Effects of Opioids, Benzodiazepines, Gabapentinoids, and Antidepressants on Fracture Risk in Alcohol‐Related Cirrhosis

BACKGROUND: Patients with alcohol-related liver cirrhosis (ALD cirrhosis) have an increased risk of falls and fractures. Opioids, benzodiazepines, gabapentinoids, and antidepressants are known to increase fall risk. AIMS: We aimed to determine the effects of opioids, benzodiazepines, gabapentinoids, and antidepressants on fracture risk in ALD cirrhosis. METHODS: Using Danish nationwide registries, we identified all patients diagnosed with ALD cirrhosis in 2000-2023 and their subsequent hospitalisations for fracture. Redeemed prescriptions defined exposure to opioids, benzodiazepines, gabapentinoids, and antidepressants. We applied Cox and Poisson regression to estimate fracture risks with and without exposure, adjusting for confounders. To minimise confounding, we also used a self-controlled case-crossover design. RESULTS: Among 24 743 patients with newly diagnosed ALD cirrhosis, the 5-year fracture risk was 19.0% (95% CI: 18.4%-19.4%). Fracture risk was increased during the first 30 days after initiation of opioids (adjusted hazard ratio [aHR]: 3.20, 95% CI: 2.30-4.45), benzodiazepines (aHR: 2.17, 95% CI: 1.37-3.76), or gabapentinoids (aHR: 2.43, 95% CI: 1.66-3.55), whereas antidepressant initiation did not affect fracture risk (aHR: 1.07, 95% CI: 0.62-1.84). Similar within-person results were obtained using the self-controlled design. Notably, the risk-increasing effects of opioids, benzodiazepines, and gabapentinoids decreased with the duration of exposure, and none of the drugs increased fracture risk if the patient had been using them for more than 365 days. CONCLUSIONS: In ALD cirrhosis, fracture risk is increased when treatment with opioids, benzodiazepines, or gabapentinoids is initiated, but not with long-term use. Precautionary measures are recommended when initiation of these drugs is indicated.