Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Hyponatremia and bone: an emerging relationship

Abstract

Hyponatremia is the most common electrolyte disorder and is mainly known for its neurological complications. New studies suggest previously unrecognized complications of hyponatremia, including falls, osteoporosis and fractures. Because these novel associations are mainly derived from epidemiological studies, it remains unclear whether hyponatremia has a direct effect on bone or whether it is a surrogate marker of another etiology. However, one animal and one in vitro study now show that hyponatremia can have direct effects on bone, mainly via activation of osteoclasts. The association between hyponatremia and fractures appears to be independent of osteoporosis (defined as low BMD). Also, data suggest that this association cannot be fully explained by the possibility that hyponatremia predisposes to falls. Hyponatremia, therefore, also has an effect on bone quality that is not captured by BMD. Here, the emerging relationship between hyponatremia and bone is reviewed, with special emphasis on possible mechanisms, unanswered questions and clinical implications.

Key Points

  • Recent studies suggest that hyponatremia, the most common electrolyte disorder, affects not only the brain but also bone

  • Several epidemiological studies have identified associations between hyponatremia and increased risk of falls and fractures and, in one study, with decreased BMD

  • The associations between mild hyponatremia and increased fracture risk cannot be fully explained by increased risk of falling and appear to be independent of BMD

  • One animal study and one cell culture study found that a low sodium concentration in serum or medium increased osteoclast activity

  • Hyponatremia could be a new clinical risk factor for osteoporosis and fractures

  • Future studies are needed to show whether the relationship between hyponatremia and fractures is causal and whether correction of hyponatremia reduces fracture risk

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Possible relationships between hyponatremia, osteoporosis, and fractures.
Figure 2: Effects of hyponatremia on bone.

Similar content being viewed by others

References

  1. Adrogué, H. J. & Madias, N. E. Hyponatremia. N. Engl. J. Med. 342, 1581–1589 (2000).

    Article  PubMed  Google Scholar 

  2. Hoorn, E. J. & Zietse, R. Hyponatremia revisited: translating physiology to practice. Nephron. Physiol. 108, p46–p59 (2008).

    Article  PubMed  Google Scholar 

  3. Hoorn, E. J., Lindemans, J. & Zietse, R. Development of severe hyponatraemia in hospitalized patients: treatment-related risk factors and inadequate management. Nephrol. Dial. Transplant. 21, 70–76 (2006).

    Article  PubMed  Google Scholar 

  4. Upadhyay, A., Jaber, B. L. & Madias, N. E. Incidence and prevalence of hyponatremia. Am. J. Med. 119, S30–S35 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Arieff, A. I. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N. Engl. J. Med. 314, 1529–1535 (1986).

    Article  CAS  PubMed  Google Scholar 

  6. Sterns, R. H., Riggs, J. E. & Schochet, S. S. Jr. Osmotic demyelination syndrome following correction of hyponatremia. N. Engl. J. Med. 314, 1535–1542 (1986).

    Article  CAS  PubMed  Google Scholar 

  7. Ayus, J. C., Achinger, S. G. & Arieff, A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am. J. Physiol. Renal Physiol. 295, F619–F624 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Ayus, J. C., Wheeler, J. M. & Arieff, A. I. Postoperative hyponatremic encephalopathy in menstruant women. Ann. Intern. Med. 117, 891–897 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Ayus, J. C., Krothapalli, R. K. & Arieff, A. I. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N. Engl. J. Med. 317, 1190–1195 (1987).

    Article  CAS  PubMed  Google Scholar 

  10. Lohr, J. W. Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia. Am. J. Med. 96, 408–413 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Renneboog, B., Musch, W., Vandemergel, X., Manto, M. U. & Decaux, G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am. J. Med. 119, 71.e1–e8 (2006).

    Article  Google Scholar 

  12. Arányi, Z., Kovács, T., Szirmai, I. & Vastagh, I. Reversible nerve conduction slowing in hyponatremia. J. Neurol. 251, 1532–1533 (2004).

    Article  PubMed  Google Scholar 

  13. Gankam Kengne, F., Andres, C., Sattar, L., Melot, C. & Decaux, G. Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM 101, 583–588 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Hoorn, E. J. et al. Mild hyponatremia as a risk factor for fractures: The Rotterdam Study. J. Bone Miner. Res. 26, 1822–1828 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Kinsella, S., Moran, S., Sullivan, M. O., Molloy, M. G. & Eustace, J. A. Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin. J. Am. Soc. Nephrol. 5, 275–280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sandhu, H. S., Gilles, E., DeVita, M. V., Panagopoulos, G. & Michelis, M. F. Hyponatremia associated with large-bone fracture in elderly patients. Int. Urol. Nephrol. 41, 733–737 (2009).

    Article  PubMed  Google Scholar 

  17. Ayus, J. C. & Arieff, A. I. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and mortality. JAMA 281, 2299–2304 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Ayus, J. C. & Moritz, M. L. Bone disease as a new complication of hyponatremia: moving beyond brain injury. Clin. J. Am. Soc. Nephrol. 5, 167–168 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Rachner, T. D., Khosla, S. & Hofbauer, L. C. Osteoporosis: now and the future. Lancet 377, 1276–1287 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Verbalis, J. G. et al. Hyponatremia-induced osteoporosis. J. Bone Miner. Res. 25, 554–563 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Fabian, T. J. et al. Paroxetine-induced hyponatremia in older adults: a 12-week prospective study. Arch. Intern. Med. 164, 327–332 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Kerse, N. et al. Falls, depression and antidepressants in later life: a large primary care appraisal. PLoS ONE 3, e2423 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ziere, G. et al. Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J. Clin. Psychopharmacol. 28, 411–417 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Ziere, G., Dieleman, J. P., van der Cammen, T. J. & Stricker, B. H. Association between SSRI use and fractures and the effect of confounding by indication. Arch. Intern. Med. 167, 2369–2370; author reply 2370–2371 (2007).

    Article  PubMed  Google Scholar 

  25. Kinsella, S., Chavrimootoo, S., Molloy, M. G. & Eustace, J. A. Moderate chronic kidney disease in women is associated with fracture occurrence independently of osteoporosis. Nephron Clin. Pract. 116, c256–c262 (2010).

    Article  PubMed  Google Scholar 

  26. Beukhof, C. M., Hoorn, E. J., Lindemans, J. & Zietse, R. Novel risk factors for hospital-acquired hyponatraemia: a matched case–control study. Clin. Endocrinol. (Oxf.) 66, 367–372 (2007).

    Article  Google Scholar 

  27. Borgens, R. B. Endogenous ionic currents traverse intact and damaged bone. Science 225, 478–482 (1984).

    Article  CAS  PubMed  Google Scholar 

  28. Ecelbarger, C. A. et al. Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat. J. Clin. Invest. 99, 1852–1863 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Machnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat. Med. 15, 545–552 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Barsony, J., Sugimura, Y. & Verbalis, J. G. Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J. Biol. Chem. 286, 10864–10875 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Basu, S., Michaëlsson, K., Olofsson, H., Johansson, S. & Melhus, H. Association between oxidative stress and bone mineral density. Biochem. Biophys. Res. Commun. 288, 275–279 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Yamaguchi, T. The calcium-sensing receptor in bone. J. Bone Miner. Metab. 26, 301–311 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Hoorn, E. J. et al. Osmomediated natriuresis in humans: the role of vasopressin and tubular calcium sensing. Nephrol. Dial. Transplant. 24, 3326–3333 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Tseng, A. S., Beane, W. S., Lemire, J. M., Masi, A. & Levin, M. Induction of vertebrate regeneration by a transient sodium current. J. Neurosci. 30, 13192–13200 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reid, B., Song, B., McCaig, C. D. & Zhao, M. Wound healing in rat cornea: the role of electric currents. Faseb J. 19, 379–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Zhao, M. et al. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN. Nature 442, 457–460 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Komarova, S. V., Dixon, S. J. & Sims, S. M. Osteoclast ion channels: potential targets for antiresorptive drugs. Curr. Pharm. Des. 7, 637–654 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Chen, L., Liu, C., Liu, L. & Cao, X. Changes in osmolality modulate voltage-gated sodium channels in trigeminal ganglion neurons. Neurosci. Res. 64, 199–207 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hoorn, E. J. & Zietse, R. Hyponatremia and mortality: how innocent is the bystander? Clin. J. Am. Soc. Nephrol. 6, 951–953 (2011).

    Article  PubMed  Google Scholar 

  40. Wald, R., Jaber, B. L., Price, L. L., Upadhyay, A. & Madias, N. E. Impact of hospital-associated hyponatremia on selected outcomes. Arch. Intern. Med. 170, 294–302 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Chawla, A., Sterns, R. H., Nigwekar, S. U. & Cappuccio, J. D. Mortality and serum sodium: do patients die from or with hyponatremia? Clin. J. Am. Soc. Nephrol. 6, 960–965 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hoorn, E. J., Hotho, D., Hassing, R. J. & Zietse, R. Unexplained hyponatremia: seek and you will find. Nephron. Physiol. 118, p66–p71 (2011).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

E. J. Hoorn researched the data for the article. E. J. Hoorn, R. Zietse and M. C. Zillikens provided a substantial contribution to discussions of the content. E. J. Hoorn, G. Liamis and M. C. Zillikens contributed equally to writing the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Ewout J. Hoorn.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoorn, E., Liamis, G., Zietse, R. et al. Hyponatremia and bone: an emerging relationship. Nat Rev Endocrinol 8, 33–39 (2012). https://doi.org/10.1038/nrendo.2011.173

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2011.173

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing