A link between depression and bone metabolism: what are the implications for treatment?

Osteoporosis and associated fragility are common health conditions among older adults. Mood disorders, such as depression, commonly co-occur with medical health conditions associated with aging [1]. The bidirectional relationship between mental and physical health conditions regarding prognosis, course and etiology has gained attention from researchers and clinicians alike in the past few decades as the role of neuroendocrine disturbances in psychiatric disorders has become better understood. Indeed, it has been suggested that depression is an unrecognized risk factor for osteoporosis [2], and a growing body of empirical work indicates this relationship exists, at least in cross-section [3].

Depression generally onsets in midlife and is characterized by an episodic course [4]. The risk profile for developing osteoporosis has two peaks over the life course, the first being during young adulthood, when there is a failure to reach peak bone mass; and later, during adulthood, when bone mass is reabsorbed into the body at an accelerated rate due to the effects of aging and the menopause [5]. Early- or mid-life depressive episodes may exert influence on bone metabolism in one or both of these periods and subsequently heighten the risk for low bone mineral density (BMD) and osteoporosis in later adulthood. Studies of depression and BMD have included samples with a wide range of ages, and the finding that depression is associated with low BMD has been shown in both younger and older cohorts [3].

In the past 20 years numerous metabolites produced by cells of bone formation (osteoblasts) and resorption (osteoclasts) have been identified. If depression is associated with markers of bone metabolism, that would provide evidence for a potential mediating mechanism by which depression directly influences BMD. Bone turnover is influenced by both local and peripheral hormonal systems, including several that are disturbed in depression, indicating a potential physiologic link between this condition and bone mass [6,7]. Depression is associated with alterations in four key physiologic systems that influence bone metabolism:

• • Inflammation, including the production of proinflammatory cytokines, such as IL-6, IL-1 and TNF-α [8–11], which stimulate bone resportion and inhibit bone formation [12];

• • Hypothalamic–pituitary–adrenal axis activation [13,14] with resultant hypercortisolism, which has potent effects on bone metabolism [15] and rate of bone loss [16,17];

• • Sympathetic nervous system (SNS) activation indicated by catecholamine synthesis (i.e., tyrosine hydroxylase and norepinephrine) [18,19], which is associated with reduced BMD [6];

• • Hypogonadalism, indicated by lower levels of both estrogen [20] and testosterone [21], key regulators of bone formation [22,23].

Despite the evidence that depression is associated with disturbances in hormonal systems that are thought to influence bone metabolism, only a handful of studies have directly examined the effect of depressive symptoms on markers of bone metabolism, with decidedly mixed results. The findings regarding osteocalcin, a marker of bone formation produced by osteoblasts, are contradictory [24–27]. Several investigations reported no difference in serum markers of bone turnover, including osteocalcin, bone-specific alkaline phosphatase and telopeptide (C- and N-terminal), in depression cases compared with controls, even when differences in BMD were found [25–30]. With few exceptions [24,29], the majority of studies have reported no difference between depression cases and controls concerning calcium metabolism indicated by levels of parathyroid hormone or 25-OH vitamin D levels [25,27,28,30,31]. The inconsistency of the existing evidence regarding depression and markers of bone turnover probably stems from issues pertaining to study design, including small sample sizes and differing sample composition, the lack of longitudinal analyses or studies in men, and the risk of residual confounding from unaccounted variables, including psychotropic medication use and chronic medical conditions.

Turning to the influence of psychotropic medications on bone turnover, there is growing evidence from animal studies that selective serotonin-reuptake inhibitors (SSRIs), a class of medication often used to treat depression in older adults [32], have direct effects on osteoblasts and trabecular bone formation [33–35]. Receptors for serotonin have been found on osteoblasts [36], and several studies have reported that SSRIs induce a loss of bone mass in mice [35,37]. This is consistent with evidence from observational studies in humans, which report that SSRI use among older adults is associated with low BMD, independent of the effects of depression [38], and heightened BMD loss over time [39]. However, the effect of SSRIs on bone metabolism may be estrogen dependent [33] and, thus, SSRIs may influence bone mass differently over the life course as individuals move through phases of development (i.e., puberty and menopause) [34]. Other medications used to treat depression that influence SNS activity (i.e., propranolol) have also been shown to affect bone metabolism by moderating the influence of physical activity on bone formation [40]. An important limitation of existing studies of SSRIs and BMD in humans, however, is the influence of polypharmacy. Polypharmacy is common among older adults [41] and many individuals who are taking SSRIs may also be prescribed other medications hypothesized to influence bone strength, for example loop diuretics for hypertension and glycemic medications for diabetes. Many factors, including pre-existing medical conditions, such as diabetes and cardiovascular disease, health behaviors, such as smoking, alcohol intake, nutritional intake and physical inactivity, and underlying frailty, probably moderate the relationship between antidepressant use and BMD, and thus groups that have a higher burden of these factors may be particularly prone to adverse effects of these medications [42].

The findings regarding the influence of SSRIs on low BMD are particularly alarming in light of evidence suggesting that potentially inappropriate prescribing of these medications is very common among community-dwelling adults [43], and that over 50% of nursing home residents who receive SSRIs can be successfully withdrawn from these medications without an increase in depressive symptomology [44]. Even if depression is associated with lower BMD, the clinical significance of this relationship remains to be established (i.e., whether the effect is large enough to warrant clinical intervention); however, there is evidence that depression, as well as antidepressant medication use, is associated with fracture risk, a clinically relevant consequence of osteoporosis [3,45,46]. As there is a growing body of evidence that depression is associated with several chronic medical conditions, including Type 2 diabetes mellitus [47], cardiovascular disease [48], obesity [49] and osteoporosis [3], depression treatment care models will need to address not only the mental health issues but also the physical consequences of depression and its treatment.

The data regarding the association of depression with BMD suggest that patients with depression should be assessed for additional risk factors for low BMD, screened for the presence of osteopenia and osteoporosis, and treated with preventive and therapeutic strategies to reduce fracture risk. This will require assembly of a multidisciplinary and collaborative treatment team of psychiatrists, endocrinologists and primary-care physicians. Additionally, psychiatrists and primary-care physicians, who provide the majority of care for patients with depression, will need to be educated about the potential impact of this disorder on BMD. Depression care plans should include osteoporosis-preventive strategies, such as calcium and vitamin D supplementation and enhancement of physical activity. As clinicians develop these plans, they should be aware that depressive symptoms are associated with discontinuation of fracture-prevention regimens (i.e., use of bisphosphates) [50] and, thus, these individuals may require more intensive patient monitoring. Individuals with comorbid medical conditions taking treatments that may lower BMD, such as thiazolidinedione use for Type 2 diabetes and loop diuretics for hypertension, should be recognized as a particularly vulnerable group. Future studies should determine whether routine screening by dual energy x-ray absorptiometry in patients with depression is a cost-effective approach to identify high-risk groups and intervene with more aggressive preventive strategies, such as antiresorptive agents.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.