Celiac disease (CD) is associated with an increased risk of osteoporotic fracture, a risk increase that persists after diagnosis. Although the gluten-free diet results in an improvement of symptoms in the majority of patients, a significant proportion have persistent villous atrophy (VA) on follow-up biopsy. It is unknown whether persistent VA impacts long-term fracture risk in patients with CD.

We identified all patients in Sweden with histologic evidence of CD in a population-based database who underwent a follow-up biopsy between six months and five years after initial CD diagnosis. We excluded patients with a history of fracture prior to their follow-up biopsy. We compared those patients with persistent VA to those with mucosal healing with regard to their risk of 1) any fracture; 2) likely osteoporotic fracture (defined as fractures of the hip, distal forearm, thoracic and lumbar spine, or proximal humerus); and 3) hip fracture. We used Cox proportional hazards, adjusting for patient age, gender, calendar period, education, and duration of celiac disease at the time of follow-up biopsy.

Of 7,648 patients with CD who had a follow-up biopsy in this time period, 502 had a fracture history preceding their follow-up biopsy, leaving 7,146 patients for the analysis. The median age of CD diagnosis was 23, and 64% were female. The median follow-up was 10.3 years after CD diagnosis, and 8.6 years after follow-up biopsy, during which 975 patients (14%) experienced a fracture. Persistent VA was present on follow-up biopsy in 43% of the patients. There was no significant association between persistent VA and fractures as a whole (Hazard Ratio [HR] 0.93, 95%CI 0.82-1.06), and there was a non-significantly increased risk of likely osteoporotic fractures (HR 1.11 95%CI 0.84-1.46). In contrast, persistent VA was associated with an increased risk of hip fracture (HR 1.67 95%CI 1.05-2.66), a risk that increased over time (HR >5 years after follow-up biopsy: 2.18 95%CI 1.17-4.05). Compared to those with mucosal healing, hip fracture risk increased depending on the degree of VA on follow-up biopsy (HR for partial VA 1.70 95%CI 0.82-3.49; HR for subtotal/total VA 2.16 95%CI 1.06-4.41).

Persistent VA on follow-up biopsy is predictive of long-term hip fracture risk, and this relationship is stronger for more severe degrees of VA. The association between persistent VA and hip fractures in particular, and not with fractures overall, suggests that osteoporosis is the mechanism by which persistent VA confers an increased fracture risk.

Benjamin Lebwohl, Karl Michaëlsson, Peter H. Green, Jonas F. Ludvigsson

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