Acromegaly is frequently complicated by fragility vertebral fractures and diabetes mellitus. Since type 2 diabetes mellitus is a cause of secondary osteoporosis in the general population, in this cross-sectional study we aimed at investigating the association between diabetes mellitus and vertebral fractures in males with acromegaly. Fifty-seven patients (median age 47 years, range: 24-85) with active (21 cases) and controlled (36 cases) acromegaly and 57 control subjects were evaluated for bone mineral density (BMD) by DXA and vertebral fractures by a quantitative morphometric analysis. Diabetes mellitus was found in 18 patients and 18 control subjects. The prevalence of vertebral fractures was higher in acromegalic patients as compared with the control subjects (50.9 vs. 10.5%; χ(2): 21.8; P < 0.001). Acromegalic patients with fractures had serum IGF-I values significantly higher (P = 0.009), longer duration of active disease (P < 0.001) and higher prevalence of active acromegaly (P = 0.007) and diabetes mellitus (P = 0.04) as compared to patients who did not fracture. When acromegaly was active, the prevalence of vertebral fractures was high independently of the coexistent diabetes mellitus. On the contrary, when acromegaly was controlled the prevalence of vertebral fractures was significantly higher in patients with diabetes as compared to patients without diabetes (62.6 vs. 28.0%; P = 0.04). In both diabetic and non diabetic patients, vertebral fractures occurred independently of BMD. In conclusion, this study suggests that diabetes mellitus may be associated with an increased prevalence of vertebral fractures in males with acromegaly. However, this effect seems to be relatively attenuated in the presence of persistent GH hypersecretion.