International Journal of Molecular Sciences Review Molecular-Based Treatment Strategies for Osteoporosis: A Literature Review Yuichiro Ukon , Takahiro Makino , Joe Kodama, Hiroyuki Tsukazaki, Daisuke Tateiwa, Hideki Yoshikawa and Takashi Kaito * Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; [email protected] (Y.U.); [email protected] (T.M.); [email protected] (J.K.); [email protected] (H.T.); [email protected] (D.T.); [email protected] (H.Y.) * Correspondence: [email protected]; Tel.: +81-6-6879-3552 Received: 25 April 2019; Accepted: 22 May 2019; Published: 24 May 2019 Abstract: Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and related peptide analogs, sclerostin inhibitors) have major roles in current treatment regimens and are used alone or in combination based on the pathological condition. Recent advancements in the molecular understanding of bone metabolism and in bioengineering will open the door to future treatment paradigms for osteoporosis, including antibody agents, stem cells, and gene therapies. This review provides an overview of the molecular mechanisms, clinical evidence, and potential adverse effects of drugs that are currently used or under development for the treatment of osteoporosis to aid clinicians in deciding how to select the best treatment option. Keywords: osteoporosis; bone metabolism; osteoblast; osteoclast; bisphosphonate; parathyroid hormone; calcitonin; receptor activator of nuclear factor κB; sclerostin; stem cell 1. Introduction At the Consensus Development Conference in 1993, osteoporosis was defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [1]. The World Health Organization Study Group has proposed general criteria for the diagnosis of osteoporosis based on dual-energy X-ray absorptiometry, which is considered the standard tool for the evaluation of osteoporosis. According to the criteria, osteoporosis is diagnosed when the bone mineral density (BMD) is 2.5 or more standard deviations below the young-adult mean [2,3]. The incidence of osteoporosis increases with aging. In addition, the population aged 60 years or older has been continuously growing in many countries [4]. More than 75 million people have osteoporosis in Europe, Japan, and the USA alone [2]. Worldwide, it is estimated that 9 million people suffer from osteoporotic fractures each year [5]. Therefore, treatments for osteoporosis with various medicines have been receiving increasing attention globally. Osteoporosis is caused by an imbalance in bone remodeling, which is an ongoing process in which mature bone tissue is removed by osteoclasts (bone resorption) and new bone tissue is formed by osteoblasts (bone formation). Excessive bone resorption or inadequate new bone formation during bone remodeling can result in osteoporosis [6]. To maintain bone homeostasis, osteoblast and osteoclast functions are coordinated by a wide variety of molecules (Figure1). Int. J. Mol. Sci. 2019, 20, 2557; doi:10.3390/ijms20102557 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 2557 2 of 24 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 24 Figure 1. SchematicSchematic diagram diagram of ofbone bone ho homeostasismeostasis and and a summary a summary of the of theaction action mechanism mechanism of the of agentsthe agents for osteoporosis. for osteoporosis. BP, bisphosphonate; BP, bisphosphonate; DKK, dickkopf; DKK, dickkopf; M-CSF, M-CSF,monocyte/macrophage monocyte/macrophage colony- stimulatingcolony-stimulating factor; PTH, factor; parathyroid PTH, parathyroid hormone; hormone; normal normalarrows arrowswith “+” with mean “+ ”positive mean positive effect; dotted effect; arrowsdotted arrowswith “− with” mean “ ”negative mean negative effect. This effect. figure This is figure copyright is copyright free. free. − Osteoblasts originate originate from from mesenchymal mesenchymal stem stem cells cells (MSCs). (MSCs). Runt-related Runt-related transcription transcription factor factor 2 (Runx2),2 (Runx2), also also known known as core-binding as core-binding factor factor subunit subunit alpha-1, alpha-1, is a key istranscription a key transcription factor for osteoblast factor for differentiationosteoblast diff erentiationfrom MSCs from and MSCspre-osteoblasts. and pre-osteoblasts. Runx2 expression Runx2 is expression the first requisite is the first step requisite in the determinationstep in the determination of osteoblast of osteoblastcommitment, commitment, followed by followed expression by expression of Sp7 and of Tcf7, Sp7 andwhich Tcf7, are which also essentialare also essentialfor osteoblastic for osteoblastic differentiation differentiation [7]. Runx2 [7]. is Runx2regulated is regulated by multiple by multiplesignals, such signals, as bone such morphogeneticas bone morphogenetic proteins proteins (BMPs) (BMPs) and Wnt/ and Wntβ-catenin./β-catenin. As for As forBMP BMP signaling, signaling, SMAD1/5/8 SMAD1/5/8 are phosphorylated particularly by BMP2 and BMP4, BMP4, and and finally, finally, stimulate osteoblast differentiation differentiation by activating Runx2. Regarding Regarding Wnt/ Wnt/β-catenin-catenin signaling, signaling, Wnt Wnt proteins proteins (particularly (particularly Wnt3a Wnt3a and and Wnt10b) Wnt10b) bind toto Frizzled Frizzled and and lipoprotein lipoprotein receptor-related receptor-relat proteined protein (LRP)-5 (LRP)-5/6/6 receptors, receptors, and consequently and consequently increase increaseRunx2 levels Runx2 through levels eitherthroughβ-catenin either β stabilization-catenin stabilization or protein or kinase protein Cδ kinase[8,9]. SclerostinCδ [8,9]. Sclerostin and dickkopf and (DKK)-1dickkopf inhibit(DKK)-1 the inhibit Wnt/β -cateninthe Wnt/ pathwayβ-catenin through pathway the through LRP-5/6 the receptor, LRP-5/6 thus receptor, leading thus to a decreaseleading to in aRunx2 decrease expression. in Runx2 expression. Osteoclasts differentiate differentiate from hematopoietic st stemem cells through monocytemonocyte/macrophage/macrophage lineage upon stimulation with monocytemonocyte/macrophage/macrophage colony-s colony-stimulatingtimulating factor factor and ac activationtivation of receptor activator ofof nuclearnuclear factorfactorκ κBB (RANK) (RANK) by by its its ligand ligand (RANKL) (RANKL) [10 [1].0]. RANKL RANKL secreted secreted by osteoblastsby osteoblasts and andosteocytes osteocytes binds binds to RANK to RANK on osteoclast on osteoclast precursor precursor cells, which cells, eventually which eventually differentiate differentiate into osteoclasts. into osteoclasts.Osteoprotegerin Osteoprotegerin (OPG), which (OPG), is also which produced is also by produced cells in the by osteoblast cells in the lineage, osteoblast is a soluble lineage, decoy is a solublereceptor decoy of RANKL receptor that of preventsRANKL that binding prevents of RANKL binding to of RANK RANKL [11 ].to RANK The RANKL-RANK-OPG [11]. The RANKL- RANK-OPGinteraction plays interaction an essential plays role an inessential bone homeostasis role in bone through homeostasis osteoclast through regulation osteoclast [12]. regulation [12]. Osteocytes, which are completely embedded in the bone matrix, descend from MSCs through osteoblastOsteocytes, differentiation which are and completely orchestrate embedded bone remodeling in the bone by regulatingmatrix, descend osteoblasts from andMSCs osteoclasts. through osteoblastEspecially, differentiation they exclusively and secrete orchestrate sclerostin bone [13 remo]. deling by regulating osteoblasts and osteoclasts. Especially,Treatments they forexclusivel osteoporosisy secrete are sclerostin divided into [13]. several groups, including therapies based on essential nutrients,Treatments anti-resorption for osteoporosis drugs, anabolic are divided drugs, into and combinationsseveral groups, of these.including Major therapies essential based nutrients on essentialfor the treatment nutrients, of anti-resorption osteoporosis are drugs, calcium, anabolic vitamin drugs, D, and combinations vitamin K2, all of of these. which Major are involvedessential nutrients for the treatment of osteoporosis are calcium, vitamin D, and vitamin K2, all of which are involved in bone metabolism. Anti-resorptive drugs, which suppress bone resorption, include Int. J. Mol. Sci. 2019, 20, 2557 3 of 24 in bone metabolism. Anti-resorptive drugs, which suppress bone resorption, include calcitonin, estrogen and selective estrogen receptor modulators (SERMs), bisphosphonates (BPs), and anti-RANKL antibody. Anabolic drugs, which enhance bone formation, include parathyroid hormone (PTH) and sclerostin inhibitors. Additionally, stem cell therapies for osteoporosis have been receiving increased attention in recent years. These therapies are helpful for the treatment of osteoporosis as evidenced by numerous clinical trials. However, nearly all these therapies have side effects because of the long-term drug administration for osteoporosis treatment. In this literature review, we summarize the mechanisms of action of current and anticipated