This is the first article to examine the association of depressive symptoms and anxiety with bone mass and density in healthy adolescent girls. We found that girls with more depressive symptoms, and in some cases anxiety, were more likely to have lower total body BMC. Subgroup analyses by ever and never having smoked either enhanced or weakened associations with bone mass or density, depending on whether depressive symptoms or anxiety was the explanatory variable of interest. For example, trait anxiety was not significantly associated with bone mass and density in the full sample. However, among ever-smokers, a negative association between anxiety and total body BMC was noted when we controlled for age at onset of smoking. Specifically, this association was stronger in those who started smoking at a younger age. Enhancement of the negative association between anxiety and depression may reflect a dose-response relationship between age and bone health. A negative effect of smoking on BMD was reported in adults23-25
; but in the only available study of adolescents, no association was found.35
The current findings indicate that anxiety and depression are implicated in bone health, but they need to be replicated.
The negative association between depressive symptoms and total body BMC and BMD held for never-smokers but not for ever-smokers. Initially this finding seems counterintuitive. It may be that smoking improved depressive symptoms in girls via self-medication resulting in no significant association between depressive symptoms and total body BMC. This interpretation is consistent with a finding that smoking reduces depressive symptoms.36
The association of smoking with depressive symptoms and anxiety needs further exploration, even in the absence of an association in adolescents, given that smoking may predict later depressive symptoms. Yet to be confirmed is the causal direction between smoking and depressive and anxiety symptoms in adults37
Race was an important factor in the association between anxiety and bone characteristics. Higher state anxiety was associated with lower BMC but only in white participants. Bone mineral density is lower in white children than in African American children.38
Thus, the effect of anxiety on bone may add to the already enhanced risk of lower BMD in white individuals. It is important to note that our minority sample was smaller than the white sample and thus power may be limited for these analyses.
The findings that depressive symptoms and state anxiety are associated with lower total body BMC may aid in identifying girls who are at risk for low bone mass and developing prevention programs during adolescence. Depression and anxiety are already indicators to health care providers that intervention may be necessary. However, knowing that affective states may also be associated with bone alerts health care providers of the need for other types of intervention. Efforts to prevent further depression or reduce its onset may be especially important in adolescent girls, particularly at pubertal stage 3 and higher, given that depression increases around this stage of development.39
Thus, when a provider is caring for a depressed or anxious girl, vigilance may be needed regarding the potential role affective states along with other known factors, like smoking, may play in bone density. Furthermore, some symptoms evident in depression (eg, appetite changes and lack of physical activity) may also have negative effects on bone mass. An additional consideration is that antidepressants, specifically selective serotonin reuptake inhibitors, reduce bone density by as much as 4% in adults.40
However, such studies have not been carried out in adolescents; clinicians will need to consider the relative risks of treating their patient’s depression and its effect on bone health.
Our objectives were not designed to examine mechanisms that affect bone in these cross-sectional analyses. We categorized adolescents into never- vs ever-smokers based on the premise that ever-smokers represented a group at risk for various negative behaviors that may in turn affect bone health. Smoking in adolescence may be a marker for an unidentified mechanism that influences BMD. Alternatively, smoking may directly influence bone health. It has been shown that nicotine was more detrimental in young, rapidly growing rats than in older rats, indicating that nicotine may suppress bone formation.41
A human analog study would require participation by adolescents and adults who smoke. Such a study may be performed in the future.
Future longitudinal analyses might profitably examine mechanisms through which smoking as well as depressive and anxiety symptoms influence bone. Smoking may influence bone by decreasing body mass and/or estrogen effects. Smoking increases irreversible 2-hydroxylation of estradiol metabolism,42
increases metabolizing enzymes CYP1A1 and 1A2 (primary enzymes catalyzing 2-hydroxylation of estradiol),43
and competes with tobacco by-products that bind to estrogen receptors,43
all factors that could affect bone. These mechanisms can be investigated when our sample transitions into heavier smoking stages of development.
With respect to depressive symptoms and anxiety, explanatory mechanisms for affective states that influence bone will also be important to consider in future studies. Earlier studies have implicated the stress system as 1 potential mechanism. In mice, chronic mild stress was associated with evidence of behavioral depression and deficits in bone when bone epinephrine levels were increased.45
In this case, the sympathetic nervous system likely mediated the bone effects of stress-induced depression while a β-blocker diminished bone mass. Similarly, other studies have reported an effect of the sympathetic nervous system on regulation of bone mass.46
Others have speculated that the mechanism of low BMD or BMC and depression in adult humans could be due to hypothalamic-pituitary-adrenal axis dysregulation, another arm of the stress system.11,47,48
Many adults with depression have hyperadrenocorticalism,49
which can reduce bone mineralization.50,51
However, literature on child and adolescent depression supports the association of depression with hyperadrenocorticalism in only a few subgroups rather than those with depression as a whole.52-54
Less evidence is available with respect to anxiety, cortisol, and bone density. Cortisol level was higher in prepubertal children with anxiety disorders around sleep onset compared with depressed children or children with no psychiatric history.55
Thus, in younger children, anxiety may play more of a role in inhibiting bone formation than depression.
Despite the major strengths of this study, some limitations are evident. First, the study’s design was cross-sectional and causation cannot be determined. Second, activity and nutrition were based on self-report, though there is a high correlation between self-report and objective measures.56
Third, in our young sample, many were just beginning their smoking trajectory and its effects may not yet be evident. Adolescents who smoke even a puff are at risk for increased smoking and dependence.57
At follow-up, we anticipate increased smoking in the older adolescents, thus allowing for examination of the effect of different levels of smoking on bone health. Finally, hormone contraception may have influenced findings in ways that could not be statistically identified. Earlier studies reveal that depot medroxyprogesterone acetate can have a negative effect on bone associated with suppression of ovulation and a resulting hypoestrogenic state.58
Lower-estrogen oral contraceptives may have an especially adverse effect on bone in adolescents.59
In 2002, nearly 47% of 15- to 19-year-old adolescent girls in the United States had sexual intercourse, and 75% used contraception during last intercourse,60
most commonly oral contraceptives and depot medroxyprogesterone acetate.61
Girls using hormone contraceptives were not excluded from this study, as this would limit generalizability to the adolescent population. In addition, hormone contraceptives were used by never- and ever-smokers and those who had high or low depressive and/or anxiety symptoms.
In conclusion, analyses that report a negative association of depressive symptoms and anxiety with bone health in adolescent girls are cause for concern and necessitate further examination. Others have echoed the necessity for such research.62
The percent difference (1.4%-6.5%) observed in BMD and BMC by change in depression and anxiety scores alone or by smoking status may be clinically relevant. To put this in perspective, postmenopausal women lose on average 2% (≤5%) of bone mass each year, and women of reproductive age using depot medroxyprogesterone acetate lose 2% to 3% of bone mass each year. In these scenarios, patients are monitored and in some cases interventions are instigated. Therefore, seeing a percentage difference in our sample in this range is worrisome given that these girls are at the age when peak mass is accrued. Longitudinal analyses are required to determine mechanisms of depressive and anxiety symptoms and smoking on bone in this crucial developmental period. Our findings support this necessary next step.