Breast cancer is the third most common cancer in the world, and in 65% to 75% of patients, with progressive disease, bone metastases are common. The balance between RANKL and OPG regulates the process of bone resorption, and the disruption of this balance is observed in many cancers, including breast cancer. Also, SNPs in the genes of RANK, RANKL and OPG are possibly associated with functional alterations and breast cancer risk. The aim of the present study was to estimate the serum levels of RANKL and OPG and detect the polymorphisms of RANKL (-643T/C), and OPG (-1181G/C) and OPG (-950T/C) in breast cancer patients (with and without metastasis) as well as in fibro-adenoma patients and healthy controls. The present study was conducted on one hundred and fifty three subjects; group I (n=25) healthy female donors as a control group, group II (n=40) fibro-adenoma patients, group III (n=48) breast cancer patients without bone metastases and group IV (n=40) breast cancer patients with bone metastases. The serum levels of RANKL showed a significant increase in bone metastatic breast cancer patients compared to non-metastatic breast cancer patients, fibro-adenoma patients and also the control subjects. Using the ROC curve for RANKL in detection of bone metastatic breast cancer patients from breast cancer patients gave 100% sensitivity and 88.6% specificity. A significant increase in OPG levels were found in bone metastasis breast cancer patients compared to the non-metastatic breast cancer, fibro-adenoma patients and control subjects. The ROC curve of OPG calculated for detection of the bone metastatic breast cancer from the non-metastatic breast cancer patients, showed 94.4% sensitivity and 100% specificity. Regarding the study of SNPs, both RANKL (-643 T/C) and OPG (-950 T/C) revealed that the mutant C allele may play a major role as a genetic safe guard against disease progression in patients with breast cancer and bone metastasis, while in the OPG (-1181 G/C) the mutant allele C was associated with the increased risk of fibro-adenoma development, breast cancer pathogenesis and cancer bone metastasis.