Improvements in long-term survival and clinical outcomes of kidney transplantation (KT) have led clinicians to focus on the quality of life of kidney transplant recipients (KTRs) [1]. Improving the quality of life of KTRs and providing posttransplantation care include preventing bone loss and fractures, as they are significant causes of mortality and morbidity in KTRs [2]. In KTRs, the loss of bone mineral density (BMD) is common, particularly in the first year after transplantation, owing to the effects of immunosuppressive medication and persistent elevation of parathyroid hormone (PTH) levels [3]. Glucocorticoids, one of the most important medications used for maintenance immunosuppressive therapy in KTRs, are known for their significant effect on bone density [4]. There are several therapeutic options for reducing bone loss, such as calcium/vitamin D supplementation or bisphosphonates. However, their use is limited because of the lack of definite evidence that they reduce fracture risk, and the presence of persistent hyperparathyroidism and hypercalcemia [5,6]. Some nephrologists have studied the early withdrawal of corticosteroids to prevent corticosteroid-induced osteoporosis, which has shown meaningful results in certain medical conditions, such as puberty or early diabetes [7]. However, it is challenging to apply this approach universally because it may increase the risk of adverse outcomes for KTRs in specific conditions [8]. Denosumab, a human monoclonal antibody for receptor activator of nuclear factor kappa-B ligand (RANKL), is an effective agent for treating osteoporosis by decreasing bone resorption, thereby increasing BMD [9]. Common adverse events of denosumab in non-transplant patients include infections, malignancies, eczema, hypocalcemia, pancreatitis, osteonecrosis of the jaw, and atypical femoral fractures [10]. However, the impact on clinical outcomes, including fracture incidence and denosumab’s safety for osteoporosis in KTRs, remains controversial. In this study, we investigated the clinical outcomes of denosumab treatment to determine whether it is effective and safe for treating osteoporosis in KTRs.

This study adhered to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Keimyung University Dongsan Medical Center (No. 2024-03-003). Informed consent was waived as the study involved a retrospective review of anonymized clinical data explained to patients before transplantation. The study did not include transplants procured from prisoners and followed all relevant guidelines and regulations.

KTRs have a high risk of fractures and bone mineral loss during the early period after receiving KT [17]. Posttransplantation BMD in KTRs is multifactorial. Multiple factors contribute to this condition, including hypocalcemia, hyperphosphatemia, vitamin D deficiency, and persistent hyperparathyroidism caused by chronic kidney disease. Additionally, damage caused by various medications, including immunosuppressants, such as corticosteroids, which play an important role in exacerbating osteoporosis, can lower BMD and worsen osteoporosis [2,18,19]. In our study, 81.6% of patients continued to use steroids for maintenance immunosuppression. Researchers have studied steroid-free protocols for KTRs to reduce the adverse effects of steroids on the BMD. Evenepoel et al. [1] suggested that reducing corticosteroid use could reduce bone loss and prevent worsening of osteoporosis. However, reducing corticosteroids or steroid-free immunosuppression protocols often raise concerns about graft function deterioration. Bae et al. [8] suggested that patients with specific conditions, such as DGF, have a higher risk of rejection with an early steroid withdrawal protocol and Aref et al. [7] reported that a steroid-free protocol showed poor outcomes in KTRs who experienced DGF. In such cases, KTRs with poor kidney conditions may require alternative options for managing osteoporosis. Denosumab can cover the various mechanisms of bone density loss mentioned above because its treatment mechanism, which interferes with the RANKL system of bone turnover, may be effective for multiple aspects of bone loss despite the use of low-dose steroids for maintenance immunosuppression [20]. The 2017 KDIGO guidelines for chronic kidney disease-mineral and bone disorder suggest that patients in the first 12 months after KT with eGFR >30 mL/min/1.73 m² and low BMD should begin with calcium/vitamin D supplementation with consideration of antiresorptive agents such as denosumab [17].

In 2016, Bonani et al. [9] conducted a prospective randomized controlled trial using denosumab to treat osteoporosis in 90 KTRs. They demonstrated that denosumab treatment had a positive effect on improving spine BMD and hip BMD after KT (5.1% [95% confidence interval (CI), 3.1%–7.0%]; p < 0.0001 and 1.9% [95% CI, 0.1%–3.7%]; p = 0.035, respectively) [9]. Another study by Brunova et al. [21] showed denosumab improves BMD in solid organ transplant recipients including KTRs (L-spine T-score, −2.7 ± 0.09 to −1.8 ± 1.0; p < 0.001). Our study also exhibited results similar to those of a previous study demonstrating that denosumab significantly increased BMD 1 year after denosumab treatment in KTRs, regardless of the patients’ use of calcium/vitamin D and sex. To our knowledge, our study showed positive results in KTR with a BMD (lumbar spine or femur) below the threshold of osteoporosis. However, there are also studies suggesting that denosumab may not significantly improve BMD in KTRs with osteoporosis [22]. To confirm the efficacy of denosumab, a randomized controlled trial (RCT) with a larger number of patients is required.

In addition, we analyzed the changes in the FRAX score after denosumab treatment. Naylor et al. [23] suggested that FRAX showed modest fracture prediction in KTRs, similar to that in the general population. Malakoutian et al. [24] suggested that the FRAX score could be used as a supplementary factor for treatment decision-making in KTRs. However, Velioglu et al. [25] suggested that assessing fracture risk in KTRs requires more longitudinal studies to validate the value of FRAX because this tool was developed for the general population and females over the age of 50 years, which may not be applicable to the KTRs population. In our study, the median 10-year probability of hip fracture, based only on the FRAX score, significantly decreased after denosumab treatment and was not a major osteoporotic fracture. These results suggest that the FRAX score could be used as an alternative for fracture risk assessment in KTRs. There were three cases of de novo fractures in our clinical outcomes. In the subgroup analysis, only patients who were not treated with calcium/vitamin D experienced fractures, and the number of de novo fractures in the female group was slightly higher than in the male group. However, the sample size was too small for statistical significance. Therefore, large-scale studies are required to verify this risk.

One of the most common adverse events mentioned in previous clinical trials of denosumab is infection [26]. Theoretically, as RANKL activation plays an important role in lymphocyte development, it makes sense that denosumab may increase the risk of infection [27]. In our study, we observed 17 cases of UTIs. As a result, the risk of infection seemed to show an increasing trend in subjects who received denosumab in our study. A study conducted by Bonani et al. [28] in 2017 suggested that using denosumab may increase the prevalence of UTIs to KTRs (24 patients vs. 11 patients; odds ratio [OR], 3.3 [95% CI, 1.3–8.0]; p = 0.008). However, our study did not show statistical significance. Therefore, although it may not be statistically significant, we can infer that monitoring the occurrence of infection is important for patients treated with denosumab, and large-scale studies are necessary to verify the risk. In addition, by analyzing the subgroups in our study, we found that only female patients had UTIs, which was statistically significant (p = 0.01). A meta-analysis conducted by Hosseinpour et al. [29] about risk factors of UTI for KTRs stated that sex plays an important role as a risk factor for UTIs in the general population (OR, 3.13 [95% Cl, 2.35–4.17]; p = 0.001). However, no study has compared the risk of using denosumab in KTRs according to sex; female KTRs using denosumab may have a higher possibility of UTIs and require careful monitoring to prevent them.

Another adverse event that has been persistently reported since the initiation of denosumab treatment for osteoporosis is denosumab-induced hypocalcemia. As denosumab-mediated bone resorption results in reduced calcium mobilization, the use of denosumab is believed to increase the risk of hypocalcemia, especially in patients with underlying BMD [26]. In our study, there were eight cases of hypocalcemic events after denosumab administration, but no statistical significance was found. In addition, the subgroup analysis according to calcium/vitamin D use and sex showed no statistical significance. There is no consensus on whether denosumab-induced hypocalcemia occurs more frequently in KTRs. Cianciolo et al. [30] reported that denosumab-induced hypocalcemia in KTRs increased only when the severity of osteoporosis increased. However, Tsai et al. [31] suggested a higher risk of hypocalcemia when using denosumab in KTRs. Further research is required to understand the relationship between denosumab-induced hypocalcemia and KTRs.

The other clinical outcomes evaluated in our study included cardiovascular events and arthralgia. Three patients had cardiovascular events and four patients complained of arthralgia in our study. In the subgroup analysis, the female group showed a higher incidence of cardiovascular events and arthralgia; however, the difference was not statistically significant. Denosumab, which inhibits the RANKL pathway, can influence vascular calcification and increase the risk of cardiovascular disease. Seeto et al. [32] suggested that denosumab might exceed the cardiovascular risk compared with bisphosphonates but not placebo in postmenopausal women. However, a study conducted by Lv et al. [33] suggested that denosumab therapy was not associated with any risk of cardiovascular outcomes. Owing to the lack of studies on KTRs, further studies are required to verify whether denosumab influences the risk of cardiovascular diseases. Regarding arthralgic risk, Aw and Walsh [34] reported flares of inflammatory arthritis following denosumab therapy, and Rhee et al. [35] showed that arthralgia is a frequent adverse event that occurs in the general population when treated with denosumab. However, no study has investigated the risk of arthralgia in KTRs and further trials are needed to verify this risk.

In our study, no cases of acute kidney injury or graft failure were observed in the patients treated with denosumab during follow-up. Denosumab is metabolized into amino acids and peptides by hepatic metabolism rather than by the kidneys [36]. Thus, there is a low risk of oversuppression of bone turnover due to drug accumulation in patients with low allograft function and a low risk of damaging graft function.

Although our study produced positive results, it has some limitations that must be considered. First, our study was retrospective and single-center based, which means that we were unable to control for all factors that might have influenced the results. Because osteoporosis is more common in females than males, the number of female patients in our study was approximately three times greater than the number of male patients. It is well known that sex is a significant risk factor for UTIs after KT [25,29]; therefore, the sex distribution of our study participants may have influenced the results. To determine whether the propensity of denosumab to increase infection varies according to sex, additional multicenter studies are required. Another limitation is that we administered denosumab along with calcium/vitamin D to patients based on clinical experience rather than definite criteria. The other limitation of our study was its relatively short retrospective follow-up duration. Three patients developed acute rejection within 1 year after denosumab developed in three patients, and there were no cases of graft failure or patient death. Because our follow-up duration may not have been long enough to determine whether denosumab directly influenced the risk of rejection or graft failure, studies with longer durations are needed to confirm these findings.

While our study has limitations as a small retrospective study, we believe that it is significant for obtaining positive results from pure KTRs with osteoporosis. Based on our results, it is reasonable to consider denosumab a good treatment option for osteoporosis because of its efficacy and safety. Although a few adverse effects, such as UTI, may occur during the use of denosumab, we believe that the incidence is low and should not be a reason to avoid its use. To use denosumab more effectively, careful monitoring of complications is essential during treatment and follow-up. Moreover, more studies, such as RCTs with eligible subjects and long-term follow-up durations, are needed in the future for further evaluation.