplement 1). The effect sizes ranged from ⫺.698 to 1.474, with two comparisons showing reduced levels, one comparison reporting no effect, and six comparisons reporting increased resorption marker levels in depressed compared with nondepressed women. The composite weighted mean effect size (d ⫽ .515) with its CI (.310 –.720) implies that, overall, individuals with depression displayed significantly higher levels of resorption markers (p ⫽ .0001). As with osteocalcin, homogeneity was rejected (p ⫽ .0001), but due to the small number of studies, further categorical model fitting was unattainable. A publication bias might occur if the probability that acceptance for publication depends on the reported results. This bias was assessed here by the funnel plot procedure (39). Indeed, the funnel plot of the overall standardized effects shown in Figure 1 was asymmetric (Figure 4), as reflected by a trend for significant rank correlation value (p ⫽ .076) and highly significant Egger regression intercept (p ⫽ .007). This asymmetry could represent
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Figure 2. Estimates of the effect sizes in all studies that quantitatively examined the association between depression and bone mineral density (BMD) in either women (A) or men (B). CI, confidence interval.
a publication bias based on the “file-drawer effect”, which could arise if studies that found a significant effect of depression on BMD would be more likely to be published than studies with negative results. Apparently, this is not the present case, because calculation of the “fail-safe number” (42) indicates that an additional 297 comparable studies with negative results should have been published for the present results to lose their significance. Considering that only 24 studies were published on depression and BMD in the 14 years that passed since the first publication on this subject, it is extremely unlikely that so many studies with null results were conducted but remained in the file-drawers. Another source of asymmetry might be an actual heterogeneity among the studies (39). In the present meta-analysis, such a source could be the distinction between studies reporting relatively small samples of patients with major depression, diagnosed by a psychiatrist on the basis of DSM criteria, and large sample studies conducted on community dwellers, diagnosed by
SR checklists. Indeed, when results of these two types of studies were analyzed separately, no significant asymmetry appeared in either funnel plot (data not shown).
Discussion The results of the present meta-analysis, comparing 2327 depressed individuals with 21,141 control subjects, indicate that depression is associated with significantly reduced BMD and increased bone turnover. In addition, the analysis enabled assessment of the magnitude of the overall effect sizes, which were d ⫽ ⫺.219 for BMD, d ⫽ .153 for osteocalcin, and d ⫽ .515 for bone resorption markers. According to Cohen’s criteria, an effect size of d ⫽ .20 is small, d ⫽ .50 is moderate, and d ⫽ .80 is large (38). Hence, the overall effect size of depression on BMD is rather small, whereas the effect on resorption markers is moderate. However, further analysis revealed that, when potential moderator variables are taken into account, the effect of www.sobp.org/journal
428 BIOL PSYCHIATRY 2009;66:423– 432
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Figure 3. Estimates of the effect sizes in all studies that quantitatively examined the association between depression and bone mineral density (BMD) with either individual psychiatric assessment according to DSM criteria (A) or self-rating questionnaires (B). CI, confidence interval.
depression on BMD in specific subgroups approaches the moderate range. Both osteoporosis and depression are approximately threefold more common in women than in men (2,41,43). Indeed, the current meta-analysis portrays women as significantly more vulnerable to depression-associated low BMD. This gender difference might be related to the greater sensitivity of women to stress in general (44) and to the greater responsiveness of depressed women to various stressors in particular (45). It should be emphasized, however, that although the effect of depression in men is smaller than in women, it is more robust, namely, it is not influenced by various moderating variables. In contrast, the association between depression and BMD in women shows significant heterogeneity, because it is significantly moderated by at least two variables, menopausal status and the depression assessment procedure. Premenopausal women displayed a greater depression-associated decrease in BMD compared with postmenopausal subjects, and after removal of a single outlier report this effect became statistically significant. This finding does not necessarily mean that depression is not associated with low BMD after menopause. However, in postmenopausal women this association might be masked by the multiplicity of factors contributing to the development of low bone mass, such as estrogen depletion, reduced physical activity, nutritional disturbances, and drug treatments (4,41). Hence, to further assess the impact of menowww.sobp.org/journal
pausal status on depression-associated low BMD, direct comparisons for the effects of depression on BMD should be undertaken between pre- and postmenopausal women, inasmuch as studies carried out so far focused mainly on either pre- or postmenopausal subjects. The present meta-analysis clearly indicates that assessment of an association between depression and BMD critically depends on the procedure employed for diagnosing the depressive condition. When depression was individually diagnosed by a psychiatrist, defining major depression by DSM criteria (41), the magnitude of the effect was substantial, namely, the effect size was d ⫽ ⫺.360, closer to a moderate effect size according to Cohen’s criteria (38). In such studies, subjects are either inpatients or are seeking psychiatric help for their depressive condition. In contrast, in studies based on SR checklists, an overall significant relationship could not be identified between depression and BMD. These checklists (e.g.,46,47) were developed as screening tools for the general population and are not customarily used to diagnose psychiatric patients. Compared with DSM-based psychiatric evaluations, they are rather heterogeneous, measure a restricted array of depressive symptoms, and assess mood and behavior over a relatively short period. Therefore, it seems that depression-associated low BMD afflicts mainly psychiatric patients diagnosed with major depression, who experience relatively severe symptoms over prolonged periods. Depressed community-dwelling individuals, whose depressive
R. Yirmiya and I. Bab
Figure 4. Funnel plot of the mean standard effect size (d) over the SEM of the selected studies. For presentation clarity, the study of Amsterdam and Hooper (15) was removed, due to its exceptionally high SEM. However, this study’s inclusion or exclusion from the meta-analysis or the publication bias analysis had a minimal effect (due to its small n) and did not change the patterns of the results.
symptoms are not severe enough to prompt them to seek psychiatric help, do not display significantly reduced BMD. Bone loss and osteoporosis involve mainly trabecular bone sites like vertebrae, the proximal femur, and the distal radius (48). Our analysis shows that depression is associated with significantly lower bone mass in both the spine (vertebrae) and hip (proximal femur) and, after removal of an outlier study, also in the distal radius. Hence, depression-associated low bone density seems to be site independent, which is consistent with systemic neuroendocrine processes rather than with moodrelated postural alterations or decreased physical activity. Due to insufficient published data, several potential moderator variables have not been addressed by the present analysis. However, their contribution to depression-associated low BMD was assessed in several individual studies, with various statistical methods. Body weight and height, number of previous depressive episodes, total duration of disease, history of estrogen treatment, smoking, and race were not found to modulate the association between depression and bone density. Low levels of physical activity, characteristic of depressed patients (41), were also suggested to be associated with low BMD (49,50). However, studies included in the present meta-analysis that assessed the levels of exercise demonstrated that adequate matching or statistical adjustment for this variable did not modulate the association between depression and BMD (16,17,23,25,28,29,33–35). The contribution of depression severity is not clear, because two studies reported significant inverse correlation between depression severity and BMD (16,28), whereas others found no such relationship (14,17,27,36). Furthermore, in several studies demonstrating depression-associated low BMD, the levels of endocrine factors believed to affect BMD (25-hydroxyvitamin D, parathyroid hormone, Free T3, insulin-like growth factor [IGF]-1 and thyroid-stimulating hormone [TSH]) did not differ between depressed and nondepressed subjects (14,19,21,24,36,37). It is therefore unlikely for these agents to be involved in the depression-associated low BMD. Antidepressant therapy, especially by selective serotonin reuptake inhibitors (SSRIs), could also be a confounding variable affecting the results of the present meta-analysis, because most
BIOL PSYCHIATRY 2009;66:423– 432 429 studies report that it is associated with low BMD (51–55) and increased fracture risk, even beyond the effects of depression by itself (32,54,56 –58). The effects of SSRIs might be related to the skeletal serotonin system, which influences the proliferation and differentiation of osteoblasts and osteoclasts, leading to alterations in BMD (59 – 64). Regrettably, most studies included in the present meta-analysis did not report sufficient data for assessing the contribution of antidepressant treatment to the association between depression and BMD. Importantly, however, four studies that did use antidepressant therapy as a covariate found no evidence for an effect of this treatment on the association between depression and BMD (16,17,23,24). Furthermore, in several additional studies that reported a significant association between depression and low BMD, none or almost none (⬍5%) of the participants was ever treated with antidepressants (14,19,28,35). At the tissue level, bone mass is determined by bone remodeling, namely, by the balance between bone formation by osteoblasts and bone resorption by osteoclasts. Consistent with the association between depression and low bone density, this balance in depressed patients seems negative. Whereas bone resorption markers are significantly elevated in these patients, osteocalcin, the so-called bone formation marker, does not exhibit any significant trend. Although it is produced by osteoblasts and discharged into the blood circulation, a significant amount of osteocalcin is incorporated into the mineralized bone matrix and further released to the circulation during osteoclastic degradation (65). Hence, in view of the apparent increase in bone resorption, the lack of association between serum osteocalcin levels and depression might reflect a decrease in bone formation, accompanied by a new balance between osteocalcin production, its direct passage into the circulation, incorporation into the bone matrix and release by osteoclasts. Such an association between depression and bone formation is supported by the results of our recent study in mice, in which we used direct bone formation measurements and showed a depression-induced inhibition of bone formation (10). The association among depression, BMD, and bone remodeling parameters can be mediated by several brain-to-bone communication pathways, including the sympathetic nervous system, glucocorticoids, sex steroids, and inflammatory cytokines. Sympathetic Nervous System. Several lines of evidence implicate the sympathetic nervous system in central regulation of bone remodeling (66 –74). Because depression, particularly the melancholic type, is associated with pronounced and enduring central and peripheral hyper-noradrenergic state (75), depression-associated increases in norepinephrine (NE) levels, particularly within bone tissue, might contribute to accrual of lower peak bone mass, bone loss, and osteoporosis. Our recent report of elevated bone NE along with bone loss in the chronic mild stress mouse model for depression and blockade of this bone loss by a -adrenoreceptor antagonist (10) provides additional support for involvement of the sympathetic nervous system in depression-associated low BMD. Glucocorticoids. The detrimental effect of glucocorticoids treatment on BMD is well-established (75–78). Thus, most studies on the association between depression and bone loss propose that hypercortisolemia is the primary mediator of this relationship. Indeed, many studies report that cortisol levels are elevated in depressed patients, concomitantly with low BMD (14,19,21,22,24), and that in these patients cortisol levels as well as the cortisol response to an acute stressor are negatively www.sobp.org/journal
430 BIOL PSYCHIATRY 2009;66:423– 432 correlated with BMD scores (14,18). However, this evidence is rather circumstantial, because data on the endogenous cortisol levels required to induce bone loss are scanty or nonexistent. Hence, it is unclear whether the increased cortisol levels in depressed patients are sufficiently high to cause low BMD. Sex Steroids. Other candidate mediators of the association between depression and low BMD are gonadal hormones. However, they do not seem to be involved in this association, because studies on depression-associated low BMD show similar estrogen levels in depressed and nondepressed women (21,35). Inflammatory Cytokines. Depression-associated dysregulation of inflammatory cytokines (78 – 81) has also been implicated in the relationship between depression and low BMD (82,83) as well as in aging-related osteoporosis (84) and stress-induced effects on the skeleton (85). However, the evidence for these assumptions is inconclusive. A study on depression-associated bone loss found elevated levels of interleukin-6 and tumor necrosis factor-␣ in depressed women, which were negatively associated with BMD and positively correlated with a bone resorption marker (22). In contrast, another study reported unchanged interleukin-6 levels in depressed women, which were not associated with bone remodeling markers (19). Future studies should further address the mechanisms underlying the association between depression and bone loss, thus unraveling respective diagnostic and therapeutic targets to identify individuals at risk of developing depression-induced osteoporosis and devising novel antidepressive therapies devoid of skeletal effects. On the basis of the findings of the present meta-analysis, it is suggested that future studies should be confined to rigorously diagnosed major depression patients and should carefully monitor and analyze the recurrence, severity, number, and duration of depressive episodes and their temporal relationship to skeletal parameters. Taken together, the present meta-analysis demonstrates a significant association between depression and low skeletal mass, thus identifying depression as a risk factor for osteoporosis. Because the etiology of osteoporosis is multifactorial, it is essential to identify and be alert to a wide range of such risk factors for the timely prevention of skeletal deterioration and increased fracture rate. On the basis of the present findings, we propose that all individuals psychiatrically diagnosed with major depression are at risk for developing osteoporosis, with depressed women—particularly those who are premenopausal— showing a higher risk than men. These patients should be periodically evaluated for progression of bone loss and imbalances in bone remodeling.
This work was supported by the Israel Science Foundation (Grant Number 107/06). Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors report no biomedical financial interests or potential conflicts of interest. Supplementary material cited in this article is available online. 1. Melton LJ III (2003): Epidemiology worldwide. Endocrinol Metab Clin North Am 32:1–13. 2. US Department of Health and Human Services: Office of the Surgeon General (2004): Bone Health and Osteoporosis: A Report of the Surgeon General. Available at: http://www.surgeongeneral.gov/library/bonehealth/. Accessed December 1, 2008.
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R. Yirmiya and I. Bab 3. Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J, et al. (2007): The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 18:1033–1046. 4. Klibanski A, Adams-Campbell L, Bassford T, Blair SN, Boden SD, Dickersin K, et al. (2001): Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795. 5. Cizza G, Ravn P, Chrousos GP, Gold PW (2001): Depression: A major, unrecognized risk factor for osteoporosis? Trends Endocrinol Metab 12: 198 –203. 6. Mezuk B, Eaton WW, Golden SH (2008): Depression and osteoporosis: Epidemiology and potential mediating pathways. Osteoporos Int 19: 1–12. 7. Williams LJ, Pasco JA, Jacka FN, Henry MJ, Dodd S, Berk M (2008): Depression and Bone Metabolism. A review. Psychother Psychosom 78:16 –25. 8. Murray CJ, Lopez AD (1997): Alternative projections of mortality and disability by cause 1990 –2020: Global burden of disease study. Lancet 349:1498 –1504. 9. Blazer DG, Kessler RC, McGonagle KA, Swartz MS (1994): The prevalence and distribution of major depression in a national community sample: The national comorbidity survey. Am J Psychiatry 151:979 –986. 10. Yirmiya R, Goshen I, Bajayo A, Kreisel T, Feldman S, Tam J, et al. (2006): Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci U S A 103:16876 –16881. 11. Gold DT, Solimeo S (2006): Osteoporosis and depression: A historical perspective. Curr Osteoporos Rep 4:134 –139. 12. Ilias I, Alesci S, Gold PW, Chrousos GP (2006): Depression and osteoporosis in men: Association or casual link? Hormones 5:9 –16. 13. Lyles KW (2001): Osteoporosis and depression: Shedding more light upon a complex relationship. J Am Geriatr Soc 49:827– 828. 14. Altindag O, Altindag A, Asoglu M, Gunes M, Soran N, Deveci Z (2007): Relation of cortisol levels and bone mineral density among premenopausal women with major depression. Int J Clin Pract 61:416 – 420. 15. Amsterdam JD, Hooper MB (1998): Bone density measurement in major depression. Prog Neuro-Psychopharmacology Biol Psychiatry 22:267–277. 16. Diem SJ, Blackwell TL, Stone KL, Yaffe K, Cauley JA, Whooley MA, et al. (2007): Depressive symptoms and rates of bone loss at the hip in older women. J Am Geriatr Soc 55:824 – 831. 17. Eskandari F, Martinez PE, Torvik S, Phillips TM, Sternberg EM, Mistry S, et al. (2007): Low bone mass in premenopausal women with depression. Arch Intern Med 167:2329 –2336. 18. Furlan PM, Ten Have T, Cary M, Zemel B, Wehrli F, Katz IR, et al. (2005): The role of stress-induced cortisol in the relationship between depression and decreased bone mineral density. Biol Psychiatry 57:911–917. 19. Herran A, Amado JA, Garcia-Unzueta MT, Vazquez-Barquero JL, Perera L, Gonzalez-Macias J (2000): Increased bone remodeling in first-episode major depressive disorder. Psychosom Med 62:779 –782. 20. Jacka FN, Pasco JA, Henry MJ, Kotowicz MA, Dodd S, Nicholson GC, et al. (2005): Depression and bone mineral density in a community sample of perimenopausal women: Geelong osteoporosis study. Menopause 12: 88 –91. 21. Kahl KG, Greggersen W, Rudolf S, Stoeckelhuber BM, Bergmann-Koester CU, Dibbelt L, Schweiger U (2006): Bone mineral density, bone turnover, and osteoprotegerin in depressed women with and without borderline personality disorder. Psychosom Med 68:669 – 674. 22. Kahl KG, Rudolf S, Stoeckelhuber BM, Dibbelt L, Gehl HB, Markhof K, et al. (2005): Bone mineral density, markers of bone turnover, and cytokines in young women with borderline personality disorder with and without comorbid major depressive disorder. Am J Psychiatry 162:168 –174. 23. Kavuncu V, Kuloglu M, Kaya A, Sahin S, Atmaca M, Firidin B (2002): Bone metabolism and bone mineral density in premenopausal women with mild depression. Yonsei Med J 43:101–108. 24. Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, Chrousos G, Gold P (1996): Bone mineral density in women with depression. N Engl J Med 335:1176 –1181. 25. Mussolino ME, Jonas BS, Looker AC (2004): Depression and bone mineral density in young adults: Results from NHANES III. Psychosom Med 66:533–537. 26. Ozsoy S, Esel E, Turan MT, Kula M, Demir H, Kartalci S, Kokbudak Z (2005): [Is there any alteration in bone mineral density in patients with depression?]. Turk Psikiyatri Derg 16:77– 82.
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R. Yirmiya and I. Bab 27. Reginster JY, Deroisy R, Paul I, Hansenne M, Ansseau M (1999): Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women. Maturitas 33:133–137. 28. Robbins J, Hirsch C, Whitmer R, Cauley J, Harris T (2001): The association of bone mineral density and depression in an older population. J Am Geriatr Soc 49:732–736. 29. Schweiger U, Deuschle M, Korner A, Lammers CH, Schmider J, Gotthardt U, et al. (1994): Low lumbar bone mineral density in patients with major depression. Am J Psychiatry 151:1691–1693. 30. Schweiger U, Weber B, Deuschle M, Heuser I (2000): Lumbar bone mineral density in patients with major depression: Evidence of increased bone loss at follow-up. Am J Psychiatry 157:118 –120. 31. Sogaard AJ, Joakimsen RM, Tverdal A, Fonnebo V, Magnus JH, Berntsen GK (2005): Long-term mental distress, bone mineral density and nonvertebral fractures. The Tromso study. Osteoporos Int 16:887– 897. 32. Spangler L, Scholes D, Brunner RL, Robbins J, Reed SD, Newton KM, et al. (2008): Depressive symptoms, bone loss, and fractures in postmenopausal women. J Gen Intern Med 23:567–574. 33. Whooley MA, Cauley JA, Zmuda JM, Haney EM, Glynn NW (2004): Depressive symptoms and bone mineral density in older men. J Geriatr Psychiatry Neurol 17:88 –92. 34. Whooley MA, Kip KE, Cauley JA, Ensrud KE, Nevitt MC, Browner WS (1999): Depression, falls, and risk of fracture in older women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 159:484 – 490. 35. Wong SY, Lau EM, Lynn H, Leung PC, Woo J, Cummings SR, Orwoll E (2005): Depression and bone mineral density: Is there a relationship in elderly Asian men? Results from Mr. Os (Hong Kong). Osteoporos Int 16:610 – 615. 36. Yazici AE, Bagis S, Tot S, Sahin G, Yazici K, Erdogan C (2005): Bone mineral density in premenopausal women with major depression. Joint Bone Spine 72:540 –543. 37. Yazici KM, Akinci A, Sutcu A, Ozcakar L (2003): Bone mineral density in premenopausal women with major depressive disorder. Psychiatry Res 117:271–275. 38. Cohen J (1977): Statistical Power Analysis for the Behavioral Sciences. New York: Academic Press. 39. Egger M, Davey SG, Schneider M, Minder C (1997): Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629 – 634. 40. Begg CB, Mazumdar M (1994): Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088 –1101. 41. American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC: American Psychiatric Press. 42. Rosenthal R (1991): Meta-analysis: A review. Psychosom Med 53:247– 271. 43. Riggs BL, Khosla S, Melton LJ, III (2002): Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279 –302. 44. Bale TL (2006): Stress sensitivity and the development of affective disorders. Horm Behav 50:529 –533. 45. Peeters F, Nicholson NA, Berkhof J (2003): Cortisol responses to daily events in major depressive disorder. Psychosom Med 65:836 – 841. 46. Yesavage JA (1988): Geriatric depression scale. Psychopharmacol Bull 24:709 –711. 47. Irwin M, Artin KH, Oxman MN (1999): Screening for depression in the older adult: Criterion validity of the 10-item Center for Epidemiological Studies Depression Scale (CES-D). Arch Intern Med 159:1701–1704. 48. Vogel JM, Wasnich RD, Ross PD (1988): The clinical relevance of calcaneus bone mineral measurements: A review. Bone Miner 5:35–58. 49. Ho AY, Kung AW (2005): Determinants of peak bone mineral density and bone area in young women. J Bone Miner Metab 23:470 – 475. 50. MacInnis RJ, Cassar C, Nowson CA, Paton LM, Flicker L, Hopper JL, et al. (2003): Determinants of bone density in 30- to 65-year-old women: A co-twin study. J Bone Miner Res 18:1650 –1656. 51. Cauley JA, Fullman RL, Stone KL, Zmuda JM, Bauer DC, Barrett-Connor E, et al. (2005): Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int 16:1525–1537. 52. Diem SJ, Blackwell TL, Stone KL, Yaffe K, Haney EM, Bliziotes MM, Ensrud KE (2007): Use of antidepressants and rates of hip bone loss in older women: The study of osteoporotic fractures. Arch Intern Med 167:1240 – 1245. 53. Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, et al. (2007): Association of low bone mineral density with selective
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432 BIOL PSYCHIATRY 2009;66:423– 432 76. Alesci S, De Martino MU, Ilias I, Gold PW, Chrousos GP (2005): Glucocorticoid-induced osteoporosis: from basic mechanisms to clinical aspects. Neuroimmunomodulation 12:1–19. 77. Berris KK, Repp AL, Kleerekoper M (2007): Glucocorticoid-induced osteoporosis. Curr Opin Endocrinol Diabetes Obes 14:446 – 450. 78. Alesci S, Martinez PE, Kelkar S, Ilias I, Ronsaville DS, Listwak SJ, et al. (2005): Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: Clinical implications. J Clin Endocrinol Metab 90:2522–2530. 79. Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, BenHur T, Yirmiya R (2008): Brain interleukin-1 mediates chronic stressinduced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry 13:717–728. 80. Goshen I, Yirmiya R (2009): Interleukin-1 (IL-1): A central regulator of stress responses. Front Neuroendocrinol 30:30 – 45.
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R. Yirmiya and I. Bab 81. Pollak Y, Yirmiya R (2002): Cytokine-induced changes in mood and behaviour: Implications for “depression due to a general medical condition”, immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol 5:389 –399. 82. Licinio J, Wong ML (1999): The role of inflammatory mediators in the biology of major depression: Central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stressresponsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 4:317–327. 83. Manolagas SC (1995): Role of cytokines in bone resorption. Bone 17:63S– 67S. 84. Manolagas SC (1998): The role of IL-6 type cytokines and their receptors in bone. Ann N Y Acad Sci 840:194 –204. 85. Kondo A, Togari A (2003): In vivo stimulation of sympathetic nervous system modulates osteoblastic activity in mouse Calvaria. Am J Physiol Endocrinol Metab 285:E661–E667.
O
steoporosis, the most common degenerative disease in developed countries (1), is characterized by low bone mass and deterioration of skeletal structure, causing bone fragility and increased fracture incidence. In the United States alone, approximately 10 million individuals over the age of 50 have osteoporosis. In addition, 33.6 million Americans in this age group have osteopenia (i.e., a decrease in bone mineral density [BMD] that precedes osteoporosis and its potential complications later in life). The estimated annual fracture rate due to an underlying bone disease is 1.5 million. These fractures lead to pain, skeletal mutilation, disability, loss of independence, and increased mortality (2). In its early stages, before the occurrence of fractures, osteoporosis is a symptom-free silent disease and hence most osteoporotic individuals are left undiagnosed. This situation is unfortunate in view of available effective antiosteoporotic preventive and curative treatment modalities, which can be initiated before the appearance of a first fracture. Moreover, it has been suggested that the bone loss that leads to osteoporosis might begin relatively early in life, at a time when treatment could potentially slow its course. Despite its inherent limitations, BMD determination is currently the main tool for diagnosing osteopenia and osteoporosis (2). Because it is
From the Department of Psychology (RY) and Bone Laboratory (IB), The Hebrew University of Jerusalem, Jerusalem, Israel. Address correspondence to Raz Yirmiya, Ph.D., Department of Psychology, The Hebrew University of Jerusalem Mount Scopus, Jerusalem 91905 Israel; E-mail: [email protected]. Received Dec 29, 2008; revised Feb 25, 2009; accepted Mar 13, 2009.
0006-3223/09/$36.00 doi:10.1016/j.biopsych.2009.03.016
impractical to perform frequent whole population screening for subjects with low BMD, knowledge of its risk factors is essential for identifying individuals in danger of developing osteoporosis, allowing a rational comprehensive assessment of these patients and the administration of preventive and therapeutic measures (3). Several risk factors have been implicated in the development of osteoporosis, including low peak bone mass, age, female gender, estrogen deficiency, calcium deficiency, low levels of physical activity, glucocorticoid therapy and other medications, and several medical conditions as well as smoking and drug abuse (2– 4). In the last 14 years, ample research implicated major depression in bone loss and osteoporosis (comprehensively reviewed in 5–7). Like osteoporosis, major depression is a prevalent disorder, considered the second leading global cause of years of life lived with disability (8). The number of patients experiencing a major depressive episode in the United States mounts to 10 –14 million annually (more than 5% of the population) (9). However, despite the high prevalence of both diseases, most official publications emanating from authorities such as the National Institutes of Health, the National Osteoporosis Foundation, the National Osteoporosis Society (United Kingdom), and Osteoporosis Canada do not fully acknowledge depression as a risk factor for low BMD and osteoporosis, apparently because the literature on the relationship between these conditions is insufficiently conclusive. Some studies report that patients with major depression present up to 15% lower BMD, whereas others, particularly large-scale population-based studies, show a weak or no relationship between the two conditions. We have recently demonstrated, in a mouse model, a causal relationship between depression and bone loss as well as the involvement of the sympathetic nervous system in this relationship (10). This study and the increasing number of publications in the field prompted us to examine the evidence in humans for a possible impact of depression on skeletal status. Indeed, with meta-analytical proBIOL PSYCHIATRY 2009;66:423– 432 © 2009 Society of Biological Psychiatry
424 BIOL PSYCHIATRY 2009;66:423– 432 cedures we portray major depression as a risk factor for low BMD, mainly in premenopausal women.
Methods and Materials Sample of Studies Studies were identified with the computerized databases MEDLINE, ISI Web of Science, BIOSIS Previews, Dissertation Abstracts, Health and Wellness Resource Center (Gale), and PsychoINFO, covering the period ending December 1, 2008. We used a combination of the keyword “depression” with keywords related to skeletal biology and pathology, including “bone”, “osteoporosis”, “osteopenia”, “osteoclast”, “osteoblast”, and “osteocalcin”. Relevant reports were also gathered from reference lists of published articles, including primary studies and several reviews (3–5,11–13). Inclusion criteria were: 1) full journal publication or dissertation, and 2) comparison of BMD and/or bone remodeling parameters between depressed individuals and matched control subjects. In total, 24 articles were identified that complied with these criteria (14 –37). Further abstract search yielded no additional publications with sufficient information for inclusion in the meta-analysis. Data Extraction Data were extracted independently by two examiners (R.Y. and I.B.), with standardized data-abstraction forms. Disagreements were resolved by discussion. The extracted information included year of publication, country where the study was conducted, gender, mean age, sample size, menopausal status, depression assessment tool, skeletal sites used for BMD determination, serum osteocalcin measurement, and levels of urinary bone resorption markers. Authors were contacted if further study details were needed. Appropriate quantitative data for inclusion in the meta-analysis could not be obtained for one study (32). In most studies, the depressed and nondepressed samples were matched on at least some variables, including age, body mass index (or body weight), race, marital and menopausal status, hormone therapy, calcium intake, physical activity, and alcohol consumption. Smoking rates were usually higher in depressed compared with nondepressed participants. For studies reporting adjusted results (e.g., for age, body mass index, estrogen usage, physical activity, alcohol consumption, smoking), we used the adjusted values. In addition, information on potential moderator variables related to the clinical manifestation of depression was extracted, including proportion of subjects taking antidepressant drugs, depression severity, illness duration, and lifetime number of depressive episodes. However, these data were absent in most reports and hence insufficient for inclusion in the meta-analysis. Statistical Analyses We carried out separate meta-analyses for BMD, serum levels of osteocalcin, and urinary levels of bone resorption markers, including deoxypyridinoline, telopeptide (with absolute values or values normalized for creatinine), and cross-laps, in depressed and nondepressed individuals. Due to the low number of studies that assessed the bone resorption markers and because most of these studies reported only one such marker, separate comparisons for each marker were unattainable. Therefore, the comparison was conducted across the three resorption markers. Analyses were performed with the Comprehensive Meta-Analysis (CMA) software (Englewood, New Jersey). In each meta-analysis, standardized effect sizes derived from the individual studies were combined to determine a composite mean weighted effect size (d) along with its 95% confidence interval (CI) and significance www.sobp.org/journal
R. Yirmiya and I. Bab level (i.e., the effect size is significant if the CI does not include a zero) (38). Greater weight is given to studies with larger samples; hence, this procedure corrects for biases associated with small sample sizes. Because the effects of depression on BMD and bone remodeling were studied in different settings (e.g., psychiatric inpatients and outpatients, community dwellers) and because participant demographic data differed greatly between studies, we assumed the presence of heterogeneity a priori, namely, that the effect of individual trials would vary more than expected by chance alone. Therefore, the variance and statistical significance of differences were assessed with randomeffect calculations in all analyses. To determine the validity of the meta-analyses, we employed funnel plots (i.e., plots of the standard difference in means [d] against the SEM) (39). This was followed by quantitative evaluation of the degree of asymmetry (39,40).
Results The 23 studies included in the analysis (14 –31,33–37) encompassed 2327 depressed and 21,141 nondepressed individuals (Table 1). The association between depression and BMD was addressed in 22 studies (with the exception of [19]). The effect of depression on serum osteocalcin and urinary bone resorption markers was assessed in 8 of these studies (14,17,19,21–24,36) and in an additional report that measured only osteocalcin and the resorption markers (19). Effect sizes, corresponding CIs for each study, and a forest plot summarizing the association between depression and BMD are presented in Figure 1. The effect sizes range from ⫺1.16 to .33, with 20 studies reporting either decreased or unchanged BMD and only 2 studies showing increased BMD in depressed versus nondepressed individuals. The composite weighted mean effect size, d, of ⫺.219, with its CI between ⫺.325 and ⫺.126, implies that overall BMD is significantly lower in depressed than in nondepressed individuals (p ⬍ .001). However, homogeneity in the overall analysis was rejected (p ⫽ .0001). Hence, we used categorical model fitting procedures to further explore whether potential moderator variables could account for this heterogeneity. Because of the well-established differences in osteoporosis prevalence between women and men, we initially analyzed gender as such a moderator variable. Both women and men with depression (n ⫽ 1870 and 457, respectively) displayed significantly lower BMD than their matched control subjects (n ⫽ 15,795 and n ⫽ 5346; p ⫽ .0001 and p ⫽ .003, respectively) (Figure 2). However, gender was found to be a significant moderator variable; in women the association of depression and BMD was significantly stronger than in men (p ⫽ .032). For men, homogeneity was not rejected (p ⫽ .36), indicating that no other moderator variables would further explain the association of depression and BMD in this gender. In contrast, in women homogeneity was rejected (p ⬍ .0001), and thus further categorical model fitting was continued only within this gender. The female skeletal site where bone density was measured was not found to be a significant moderating variable of the association between depression and BMD (p ⫽ .59) (Figure 1 in Supplement 1). Both spine and hip BMD was significantly lower in depressed than in nondepressed women (p ⫽ .002 and p ⫽ .003, respectively). Although in the forearm the association was statistically insignificant (p ⫽ .128), this result should be interpreted cautiously because forearm BMD was measured in only 5
Year
Country
Gender
Schweiger et al. (29)
1994
Germany
Michelson et al. (24) Amsterdam et al. (15)
1996 1998
US US
Reginster et al. (27) Wooley et al. (34) Herran et al. (19) Schweiger et al. (30)
1999 1999 2000 2000
Belgium US Spain Germany
Robbins et al. (28)
2001
US
Kavunco et al. (23) Yazici et al. (37) Mussolino et al. (25)
2002 2003 2004
Turkey Turkey US
Whooley et al. (33) Furlan et al. (18) Jacka et al. (20) Kahl et al. (22) Ozsoy et al. (26)
2004 2005 2005 2005 2005
US US Australia Germany Turkey
Sogaard et al. (31) Wong et al. (35)
2005 2005
53/27 27/30 24/24 4/3 2/2 12/12 461/6,895 19/19 8/7 10/14 145/758 85/561 42/42 25/15 297/2,346 127/2,401 16/497 9/10 14/64 10/16 21/12 21/11 343/1437 169/1830
Yazici et al. (36) Kahl et al. (21) Altindag et al. (14) Diem et al. (16) Eskandari et al. (17) Spangler et al. (32)e
2005 2006 2007 2007 2007 2008
Norway Hong Kong Turkey Germany Turkey US US US
Women Men Women Women Men Women Women Women Womenc Menc Women Men Women Women Women Men Men Women Women Womend Women Men Women Men Women Womend Women Women Women US
35/30 23/16 36/41 200/3,977 89/44 e
Bone Sitea spine spine, hip, forearm spine spine, hip spine, hip
Menopausal Status
60.7 60.6 41.0 39.6
post
DSM
BMD
preb preb
DSM DSM
BMD, osteocalcin, osteoclastic markers BMD
post post preb post
SR (GHQ-28) SR (GDS) DSM (SCAN) DSM
BMD BMD osteocalcin, osteoclastic markers BMD
post
SR (CES-D)
BMD
pre pre pre
DSM DSM SR (DIS)
BMD, osteocalcin, osteoclastic markers BMD BMD
post post pre pre
SR (GDS) DSM SR (DSM-based) DSM DSM
BMD BMD BMD BMD, osteocalcin, osteoclastic markers BMD
post
SR (custom) SR (GDS)
BMD BMD
post pre pre post pre post
DSM DSM DSM SR (GDS) DSM SR (CES-D)
BMD, osteocalcin, osteoclastic markers BMD, osteocalcin, osteoclastic markers BMD, osteocalcin, osteoclastic markers BMD BMD, osteocalcin, osteoclastic markers BMD
forearm spine, hip
63.4 73.4 44.1 61.9 61.7 74.0 74.8 36.1 30.1 30.1 29.6 66.6 64.2 52.9 25.2 36.2 36.2 50.6 72.4
spine, hip spine, hip, forearm spine, hip hip spine, hip, forearm spine, hip
45.4 27.5 41.4 75.7 35.0 63.8
spine hip spine, hip spine, hip hip spine, hip spine, hip spine, hip spine, hip, forearm spine, hip
Depression Assessment Toola
Mean Age
Outcome
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BMD, bone mineral density; SR, self-rating; GHQ-28, General Health Questionnaire-28; GDS, Geriatric Depression Scale; SCAN, Schedule for Clinical Assessment in Neuropsychiatry; CES-D, Center for Epidemiologic Studies Depression Scale; DIS, Diagnostic Interview Schedule. a Measurements of hip BMD were reported either for the “total hip” or for specific parts of the hip (including the femoral neck, trochanter, intertrochanter, and Ward’s triangle). In the latter case, the data of the femoral neck (which is more sensitive to bone loss due to various causes) were used in the analysis. b This study included both pre- and postmenopausal women in the analysis. However the study was coded as premenopausal, because the subjects were relatively young (⬍44.7 years on average) and the proportion of postmenopausal women was not high (⬍one-third). c In this longitudinal study, BMD was measured both at the beginning of the study and at follow-up; only the follow-up data were used in the analysis. d In this study, depression-associated BMD differences were measured in the context of borderline personality disorder (BPD) (which by itself had no effect on BMD). Thus, the experimental group comprised women with comorbid major depressive disorder and BPD, whereas the control group comprised women with BPD only. e The results of this study were not included in the meta-analysis, because appropriate quantitative data could not be obtained. The total number of participants in this study was 4539, but no information on the number of depressed versus nondepressed control subjects could be obtained.
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Study Name
Depressive/ Control Subjects (n)
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Table 1. Characteristics of All Studies That Quantitatively Addressed the Relationship Between Depression and Skeletal Status
426 BIOL PSYCHIATRY 2009;66:423– 432
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Figure 1. Estimates of the effect sizes in all studies that quantitatively examined the association between depression and bone mineral density (BMD). For each study, the square in the forest plot denotes the value of the effect size (d), and the horizontal lines extending to the right and left of the square indicate the widths of the 95% confidence intervals (CIs)—also presented numerically in the second column from the left. The size of the square represents the relative weight of the particular study in the overall meta-analysis, which is also presented numerically in the right column. The circle at the bottom of the graph represents the overall estimate of the association between depression and BMD.
studies. Moreover, one of these studies (31), which had been performed in a large sample and therefore had a high weight in the meta-analysis, was methodologically problematic. It was conducted longitudinally, and some of the women had a depressive episode many years before the BMD measurement. Furthermore, in that study, depression was assessed quite crudely with a 1-item evaluation, namely, “Have you felt unhappy and depressed during the past couple of weeks?” Excluding this study from the meta-analysis led to a significant association between depression and BMD in the forearm too (p ⫽ .011). Examination of the moderating effect of menopausal status revealed that both pre- and postmenopausal women displayed a significant association between depression and decreased BMD (p ⫽ .0001 and p ⫽ .01, respectively) (Figure 2 in Supplement 1). The association was stronger in pre- than in postmenopausal subjects, but the difference did not reach statistical significance (p ⫽ .124). This difference could be rendered significant (p ⫽ .047) by excluding one report (36). Surprisingly, in contrast with almost all other studies, including a previous report by the same group (37), this report suggests that BMD is increased in women with “mild to moderate depression.” Analyzing the effect of the depression assessment procedure used in the various studies revealed a significantly stronger association between depression and BMD in women diagnosed individually by a psychiatrist according to the DSM (41) criteria, compared with subjects assessed with self-rating (SR) questionnaires (p ⫽ .002) (Figure 3). Specifically, BMD was significantly lower in depressed women who had been formally diagnosed as suffering from major depression according to DSM criteria (p ⫽ .0001), whereas in women diagnosed by SR questionnaires the effects of depression on BMD did not reach statistical significance (p ⫽ .079). www.sobp.org/journal
Collectively, the studies addressing the relationship between depression and bone turnover markers compared 256 depressed with 232 nondepressed individuals (Figure 3A in Supplement 1). The effect sizes of the association between depression and serum osteocalcin levels ranged from ⫺.676 to 1.047, with two studies showing reduced levels, two studies reporting no effect, and four studies reporting increased osteocalcin levels in depressed compared with nondepressed women. The composite weighted mean effect size (d ⫽ .153) with its CI (⫺.049 to .356) implies that, overall, individuals with depression did not display a significant alteration in osteocalcin levels (p ⫽ .14). Homogeneity was rejected (p ⫽ .0001), but due to the small number of studies, further categorical model fitting was unattainable. Five studies assessed the association between depression and urinary levels of one bone resorption marker, and two additional studies reported associations with two markers (Figure 3B in Supplement 1). The effect sizes ranged from ⫺.698 to 1.474, with two comparisons showing reduced levels, one comparison reporting no effect, and six comparisons reporting increased resorption marker levels in depressed compared with nondepressed women. The composite weighted mean effect size (d ⫽ .515) with its CI (.310 –.720) implies that, overall, individuals with depression displayed significantly higher levels of resorption markers (p ⫽ .0001). As with osteocalcin, homogeneity was rejected (p ⫽ .0001), but due to the small number of studies, further categorical model fitting was unattainable. A publication bias might occur if the probability that acceptance for publication depends on the reported results. This bias was assessed here by the funnel plot procedure (39). Indeed, the funnel plot of the overall standardized effects shown in Figure 1 was asymmetric (Figure 4), as reflected by a trend for significant rank correlation value (p ⫽ .076) and highly significant Egger regression intercept (p ⫽ .007). This asymmetry could represent
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Figure 2. Estimates of the effect sizes in all studies that quantitatively examined the association between depression and bone mineral density (BMD) in either women (A) or men (B). CI, confidence interval.
a publication bias based on the “file-drawer effect”, which could arise if studies that found a significant effect of depression on BMD would be more likely to be published than studies with negative results. Apparently, this is not the present case, because calculation of the “fail-safe number” (42) indicates that an additional 297 comparable studies with negative results should have been published for the present results to lose their significance. Considering that only 24 studies were published on depression and BMD in the 14 years that passed since the first publication on this subject, it is extremely unlikely that so many studies with null results were conducted but remained in the file-drawers. Another source of asymmetry might be an actual heterogeneity among the studies (39). In the present meta-analysis, such a source could be the distinction between studies reporting relatively small samples of patients with major depression, diagnosed by a psychiatrist on the basis of DSM criteria, and large sample studies conducted on community dwellers, diagnosed by
SR checklists. Indeed, when results of these two types of studies were analyzed separately, no significant asymmetry appeared in either funnel plot (data not shown).
Discussion The results of the present meta-analysis, comparing 2327 depressed individuals with 21,141 control subjects, indicate that depression is associated with significantly reduced BMD and increased bone turnover. In addition, the analysis enabled assessment of the magnitude of the overall effect sizes, which were d ⫽ ⫺.219 for BMD, d ⫽ .153 for osteocalcin, and d ⫽ .515 for bone resorption markers. According to Cohen’s criteria, an effect size of d ⫽ .20 is small, d ⫽ .50 is moderate, and d ⫽ .80 is large (38). Hence, the overall effect size of depression on BMD is rather small, whereas the effect on resorption markers is moderate. However, further analysis revealed that, when potential moderator variables are taken into account, the effect of www.sobp.org/journal
428 BIOL PSYCHIATRY 2009;66:423– 432
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Figure 3. Estimates of the effect sizes in all studies that quantitatively examined the association between depression and bone mineral density (BMD) with either individual psychiatric assessment according to DSM criteria (A) or self-rating questionnaires (B). CI, confidence interval.
depression on BMD in specific subgroups approaches the moderate range. Both osteoporosis and depression are approximately threefold more common in women than in men (2,41,43). Indeed, the current meta-analysis portrays women as significantly more vulnerable to depression-associated low BMD. This gender difference might be related to the greater sensitivity of women to stress in general (44) and to the greater responsiveness of depressed women to various stressors in particular (45). It should be emphasized, however, that although the effect of depression in men is smaller than in women, it is more robust, namely, it is not influenced by various moderating variables. In contrast, the association between depression and BMD in women shows significant heterogeneity, because it is significantly moderated by at least two variables, menopausal status and the depression assessment procedure. Premenopausal women displayed a greater depression-associated decrease in BMD compared with postmenopausal subjects, and after removal of a single outlier report this effect became statistically significant. This finding does not necessarily mean that depression is not associated with low BMD after menopause. However, in postmenopausal women this association might be masked by the multiplicity of factors contributing to the development of low bone mass, such as estrogen depletion, reduced physical activity, nutritional disturbances, and drug treatments (4,41). Hence, to further assess the impact of menowww.sobp.org/journal
pausal status on depression-associated low BMD, direct comparisons for the effects of depression on BMD should be undertaken between pre- and postmenopausal women, inasmuch as studies carried out so far focused mainly on either pre- or postmenopausal subjects. The present meta-analysis clearly indicates that assessment of an association between depression and BMD critically depends on the procedure employed for diagnosing the depressive condition. When depression was individually diagnosed by a psychiatrist, defining major depression by DSM criteria (41), the magnitude of the effect was substantial, namely, the effect size was d ⫽ ⫺.360, closer to a moderate effect size according to Cohen’s criteria (38). In such studies, subjects are either inpatients or are seeking psychiatric help for their depressive condition. In contrast, in studies based on SR checklists, an overall significant relationship could not be identified between depression and BMD. These checklists (e.g.,46,47) were developed as screening tools for the general population and are not customarily used to diagnose psychiatric patients. Compared with DSM-based psychiatric evaluations, they are rather heterogeneous, measure a restricted array of depressive symptoms, and assess mood and behavior over a relatively short period. Therefore, it seems that depression-associated low BMD afflicts mainly psychiatric patients diagnosed with major depression, who experience relatively severe symptoms over prolonged periods. Depressed community-dwelling individuals, whose depressive
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Figure 4. Funnel plot of the mean standard effect size (d) over the SEM of the selected studies. For presentation clarity, the study of Amsterdam and Hooper (15) was removed, due to its exceptionally high SEM. However, this study’s inclusion or exclusion from the meta-analysis or the publication bias analysis had a minimal effect (due to its small n) and did not change the patterns of the results.
symptoms are not severe enough to prompt them to seek psychiatric help, do not display significantly reduced BMD. Bone loss and osteoporosis involve mainly trabecular bone sites like vertebrae, the proximal femur, and the distal radius (48). Our analysis shows that depression is associated with significantly lower bone mass in both the spine (vertebrae) and hip (proximal femur) and, after removal of an outlier study, also in the distal radius. Hence, depression-associated low bone density seems to be site independent, which is consistent with systemic neuroendocrine processes rather than with moodrelated postural alterations or decreased physical activity. Due to insufficient published data, several potential moderator variables have not been addressed by the present analysis. However, their contribution to depression-associated low BMD was assessed in several individual studies, with various statistical methods. Body weight and height, number of previous depressive episodes, total duration of disease, history of estrogen treatment, smoking, and race were not found to modulate the association between depression and bone density. Low levels of physical activity, characteristic of depressed patients (41), were also suggested to be associated with low BMD (49,50). However, studies included in the present meta-analysis that assessed the levels of exercise demonstrated that adequate matching or statistical adjustment for this variable did not modulate the association between depression and BMD (16,17,23,25,28,29,33–35). The contribution of depression severity is not clear, because two studies reported significant inverse correlation between depression severity and BMD (16,28), whereas others found no such relationship (14,17,27,36). Furthermore, in several studies demonstrating depression-associated low BMD, the levels of endocrine factors believed to affect BMD (25-hydroxyvitamin D, parathyroid hormone, Free T3, insulin-like growth factor [IGF]-1 and thyroid-stimulating hormone [TSH]) did not differ between depressed and nondepressed subjects (14,19,21,24,36,37). It is therefore unlikely for these agents to be involved in the depression-associated low BMD. Antidepressant therapy, especially by selective serotonin reuptake inhibitors (SSRIs), could also be a confounding variable affecting the results of the present meta-analysis, because most
BIOL PSYCHIATRY 2009;66:423– 432 429 studies report that it is associated with low BMD (51–55) and increased fracture risk, even beyond the effects of depression by itself (32,54,56 –58). The effects of SSRIs might be related to the skeletal serotonin system, which influences the proliferation and differentiation of osteoblasts and osteoclasts, leading to alterations in BMD (59 – 64). Regrettably, most studies included in the present meta-analysis did not report sufficient data for assessing the contribution of antidepressant treatment to the association between depression and BMD. Importantly, however, four studies that did use antidepressant therapy as a covariate found no evidence for an effect of this treatment on the association between depression and BMD (16,17,23,24). Furthermore, in several additional studies that reported a significant association between depression and low BMD, none or almost none (⬍5%) of the participants was ever treated with antidepressants (14,19,28,35). At the tissue level, bone mass is determined by bone remodeling, namely, by the balance between bone formation by osteoblasts and bone resorption by osteoclasts. Consistent with the association between depression and low bone density, this balance in depressed patients seems negative. Whereas bone resorption markers are significantly elevated in these patients, osteocalcin, the so-called bone formation marker, does not exhibit any significant trend. Although it is produced by osteoblasts and discharged into the blood circulation, a significant amount of osteocalcin is incorporated into the mineralized bone matrix and further released to the circulation during osteoclastic degradation (65). Hence, in view of the apparent increase in bone resorption, the lack of association between serum osteocalcin levels and depression might reflect a decrease in bone formation, accompanied by a new balance between osteocalcin production, its direct passage into the circulation, incorporation into the bone matrix and release by osteoclasts. Such an association between depression and bone formation is supported by the results of our recent study in mice, in which we used direct bone formation measurements and showed a depression-induced inhibition of bone formation (10). The association among depression, BMD, and bone remodeling parameters can be mediated by several brain-to-bone communication pathways, including the sympathetic nervous system, glucocorticoids, sex steroids, and inflammatory cytokines. Sympathetic Nervous System. Several lines of evidence implicate the sympathetic nervous system in central regulation of bone remodeling (66 –74). Because depression, particularly the melancholic type, is associated with pronounced and enduring central and peripheral hyper-noradrenergic state (75), depression-associated increases in norepinephrine (NE) levels, particularly within bone tissue, might contribute to accrual of lower peak bone mass, bone loss, and osteoporosis. Our recent report of elevated bone NE along with bone loss in the chronic mild stress mouse model for depression and blockade of this bone loss by a -adrenoreceptor antagonist (10) provides additional support for involvement of the sympathetic nervous system in depression-associated low BMD. Glucocorticoids. The detrimental effect of glucocorticoids treatment on BMD is well-established (75–78). Thus, most studies on the association between depression and bone loss propose that hypercortisolemia is the primary mediator of this relationship. Indeed, many studies report that cortisol levels are elevated in depressed patients, concomitantly with low BMD (14,19,21,22,24), and that in these patients cortisol levels as well as the cortisol response to an acute stressor are negatively www.sobp.org/journal
430 BIOL PSYCHIATRY 2009;66:423– 432 correlated with BMD scores (14,18). However, this evidence is rather circumstantial, because data on the endogenous cortisol levels required to induce bone loss are scanty or nonexistent. Hence, it is unclear whether the increased cortisol levels in depressed patients are sufficiently high to cause low BMD. Sex Steroids. Other candidate mediators of the association between depression and low BMD are gonadal hormones. However, they do not seem to be involved in this association, because studies on depression-associated low BMD show similar estrogen levels in depressed and nondepressed women (21,35). Inflammatory Cytokines. Depression-associated dysregulation of inflammatory cytokines (78 – 81) has also been implicated in the relationship between depression and low BMD (82,83) as well as in aging-related osteoporosis (84) and stress-induced effects on the skeleton (85). However, the evidence for these assumptions is inconclusive. A study on depression-associated bone loss found elevated levels of interleukin-6 and tumor necrosis factor-␣ in depressed women, which were negatively associated with BMD and positively correlated with a bone resorption marker (22). In contrast, another study reported unchanged interleukin-6 levels in depressed women, which were not associated with bone remodeling markers (19). Future studies should further address the mechanisms underlying the association between depression and bone loss, thus unraveling respective diagnostic and therapeutic targets to identify individuals at risk of developing depression-induced osteoporosis and devising novel antidepressive therapies devoid of skeletal effects. On the basis of the findings of the present meta-analysis, it is suggested that future studies should be confined to rigorously diagnosed major depression patients and should carefully monitor and analyze the recurrence, severity, number, and duration of depressive episodes and their temporal relationship to skeletal parameters. Taken together, the present meta-analysis demonstrates a significant association between depression and low skeletal mass, thus identifying depression as a risk factor for osteoporosis. Because the etiology of osteoporosis is multifactorial, it is essential to identify and be alert to a wide range of such risk factors for the timely prevention of skeletal deterioration and increased fracture rate. On the basis of the present findings, we propose that all individuals psychiatrically diagnosed with major depression are at risk for developing osteoporosis, with depressed women—particularly those who are premenopausal— showing a higher risk than men. These patients should be periodically evaluated for progression of bone loss and imbalances in bone remodeling.
This work was supported by the Israel Science Foundation (Grant Number 107/06). Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors report no biomedical financial interests or potential conflicts of interest. Supplementary material cited in this article is available online. 1. Melton LJ III (2003): Epidemiology worldwide. Endocrinol Metab Clin North Am 32:1–13. 2. US Department of Health and Human Services: Office of the Surgeon General (2004): Bone Health and Osteoporosis: A Report of the Surgeon General. Available at: http://www.surgeongeneral.gov/library/bonehealth/. Accessed December 1, 2008.
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