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.

  • Population Study Article
  • Published:

Fracture risk among children and adolescents with celiac disease: a nationwide cohort study

Pediatric Research volume 95, pages 386–392 (2024)Cite this article

Abstract

Background

Metabolic bone disease is a common manifestation of celiac disease (CD). We aimed to assess fracture risk among children and adolescents with CD compared with a matched group.

Methods

This registry-based cohort study included 2372 children with CD who were matched 1:5 to 11,860 children without CD. Demographic and clinical data were obtained from the electronic database of Meuhedet, a health maintenance organization. Fracture events at ages 1–18 years were identified by coded diagnoses.

Results

The overall fracture incidence rate was 256 per 10,000 patient-years (PY) in the CD group and 165 per 10,000 PY in the comparison group (p < 0.001). The hazard ratio (HR) to have a fracture was 1.57 (95% CI 1.43–1.73, p < 0.001) for the CD group compared to the matched group. The HR for multiple fractures was 1.67 (95% CI 1.38–2.01, p < 0.001). Analysis of the pre- and post-diagnosis periods separately showed that the HR for fractures in the pre-diagnosis period was 1.64 (95% CI 1.42–1.88, p < 0.001) for the CD group compared to the matched group, and 1.52 (95% CI 1.26–1.71, p < 0.001) in the period from diagnosis to the end of the follow-up period.

Conclusions

Children with CD had increased fracture risk both preceding and following the diagnosis of CD.

Impact

  • One manifestation of celiac disease (CD) is metabolic bone disease, including osteoporosis and impaired bone mineralization.

  • We found increased fracture risk among children with CD, both preceding the CD diagnosis and during the years following the diagnosis.

  • Recognition of the high risk of fractures in this population may help promote prevention.

  • Further studies are needed to evaluate changes in bone quantity and quality after initiation of a gluten-free diet, and to identify those at risk for persistent metabolic bone disease.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Cumulative incidence curves demonstrating the incidence of fractures between ages 1 and 18 years, in children diagnosed with celiac disease (n = 2372) and in a matched comparison group (n = 11,860).

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Lebwohl, B. & Rubio-Tapia, A. Epidemiology, presentation, and diagnosis of celiac disease. Gastroenterology 160, 63–75 (2021).

    Article  CAS  PubMed  Google Scholar 

  2. Caio, G. et al. Celiac disease: a comprehensive current review. BMC Med. 17, 142 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gujral, N., Freeman, H. J. & Thomson, A. B. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J. Gastroenterol. 18, 6036–6059 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  4. King, J. A. et al. Incidence of celiac disease is increasing over time: a systematic review and meta-analysis. Am. J. Gastroenterol. 115, 507–525 (2020).

    Article  PubMed  Google Scholar 

  5. Andren Aronsson, C. et al. Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among children at increased risk. JAMA 322, 514–523 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Collin, P., Vilppula, A., Luostarinen, L., Holmes, G. K. T. & Kaukinen, K. Review article: coeliac disease in later life must not be missed. Aliment Pharm. Ther. 47, 563–572 (2018).

    Article  CAS  Google Scholar 

  7. Zanchetta, M. B., Longobardi, V. & Bai, J. C. Bone and celiac disease. Curr. Osteoporos. Rep. 14, 43–48 (2016).

    Article  PubMed  Google Scholar 

  8. Larussa, T. et al. Bone mineralization in celiac disease. Gastroenterol. Res. Pract. 2012, 198025 (2012).

  9. Bianchi, M. L. & Bardella, M. T. Bone in celiac disease. Osteoporos. Int. 19, 1705–1716 (2008).

  10. Xing, Y. & Morgan, S. L. Celiac disease and metabolic bone disease. J. Clin. Densitom. 16, 439–444 (2013).

    Article  PubMed  Google Scholar 

  11. Fedewa, M. V. et al. Celiac disease and bone health in children and adolescents: a systematic review and meta-analysis. J. Clin. Densitom. 23, 200–211 (2020).

    Article  PubMed  Google Scholar 

  12. Kondapalli, A. V. & Walker, M. D. Celiac disease and bone. Arch. Endocrinol. Metab. 66, 756–764 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Rubio-Tapia, A., Hill, I. D., Semrad, C., Kelly, C. P. & Lebwohl, B. American College of Gastroenterology Guidelines Update: diagnosis and management of celiac disease. Am. J. Gastroenterol. 118, 59–76 (2023).

    Article  CAS  PubMed  Google Scholar 

  14. Al-Toma, A. et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. U. Eur. Gastroenterol. J. 7, 583–613 (2019).

    Article  Google Scholar 

  15. Galindo-Zavala, R. et al. Expert panel consensus recommendations for diagnosis and treatment of secondary osteoporosis in children. Pediatr. Rheumatol. Online J. 18, 20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ciancia, S. et al. Osteoporosis in children and adolescents: how to treat and monitor? Eur. J. Pediatr. 182, 501–511 (2023).

    Article  PubMed  Google Scholar 

  17. Micic, D., Rao, V. L. & Semrad, C. E. Celiac disease and its role in the development of metabolic bone disease. J. Clin. Densitom. 23, 190–199 (2020).

    Article  PubMed  Google Scholar 

  18. Olmos, M. et al. Systematic review and meta-analysis of observational studies on the prevalence of fractures in coeliac disease. Dig. Liver Dis. 40, 46–53 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Heikkila, K., Pearce, J., Maki, M. & Kaukinen, K. Celiac disease and bone fractures: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 100, 25–34 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Hjelle, A. M. et al. Celiac disease and risk of fracture in adults—a review. Osteoporos. Int. 25, 1667–1676 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. West, J., Logan, R. F., Card, T. R., Smith, C. & Hubbard, R. Fracture risk in people with celiac disease: a population-based cohort study. Gastroenterology 125, 429–436 (2003).

    Article  PubMed  Google Scholar 

  22. Ludvigsson, J. F., Michaelsson, K., Ekbom, A. & Montgomery, S. M. Coeliac disease and the risk of fractures – a general population-based cohort study. Aliment Pharm. Ther. 25, 273–285 (2007).

    Article  CAS  Google Scholar 

  23. Jafri, M. R. et al. Long-term fracture risk in patients with celiac disease: a population-based study in Olmsted County, Minnesota. Dig. Dis. Sci. 53, 964–971 (2008).

    Article  PubMed  Google Scholar 

  24. Canova, C. et al. Risk of fractures in youths with celiac disease-a population-based study. J. Pediatr. 198, 117–120 (2018).

    Article  PubMed  Google Scholar 

  25. Husby, S. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 54, 136–160 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Lau, W. S., Heaton, P. A. & Paul, S. P. Improved adherence to the ESPGHAN Guidelines is necessary for diagnosing celiac disease in children: a single-center experience. Arq. Gastroenterol. 58, 164–167 (2021).

    Article  PubMed  Google Scholar 

  27. Tashtoush, L. B., Broad, S. R. & Paul, S. P. Pediatric celiac disease diagnosis and adherence to the ESPGHAN 2012 and 2020 Guidelines: a single centre experience. Arq. Gastroenterol. 59, 150–151 (2022).

    Article  PubMed  Google Scholar 

  28. Paul, S. P., Chan, Y. J. & Bailey, J. R. Diagnosing childhood celiac disease using ESPGHAN 2012 and 2020 guidelines: tighter adherence is required! Indian J. Gastroenterol. 39, 621–623 (2020).

    Article  PubMed  Google Scholar 

  29. Guz-Mark, A. et al. High rates of serology testing for coeliac disease, and low rates of endoscopy in serologically positive children and adults in Israel: lessons from a large real-world database. Eur. J. Gastroenterol. Hepatol. 32, 329–334 (2020).

    Article  PubMed  Google Scholar 

  30. Husby, S. et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J. Pediatr. Gastroenterol. Nutr. 70, 141–156 (2020).

    Article  PubMed  Google Scholar 

  31. Zacay, G., Dubnov-Raz, G., Modan-Moses, D., Tripto-Shkolnik, L. & Levy-Shraga, Y. Epidemiology of childhood fractures in Israel during 2000–2019. Bone 154, 116174 (2022).

  32. Sanchez, M. I. et al. Risk of fracture in celiac disease: gender, dietary compliance, or both? World J. Gastroenterol. 17, 3035–3042 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Makharia, G. K. Current and emerging therapy for celiac disease. Front. Med. (Lausanne) 1, 6 (2014).

    PubMed  Google Scholar 

  34. Grace-Farfaglia, P. Bones of contention: bone mineral density recovery in celiac disease-a systematic review. Nutrients 7, 3347–3369 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Verma, A. et al. Study of effect of gluten-free diet on vitamin D levels and bone mineral density in celiac disease patients. J. Fam. Med Prim. Care 11, 603–607 (2022).

    Article  Google Scholar 

  36. Mora, S. et al. A prospective, longitudinal study of the long-term effect of treatment on bone density in children with celiac disease. J. Pediatr. 139, 516–521 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Bjorck, S., Brundin, C., Karlsson, M. & Agardh, D. Reduced bone mineral density in children with screening-detected celiac disease. J. Pediatr. Gastroenterol. Nutr. 65, 526–532 (2017).

    Article  PubMed  Google Scholar 

  38. Zanchetta, M. B. et al. Impaired bone microarchitecture improves after one year on gluten-free diet: a prospective longitudinal HRpQCT study in women with celiac disease. J. Bone Min. Res. 32, 135–142 (2017).

    Article  CAS  Google Scholar 

  39. Zanchetta, M. B. et al. Improved bone microarchitecture in patients with celiac disease after 3 years on a gluten-free diet. Clin. Gastroenterol. Hepatol. 16, 774–775 (2018).

    Article  PubMed  Google Scholar 

  40. Lebwohl, B., Michaelsson, K., Green, P. H. & Ludvigsson, J. F. Persistent mucosal damage and risk of fracture in celiac disease. J. Clin. Endocrinol. Metab. 99, 609–616 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mehta, P. et al. Gluten-free diet adherence in children with screening-detected celiac disease using a prospective birth cohort study. PLoS One 18, e0275123 (2023).

  42. Barone, M. V. et al. Pivotal role of inflammation in celiac disease. Int. J. Mol. Sci. 23, 7177 (2022).

  43. Mandile, R. et al. Mucosal healing in celiac disease: villous architecture and immunohistochemical features in children on a long-term gluten free diet. Nutrients 14, 3696 (2022).

  44. Vici, G., Belli, L., Biondi, M. & Polzonetti, V. Gluten free diet and nutrient deficiencies: a review. Clin. Nutr. 35, 1236–1241 (2016).

    Article  CAS  PubMed  Google Scholar 

  45. McGrogan, L. et al. Micronutrient deficiencies in children with coeliac disease; a double-edged sword of both untreated disease and treatment with gluten-free diet. Clin. Nutr. 40, 2784–2790 (2021).

    Article  CAS  PubMed  Google Scholar 

  46. Jivraj, A. et al. Micronutrient deficiencies are frequent in adult patients with and without celiac disease on a gluten-free diet, regardless of duration and adherence to the diet. Nutrition 103–104, 111809 (2022).

  47. Patwari, A. K. et al. Catch-up growth in children with late-diagnosed coeliac disease. Br. J. Nutr. 94, 437–442 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Assa, A. et al. Anthropometric measures and prevalence trends in adolescents with coeliac disease: a population based study. Arch. Dis. Child 102, 139–144 (2017).

    Article  PubMed  Google Scholar 

  49. Modan-Moses, D. et al. High prevalence of vitamin D deficiency and insufficiency in adolescent inpatients diagnosed with eating disorders. Int. J. Eat. Disord. 48, 607–614 (2015).

    Article  PubMed  Google Scholar 

  50. Oren, Y. et al. Vitamin D insufficiency in a sunny environment: a demographic and seasonal analysis. Isr. Med. Assoc. J. 12, 751–756 (2010).

    PubMed  Google Scholar 

  51. Saliba, W., Rennert, H. S., Kershenbaum, A. & Rennert, G. Serum 25(OH)D concentrations in sunny Israel. Osteoporos. Int. 23, 687–694 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Aydemir, Y., Erdogan, B. & Turkeli, A. Vitamin D deficiency negatively affects both the intestinal epithelial integrity and bone metabolism in children with celiac disease. Clin. Res. Hepatol. Gastroenterol. 45, 101523 (2021).

Download references

Acknowledgements

The authors would like to acknowledge Cindy Cohen for linguistic support and for valuable remarks that contributed to the writing of this article.

Author information

Authors and Affiliations

  1. Meuhedet Health Services, Tel Aviv, Israel

    Galia Zacay, Ilana Weintraub, Ravit Regev, Dalit Modan-Moses & Yael Levy-Shraga

  2. Sackler School of Medicine, University of Tel Aviv, Tel Aviv, Israel

    Galia Zacay, Ilana Weintraub, Ravit Regev, Dalit Modan-Moses & Yael Levy-Shraga

  3. Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel

    Ilana Weintraub

  4. Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Ravit Regev

  5. Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel

    Dalit Modan-Moses & Yael Levy-Shraga

Authors
  1. Galia Zacay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilana Weintraub
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ravit Regev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dalit Modan-Moses
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yael Levy-Shraga
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.L.-S., G.Z.: conception and design of the study and acquisition of data. G.Z., Y.L.-S., I.W., D.M.-M. and R.R.: analysis and interpretation of data. Y.L.-S., G.Z.: drafting the initial manuscript and editing it. All the authors reviewed the manuscript, revised it and approved the final manuscript as submitted.

Corresponding author

Correspondence to Yael Levy-Shraga.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Meuhedet Health Services (number 01-10.06.20). Informed consent was not required, as the data were de-identified.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zacay, G., Weintraub, I., Regev, R. et al. Fracture risk among children and adolescents with celiac disease: a nationwide cohort study. Pediatr Res 95, 386–392 (2024). https://doi.org/10.1038/s41390-023-02826-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-023-02826-5

Search

Advanced search

Quick links