Editorial: Inflammation and Not Glucocorticoid Therapy is the Key Driver of Fracture Risk in IBD

Risk for osteoporosis and fragility fracture is increased in patients with inflammatory bowel disease (IBD) [1, 2], with attendant morbidity. However, the extent to which this increase is due to the disease, disease-associated risk factors, such as malnutrition, or its treatment—particularly with glucocorticoids—has been difficult to differentiate [3, 4]. In their cohort study [5], Mårild et al. used a national database of gastrointestinal histology reports, linked to the Swedish National Patient Register (NPR), to identify over 54,000 patients with IBD who had ileo-colorectal biopsies between 1990 and 2016. The NPR identified fractures occurring within 12 months of biopsy; patients with inflammation on biopsy had a 12% increased risk of fracture, with the highest risk being a 41% increase in glucocorticoid-naïve patients with inflammation. Inflammation conferred a 21% increased risk in men, but not in women. In patients diagnosed within the previous 2 years, histological inflammation was associated with a 33% increased risk. Hip fracture risk was not increased, perhaps due to their relatively young age.

This study is novel in linking histological inflammation with fracture risk independent of glucocorticoid use. Histological healing is a stringent endpoint, often unattainable in IBD treatment, thus it is not recommended as a treatment goal by the International Organisation for the Study of Inflammatory Bowel Diseases (IOIBD) [6]. However, in this study, examining short-term fracture risk, it may act as an objective marker for active or undertreated disease.

While histological inflammation is associated with a higher risk of clinical relapse in patients with ulcerative colitis (UC), this is not true in Crohn's disease (CD) [7]. Its discriminant value may be greater for disease complications in UC: in patients with CD or unclassified IBD in this study, there was no difference in fracture risk based on biopsy findings. Using the same data set, the authors have previously found that histological inflammation was a risk factor for pre-term birth in UC [8].

Selection biases were inherent in this cohort study. As the decision to undertake colonoscopy was on clinical grounds, individuals with more severe diseases were more likely to have had biopsies, and those with inflammation on biopsy were likelier to be biopsied more than once. This may have led to underrepresentation of patients with mild or well-controlled disease. Biopsies taken over later years were also more likely to show remission, suggesting either improved disease control or different indications for endoscopy, such as dysplasia screening. Patients with prior fractures—more prevalent in the group without inflammation—were excluded from the analysis, potentially reducing risk in the control group. There was a notable lack of data regarding bone mineral density, clinical or endoscopic disease activity, and other clinical risk factors for osteoporosis, including smoking and nutritional status.

The study has highlighted inflammation as an independent, modifiable risk factor for fracture in IBD, as it is in rheumatological immune-mediated inflammatory diseases [9]. It supports new ECCO guidelines [10] recommending screening for osteoporosis and adds to burgeoning evidence suggesting early intervention to reduce inflammation, rather than merely symptoms, improves health outcomes in IBD.

Darcy Quinn Holt: writing – original draft, writing – review and editing. Peter R. Ebeling: writing – review and editing.

This article is linked to Mårild et al paper. To view this article, visit https://doi.org/10.1111/apt.18275.