Acromegaly is considered an important cause of secondary osteoporosis. However, studies on bone mineral density (BMD) have yielded conflicting results and there are few studies that evaluate an accurate imaging method for early diagnosis of osteoporosis in these patients. The objective of this study was to assess whether entropy and uniformity on computed tomography (CT) scans are useful parameters for optimization of assessment of bone fragility in patients with acromegaly. We included 34 patients and 36 controls matched for age and sex in a cross-sectional study. Patients and controls underwent CT scan of the lumbosacral spine, dual-energy x-ray absorptiometry (DXA) and blood tests. A software was developed to calculate the entropy and uniformity by a region of interest (ROI) of the trabecular bone of the first lumbar vertebra (L1). The acromegalic group presented higher mean bone entropy (6.87 ± 0.98 vs. 6.03 ± 1.68, p = 0.013) and lower mean bone uniformity (0.035 ± 0.704 vs. 0.113 ± 0.205, p = 0.035) than control group. Analyzing only acromegalics, mean bone entropy was higher and bone uniformity was lower in patients with hypogonadism than patients without hypogonadism (7.28 ± 0.36 vs. 6.74 ± 1.08, p = 0.038 and 0.008 ± 0.002 vs. 0.043 ± 0.079, p = 0.031) respectively. Patients with acromegaly presented higher BMD and Z-score in the femoral neck than control group (1.156 ± 0.108 vs. 0.925 ± 0.326 g/cm2, p = 0.043 and 0.6 ± 0.6 vs. -0.05 ± 0.8, p = 0.041, respectively). Entropy was negatively correlated with T-score of the lumbar spine (rp = -0.357, p = 0.033) in control group and uniformity was positively correlated with T-score of the lumbar spine, neck, and total hip, respectively (rp = 0.371, p = 0.031; rp = 0.348, p = 0.043 and rp = 0.341, p = 0.049) in acromegalic group. The study identified that entropy and uniformity are a relevant parameters data in bone fragility assessment in acromegalic patients.