MON-797 - Hyperglycemia, Not Obesity, Accounts for Reduced Bone Turnover in Type 2 Diabetes

Patients with type 2 diabetes mellitus (T2D) have elevated fracture risk despite normal or increased bone mineral density (BMD), but the mechanisms underlying this risk are only partially understood. This effect is confounded by the frequent co-occurrence and interrelationship of T2D with obesity, with higher body weight providing a larger mechanical load to the skeleton and tending to increase BMD. Previous studies have suggested that T2D is a low-turnover state, but no studies have distinguished the relative contributions of T2D and obesity to this low-turnover state in postmenopausal (PM) women.
Thus, we measured bone turnover markers in a cohort of PM women with T2D (n = 27, age 66.7 [62.8–71.4], 96.3% White, BMI 36.6 [34.1–38.5] kg/m2, A1c 7.6 [7.2–8.0]%) compared to a cohort of BMI-matched women with obesity but not T2D (n = 29, age 64.7 [59.8–73.7], 96.6% White, BMI 34.7 [32.0–40.0] kg/m2, A1c 5.5 [5.4–5.6]%) as well as a lean, nondiabetic control cohort (n = 37, age 70.1 [63.0–72.2], 97.3% White, BMI 22.7 [21.6–23.7] kg/m2, A1c 5.4 [5.2–5.6]%). Women with T2DM and with obesity alone had significantly higher BMD by dual-energy X-ray absorptiometry at all standard sites compared to their lean counterparts. The same pattern held true for bone parameters measured by high-resolution peripheral quantitative computed tomography. The only significantly different skeletal parameter between the T2D and obese groups was a higher total hip bone density in the T2D group (1.045 [1.13–1.51] vs. 0.971 [0.925–1.064] g/cm2, P < 0.05).
However, when bone turnover markers were measured, women with T2D were significantly different from either of the other groups. Women with T2D had significantly lower C-terminal telopeptide of type I collagen (CTx) and type I N-terminal propeptide (P1NP) compared to lean controls (CTx: 340 [142] pg/mL vs. 596 [207] pg/mL; P1NP: 35.8 [9.1] μg/L vs. 52.4 [13.4] μg/L; expressed as mean [SD], both P < 0.001) and compared to women with obesity alone (CTx: 520 [258] pg/mL, P = 0.004; P1NP: 47.1 [14.8] μg/L, P = 0.006), indicating significantly reduced bone resorption and bone formation, respectively. In contrast, there was not a significant difference in CTx or P1NP between women with obesity alone and lean controls. The inverse pattern was seen in levels of circulating sclerostin. Women with T2D had significantly higher levels of sclerostin (94.3 [22.5] pM) than either women with obesity alone (77.4 [13.3] pM, P = 0.015) or lean controls (78.2 [18.5] pM, P = 0.009). Thus, the higher fracture risk despite normal/high BMD observed in patients with T2D may at least in part be due to a low-turnover state which is associated with hyperglycemia itself and not comorbid obesity. To our knowledge, this is the first study to differentiate the skeletal effects of hyperglycemia and obesity in PM women with T2D. Additional studies are needed to validate these findings in a larger and more diverse population.

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