Molecular Mechanisms and Emerging Therapeutics for Osteoporosis

Abstract

Osteoporosis is the most common chronic metabolic bone disease. It has been estimated that more than 10 million people in the United States and 200 million men and women worldwide have osteoporosis. Given that the aging population is rapidly increasing in many countries, osteoporosis could become a global challenge with an impact on the quality of life of the affected individuals. Osteoporosis can be defined as a condition characterized by low bone density and increased risk of fractures due to the deterioration of the bone architecture. Thus, the major goal of treatment is to reduce the risk for fractures. There are several treatment options, mostly medications that can control disease progression in risk groups, such as postmenopausal women and elderly men. Recent studies on the basic molecular mechanisms and clinical implications of osteoporosis have identified novel therapeutic targets. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for osteoporosis management in the future. Here, we review the etiology of osteoporosis and the molecular mechanism of bone remodeling, present current pharmacological options, and discuss emerging therapies targeting novel mechanisms, investigational treatments, and new promising therapeutic approaches.

Keywords: fracture; medication; molecular mechanism; novel approach; osteoporosis.

Figure 1

Risk factors for osteoporosis. Risk factors can cause an imbalance in the remodeling process leading to osteoporosis. The postmenopausal period and old age are the major causes of osteoporosis.

Figure 2

Differentiation of bone cells, bone remodeling process, and various therapeutic agents for osteoporosis. Hematopoietic stem cells (HSCs) are differentiated into osteoclasts, mediated through stimulation of receptor activator of nuclear factor kappaB ligand (RANKL), generated from osteoblasts. Osteoclasts can be further maturated by monocyte-colony stimulating factor (M-CSF). The bone resorption occurs by matrix metalloproteinases and cathepsin K, secreted by mature osteoclasts. Osteoblasts are derived from the mesenchymal stem cells (MSCs) and involved in bone formation. The major roles of osteoblasts in bone remodeling are activation of osteoclasts differentiation and generation of bone cells including osteocytes. Various signaling molecules, such as insulin-like growth factor 1 (IGF-1), transforming growth factor β (TGF-β), and Wnt induce osteoblast differentiation. Osteocytes are embedded in the bone matrix and orchestrate the bone remodeling. They promote bone formation by releasing osteoprotegerin together with osteoblasts, whereas suppress osteoblastogenesis by secretion of sclerostin and Dickkopf-related protein 1 (DKK-1), inhibitors of Wnt signaling. Many therapeutic agents are being developed based on the molecular biology of bone and used clinically. Anti-resorptive agents are bisphosphonates (BPs), anti-RANKL antibodies (e.g., denosumab), selective estrogen receptor modulators (SERMs), and calcitonin. Parathyroid hormone (PTH) analogues, strontium ranelate, and anti-sclerostin antibodies can be categorized as anabolic agents for osteoporosis.