Elsevier

Maturitas

Volume 82, Issue 2, October 2015, Pages 245-255
Maturitas

Review article
Bone biology, signaling pathways, and therapeutic targets for osteoporosis

https://doi.org/10.1016/j.maturitas.2015.07.003Get rights and content

Highlights

  • Major advances have occurred recently in the treatment of osteoporosis, but current therapies are limited by their moderate efficacy and rare but severe toxicities.

  • Molecular targets in signaling pathways vital to osteoclast and osteoblast function have generated new opportunities to treat osteoporosis.

  • The Wnt signaling pathway is critical to osteoblast function and new bone formation.

  • Antagonists to endogenous inhibitors of the Wnt signaling pathway are being developed as anabolic therapies.

  • New agents targeting other signaling pathways will further expand the options available for treatment of osteoporosis.

Abstract

Major advances have occurred recently in the treatment of osteoporosis in recent years. Most patients are currently treated with bisphosphonates, denosumab, raloxifene, or teriparatide, and in some countries, strontium ranelate. Strontium ranelate and calcitonin have recently had their use restricted due to cardiovascular concerns and malignancy, respectively. The available agents have generally provided excellent options that effectively reduce fracture risk. New targets are being sought based on appreciation of the bone biology and signaling pathways involved in bone formation and resorption. These agents will directly target these signaling pathways, and further expand the options available for treatment of osteoporosis.

Introduction

Discovery of new therapeutic targets for treatment of osteoporosis is important because of the limited efficacy and variable toxicities of currently approved agents. These agents, while significantly more effective than estrogen, have a relatively moderate ability to reduce hip, vertebral, and non-vertebral fractures. Current treatments reduce vertebral fracture risk significantly more than hip or nonvertebral fracture risk.

Currently approved agents in the U.S. include bisphosphonates, hormone therapy, raloxifene, calcitonin, teriparatide, or denosumab. Calcitonin was recently removed from the market in several countries due to concerns regarding cancer risk with an oral formulation used in clinical trials, and the FDA recently recommended against long-term treatment of osteoporosis with calcitonin. Teriparatide (PTH 1–34) and PTH 1–84 remain the only approved agents for stimulating new bone formation in some countries.

This narrative review will briefly summarize the bone biology relevant for understanding osteoporosis, describe the critical signaling pathways involved in bone resorption and bone formation and discuss potential therapeutic targets, and review data available for some of the newer agents developed against these targets.

Section snippets

Bone modeling and remodeling

The skeleton undergoes longitudinal and radial growth, modeling, and remodeling during life. Longitudinal and radial growth occurs during childhood and adolescence. Growth plates cause longitudinal growth due to cartilage proliferation in the epiphyseal and metaphyseal regions of long bones. Newly-produced cartilage mineralizes to form primary new bone. Radial growth occurs due to periosteal apposition during and after puberty, and also later in life with normal aging.

Modeling results in bones

Signaling pathways

Signaling pathways are critical in regulation of how osteoclasts and osteoblasts control bone turnover leading to bone loss after menopause and during normal aging. Activation of pathways that stimulate osteoclast recruitment and activation lead to bone loss unless other factors prevent this, and those that stimulate osteoblast recruitment and activation lead to bone formation, unless other factors prevent this. Whereas currently available agents used to treat osteoporosis mostly inhibit bone

Antiresorptive pathways

Antiresorptive agents reduce bone turnover relatively rapidly, by reducing bone resorption initially, follow by a slower reduction in bone formation. These changes lead to an altered balance between bone resorption and formation at a lower rate of bone turnover that favors an increase in BMD, preservation or strengthening of structural and material properties of bone, increase in bone strength, and reduction in fractures [39].

Anabolic pathways

Anabolic agents stimulate bone turnover significantly and relatively rapidly by stimulating bone formation initially, followed by slower stimulation of bone resorption. These changes lead to an altered balance between bone formation and resorption, at a higher rate of bone turnover, which leads to an increase in BMD, preservation or strengthening of structural and material properties of bone, increase in bone strength, and reduction in fractures.

Therapeutic targets for osteoporosis

Newer therapies for osteoporosis are targeted to molecules discovered during elucidation of signaling pathways in osteoclasts and osteoblasts (Table 1). The limitations of new therapies are mostly related to their specificity of action and safety. Agents that also affect tissues other than bone may result in off-target effects, which cause adverse events in clinical trials.

Antiresorptive agents

Most currently approved therapeutic agents primarily prevent bone loss. There is continued interest in development of new antiresorptive agents that offer selective advantages over existing agents. Because newer antiresorptive agents do not markedly suppress bone formation, and may uncouple bone formation from resorption, these compounds offer the potential of creating anabolic windows of variable magnitude and duration to stimulate new bone formation.

Anabolic agents

Anabolic agents increase bone strength by directly stimulating new bone formation. A number of potential targets for anabolic agents have been identified [68]. New parathyroid hormone (PTH) and PTH-related protein (PTHrP) analogues remain under development. New anabolic targets being evaluated stimulate the Wnt-signaling pathway in osteoblasts. Monoclonal antibodies to these targets block inhibition of the pathway, leading to stimulation of new bone formation.

Conclusions

Major advances have occurred recently in the treatment of osteoporosis. Patients are most often treated currently with bisphosphonates, denosumab, raloxifene, or teriparatide, and in some countries, strontium ranelate. Calcitonin has been removed from the market in some countries, and its use restricted in others, due to risk of malignancy. Use of strontium ranelate has been reduced due to cardiovascular concerns. These agents have generally provided excellent options that effectively reduce

Practice points

  • Until the newer anabolic or antiresorptive agents are approved, physicians should continue to prescribe the current best agent uniquely suited for each patient.

  • Use of the currently available agents should not preclude the use of new agents when these become available.

  • Physicians and patients should be aware that, unlike the longer-acting bisphosphonates, all the newer agents are relatively shorter-acting, and have reasonably rapid offset of action.

  • Physicians should consider using longer-acting

Research agenda

  • Continue clinical trials of the available new antiresorptive and anabolic agents.

  • Continue development of newer therapeutic agents currently undergoing preclinical evaluation.

  • Continue preclinical research on agents targeting anabolic pathways other than the Wnt/β-catenin signaling pathway to expand options for treatment.

Conflict of interest

The authors declare no conflict of interest.

Authors’ contribution

Both authors contributed equally to the design, writing, and editing of this narrative review, submitted at the invitation of the Editor-in-Chief, Dr. Margaret Rees.

Funding

The authors have received no funding for this article.

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