Hemoglobin A1c Threshold for Reduction in Bone Turnover in Men With Type 2 Diabetes Mellitus

Abstract

Background: Emerging data suggest that type 2 diabetes mellitus (T2D) is associated with an increased risk for fractures despite relatively normal or increased bone mineral density (BMD). Although the mechanism for bone fragility in T2D patients is multifactorial, whether glycemic control is important in generating this impairment in bone metabolism remains unclear. The purpose of our study is to identify a hemoglobin A1c (A1c) threshold level by which reduction in bone turnover begins in men with T2D.

Method: A cross-sectional analysis of baseline data was obtained from 217 men, ages 35-65, regardless of the presence or absence of hypogonadism or T2D, who participated in 2 clinical trials. The following data were obtained: A1c by HPLC, testosterone and estradiol by LC/MS, bone turnover markers Osteocalcin [OC], C-terminal telopeptide [CTx], and sclerostin by ELISA, and BMD by DXA. Patients were grouped into 4 categories based of A1c (group I: <6%, group II: 6.0-6.4%, group III: 6.5-6.9%, and group IV: ≥7%). Threshold models were fit to the data using nonlinear regression and group comparisons among the different A1c categories performed by ANOVA.

Results: Threshold model and nonlinear regression showed an A1c cut-off of 7.0, among all choices of A1cs, yields the least sum of squared errors. A comparison of bone turnover markers revealed relatively lower OC (p = 0.002) and CTx (p = 0.0002) in group IV (A1c ≥7%), compared to the other groups. An analysis of men with T2D (n = 94) showed relatively lower OC (p=0.001) and CTx (p=0.002) in those with A1c ≥7% compared to those with <7%, respectively. The significance between groups persisted even after adjusting for medications and duration of diabetes.

Conclusion: An analysis across our entire study population showed a breakpoint A1c level of 7% or greater is associated with lower bone turnover. Also in men with T2D, an A1c ≥7% is associated with low bone turnover.

Trial registration: ClinicalTrials.gov NCT01378299 NCT03490513.

Keywords: CTX; Hemoglobin A1c; bone turnover markers; osteocalcin; type 2 diabetes mellitus.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Joad, Ballato, Deepika, Gregori, Fleires-Gutierrez, Colleluori, Aguirre, Chen, Russo, Fuenmayor Lopez, Qualls, Villareal and Armamento-Villareal.

Figures

Figure 1

(A) Threshold model of Osteocalcin versus Hemoglobin A1c by nonlinear regression (multiple correlation r=0.31, p<0.001) with least squares fitted (optimal) threshold A1c=7.0. Model Osteocalcin values= 6.57 for A1c< 7.0 and 3.86 for A1c ≥ 7.0. The threshold model is statistically significant compared to a null hypothesis of no threshold (P<0.001). (B) Threshold model of C-telopeptide versus Hemoglobin A1c by nonlinear regression (multiple correlation r=0.31, p<0.001 with least squares fitted (optimal) threshold A1c=7.0. Model C-telopeptide values= 0.311 for A1c < 7.0 and 0.182 for A1c ≥ 7.0. The threshold model is statistically significant compared to a null hypothesis of no threshold (p<0.001).

Figure 2

(A) Osteocalcin (OC) in group IV (A1c<7%), compared to groups with A1cs ≥7%, i.e. I II, and III (4.04 ± 2.64 vs 6.53 ± 3.18, 5.99 ± 3.16 and 6.09 ± 3.16 ng/mL, respectively, p = 0.002). (B) C-telopeptide (CTx) was lower in group IV compared to groups I, II, and III (0.1 9 ± 0.12 ng/mL vs 0.34 ± 0.17, 0.32 ± 0.18 and 0.28 ± 0.14 ng/mL, respectively, p=0.0002). *Post-hoc analysis: p<0.05 showed significant difference in OC and CTx in group IV compared group I, II and III.

Figure 3

(A) Analysis of the subgroup of men with T2D (n=94) showing lower Osteocalcin (3.95 ± 2.68 vs. 6.34 ± 2.77, p=0.001) and (B) showing lower C-telopeptide (0.18 ± 0.13 vs. 0.31 ± 0.15, p=0.002) in those with A1c ≥7% compared to those ≤7%, respectively.