Improving Bone Health in Type 1 Diabetes and Chronic Kidney Disease: The Overlooked Benefit of Simultaneous Pancreas-Kidney Transplantation

Type 1 diabetes (T1D) is traditionally associated with microvascular and macrovascular complications; however, other comorbidities are often underrecognized in routine clinical practice. Among these, bone health deserves particular attention, as individuals with T1D have been reported to exhibit up to a 6-fold higher risk of hip fractures compared with those without diabetes. Moreover, these fractures tend to occur 10–15 y earlier than in the general population.1 In addition to longer diabetes duration, suboptimal glycemic control or hypoglycemic episodes, microvascular complications are also important risk factors for bone metabolism impairment in this population.1 Among these, chronic kidney disease (CKD) stands out as a major contributor. Bone health is profoundly compromised in individuals with CKD alone2; however, the coexistence of T1D and CKD appears to exert an especially deleterious effect. Recent studies in patients with T1D awaiting simultaneous pancreas-kidney transplantation (SPKT) indicate that >80% present with low bone mineral density (BMD), despite a median age of only 40 y.3 Pancreas transplantation is associated with marked benefits in reducing long-term diabetes complications and improving survival outcomes.4,5 Nevertheless, evidence on its impact on nonclassical complications of T1D, such as bone health, remains scarce. Existing studies are often limited by small sample sizes and substantial heterogeneity.6,7 In this issue of Transplantation, Kratochvílová et al report findings from a retrospective, single-center, intraindividual comparison study in patients with T1D and CKD stage G4–5 undergoing SPKT, with a particular focus on changes in dual-energy X-ray absorptiometry during both the pre- and posttransplant periods.8 After excluding patients with a short waiting time, early pancreas graft failure, or treatment with bisphosphonates or denosumab during the study period, the authors ultimately included a relatively homogeneous cohort of 48 individuals. In addition to its intraindividual design, which minimizes between-patient variability, 1 of the main strengths of the study is the use of a standardized corticosteroid-sparing immunosuppressive protocol, with prednisone administered only during the first 4 wk post-SPKT—a drug known for its deleterious effects on bone metabolism. Overall, they found that after the pretransplant period was marked by a decline in BMD at several sites—particularly the femoral neck—and in trabecular bone score (TBS), after SPKT lumbar spine BMD increased (+0.039 g/cm²/y), TBS improved (+0.019/y), and the decline at the femoral neck stabilized. However, the decrease in distal radius BMD persisted. These findings suggest a reassuring effect of SPKT on bone health, especially in weight-bearing regions and trabecular bone. Nevertheless, dual-energy X-ray absorptiometry–derived advanced hip analysis, which has been associated with fracture risk after kidney transplantation and SPKT,9 showed no significant changes in this study. Several aspects of this study merit discussion. First, the corticosteroid-sparing immunosuppressive protocol used,8 although shorter than those commonly reported in the literature7 and potentially advantageous for bone health, was not applied to a significant proportion of patients (10/48) due to intolerance to maintenance immunosuppression. Additionally, up to 12 patients required methylprednisolone pulses to manage rejection episodes. Corticosteroid exposure has been consistently linked to both an increased risk of fractures after transplantation7 and reductions in BMD (total hip: −0.0235 g/cm²; P = 0.028 for prolonged corticosteroid use; −0.0230 g/cm²; P = 0.014 for methylprednisolone pulses, as reported by Kratochvílová et al8). Given the widespread use of corticosteroids in individuals undergoing SPKT, future research should focus on clarifying their specific impact on bone health in this population and on developing optimal therapeutic strategies to counteract their adverse effects. Second, it is well established that in individuals with T1D, reductions in BMD alone do not account for the disproportionate increase in fracture risk. Instead, alterations in bone microarchitecture are considered an important contributing factor.1,10 Although TBS may partially address this limitation, advanced imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) could provide further insights. Recent studies using the Epidemiology of Diabetes Interventions and Complications subcohort (n = 183) compared with individuals without diabetes (n = 94) have demonstrated deficits in both trabecular and cortical bone microstructure using HR-pQCT analysis.10 Moreover, these alterations were correlated with established fracture risk factors in this population, including hemoglobin A1c, advanced glycation end products, and microvascular complications (retinopathy, kidney disease, and neuropathy), reinforcing the clinical relevance of these findings.10 Future research should also explore HR-pQCT-derived changes to improve fracture risk assessment after SPKT. Finally, beyond imaging techniques, and considering the disproportionate fracture risk observed in individuals with T1D, future research should prioritize hard outcomes in bone health after SPKT, particularly fracture incidence. In this regard, the study by Kratochvílová et al8 reported only 4 fractures, without accounting for asymptomatic vertebral fractures, and previous studies6,7 have similarly documented a limited number of events. Greater efforts are needed to collect larger data sets of clinically relevant fractures to better address the ultimate goal of bone health research: preventing fractures that significantly compromise patients’ quality of life. In summary, although further mechanistic studies are warranted, Kratochvílová et al8 reinforced previous evidence suggesting that SPKT may improve bone health in a population at particularly high risk, such as individuals with T1D and CKD, especially when corticosteroid-sparing immunosuppressive protocols are used. These findings contribute to growing evidence that targeted interventions can mitigate diabetes-related complications beyond the classical micro- and macrovascular domains. Moreover, although bone health has not traditionally been incorporated into pre- and posttransplant evaluations for SPKT, the insights from this study may prompt revisions to current protocols. Given that fractures significantly increase morbidity and mortality in this already high-risk population, systematic fracture risk assessment should become an integral part of the management of patients after SPKT.