Bisphosphonate effectiveness in patients with cirrhosis: An emulated clinical trial

Summary Background Falls and fractures are common and morbid for patients with cirrhosis. Bisphosphonates are recommended for the prevention of fractures for people with osteoporosis cirrhosis; however, data supporting effectiveness in cirrhosis are lacking. Aim We sought to emulate a clinical trial of bisphosphonates in cirrhosis. Methods We used national Medicare data (2008–2020) to examine the 5‐year risk of fractures in patients who did or did not receive bisphosphonates with a new‐user design among people diagnosed with cirrhosis and osteoporosis. We balanced treated and untreated with inverse probability of treatment weighting, evaluated intention‐to‐treat and as‐treated effects, and examined both control exposures (statin use) and outcomes (decompensation) to test causal relationships. Results There were 253 and 20,888 new users and non‐users of bisphosphonates, respectively. The median age was 74 years. The most common bisphosphonate used was alendronate (73.6%). Bisphosphonates significantly reduced fractures overall (27.5% vs. 33.0%, p = 0.0004) in the intention‐to‐treat analysis, particularly for people <65 years (sHR 0.56) old, men (sHR 0.64) and those with non‐alcohol related liver disease (sHR 0.85). Though there were fewer arm (20.7% vs. 26.4%, p < 0.0001) and femur (28.9% vs. 31.2%, p = 0.005), there were more spinal (25.8% vs. 19.0%), rib (40.0% vs. 32.2%) and skull (10.1% vs. 8.7%) fractures. In the as‐treated analysis, cumulative bisphosphonate exposure significantly reduced fractures, sHR 0.95 95% CI (0.91, 0.98). Treatment was inconsistent; bisphosphonate users spent 29.9% person‐years of follow‐up on the drug. Conclusion In a nationally representative cohort of elderly patients with cirrhosis, bisphosphonates reduced fractures overall. Efforts to increase uptake and drug continuation are needed.