Gastroenterology

Gastroenterology

Volume 119, Issue 4, October 2000, Pages 909-920
Gastroenterology

Alimentary Tract
Genetic factors determine extent of bone loss in inflammatory bowel disease

https://doi.org/10.1053/gast.2000.18158Get rights and content

Abstract

Background & Aims: Although bone loss and osteoporosis are well-known long-term sequelae of inflammatory bowel disease (IBD), the risk factors for increased bone loss have not been identified. Balances of pro- and anti-inflammatory cytokines influence mechanisms of both chronic inflammation and bone resorption. The aim of this study was to identify genetic risk factors for rapid bone loss in IBD patients as a model of disease- and inflammation-associated bone loss. Methods: Multiple clinical parameters, biochemical markers of bone metabolism (vitamin D, parathyroid hormone, N-terminal telopeptide of type-I collagen, desoxypyridinoline, bone alkaline phosphatase), and bone mineral density were prospectively assessed in 83 IBD patients over 1.6 ± 0.3 years. Eighty-six healthy bone marrow donors served as controls for allelotyping. The allele status of the interleukin 1 receptor antagonist (IL-1ra), IL-6, heat shock protein 70-2 (hsp 70-2), and heat shock protein 70-hom (hsp hom) genes was typed and correlated with clinical course of IBD and extent of bone loss. Results: The extent of bone loss was not correlated to clinical severity of disease or application of corticosteroids. Noncarriage of the 240–base pair allele of the IL-1ra gene and carriage of the 130–base pair allele of IL-6 were independently associated with increased bone loss. Genetic variations of the hsp genes were not associated with degree of bone loss. The combined presence of the named risk factors was significantly associated with increasing bone loss. Conclusions: Genetic variations in the IL-6 and IL-1ra gene identify IBD patients at risk for increased bone loss.

GASTROENTEROLOGY 2000;119:909-920

Section snippets

Subjects

The study group consisted of 83 patients with IBD. Sixty (72%) patients had Crohn's disease, and 23 (28%) patients had ulcerative colitis. The diagnosis of IBD was established on the basis of standard clinical, radiologic, endoscopic, and pathologic criteria. Exclusion criteria included borderline manifestations; unclear subtype or uncertain diagnosis; former organ transplantation; other systemic inflammatory disease; medication with bone-toxic agents (exept steroids) such as heparin,

Study population

The characteristics of the study population at baseline are summarized in Table 1.

. Characteristics of the study population of 83 patients with IBD at baseline

Empty Celln%
Type of IBD
 Crohn's disease60
  Involvement of
   Colon5083
   Distal small bowel4575
   Upper GI tract1017
  Resection of
   Ileocecal valve2948
   Colon (subtotal or total)1119
   Upper GI tract47
 Ulcerative colitis23
  Pancolitis1043.5
  Left-sided colitis626
  Proctosigmoiditis730.5
Sex
 Male4554
 Female3846
  Pre/postmenopausal29/9
Empty CellMeanSDMedianRange
Age (yr)37143317–75
Duration of

Discussion

Our study shows that variations of the IL-6 and IL1-ra genes, but not the hsp 70 gene, are independent determinants of bone loss in the setting of IBD. The IL-6 and IL1-ra genes have been identified as independent predictors of bone loss in the setting of postmenopausal osteoporosis. That they function in a similar way in our study group of IBD patients may signify that they specifically determine the response of bone to different stressors such as the postmenopausal status or systemic

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      Citation Excerpt :

      One study from the Netherlands showed that individuals with polymorphism of the IL-1beta and IL-1 receptor (IL-1ra) (particularly carriers of IL1B-511*2, which leads to hypersecretion of IL-1) had a higher risk of presenting with low bone mass in IBD (26). Another study from Germany showed that noncarriage of the 240-base pair allele of the IL-1ra gene and carriage of the 130-base pair allele of IL-6 were independently associated with increased bone loss (27). This suggests a genetic predisposition to increased bone loss in some patients with IBD.

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    Address requests for reprints to: Claudia M. S. Schulte, M.D., Division of Endocrinology, Department of Internal Medicine, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany. e-mail: [email protected]; fax: (49) 201-268988.

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