A large-scale observational study from Japan has revealed that denosumab offers superior fracture protection for dialysis patients compared to oral bisphosphonates, though this benefit comes with potential cardiovascular risks. The study, published in Annals of Internal Medicine, provides crucial insights for managing osteoporosis in this complex patient population.
Significant Fracture Risk Reduction
The research, led by Dr. Koji Kawakami and colleagues at Kyoto University, analyzed 1,032 dialysis patients receiving osteoporosis treatment. Denosumab demonstrated a 45% lower risk for all fractures compared to oral bisphosphonates over three years (RR 0.55, 95% CI 0.28-0.93). This translated to a significant 5.3-percentage point reduction in weighted 3-year risk for composite fractures.
The protective effect was particularly pronounced for nonvertebral fractures, showing a risk difference of -5.8 percentage points (RR 0.38, 95% CI 0.18-0.71). These improvements encompassed fractures of the hip, shoulder, forearm, leg, femur, and ankle.
Cardiovascular Safety Considerations
Despite the positive fracture prevention outcomes, the study identified important safety signals. Denosumab users experienced a notably higher risk of acute myocardial infarction, with 24 cases among 658 denosumab users compared to just four cases in 374 bisphosphonate users (weighted RR 3.50, 95% CI 1.44-21.4).
"Among dialysis patients with osteoporosis, denosumab may be more effective than oral bisphosphonates in reducing fracture risk, but it might also increase the risk of MACE," explained Dr. Soichiro Masuda of Kyoto City Hospital, the lead study author.
Clinical Context and Implications
The findings are particularly relevant given the recent FDA boxed warning for denosumab regarding severe hypocalcemia risk in advanced CKD patients. The warning, issued in January 2024, was based on Medicare data showing a 20-fold higher risk of severe hypocalcemia in denosumab users compared to those taking oral bisphosphonates.
The study utilized a Japanese commercial administrative database covering claims from April 2014 to October 2022, focusing on patients 50 and older undergoing dialysis with an osteoporosis diagnosis. After weighting, the cohort consisted of approximately 63% women, with an average age of 75 years and a mean duration of 3.5 years since initial osteoporosis diagnosis.
Treatment Selection Considerations
Denosumab's independence from kidney clearance makes it an attractive option for dialysis patients, potentially explaining its increasing adoption in this population. However, Dr. Masuda notes that the overall net benefit requires further investigation, particularly regarding renal outcomes that weren't assessed in this study.
The researchers acknowledge certain limitations, including the inability to adjust for specific cardiovascular risk factors and baseline electrolyte imbalances that might influence treatment selection. These factors could potentially lead to an overestimation of cardiovascular event risk associated with denosumab use.
Future Research Directions
Given the challenges of conducting large-scale trials in dialysis populations, the researchers emphasize the need for comprehensive prospective studies to validate these findings. The balance between fracture prevention benefits and cardiovascular risks will remain a crucial consideration for clinicians managing osteoporosis in dialysis patients.
