REVIEW

Involvement of WNT/b-catenin Signaling in the Treatmentof Osteoporosis

Maurizio Rossini • Davide Gatti • Silvano Adami

Received: 8 March 2013 / Accepted: 5 May 2013 / Published online: 11 June 2013

� Springer Science+Business Media New York 2013

Abstract Osteoblast differentiation is predominantly reg-

ulated by the WNT/b-catenin signaling (canonical WNT

pathway), which, together with bone morphogenetic proteins,

acts as the master regulator of osteogenesis. The recent

characterization of the canonical WNT pathway in the regu-

lation of bone modeling and remodeling provided important

insights for our understanding of the pathophysiology of a

number of conditions and of the mechanism of action of

hormones or drugs with important effect on bone metabolism.

This review is mainly focused on the growing therapeutic

implications of these new findings. WNT/b-catenin signaling

plays a key role in bone tissue by determining the differen-

tiation of stem cells into mature osteoblasts rather than into

chondrocytes and adipocytes. Its regulation is predominantly

driven by the production of two WNT signaling antagonists:

sclerostin (SOST) and Dickkopf-related protein 1 (DKK1).

The most proximate regulator of SOST expression by

osteocytes and its serum levels is bone mechanical load.

SOST expression is increased with advancing age, by glu-

cocorticoid treatment and during treatment with antiresorp-

tive agents such as bisphosphonates and denosumab, while it

is decreased by parathyroid hormone excess or administration

of estrogens. Correlation between DKK1 serum levels and

bone formation in various pathological conditions or during

osteoporosis treatment has been reported. Inhibitors of the

negative regulators of WNT/b-catenin signaling (‘‘inhibiting

the endogenous inhibitors’’) are potential candidates for the

prevention and treatment of bone loss. Inactivating mono-

clonal antibodies against SOST appears to be the most

attractive strategy because SOST is the only component of the

WNT pathway expressed almost exclusively by osteocytes.

Keywords Osteoblast � Osteoclast � Osteocyte �Osteoporosis � WNT signaling

WNT/b-catenin Signaling and Bone

Osteoblast differentiation is predominantly regulated by

the WNT/b-catenin signaling (canonical WNT pathway)

(Fig. 1), which acts as the master regulator of osteogenesis

together with bone morphogenetic proteins [1, 2]. Canon-

ical WNT pathway plays also a key role in determining the

fate of mesenchymal stem cells. In the absence of b-cate-

nin, these cells do not differentiate into mature osteocalcin-

expressing osteoblasts [3, 4] but into chondrocytes [5, 6]. It

also promotes osteoblastogenesis by suppressing adipo-

genesis, thus contrasting peroxisome proliferator activated

receptor gamma (PPARgamma) that induces adipogenesis

and inhibits osteoblastogenesis [7–9] (Fig. 2).

Increased WNT signaling might also, in some circum-

stances, result in a reduced osteoclastogenesis and bone

resorption [10] by promoting the osteoblast expression of

osteoprotegerin [11] (Fig. 2).

The regulation of canonical WNT pathway in bone is

driven by the production of receptor inhibitors such as

Sclerostin (SOST) and Dickkopf-related protein 1 (DKK1)

(Fig. 1). The understanding of their role and of the regu-

lation of their expression in diseases and during bone active

therapies was enhanced by the recent commercial avail-

ability of ELISA kits for their measurement in serum

samples.

The authors report that they have no conflict of interest.

M. Rossini � D. Gatti � S. Adami (&)

Department of Medicine, Rheumatology Section, Policlinico

Borgo Roma, University of Verona, Piazzale Scuro, 10,

37134 Verona, Italy

e-mail: silvano.adami@univr.it

123

Calcif Tissue Int (2013) 93:121–132

DOI 10.1007/s00223-013-9749-z

Role of SOST

The role of SOST in the regulation of bone remodeling in

both physiological and pathological conditions has been

extensively studied (Table 1). The most proximate

regulator of SOST expression by osteocytes and its serum

levels is bone mechanical load. Immobilization is associ-

ated with higher SOST levels and reduced bone formation,

confirming that SOST is likely to be the most important

link between mechanical unloading and disuse osteoporosis

Fig. 1 The binding of WNT

with specific cell surface

receptors (Frizzled and LRP

5/6) lead to binding of Axin,

which otherwise favors the

proteolysis of b-catenin. Thus,

b-catenin can enter into the

nucleus and stimulate the

transcription process. DKK1

and SOST block the activation

of WNT canonical pathway and

so b-catenin is sequestered and

degraded as in absence of WNT

stimulation. DKK1 also

interacts with another class of

receptors (Kremen 1 and 2) to

form a ternary complex

(Kremen–DKK1–LRP6) that

blocks WNT–LRP6 signaling

by inducing endocytosis and

removal of WNT receptor from

the plasma membrane. SOST

antagonizes WNT/b-catenin

signaling in osteoblasts by

binding to LRP6 and preventing

its association with WNT

Fig. 2 Mesenchymal stem cells

resided in the bone cavity give

rise to most stromal cell

lineages including

chondrocytes, osteoblasts,

adipocytes. Canonical WNT

signaling prevents the

differentiation down the

chondrocyte and adipocyte

lineage and targets them instead

to the osteoblast lineage. WNT

canonical signaling favors also

maturation and survival of

osteoblasts and promotes the

expression of osteoprotegerin

rather than RANKL, thus

indirectly inhibiting osteoclast

activity

122 M. Rossini et al.: WNT/b-catenin Signaling in Osteoporosis

123

in humans. The evidence in humans for this role of SOST is

coming from two small studies involving subjects com-

pelled to bed for either a stroke [12] or experimentally in

healthy subjects for several weeks [13]. In a number of

studies including overall thousands of subjects, values of

serum SOST were found to increase with aging, particu-

larly soon after menopause [14, 15], and to correlate pos-

itively with body mass index and bone mineral content

[15, 16] by controlling for confounding factors. Men have

significantly higher SOST levels than women, but the dif-

ference disappears for values adjusted for age, bone min-

eral content, physical activity, body mass index, and renal

function [15]. Circulating SOST is increased in type 2

diabetes mellitus independently of gender and age [17].

It has been observed that SOST expression diminish

within the first few days after a major fracture, and this

might be triggered by the inflammatory process resulting

from local destruction of bone tissue [18]. This may favor

fracture healing, even though the consequences of sub-

sequent limb unloading on SOST have not been investi-

gated. The later increase in SOST due to unloading may

indeed slow the healing process.

A number of experimental models and clinical obser-

vations consistently suggest that SOST is down-regulated

by parathyroid hormone (PTH) in humans. Serum SOST

was found to be significantly lower in patients with primary

hyperparathyroidism compared to healthy controls but

significantly higher in hypoparathyroid subjects. In the

latter patients, but also in patients with secondary hyper-

parathyroidism due to vitamin D deficiency, SOST levels

negatively correlated with serum PTH even for values

adjusted for confounding factors such as age or body

weight [19–21]. In patients with severe chronic renal fail-

ure and secondary hyperparathyroidism, serum levels of

SOST and PTH were inversely correlated, and in adjusted

analyses, SOST remained a strong predictor of parameters

of bone turnover and osteoblast number [22].

The specific effect of glucocorticoids on SOST expres-

sion depends on the experimental conditions. SOST

expression was found both decreased [23] and increased

[24] after bone cell exposure to glucocorticoids. Chronic

endogenous hypercortisolism is associated with decreased

SOST levels [25] despite depressed bone formation. All

these results are hard to interpret. It is likely that chronic

exposure to glucocorticoids affects the number or function

of osteocytes directly rather than by modulating SOST

expression. The direct negative effect of glucocorticoids on

osteocyte number decreases is inevitably associated with

lower circulating SOST levels. On the other hand, it has

been recently reported that osteocyte apoptosis induced by

glucocorticoid is prevented and reversed by antisclerostin

antibody in a male rat model [26].

Of relevance is also the crosstalk between WNT/

b-catenin signaling and sex steroid hormones. Postmeno-

pausal women have higher serum SOST levels compared to

premenopausal women, and in postmenopausal women,

serum SOST levels are inversely associated with the cir-

culating free estradiol index [27]. SOST levels were sig-

nificantly lower in the estrogen-treated compared to control

postmenopausal women both in peripheral serum (by

32 %) and in bone marrow plasma (by 34 %) [28]. All

these findings suggest that estrogens directly suppress

SOST expression.

Because WNT signaling is implicated in regulating not

only bone formation but also bone resorption, through down-

regulation of RANKL expression in osteoblasts [10, 11], it is

conceivable that changes in SOST production may also

contribute to the effects of estrogens on bone resorption.

The Role of DKK1

DKK1, a secreted glycoprotein, is another soluble inhibitor

of Wnt/b-catenin signaling that binds to Lrp5 and Lrp6 [1].

WNT signaling antagonists, including DKK1, are strongly

up-regulated during the late phase of osteoblast differen-

tiation [1]. DKK1 expression is predominantly limited to

bone (osteoblasts and maturing osteocytes) in adult animals

[29], but its expression in growing subjects is unknown,

and DKK1 expression was detected in neoplastic cells of

multiple myeloma patients with widespread osteolytic bone

lesions [30]. The role of DKK1 in the regulation of bone

Table 1 Factors associated with changes in serum SOST levels

Increase in SOST

Mechanical unloading

Immobilization

Low physical activity

Aging

Menopause

Weight loss

Type 2 diabetes mellitus

Glucocorticoids

Bisphosphonates

Denosumab

Decrease in SOST

Mechanical loading

Exercise training

PTH

Oestrogens

First days after major fractures

Chronic endogenous hypercortisolism

Raloxifene

Strontium

M. Rossini et al.: WNT/b-catenin Signaling in Osteoporosis 123

123

remodeling in both physiological and pathological condi-

tions is less well characterized. Changes in production or

activity of DKK1 in aging-related osteoporosis have not

been yet reported. Aberrant expression of DKK1 in mye-

loma cells was shown to be associated with increased

osteolytic lesions in human multiple myeloma [30]. DKK1

appears to be a master regulator of joint remodeling [31]: it

correlates with bone erosions and inflammation in rheu-

matoid arthritis [32], and this might suggest that overex-

pression of DKK1 in rheumatoid arthritis patients might

account for low bone formation and secondary osteoporosis

and joint bone destruction. An additional predictor of bone

erosions in rheumatoid arthritis is also PTH [33], which

was found in these patients to be significantly correlated

with DKK1 serum levels [34].

In patients with ankylosing spondylitis, the formation of

syndesmophytes was less evident in patients with higher

functional DKK1 levels, suggesting that blunted WNT

signaling suppresses new bone formation and consequently

syndesmophyte growth and spinal ankylosis [35]. Elevated

circulating levels of DKK1 appears to be associated with

reduced progression of radiographic hip osteoarthritis in

elderly women [36], and the levels of serum DKK1 are

significantly lower in patients with diffuse idiopathic

skeletal hyperostosis [37] (Fig. 3).

PTH is negatively correlated with SOST expression but

positively correlated with DKK1. In a recent study including

both healthy subjects and primary hyperparathyroid patients,

serum PTH was confirmed to be negatively correlated with

SOST, but it was found to be positively correlated with

DKK1. It was suggested that the balance between the two

WNT pathway inhibitors might explain the variable skeletal

involvement in primary hyperparathyroidism [21].

Genetic Disorders of Bone, Osteoporosis, and WNT/

b-catenin Signaling

The involvement in the regulation of bone mass of com-

ponents of the canonical WNT pathway was first shown

after identification of homozygous loss-of-function muta-

tions of LRP5 in osteoporosis–pseudoglioma syndrome, in

which patients have reduced bone mineral density (BMD),

skeletal fragility, and congenital blindness [38]. On the

other hand, a heterozygous G171V point mutation in LRP5

causes an autosomal-dominant high bone mass trait [39,

40]. The mutant LRP5 protein has impaired binding to

DKK1, SOST, and other soluble inhibitors of WNT sig-

naling, and this mechanism is thought to result in increased

osteoblastic bone formation [41, 42]. LRP5 variants sig-

nificantly contribute to lumbar spine bone mass and size

determination in men by influencing vertebral bone growth

during childhood [43].

Mutations in the SOST gene encoding SOST result in

two different diseases well known for decades: the scler-

osteosis syndrome, which is characterized by cortical

hyperostosis and syndactyly [44], and van Buchem disease,

which is similarly characterized by cortical hyperostosis

and cranial nerve entrapment, often requiring surgical

decompression [45]. The role of WNT pathway on bone

Fig. 3 Reported correlation

between DKK1 serum levels

and bone mass in various

pathological conditions.

Aberrant expression of DKK1 in

myeloma cells was shown to be

associated with increased

osteolytic lesions and severe

osteoporosis. DKK1 appears to

be a master regulator of joint

remodeling in rheumatoid

arthritis (RA) and ankylosing

spondylitis (SA), and with lower

evidence in osteoarthritis (OA)

and diffuse idiopathic skeletal

hyperostosis (DISH)

124 M. Rossini et al.: WNT/b-catenin Signaling in Osteoporosis

123

metabolism was later characterized by a number of genetic

studies in animal models. Transgenic studies in which the

LRP5 gene was disrupted or overexpressed in mice resulted

in a phenotype identical to the human diseases with either

osteoporosis [46] or increased bone mass [47].

WNT signaling activity is likely to be linked with genetic

polymorphisms: low BMD and excess fracture risk have

been associated with polymorphisms for LRP5 [48, 49],

SOST [50], and WNT 16 [51, 52]. Two recent studies found

also an association between genetic polymorphisms in the

gene encoding Frzp, a WNT antagonist, and the risk of hip

osteoarthritis [53, 54]. All these studies raise a number of

interesting questions as to possible functional relationships

between osteoarthritis and osteoporosis. For example, if

osteoblasts and chondrocytes are influenced by common

WNT pathways, this may help to explain inverse associa-

tions between osteoarthritis and osteoporosis, whereby a

genetic variant favoring chondrogenesis might have reci-

procal effects on osteoblasts, leading to reduced BMD [55].

Thus, changes in the expression activity of WNT path-

way in bone may explain a variety of bone mass pheno-

types, ranging from sclerosteosis to severe osteoporosis

(Fig. 4). Serum SOST levels increase markedly with age

and even more for values adjusted for the prevailing bone

mass [56]. Its production rises also as a consequence of

declining physical activity [57] and deterioration of renal

function [58]. Thus, overexpression of SOST may ensue as

a result of both aging per se and age-dependent decreased

renal function and mechanical stimulation.

The association between SOST levels and the risk of

osteoporosis has yielded conflicting results. In a population-

based study including 707 postmenopausal women, high

SOST levels were strong and independent risk factors for

osteoporosis-related fractures: the risk increased[7-fold for

each SD increment increase in SOST level [59]. In another

study, the risk of hip fracture was significantly elevated

among those in the highest quartile compared with women in

the lowest SOST quartile, after adjusting for the confounder

factors [60]. However, in older men, higher serum levels of

SOST were found to be associated with lower risk of fracture

[61], and serum SOST levels were found to be positively

correlated with BMD [56, 60–63]. These latter findings were

explained by the association between bone mass and the

number of osteocytes secreting SOST.

A weak negative correlation between SOST and bone

turnover markers has been reported [61, 63], but an

opposite positive association was found in a cohort of

patients with Paget disease, bone metastatic cancer, and a

wide range of bone turnover in healthy subjects [64].

In conclusion, although genetic disorders of the WNT

pathway are associated with gross changes in skeletal

structure, the genetic polymorphisms so far identified and

the changes in serum levels of WNT components seem to

play a marginal role in explaining the variation in BMD or

bone metabolism in the general population.

Bone Active Agents and WNT/b-catenin Signaling

Bone active agents used for the treatment of postmeno-

pausal and male osteoporosis include a number of inhibi-

tors of bone resorption, such as estrogens, bisphosphonates,

Fig. 4 The canonical WNT

signaling pathway influences

both the acquisition and the

maintenance of bone mass.

Congenital changes in its

expression or functionality of

LRP5 or SOST explain a wide

variance in bone mass ranging

from sclerosteosis to severe

osteoporosis

M. Rossini et al.: WNT/b-catenin Signaling in Osteoporosis 125

123

and denosumab, strontium ranelate with an unidentified

mechanism of action, and a unique anabolic agent,

recombinant human PTH(1–34) (teriparatide). Some of

their effects on bone turnover are related with changes in

WNT/b-catenin signaling.

Treatment with estrogens or raloxifene, but not with

androgens, is associated with a decrease in SOST levels

[65, 66].

Bisphosphonate are known to directly suppress osteo-

clastic activity, but the suppression of bone resorption is

typically associated with a later decrease also of bone

formation. It has been recently shown that chronic treat-

ment with a bisphosphonate in osteoporotic women is

associated with gradual increases in the serum levels of

SOST, which mirrors the decline in bone formation

markers [67]. Osteoclast progenitors, but not the mature

osteoclasts, are the only cells in addition to osteocytes that

express SOST [68], and bisphosphonate therapy induces

the apoptosis of the mature osteoclasts, while the number

of osteoclast progenitors increases [69]. This increase in

the number of preosteoclasts might represent the most

likely explanation for the observed increase in SOST dur-

ing bisphosphonate therapy. However, this hypothesis was

not supported by data coming from osteoporotic women

receiving treatment with denosumab, which was also found

to be associated with increasing serum SOST levels [70];

however, denosumab, by fully suppressing RANKL activ-

ity, lowers the number of not only actively resorbing

osteoclasts (as bisphosphonates) but also osteoclast pre-

cursors. Denosumab treatment was associated with

declining serum levels of DKK1 [70], and this might

explain the apparent persistent slight positive imbalance

between suppressed bone resorption and formation during

denosumab treatment (Fig. 5).

It has been reported that treatment with analogs of PTH or

teriparatide is associated with decreases in serum SOST

[71–73]. These observations strongly suggest that the posi-

tive effect of PTH on osteoblast activity is at least in part

mediated by changes in the WNT/b-catenin signaling. It was

also found that the effect of teriparatide on SOST disappears

within a few months and that long-term treatment is asso-

ciated with an increase in DKK1 [74]. This might explain the

loss of the bone anabolic effect of teriparatide after

18–24 months of continuous treatment.

Recently it has been proposed that two discrete pathways

linked to canonical WNT signaling contribute to strontium-

induced osteogenic effects in osteoblasts: the exposure of

human osteoblasts in primary culture to strontium decreased

the expression of SOST and activated an Akt-dependent

signaling cascade via the calcium-sensing receptor that

promoted the nuclear translocation of b-catenin [75]

Rationale of Manipulating Components of WNT/b-

catenin Signaling for the Treatment of Osteoporosis

The important role of WNT/b-catenin signaling in the

control of bone formation suggests that this pathway may

be a potential therapeutic target. The therapeutic options

for the treatment of osteoporosis have so far comprised

mostly antiresorptive drugs, in particular bisphosphonates

and more recently denosumab, and, for women, estrogens

or selective estrogen receptor modulators. These drugs

decrease the rate of formation of new bone metabolic

units, or BMU (activation frequency), thereby causing a

secondary decrease in bone formation rate (Fig. 6).

The only anabolic agent currently on the market is ter-

iparatide, which, when given intermittently, stimulates new

Fig. 5 This is a schematic

hypothetical explanation for the

observed different duration of

the therapeutic window for

denosumab and

bisphosphonates. Both drugs are

potent inhibitors of bone

resorption that for a few months

are not associated with equal

suppression of bone formation

(therapeutic window). Within a

few months, bone formation is

also suppressed possibly as a

consequence of overexpression

of SOST. This is partially

counterbalanced only during

denosumab treatment by

decreased expression of DKK1

126 M. Rossini et al.: WNT/b-catenin Signaling in Osteoporosis

123

bone formation but also bone turnover, and this, together

with the increase in activation frequency, limits the thera-

peutic window of teriparatide treatment (Fig. 6).

Blocking SOST

Inhibitors of the negative regulators of WNT signaling

(‘‘inhibiting the endogenous inhibitors’’) are potential

candidates for the prevention and treatment of bone loss.

Inactivating monoclonal antibodies against SOST appears

to be the most attractive strategy because SOST is the only

component of the WNT pathway expressed exclusively by

osteocytes [76, 77], even though an expression by osteo-

clast precursors has also been reported [68].

This selectivity appears to be supported by the lack of

extraskeletal manifestations of aberrant SOST expression,

both in humans [78] and in genetic animal models [79].

SOST-neutralizing monoclonal antibodies have been tested

in animal models of osteoporosis, ovariectomized rats, and

aged male rats. In both models, anti-SOST antibody treat-

ment enhanced bone formation, resulting in increased bone

mass and bone strength [79, 80].

In a model of hind limb immobilization, antibody-

mediated blockade of SOST resulted in a rapid increase in

cortical and trabecular bone mass in both ambulated and

immobilized bones, but also in a decrease in bone resorp-

tion [81], resulting in accelerated fracture healing and

increased mechanical strength [82, 83].

In gonad-intact female monkeys, anti-SOST antibodies

were found to enhance bone formation on the remodeling

surfaces and along resting surfaces (modeling effect) [83].

This was also observed in SOST knockout mice and in

ovariectomized rats treated with anti-SOST antibodies [79,

84]. It has been attributed to down-regulation of RANKL

expression in osteoblasts [10, 11].

This implies that the treatment with anti-SOST neu-

tralizing antibodies might exert a modeling effect, with

bone formation also occurring at resting skeletal surfaces.

This might be seen as a potential plus, but it may also be

associated with new bone formation at skeletal surfaces

where this is not warranted.

Anti-SOST therapy was also shown to enhance fracture

healing and bone repair, with increased callus density,

increased bone strength at the fracture site, and accelerated

Fig. 6 The therapeutic window is represented by the uncoupling

between bone resorption and formation. During treatment with

antiresorptive agents, inhibition of bone resorption precedes a later

decrease in bone formation. For PTH treatment, the therapeutic

window corresponds to the lag time required for the increased bone

formation to be coupled with increased bone resorption. The

therapeutic window during treatment with neutralizing anti-SOST

antibodies is expected to be considerably larger since the increase in

bone formation is associated with a slight decline in bone resorption

M. Rossini et al.: WNT/b-catenin Signaling in Osteoporosis 127

123

bone repair in rodent studies [82, 85], as well as improved

bone healing (increased callus area, increased callus bone

mineral content, and increased torsional stiffness) in

cynomolgus monkeys after bilateral fibular osteotomies

compared to vehicle [86].

As a result of these encouraging findings, the clinical

efficacy of a SOST-neutralizing antibody (AMG 785) is

being tested in human studies to investigate its effect on the

healing of tibial diaphyseal or proximal femur fractures.

Recently, Padhi et al. [87] reported the results of the first

human phase 1 randomized, double-blind, placebo-con-

trolled clinical trial testing ascending single doses of AMG

785, a humanized monoclonal SOST antibody, in healthy

men and postmenopausal women. Bone formation markers

increased within 1 month after a single subcutaneous dose

of 10 mg/kg AMG 785 to levels similar to daily injections

of recombinant human PTH for 6 months. Interestingly,

markers of bone resorption decreased markedly. This

antiresorptive effect was somewhat unexpected even

though in experimental conditions WNT activation was

found to increase in osteoprotegerin expression. The

increase in bone formation markers 1 month after receiving

AMG 785 in the phase 1 clinical trial [87] was similar to

that seen with teriparatide at 6 months [88], suggesting a

more rapid onset of osteoanabolic effect with AMG 785

compared to teriparatide. The sustained decrease in serum

C-telopeptide collagen type I with AMG 785 is at

remarkable variance with teriparatide, which increases

bone resorption within a few weeks of treatment [2, 89]

(Fig. 6)

The results of a phase 2 study, comparing the anti-SOST

antibody AMG 785 to placebo or an active comparator

(teriparatide or alendronate) in approximately 400 post-

menopausal women with low BMD, was recently partially

reported [90]. Preliminary 12-month data met the primary

end point of the study, with significant greater increases in

both lumbar spine and hip BMD for the AMG 785 arm.

The overall incidence of adverse events was generally

balanced between groups, with the exception of mild

injection site reactions (4 % placebo vs. 12 % AMG 785).

These promising results prompted the initiation of a phase

3 placebo or alendronate-controlled three-arm trial to

assess the efficacy and safety of AMG 785 treatment in

postmenopausal women with osteoporosis, with the inci-

dence of vertebral and nonvertebral fractures as primary

outcome. Approximately 10,000 subjects will be random-

ized to receive either 210 mg AMG 785 subcutaneously

every month or placebo, or 70 mg alendronate orally every

week in a blinded fashion for the duration of the 12-month.

If the primary objective of superiority of AMG 785 over

alendronate on fracture risk is proven, the drug is likely to

represent a true breakthrough for the treatment of patients

at high risk for fracture.

Blocking DKK1

DKK1 is also a potential target for the treatment of bone

diseases. Treatment of rats with antisense DKK1 oligonu-

cleotides prevents the detrimental effects of ovariectomy

by improving bone mineral content, BMD, and bone

strength [91], and inhibiting DKK1 expression retards

glucocorticoid-induced osteopenia [92].

In multiple myeloma, DKK1 levels are associated with

the extent of osteolysis [30], and an effective treatment of

the disease is accompanied by a reduction in serum DKK1

levels [93]. Fully human monoclonal DKK1-neutralizing

antibodies were found to effectively treat the osteolytic

lesions in a murine model of multiple myeloma [94, 95].

Antibody-mediated DKK1 neutralization is also an

attractive therapeutic option in patients with erosive rheu-

matoid arthritis, as suggested by the results obtained in an

experimental model of this disease [31, 96].

Neutralizing DKK1 antibodies could also find their

way to a more general indication in low-bone-mass dis-

eases, although the lower specificity for bone may raise

more concerns about off-target effects for long-term

treatments. The development of such a treatment is still

pending and may possibly be limited to the treatment of

myeloma.

Safety Concerns

The manipulation of the WNT pathway has obvious

important potential for the treatment of bone-related con-

ditions such as osteoporosis, multiple myeloma, or fracture

repair. However, WNT pathway is expressed in many cells,

and this is currently likely to limit the pharmacological

research to bone-selective agents, such as anti-SOST neu-

tralizing antibodies.

Several caveats remain open also for SOST inhibition.

Studies with human osteosarcoma cell lines showed activa-

tion of WNT signaling [97], suggesting the possibility that

SOST inhibition could increase the risk of osteosarcoma.

The activation of the WNT pathway is associated with

a tremendous stimulus of generalized bone formation.

This excess bone formation may be deleterious in some

skeletal segments, with the occurrence of nerve entrap-

ments similar to those described in van Buchem disease

[45] or the worsening of initial nerve compression

symptoms in patients with osteoarthritis of the spine. It is

not currently clear whether the bone anabolic effect of

neutralizing anti-SOST antibodies is sustained; it is likely

that it might decline after months of treatment. It is also

for these reasons that at this stage of development, anti-

SOST antibodies are tested with short-term treatment

courses.

128 M. Rossini et al.: WNT/b-catenin Signaling in Osteoporosis

123

Conclusions

The recent characterization of the canonical WNT pathway

in the regulation of bone modeling and remodeling pro-

vided important insights for our understanding of the

pathophysiology of a number of conditions such as rheu-

matoid arthritis, ankylosing spondylitis, bone metastatic

cancer, and multiple myeloma. Better knowledge of the

WNT pathway is also helping us better understand the

mechanism of action of hormones or drugs with important

effects on bone metabolism. The development of drugs

acting specifically on the WNT pathway, such as neutral-

izing anti-SOST antibodies, is opening unexpected new

horizons for the treatment of many bone diseases.

Disclosures The authors are participating in the Amgen phase 3

trial of the anti-SOST antibodies.

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