The aim of this study was to determine the prevalence of known gene polymorphisms associated with osteoporosis in postmenopausal normal women from Burkina Faso and Sicily, compared to postmenopausal Sicilian women with osteoporosis, and to establish the weight of environmental factors in the mechanism of osteoporosis. Bone mass density (BMD) was measured by phalangeal quantitative ultrasound (QUS) in Burkinabe woman and by the dual X-ray absorptiometry at the femoral neck in Sicilian women. The polymorphisms of the vitamin D receptor (VDR) gene, estrogen receptor (ESR) gene, calcitonin receptor (CTR) gene and COL1A1 collagen gene were characterized by PCR. The social characteristics of studied women were evaluated by a specific questionnaire. The observed percentages of single specific polymorphisms did not differ from that expected with exception of VDR B allele and ESR X and P allele in Burkinabe and Sicilian women, respectively. Association analyses and multivariate two-step regression model of social and molecular parameters, demonstrated that in comparison to the VDR, ESR, CTR polymorphisms, physical activities and healthy diet, associated with outdoor work are the best favourable prognostic factors for osteoporosis. A diet rich in calcium, other minerals and vitamin D in association with physical activity represents the most effective way to maintain not only a healthy bone structure but also an acceptable BMD. This is particularly true for Sub-Saharan women.