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

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. Access through your institution

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COMPARATIVE EFFECTIVENESS OF ANABOLIC THERAPIES FOR OSTEOPOROSIS Article 04 November 2020 REVERSAL OF THE DIABETIC BONE SIGNATURE WITH ANABOLIC THERAPIES IN MICE Article Open access 19 April

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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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Center for Bone Quality, Leiden University Medical Center, Leiden,

Netherlands Natasha M. Appelman-Dijkstra & Socrates E. Papapoulos Authors * Natasha M. Appelman-Dijkstra View author publications You can also search for this author inPubMed Google

Scholar * Socrates E. Papapoulos View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors contributed equally to researching the data

for the article, discussion of content, writing the article and reviewing and/or editing the manuscript. CORRESPONDING AUTHOR Correspondence to Socrates E. Papapoulos. ETHICS DECLARATIONS

COMPETING INTERESTS 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.

ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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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