The results of this research synthesis with meta-analysis prove that MDDs are associated with low bone mass and should therefore be considered a risk factor for osteoporosis (). According to our meta-analysis, BMD in subjects with MDDs was 4.7 % lower at the AP spine, 3.5 % lower at the total femur, and 7.3 % lower at the femoral neck as compared to healthy controls. These differences translate to an approximate 1 SD deficit in spine and 0.6 SD in total femur and are similar or greater than those produced by recognized risk factors for osteoporosis, including life style factors. For example, smoking is associated with an approximately 0.1 SD deficit in BMD for combined skeletal sites [46
], lack of exercise (aerobics and weight bearing) with a 0.3 SD deficit in the spine and 0.1 SD deficit in the femur [47
], and absence of calcium supplementation with a 0.4 SD deficit in whole body BMD [48
BMD is a strong predictor of fracture risk. Large, prospective studies conducted mostly in postmenopausal women showed that the absolute risk for fractures increases with increasing age for the same level of BMD. As an example, the NORA study convincingly demonstrated that for a T score of −2.0 to −1.0 there is a four-fold increase in the risk for femur and vertebral fractures in women aged 70 to 79 compared to women aged 50 to 59 [49
]. Therefore, the percent loss in BMD observed in subjects with depression likely translates to increasing fracture risk with age, even in the absence of further bone loss. Of note is that the largest deficit in bone mass was observed at the femoral neck in subjects with depression. This important finding makes depression-related osteoporosis a particularly serious medical problem, since femur fractures are far more serious than fractures at other skeletal sites.
The 6 studies available for assessment detected no difference in osteocalcin levels between subjects with depression and controls. More information on changes in biochemical markers of bone turnover is needed to clarify whether the bone deficit in depression is caused by increased bone resorption, decreased bone formation, or both. Such information could guide pharmacological treatments for osteoporosis in this population. In a recently published meta-analysis of 14 studies on the same topic, Wu et al. [50
] found a similar relationship of BMD and depression after pooling together skeletal sites into two regions: femur and spine. In the present meta-analysis of 20 studies, we determined the effects of depression on BMD at the AP spine, the total femur, and the femoral neck. In another recent meta-analysis, Yirmia et al. [51
] found a similar relationship between depression and decreased BMD; in their study they did not, however, perform subanalyses of males, females and mixed populations as we did here. In addition, unlike Wu et al. [50
] and Yirmia et al. [51
], we report the effects of depression on BMD in percent differences, a value that is clinically more meaningful and intuitive than the absolute difference in BMD or the effect size. Despite an earlier cutoff date, our meta-analysis includes more studies, with data from a greater number of depressed subjects than the two recently published articles [50
Potential mechanisms of bone loss in depression
Several endocrine alterations observed during the depressive state may induce bone loss [52
]. Depression is associated with alterations of the hypothalamic-pituitary-adrenal (HPA) axis at multiple levels, including altered secretion of hypothalamic corticotropin-releasing hormone (CRH), as indicated by CRH levels in the cerebrospinal fluid, and change in the set point threshold for negative feedback; these changes generally result into hyper-cortisolism, as recently reviewed [52
]. In an animal model, increased sympathetic tone induced via chronic and severe stress caused bone loss [53
]. Evidence in humans is scanty but a recent survey conducted in Israel reported an association between generalized anxiety disorder and osteoporosis [54
]. A secular trend to increased psychosocial stress has been reported which may be contributing to the obesity epidemics as well [55
]. Although alterations in leptin levels, often of opposite sign, have been reported in subjects with depression, the effects of hyper-leptinemia on bone mass in humans are not clear [52
]. In the ob/ob
mouse, a genetic model of leptin deficiency, intracerebrov-entricular leptin administration causes bone loss by inhibiting bone formation [52
]. Proinflammatory cytokines are increased in depression and IL-6 is a potent activator of the osteoclast [52
]. Both estrogen deficiency in women and androgen deficiency in men may affect bone mass and there is at least theoretical evidence for decreased sexual hormones in both genders during the acute phases of depression. Serotonin transporter receptors are present on the osteoblast and use of antidepressants has been associated with more fractures [52
]. Commonly accepted life style risk factors for osteoporosis include smoking, inadequate calcium intake, excessive alcohol intake, and physical inactivity. Although in theory these factors may all contribute to bone loss in subjects with depression [52
] at the present time, there is little evidence from studies of depressed subjects that poor lifestyle was more prevalent in subjects with depression than controls.
Recently, an unexpected link between bone and energy metabolism has been reported: physiological amounts of osteocalcin increase the expression of insulin in the pancreatic beta cell, increase glucose utilization in muscle and other peripheral tissues, and stimulate the production of adiponectin by the adipocye [56
]. Major depressive disorders are known to increase the risk for type II diabetes with an hazard ratio of 1.62, an effect that does not appear to be mediated by poor health behaviors [57
] and osteocalcin levels are inversely related to metabolic syndrome [58
] and diabetes [59
]. Further studies are warranted in subjects with depression to investigate the clinical implications of these novel pathways linking bone and energy metabolism.
The studies included in our meta-analysis had several limitations. There was a significant heterogeneity among the various studies in terms of differences in BMD that was most likely real, rather than attributable to measurement error. In the case of DXA, the error is remarkably small (about 1 %). Even after removing the most extreme studies from the meta-analysis for AP spine and total femur, a significant amount of heterogeneity remained (with I2 above 60 %). Possible reasons for the heterogeneity include: a) Differences in methodology. All articles had a cross-sectional design, but some were case series collected prospectively mostly for reasons different from observing the natural history of bone turn-over in depression, whereas others represented retrospective analyses. b) Differences in the diagnosis and definition of depression. As an example, the DSM criteria for depression have evolved over time and were used inconsistently in various studies. c) Differences in age, gender, sample size, geographic location, and use of antidepressant medication among study populations. d) Differences in adjustment for known osteoporosis risk factors ().
Fig. 3 Funnel plots for AP spine BMD, total femur BMD and femoral neck. a: AP Spine BMD: Funnel plot shows slight asymmetry with several outliers, which may be due to different effect sizes of depression in men and women, or depression treatment effects. To (more ...)