Impact of psychiatric disease on bone health



Bernard CORTET, MD, PhD
Isabelle LEGROUX-GÉROT, MD
Département Universitaire
de Rhumatologie
Université de Lille 2
FRANCE

Impact of psychiatric disease on bone health

by B. Cortet and I. Legroux-Gérot, France

Psychiatric diseases may, via direct and indirect mechanisms, induce bone fragility. This is particularly the case with depression and anorexia nervosa. Studies show a moderate decrease in bone mineral density (of the order of 6%) in the spine and hip of depressed patients vs controls. Similarly, a significant increase in fracture risk is observed, with an up to 2-fold increase in hip fracture risk. The mechanisms of bone fragility in depressed subjects are complex, multifactorial, and have yet to be fully elucidated. One of themajor directmechanisms involves endogenous hyperadrenocorticism— which is less pronounced than in Cushing’s syndrome, and may be due in part to a rise in proinflammatory cytokines (notably interleukin 6), which is reported in depressed patients. Also, antidepressant treatment—in particular serotonin reuptake inhibitors—may have a negative impact on bone. Indirect factors, whose role is disputed, include weight loss and cigarette and alcohol abuse, often reported in depressed subjects. Anorexia nervosa (AN) has become a major problem in recent years. AN gives rise to multiple complications and is frequently associated with bone loss, with osteoporosis occurring in 38% to 50%of cases. Estrogen deficiency has long been known to play amajor role, but cannot alone explain bone loss. Recent publications have highlighted the essential role of undernourishment and factors influenced by nutritional status, in particular the growth hormone–insulin-like growth factor I (GH-IGF-I) axis. Themanagement of anorexia nervosa–related bone loss is debated.While restoring menstruation and body weight is mandatory, it does not always ensure correction of bone loss. Studies have failed to show any effectiveness of estrogen treatment.

Medicographia. 2010;32:349-356 (see French abstract on page 356)

Certain psychiatric disorders may have a deleterious impact on bone. This occurs via direct and indirect mechanisms, not all of which have been elucidated. Essentially two psychiatric disorders have undergone extensive research to evaluate this relationship: depression and anorexia nervosa (AN). These two diseases will therefore be addressed in this paper.

IMPACT OF DEPRESSION ON BONE

Depression is a frequent disease, affecting about 16% of the North-American population.1 One of the first publications to link depression and impact on bone was published by Schweiger et al in 1994.2 These authors determined bone mineral density (BMD) by quantitative computerized tomography (QCT) in 70 depressed subjects and 88 controls. The female/male ratio was the same in both groups. The authors found an approximately 15% reduction in BMD in the depressed subjects, after adjustment for age. Subsequently, several articles on the same topic were published in which BMD was measured by dual-energy x-ray absorptiometry (DXA), the current consensus method; but the findings disagreed: certain authors reported a link between depression and low BMD,3-14 while others found no such link.15-21 This discrepancy is undoubtedly related to the heterogeneity of the disease itself. In addition, it is to be noted that most of the subjects enrolled in the studies were, quite logically, on antidepressant treatment, often serotonin reuptake inhibitors (SSRIs), known to have an impact on bone.

Figure 1
Figure 1. Mean differences in bone mineral density (BMD) between depressed and nondepressed groups and corresponding 95% confidence intervals (CI) for the spine (A) and hip (B) in 12 studies.

Reproduced from reference 22: Wu et al. Osteoporos Int. 2009;20:1309-1320. © 2009, Springer.

Epidemiology of bone impact in depression

_ Densitometric data
A meta-analysis, avoiding the aforementioned pitfalls, was recently published,22 which included 8 cross-sectional and 6 case-control studies. Cohort studies were also evaluated when densitometric data were available. In all the studies, BMD was determined by DXA. In the cross-sectional studies, confounding factors such as age, gender, menopausal status, weight, and body mass index (BMI) were taken into account in the analysis of the results. The studies are summarized in Figure 1.5,7,11-14,16,17,19-24 Of the 14 studies, BMD data for all sites (lumbar spine and hip) were only reported in 12 studies, which were thus finally selected for the meta-analysis. The decrease in BMD was only significant in 6 cases. Mean between-group BMD difference was only slight: 53 mg/cm2 (95% confidence interval [CI], 18-87) for the lumbar spine. The difference was very similar for the hip: 52 mg/cm2 (95% CI, 22-83). In the depressed subjects, the percentage decrease in BMD was 5.9% for the lumbar spine and 6% for the hip.

When results were expressed as T-scores and Z-scores, the trend was similar, as expected. The decrease, while real, was onlymodest. Thus,mean T-scores in depressed subjects were –0.73 (95%CI, –1.32/–0.146) for the lumbar spine and –0.627 (95% CI, –1.02/–0.233) for the hip. The Z-scores were again, as expected, fairly similar. Various sensitivity analyses were conducted, but did not change the results. It should, however, be noted that when depression was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, the differences were a little more marked. The results for men, while also significant, were of lesser magnitude.

Depression and fracture risk

Bone densitometry is only a surrogate marker and the most important issue is whether depressed subjects are at greater fracture risk. As is the case for densitometric assessment, this requires taking into account numerous factors well known to influence fracture risk. It should be pointed out that studies aimed at determining fracture risk are few. Moreover, some of them are open to methodological criticism, particularly those of Kessler et al,1 due to the fact that they are retrospective studies.

Four of the 5 prospective studies on fracture risk available to date concluded that depression was associated with an increase in fracture risk. In the remaining study, by Greendale et al,25 which evidenced no such increase, the authors nonetheless showed that those patients with the highest urinary cortisol level were at increased risk of fracture. The main findings from these studies are summarized in Table I.15,20,25-27 Thus, for example, in 467 depressed subjects from a cohort of 7414, Whooley et al20 reported an increase in relative nonvertebral fracture risk, of 1.3 (95% CI, 1.1-1.6), after multiple adjustments. Similarly, vertebral fracture risk was 2.1 (95% CI, 1.4-4.2), after multiple adjustments. The authors concluded to a relationship between depression severity and the magnitude of the increase in fracture risk (Table I). Generally speaking, the risk of fracture, particularly peripheral fracture, is conditioned by 3 factors: BMD, the magnitude of the impact, and the angle of the impact. This likely applies to depressed patients as well. Lastly, it was shown that there is an increased risk of falls in depression.20,28

Table I
Table I. Depression and fracture risk.

Abbreviations: BMD, bone mineral density; BMI, body mass index.

Pathophysiology of bone impact in depression

_ Hypothalamic-pituitary axis
The various hypotheses are summarized in Figure 2 (page 352). There is substantial evidence to confirm the presence of hyperadrenocorticism in the context of depression. The latter results from chronic exposure to stress, which triggers the release of corticotropin-releasing hormone (CRH) by the paraventricular nucleus of the hypothalamus. The process involves frontal cortex, hippocampus, amygdala, and hypothalamus pathways. There is no autonomous hypersecretion of cortisol in depression, so that cortisol levels are markedly lower than those observed in Cushing’s syndrome. This hypothesis is corroborated by clinical data,13-23 which show an increase in plasma cortisol. An increase in urinary cortisol has also been observed, though some authors failed to evidence any such increase.29

Figure 2
Figure 2. Pathophysiology of the bone impact of depression.

_ Autonomic nervous system
Animal data suggest that there is a relationship between hyperactivity of the efferent autonomic nervous system and risk of bone demineralization. However, the implications of this finding in depression are still the subject of considerable debate.

_ Leptin
The relationship between leptin metabolism and bone metabolism is complex. Findings relating to circulating leptin levels in depressed subjects are contradictory. Thus, understanding of the pathophysiological role of leptin as a factor liable to explain the bone impact in depression requires further investigation.

_ Impairment of the immune system
Impairment of the immune system in depression has been fairly well established, with an increase in proinflammatory cytokines such as interleukins (IL) 1 and 6 and tumor necrosis factor.30 Cytokines are stimulants of the hypothalamic-pituitary- adrenal axis, which may account for the hyperadrenocorticism observed in depression. This has been confirmed by a recent study by Eskandari et al,29 which also reported a reduction in anti-inflammatory cytokines (IL-10 and IL-13) in depressed subjects. This reduction was only significant for IL-13. However, the study population was small, limiting the scope of the study.

Impact of depression on bone and confounding factors

Confounding factors include the classic risk factors for osteoporosis, which can be present in depressed subjects just as in the general population, and a risk factor specific to depression: antidepressant treatment.

_ Osteoporosis risk factors in depressed subjects
Certain risk factors for bone fragility are more frequently encountered in depressed subjects, eg, tobacco and alcohol abuse. Similarly, one of the symptoms of depression, namely, weight loss, is associated with an increase in fracture risk. These confounding factors are sometimes taken into account in the studies previously cited, but not always, which makes it difficult to interpret findings.

_ Antidepressants and bone metabolism
Antidepressants, in particular SSRIs, undoubtedly are themost important confounding factor. The presence of serotonin receptors on the osteoblasts and osteocytes lends support to the involvement of these agents. Some studies are adjusted to take into account antidepressant intake, but this is not always the case. The adverse effect on bone of SSRIs is supported by in vitro and animals studies. Severe osteoporosis has been evidenced in serotonin-deficient mice. A clinical study by Cauley et al31 showed that only SSRIs (and not tricyclic antidepressants) have an adverse impact on bone. More recently, Diem et al32 were able to show that the effect of SSRIs persisted even after adjustment for the symptoms of depression. They also reported accelerated bone loss in subjects on SSRIs vs nonusers and vs tricyclic antidepressant users.

Obviously, the most important issue is to determine whether antidepressants are associated with an increase in fracture risk. Quite logically, and in line with previous studies, a recent large-scale study33 in 6763 subjects on tricyclic antidepressants or SSRIs vs 26 341 controls matched for age, gender, and geographic origin, reported an increase in hip and femur fracture risk in patients receiving SSRIs: relative risk (RR), 2.35 (95% CI, 1.94-2.84). An increase in fracture risk, albeit of lesser amplitude, was also found in patients on tricyclic antidepressants: RR, 1.76 (95% CI, 1.45-2.15). The strength of the causal relationship was confirmed by the fact that fracture risk rapidly decreased following antidepressant treatment discontinuation. In patients receiving SSRIs, there was a parallel between the latter’s potency in inhibiting serotonin reuptake and the magnitude of the fracture risk increase. The potential increase in the risk of other fractures due to bone fragility was not clearly established. strength of the causal relationship was confirmed by the fact that fracture risk rapidly decreased following antidepressant treatment discontinuation. In patients receiving SSRIs, there was a parallel between the latter’s potency in inhibiting serotonin reuptake and the magnitude of the fracture risk increase. The potential increase in the risk of other fractures due to bone fragility was not clearly established.

Animal models

Yirmiya et al34 developed an experimental model of depression in the mouse, enabling micro-CT scan analysis of the distal metaphysis of the femur and the vertebrae. In both sites, the authors showed, under physiological and pathological conditions, a decrease in trabecular bone volume, compared with controls.

IMPACT OF ANOREXIA NERVOSA ON BONE

Anorexia nervosa (NA) has become a major public health concern in industrial countries in recent years. Its prevalence is 0.5%, vs 2%for bulimia. AN is a syndrome combining an exaggerated fear of excessive weight, a disorder of body image, significant weight loss, refusal to maintain a minimum normal weight, and amenorrhea.

The course of the disease is accompanied by a variety of disorders and complications. Bone health is much affected, with a decrease ofmore than 1 standard deviation (SD) in spine and femur neck bone mass in 92% of female patients, which exceeds 2.5 SD in 38% of cases.35 The mechanisms of bone loss in AN patients are multiple: hormonal, endocrine, and nutritional. The disease is more severe when it develops during adolescence, a critical period for acquisition of peak bone mass. Bone mass increases gradually through childhood and accelerates during adolescence to reach a peak during Tanner stages 4 and 5. The greater part of bone mass peak determination seems to be genetic (60% to 80%); the remaining 20% to 40% of determination is influenced by nutritional and hormonal factors.36 For a given age, bone loss is more marked in anorexic women than women with normal BMI and amenorrhea of hypothalamic origin. Forty percent of anorexic women are osteoporotic vs 16% in the second group.37 BMI in women in whom AN develops before age 18 years is significantly lower than those in whom it develops later, reflecting the impact of the disease on bone formation.38

Assessment of the bone impact of anorexia nervosa

_ Bone mineral density
BMD is determined in the spine and femur neck by means of bone densitometry measurements using low-dose radiation. TheWorld Health Organization defines osteoporosis as a BMD that is at least 2.5 SD lower than the mean for young women (T-score < –2.5 SD). However, this definition only applies to postmenopausal women, a fact that must be taken into account when dealing with adolescents who have not always achieved peak bone mass. Lower BMD is consistently reported in anorexic female patients, and osteoporosis is present in about 30% of them.35,39-41

_ Bone remodeling markers
Bone markers, used to assess bone remodeling, are complementary to BMD determination, but are not diagnostic tools. The most frequently used bone-formation markers are osteocalcin and bone alkaline phosphatase (BAP); bone-resorption markers include deoxypyridinoline (DPD), C-terminal (crosslaps or CTX), and N-terminal (NTX) extension peptides and telopeptides (carboxyl terminal telopeptide of collagen I [ICTP]).39,40 Thesemarkers aremainly used in postmenopausal women and their interpretation is more difficult in young women and adolescents. The literature shows wide divergence in findings; study populations are frequently small and it is necessary to distinguish between the studies conducted on female adolescents and those conducted on adult anorexic patients. Like postmenopausal women, AN women show an increase in bone resorption, but studies have also shown that there is a marked decrease in bone formation.42

This shows that the bone loss in AN patients is also related to other mechanisms, such as estrogen deficiency, and that nutritional or nutrition-dependent factors are also involved. This is confirmed in the literature by the fact that bone loss in AN patients is more marked than that in women of the same age suffering from hypogonadism.

Few studies have addressed fracture risk in AN populations. Lucas et al43 reported a retrospective study in 208 AN patients over 13 years with 58 fractures. Compared with the expected number of fractures, the risk in AN patients was 3-fold greater. Fractures occurred more frequently in inpatients than in outpatients, and bone insufficiency–related cracks were also more frequent in inpatients. A study in female patients with a mean AN duration of 5.8 years reported a 7-fold greater fracture risk than in healthy women of the same age.44 Fractures occurred more frequently at the usual sites (vertebrae, followed by the radius and the distal extremity of the femur).44

_ Hormonal factors
Studies of the time course of BMD in female AN patient populations show that when AN is diagnosed before age 18, BMD is significantly lower than when diagnosed at a later age, reflecting the impact of the disease on acquisition of peak bone mass.35,39,40,44,45

Amenorrhea is a diagnostic criterion for AN. Estrogen deficiency is known to play a major role in bone mass loss in the AN population. The mechanisms underlying estrogen deficiency in AN have yet to be fully elucidated. They are probably multifactorial, and include hypothalamic dysfunction, weight loss, and dysregulation of neurotransmitters such as GnRH. The literature shows a correlation between BMD and the duration and age of onset of amenorrhea.35,39,44-46

Estrogen deficiency alone cannot explain bone loss in anorexic female patients. Bone mass gain precedes resumption of menstrual cycles in recovering anorexic patients, while estrogen therapy does not prevent bone loss in adolescents.42 Other factors are involved in bone loss in AN. Bone remodeling is differently affected in AN female patients compared with postmenopausal osteoporotic women. Bone resorption and formation are increased, with a balance in favor of resorption, in postmenopausal women, whereas in AN, although bone resorption is slightly greater, the predominant disorder is decreased bone formation,37,39 though some authors report that it is normal.35 In any event, it is never increased. Reduced bone formation in AN explains the relative failure of antiresorptive treatments and, particularly, estrogens.42 In all, this suggests an essential role for undernourishment and factors influenced by nutritional status in the bone loss of AN.

_ Nutritional and endocrine factors
The role of nutritional and endocrine factors is supported by the literature, which shows a strong correlation between female patient BMD and nutritional indices such as BMI, lean mass, fat mass, insulin-like growth factor–I (IGF-I), and leptin.37,39 In a previous study, the author and his colleagues showed a correlation between hip BMD and IGF-I in 113 female patients with AN.46 Hotta et al47 showed that the osteoporotic risk is higher when BMI is less than 15 kg/m2. Other authors39,47 have also reported a correlation between bone formation markers (osteocalcin and BAP) and nutritional markers such as BMI, fat mass percentage, IGF-I, and a negative correlation between estradiol and bone resorption markers.

At puberty, the levels of GH-IGF axis hormones increase to stimulate the proliferation and differentiation of osteoblastic precursors. IGF-I is a bone tropism hormone that stimulates bone formation and growth by acting on osteoblasts and stimulating collagen synthesis. Studies have shown an impairment of the GH-IGF-I axis in AN patients.48,49 Female AN patients display resistance to GH, with high GH levels, but low IGF-I levels. Stoving et al48 monitored 24-hour GH secretion in 8 anorexic female patients and showed an increase in the number, duration, and intensity of GH peaks. The authors also showed an increase in basal secretion (20-fold vs 4 fold for pulsatile secretion). The increase in the intensity of GH peaks is ascribed to weight loss, while the number of peaks is related to hypoestrogenism. There was no difference in GH half-life in anorexic patients compared with healthy controls. Sacchi et al49 published similar results. Several authors have reported a decrease in IGF-I levels, but also in binding proteins (IGFBP), in particular IGFBP3 and 2, in anorexic female patients,50,51 sometimes with an increase in IGFBP1. The decrease in circulating binding-protein levels may in part explain the resistance to GH, preventing the transfer of IGF-I toward the target organs. In addition, IGFBP3 is reported to be a good predictive factor for bone loss in anorexic patients, independently of BMI and IGF-I.

Figure 3
Figure 3. Relationship between circulating leptin level (abscissa:
tertiles 1, 2 and 3) and bone mineral density expressed as lumbar
spine Z-score (as ordinates).

Modified from reference 52: Legroux-Gérot I et al. Osteoporos Int. 2010 Jan 6.
[Epub ahead of print] DOI 10.1007/s00198-009-1120-x. © 2010, International
Osteoporosis Foundation and National Osteoporosis Foundation.

An important role is played by the hormone leptin, an antiorexigenic adipokine secreted by adipose tissue. Leptin’s physiological effects on bone are debated, particularly as they differ depending on whether its peripheral or central action is considered. Measuring BMD and several hormonal factors in a recent cohort study of 103 young women with AN,52 the authors found a mean Z-score of –1.17 for the spine, –1.33 for the hip, and –1.11 for the femur neck, and a modest, but significant, positive correlation between leptin levels and spinal BMD (r = 0.30). The correlations were significant, but of lesser amplitude, for the femur neck and whole hip (r = 0.23 and r = 0.21, respectively). Multiple regression analysis showed that 27%of spinal BMD variability was explained by differences in duration of amenorrhea and leptin levels. Figure 3, which plots BMD values as a function of leptin level divided into 3 tertiles, shows a marked and significant difference between the patients in the lowest tertile (mean Z-score: –1.25) and higher tertile (mean Z-score: +0.75).52

Hyperadrenocorticism and calcium and vitamin D deficiency are reported in AN, in some cases compounded by excessive exercise. Thus, high cortisol levels can be found,38,46 although the circadian rhythm is spared. Similarly, the dexamethasone suppression test frequently evidences an increase in urinary free cortisol. Hyperadrenocorticism may be related to impairment of hypothalamic function or CRH hypersecretion. Grinspoon et al35 reported hyperadrenocorticism in only 22% of anorexic patients with severe bone loss. We found similar results in our study.46 Audi et al53 did not find any signif- icant difference in urinary free cortisol levels between AN patients and controls. This suggests that while hyperadrenocorticism is a potential cause of bone loss, it is not the only mechanism involved. The role of vitamin and calcium deficiency in bone loss remains uncertain. In the study by Audi et al53 vitamin D deficiency (25-OH-D3) was observed in 24.6% of AN patients. Urinary calcium was somewhat higher in the group of AN patients in the active phase, and lower in those having regained weight, but still with amenorrhea, and those who had recovered. Soyka et al40 reported dietary calcium deficiency (<1300 mg/day) in 42% of the AN patients in their study population, but also in 50% of the controls. Similarly, vitamin D deficiency was present in 42% of AN patients and 44% of controls.

Course of bone loss after weight recovery

A few studies have addressed the time course of BMD in recovered anorexic patients.40,44,54 Despite the improvement in bone mass with body weight normalization, certain studies report persistent osteopenia in a high proportion of postanorexic patients. Hartman et al,54 in a study of 19 female patients with a history of AN, determined bone mass at age 21 years and found, despite body weight recovery, that femur bone mass was lower than that of the control group. In Zipfel’s study,44 monitoring of spine BMD showed bone gain after body weight recovery with a decrease in the percentage of osteopenic and osteoporotic female patients (35% to 13% and 54 to 21%, respectively),but a large proportion of the patients continued to have low BMD values. However, in a recent study, Wentz et al55 did not confirm those results and found no significant difference in BMD between the patients with a history of AN (11 years previously on average) and the controls.

Overall, specific bone-targeting treatments are of little efficacy in AN. As indicated previously, the primary objective is to achieve body weight recovery, which has a proven beneficial impact on bone. Various studies, including a recent one by us, have shown that hormonal treatment is not effective.56 In contrast, achieving a BMI greater than 19 kg/m2 and resumption of menstrual periods results in bone gains.

In conclusion, bone loss in female patients with AN is rapid and severe and is associated with a substantial fracture risk, the mechanism of which has yet to be fully elucidated and is probably multifactorial. Early screening is necessary and BMD must be determined as soon as AN is diagnosed. _

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Keywords: psychiatric disorder; depression; anorexia nervosa; hyperadrenocorticism; estrogen; osteoporosis