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Emerging Therapeutic Targets for Osteoporosis

Luigi Gennari 1, Daniela Merlotti 1, Alberto Falchetti 2, Cristina Eller Vainicher 3, Roberta Cosso 4, Iacopo Chiodini 2

DOI: 10.1080/14728222.2020.1726889

Abstract
Introduction: Osteoporosis is a chronic, skeletal disorder characterized by compromised bone strength and increased fracture risk; it affects 50% of women and 20% of men. In the past two decades, there have been substantial improvements in the pharmacotherapy of osteoporosis which have yielded potent inhibitors of bone resorption or stimulators of bone formation.Areas covered: This review discusses newly identified targets and pathways and conceptual approaches to the prevention of multiple age-related disorders. Furthermore, it summarizes existing therapeutic strategies for osteoporosis.Expert opinion: Our enhanced understanding of bone biology and the reciprocal interactions between bone and other tissues have allowed the identification of new targets that may facilitate the development of novel drugs. These drugs will hopefully achieve the uncoupling of bone formation from resorption and possibly exert a dual anabolic and antiresorptive effect on bone. Alas, limitations regarding adherence, efficacy on nonvertebral fracture prevention and the long-term adverse events still exist for currently available therapeutics. Moreover, the efficacy of most agents is limited by the tight coupling of osteoblasts and osteoclasts; hence the reduction of bone resorption invariably reduces bone formation, and vice versa. This field is very much ‘a work in progress.’

Expert opinion

Over the past two decades, the range of therapeutic options for the prevention and treatment of osteoporosis has increased dramatically (Figure 1). New and more potent antiresorptive agents have been developed that overcome firstgeneration BPs for the prevention of fractures. At the same time, the introduction of compounds with anabolic activity on bone has consistently improved our options, thus allowing a more personalized approach to the management of osteoporosis. Indeed, recent trials demonstrated the superiority of bone-forming treatments over antiresorptives in patients with severe osteoporosis [39,45]. Particularly relevant for the identification of new pharmacological targets and the development of the more recent compounds (e.g. denosumab and romosozumab) have been studies of rare human bone diseases and the progresses in animal genetics [168]. Despite the increase in treatment options, all the approved therapeutic strategies for osteoporosis have some limitations. First, their efficacy on the prevention of nonvertebral fractures (particularly concerning hip fractures) appears lower than that observed on vertebral fractures. In addition, concerns about the long-term safety of either N-BPs or denosumab arose, due to the occurrence of rare but serious adverse events such as atypical femoral fractures and jaw osteonecrosis. Albeit the concept of a drug holiday with long-term antiresorptive treatment has emerged, major uncertainties remain to establish when treatment should be restarted and what alternative drug should be used. More importantly, the effects of either antiresorptive or anabolic agents is short-lived and, upon discontinuation, the gain in bone mass and strength cannot be maintained over time. Indeed, in the case of denosumab, rebound bone loss and increase in fracture risk has been described in some patients after treatment discontinuation.

Finally, there is actually a major intrinsic critical drawback for most of the marketed compounds, since their action is limited by the tight coupling of OB and OC activity. Thus, either BPs or denosumab by reducing bone resorption invariably slow down bone formation. Likewise, the anabolic effect of teriparatide and abaloparatide is followed by a coupled increase in bone resorption. Actually, the only exception comes from romosozumab that, due to its uncoupling action on bone cells, exerts, at least transiently, a dual positive effect by increasing bone formation and reducing bone resorption. However, some concerns have been raised regarding its cardiovascular side-effects. Thus, there is still a crucial need to identify novel approaches and new targets to treat osteoporosis over the next few years, in order to reduce the health and economic burden of fragility fractures. Remarkably, over the past few years, there has been a huge improvement in technology which is now expected to revolutionize the management of many disorders, including osteoporosis. Not only our increased understanding of molecular biology and the advances in sequencing techniques have make possible to identify the mechanisms of many skeletal diseases, but also allowed a more rapid approach for the identification of novel molecular pathways and/or targets for the development of more effective compounds. As outlined in this review, many new molecules are actually under preclinical investigation as new therapeutics for osteoporosis, and it is likely that other relevant pathways or targets will be soon identified in the years to come. Based on the recent experience with odanacatib and romosozumab, in the development plan of these new drugs, together with the assessment of their efficacy in the maintenance of bone strength and quality, a thorough evaluation of their potential offtarget effects (possibly over a long-term) will be mandatory. Together with functional genomics, next approaches and technologies for drug discovery in osteoporosis might involve RNA silencing, microRNA antagonism, quantitative proteomics, metabolomics, and the use of MSCs. All these efforts could hopefully lead to the marketing of drugs allowing to more effectively prevent bone fragility and achieve the uncoupling of bone formation from resorption or, possibly, exert a dual anabolic and antiresorptive effect on bone. Importantly, the development of new classes of drugs targeting common age-related mechanisms, the microbiome or the interaction between bone cells and cells from other tissues (e.g. the endothelium, the muscle, or the adipose tissue) will also have the potential to treat simultaneously osteoporosis and other age-related disorders.