[7] OPG has been identified as having a role in tumour growth and metastasis,[6] heart disease,[8][9][10] immune system development and signalling,[7] mental health,[11] diabetes,[12] and the prevention of pre-eclampsia[13] and osteoporosis during pregnancy.

[17] As a monomer, OPG would have insufficient affinity for RANKL to compete with RANK and effectively suppress RANK-RANKL interactions.

[21][25] E2 transcriptionally regulates OPG expression through binding estrogen receptors (predominantly ER-α) on osteoblast lineage cell surfaces.

[26] Estrogen binds its ER-β receptor on the cell surface to suppress many miRNAs, including miR-145,[27] thus blocking inhibition of OPG mRNA translation.

[5] OPG has also been shown to bind and inhibit TNF-related apoptosis-inducing ligand (TRAIL) which is responsible for inducing apoptosis in tumour, infected and mutated cells.

[31] As a decoy receptor for RANKL, OPG inhibits RANK-RANKL interactions thus suppressing osteoclastogenesis and bone resorption.

A normal steady state of bone metabolism seems to be present in patients with atrophic nonunion fractures, despite the high serum OPG.

[39] Osteoporosis is often triggered in post-menopausal women due to reduced estrogen levels associated with the depletion of hormone-releasing ovarian follicles.

[21][26] Decreased estrogen is a common cause of osteoporosis that can be seen in other conditions such as ovariectomy, ovarian failure, anorexia, and hyperprolactinaemia.

[44] These cytokines act on osteoblasts to increase RANKL and decrease OPG expression resulting in excess bone resorption.

[44] During resorption osteoclasts release nutrients such as growth factors and calcium from the mineralised bone matrix which cultivates a supportive environment for the proliferation and survival of tumour cells.

[44] Wnt proteins also act on osteoblasts to upregulate OPG expression through β-catenin signalling and suppress osteoclastic bone resorption.

Otosclerosis is a disorder of the middle ear, characterized by abnormal bone growth at the foot plate of the stapes which affect its mobility, resulting in progressive hearing loss.

Some of the reports have shown significantly reduced or missing OPG expression in otosclerotic tissues which might be a causal factor for abnormal bone remodeling during disease manifestation.