Macrophage polarization regulates bone homeostasis: a potential etiology and therapy for postmenopausal osteoporosis

Osteoporosis is a very common disease nowadays, and it is mostly seen in postmenopausal women. In postmenopausal women, with the decrease of estrogen, directly or indirectly, it makes the decrease of bone mineral density more significant, and increases the loss of bone mass, so the osteoporosis due to the decrease of estrogen is called postmenopausal osteoporosis. Macrophages play an important role in the regulation of bone metabolism, and different polarization states have different effects, promoting bone resorption when polarized to M1-type macrophages and bone formation when polarized to M2-type macrophages. In terms of bone metabolism regulation, these two polarized states are functionally opposed, yet they can transition into one another, forming a dynamic continuum; M0, M1, and M2 can all polarize one another. With the rapid development of bone immunology in recent years, this paper will first focus on macrophages, detailing their effects on osteoblasts, osteoclasts, angiogenesis, and anastomosis under different polarization states. It will then discuss estrogen, a key regulatory factor involved in both macrophage polarization and bone homeostasis, with a particular emphasis on its enhancing effects on immune cells (especially its protective role for M2 macrophages), its regulation of cytokines (directly or indirectly reducing the expression of RANK, M-CSF, IL-1, IL-6, and TNF-α, while increasing OPG expression), as well as its role in promoting angiogenesis through increased VEGF production and protecting blood vessels to exert anti-inflammatory effects. Current treatments are primarily pharmacological and faces challenges such as long treatment cycles, slow onset of action, high demands on patient compliance, and significant relapse upon discontinuation of medication. Therefore, immunomodulatory biomaterials could represent a new therapeutic approach for postmenopausal osteoporosis. In the future, if biomaterials can be used to release or modulate local signaling in an orderly and controlled manner, thereby precisely upregulating M2 macrophage markers (CD206, CD163) and promoting the polarization of M1 to M2 macrophages. We could then combine drugs with biomaterials to provide both local and systemic treatment simultaneously, thereby exerting a more effective and long-lasting effect on postmenopausal osteoporosis. Therefore, the use of immune-modulating biomaterials targeting macrophages for the treatment of osteoporosis is highly worthy of further research. Key message: By elucidating the roles of macrophages and estrogen in bone homeostasis, the targeted regulation of macrophage polarization to the M2 phenotype and the maintenance of this M2 state are key to restoring the immune-bone microenvironment homeostasis in postmenopausal osteoporosis.