Cardiovascular safety and efficacy of denosumab in people on dialysis

People with chronic kidney disease (CKD) are at a much greater risk of osteoporotic fractures than the general population. This is particularly so in those receiving dialysis, for whom osteoporosis management is a major challenge, partly owing to scarce evidence on effective strategies. 

Denosumab, a human monoclonal antibody, exerts a preventive effect against fracture regardless of degree of renal impairment. Consequently, its adoption in the management of osteoporosis in people on dialysis has increased. Bisphosphonates, the usual first-line treatment in the prevention of fractures in people with osteoporosis, are associated with progression of existing CKD. However, clinical trials have not compared the safety and fracture prevention effects of denosumab and bisphosphonates in people on dialysis. 

To address this evidence gap, the present study used observational data from an insurance claims database in Japan (April 2014 to October 2022). A target trial of denosumab versus oral bisphosphonates was emulated regarding the risk for major adverse cardiac events (MACE) and the effectiveness in composite fracture prevention among dialysis-dependent individuals. 

A total of 1032 people aged ≥50 years were identified as having initiated denosumab (n=658) or oral bisphosphonates (n=374). Their average age was 74.5 years and 62.9% were women. 

During 3 years’ follow-up, 146 denosumab users experienced MACE compared with 54 oral bisphosphonate users (weighted 3-year risk difference, 8.2% [CI, –0.2% to 16.7%]; weighted 3-year risk ratio, 1.36 [CI, 0.99 to 1.87]). 

In the effectiveness analysis, 25 denosumab users experienced a composite fracture compared with 29 oral bisphosphonate users (weighted 3-year risk difference, –5.3% [CI, –11.3% to –0.6%]; weighted 3-year risk ratio, 0.55 [CI, 0.28 to 0.93]).

The study authors acknowledged several limitations, including a lack of clinical data on kidney or osteoporosis disease severity and cardiovascular or other metabolic risk with residual confounding. Kidney endpoints were not included in the safety outcomes.

Overall, denosumab lowered the risk for fractures by 45% and increased the risk for MACE by 36%, compared with oral bisphosphonates, but the authors suggest the estimates for MACE are imprecise and need to be confirmed in further studies. 

The full article can be read here.