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

2023 MECHANISMS UNDERLYING THE LONG-TERM AND WITHDRAWAL EFFECTS OF DENOSUMAB THERAPY ON BONE Article 06 April 2023 REFERENCES * Harvey, N. C. et al. Mind the (treatment) gap: a global

perspective on current and future strategies for prevention of fragility fractures. _Osteoporos. Int._ 28, 1507–1529 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Khosla, S. &

Shane, E. A. Crisis in the treatment of osteoporosis. _J. Bone Miner. Res._ 31, 1485–1487 (2016). PubMed  Google Scholar  * Kanis, J. A. et al. Identification and management of patients at

increased risk of osteoporotic fracture: outcomes of an ESCEO expert consensus meeting. _Osteoporos. Int._ 28, 2023–2034 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Khosla, S.

& Hofbauer, L. C. Osteoporosis treatment: recent developments and ongoing challenges. _Lancet Diabetes Endocrinol._ 11, 898–907 (2017). Google Scholar  * Langdahl, B., Ferrari, S. &

Dempster, D. W. Bone modeling and remodeling: potential therapeutic targets for the treatment of osteoporosis. _Ther. Adv. Musculoskelet. Dis._ 8, 225–235 (2016). CAS  PubMed  PubMed Central

  Google Scholar  * Seeman, E. Age- and menopause-related bone loss compromise cortical and trabecular microstructure. _J. Gerontol. A. Biol. Sci. Med. Sci._ 68, 1218–1225 (2013). PubMed 

Google Scholar  * Dallas, S. L., Prideaux, M. & Bonewald, L. F. The osteocyte: an endocrine cell… and more. _Endocr. Rev._ 34, 658–690 (2013). CAS  PubMed  PubMed Central  Google Scholar

  * Plotkin, L. I. & Bellido, T. Osteocytic signalling pathways as therapeutic targets for bone fragility. _Nat. Rev. Endocrinol._ 12, 593–605 (2016). CAS  PubMed  PubMed Central  Google

Scholar  * McClung, M. R. et al. Odanacatib efficacy and safety in postmenopausal women with osteoporosis; 5-year data from the extension of the phase 3 long-term odanacatib fracture trial

[abstract 1027]. _Arthritis Rheumatol._ 68, S10 (2016). Google Scholar  * Martin, T. J. Parathyroid hormone-related protein, its regulation of cartilage and bone development, and role in

treating bone diseases. _Physiol. Rev._ 96, 831–871 (2016). CAS  PubMed  Google Scholar  * Zebaze, R. et al. Increased cortical porosity is associated with daily, not weekly, administration

of equivalent doses of teriparatide. _Bone_ 99, 80–84 (2017). CAS  PubMed  Google Scholar  * Martin, T. J. & Seeman, E. Abaloparatide is an anabolic, but does it spare resorption? _J.

Bone Miner. Res._ 32, 11–16 (2017). PubMed  Google Scholar  * Miller, P. D. et al. Effect of abaloparatide versus placebo on new vertebral fractures in postmenopausal women with

osteoporosis: a randomized clinical trial. _JAMA_ 316, 722–733 (2016). THIS IS THE FIRST PHASE III RCT WITH ABALOPARATIDE. CAS  PubMed  Google Scholar  * Moreira, C. A., Fitzpatrick, L. A.,

Wang, Y. & Recker, R. R. Effects of abaloparatide-SC (BA058) on bone histology and histomorphometry: the ACTIVE phase 3 trial. _Bone_ 97, 314–319 (2017). CAS  PubMed  Google Scholar  *

Arlot, M. et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. _J. Bone Miner. Res._ 20, 1244–1253

(2005). CAS  PubMed  Google Scholar  * Dempster, D. W. et al. Remodeling- and modeling-based bone formation with teriparatide versus denosumab: a longitudinal analysis from baseline to 3

months in the AVA study. _J. Bone Miner. Res._ 33, 298–306 (2018). CAS  PubMed  Google Scholar  * Jiang, Y. et al. Recombinant human parathyroid hormone (1–34) [teriparatide] improves both

cortical and cancellous bone structure. _J. Bone Miner. Res._ 18, 1932–1941 (2003). CAS  PubMed  Google Scholar  * Tsai, J. N. et al. Teriparatide and denosumab, alone or combined, in women

with postmenopausal osteoporosis: the DATA study randomised trial. _Lancet_ 382, 50–56 (2013). THIS STUDY SHOWS THAT CONCURRENT STIMULATION OF BONE FORMATION AND REDUCTION OF BONE RESORPTION

LEADS TO HIGHER INCREASES IN BMD. CAS  PubMed  PubMed Central  Google Scholar  * Tsai, J. N. et al. Comparative effects of teriparatide, denosumab, and combination therapy on peripheral

compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT Study. _J. Bone Miner. Res._ 30, 39–45 (2015). CAS  PubMed  Google Scholar  * Tsai, J. N. et al.

Effects of two years of teriparatide, denosumab, or both on bone microarchitecture and strength (DATA-HRpQCT study). _J. Clin. Endocrinol. Metab._ 101, 2023–2030 (2016). CAS  PubMed  PubMed

Central  Google Scholar  * McClung, M. R. Using osteoporosis therapies in combination. _Curr. Osteoporos. Rep._ 15, 343–352 (2017). PubMed  Google Scholar  * Seeman, E. & Martin, T. J.

Co-administration of antiresorptive and anabolic agents: a missed opportunity. _J. Bone Miner. Res._ 30, 753–764 (2015). CAS  PubMed  Google Scholar  * Gong, Y. et al. LDL receptor-related

protein 5 (LRP5) affects bone accrual and eye development. _Cell_ 107, 513–523 (2001). THIS STUDY, ALONG WITH REFERENCES 22 AND 23, REVEALS THE IMPORTANT ROLE FOR THE WNT SIGNALLING PATHWAY

IN BONE METABOLISM. CAS  PubMed  Google Scholar  * Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor–related protein 5. _N. Engl. J. Med._ 346, 1513–1521 (2002). CAS 

PubMed  Google Scholar  * Little, R. D. et al. A mutation in the LDL receptor–related protein 5 gene results in the autosomal dominant high–bone-mass trait. _Am. J. Hum. Genet._ 70, 11–19

(2002). CAS  PubMed  Google Scholar  * Brunkow, M. E. et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. _Am. J. Hum.

Genet._ 68, 577–589 (2001). THIS STUDY, ALONG WITH REFERENCE 25, DESCRIBES THE DISCOVERY OF SOST. CAS  PubMed  PubMed Central  Google Scholar  * Balemans, W. et al. Increased bone density in

sclerosteosis is due to the deficiency of a novel secreted protein (SOST). _Hum. Mol. Genet._ 10, 537–543 (2001). CAS  PubMed  Google Scholar  * Balemans, W. et al. Identification of a 52

kb deletion downstream of the SOST gene in patients with van Buchem disease. _J. Med. Genet._ 39, 91–97 (2002). CAS  PubMed  PubMed Central  Google Scholar  * Staehling-Hampton, K. et al. A

52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. _Am. J. Med. Genet._ 110, 144–152 (2002). PubMed  Google

Scholar  * van Bezooijen, R. L. et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. _J. Exp. Med._ 199, 805–814 (2004). THIS

STUDY IS THE FIRST DEMONSTRATION THAT SCLEROSTIN IS PRODUCED BY OSTEOCYTES. PubMed  PubMed Central  Google Scholar  * Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt

signaling. _J. Biol. Chem._ 280, 19883–19887 (2005). CAS  PubMed  Google Scholar  * Semenov, M., Tamai, K. & He, X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. _J.

Biol. Chem._ 280, 26770–26775 (2005). CAS  PubMed  Google Scholar  * van Bezooijen, R. L. et al. Sclerostin inhibits BMP-stimulated bone formation by antagonising Wnt signaling. _J. Bone

Miner. Res._ 22, 19–28 (2007). PubMed  Google Scholar  * Baron, R. & Kneissel, M. Wnt signaling in bone homeostasis and disease: from human mutations to treatments. _Nat. Med._ 19,

179–192 (2013). CAS  PubMed  Google Scholar  * Kahn, M. Can we safely target the WNT pathway? _Nat. Rev. Drug Discov._ 13, 513–532 (2014). CAS  PubMed  PubMed Central  Google Scholar  *

Vestergaard, P., Rejnmark, L. & Mosekilde, L. Reduced relative risk of fractures among users of lithium. _Calcif. Tissue Int._ 77, 1–8 (2005). CAS  PubMed  Google Scholar  *

Clement-Lacroix, P. et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. _Proc. Natl Acad. Sci. USA_ 102, 17406–17411

(2005). CAS  PubMed  PubMed Central  Google Scholar  * Kulkarni, N. et al. Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone

mass in vivo. _J. Bone Miner. Res._ 21, 910–920 (2006). CAS  PubMed  Google Scholar  * Chen, Y. et al. Beta-catenin signaling plays a disparate role in different phases of fracture repair:

implications for therapy to improve bone healing. _PLOS Med._ 4, e249 (2007). PubMed  PubMed Central  Google Scholar  * Amirhosseini, M. et al. GSK-3β inhibition suppresses

instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation. _J. Cell. Physiol._ 233, 2398–2408 (2018). CAS  PubMed  Google Scholar  * Hall, A. P., Escott,

K. J., Sanganee, H. & Hickling, K. C. Preclinical toxicity of AZD7969: effects of GSK3β inhibition in adult stem cells. _Toxicol. Pathol._ 43, 384–399 (2015). CAS  PubMed  Google Scholar

  * Ting, K. et al. Human NELL-1 expressed in unilateral coronal synostosis. _J. Bone Miner. Res._ 14, 80–89 (1999). CAS  PubMed  Google Scholar  * Aghaloo, T. et al. Nell-1-induced bone

regeneration in calvarial defects. _Am. J. Pathol._ 169, 903–915 (2006). CAS  PubMed  PubMed Central  Google Scholar  * Zhang, X. et al. Nell-1, a key functional mediator of Runx2, partially

rescues calvarial defects in Runx2(+/−) mice. _J. Bone Miner. Res._ 26, 777–791 (2011). CAS  PubMed  Google Scholar  * Pakvasa, M. et al. Neural EGF-like protein 1 (NELL-1): signaling

crosstalk in mesenchymal stem cells and applications in regenerative medicine. _Genes Dis._ 4, 127–137 (2017). CAS  PubMed  PubMed Central  Google Scholar  * James, A. W. et al. A new

function of Nell-1 protein in repressing adipogenic differentiation. _Biochem. Biophys. Res. Commun._ 411, 126–131 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Karasik, D. et al.

Genome-wide pleiotropy of osteoporosis-related phenotypes: the Framingham Study. _J. Bone Miner. Res._ 25, 1555–1563 (2010). PubMed  PubMed Central  Google Scholar  * James, A. W. et al.

NELL-1 in the treatment of osteoporotic bone loss. _Nat. Commun._ 6, 7362 (2015). THIS STUDY DESCRIBES A SERIES OF EXPERIMENTS ON THE ROLE OF NELL1 AS A POTENTIAL TREATMENT OF OSTEOPOROSIS.

CAS  PubMed  Google Scholar  * Siu, R. K. et al. Nell-1 protein promotes bone formation in a sheep spinal fusion model. _Tissue Eng. Part A_ 17, 1123–1135 (2011). CAS  PubMed  PubMed Central

  Google Scholar  * Li, W. et al. Delivery of lyophilized Nell-1 in a rat spinal fusion model. _Tissue Eng. Part A_ 16, 2861–2870 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Lu,

S. S. et al. The osteoinductive properties of Nell-1 in a rat spinal fusion model. _Spine J._ 7, 50–60 (2007). PubMed  Google Scholar  * James, A. W. et al. Vertebral implantation of NELL-1

enhances bone formation in an osteoporotic sheep model. _Tissue Eng. Part A_ 22, 840–849 (2016). CAS  PubMed  PubMed Central  Google Scholar  * James, A. W. et al. NELL-1 induces Sca-1+

mesenchymal progenitor cell expansion in models of bone maintenance and repair. _JCI Insight_ 2, 92573 (2017). PubMed  Google Scholar  * Kwak, J. et al. NELL-1 injection maintains long bone

quantity and quality in an ovariectomy-induced osteoporotic senile rat model. _Tissue Eng. Part A_ 19, 426–436 (2013). CAS  PubMed  Google Scholar  * Kwak, J. H. et al. Pharmacokinetics and

osteogenic potential of PEGylated NELL-1 in vivo after systemic administration. _Biomaterials_ 57, 73–83 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Tanjaya, J. et al. The effects

of systemic therapy of PEGylated NELL-1 on fracture healing in mice. _Am. J. Pathol._ 188, 715–727 (2017). PubMed  Google Scholar  * Jin, Z. et al. Hypermethylation of the nell-like 1 gene

is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma. _Oncogene_ 26, 6332–6340 (2007). CAS  PubMed  Google Scholar  * O’Callaghan, C.

& Vassilopoulos, A. Sirtuins at the crossroads of stemness, aging, and cancer. _Aging Cell_ 16, 1208–1218 (2017). PubMed  PubMed Central  Google Scholar  * Mendes, K. L., Lelis, D. F.

& Santos, S. H. S. Nuclear sirtuins and inflammatory signaling pathways. _Cytokine Growth Factor Rev._ 38, 98–105 (2017). CAS  PubMed  Google Scholar  * Bae, E. J. Sirtuin 6, a possible

therapeutic target for type 2 diabetes. _Arch. Pharm. Res._ 40, 1380–1389 (2017). CAS  PubMed  Google Scholar  * Cohen-Kfir, E. et al. Sirt1 is a regulator of bone mass and a repressor of

Sost encoding for sclerostin, a bone formation inhibitor. _Endocrinology_ 152, 4514–4524 (2011). CAS  PubMed  Google Scholar  * Artsi, H. et al. The Sirtuin1 activator SRT3025 down-regulates

sclerostin and rescues ovariectomy-induced bone loss and biomechanical deterioration in female mice. _Endocrinology_ 155, 3508–3515 (2014). PubMed  Google Scholar  * Zainabadi, K., Liu, C.

J., Caldwell, A. L. M. & Guarente, L. SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis. _PLOS ONE_ 12, e0185236 (2017). PubMed  PubMed Central

  Google Scholar  * Krueger, J. G. et al. A randomized, placebo-controlled study of SRT 2104, a SIRT1 activator, in patients with moderate to severe psoriasis. _PLOS ONE_ 10, e0142081

(2015). PubMed  PubMed Central  Google Scholar  * Noh, R. M. et al. Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus. _Open Heart_ 4,

e000647 (2017). PubMed  PubMed Central  Google Scholar  * Sands, B. E. et al. Assessing colonic exposure, safety and clinical activity of SRT2104, a novel oral SIRT1 activator in patients

with mild to moderate ulcerative colitis. _Inflam. Bowel Dis._ 22, 607–614 (2016). Google Scholar  * Kurylowicz, A. In search of new therapeutic targets for obesity treatment: Sirtuins.

_Int. J. Mol. Sci._ 17, 572 (2016). PubMed Central  Google Scholar  * Pinzone, J. J. et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. _Blood_ 113, 517–525 (2009).

CAS  PubMed  PubMed Central  Google Scholar  * Christodoulides, C. et al. The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis. _J.

Cell Sci._ 119, 2613–2620 (2006). CAS  PubMed  Google Scholar  * Mukhopadhyay, M. et al. Dickkopf 1 is required for embryonic head induction and limb morphogenesis in the mouse. _Dev. Cell_

1, 423–434 (2001). CAS  PubMed  Google Scholar  * Li, J. et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. _Bone_ 39, 754–766 (2006). CAS  PubMed  Google

Scholar  * Morvan, F. et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. _J. Bone Miner. Res._ 21, 934–945 (2006). CAS  PubMed  Google

Scholar  * Yao, G. Q., Wu, J. J., Troiano, N. & Insogna, K. Targeted overexpression of Dkk1 in osteoblasts reduces bone mass but does not impair the anabolic response to intermittent PTH

treatment in mice. _J. Bone Miner. Metab._ 29, 141–148 (2011). CAS  PubMed  Google Scholar  * Ke, H. Z., Richards, W. G., Li, X. & Ominsky, M. S. Sclerostin and Dickkopf-1 as

therapeutic targets in bone diseases. _Endocr. Rev._ 33, 747–783 (2012). CAS  PubMed  Google Scholar  * Glantschnig, H. et al. A rate-limiting role for Dickkopf-1 in bone formation and the

remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. _J. Pharmacol. Exp. Ther._ 338, 568–578 (2011). CAS  PubMed 

Google Scholar  * Li, X. et al. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. _J. Bone Miner. Res._ 26, 2610–2621 (2011). CAS  PubMed  Google

Scholar  * Richards, W. G. et al. _Proc 33rd Ann. Meet. American Soc. Bone Miner. Res_. S67 (San Diego, CA, 2011). * Tian, E. et al. The role of the Wnt-signaling antagonist DKK1 in the

development of osteolytic lesions in multiple myeloma. _N. Engl. J. Med._ 349, 2483–2494 (2003). CAS  PubMed  Google Scholar  * Yaccoby, S. et al. Antibody-based inhibition of DKK1

suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. _Blood_ 109, 2106–2111 (2007). CAS  PubMed  PubMed Central  Google Scholar  * Heath, D. J. et al. Inhibiting

Dickkopf 1 (DKK1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. _J. Bone Miner. Res._ 24, 425–436 (2009). CAS  PubMed 

Google Scholar  * Pozzi, S. et al. In vivo and in vitro effects of a novel anti-DKK1 neutralizing antibody in multiple myeloma. _Bone_ 53, 487–496 (2013). CAS  PubMed  PubMed Central  Google

Scholar  * Iyer, S. P. et al. A phase IB multicentre dose-determining study of BHQ880 in combination with antimyeloma therapy and zoledronic acid in patients with relapsed or refractory

multiple myeloma and prior skeletal-related events. _Br. J. Haematol._ 167, 366–375 (2014). CAS  PubMed  Google Scholar  * Wang, Y. et al. Sodium fluoride PET imaging as a quantitative

pharmacodynamic biomarker for bone homeostasis during anti-DKK1 therapy for multiple myeloma. _Blood Cancer J._ 7, e615 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Leupin, O. et

al. Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. _J. Biol. Chem._ 286, 19489–19500 (2011). CAS  PubMed  PubMed Central  Google Scholar  *

Fijalkowski, I. et al. A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone. _J. Bone Miner. Res._ 31, 874–881

(2016). CAS  PubMed  Google Scholar  * Xiong, L. et al. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. _Proc. Natl Acad. Sci. USA_ 112,

3487–3492 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Chang, M. K. et al. Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum

sclerostin levels. _Proc. Natl Acad. Sci. USA_ 111, E5187–E5195 (2014). THIS STUDY PROVIDES THE FIRST EVIDENCE THAT SCLEROSTIN REQUIRES A CO-RECEPTOR TO FACILITATE ITS ACTION. CAS  PubMed 

PubMed Central  Google Scholar  * Ominsky, M. S. et al. Effects of sclerostin antibodies in animal models of osteoporosis. _Bone_ 96, 63–75 (2017). CAS  PubMed  Google Scholar  * Kim, S. W.

et al. Sclerostin antibody administration converts bone lining cells into active osteoblasts. _J. Bone Miner. Res._ 32, 892–901 (2017). CAS  PubMed  Google Scholar  * Ross, R. D. et al. Bone

matrix quality of sclerostin antibody treatment. _J. Bone Miner. Res._ 29, 1597–1607 (2014). CAS  PubMed  Google Scholar  * Ominsky, M. S., Niu, Q. T., Li, C., Li, X. & Ke, H. Z.

Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. _J. Bone Miner. Res._ 29, 1424–1430 (2014). THIS STUDY PROVIDES EVIDENCE THAT A

SCLEROSTIN ANTIBODY STIMULATES PREDOMINANTLY MODELLING-BASED BONE FORMATION. CAS  PubMed  Google Scholar  * Boyce, R. W., Niu, Q. T. & Ominsky, M. S. Kinetic reconstruction reveals

time-dependent effects of romosozumab on bone formation and osteoblast function in vertebral cancellous and cortical bone in cynomolgus monkeys. _Bone_ 101, 77–87 (2017). CAS  PubMed  Google

Scholar  * Ominsky, M. S. et al. Romosozumab improves bone mass and strength while maintaining bone quality in ovariectomized cynomolgus monkeys. _J. Bone Miner. Res._ 32, 788–801 (2017).

CAS  PubMed  Google Scholar  * van Lierop, A. H. et al. Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover. _J. Bone Miner. Res._ 26,

2804–2811 (2011). PubMed  Google Scholar  * Florio, M. et al. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. _Nat. Commun._ 27, 11505

(2016). THIS STUDY REPORTS SUPERIOR EFFICACY OF CONCURRENT INHIBITION OF SCLEROSTIN AND DKK1 ON BONE METABOLISM IN ANIMALS. Google Scholar  * Holdsworth, G. et al. Dampening of the bone

formation response following repeat dosing with sclerostin antibody in mice is associated with up-regulation of Wnt antagonists. _Bone_ 107, 93–103 (2018). CAS  PubMed  Google Scholar  *

Grafe, I. et al. Sclerostin antibody treatment improves the bone phenotype of Crtap(−/−) mice, a model of recessive osteogenesis imperfecta. _J. Bone Miner. Res._ 31, 1030–1040 (2016). CAS 

PubMed  Google Scholar  * Sinder, B. P. et al. Adult Brtl/+mouse model of Osteogenesis Imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and

strength. _Osteoporos. Int._ 25, 2097–2107 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Sinder, B. P. et al. Rapidly growing Brtl/+mouse model of osteogenesis imperfecta improves

bone mass and strength with sclerostin antibody treatment. _Bone_ 71, 115–123 (2015). CAS  PubMed  Google Scholar  * Kedlaya, R. et al. Sclerostin inhibition reverses skeletal fragility in

an Lrp5-deficient mouse model of OPPG syndrome. _Sci. Transl. Med._ 5, 211ra158 (2013). PubMed  PubMed Central  Google Scholar  * Moe, S. M. et al. Anti-sclerostin antibody treatment in a

rat model of progressive renal osteodystrophy. _J. Bone Miner. Res._ 30, 499–509 (2015). PubMed  Google Scholar  * Hamann, C. et al. Sclerostin antibody treatment improves bone mass, bone

strength, and bone defect regeneration in rats with type 2 diabetes mellitus. _J. Bone Miner. Res._ 28, 627–638 (2013). CAS  PubMed  Google Scholar  * Yee, C. S. et al. Sclerostin antibody

treatment improves fracture outcomes in a type I diabetic mouse model. _Bone_ 82, 122–134 (2016). CAS  PubMed  Google Scholar  * Yao, W. et al. Sclerostin-antibody treatment of

glucocorticoid-induced osteoporosis maintained bone mass and strength. _Osteoporos. Int._ 27, 283–294 (2016). CAS  PubMed  Google Scholar  * Marenzana, M. et al. Sclerostin antibody

treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone. _Arthritis Rheum._ 63, 2385–2395 (2011). CAS  PubMed  Google Scholar  *

Achiou, Z. et al. Sclerostin antibody and interval treadmill training effects in a rodent model of glucocorticoid-induced osteopenia. _Bone_ 81, 691–701 (2015). CAS  PubMed  Google Scholar 

* Tsourdi, E. et al. Sclerostin blockade and zoledronic acid improve bone mass and strength in male mice with exogenous hyperthyroidism. _Endocrinology_ 158, 3765–3777 (2017). PubMed  Google

Scholar  * McDonald, M. M. et al. Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma. _Blood_ 129, 3452–3464 (2017). CAS 

PubMed  PubMed Central  Google Scholar  * Liu, V. et al. Effects of sclerostin antibody on the healing of femoral fractures in ovariectomized rats. _Calcif. Tissue Int._ 98, 263–274 (2016).

CAS  PubMed  Google Scholar  * Tinsley, B. A. et al. Systemic administration of sclerostin antibody enhances bone morphogenetic protein-induced femoral defect repair in a rat model. _J. Bone

Joint Surg. Am._ 97, 1852–1859 (2015). PubMed  Google Scholar  * Jin, H. et al. Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling. _Bone_ 71, 63–75

(2015). CAS  PubMed  Google Scholar  * Goldhan, J. et al. Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. _Calcif. Tissue Int._ 90,

343–353 (2012). Google Scholar  * Larsson, S. Anti-sclerostin — is there an indication? _Injury_ 47, S31–S35 (2016). PubMed  Google Scholar  * Shen, C. H., Xiong, W.-C. & Mei, L. LRP4 in

neuromuscular junction and bone development and diseases. _Bone_ 80, 101–108 (2015). CAS  PubMed  Google Scholar  * Bellido, T., Saini, V. & Pajevic, P. D. Effects of PTH on osteocyte

function. _Bone_ 54, 250–257 (2013). CAS  PubMed  Google Scholar  * Lotinum, S. et al. A soluble activin receptor type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic

antiresorptive effect in cynomologous monkeys. _Bone_ 46, 1082–1088 (2010). Google Scholar  * Pearsall, R. S. et al. A soluble activin type IIA receptor induces bone formation and improves

skeletal integrity. _Proc. Natl Acad. Sci. USA_ 105, 7082–7087 (2008). CAS  PubMed  PubMed Central  Google Scholar  * Yu, F., Liu, Z., Tong, Z., Zhao, Z. & Liang, H. Soybean isoflavone

treatment induces osteoblast differentiation and proliferation by regulating analysis of Wnt/β-catenin pathway. _Gene_ 573, 273–277 (2015). CAS  PubMed  Google Scholar  * Wang, D. et al.

Stimulation of Wnt/β-catenin signaling to improve bone development by naringin via interacting with AMPK and Ak. _Cell Physiol. Biochem._ 36, 1563–1576 (2015). CAS  PubMed  Google Scholar  *

Chen, G. et al. Antiosteoporotic effect of icariin in ovariectomized rats is mediated via the Wnt/β-catenin pathway. _Exp. Ther. Med._ 12, 279–287 (2016). CAS  PubMed  PubMed Central 

Google Scholar  * Liu, Y. et al. Use of an osteoblast overload damage model to probe the effect of icariin on the proliferation, differentiation and mineralization of MC3T3-E1 cells through

the Wnt/β-catenin signalling pathway. _Cell Physiol. Biochem._ 41, 1605–1615 (2017). CAS  PubMed  Google Scholar  * US National Library of Medicine. _ClinicalTrials.gov_

http://www.clinicaltrials.gov/ct2/show/NCT01575834?term=NCT01575834&rank=1 (2018). * US National Library of Medicine. _ClinicalTrials.gov_

http://www.clinicaltrials.gov/ct2/show/NCT01796301?term=NCT01796301&rank=1 (2017). * US National Library of Medicine. _ClinicalTrials.gov_

http://www.clinicaltrials.gov/ct2/show/NCT01631214?term=NCT01631214&rank=1 (2017). * US National Library of Medicine. _ClinicalTrials.gov_

http://www.clinicaltrials.gov/ct2/show/NCT01144377?term=NCT01144377&rank=1 (2017). * Glorieux, F. H. et al. BPS804 anti-sclerostin antibody in adults with moderate osteogenesis

imperfecta: results of a randomized phase 2a trial. _J. Bone Miner. Res._ 32, 1496–1504 (2017). CAS  PubMed  Google Scholar  * Seefried, L. et al. Efficacy of anti-sclerostin monoclonal

antibody BPS804 in adult patients with hypophosphatasia. _J. Clin. Invest._ 127, 2148–2158 (2017). PubMed  PubMed Central  Google Scholar  * Padhi, D., Jang, G., Stouch, B., Fang, L. &

Posvar, E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. _J. Bone Miner. Res._ 26, 19–26 (2011). THIS STUDY IS THE FIRST HUMAN STUDY SHOWING

THE DUAL ACTION OF A SCLEROSTIN ANTIBODY ON BONE TURNOVER. CAS  PubMed  Google Scholar  * Padhi, D. et al. Multiple doses of sclerostin antibody romosozumab in healthy men and

postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. _J. Clin. Pharmacol._ 54, 168–178 (2014). CAS  PubMed  Google Scholar  * McColm, J., Hu, L.,

Womack, T., Tang, C. C. & Chiang, A. Y. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. _J. Bone

Miner. Res._ 29, 935–943 (2014). CAS  PubMed  Google Scholar  * Recker, R. R. et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal

women with low bone mineral density. _J. Bone Miner. Res._ 30, 216–224 (2015). CAS  PubMed  Google Scholar  * McClung, M. R. et al. Romosozumab in postmenopausal women with low bone mineral

density. _N. Engl. J. Med._ 370, 412–420 (2014). CAS  PubMed  Google Scholar  * Graeff, C. et al. Administration of romosozumab improves vertebral trabecular and cortical bone as assessed

with quantitative computed tomography and finite element analysis. _Bone_ 81, 364–369 (2015). CAS  PubMed  Google Scholar  * Genant, H. K. et al. Effects of romosozumab compared with

teriparatide on bone density and mass at the spine and hip in postmenopausal women with low bone mass. _J. Bone Miner. Res._ 32, 181–187 (2017). CAS  PubMed  Google Scholar  * McClung, M. R.

et al. Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: a randomized, double-blind,

phase 2, parallel group study. _J. Bone Miner. Res_. 33, 1397–1406 (2018). Article  PubMed  Google Scholar  * Bone, H. G. et al. Ten years of denosumab treatment in postmenopausal women with

osteoporosis: results from the phase 3 randomized FREEDOM trial and the open-label extension. _Lancet Diabetes Endocrinol._ 5, 513–521 (2017). CAS  PubMed  Google Scholar  * Recknor, C. P.

et al. The effect of discontinuing treatment with Blosozumab: follow-up results of a phase 2 randomized clinical trial in postmenopausal women with low bone mineral density. _J. Bone Miner.

Res._ 30, 1717–1725 (2015). CAS  PubMed  Google Scholar  * Bone, H. G. et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turover markers in

postmenopausal women with low bone mass. _J. Clin. Endocrinol. Metab._ 96, 972–980 (2011). CAS  PubMed  Google Scholar  * Weivoda, M. M. et al. Wnt signaling inhibits osteoclast

differentiation by activating canonical and noncanonical cAMP/PKA pathways. _J. Bone Miner. Res._ 31, 65–75 (2016). CAS  PubMed  Google Scholar  * Cosman, F. et al. Romosozumab treatment in

postmenopausal women with osteoporosis. _N. Engl. J. Med._ 375, 1532–1543 (2016). THIS IS THE FIRST PHASE III RCT WITH ROMOSOZUMAB. CAS  PubMed  Google Scholar  * Langdahl, B. L. et al.

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3

trial. _Lancet_ 390, 1585–1594 (2017). THIS IS A PHASE III STUDY SHOWING THE SUPERIORITY OF ROMOSOZUMAB TO TERIPARATIDE ON BMD AND BONE STRENGTH IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS.

CAS  PubMed  Google Scholar  * Saag, K. G. et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. _N. Engl. J. Med._ 377, 1417–1427 (2017). THIS IS A PHASE III

RCT DEMONSTRATING THE SUPERIORITY OF ROMOSOZUMAB TO ALENDRONATE IN REDUCING THE RISK OF FRACTURES IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS AT HIGH RISK OF FRACTURES. CAS  PubMed  Google

Scholar  * Cummings, R. C. et al. Denosumab for prevention of fractures in women with postmenopausal osteoporosis. _N. Engl. J. Med._ 361, 756–765 (2009). CAS  PubMed  Google Scholar  *

Chavassieux, P. et al. _American Soc. Bone Miner. Res. 2017 Ann. Meeting_ 1072 (Denver, CO, 2017). * Papapoulos, S. E. Romosozumab — getting there but not quite yet. _Nat. Rev. Endocrinol._

12, 691–692 (2016). CAS  PubMed  Google Scholar  * Rosen, C. J. & Ingelfinger, J. R. Building better bones with biologics — a new approach to osteoporosis? _N. Engl. J. Med._ 375,

1583–1584 (2016). PubMed  Google Scholar  * Li, X. et al. Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or cotreatment with

alendronate in osteopenic, ovariectomized rats. _Endocrinology_ 152, 3312–3322 (2011). CAS  PubMed  Google Scholar  * Kendler, D. L. et al. Effects of teriparatide and risedronate on new

fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. _Lancet_ 391, 230–240 (2018). CAS  PubMed  Google

Scholar  * Browner, W. S., Seeley, D. G., Vogt, D. M. & Cummings, S. R. Non-trauma mortality in elderly women with low bone mineral density, Study of osteoporotic fractures research

group. _Lancet_ 338, 355–358 (1991). CAS  PubMed  Google Scholar  * von der Recke, P., Hnasen, M. A. & Hassager, C. The association between low bone mass at the menopause and

cardiovascular mortality. _Am. J. Med._ 106, 273–278 (1999). PubMed  Google Scholar  * Kado, D. M., Browner, W. S., Blackwell, T., Gove, R. & Cummongs, S. R. Rate of bone loss is

associated with mortality in older women: a prospective study. _J. Bone Miner. Res._ 15, 1974–1980 (2000). CAS  PubMed  Google Scholar  * Jorgensen, L., Engstad, T. & Jacobsen, B. K. Low

mineral density in acute stroke patients; low bone mineral density may predict first stroke in women. _Stroke_ 32, 47–51 (2001). CAS  PubMed  Google Scholar  * Samelson, E. J. et al.

Metacarpal cortical area and risk of coronary heart disease; the Framingham study. _Am. J. Epidemiol._ 159, 589–595 (2004). PubMed  Google Scholar  * Tanko, L. B. et al. Relationship between

osteoporosis and cardiovascular disease in postmenopausal women. _J. Bone Miner. Res._ 20, 1912–1920 (2005). PubMed  Google Scholar  * Ye, C. et al. Decreased bone mineral density is an

independent predictor for the development of atherosclerosis: a systematic review and meta-analysis. _PLOS ONE_ 11, e0154740 (2016). PubMed  PubMed Central  Google Scholar  * Laroche, M. et

al. Osteoporosis and ischemic cardiovascular disease. _Joint Bone Spine_ 84, 427–432 (2017). CAS  PubMed  Google Scholar  * Veronese, N. et al. Relationship between low bone mineral density

and fractures with incident cardiovascular disease: a systematic review and meta-analysis. _J. Bone Miner. Res._ 32, 1126–1135 (2017). PubMed  Google Scholar  * Rosen, C. J. Romosozumab —

promising or practice changing? _N. Engl. J. Med._ 377, 1479–1480 (2017). PubMed  Google Scholar  * Khosla, S. Romosozumab — on track or derailed? _Nat. Rev. Endocrinol._ 13, 697–698 (2017).

PubMed  PubMed Central  Google Scholar  * Kim, D. H. et al. Bisphosphonates and risk of cardiovascular events; a meta-analysis. _PLOS ONE_ 10, e0122646 (2015). PubMed  PubMed Central 

Google Scholar  * Kranenburg, G. et al. Bisphosphonates for cardiovascular risk reduction: a systematic review and meta-analysis. _Atherosclerosis_ 252, 106–115 (2016). CAS  PubMed  Google

Scholar  * Eastell, R. et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis; the OCEAN study. _J. Bone Miner. Res._ 26, 1302–1312 (2011). Google

Scholar  * Huang, B. T. et al. Association between bisphosphonates therapy and incident myocardial infarction: meta-analysis and trial sequential analysis. _J. Cardiovasc. Pharmacol._ 66,

468–477 (2015). CAS  PubMed  Google Scholar  * Vestergaard, P. Acute myocardial infarction and atherosclerosis of the coronary arteries in patients treated with drugs against osteoporosis:

calcium in the vessels and not the bones? _Calcif. Tissue Int._ 90, 22–29 (2012). CAS  PubMed  Google Scholar  * Lu, P.-Y., Hsieh, C.-F., Tsai, Y.-W. & Huang, W.-F. Alendronate and

raloxifene use related to cardiovascular diseases: differentiation by different dosing regimens of alendronate. _Clin. Ther._ 33, 1173–1179 (2011). CAS  PubMed  Google Scholar  * Kang,

J.-H., Keller, J. J. & Lin, H.-C. Bisphosphonates reduced the risk of acute myocardial infarction, a 2-year follow-up study. _Osteoporos. Int._ 24, 271–277 (2013). CAS  PubMed  Google

Scholar  * Kang, J.-H., Keller, J. J. & Lin, H.-C. A population-based 2-year follow-up study on the relationship between bisphosphonates and the risk of stroke. _Osteoporos. Int._ 23,

2551–2557 (2012). CAS  PubMed  Google Scholar  * Sing, C. W. et al. Association of alendronate and risk of cardiovascular events in patients with fractures. _J. Bone Miner. Res_. 33,

1422–1434 (2018). Article  PubMed  Google Scholar  * Vliegenthart, R. et al. Stroke is associated with coronary calcification as detected by electron-beam CT: the Rotterdam coronary

calcification study. _Stroke_ 33, 462–465 (2002). PubMed  Google Scholar  * Vliegenthart, R. et al. Coronary calcification improves risk prediction in the elderly. _Circulation_ 112, 572–577

(2005). PubMed  Google Scholar  * Hollander, M. et al. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam study. _Stroke_ 34, 2367–2372 (2003). CAS  PubMed 

Google Scholar  * Boukhris, R. & Becker, K. L. Calcification of the aorta and osteoporosis. a roentgenographic study. _JAMA_ 219, 1307–1311 (1972). CAS  PubMed  Google Scholar  * Hak, A.

E., Pols, H. A., van Hemert, A. M., Hofman, A. & Witteman, J. C. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based

longitudinal study. _Arterioscler. Thromb. Vasc. Biol._ 20, 1926–1931 (2000). CAS  PubMed  Google Scholar  * Schultz, E., Xiaodong, K. A., Sayre, J. & Gilsanz, V. Aortic calcification

and the risk of osteoporosis and fractures. _J. Clin. Endocrinol Metab._ 89, 4246–4253 (2004). Google Scholar  * Bagger, Y. Z., Tanko, L. B., Alexandersen, P., Qin, G. & Christiansen, C.

Radiographic measure of aorta calcification is a site-specific predictor of bone loss and fracture risk at the hip. _J. Int. Med._ 259, 590–605 (2006). Google Scholar  * Marcovitz, P. A. et

al. Usefulness of bone mineral density to predict significant coronary artery disease. _Am. J. Cardiol._ 96, 1059–1063 (2005). PubMed  Google Scholar  * Hofbauer, L. C., Brueck, C. C.,

Shanahan, C. M., Schoppet, M. & Dobnig, H. Vascular calcification and osteoporosis — from clinical observation towards molecular understanding. _Osteoporos. Int._ 18, 251–259 (2007). CAS

  PubMed  Google Scholar  * Zhang, Y. & Feng, B. Systematic review and meta-analysis of the association of bone mineral density and osteoporosis/osteopenia with vascular calcification in

women. _Int. J. Rheum. Dis._ 20, 154–160 (2017). PubMed  Google Scholar  * Wei, D., Zheng, G., Gao, Y., Guo, J. & Zhang, T. Abdominal aortic calcification and the risk of bone

fractures: a meta-analysis of prospective cohort studies. _J. Bone Miner. Metab._ 36, 439–446 (2017). CAS  PubMed  Google Scholar  * Szulc, P. et al. Abdominal aortic calcification and risk

of fracture among older women — the SOF study. _Bone_ 81, 16–23 (2015). PubMed  PubMed Central  Google Scholar  * Kiel, D. P. et al. Bone loss and the progression of abdominal aortic

calcification over a 25 year period: the Framingham Heart Study. _Calcif. Tissue Int._ 68, 271–276 (2001). CAS  PubMed  Google Scholar  * Doherty, T. M. et al. Calcification in

atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. _Proc. Natl Acad. Sci. USA_ 100, 11201–11206 (2003). CAS  PubMed  PubMed Central  Google Scholar  *

Doherty, T. M. et al. Molecular, endocrine, and genetic mechanisms of arterial calcification. _Endocr. Rev._ 25, 629–672 (2004). CAS  PubMed  Google Scholar  * Johnson, R. C., Leopold, J. A.

& Loscalzo, J. Vascular calcification; pathobiological mechanisms and clinical implications. _Circ. Res._ 99, 1044–1059 (2006). CAS  PubMed  Google Scholar  * Demer, L. L. & Tintut,

Y. Vascular calcification; pathobiology of a multifaceted disease. _Circulation_ 117, 2938–2948 (2008). PubMed  PubMed Central  Google Scholar  * Thompson, B. & Towler, D. A. Arterial

calcification and bone physiology: role of the bone-vascular axis. _Nat. Rev. Endocrinol._ 8, 529–543 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Leszczynska, A. et al.

Differentiation of vascular stem cells contributes to ectopic calcification of atherosclerotic plaque. _Stem Cells_ 34, 913–923 (2016). CAS  PubMed  Google Scholar  * Towler, D. A.

commonalities between vasculature and bone; an osseocentric view of arteriosclerosis. _Circulation_ 135, 320–322 (2017). PubMed  PubMed Central  Google Scholar  * Papapoulos, S. E.

Bisphosphonates: how do they work? _Best Pract. Res. Clin. Endocrinol. Metab._ 22, 831–847 (2008). CAS  PubMed  Google Scholar  * Cremers, S. & Papapoulos, S. Pharmacology of

bisphosphonates. _Bone_ 49, 42–49 (2011). CAS  PubMed  Google Scholar  * Zaheer, A. et al. Optical imaging of hydroxyapatite in the calcified vasculature of transgenic animals.

_Arterioscler. Thromb. Vasc. Biol._ 26, 1132–1136 (2006). THIS STUDY PROVIDES EVIDENCE THAT A NITROGEN-CONTAINING BISPHOSPHONATE IS TAKEN UP RAPIDLY BY CALCIFIED SMALL VESSELS. CAS  PubMed 

PubMed Central  Google Scholar  * Papapoulos, S. E. Bisphosphonate actions: physical chemistry revisited. _Bone_ 38, 613–616 (2006). PubMed  Google Scholar  * Price, P. A., Faus, S. A. &

Williamson, M. K. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. _Arterioscler. Thromb. Vasc. Biol._ 21,

817–824 (2001). CAS  PubMed  Google Scholar  * Price, P. A., Roublick, A. M. & Williamson, M. K. Artery calcification in uremic rats is increased by low protein diet and prevented by

treatment with ibandronate. _Kidney Int._ 70, 1577–1583 (2006). CAS  PubMed  Google Scholar  * Percy, V., de Broe, M. & Ketteler, M. Bisphosphonates prevent experimental vascular

calcification: treat the bone to cure the vessels? _Kidney Int._ 70, 1537–1538 (2006). Google Scholar  * Li, Q., Kingman, J., Sundberg, J. P., Levine, M. A. & Uitto, J. Dual effects of

bisphosphonates on ectopic skin and vascular soft tissue mineralization versus bone microarchitecture in a mouse model of generalized arterial calcification of infancy. _J. Invest.

Dermatol._ 136, 275–283 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Ramjan, K. A., Roscioli, T., Rutsch, F., Sillence, D. & Munns, C. F. Generalized arterial calcification of

infancy: treatment with bisphosphonates. _Nat. Rev. Endocrinol. Metab._ 5, 167–172 (2009). CAS  Google Scholar  * Elmariah, S. et al. Bisphosphonate use and prevalent valvular and vascular

calcification in women: the multi-ethnic study of atherosclerosis. _J. Am. Coll. Cardiol._ 50, 1752–1759 (2010). Google Scholar  * Bennett, B. J. et al. Osteoprotegerin inactivation

accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice. _Arterioscler. Thromb. Vasc. Biol._ 26, 2117–2124 (2006). CAS  PubMed  Google Scholar  * Van

Campenhout, A. & Golledge, J. Osteoprotegerin, vascular calcification and atherosclerosis. _Atherosclerosis_ 204, 321–329 (2009). PubMed  Google Scholar  * Wu, M., Rementer, C. &

Giachelli, C. M. Vascular calcification: an update on mechanisms and challenges in treatment. _Calcif. Tissue Int._ 93, 365–373 (2013). CAS  PubMed  PubMed Central  Google Scholar  *

Davenport, C. et al. RANKL promotes osteoblastic activity in vascular smooth muscle cells by upregulating endothelial BMP-2 release. _Int. J. Biochem. Cell Biol._ 77, 171–180 (2016). CAS 

PubMed  Google Scholar  * Boström, K. I., Rajamannan, N. M. & Towler, D. A. The regulation of valvular and vascular sclerosis by osteogenic morphogens. _Circ. Res._ 109, 564–577 (2011).

PubMed  PubMed Central  Google Scholar  * Hénaut, L., Sanchez-Nino, M. D., Aldamiz-Echevarría Castillo, G., Sanz, A. B. & Ortiz, A. Targeting local vascular and systemic consequences of

inflammation on vascular and cardiac valve calcification. _Expert Opin. Ther. Targets_ 20, 89–105 (2016). PubMed  Google Scholar  * Rochette, L. et al. The role of osteoprotegerin in the

crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases. _Pharmacol. Ther._ 182, 115–132 (2018). CAS  PubMed  Google Scholar  * Badimon, L. &

Borrell-Pages, M. Wnt signaling in the vessel wall. _Curr. Opin. Hematol._ 24, 230–239 (2017). CAS  PubMed  Google Scholar  * Gay, A. & Towler, D. A. Wnt signaling in cardiovascular

disease: opportunities and challenges. _Curr. Opin. Lipidol._ 28, 387–396 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Towler, D. A. “Osteotropic” Wnt/LRP signals: high-wire

artists in a balancing act regulating aortic structure and function. _Arterioscler. Thromb. Vasc. Biol._ 37, 392–395 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Tschiderer, L.,

Willeit, J., Schett, G., Kiechl, S. & Willeit, P. Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: literature-based meta-analysis

involving 26,442 participants. _PLOS ONE_ 12, e0183910 (2017). PubMed  PubMed Central  Google Scholar  * Mani, A. et al. LRP6 mutation in a family with early coronary disease and metabolic

risk factors. _Science_ 315, 1278–1282 (2007). THIS STUDY PROVIDES THE FIRST CLINICAL DEMONSTRATION OF THE ROLE OF WNT SIGNALLING IN ARTERIAL DISEASE AND OSTEOPOROSIS. CAS  PubMed  PubMed

Central  Google Scholar  * Cheng, S. L. et al. Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR−/− mice by restraining noncanonical Wnt signals. _Circ.

Res._ 117, 142–156 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Borrell-Pagès, M., Romero, J. C. & Badimon, L. LRP5 deficiency down-regulates Wnt signalling and promotes aortic

lipid infiltration in hypercholesterolaemic mice. _J. Cell. Mol. Med._ 19, 770–777 (2015). PubMed  PubMed Central  Google Scholar  * Borrell-Pages, M., Romero, J. C. & Badimon, L.

Cholesterol modulates LRP5 expression in the vessel wall. _Atherosclerosis_ 235, 363–370 (2014). CAS  PubMed  Google Scholar  * Caira, F. C. et al. Human degenerative valve disease is

associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. _J. Am. Coll. Cardiol._ 47, 1707–1712 (2006). CAS  PubMed  PubMed

Central  Google Scholar  * van Bezooijen, R. L. et al. SOST expression is restricted to the great arteries during embryonic and neonatal cardiovascular development. _Dev. Dyn._ 236, 606–612

(2007). PubMed  Google Scholar  * van Bezooijen, R. L. et al. Sclerostin in mineralized matrices and van Buchem disease. _J. Dent. Res._ 88, 569–574 (2009). PubMed  Google Scholar  *

Didangelos, A. et al. Proteomics characterization of extracellular space components in the human aorta. _Mol. Cell. Proteomics_ 9, 2048–2062 (2010). CAS  PubMed  PubMed Central  Google

Scholar  * Krishna, S. M. et al. Wnt signaling pathway inhibitor sclerostin inhibits angiotensin II-induced aortic aneurysm and atherosclerosis. _Arterioscler. Thromb. Vasc. Biol._ 37,

553–566 (2017). CAS  PubMed  Google Scholar  * Moran, C. S., Jose, R. J., Biros, E. & Golledge, J. Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture

in the apolipoprotein E-knockout mouse. _Arterioscler. Thromb. Vasc. Biol._ 34, 2609–2616 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Bucay, N. et al. Osteoprotegerin-deficient

mice develop early onset osteoporosis and arterial calcification. _Genes Dev._ 12, 1260–1268 (1998). CAS  PubMed  PubMed Central  Google Scholar  * Tsai, S.-H. et al. Zoledronate attenuates

angiotensin II-induced abdominal aortic aneurysm through inactivation of Rho/ROCK-dependent JNK and NF-κB pathway. _Cardiovasc. Res._ 100, 501–510 (2013). CAS  PubMed  Google Scholar  * Li,

Y. et al. Inhibition of endoplasmic reticulum stress signaling pathway: a new mechanism of statins to suppress the development of abdominal aortic aneurysm. _PLOS ONE_ 12, e0174821 (2017).

PubMed  PubMed Central  Google Scholar  * Angelov, S. N. et al. TGF-β (transforming growth factor-β) signaling protects the thoracic and abdominal aorta from angiotensin II-induced pathology

by distinct mechanisms. _Arterioscler. Thromb. Vasc. Biol._ 37, 2102–2113 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Ren, H. et al. Inhibition of proteasome activity by low-dose

bortezomib attenuates angiotensin II-induced abdominal aortic aneurysm in Apo E(−/−) mice. _Sci. Rep._ 5, 15730 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Yu, H. et al.

Angiopoietin-2 attenuates angiotensin II-induced aortic aneurysm and atherosclerosis in apolipoprotein E-deficient mice. _Sci. Rep._ 21, 35190 (2016). Google Scholar  * Takahara, Y.,

Tokunou, T., Kojima, H., Hirooka, Y. & Ichiki, T. Deletion of hypoxia-inducible factor-1α in myeloid lineage exaggerates angiotensin II-induced formation of abdominal aortic aneurysm.

_Clin. Sci._ 131, 609–620 (2017). CAS  Google Scholar  * Ijaz, T. et al. Deletion of NF-κB/RelA in angiotensin II-sensitive mesenchymal cells blocks aortic vascular inflammation and

abdominal aortic aneurysm formation. _Arterioscler. Thromb. Vasc. Biol._ 37, 1881–1890 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Hayashi, T. et al. Ultraviolet B exposure

inhibits angiotensin II-induced abdominal aortic aneurysm formation in mice by expanding CD4+Foxp3+ regulatory T cells. _J. Am. Heart Assoc._ 6, e007024 (2017). PubMed  PubMed Central 

Google Scholar  * Liu, Y. et al. Calorie restriction protects against experimental abdominal aortic aneurysms in mice. _J. Exp. Med._ 213, 2473–2488 (2016). CAS  PubMed  PubMed Central 

Google Scholar  * Yoshihara, T. et al. Omega 3 polyunsaturated fatty acids suppress the development of aortic aneurysms through the inhibition of macrophage-mediated inflammation. _Circ. J._

79, 1470–1478 (2015). CAS  PubMed  Google Scholar  * Kohashi, K. et al. A dipeptidyl peptidase-4 inhibitor but not incretins suppresses abdominal aortic aneurysms in angiotensin II-infused

apolipoprotein E-null mice. _J. Atheroscler. Thromb._ 23, 441–454 (2016). CAS  PubMed  Google Scholar  * Pope, N. H. et al. D-Series resolvins inhibit murine abdominal aortic aneurysm

formation and increase M2 macrophage polarization. _FASEB J._ 30, 4192–4201 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Duan, Q. et al. Inhibition of BET bromodomain attenuates

angiotensin II induced abdominal aortic aneurysm in ApoE−/− mice. _Int. J. Cardiol._ 223, 428–432 (2016). PubMed  Google Scholar  * Vorkapic, E. et al. Imatinib treatment attenuates growth

and inflammation of angiotensin II induced abdominal aortic aneurysm. _Atherosclerosis_ 249, 101–109 (2016). CAS  PubMed  Google Scholar  * Yan, H. et al. Antagonism of toll-like receptor 2

attenuates the formation and progression of abdominal aortic aneurysm. _Acta Pharm. Sin. B_ 5, 176–187 (2015). PubMed  PubMed Central  Google Scholar  * Yan, P. et al. UCP-2 is involved in

angiotensin-II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice. _PLOS ONE_ 6, e0179743 (2017). Google Scholar  * Tarín, C. et al. Lipocalin-2 deficiency or blockade

protects against aortic abdominal aneurysm development in mice. _Cardiovasc. Res._ 111, 262–273 (2016). PubMed  Google Scholar  * Li, X. et al. Targeted deletion of the sclerostin gene in

mice results in increased bone formation and bone strength. _J. Bone Miner. Res._ 23, 860–869 (2008). PubMed  Google Scholar  * van Lierop, A., Appelman-Dijkstra, N. M. & Papapoulos, S.

E. Human sclerostin deficiency. _Bone_ 96, 51–62 (2017). PubMed  Google Scholar  * Beighton, P., Durr, L. & Hamersma, H. The clinical features of sclerosteosis. A review of the

manifestations in twenty-five affected individuals. _Ann. Intern. Med._ 84, 393–397 (1976). CAS  PubMed  Google Scholar  * Hamersma, H., Gardner, J. & Beighton, P. The natural history of

sclerosteosis. _Clin. Genet._ 63, 192–197 (2003). CAS  PubMed  Google Scholar  * Beighton, P., Barnard, A., Hamersma, H. & van der Wouden, A. The syndromic status of sclerosteosis and

van Buchem disease. _Clin. Genet._ 25, 175–181 (1984). CAS  PubMed  Google Scholar  * Van Buchem, F. S. Hyperostosis corticalis generalisata; eight new cases. _Acta Med. Scand._ 189, 257–267

(1971). PubMed  Google Scholar  * Van Buchem, F. S., Hadders, H. N. & Ubbens, R. An uncommon familial systemic disease of the skeleton: hyperostosis corticalis generalisata familiaris.

_Acta Radiol._ 44, 109–120 (1955). Google Scholar  * van Lierop, A. H. et al. Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. _J. Bone

Miner. Res._ 28, 848–854 (2013). PubMed  Google Scholar  * Kaesler, N. et al. Sclerostin deficiency modifies the development of CKD-MBD in mice. _Bone_ 107, 115–123 (2018). CAS  PubMed 

Google Scholar  * Tonelli, M. et al. Chronic kidney disease and mortality risk: a systematic review. _J. Am. Soc. Nephrol._ 17, 2034–2047 (2006). PubMed  Google Scholar  * Wanner, C., Amann,

K. & Shoji, T. The heart and vascular system in dialysis. _Lancet_ 388, 276–284 (2016). PubMed  Google Scholar  * Schiffrin, E. L., Lipman, M. L. & Mann, J. F. E. Chronic kidney

disease: effects on the cardiovascular system. _Circulation_ 116, 85–97 (2007). PubMed  Google Scholar  * Hruska, K. A., Mathew, S., Lund, R. J., Memon, I. & Saab, G. The pathogenesis of

vascular calcification in the chronic kidney disease mineral bone disorder: the links between bone and the vasculature. _Semin. Nephrol._ 29, 156–165 (2009). CAS  PubMed  PubMed Central 

Google Scholar  * Evenepoel, P., D’Haese, P. & Brandenburg, V. Sclerostin and DKK1: new players in renal bone and vascular disease. _Kidney Int._ 88, 235–240 (2015). CAS  PubMed  Google

Scholar  * Yamada, S. & Giachelli, C. M. Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. _Bone_ 100, 87–93 (2017). CAS  PubMed  Google Scholar  * Hruska, K.

A., Sugatani, T., Agapova, O. & Fang, Y. The chronic kidney disease — mineral bone disorder (CKD-MBD): advances in pathophysiology. _Bone_ 100, 80–86 (2017). CAS  PubMed  PubMed Central

  Google Scholar  * Wesseling-Perry, K. & Juppner, H. The osteocyte in CKD: new concepts regarding the role of FGF23 in mineral metabolism and systemic complications. _Bone_ 54, 222–229

(2013). CAS  PubMed  Google Scholar  * Zhu, D., Mackenzie, N. C., Millán, J. L., Farquharson, C. & MacRae, V. E. The appearance and modulation of osteocyte marker expression during

calcification of vascular smooth muscle cells. _PLOS ONE_ 6, e19595 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Sciavi, S. C. Sclerostin and CKD-MBD. _Curr. Osteoporos. Rep._ 13,

159–165 (2015). Google Scholar  * Brandenburg, V. M. et al. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study. _BMC Nephrol._

14, 219 (2013). PubMed  PubMed Central  Google Scholar  * Qureshi, A. R. et al. Increased circulating sclerostin levels in end-stage renal disease predict biopsy-verified vascular medial

calcification and coronary artery calcification. _Kidney Int._ 88, 1356–1364 (2015). CAS  PubMed  Google Scholar  * Kanbay, M. et al. Serum sclerostin and adverse outcomes in nondialyzed

chronic kidney disease patients. _J. Clin. Endocrinol. Metab._ 99, E1854–E1861 (2014). CAS  PubMed  Google Scholar  * Koos, R. et al. Sclerostin as a potential novel biomarker for aortic

valve calcification: an in-vivo and ex-vivo study. _J. Heart Valve Dis._ 22, 317–325 (2013). PubMed  Google Scholar  * Cejka, D. et al. Renal elimination of sclerostin increases with

declining kidney function. _J. Clin. Endocrinol. Metab._ 99, 248–255 (2014). CAS  PubMed  Google Scholar  * Evenepoel, P. et al. Sclerostin serum levels and vascular calcification

progression in prevalent renal transplant recipients. _J. Clin. Endocrinol. Metab._ 100, 4669–4676 (2015). CAS  PubMed  Google Scholar  * Drechsler, C. et al. High levels of circulating

sclerostin are associated with better cardiovascular survival in incident dialysis patients: results from the NECOSAD study. _Nephrol. Dial. Transplant._ 30, 288–293 (2015). CAS  PubMed 

Google Scholar  * Zeng, C., Guo, C., Cai, J., Tang, C. & Dong, Z. Serum sclerostin in vascular calcification and clinical outcome in chronic kidney disease. _Diab. Vasc. Dis. Res._ 15,

99–105 (2018). CAS  PubMed  Google Scholar  * Behets, G. J. et al. Circulating levels of sclerostin but not DKK1 associate with laboratory parameters of CKD-MBD. _PLOS ONE_ 12, e0176411

(2017). PubMed  PubMed Central  Google Scholar  * McNulty, M. et al. Determination of serum and plasma sclerostin concentrations by enzyme-linked immunoassays. _J. Clin. Endocrinol. Metab._

96, E1159–E1162 (2011). PubMed  PubMed Central  Google Scholar  * Durosier, C. et al. Association of circulating sclerostin with bone mineral mass, microstructure, and turnover biochemical

markers in healthy elderly men and women. _J. Clin. Endocrinol. Metab._ 98, 3873–3883 (2013). CAS  PubMed  Google Scholar  * Clarke, B. L. & Drake, M. T. Clinical utility of serum

sclerostin measurements. _Bonekey Rep._ 2, 361 (2013). PubMed  PubMed Central  Google Scholar  * Mause, S. F. et al. Validation of commercially available ELISAs for the detection of

circulating sclerostin in hemodialysis patients. _Discoveries_ 4, e55 (2016). PubMed  Google Scholar  * Delanaye, P. et al. Sclerostin and chronic kidney disease: the assay impacts what we

(thought to) know. _Nephrol. Dial. Transplant_. 2017 Oct 18. https://doi.org/10.1093/ndt/gfx282. Article  PubMed  PubMed Central  Google Scholar  * Fulzele, K. et al. Osteocyte-secreted Wnt

signaling inhibitor sclerostin contributes to beige adipogenesis in peripheral fat depots. _J. Bone Miner. Res._ 32, 373–384 (2017). CAS  PubMed  Google Scholar  * Delgado-Calle, J. &

Bellido, T. New insights into the local and systemic functions of sclerostin: regulation of quiescent bone lining cells and beige adipogenesis in peripheral fat depots. _J. Bone Miner. Res._

32, 889–891 (2017). PubMed  Google Scholar  * van Lierop, A. & Papapoulos, S. E. in _Biomarkers in Bone Disease, Biomarkers in Disease, Methods, Discoveries and Applications_ (eds

Patel, V. B. & Preedy, V. R.) 221–237 (Springer, Doordrecht, 2017). Google Scholar  * Sabbagh, Y. et al. Repression of osteocyte Wnt/β-catenin signaling is an early event in the

progression of renal osteodystrophy. _J. Bone Miner. Res._ 27, 1757–1772 (2012). CAS  PubMed  Google Scholar  * Zhou, H., Yang, M., Li, M. & Cui, L. Radial artery sclerostin expression

in chronic kidney disease stage 5 predialysis patients: a crossectional observational study. _Int. Urol. Nephrol._ 49, 1433–1437 (2017). CAS  PubMed  Google Scholar  * Garnero, P. The

utility of biomarkers in osteoporosis management. _Mol. Diagn. Ther._ 21, 401–418 (2017). CAS  PubMed  Google Scholar  * Yavropoulou, M. P., van Lierop, A. H., Hamdy, N. A., Rizzoli, R.

& Papapoulos, S. E. Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. _Bone_ 51, 153–157 (2012). CAS  PubMed  Google

Scholar  * Hampson, G. et al. The relationship between inhibitors of the Wnt signalling pathway (Dickkopf-1(DKK1) and sclerostin), bone mineral density, vascular calcification and arterial

stiffness in post-menopausal women. _Bone_ 56, 42–47 (2013). CAS  PubMed  Google Scholar  * Morales-Santana, S. et al. Atherosclerotic disease in type 2 diabetes is associated with an

increase in sclerostin levels. _Diabetes Care_ 36, 1667–1674 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Paccou, J. et al. The relationships between serum sclerostin, bone mineral

density, and vascular calcification in rheumatoid arthritis. _J. Clin. Endocrinol. Metab._ 99, 4740–4748 (2014). CAS  PubMed  Google Scholar  * Szulc, P., Schoppet, M., Rachner, T. D.,

Chapurlat, R. & Hofbauer, L. C. Severe abdominal aortic calcification in older men is negatively associated with DKK1 serum levels: the STRAMBO study. _J. Clin. Endocrinol. Metab._ 99,

617–624 (2014). CAS  PubMed  Google Scholar  * Touw, W. A. et al. Association of circulating Wnt antagonists with severe abdominal aortic calcification in elderly women. _J. Endocr. Soc._ 1,

26–38 (2017). PubMed  PubMed Central  Google Scholar  * Register, T. C. et al. Plasma Dickkopf1 (DKK1) concentrations negatively associate with atherosclerotic calcified plaque in

African-Americans with type 2 diabetes. _J. Clin. Endocrinol. Metab._ 98, E60–65 (2013). CAS  PubMed  Google Scholar  * Fang, Y. et al. CKD-induced wingless/integration1 inhibitors and

phosphorus cause the CKD-mineral and bone disorder. _J. Am. Soc. Nephrol._ 25, 1760–1773 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Chouinard, L. et al. Carcinogenicity risk

assessment of romosozumab: a review of scientific weight-of-evidence and findings in a rat lifetime pharmacology study. _Regul. Toxicol. Pharmacol._ 81, 212–222 (2016). THIS IS A

COMPREHENSIVE REPORT OF ANIMAL TOXICOLOGY WITH ROMOSOZUMAB. CAS  PubMed  Google Scholar  * Jolette, J. et al. Comparing gthe incidence of bone tumors in rats chronically exposed to the

selective PTH type receptor 1 agonist abaloparatide or PTH (1–34). _Regul. Toxicol. Pharmacol._ 86, 356–365 (2017). CAS  PubMed  Google Scholar  * Stolina, M. et al. Temporal change s in

systemic and local expression of bone turnover markers during six months of sclerostin antibody administration to ovariectomized rats. _Bone_ 67, 305–313 (2014). CAS  PubMed  Google Scholar

  * Ueland, T. et al. Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis. _Arterioscler. Thromb. Vasc.

Biol._ 29, 1228–1234 (2009). CAS  PubMed  Google Scholar  * Cheng, S. L., Shao, J. S., Behrmann, A., Krchma, K. & Towler, D. A. Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the

endothelial-mesenchymal transition in aortic endothelial cells. _Arterioscler. Thromb. Vasc. Biol._ 33, 1679–1689 (2013). CAS  PubMed  Google Scholar  * Ezan, J. et al. FrzA/sFRP-1, a

secreted antagonist of the Wnt-frizzled pathway, controls vascular cell proliferation in vitro and in vivo. _Cardiovasc. Res._ 63, 731–738 (2004). CAS  PubMed  Google Scholar  * Dufourcq, P.

et al. Regulation of endothelial cell cytoskeletal reorganization by a secreted frizzled-related protein-1 and frizzled 4- and frizzled 7-dependent pathway: role in neovessel formation.

_Am. J. Pathol._ 172, 37–49 (2008). CAS  PubMed  PubMed Central  Google Scholar  * Di, M. et al. Dickkopf1 destabilizes atherosclerotic plaques and promotes plaque formation by inducing

apoptosis of endothelial cells through activation of ER stress. _Cell Death Dis._ 8, e2917 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Baron, R. & Hesse, E. Update on bone

anabolics in osteoporosis treatment, rationale, current status and persectives. _J. Clin. Endocrinol. Metab._ 97, 311–325 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Black, D. M.

et al. One year alendronate after one year of parathyroid hormone (1–84) for postmenopausal osteoporosis. _N. Engl. J. Med._ 353, 555–565 (2005). CAS  PubMed  Google Scholar  * Adami, S. et

al. Effect of raloxifene after recombinant teriparatide [hPTH(1–34)] treatment in postmenopausal women with osteoporosis. _Osteoporos. Int._ 19, 87–94 (2008). CAS  PubMed  Google Scholar  *

Greenspan, S. L. et al. Significant differential effects of alendronate, estrogen or combination therapy on the rate of bon loss after discontinuation of treatment of postmenopausal

osteoporosis. _Ann. Int. Med._ 137, 875–883 (2002). CAS  PubMed  Google Scholar  * Black, D. M. et al. The effects of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a

randomized extension to the HORIZON-pivotal fracture trial (PFT). _J. Bone Miner. Res._ 27, 243–254 (2012). CAS  PubMed  Google Scholar  * Li, X. et al. Sclerostin antibody treatment

increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. _J. Bone Miner. Res._ 24, 578–588 (2009). CAS  PubMed  Google Scholar  * Li, X. et al.

Progressive increases in bone mass and bone strength in an ovariectomized rat model of osteoporosis after 26 weeks of treatment with a sclerostin antibody. _Endocrinology_ 155, 4785–4797

(2014). PubMed  Google Scholar  * Li, X. et al. Sclerostin antibody reverses bone loss by increasing bone formation and decreasing bone resorption in a rat model of male osteoporosis.

_Endocrinology_ 159, 260–271 (2018). PubMed  Google Scholar  * Suen, P. K. et al. Sclerostin antibody treatment increases bone formation, bone mass and bone strength of intact bones in adult

male rats. _Sci. Rep._ 51, 15632 (2015). Google Scholar  * Ominsky, M. S. et al. Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength

of nonfractured bones. _J. Bone Miner. Res._ 26, 1012–1021 (2011). CAS  PubMed  Google Scholar  * Li, X. et al. Inhibition of sclerostin by monoclonal antibody increases bone formation,

bone mass, and bone strength in aged male rats. _J. Bone Miner. Res._ 25, 2647–2656 (2010). PubMed  Google Scholar  * Ominsky, M. S. et al. Two doses of sclerostin antibody in cynomolgus

monkeys increases bone formation, bone mineral density, and bone strength. _J. Bone Miner. Res._ 25, 948–959 (2010). CAS  PubMed  Google Scholar  Download references 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. 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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