We read with great interest the recent study by Maddaloni et al. (1), published in Diabetes Care, which provides valuable insights into the potential role of bone metabolism markers in predicting cardiovascular risk among patients with type 2 diabetes. However, we believe that addressing certain limitations and expanding on key aspects could further enhance these findings' impact and clinical applicability.
First, the representativeness and generalizability of the results warrant further discussion. While the authors acknowledge that the study included only a subset of the EXSCEL (Exenatide Study of Cardiovascular Event Lowering) trial population (1), a more detailed comparison of the baseline characteristics between this subset and the overall population would help readers better understand the limitations of extrapolating the results. Future research should also consider the selection of study populations to ensure broader applicability of the findings.
Second, standardization of bone metabolism marker measurements is crucial for clinical implementation (2). The authors should provide more information on the principles, reliability, and limitations of the SomaScan technology used to measure relative concentrations of bone markers. Discussing the differences between this technology and conventional clinical detection methods and their potential impact on the results would be beneficial. We also encourage the authors to report the coefficients of variation for each bone marker and assess intra- and interassay reproducibility to demonstrate the robustness of the detection method. Establishing standardized operating procedures and quality control standards for bone marker measurements is essential for translating research findings into clinical practice.
Third, potential unmeasured confounding factors should be further addressed. The authors could expand on how bone mineral density, fracture history, and vitamin D levels influence the observed associations. For special populations, such as those receiving bone metabolism–related medications, subgroup analyses could help clarify the impact of drug interventions on the relationship between bone markers and cardiovascular risk (3). Suggestions for optimizing study designs to improve the reliability of the results would be valuable for future research.
Lastly, the nonlinear relationship between osteocalcin levels and mortality risk deserves further exploration. The authors should delve into the potential mechanisms underlying this relationship and propose strategies for future studies to elucidate it further (4). Analyzing the association between dynamic changes in osteocalcin levels and prognosis could provide additional insights for clinical monitoring and intervention (1,5). Prospective studies are needed to systematically evaluate the optimal cut-off values for interpreting osteocalcin levels based on patient characteristics and disease spectrum, ultimately leading to the development of practical clinical application guidelines.
In conclusion, this well-conducted study by Maddaloni et al. contributes significantly to our understanding of the role of bone metabolism markers in cardiovascular risk prediction among patients with type 2 diabetes. By addressing the limitations and expanding on the key aspects discussed above, future research can further enhance the clinical value of these findings and advance the field of precision medicine in preventing and treating cardiovascular complications in diabetes.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Steven E. Kahn and Vanita R. Aroda.
