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  • Review Article
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Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway

Abstract

The WNT signalling pathway is a key regulator of bone metabolism, particularly bone formation, which has helped to define the role of osteocytes — the most abundant bone cells — as orchestrators of bone remodelling. Several molecules involved in the control of the WNT signalling pathway have been identified as potential targets for the development of bone-building therapeutics for patients with osteoporosis. Several of these molecules have been investigated in animal models, but only inhibitors of sclerostin (which is produced by osteocytes) have been investigated in phase III clinical studies. Here, we review the rationale for these developments and the specificity and potential off-target actions of WNT-based therapeutics. We also describe the available preclinical and clinical studies and discuss the benefits and risks of using sclerostin inhibitors for the management of patients with osteoporosis.

Key points

  • Bone-building therapeutics for patients with severe osteoporosis and high fracture risk are needed.

  • Components of the WNT signalling pathway were investigated as potential therapeutic targets in animal models, but only inhibitors of sclerostin were tested in clinical studies.

  • Sclerostin inhibitors stimulate bone formation and decrease bone resorption, thereby rapidly increasing bone mass to levels higher than other antiosteoporotic agents, including teriparatide, after 1-year treatment.

  • Phase III clinical studies of the sclerostin inhibitor romosozumab with different comparators given for 1 year included >10,000 women with postmenopausal osteoporosis; compared with alendronate, romosozumab decreased the risk of all osteoporotic fractures.

  • In one study, a small but significant increase in serious cardiovascular events was observed in women treated with romosozumab compared with those treated with alendronate for 1 year.

  • No mechanism responsible for the difference in serious cardiovascular events between romosozumab and alendronate treatment can be offered presently.

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Fig. 1: Will we ever be able to reverse bone tissue abnormalities of severe osteoporosis?
Fig. 2: Components of the canonical WNT signalling pathway investigated as targets for treatments for osteoporosis in preclinical in vivo studies.
Fig. 3: Lumbar spine BMD 1 year after cessation of treatments for osteoporosis.
Fig. 4: Incident vertebral fractures in the FRAME and ARCH studies.
Fig. 5: Mechanism of action of sclerostin inhibitors in postmenopausal women with osteoporosis.

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Acknowledgements

The authors’ studies on sclerostin deficiency were funded by the European Commission (grant number: TALOS: HEALTH-F2-2008-201099). The authors thank N. Bravenboer, Leiden, Netherlands, and E. Seeman, Melbourne, Australia, for providing the images used in Fig. 1.

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All authors contributed equally to researching the data for the article, discussion of content, writing the article and reviewing and/or editing the manuscript.

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Correspondence to Socrates E. Papapoulos.

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S.E.P. has received consulting fees from Amgen, Axsome, Gador, Radius Health and UCB and speaking fees from Amgen and UCB. N.M.A.-D. declares no competing interests.

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Glossary

Frizzled co-receptors

(FZD co-receptors). A family of transmembrane, G protein-coupled proteins that serve as co-receptors in the WNT signalling pathway.

Cystine-knot

A protein structural motif containing three disulfide bridges formed from pairs of cysteine residues. It is present in different proteins and growth factors and provides structural stability.

FRAME

(Fracture Study in Postmenopausal Women with Osteoporosis). A phase III randomized controlled trial of women with postmenopausal osteoporosis treated with romosozumab or placebo for 12 months followed by denosumab for 12 months.

STRUCTURE

(The Study Evaluating Effect of Romosozumab Compared with Teriparatide in Postmenopausal Women with Osteoporosis at High Risk of Fracture Previously Treated with Bisphosphonate Therapy). A phase III open-label study that evaluated the effect of romosozumab or teriparatide for 12 months in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy.

ARCH

(The Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk). A phase III randomized controlled trial that compared the efficacy and tolerability of romosozumab with those of alendronate in women with severe osteoporosis at increased risk of fractures.

Activin A

Member of the transforming growth factor-β superfamily that antagonizes osteoblast differentiation and stimulates osteoclastogenesis.

Cathepsin K

A lysosomal cystine protease abundantly expressed in osteoclasts that is involved in the degradation of type I collagen and other bone matrix proteins during bone resorption. Inhibitors of cathepsin K have been investigated as treatments of osteoporosis.

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Appelman-Dijkstra, N.M., Papapoulos, S.E. Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway. Nat Rev Endocrinol 14, 605–623 (2018). https://doi.org/10.1038/s41574-018-0087-0

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