Osteoporosis is a common skeletal disease characterized by a combination of low bone mass and increased fragility. In this case-control study, we investigated the possible association of two novel candidate genes, CER1 and TOB1, with bone mineral density (BMD) and fragility risk in 300 postmenopausal women of Hellenic origin. The entire CER1 and TOB1 gene sequences were amplified and resequenced to assess whether there is a correlation between these genes and BMD. We identified 26 variants in both genes. Statistical analysis did not reveal any correlation between TOB1 and osteoporosis. However, CER1 genetic analysis indicated that five polymorphisms, c.194C>G, c.507+506G>T, c.508-182A>G, c.531A>G, and c.*121T>C, were correlated, with a mean T score ≤-2.2. In particular, the greater number of vertebral fractures was found in patients with osteoporosis carrying the G allele of c.531A>G SNP (p = 0.015). When multiple logistic regression analysis was performed, only the c.507+506G>T polymorphism was independently associated with hip fractures or the presence of any fracture (OR = 6.95, p = 0.016, and OR = 5.33, p < 0.001, respectively). These results suggest that CER1 gene variations play a significant role in determining BMD and vertebral or hip fractures, which might be helpful in clinical practice to identify patients with increased fracture risk.