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Increased Bone Remodeling in First-Episode Major Depressive Disorder

From the Departments of Psychiatry (A.H., J.L.V.-B), Endocrinology (J.A.A., M.T.G.-U., L.P.), and Internal Medicine (J.G.-M.), University Hospital Marqués de Valdecilla, Santander, Spain.

Address reprint requests to: Andrés Herrán, MD, Clinical and Social Psychiatry Research Unit, Department of Psychiatry, University Hospital Marqués de Valdecilla, Avda. de Valdecilla s/n, 39008, Santander, Spain. Email: herran{at}humv.es

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVE: Bone mineral density is decreased in patients with depressive disorder. This study evaluated biochemical bone remodeling markers in patients having their first depressive episode who had not taken psychotropic medications to evaluate possible pathogenic mechanisms implicated in the loss of bone mineral density in early states of this illness.

METHODS: Serum osteocalcin, parathyroid hormone, bone alkaline phosphatase, telopeptide, collagen type I C-terminal propeptide, cross-laps, and 25-hydroxyvitamin D levels were measured in 19 depressive patients and 19 age-matched healthy women. In addition, serum cortisol and interleukin-6 were determined. Patients were assessed with the Schedules for Clinical Assessment in Neuropsychiatry interview and met criteria for a single depressive episode.

RESULTS: Depressed patients had increased levels of osteocalcin (p = .003), an osteoblastic marker; telopeptide (p = .01), an osteoclastic marker; and cross-laps (p = .000), another osteoclastic marker. Parathyroid hormone was lower in patients (p = .02), whereas the rest of the markers were comparable between patients and healthy control subjects. Serum cortisol was higher in depressed patients than in control subjects (p = .003), but cortisolemia and interleukin-6 did not show any relationship with bone markers in patients. Clinical severity of the illness and weight loss due to depression in patients did not correlate with bone remodeling markers.

CONCLUSIONS: These data suggest that an increase in bone remodeling not due to vitamin D deficiency induces a release of calcium from bone and inhibition of parathyroid hormone secretion.

Key Words: depressive disorder • bone density • bone remodeling markers • osteoporosis.

Abbreviations: BMD = bone mineral density; CV = coefficient of variation; ICD-10 = International Classification of Diseases, 10th revision; IL-6 = interleukin-6; PTH = parathyroid hormone; RIA = radioimmunoassay.

	INTRODUCTION

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After initial case reports described osteoporosis-related fractures in patients affected by depressive disorder (1), studies using quantitative computerized tomography and photon absorptiometry showed a decrease in BMD in these patients (2–4). One study also analyzed biochemical bone remodeling markers (4) and found altered parameters in patients with depressive disorder (lower serum levels of osteocalcin and lower urinary excretion of deoxypyridinoline). However, pathogenic mechanisms that could lead to loss of bone mass in depression have not been sufficiently elucidated. Some authors (5) have suggested a number of factors that could be implicated in reduced BMD in patients with depressive and other psychiatric disorders, including overactivity of the hypothalamic-pituitary-adrenal axis and increased interleukin activity. In addition, other disease- and medication-related processes, such as impaired fluid and electrolyte balance, smoking-related processes, dietary and vitamin deficiencies, decreased exercise, and exposure to sunshine, could play a role in the loss of BMD. These latter factors might reflect long-term effects of medications and/or long-term duration of the illness.

Bone formation is a complex process initiated by activation of osteoclasts (to remove old bone) and followed by activation of osteoblasts (to form new bone). Osteoblasts and osteoclasts are controlled by systemic hormones, cytokines, and other local factors (eg, PTH and 25-hydroxyvitamin D). Bone remodeling can be assessed by a number of serum markers of bone formation, such as alkaline phosphatase (a useful measure, but one with very low sensitivity and specificity), osteocalcin (a specific protein of bone and related tissues), and type I collagen propeptide (a by-product of the extracellular metabolism of type I collagen). On the other hand, some degradation products (eg, telopeptide and cross-laps) are highly specific markers of bone resorption.

The aim of this study was to evaluate biochemical bone remodeling markers in a sample of patients having their first depressive episode who had not taken psychotropic medications to evaluate possible pathogenic mechanisms implicated in the loss of BMD in early stages of depression.

	PATIENTS AND METHODS

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Patients
Thirty-seven outpatients suspected of having their first depressive episode were referred for evaluation from a mental health unit. Patients were evaluated with the Schedules for Clinical Assessment in Neuropsychiatry interview (6, 7) to diagnose a single depressive episode according to ICD-10 criteria (8). When the data were analyzed using the CATEGO program, 10 patients did not meet the ICD-10 criteria for a depressive episode. Five men and 1 woman (age = 80 years) were excluded from the analysis to improve the homogeneity of the sample. In addition, two patients refused to provide informed consent and were not enrolled in the study. Thus, 19 women having a single depressive episode but no psychiatric antecedents made up the final sample of patients.

The same number of healthy women were selected from the hospital staff. Lack of psychiatric disorders in this group was determined by using a semistructured interview. Lack of physical diseases was determined in both groups by physical examination and review of patients’ medical records. Results of laboratory work (ie, complete blood count, biochemical testing, urine analysis, and tests for proteins, hepatic enzymes, and thyroid hormones) were normal for patients and control subjects. All patients and control subjects were white, none took calcium supplements, none consumed a vegetarian diet, and none had ever taken psychotropic drugs (except benzodiazepines). Severity of depression was evaluated with the Spanish version of the 17-item Hamilton Depression Scale (9). The study was explained to the subjects, and written informed consent was obtained.

Procedures
Fasting blood samples were withdrawn from an antecubital vein between 8:00 and 9:00 AM. Samples were centrifuged immediately, and serum was stored at -40°C until assayed. Samples were obtained simultaneously from both patients and control subjects during a 5-month period to avoid seasonal changes in bone remodeling markers (10).

Laboratory Measures of Bone Metabolism
Serum osteocalcin and intact PTH were measured by immunoradiometric assay (ELSA-OSTEO kit, CIS Bio International, Gif-sur-Yvette, France, and Nichols Institute kit, San Juan Capistrano, CA, respectively). The sensitivity of the osteocalcin test is 0.4 ng/ml. Intra- and interassay CVs are 3.8 and 4.8%, respectively. The sensitivity of the intact PTH test is 1 pg/ml, and the CVs are 2.6 and 5.8%, respectively. Bone alkaline phosphatase was determined by immunoassay (Alkphase B kit, Metra Biosystems, Mountain View, CA). The minimal detectable dose is 0.7 U/liter. Intra- and interassay CVs are 3.5 and 6.2%, respectively. Telopeptide was measured by RIA (Orion Diagnostica kit, Espoo, Finland). Sensitivity is 0.5 (µg/liter), and intra- and interassay CVs are 4.8 and 5.7%, respectively. Collagen type I C-terminal propeptide levels were measured by enzyme-linked immunosorbent assay (Prolagen C kit, Metra Biosystems). Sensitivity of the propeptide test is 0.2 ng/ml. Intra- and interassay CVs are <10 and <15%. 25-Hydroxyvitamin D was measured by RIA after extraction with acetonitrile (DiaSorin, Stillwater, MN). The minimum detectable concentration is estimated to be 1.5 ng/ml. Intra- and interassay CVs are 9.4 and 10.8%, respectively. Cross-laps were measured by enzyme-linked immunosorbent assay (Osteometer Biotech, Herlev, Denmark). Sensitivity is 92 pmol/L, and intra- and interassay CVs are <5 and <8%.

Total calcium was measured by standard automated methods (Hitachi 704, Tokyo, Japan), and creatinine levels were measured by automated methods using a Technicon Dax (Technicon Instruments Corp., Tarrytown, NY) with reagents supplied by Boehringer-Mannheim (Mannheim, Germany).

Endocrine and Cytokine Determinations
Cortisol was measured by RIA (Coat-A-Count Cortisol DPC kit, Los Angeles, CA). The minimal detectable dose is 0.2 µg/dl. Intra- and interassay CVs are 4.3 and 5.2%, respectively.

IL-6 was measured by enzyme-linked immunosorbent assay (Human Interleukin-6 Ultrasensitive kit, BioSource International, Camarillo, CA). The minimum detectable concentration is estimated to be <0.1 pg/ml. Intra- and interassay CVs are 6.4 and 7.8%, respectively.

Statistical Analysis
Data were analyzed with SPSS 7.0 (11). Laboratory measures of bone metabolism and cortisol fit a normal distribution, but IL-6 did not. Differences were tested by Student’s t test, and correlations with other parameters were tested using a simple Pearson’s coefficient. When analyzing IL-6, Hamilton scores, and weight loss due to depression, the Mann-Whitney U test and Spearman’s correlation were used. Tests were two-tailed, and differences of <.05 were considerate significant.

	RESULTS

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The final patient sample was composed of 19 women with a mean score of 20.6 on the Hamilton Depression Scale. The main demographic and clinical features of patients and control subjects are given in Table 1.

Endocrine and Cytokine Determinations
Serum cortisol was higher in depressed patients (mean = 18.4 µg/dl, SD = 6.5 µg/dl) than in control subjects (mean = 12.6, SD = 4.1) (t = 2.25, df = 35, p = .003). IL-6 levels did not differ between the two groups (mean = 1.0, SD = 0.6 vs. mean = 1.5, SD = 1.6 pg/ml, respectively) (U = 156.0, p = .4).

Relationship Between Bone Remodeling Markers and Other Laboratory Measures and Clinical Features
Serum cortisol was positively correlated with cross-laps (r = 0.48, df = 17, p = .04) and osteocalcin (r = 0.63, df = 18, p = .004) in controls subjects but not in depressed women. Clinical severity of the illness and weight loss due to depression in patients and IL-6 in both patients and control subjects did not show any relationship with bone remodeling markers.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
This is the first study assessing biochemical bone remodeling markers in depressed patients who had not taken psychotropic medications. Moreover, because patients were having their first depressive episode, we were able to analyze bone turnover in early stages of their illness. On the other hand, one of the limitations of our study is its cross-sectional design, so the findings should be interpreted with caution. In addition, we cannot exclude a number of confounding factors related to lifestyle of outpatients with symptoms of depressive disorder (eg, lack of exposure to sunshine and type of exercise), but the fact that our patients had no previous psychiatric illnesses limits this problem.

Our data show an increase in some osteoblastic (osteocalcin) and osteoclastic (telopeptide and cross-laps) markers, whereas bone alkaline phosphatase and collagen type I C-terminal propeptide were normal. Furthermore, 25-hydroxyvitamin D levels were normal, whereas PTH was decreased. These findings exclude vitamin D deficiency.

Bone remodeling is a process characterized by the removal of old bone by osteoclastic resorption, followed by coupled osteoblastic formation of new bone (12). Hormones and local factors regulate this process. Serum levels of alkaline phosphatase, osteocalcin, and collagen type I C-terminal propeptide reflect different aspects of osteoblastic activity, whereas telopeptide and cross-laps reflect osteoclastic activity. Moreover, the different bone formation markers reflect different types of osteoblastic differentiation. Procollagen peptides are mostly produced by proliferating osteoblasts; alkaline phosphatase, by mature cells; and osteocalcin, during the mineralization phase. These markers are usually well correlated, and patients with diseases marked by high turnover of bone (eg, hyperparathyroidism and hyperthyroidism) have increased levels of both (formation and resorption) markers. But different clinical situations can induce discrepant results in the different bone formation markers; for example, in hypercortisolism and stress, there is uncoupling between bone formation and bone resorption and osteocalcin, but alkaline phosphatase is not suppressed, whereas bone resorption markers are increased (13, 14).

Previous studies have demonstrated reduced BMD in patients with past or current depression (2–4), and only one (15) did not find differences (this work included only six patients and five control subjects). Furthermore, a recent community study in women (16) demonstrated that women with osteoporosis have significantly higher levels of depressive symptoms. Only one previous study (4) has analyzed bone remodeling markers, but it had a number of limitations, such as heterogeneity of patients (past or current depression), prolonged length of evolution of the illness, and inclusion of medicated patients. Thus, it is not surprising that their results (lower serum osteocalcin and lower urinary excretion of deoxypyridinoline) are difficult to interpret.

Our data (which showed increases of osteocalcin, telopeptide, and cross-laps and a decrease of PTH) suggest an increase in bone remodeling that induces release of calcium from the bone and inhibition of PTH secretion. Hypercortisolemia per se does not seem to be responsible for the changes found. The pattern of bone remodeling markers found is quite similar to that found in hypoestrogenism. Regrettably, we did not measure estrogen levels in our patients. Halbreich et al. (3) found a significant correlation between BMD (measured with dual-photon absorptiometry) and both plasma total and free testosterone in medicated men with psychiatric illnesses (21 depressives among them) and a significant negative correlation between BMD and both cortisolemia and prolactinemia in the depressive subgroup. These data support our results.

IL-6 and other cytokines have been proposed as stimulants of bone resorption activity and decreased BMD in mental disorders (5), but in the acute state of their depressive illness, our patients did not show an elevation of IL-6, and serum levels of this cytokine did not correlate with bone markers. On the other hand, clinical severity, measured with the Hamilton Depression Scale, did not show any relation with remodeling markers, but scores on this scale reflect a homogeneous sample of patients with moderate depressive illness, and given the relatively small sample size, we cannot exclude a type 2 error.

Additional studies are needed to describe the processes contributing to increased bone remodeling in depressive patients, including patients with more severe illness, and to analyze the role of hypogonadism.

	ACKNOWLEDGMENTS

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This study was supported in part by a grant from the Fundación Marqués de Valdecilla.

Received for publication January 25, 2000.

	REFERENCES

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