[5][6] RANKL is known as a type II membrane protein and is a member of the tumor necrosis factor (TNF) superfamily.

RANKL is an apoptosis regulator gene, a binding partner of osteoprotegerin (OPG), a ligand for the receptor RANK and controls cell proliferation by modifying protein levels of Id4, Id2 and cyclin D1.

Low protein expression is found in bone marrow, the stomach, peripheral blood, the spleen, the placenta, leukocytes, the heart, the thyroid, and skeletal muscle.

This surface-bound molecule (also known as CD254), found on osteoblasts, serves to activate osteoclasts, which are critically involved in bone resorption.

[10][11][12][13] RANKL derived from other cell types contributes to bone loss in conditions involving inflammation such as rheumatoid arthritis, and in lytic lesions caused by cancer, such as in multiple myeloma.

[15] RANKL’s extracellular domains are similar to other TNF family members in regards to the structural homology and are able to cleave from the cell surface.

It binds to RANK on cells of the myeloid lineage and functions as a key factor for osteoclast differentiation and activation.

Deficient mice, with an inactivation of RANKL or its receptor RANK, exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy.

[9][17] It was observed that during pregnancy, RANK-RANKL signaling played a critical role in regulating skeletal calcium release; in which contributed to the hormone response that stimulated proliferation in the mammary cells.

Some studies suggest the expression of RANKL allows sufficient micro environmental conditions to influence cancer cell migration (i.e. chronic lymphocytic leukemia (CLL) and multiple myeloma).

Some examples of these complications that are a consequence of bone metastasis are: hypercalcemia, pathological fractures and spinal cord compression.

[21] Denosumab is an FDA-approved fully human monoclonal antibody to RANKL and during pre-clinical trials was first used to treat postmenopausal patients suffering with osteoporosis (PMO).

[21] Hormone receptor positive breast cancer patients have a significant increased risk of complications such as osteopenia and osteoporosis.

[25] In the past several years, denosumab has been used in clinical trials, primarily because a large population is affected by bone complication among those who have breast cancer.

[20][21] In a stage II clinical trial, denosumab decreased bone turnover markers by blocking the RANKL/RANK pathway.

[21] In both breast and prostate cancers, patients in either denosumab or zoledronic acid groups both appeared to have comparable adverse events and survival rates.

[29] Medroxyprogesterone acetate (MPA) is a synthetic progestin and was commonly used as a contraceptive or used as a hormone therapy for endometriosis or osteoporosis.