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Seventeen percent of women with MDD were currently depressed defined as a depressive episode during the preceding 4 weeks. On average, women with MDD exhibited mild symptoms of depression and anxiety. An average score of 63 on the Global Assessment of Functioning Scale indicated a good level of functioning.

However, patients with MDD had a cumulative history of depression of approximately 5 years and 4 episodes of depression. Age at onset of depression was in the late teens, and approximately half the women with MDD also currently or previously had anxiety disorders. Eighty-two percent of the women with MDD were taking antidepressants. The matched subgroup of women with MDD had a lower BMD than controls, but the difference was significant only at the radius.

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Among the 89 women with MDD, no significant relationships were found between T score and the duration or severity of depression or anxiety, as measured by the age at onset of depression, the number of depressive episodes, the cumulative months of depression, or the Global Assessment of Functioning Scale, the Hamilton Depression Scale, or the Hamilton Anxiety Scale scores data not shown. None of the study participants had atraumatic fractures.

No differences were observed in age, age at menarche, smoking, or calcium, caffeine, or alcohol intake between these 25 patients and the remaining women with MDD. Of 73 women with MDD who were taking an antidepressant medication at the time of enrollment, 54 were taking 1 form of selective serotonin reuptake inhibitor. Table 4 presents the findings for the bone biochemical markers, calcium metabolism parameters, and urinary-free cortisol and catecholamine excretion in patients with MDD and control subjects.

Overall, bone biochemical markers were within the reference range in both women with MDD and controls. No differences were observed in serum osteocalcin levels, another bone formation marker. The iPTH level was slightly higher, whereas serum ionized calcium and plasma hydroxyvitamin D concentrations were lower, although within normal limits, in the MDD group compared with controls. Urinary-free cortisol and urine catecholamine concentrations were within the reference ranges and similar between women with MDD and controls.

Furthermore, no differences were found in the levels of urinary cortisol and urinary catecholamines between women with MDD and normal vs low BMD data not shown. Urinary concentrations of epinephrine, norepinephrine, and dopamine were similar between women with MDD and controls. The plasma cytokine concentration was measured hourly for 25 hours in 17 women with MDD and 14 controls Table 5. Demographic, endocrine, and metabolic characteristics in these subgroups were similar to those in the overall study sample data not shown.

Decreased bone mass was especially common at the hip, which is important because hip fractures are the most serious consequence of osteoporosis. The bone mass deficits observed are of clinical significance. Because the relationship between BMD and fracture risk is exponential, small deficits in BMD translate into larger increases in fracture rates. We confirmed the existence of low bone mass originally reported by Michelson et al 15 in a smaller sample of premenopausal women with MDD.

In that report, bone loss was also more accentuated at the femoral neck than at the anteroposterior spine. In that study, the magnitude of bone loss was greater than what we observed probably because their patients were more severely depressed. In addition, women with MDD in our cohort were approximately 5 kg heavier than controls, which is consistent with prior epidemiologic data. We found no significant relationships between BMD and chronicity or severity of depression.

This finding is consistent with reports that show no relationships between BMD and the number of depressive episodes, 6 antidepressant use, 15 depressive vulnerability, 23 or severity of depression. Moreover, they may also have been inadequately powered to detect a relationship between MDD and bone loss. We observed a striking difference in plasma cytokine concentrations between the MDD group and controls. Proinflammatory cytokine levels were substantially higher and anti-inflammatory cytokine levels were lower in our MDD group.

Several of these cytokines, including IL-6, have bone resorptive properties. By measuring cytokines every hour for 25 hours, we detected increased mean hourly concentrations of proinflammatory cytokines and decreased concentrations of anti-inflammatory cytokines, which is consistent with a systemic proinflammatory state. Such shifts in immune or inflammatory imbalance have previously been associated with other medical illnesses, including coronary heart disease and insulin resistance.

Although increased cytokine concentrations have previously been noted in severe depression, 29 to our knowledge this is the first report of elevated plasma cytokine levels in mildly depressed women. Of note, cytokine concentrations are known to increase in women after menopause, 30 whereas we observed elevations before menopause. In addition, we used a highly sensitive method to measure a large number of cytokines that were functionally related, including the less well-described anti-inflammatory cytokines.


Our analytical determinations were confirmed by mass spectrometry, adding validity to our findings. No increases in plasma cortisol, urinary-free cortisol, or catecholamine concentrations were seen, most likely because these patients were treated and in clinical remission.

We previously reported that patients with active depression exhibit both sustained activation of the sympathetic nervous system 7 and augmented IL-6 secretion. Recently, a direct cause-effect relationship between stress and bone loss was demonstrated in mice. Levels of serum bone-specific alkaline phosphatase, a bone formation marker, were higher in the MDD group, whereas levels of urinary N-telopeptide, a bone resorption marker, tended to be lower.

Bone formation may have been activated as an attempt to recover from previous periods of loss. Women with MDD exhibited slightly but nonsignificantly higher intact PTH concentrations and lower hydroxyvitamin D and ionized calcium levels compared with controls. These variations were within the reference range. One contributory factor to low BMD may have been failure to achieve optimal peak bone mass.

Because in our study the first depressive episode occurred in the late teens, it is possible that early depression may have interfered with achievement of full bone mass. The role that traditional osteoporosis risk factors play in premenopausal women is not well established.

Insufficient calcium intake, smoking, and inadequate physical activity were not related to bone loss in a large prospective study of premenopausal women. Episodes of amenorrhea were not reported, and use of oral contraceptives, which has been associated with increased bone mass, 35 was similar between groups. In a recent prospective cohort study, 32 use of selective serotonin reuptake inhibitors was found to be associated with a 2-fold increase in risk of clinical fragility fracture.

In the current study, use of selective serotonin reuptake inhibitors was not associated with low BMD. This study had several strengths. To minimize recall bias, only individuals with a current or recent history of depression were enrolled. Participants were predominantly white and drawn from a community sample and consisted of women with MDD mostly in remission.

Few data points were missing in this large data set, limiting the possibility of a nondirectional bias.

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This study had several limitations, including racial homogeneity of the study participants and use of medications for their depression by most participants, most of whom were in remission. The latter factor may have been associated with correction of hypothalamic-pituitary-adrenal axis disturbances described in patients with active depression. In addition, the effect of antidepressants on BMD may have confounded the results of the study.

Known risk factors for osteoporosis, such as exercise, smoking, and calcium intake, were assessed cross-sectionally and relied on recollection. Finally, cytokine measurements were performed in only a subset of participants, preventing us from establishing a statistically meaningful association between cytokine levels and BMD. The usefulness of antidepressants for bone loss in MDD should be evaluated.

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Prospective studies should establish whether women with MDD experience a more sustained bone loss during the perimenopausal or postmenopausal period than women without depression. Exploratory studies of bone mass should be conducted in conditions associated with an activation of the sympathetic nervous system, such as posttraumatic stress disorders.

The possibility that patients with depression may fail to reach peak bone mass should be investigated. Fracture risk may be increased in women with MDD, especially after the onset of menopause.

Osteoporosis: Practice Essentials, Background, Pathophysiology

Given that MDD is a common chronic condition and that osteopenia is often clinically silent, our sample may be representative of a large population with undiagnosed conditions until the time of fracture. Author Contributions: Dr Cizza had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Obtained funding : Sternberg, Gold, and Cizza. Study supervision : Eskandari, Sternberg, Gold, and Cizza. Additional Contributions: We thank Kate Musallam nurse manager and all the other National Institutes of Mental Health nurses who supported these studies and Meredith Coyle for careful editing of the manuscript. Finally, we thank all the individuals who participated in this study.

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All Rights Reserved. View Large Download. Table 1. Characteristics of Study Participants a. Mood disorders in the medically ill: scientific review and recommendations. Low lumbar bone mineral density in patients with major depression. Cardiac implications of increased arterial entry and reversible h central and peripheral norepinephrine levels in melancholia. 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.

Depression induces bone loss through stimulation of the sympathetic nervous system. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Measurement of cytokines in sweat patches and plasma in healthy women: validation in a controlled study. Bone mineral density in women with depression. Exercise for preventing and treating osteoporosis in postmenopausal women. Calcium supplementation on bone loss in postmenopausal women.

1. Introduction

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