15 Oct 2012: (2012) Correction: Do Premenopausal Women with Major Depression Have Low Bone Mineral Density? A 36-Month Prospective Study. PLoS ONE 7(10): 10.1371/annotation/193f2b29-b8b0-41e8-808a-290df5577a53. doi: 10.1371/annotation/193f2b29-b8b0-41e8-808a-290df5577a53 | View correction
An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking.
Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline.
At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study.
Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis.
ClinicalTrials.gov NCT 00006180
Citation: Cizza G, Mistry S, Nguyen VT, Eskandari F, Martinez P, et al. (2012) Do Premenopausal Women with Major Depression Have Low Bone Mineral Density? A 36-Month Prospective Study. PLoS ONE 7(7): e40894. doi:10.1371/journal.pone.0040894
Editor: Massimo Federici, University of Tor Vergata, Italy
Received: March 12, 2012; Accepted: June 18, 2012; Published: July 27, 2012
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: This study was fully supported by the National Institutes of Health (NIH), Intramural Research Program: National Institute of Mental Health (NIMH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Alendronate and Placebo were generously provided by Merck Research Laboratories, Rahway, NJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Alendronate and Placebo were generously provided by Merck Research Laboratories, Rahway, NJ. The informatics support for this study was provided by Mr. Frank Pierce from ®Esprit Health. Giovanni Cizza was a former Merck Employee and currently owns Merck stock options. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Major Depressive Disorder (MDD) is a common condition affecting 98.7 million people globally  and nearly 35 million adults in the United States . This chronic condition, characterized by depressed mood and/or anhedonia that interfere with activities of daily living, is a major cause of disability worldwide. By the year 2020, MDD will become second only to ischemic heart disease in the amount of disability experienced by sufferers of all ages according to the World Health Organization Global Burden of Disease Survey. The economic impact of depression is estimated in the tens of billions of dollars: depression cost employers over $40 billion dollars annually in lost productive work time . MDD, once considered a disease only of the psyche, is now known to be associated with a number of medical conditions including cardiovascular disease –, immune alterations –, insulin resistance –, diabetes mellitus –, and obesity –. We and others have shown that depression is also associated with osteoporosis –, yet depression is rarely listed as a risk factor for osteoporosis.
Unlike most physical illnesses observed in conjunction with MDD, osteoporosis is primarily asymptomatic and often remains undiagnosed until patients sustain pathologic fractures later in their lives. Due to the insidious presentation of osteoporosis, any concomitant mood change is unlikely to be reactive in nature. Although a few cross-sectional and cohort studies examining the relationship between depression and low bone mineral density (BMD) have been reported in pre- and post-menopausal women, there has been no prospective evaluation in premenopausal women . Therefore, to investigate over time the association between BMD and depression in this population, we conducted a three-year prospective study by monitoring BMD over time in premenopausal women with MDD and healthy controls.
Materials and Methods
Participants of the Premenopausal, Osteoporosis, Women, Alendronate, Depression (POWER) study were 21- to 45-year-old premenopausal women with current or recent MDD (n = 92) and healthy control women (n = 44). Recruitment took place from July 1, 2001, to February 28, 2003, in the Washington, DC, metropolitan area by newspaper and radio. Internet and flyer advertisement . Women with MDD were enrolled if they met the Diagnostic and Statistical Manual of Mental Disorders, 4th. Edition (DSM-IV) criteria for MDD and experienced a depressive episode in the preceding three years; a limit chosen to minimize recall bias associated with more remote depressive episodes.
Exclusion criteria for women with MDD included eating disorders, bipolar disorders, schizophrenia, schizoaffective disorder, and suicidal risk. Patients with anxiety disorders or a history of drug or alcohol dependence in remission for at least five years were eligible. Subjects were allowed to continue their antidepressant treatments under the care of their physician. Hyperthyroidism, vitamin D deficiency and other conditions and treatments that affect bone turnover were additional exclusion criteria. Exclusion criteria for controls were a T-score equal to or lower than −1.5 at the anterior-posterior (AP) lumbar spine, femoral neck or total hip and a history of any DSM-IV diagnosis apart from prior alcohol abuse. Pregnancy and menopause were additional exclusion criteria .
The health status of each subject was evaluated by medical history and physical examination. Screening electrocardiogram, serum pregnancy test, complete metabolic panel, complete blood count, 25-hydroxyvitamin D, intact parathyroid hormone (iPTH), thyrotropin, and free thyroxine and urine toxicology screen were obtained. Figure 1 describes the number of individuals screened and the reasons for exclusion. Of note, none of the control subject screened had a T-score equal to or lower than −1.5 at the anterior-posterior (AP) lumbar spine, femoral neck or total hip. The National Institute of Mental Health's Institutional Review Board and the Scientific Review Board approved the original 12 month study and its subsequent extension to 36 month. In addition, all subjects provided written informed consent. The trial was registered in ClinicalTrials.gov, NCT 00006180.
Figure 1. Study flow diagram.
Note: The number of exclusions does not match the number of people as some participants were found to have more than one exclusionary criterion.doi:10.1371/journal.pone.0040894.g001
The POWER Study was designed as a 12-month investigation consisting of: 1) a longitudinal follow-up comparison of BMD in women with MDD and controls (Natural History Arm) and; 2) a randomized, double-blind, placebo-controlled, 12- month trial of alendronate in women with MDD with moderate osteopenia (Clinical Trial Arm). Further details on study design have been previously reported . In the Clinical Trial Arm women with MDD, who at baseline had a T-score equal to or lower than −1.5 at the anterior-posterior (AP) lumbar spine, femoral neck or total hip (n = 14), were randomized to 70 mg of alendronate (n = 7) or matching placebo tablets (n = 7) orally once a week (Merck & Co., Inc., Rahway, NJ). In addition, both groups in the Clinical Trial Arm received 500 mg daily of elemental calcium and 400 IU of vitamin D.
We subsequently extended the study to a total of 36 months (Figure 1). At the end of the 12-month main study, subjects from the Natural History Arm and those subjects in the Clinical Trial Arm that were randomized to placebo were offered continued participation in an additional 24-month study extension to assess bone mineral density and biochemical markers of bone turnover at yearly intervals (“Extended Natural History Arm”).
BMD, biochemical markers of bone turnover, and hormonal measurements.
BMD was measured by dual-energy x-ray absorptiometry (DXA QDR 4500 machine; Hologic Inc., Bedford, MA) at the following sites: anteroposterior lumbar (L1–L4) spine, total hip, femoral neck, trochanter, Ward's triangle, and mid-distal radius. The coefficient of variation was <0.4% at each site. DXAs were analyzed by the study radiologist, J.R., blinded to group allocation. Two markers of bone formation, serum bone-specific alkaline phosphatase and 8:00 AM osteocalcin, and a marker of bone resorption, urinary N-telopeptide, were assessed. 8:00 AM plasma adrenocorticotropic hormone (ACTH), 8:00 AM serum cortisol, 24-hour urinary-free cortisol, serum iPTH, plasma 25-hydroxyvitamin D and ionized serum calcium were also obtained. These measurements were obtained at 0, 6, 12, 24 and 36 month. 25-Hydroxyvitamin D plasma levels were only measured at baseline.
We administered the structured clinical interview (SCID) for DSM-IV Axis I disorders and enrolled subjects if they met DSM-IV criteria for MDD and had an episode of major depression in the past three years (SCID). The Hamilton Depression Scale (HAM-D) and Hamilton Anxiety Scales (HAM-A) were used to determine the severity of depression and anxiety in study participants at baseline, 12, 24 and 36 months.
Life style risk factors for osteoporosis.
Calcium from food and supplements, caffeine, and alcohol intake were assessed using a food frequency questionnaire. A nutritionist informed the subjects of their calcium intake and recommended to consume 1000 mg/day of calcium . Cigarette smoking history and oral contraceptive use were also recorded. The Cooper test (12-minute walk/run test) was administered as an indirect index of physical fitness, and was measured in meters traversed within 12-minutes on a standardized treadmill .
As previously described, height was measured to the nearest 0.1 cm using a stadiometer and weight to the nearest 0.1 kg using a digital scale . BMI was calculated as kg/m2.
Data are reported as mean (SD) or by frequencies and percents, unless otherwise indicated. Differences between groups (MDD and control subjects, or between the clinical trial treatment arms) were tested by the t-test (or non-parametric parallel, as necessary) and Fisher exact test, as appropriate. Paired data between time intervals utilized the paired t-test (or non-parametric parallel, as necessary) for continuous variables or McNemar test for categorical ones. The relationship between depression and BMD was assessed by analysis of covariance, adjusting for BMI. In women with MDD, the association of BMD with clinical parameters of depression and anxiety was assessed by linear regression. Repeated-measures analysis of variance (ANOVA) using mixed modeling was used to compare changes in BMD over time, and was adjusted for BMI. All analyses were done using SAS v9.2 (SAS Institute Inc, Cary, NC), and all tests were 2-sided with a significance level of 0.05.
Clinical characteristics of study participants over time
Participant retention rate over the course of the main study was not significantly different between groups (women with MDD 78%; control women 68%; P = 0.211). The subjects who elected to enroll in the study extension did not differ in demographic characteristics from those who did not (data not shown). Of note, only 2 of the 18 women with depression participating in the Clinical Trial Arm were lost to follow-up.
Our sample was composed of mostly white, college-educated women (Table 1). Demographic characteristics were not different between women with MDD and controls at any of the study follow-up phases, but women with MDD tended to have a higher BMI and tended to be less often married than control women. Women with MDD reached menarche one year earlier than controls but had a similar number of pregnancies and a similar current use of OCP than controls. Alcohol use was less common in women with MDD.
Table 1. Baseline demographic, lifestyle and clinical characteristics of study participants included at various study follow-up phases.*doi:10.1371/journal.pone.0040894.t001
At baseline, only one-fifth of women with MDD (17/92) had current depression defined as a major episode within the last month. This sample of women with MDD however, had a considerable lifetime burden of depression, as indicated by cumulative history (68.6±77.9 months) and total number of depressive episodes (5.9±11.4). Age of onset was in the late teens (19±9 years old). Approximately half (52%) of the women had other DSM-IV axis I diagnoses, mostly anxiety disorders (not shown). Finally, 81 out of 92 women were taking antidepressants, 70% a selective serotonin reuptake inhibitor (SSRI), and 30% another antidepressant. Hamilton anxiety and depression scores were relatively low in women with depression consistent with their remission state, and remained stable over time (Figure 2).
Figure 2. Hamilton depression (upper panel) and anxiety (lower panel) scores in women with MDD and control women over time.
Both depression and anxiety scores were relatively low and remained stable over time in women with MDD. As expected, scores for depression and anxiety were much higher in women with MDD vs. control women.doi:10.1371/journal.pone.0040894.g002
BMD over time in the Extended Natural History Arm
At baseline, BMD was between 2% and 3% lower in women with MDD at the main skeletal sites, however, these differences did not reach statistical significance (Table 2). The prevalence of osteopenia appeared consistently greater in women with MDD compared to control women at the total hip and femoral neck. Over 36 months, there was no decline in BMD in either group.
Table 2. BMD values adjusted by BMI in women with depression versus control women at each main skeletal site.*doi:10.1371/journal.pone.0040894.t002
Biochemical markers of bone turnover and hormones of hypothalamic-pituitary-adrenal (HPA) axis in the Extended Natural History Arm
Intact PTH levels were significantly higher in women with MDD vs. control women and generally remained higher up to 36 months (Table 3). Ionized calcium was lower in women with MDD at baseline and this difference was maintained across study duration. Vitamin D levels at baseline were significantly lower in women with MDD. Bone specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD at baseline and remained higher in this group across study duration, although only statistically significantly different at 12 months. Another marker of bone formation, serum osteocalcin, was not different between groups and neither was urinary N-telopeptide, a marker of bone resorption. The 8 am plasma ACTH was higher in women with MDD at baseline and 6 months only. The 8 am serum cortisol and urinary free cortisol levels were not different between groups at any time point.
Table 3. Calcium metabolism, bone turnover markers, and hormonal measurements in women with depression compared to control women.*doi:10.1371/journal.pone.0040894.t003
Relationship between plasma cortisol and indices of clinical severity of depression and anxiety and BMD over time in the Extended Natural History Arm
There was no relationship between current depression, current treatment or current SSRI treatment vs. BMD and biochemical markers of bone turnover. Surprisingly, in women with MDD, both depression and anxiety scores were slightly positively related with BMD at the AP spine (BMD values after adjustment for BMI versus depression and anxiety scores, respectively: r = 0.173; p = 0.005; r = 0.136; p = 0.029) and trochanter (data not shown).
BMD over time in the Clinical Trial Arm
Fourteen out of 92 of women with MDD (20%) and none of the controls exhibited a T-score lower than −1.5 in at least one skeletal site. Thirteen of these women with MDD participated in the Clinical Trial Arm of the study (Figure 3). Patients in the placebo group compared to those randomized to alendronate had similar characteristics. Treatment with alendronate significantly increased BMD at the lumbar spine (0.8525±0.0312 g/cm2 vs. 0.8792±0.0379 g/cm2, P = 0.003; C.I., 0.01 to 0.04, baseline vs. 12-month) and tended to increase BMD at the femoral neck (0.7423±0.0735 vs. 0.7588±0.0709 g/cm2, P = 0.06). No changes over time were observed in the placebo group. Alendronate treatment decreased osteocalcin concentration (4.2±1.6 vs. 2.1±1.1 ng/ml, P = 0.04; C.I., −4.0 to −0.2, baseline vs. 12-month), but did not significantly affect bone-specific alkaline phosphatase or urinary N-telopeptide. There were no changes in biochemical markers in the placebo group.
Figure 3. Bone mineral density measurements in women with MDD and moderate osteopenia or osteoporosis randomized to alendronate vs. placebo.
Over 12 months, the Alendronate group showed a significant increase in BMD at the lumbar spine (P = 0.003), and there was a trend for increased BMD at the femoral neck (P = 0.06). No changes over time were observed in the Placebo group.doi:10.1371/journal.pone.0040894.g003
Osteoporosis is a significant cause of morbidity and mortality in the US and costs approximately $17 billion dollars annually . It results in over two million fractures annually in the US, 71% of which occur in women . Therefore, investigation and identification of risk factors are of great importance. There have been several studies with conflicting findings regarding the possible influence of depression on BMD –; most of these studies were retrospective analyses conducted in post-menopausal women. In this study, we followed a group of premenopausal women with MDD and healthy controls prospectively and measured their BMD at regular intervals. Our finding that neither group exhibited a substantial change in BMD at any skeletal site over time may not be surprising since BMD has been reported to remain relatively stable in healthy premenopausal women –. The observation that women with MDD maintained their BMD throughout the study is reassuring as it implies that little, if any, bone loss was associated with MDD in this age range and time span. It should be however noted that these subjects were aware that they were participating in a clinical experiment, thus we cannot exclude a non specific “Hawthorne effect”. In this particular case, regular encounters with the research team may have positively influenced their mood and induced improvements in life style conditions. Our observation allows for considering prophylactic treatment of these women to prevent osteoporosis after menopause, when their risk is magnified. Women reach peak bone mass by their third decade ,  and BMD remains relatively stable until menopause where women begin to lose up to 1–2% of the BMD annually –.
Alterations in the HPA axis are significant findings in biological psychiatry . Several studies have investigated the possible pathophysiology of osteoporosis in psychiatric patients and have hypothesized a link between depression and low BMD . Elevated ACTH and cortisol levels, and enhanced cortisol responsiveness have been demonstrated in depressed individuals , , , –. Similar to the bone loss observed in Cushing syndrome as a result of hypercortisolemia, women with depression could thus have decreased BMD, albeit not as pronounced as in Cushing syndrome. We found that ACTH levels and bone-specific alkaline phosphatase levels tended to be elevated in women with depression compared to controls. Serum and urinary free cortisol, osteocalcin, and urinary N-telopeptide levels were not different between participants with depression and controls throughout the study.
In an ancillary investigation, we reported that women with depression had a greater prevalence of Bcl1 polymorphism, which is associated with glucocorticoid hypersensitivity –. Therefore, women with MDD may also have a greater HPA activity at tissue level. The cortisol plasma levels were not elevated in our study of women with MDD, but hyperactivity of the HPA axis is not always accompanied by hypercortisolism . Alterations in the HPA axis tend to occur during acute depressive states and normalize after treatment , . Given that the majority of the subjects with depression were being pharmacologically treated throughout the duration of the study as previously reported , increases in cortisol levels may not have occurred, as these patients were likely to be in clinical remission. As we have recently reported in greater detail in a related manuscript , approximately half of the sample was comprised of women with melancholic depression, and the remaining subjects suffered either from undifferentiated or atypical depression. Women with atypical features of depression had higher ACTH levels during the night and women with undifferentiated depression had a significantly higher prevalence of low BMD at the femoral neck than controls. Thus, the clinical subtype of depression may influence bone and endocrine features, among other parameters.
In the women with MDD and moderate osteopenia or osteoporosis, weekly alendronate was effective in increasing BMD. This is the first pharmacotherapeutic study of osteoporosis in younger women with MDD and one of the few controlled studies of alendronate treatment in premenopausal women –. Of note, in this arm the drop-out rate was only 10%, much smaller than in the overall cohort. In future research, it would be interesting to identify the predictors of drop-out rate in studies of women with depression. It is possible that the women participating in the randomized controlled arm of this trial may have been more motivated to remain in the study than the women with depression in the natural history arm and the normal controls, possibly because of the therapeutic advantages of the drug being received. As estrogens are not a treatment option in this population, our study supports the possible use of alendronate in this population. Recently the use of selective serotonin reuptake inhibitors has been linked to an increased risk of fractures and bone loss . As reported , in our study the use of selective serotonin reuptake inhibitors was not associated with low BMD.
Vitamin D levels were lower in women with MDD than controls. Consistent with decreased vitamin D levels, women with MDD had significantly higher iPTH and ionized calcium levels, highly suggestive of secondary hyperparathyroidism. PTH levels remained elevated in women with MDD compared to controls. While elevated PTH levels have been demonstrated in depressed elderly women and young men , , , to the best of our knowledge, this is the first time elevated PTH plasma levels are observed in premenopausal women with MDD. Future studies should be conducted to evaluate the pathogenetic role of secondary hyperparathyroidism in subjects with depression.
Study limitations and merits
The small sample size, together with a drop-out rate of approximately 30% in the first year, may have reduced our ability to detect some associations. Vitamin D levels were only measured at baseline. Furthermore, since there is little bone loss in this age range –, the duration of the study and the age of the participants may have limited our ability to identify a subtle decrease in BMD. Our results may have failed to detect significant changes in biochemical markers and hormones in patients who were in remission since abnormalities in many of these parameters might only be apparent during acute disease states , . Our sample was well characterized and homogeneous, and the length of follow-up was longer than most studies of this kind.
Premenopausal women with MDD had lower BMD than controls over a sustained period of time. Larger and longer studies are needed to confirm and extend these observations. The effects of antidepressants and other psychotropic medications on bone mass per se should be assessed. The reversibility of bone loss due to successful behavioral or pharmacologic interventions or to spontaneous resolution of depression should be considered. Lastly, studies examining the role of genetics leading to enhanced susceptibility to reductions in BMD need to be conducted.
Alendronate and Placebo were generously provided by Merck Research Laboratories, Rahway, NJ. The informatics support for this study was provided by Mr. Frank Pierce from ®Esprit Health. The following individuals were investigators of the POWER Protocol: (Premenopausal Osteoporosis Women Alendronate Depression): Giovanni Cizza (Principal Investigator), Ann Berger, Marc R. Blackman, Karim A. Calis, Gyorgy Csako, Bart Drinkard, Farideh Eskandari, Philip W. Gold, McDonald Horne, Christine Kotila, Pedro Martinez, Kate Musallam, Terry M. Phillips, James. C. Reynolds, Nancy G. Sebring, Esther Sternberg and Sara Torvik.
We wish to thank: all the subjects participating in this study and the NIMH nurses who supported these studies. The informatics support for this study was provided by Mr. Frank Pierce from ®Esprit Health.
Conceived and designed the experiments: G. Cizza PWG G. Csako. Performed the experiments: G. Cizza FE PM ST JCR. Analyzed the data: G. Cizza SM VTN FE ST NS G. Csako. Wrote the paper: G. Cizza SM PM ST G. Csako.
- 1. World Health Organization (2008) The global burden of disease: 2004 update. Geneva: World Health Organization ISBN 92 4 156257 9.
- 2. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, et al. (2003) The epidemiology of major depressive disorder: results from the national comorbidity survey replication (NCS-R). JAMA 289: 3095–3105.
- 3. Stewart WF, Ricci JA, Chee E, Hahn SR, Morganstein D (2003) Cost of lost productive work time among US workers with depression. JAMA 289: 3135–3144.
- 4. Licinio J, Wong ML (1999) The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 4: 317–327.
- 5. Barth J, Schumacher M, Herrmann-Lingen C (2004) Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 66: 802–813.
- 6. Lett HS, Blumenthal JA, Babyak MA, Sherwood A, Strauman T, et al. (2004) Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med 66: 305–315.
- 7. Whang W, Kubzansky LD, Kawachi I, Rexrode KM, Kroenke CH, et al. (2009) Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses' Health Study. J Am Coll Cardiol 53: 950–958.
- 8. Rubinow DR, Girdler S (2011) Hormones, heart disease, and health: individualized medicine versus throwing the baby out with the bathwater. Depress Anxiety 28: E1–E15.
- 9. Alesci S, Martinez PE, Kelkar S, Ilias I, Ronsaville DS, et al. (2005) 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. J Clin Endocrinol Metab 90: 2522–2530.
- 10. Anisman H, Merali Z, Hayley S (2008) Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol 85: 1–74.
- 11. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9: 46–56.
- 12. Blume J, Douglas SD, Evans DL (2011) Immune suppression and immune activation in depression. Brain Behav Immun 25: 221–229.
- 13. Brown ES, Varghese FP, McEwen BS (2004) Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 55: 1–9.
- 14. Timonen M, Laakso M, Jokelainen J, Rajala U, Meyer-Rochow VB, et al. (2005) Insulin resistance and depression: cross sectional study. BMJ 330: 17–18.
- 15. Adriaanse MC, Dekker JM, Nijpels G, Heine RJ, Snoek FJ, et al. (2006) Associations between depressive symptoms and insulin resistance: the Hoorn Study. Diabetologia 49: 2874–2877.
- 16. Skilton MR, Moulin P, Terra JL, Bonnet F (2007) Associations between anxiety, depression, and the metabolic syndrome. Biol Psychiatry 62: 1251–1257.
- 17. Everson-Rose SA, Meyer PM, Powell LH, Pandey D, Torréns JI, et al. (2004) Depressive symptoms, insulin resistance, and risk of diabetes in women at midlife. Diabetes Care 27: 2856–2862.
- 18. Mezuk B, Eaton WW, Albrecht S, Golden SH (2008) Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 31: 2383–90.
- 19. Golden SH, Lazo M, Carnethon M, Bertoni AG, Schreiner PJ, et al. (2008) Examining a bidirectional association between depressive symptoms and diabetes. JAMA 299: 2751–2759.
- 20. Pan A, Lucas M, Sun Q, van Dam RM, Franco OH, et al. (2010) Bidirectional association between depression and type 2 diabetes mellitus in women. Arch Intern Med 170: 1884–1891.
- 21. Onyike CI, Crum RM, Lee HB, Lyketsos CG, Eaton WW (2003) Is obesity associated with major depression? results from the Third National Health and Nutrition Examination Survey. Am J Epidemiol 158: 1139–1147.
- 22. Blaine B (2008) Does depression cause obesity? A meta-analysis of longitudinal studies of depression and weight control. J Health Psychol 13: 1190–1197.
- 23. Simon GE, Ludman EJ, Linde JA, Operskalski BH, Ichikawa L, et al. (2008) Association between obesity and depression in middle-aged women. Gen Hosp Psychiatry 30: 32–39.
- 24. Allison DB, Newcomer JW, Dunn AL, Blumenthal JA, Fabricatore AN, et al. (2009) Obesity among those with mental disorders: a National Institute of Mental Health meeting report. Am J Prev Med 36: 341–350.
- 25. Amsterdam J, Hooper M (1998) Bone density measurement in major depression. Prog Neuropsychopharmacol Biol Psychiatry 22: 267–277.
- 26. Cizza G, Ravn P, Chrousos GP, Gold PW (2001) Depression: a major, unrecognized risk factor for osteoporosis? Trends Endocrinol Metab 12: 198–203.
- 27. Eskandari F, Martinez PE, Torvik S, Phillips TM, Sternberg EM, et al. (2007) Low bone mass in premenopausal women with depression. Arch Intern Med 167: 2329–2336.
- 28. Cizza G, Primma S, Csako G (2009) Depression as a risk factor for osteoporosis. Trends Endocrinol Metab 20: 367–373.
- 29. Yirmiya R, Bab I (2009) Major depression is a risk factor for low bone mineral density: a meta-analysis. Biol Psychiatry 66: 423–43.
- 30. Cizza G, Primma S, Coyle M, Gourgiotis L, Csako G (2010) Depression and osteoporosis: a research synthesis with meta-analysis. Horm Metab Re 42: 467–482.
- 31. Williams LJ, Bjerkeset O, Langhammer A, Berk M, Pasco JA, et al. (2011) The association between depressive and anxiety symptoms and bone mineral density in the general population: the HUNT Study. J Affect Disord 131: 164–171.
- 32. Mussolino ME, Jonas BS, Looker AC (2004) Depression and bone mineral density in young adults: results from NHANES III. Psychosom Med 66: 533–537.
- 33. Mussolino ME (2005) Depression and hip fracture risk: the NHANES I epidemiologic follow-up study. Public Health Rep 120: 71–75.
- 34. Kahl KG, Greggersen W, Rudolf S, Stoeckelhuber BM, Bergmann-Koester CU, et al. (2006) Bone mineral density, bone turnover, and osteoprotegerin in depressed women with and without borderline personality disorder. Psychosom Med 68: 669–674.
- 35. Petronijevic M, Petronijevic N, Ivkovic M, Stefanović D, Radonjić N, et al. (2008) Low bone mineral density and high bone metabolism turnover in premenopausal women with unipolar depression. Bone 42: 582–590.
- 36. Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, et al. (1996) Bone mineral density in women with depression. N Engl J Med 335: 1176–1181.
- 37. Ozsoy S, Esel E, Turan MT, Kula M, Demir H, et al. (2005) Is there any alteration in bone mineral density in patients with depression? Turk Psikiyatri Derg 16: 77–82.
- 38. Reginster JY, Deroisy R, Paul I, Hansenne M, Ansseau M (1999) Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women. Maturitas 33: 133–137.
- 39. Whooley MA, Cauley JA, Zmuda JM, Haney EM, Glynn NW (2004) Depressive symptoms and bone mineral density in older men. J Geriatr Psychiatry Neurol 17: 88–92.
- 40. Yazici AE, Bagis S, Tot S, Sahin G, Yazici K, et al. (2005) Bone mineral density in premenopausal women with major depression. Joint Bone Spine 72: 540–543.
- 41. Halbreich U, Rojansky N, Palter S, Hreshchyshyn M, Kreeger J, et al. (1995) Decreased bone mineral density in medicated psychiatric patients. Psychosom Med 57: 485–491.
- 42. Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, et al. (1996) Bone mineral density in women with depression. N Engl J Med 16: 1176–1181.
- 43. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, et al. (2007) Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res 22: 465–475.
- 44. Bouxsein ML, Myburgh KH, van der Meulen MC, Lindenberger E, Marcus R (1994) Age-related differences in cross-sectional geometry of the forearm bones in healthy women. Calcif Tissue Int 54: 113–118.
- 45. Burger H, van Daele PLA, Algra D, van den Ouweland FA, Grobbee DE, et al. (1994) The association between age and bone mineral density in men and women aged 55 years and over: The Rotterdam Study. Bone Miner 25: 1–13.
- 46. Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK (2003) Bone loss and bone size after menopause. N Engl J Med 349: 327–334.
- 47. Emaus N, Berntsen GK, Joakimsen RM, Fønnebø V (2005) Longitudinal changes in forearm bone mineral density in women and men aged 25–44 years: the Tromsø study: a population-based study. Am J Epidemiol 162: 633–643.
- 48. Matkovic V, Jelic T, Wardlaw GM, Ilich JZ, Goel PK, et al. (1994) Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. J Clin Invest 93: 799–808.
- 49. Heaney RP, Abrams S, Dawson-Hughes B, Looker A, Marcus R, et al. (2000) Peak bone mass. Osteoporos Int 11: 985–1009.
- 50. Stetler C, Miller GE (2011) Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med 73: 114–126.
- 51. Aihara M, Ida I, Yuuki N, Oshima A, Kumano H, et al. (2007) HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions. Neuroimaging 155: 245–256.
- 52. Heuser I, Yassouridis A, Holsboer F (1994) The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res 28: 341–356.
- 53. Kunugi H, Ida I, Owashi T, Kimura M, Inoue Y, et al. (2006) Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitaryadrenal (HPA) axis abnormalities in major depressive episode: a multicenter study. Neuropsychopharmacology 31: 212–220.
- 54. Krishnamurthy P, Romagni P, Torvik S, Gold PW, Charney DS, et al. (2008) Glucocorticoid receptor gene polymorphisms in premenopausal women with depression. Horm Metab Res 40: 194–198.
- 55. van Rossum EF, Koper JW, van den Beld AW, Uitterlinden AG, Arp P, et al. (2003) Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin Endocrinol 59: 585–592.
- 56. van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, et al. (2006) Polymorphisms of the glucocorticoid receptor gene and major depression. Biol Psychiatry 59: 681–688.
- 57. Nemeroff CB (1996) The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry 1: 336–342.
- 58. Cizza G, Ronsaville DS, Kleitz H, Eskandari F, Mistry S, et al. (2012) Clinical subtypes of depression are associated with specific metabolic parameters and circadian endocrine profiles in women: the power study. PLoS One 7(1): e28912.
- 59. Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, et al. (2001) Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids. Arthritis Rheum 4444: 202–211.
- 60. Gourlay M, Brown SA (2004) Clinical considerations in premenopausal osteoporosis. Arch Intern Med 164: 603–614.
- 61. Bhalla A (2010) Management of osteoporosis in a pre-menopausal woman. Best Pract Res Clin Rheumatol 24: 313–332.
- 62. Wu Q, Bencaz AF, Hentz JG, Crowell MD (2012) Selective serotonin reuptake inhibitor treatment and risk of fractures: a meta-analysis of cohort and case-control studies. Osteoporos Int 23: 365–375.
- 63. Hoogendijk WJG, Lips P, Dik MG, Deeg DJ, Beekman AT, et al. (2008) Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry 65: 508–512.
- 64. Zhao G, Ford ES, Li C, Balluz LS (2010) No associations between serum concentrations of 25-hydroxyvitamin D and parathyroid hormone and depression among US adults. Br J Nutr 104: 1696–1702.