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Increased risk of fracture in patients with bipolar disorder: a nationwide cohort study

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Abstract

Objectives

Bipolar disorder (BD) is a systemic inflammatory disease, and disrupted bone metabolism due to the inflammatory process can cause fracture. Despite evidence of an association between lower bone mineral density and an increased risk of fracture among patients with depression, schizophrenia, and anorexia nervosa, whether BD is a risk factor for subsequent fracture is unknown. To determine the association between BD and fracture and to examine the risk factors for fracture among patients with BD.

Methods

In this study, we enrolled patients diagnosed with BD from the Taiwan National Health Insurance Research Database. Patients newly diagnosed with BD (ICD-9-CM 296) from 2001 to 2008 were included in the BD cohort, and the date of the initial diagnosis of BD was used as the index date. The comparison cohort, comprising participants without BD, was frequency matched to the BD cohort by age, sex, and index year, and the occurrence of fracture was evaluated in both cohorts.

Results

The BD and comparison cohorts were comprised of 47,271 patients with BD and 1,89,084 frequency-matched participants without BD, respectively. The incidence of fracture was higher among patients with BD than among the controls. Cox models showed that BD was an independent risk factor for fracture irrespective of comorbidities [hazard ratio (HR) = 1.79, 95 % confidence interval (CI) = 1.73–1.84, p < .001].

Conclusion

Our study showed that patients with BD have a higher risk of subsequent fracture. Additional prospective clinical studies investigating the relationship between BD and fracture are warranted.

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References

  1. Phillips ML, Kupfer DJ (2013) Bipolar disorder diagnosis: challenges and future directions. Lancet (London, England) 381(9878):1663–71 (PubMed PMID: 23663952. Epub 2013/05/15. eng)

  2. McCormick U, Murray B, McNew B (2015) Diagnosis and treatment of patients with bipolar disorder: a review for advanced practice nurses. J Am Assoc Nurse Pract 27(9):530–542 (PubMed PMID: 26172568. Epub 2015/07/15. eng)

  3. Buoli M, Serati M, Altamura AC (2014) Is the combination of a mood stabilizer plus an antipsychotic more effective than mono-therapies in long-term treatment of bipolar disorder? A systematic review. J Affect Disord 152–154:12–8 (PubMed PMID: 24041717. Epub 2013/09/18. eng)

  4. Geoffroy PA, Bellivier F, Henry C (2014) Treatment of manic phases of bipolar disorder: critical synthesis of international guidelines. L’Encephale 40(4):330–7 (PubMed PMID: 24513018. Epub 2014/02/12). Traitement du trouble bipolaire en phase maniaque : synthese critique des recommandations internationales. fre

  5. Maina G, Bechon E, Rigardetto S, Salvi V (2013) General medical conditions are associated with delay to treatment in patients with bipolar disorder. Psychosomatics 54(5):437–42 (PubMed PMID: 23352046. Epub 2013/01/29. eng)

  6. Vancampfort D, Mitchell AJ, De Hert M, Sienaert P, Probst M, Buys R et al (2015) Prevalence and predictors of type 2 diabetes mellitus in people with bipolar disorder: a systematic review and meta-analysis. J Clin Psychiatry 76(11):1490–1499 (PubMed PMID: 26214054. Epub 2015/07/28. Eng)

  7. Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB et al (2015) Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World psychiatry: Off J World Psychiatric Association (WPA) 14(3):339–47 (PubMed PMID: 26407790. Pubmed Central PMCID: PMC4592657. Epub 2015/09/27. eng)

  8. Hsu CC, Chen SC, Liu CJ, Lu T, Shen CC, Hu YW et al (2014) Rheumatoid arthritis and the risk of bipolar disorder: a nationwide population-based study. PLoS One 9(9):e107512 (PubMed PMID: 25229610. Pubmed Central PMCID: 4167853)

  9. Stich O, Andres TA, Gross CM, Gerber SI, Rauer S, Langosch JM (2015) An observational study of inflammation in the central nervous system in patients with bipolar disorder. Bipolar Disord 17(3):291–302 (PubMed PMID: 25109751. Epub 2014/08/12. eng)

  10. Wieck A, Grassi-Oliveira R, do Prado CH, Rizzo LB, de Oliveira AS, Kommers-Molina J et al (2014) Pro-inflammatory cytokines and soluble receptors in response to acute psychosocial stress: differential reactivity in bipolar disorder. Neurosci Lett 580:17–21 (PubMed PMID: 25092610. Epub 2014/08/06. eng)

  11. Kunz M, Cereser KM, Goi PD, Fries GR, Teixeira AL, Fernandes BS et al (2011) Serum levels of IL-6, IL-10 and TNF-alpha in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Revista brasileira de psiquiatria (Sao Paulo, Brazil: 1999) 33(3):268–74 (PubMed PMID: 21971780. Epub 2011/10/06. eng)

  12. Munkholm K, Brauner JV, Kessing LV, Vinberg M (2013) Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatric Res 47(9):1119–33 (PubMed PMID: 23768870. Epub 2013/06/19. eng)

  13. Patel JP, Frey BN (2015) Disruption in the blood–brain barrier: the missing link between brain and body inflammation in bipolar disorder? Neural Plasticity 2015:708306 (PubMed PMID: 26075104. Pubmed Central PMCID: PMC4444594. Epub 2015/06/16. Eng)

  14. Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R et al (2012) Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Disord 141(1):1–10 (PubMed PMID: 22497876. Pubmed Central PMCID: PMC3498820. Epub 2012/04/14. eng)

  15. Weitzmann MN (2014) T-cells and B-cells in osteoporosis. Current Opin Endocrinol Diabetes Obes 21(6):461–7 (PubMed PMID: 25191854. Pubmed Central PMCID: PMC4313123. Epub 2014/09/06. eng)

  16. Spyropoulou A, Karamesinis K, Basdra EK (2015) Mechanotransduction pathways in bone pathobiology. Biochimica et biophysica acta. 1852(9):1700–8 (PubMed PMID: 26004394. Epub 2015/05/26. Eng)

  17. Zhou Y, Deng HW, Shen H (2015) Circulating monocytes: an appropriate model for bone-related study. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 26(11):2561–2572 (PubMed PMID: 26194495. Epub 2015/07/22. Eng)

  18. Dischereit G, Lange U (2014) Osteoporosis—inflammatory effects on bone metabolism and fracture risk. Zeitschrift fur Orthopadie und Unfallchirurgie 152(2):170–6 (PubMed PMID: 24760457. Epub 2014/04/25). Osteoporose - inflammatorische Effekte auf den Knochenstoffwechsel und das Frakturrisiko. ger

  19. Bai P, Sun Y, Jin J, Hou J, Li R, Zhang Q et al (2011) Disturbance of the OPG/RANK/RANKL pathway and systemic inflammation in COPD patients with emphysema and osteoporosis. Respir Res 12:157 (PubMed PMID: 22176920. Pubmed Central PMCID: PMC3260206. Epub 2011/12/20. eng)

  20. Crotti TN, Dharmapatni AA, Alias E, Haynes DR (2015) Osteoimmunology: major and costimulatory pathway expression associated with chronic inflammatory induced bone loss. J Immunol Res 2015:281287 (PubMed PMID: 26064999. Pubmed Central PMCID: PMC4433696. Epub 2015/06/13. Eng)

  21. Amarasekara DS, Yu J, Rho J (2015) Bone loss triggered by the cytokine network in inflammatory autoimmune diseases. J Immunol Res 2015:832127 (PubMed PMID: 26065006. Pubmed Central PMCID: PMC4434203. Epub 2015/06/13. Eng)

  22. Cannata-Andia JB, Rodriguez Garcia M, Gomez Alonso C (2013) Osteoporosis and adynamic bone in chronic kidney disease. J Nephrol 26(1):73–80 (PubMed PMID: 23023723. Epub 2012/10/02. eng)

  23. Rubin MR (2015) Bone cells and bone turnover in diabetes mellitus. Curr Osteoporos Reports 13(3):186–91 (PubMed PMID: 25740570. Epub 2015/03/06. eng)

  24. Lee CW, Liao CH, Lin CL, Liang JA, Sung FC, Kao CH (2015) Increased risk of osteoporosis in patients with depression: a population-based retrospective cohort study. Mayo Clin Proc 90(1):63–70 (PubMed PMID: 25572194. Epub 2015/01/13. eng)

  25. Fazeli PK, Klibanski A (2014) Anorexia nervosa and bone metabolism. Bone 66:39–45 (PubMed PMID: 24882734. Pubmed Central PMCID: PMC4125514. Epub 2014/06/03. eng)

  26. Kishimoto T, De Hert M, Carlson HE, Manu P, Correll CU (2012) Osteoporosis and fracture risk in people with schizophrenia. Curr Opin Psychiatry 25(5):415–29 (PubMed PMID: 22744405. Pubmed Central PMCID: PMC3566242. Epub 2012/06/30. eng)

  27. Stubbs B, De Hert M, Sepehry AA, Correll CU, Mitchell AJ, Soundy A et al (2014) A meta-analysis of prevalence estimates and moderators of low bone mass in people with schizophrenia. Acta Psychiatrica Scand 130(6):470–86 (PubMed PMID: 25041606. Epub 2014/07/22. eng)

  28. Stubbs B, Gaughran F, Mitchell AJ, De Hert M, Farmer R, Soundy A et al (2015) Schizophrenia and the risk of fractures: a systematic review and comparative meta-analysis. Gen Hosp Psychiatry 37(2):126–33 (PubMed PMID: 25666994. Epub 2015/02/11. eng)

  29. Rege S, Hodgkinson SJ (2013) Immune dysregulation and autoimmunity in bipolar disorder: synthesis of the evidence and its clinical application. Aust N Z J Psychiatry 47(12):1136–51 (PubMed PMID: 23908311. Epub 2013/08/03. eng)

  30. Schett G (2011) Effects of inflammatory and anti-inflammatory cytokines on the bone. Eur J Clin Investig 41(12):1361–6 (PubMed PMID: 21615394. Epub 2011/05/28. eng)

  31. Nakamura M, Uehara S, Nakamura H, Udagawa N (2014) Cytokine-mediated bone resorption. Clinical Calcium 24(6):837–44 (PubMed PMID: 24870834. Epub 2014/05/30. jpn)

  32. Kohli SS, Kohli VS (2011) Role of RANKL-RANK/osteoprotegerin molecular complex in bone remodeling and its immunopathologic implications. Indian J Endocrinol Metabol 15(3):175–81 (PubMed PMID: 21897893. Pubmed Central PMCID: PMC3156536. Epub 2011/09/08. eng)

  33. Kitaura H, Kimura K, Ishida M, Kohara H, Yoshimatsu M, Takano-Yamamoto T (2013) Immunological reaction in TNF-alpha-mediated osteoclast formation and bone resorption in vitro and in vivo. Clin Dev Immunol 2013:181849 (PubMed PMID: 23762085. Pubmed Central PMCID: PMC3676982. Epub 2013/06/14. eng)

  34. Goto H, Hozumi A, Osaki M, Fukushima T, Sakamoto K, Yonekura A et al (2011) Primary human bone marrow adipocytes support TNF-alpha-induced osteoclast differentiation and function through RANKL expression. Cytokine 56(3):662–8 (PubMed PMID: 21963155. Epub 2011/10/04. eng)

  35. Belvederi Murri M, Prestia D, Mondelli V, Pariante C, Patti S, Olivieri B et al (2016) The HPA axis in bipolar disorder: systematic review and meta-analysis. Psychoneuroendocrinology 63:327–42 (PubMed PMID: 26547798. Epub 2015/11/09. eng)

  36. Young AH (2014) The effects of HPA axis function on cognition and its implications for the pathophysiology of bipolar disorder. Harvard Rev Psychiatry 22(6):331–3 (PubMed PMID: 25377604. Epub 2014/11/08. eng)

  37. Azuma K, Adachi Y, Hayashi H, Kubo KY (2015) Chronic psychological stress as a risk factor of osteoporosis. J UOEH 37(4):245–53 (PubMed PMID: 26667192. Epub 2015/12/17. eng)

  38. Geoffroy PA, Etain B, Sportiche S, Bellivier F (2015) Circadian biomarkers in patients with bipolar disorder: promising putative predictors of lithium response. Int J Bipolar Disord 2(1):28 (PubMed PMID: 26092399. Pubmed Central PMCID: PMC4447721. Epub 2015/06/21. eng)

  39. Dubovsky SL (2015) Mania. Continuum (Minneapolis, Minn) 21(3 Behavioral Neurology and Neuropsychiatry):737–55 (PubMed PMID: 26039851. Epub 2015/06/04. eng)

  40. Mason L, O’Sullivan N, Montaldi D, Bentall RP, El-Deredy W (2014) Decision-making and trait impulsivity in bipolar disorder are associated with reduced prefrontal regulation of striatal reward valuation. Brain: J Neurol 137(Pt 8):2346–55 (PubMed PMID: 25009169. Pubmed Central PMCID: PMC4107743. Epub 2014/07/11. eng)

  41. Volavka J (2013) Violence in schizophrenia and bipolar disorder. Psychiatria Danubina 25(1):24–33 (PubMed PMID: 23470603. Epub 2013/03/09. eng)

  42. Martin Jimenez JA, Consuegra Moya B, Martin Jimenez MT (2015) Nutritional factors in preventing osteoporosis. Nutricion Hospitalaria 32(Suppl 1):49–55 (PubMed PMID: 26267775. Epub 2015/08/13. Factores nutricionales en la prevencion de la osteoporosis. spa)

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Acknowledgments

This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. We appreciate the financial support by grants from Ministry of Science and Technology (MOST103-2314-B-715-001-MY2, and MOST104-2314-B-715-003-MY3), Mackay Medical College (MMC 1012A10, RD1010061, RD1020038, RD1020047, RD1012B13, RD1031B05, RD1030053, RD1030076, RD1040109), and Mackay Memorial Hospital (MMH-MM-10304, MMH-MM-10405). No additional external funding received for this study.

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    Authors and Affiliations

    1. Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

      Chih-Chao Hsu

    2. Institute of Biomedical Sciences, Mackay Medical College, New Taipei, Taiwan

      Yi-Chao Hsu

    3. Department of Public Health, China Medical University, Taichung, Taiwan

      Kuang-Hsi Chang

    4. College of Medicine, The School of Chinese Medicine for Post Baccalaureate, I-Shou University (Yancho Campus), Kaohsiung, Taiwan

      Chang-Yin Lee

    5. Department of Chinese Medicine, E-DA Hospital, Kaohsiung, Taiwan

      Chang-Yin Lee

    6. Division of Hepatology and Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

      Lee-Won Chong

    7. Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan

      Yu-Chiao Wang

    8. Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung, 40447, Taiwan

      Chung-Y Hsu & Chia-Hung Kao

    9. Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan

      Chia-Hung Kao

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    C.-C. Hsu and Y.-C. Hsu contributed equally to this work.

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    Hsu, CC., Hsu, YC., Chang, KH. et al. Increased risk of fracture in patients with bipolar disorder: a nationwide cohort study. Soc Psychiatry Psychiatr Epidemiol 51, 1331–1338 (2016). https://doi.org/10.1007/s00127-016-1242-3

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