Emerging therapeutic targets for osteoporosis

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.’

KEYWORDS:

• Aging
• bone anabolic drugs
• bone antiresorptive drugs
• bone turnover
• fractures
• osteoporosis
• therapeutic target

Acknowledgments

This work has been partially supported by the Research Grant RF-2016-02362238 from the Italian Ministry of Health which was awarded to L Gennari.

Declaration of interest

I Chiodini has received fees from Italfarmaco and personal fees from Sandoz, Eli-Lilly and Kyowa-Kiri. L Gennari has received personal fees from Sandoz and Abiogen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has received consultancy fees from major companies in the field of osteoporosis and the list is as follows: Amgen, Alexion, Kyowa Kirin, Novartis, Sandoz, Takeda and UCB. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Article Highlights

• Osteoporosis is a common skeletal disorder characterized by compromised bone strength and increased fracture risk, representing a growing health and health-economic problem worldwide.

• Treatment of osteoporosis has advanced significantly over the past decades and now include potent antiresorptive drugs (e.g. aminobisphosphonates or denosumab) and compounds with an anabolic effect on bone (e.g. teriparatide, abaloparatide, and romosozumab).

• However, these therapeutic agents still have limitations either concerning the efficacy on non-vertebral fracture prevention or the concern about long-term adverse events.

• Over the past few years, the improved understanding of the mechanisms of bone remodeling has led to the identification of targets for the development of novel compounds that are able to selectively inhibit bone resorption or stimulate bone formation and, hopefully, dual-acting agents (with either antiresorptive and anabolic activity on bone).

• Despite these advances, only a few compounds have been actually selected for the clinical development.

• The continuous advances in functional genomics together with the development of new technological approaches are further expected to widen our ways to enhance bone strength and prevent the occurrence of fractures in the next few years.

• Importantly, an alternative approach has more recently emerged, aimed at the development of new classes of drugs targeting common age-related mechanisms (e.g. cellular senescence), the microbiome or other tissues interacting with the skeleton.

This box summarizes key points contained in the article.

Additional information

Funding

This paper was not funded.