While patients with type 2 diabetes (T2D) are at significant risk for well recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to non-diabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone “quality”). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50–80 yrs) including 30 patients diagnosed with T2D for >10 yrs and 30 age-matched, non-diabetic controls. Regional BMD was measured by DXA; cortical and trabecular bone microarchitecture was assessed from HRpQCT images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (−11.7%; p<0.001); following adjustment for BMI (−10.5%; p<0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (−9.2%; p=0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p<0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 yrs was negatively correlated with BMS (r = −0.41; p=0.026). In conclusion, these findings represent the first demonstration of compromised bone material strength in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications.

This research was supported by the NIH (AG004875 and AR027065) and a Mayo Clinic Clinical and Translational Science Award (CTSA) (UL1 TR002377).

Background: Several studies reported high prevalence of bone disease (osteoporosis/osteopenia) in patients with mild autonomous cortisol secretion (MACS), discordant to the degree of bone density deterioration. Bone turnover marker (BTM) measurements can potentially elucidate the underlying mechanism of MACS-related bone disease. Objective: To describe the relationship between BTMs and glucocorticoid autonomy in patients with adrenal adenomas Methods: Patients were prospectively enrolled from adrenal clinics over 3 years. Inclusion criteria were adults with adrenal adenomas diagnosed with nonfunctioning adrenal tumor (NFAT), MACS (based on cortisol after 1 mg dexamethasone suppression, DST>1.8 mcg/dl) or overt Cushing syndrome (CS). Exclusion criteria were malignancy, exogenous steroid use, bone disease from other causes or receiving therapy for osteoporosis. Osteocalcin, Procollagen I Intact N-Terminal (PINP), C-terminal telopeptide (CTX), and Sclerostin were measured blinded to diagnosis. Ten patients had paired measurements of BTMs before and after adrenalectomy (2 CS, 5 MACS, 3 NFAT). Results: Of 213 patients with adrenal adenomas, CS was diagnosed in 22, MACS in 92 (median DST of 3mcg/dl [1.9-16]) and NFAT in 99, (median DST of 1.2mcg/dl [0.9-1.8]). Median age was 58 years (range, 18-93), 67% were women, median BMI was 31 kg/m 2 (range, 15-53) and median tumor size was 2.5 cm (range, 0.5-14.4). Bone disease was diagnosed in 41% vs 42% vs 23% ( P =0.001), osteoporosis in 18% vs 13% vs 6% ( P =0.1) and osteopenia in 23% vs 29% vs 17% ( P =0.13) of patients with CS, MACS and NFAT, respectively. DST > 1.8 mcg/dl was a significant predictor of bone disease after adjusting for age, sex, and BMI (OR 2.7, P =0.006). Severity of cortisol excess was inversely associated with BTM values; for CS vs MACS vs NFAT: Osteocalcin (median 10 [2.2-80] vs 17 [5-54] vs 19 [2-79] ng/mL ( P <0.0001)), PINP (median 29 [12-92] vs 43 [13-123] vs 46 [3-152] µg/L ( P =0.003)) and Sclerostin (median 381 [73-935] vs 498 [111-2000] vs 571 [202-1273] ng/L , ( P <0.0001)). In MACS patients, Sclerostin was a significant predictor of bone disease in a multivariable model of age, sex, BMI, DST cortisol and BTMs (OR 0.77 [CI95% 0.6-0.99] for each 100 ng/L of sclerostin increase, P =0.03). In 10 patients with available BTM measurements after adrenalectomy, Osteocalcin and CTX increased significantly by mean difference of 11.01 ng/mL ( SEM =3.63, P = 0.001) and 0.17 ng/mL ( SEM = 0.08, P =0.03), respectively. Conclusion: DST>1.8 mcg/dL significantly predicts bone disease in patients with adrenal adenomas. Sclerostin (secreted...

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