Over the past few decades, multiple anti-osteoporotic agents have been developed, with bisphosphonates being the most prescribed. However, bisphosphonates are renally excreted, raising concerns regarding their prolonged serum half-life and potential accumulation in patients with CKD. Although alternative dosing strategies—such as reducing the dosage or extending the dosing interval—may be theoretically reasonable, clinical evidence supporting these approaches in patients with CKD remains limited [3]. Consequently, bisphosphonates are generally considered suboptimal for patients with impaired kidney function. Denosumab—a human monoclonal antibody targeting receptor activator of nuclear factor kappa-Β ligand (RANKL)—has become a widely adopted antiresorptive agent owing to its potent efficacy and renal safety profile. Unlike bisphosphonates, which are cleared by the kidneys and are contraindicated in advanced CKD, denosumab is metabolized via the reticuloendothelial system and does not require renal excretion [4]. This pharmacokinetic profile makes it an attractive option for patients with impaired renal function.

The pivotal FREEDOM trial demonstrated that denosumab significantly increases bone mineral density (BMD) and reduces the risk of vertebral, non-vertebral, and hip fractures in postmenopausal women with osteoporosis [5]. Furthermore, in a subgroup analysis stratified by kidney function, denosumab remained effective even in patients with moderate-to-severe kidney disease (CKD stages 3–4) [6]. No significant interaction between kidney function and treatment effects was observed, and the safety profile remained favorable. However, this study did not include patients undergoing dialysis or KTRs, who represent a distinct group with complex bone mineral abnormalities. Therefore, direct evidence supporting the use of denosumab in KTRs is scarce.

In this issue of Kidney Research and Clinical Practice, Kwon et al. [7] present a retrospective study evaluating the effectiveness and safety of denosumab in 98 KTRs from a single center over 1 year. Their findings offer valuable clinical insights into a population often excluded from pivotal osteoporosis trials. The authors reported significant BMD improvements in the femoral neck and lumbar spine 1-year posttreatment. The mean femoral neck T-score improved from –2.81 to –2.68 and the spine T-score from –3.21 to –2.78 (both p < 0.001). Additionally, the 10-year probability of hip fractures, as calculated using the fracture risk assessment tool (FRAX), significantly decreased posttreatment. Graft loss, acute kidney injury, and rejection were not observed during the follow-up period. These findings are consistent with previous evidence, such as the 2016 randomized controlled trial by Bonani et al. [8], which demonstrated significant improvements in spinal BMD. These results are reassuring and provide supportive evidence for the safety and efficacy of denosumab for KTRs.

Moreover, this study meaningfully addresses an important gap in the literature. To date, only about 13 original studies—including randomized controlled trials and prospective or retrospective cohorts—have evaluated denosumab use in KTRs, most of which enrolled fewer than 60 patients treated with denosumab. Furthermore, most of these studies were conducted on Western populations, with limited data available from Asian cohorts. The study by Kwon et al. [7] is significant because of its exclusive focus on Korean KTRs and its contribution to the limited body of evidence in this field. The inclusion of detailed subgroup analyses, accounting for calcium and vitamin D supplementation and sex, enhances its clinical relevance and reflects real-world practice, thereby strengthening its value in the existing literature.

In contrast, this study has several limitations. The retrospective design precludes causal inference, and the lack of a control group limits comparative evaluations. Additionally, the short follow-up period (1 year) was insufficient to assess long-term fracture risk or adverse events, such as atypical femoral fractures and osteonecrosis of the jaw, which are relevant concerns for long-term denosumab users. Moreover, the strong female predominance (77.6%) raises concerns regarding sex-based bias, particularly for outcomes such as urinary tract infections and BMD changes, which differ between men and women. Therefore, steroid use warrants further investigation. While 81.6% of the cohort remained on maintenance corticosteroids, their doses and cumulative exposures were not explicitly analyzed in relation to BMD changes. Because glucocorticoids are major contributors to bone loss, future studies should address this interaction more rigorously.

Furthermore, an important consideration in the use of denosumab in KTRs is the sequential management strategy after discontinuation. It is well established that the cessation of denosumab can lead to rapid bone loss and a rebound increase in bone turnover, which has been associated with an elevated risk of fractures [9]. To mitigate this risk, current guidelines recommend transitioning to a bisphosphonate for at least 1 to 2 years after discontinuing denosumab to maintain BMD and reduce the fracture risk [9]. Although bisphosphonate use is suggested in KTRs within the first 12 months posttransplantation, particularly in those with low BMD and an estimated glomerular filtration rate above 30 mL/min/1.73 m², evidence to support the use of any anti-osteoporotic agents beyond the first year posttransplantation is limited [10]. Bisphosphonate-based sequential therapy after denosumab treatment has not been well validated in KTRs, highlighting the need for evidence-based protocols tailored to this population.

A visual summary of the study’s clinical context, key findings, and remaining questions is provided in Fig. 1. Future prospective multicenter trials with longer follow-up periods and broader demographic representations are warranted to validate and expand the findings of Kwon et al. [7]. In addition, developing transplant-specific fracture risk tools may overcome the limitations of the FRAX tool in this unique population.

In conclusion, the study by Kwon et al. [7] represents a valuable addition to the limited literature on osteoporosis management in KTRs. Although further evidence is needed, these findings suggest that denosumab may be a viable therapeutic option—when appropriately monitored, alongside individualized calcium and vitamin D supplementation. As the transplant community strives to improve long-term outcomes, bone health should remain an important consideration in posttransplant care, and further research in this area is warranted.