Hemoglobin A1c of 7% is the Threshold For Bone Impairment in Men With Type 2 Diabetes Mellitus
Authors: Joad Sabaa Salim , Gregori Giulia , Russo Vittoria , Aguirre Lina E , Colleluori Georgia , Chen Rui , Vigevano Francesca , Villareal Dennis Tan , Qualls Clifford , Villareal Reina Condevillamar 
Published: May 2021

Abstract
Background: Emerging data suggest that type 2 diabetes mellitus (T2DM) is associated with increased risk for fractures despite relatively normal or increased bone mineral density (BMD). Furthermore, it is now known that decreased bone turnover mainly due to reduced bone formation is the hallmark for bone disease in T2DM. Whether glucose control is important in generating this impairment in bone metabolism remains unknown and to what extent it would reflect this abnormality is undetermined. The purpose of our study is to identify Hemoglobin A1c (A1c) level threshold by which reduction in bone turnover begins. Method: Baseline data from 217 men between age of 35–65 who were participants in 2 clinical trials conducted at the Michael DeBakey VA Medical Center and the New Mexico VA Health Care System were analyzed. A1c was measured by high performance liquid chromatography, testosterone and estradiol measured by liquid chromatography/mass spectrometry (LC/MS). Bone turnover markers (Osteocalcin [OC],C-telopeptide of type 1 Collagen [CTx]) and sclerostin were measured by enzyme-linked immunosorbent assay. Bone mineral density was assessed by dual energy X-ray absorptiometry. Patients were grouped into 4 categories based of A1c values (%) (group 1:&lt;6, group 2:6.1–6.5, group 3: 6.6–7 and group 4: &gt;7). Simple correlations were assessed by simple regression analysis and group comparisons among the different A1c categories were performed by analysis of variance (ANOVA). Results: The mean age of the participants was 55±9 years old with mean BMI of 36.15±6.44 kg/m2. Participants mean A1c was 6.1±1.5%. Simple correlation analysis showed a significant negative correlation between A1C and OC (r=-0.32, p&lt;0.001) and CTx (r=-0.32, p&lt;0.001). Comparison of bone turn over markers among different A1c groups revealed significantly lower OC in group 4 (A1C&gt;7%), compared to groups with A1Cs ≤7%, i.e. 1, 2 and 3 (4.04 ± 2.64 vs 6.53 ± 3.18, 5.99 ± 3.16 and 6.09 ± 3.16 ng/mL, respectively, p = 0.002). Similarly, CTx was lower in group 4 compared to groups 1, 2, and 3 (0.19 ± 0.12 ng/mL vs 0.34 ± 0.17, 0.32 ± 0.18 and 0.28 ± 0.14 ng/mL, respectively, p=0.0002). Sclerostin levels were comparable among all the A1c categories. Analysis of the subgroup of men with T2DM (n=71) again showed lower OC (3.95 ± 2.68 vs. 6.34 ± 2.77, p=0.007) and CTx (0.18 ± 0.13 vs. 0.31 ± 0.15, p&lt;0.001) in those with A1c &gt;7% compared to those ≤7%, respectively. The significance between the groups persisted even after adjusting for medications, p=0.003. Analysis adjusted for baseline age, weight and testosterone showed no significant difference in areal BMD at all sites in the general population and in the subset of men with T2DM according to A1C categories. Conclusion: Our data analysis showed breakpoint A1c level of 7% or greater is associated with lower bone turnover irrespective of medication use in patients with T2DM.