Advances in Our Understanding of the Mechanism of Action of Drugs (including Traditional Chinese Medicines) for the Intervention and Treatment of Osteoporosis

Abstract

Osteoporosis (OP) is known as a silent disease in which the loss of bone mass and bone density does not cause obvious symptoms, resulting in insufficient treatment and preventive measures. The losses of bone mass and bone density become more severe over time and an only small percentage of patients are diagnosed when OP-related fractures occur. The high disability and mortality rates of OP-related fractures cause great psychological and physical damage and impose a heavy economic burden on individuals and society. Therefore, early intervention and treatment must be emphasized to achieve the overall goal of reducing the fracture risk. Anti-OP drugs are currently divided into three classes: antiresorptive agents, anabolic agents, and drugs with other mechanisms. In this review, research progress related to common anti-OP drugs in these three classes as well as targeted therapies is summarized to help researchers and clinicians understand their mechanisms of action and to promote pharmacological research and novel drug development.

Keywords: antiresorptive agent; bone; fracture; osteoblast; osteoclast; osteoporosis; pharmacological mechanism.

FIGURE 1

Mechanism diagram of bone formation and loss. Bone marrow-derived hematopoietic stem cells differentiate into monocytes or macrophages, which then differentiate into osteoclast precursor cells, then differentiate into osteoclasts and participate in bone loss. When estrogen levels are reduced or inflammatory factors are activated, the RANKL/RANK signaling pathway is activated, leading to increased osteoclast differentiation. The increased ROS levels or endoplasmic reticulum stress also leads to increased osteoclast differentiation. Bone marrow-derived mesenchymal stem cells differentiate into osteoblast precursor cells, which then differentiate into osteoblasts and participate in bone formation. The Osteoblasts produce OPG, competitively bind RANKL and inhibit osteoclast differentiation, thereby reducing osteoclast production. Bone formation and bone loss are in dynamic balance to maintain bone integrity and normal bone structure and function. Bone formation and bone loss are in dynamic balance to maintain skeletal integrity, normal bone structure and function.

FIGURE 2

Targets and mechanisms of anti-osteoporosis drug action with different mechanisms. Pharmacological mechanism of anti-osteoporosis drugs affecting bone formation and bone resorption.

FIGURE 3

Mechanism diagram of RANKL/RANK/OPG signaling pathway cascade in osteoclastogenesis. Binding of RANKL to RANK leads to TRAF6 recruitment and thus activation of NF-kB and MAPK pathways. TRAF6 recruitment activates the NF-kB and JNK/ERK/p38 MAPK signaling pathways, and activation of the transcription factor Fos/AP-1 is also dependent on TRAF6 recruitment and JNK/ERK activation, together, these activated signals lead to activation of NFATc1, a key transcription factor for downstream osteoclast formation. In addition, RANKL activation stimulates the protein DAP12 or FcRγ of the tyrosine-activating motif ITAM, forming a complex of phospholipase C-γ and dephosphorylated tyrosinase, which activates calcium ion signaling and induces NFATc1 translocation into the nucleus of osteoclasts, and again here, NFATc1 works together with other transcription factors to induce osteoclast activation, thus NFATc1 is a marker event for osteoclast formation. The osteoclastogenesis inhibitory factor competitively binds RANKL and inhibits osteoclast differentiation thereby reducing osteoclast production.

FIGURE 4

TCM for the treatment of osteoporosis. (A,B) The image of Psoralea corylifolia Linn and Eucommia ulmoides Oliver, both of them are the monarch drugs of Qing’ E formula; (C) The 2D chemical structure of bakuchiol, which is one of the main components in Psoralea corylifolia Linn. (D) showed the six main mechanisms that bakuchiol exerts anti-osteoporosis.