Joint Bone Spine 77 (2010) 222–228
Review
New treatment targets in osteoporosis
Sophie Roux ∗
Service de rhumatologie, département de médecine, université de Sherbrooke, 12e avenue Nord, 3001 Sherbrooke, QC, J1H 5N4, Canada
a r t i c l e
i n f o
Article history:
Accepted 25 January 2010
Available online 8 April 2010
Keywords:
Osteoporosis
Catabolism inhibitors
Anabolic agents
RANKL inhibitors
Cathepsin K inhibitors
Calcilytic drugs
Wnt
a b s t r a c t
Postmenopausal osteoporosis is characterized by bone remodeling alterations with an imbalance
between excessive bone resorption and inadequate bone formation. At present, osteoporosis treatment
rests on bone resorption inhibitors and, more specifically, on bisphosphonates. However, the introduction of anabolic agents such as parathyroid hormone that stimulate bone formation has expanded the
range of treatment options. New treatment targets have been identified via improved knowledge on
bone pathophysiology, bone remodeling, bone cells and intracellular signaling pathways. RANKL inhibition by anti-RANKL antibodies is undergoing considerable development as a treatment for osteoporosis.
Also under development are anti-catabolic drugs that target the molecular mechanisms involved in bone
resorption, including cathepsin K inhibitors and integrin ␣v ␤3 antagonists. The identification of new
pathways involved in bone formation is directing clinical research efforts toward the development of
anabolic agents. The signaling pathways involved in bone formation, most notably the Wnt-pathway,
hold considerable promise as treatment targets in conditions characterized by insufficient bone formation. Current focuses of interest include antibodies against naturally occurring Wnt-pathway antagonists
(e.g., sclerostin and Dkk1) and modulators of parathyroid hormone production (calcilytic agents). Thus,
active research is ongoing to improve the treatment of osteoporosis, a disease whose high prevalence and
considerable functional and socioeconomic impact will raise formidable challenges in the near future.
© 2010 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
The management of osteoporosis is among the greatest challenges faced by modern medicine. Indeed, the aging of the
population is increasing the prevalence of osteoporosis, which
is associated with tremendous psychological, social and economic burdens. New treatment targets have been identified via
improvements in the knowledge of bone pathophysiology, bone
remodeling, bone cells and intracellular signaling pathways. These
improvements constitute evidence of the considerable research
efforts that are being expended to ameliorate the treatment of
osteoporosis.
1. Bone remodeling and bone cells
Bone remodeling is a physiological process whereby bone tissue is continuously renewed. Mineralized old bone is removed
and replaced by an equivalent amount of new bone matrix, which
then undergoes mineralization. The removal of mineralized bone,
or bone resorption, is achieved by osteoclasts. The osteoclast is
a polarized cell that develops a ruffled border at sites of active
bone resorption [1]. Osteoclasts adhere to the bone surface via
interactions between osteoclast integrins, chiefly ␣v␤3, and bone
∗ Tel.: +1 819 564 5261; fax: +1 819 564 5265.
E-mail address: [email protected].
matrix proteins. Osteoclasts have the enzyme machinery needed to
excrete H+ and Cl− ions through the ruffled border into the resorptive cavity. The resulting acidification contributes to dissolve the
mineralized bone matrix [2,3]. Osteoclasts also have proteolytic
enzymes that break down the matrix proteins [4] (Fig. 1).
Osteoclast differentiation and activation involve interactions
with osteoblasts and stromal cells, chiefly via cell-to-cell contact.
Osteoclast differentiation and activation are regulated by three
signaling pathways, which are activated by macrophage colonystimulating factor (M-CSF), receptor activator of NK-␬B ligand
(RANKL), and a co-stimulation pathway dependent on immunoreceptor tyrosine-based activation motif (ITAM) [5]. RANKL, the main
factor involved in osteoclast differentiation and activation, is inhibited by osteoprotegerin, a soluble decoy RANKL receptor. In bone
tissue, osteoprotegerin and RANKL are expressed by osteoblastic
and stromal cells, and the local and systemic factors that affect
bone resorption ultimately act via modulation of RANKL/RANK
and osteoprotegerin expression [6] (Fig. 2). Interactions between
RANKL and RANK induce the transduction of signals that activate
numerous factors including the transcription factors NF-␬B and
NFATc1. These factors modulate the expression of effector genes
involved in osteoclast survival, differentiation and activation.
The osteoblasts form new bone by secreting matrix proteins
and are required for bone mineralization to occur. Osteoblast
differentiation and activation depend on multiple local and sys-
1297-319X/$ – see front matter © 2010 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2010.02.004
S. Roux / Joint Bone Spine 77 (2010) 222–228
Fig. 1. The osteoclast.
The osteoclast is a multinucleated cell of hematopoietic lineage that is responsible
for bone resorption. Surface receptors characteristic of osteoclasts include the calcitonin receptor CTR. Osteoclasts strongly express two integrins, ␣v␤3 and ␣2␤1,
which interact with matrix proteins expressing the tripeptide motif RGD. Osteoclast enzymes consist chiefly of acid hydrolases such as TRAP, cysteine proteases
such as cathepsin K and metalloproteases including MMP-9. Another characteristic
of osteoclasts is the presence of carbonic anhydrase, which allows the production
of protons (H+ ).
temic factors including TGF␤, FGF, bone morphogenetic proteins
(BMPs), parathyroid hormone (PTH), 1-25(OH)2 vitamin D and
estrogens. The main gene involved in osteoblast differentiation
and bone formation is RUNX2 (CBFA1). The corresponding protein
is a transcription factor whose many regulatory effects include
Fig. 2. Regulation of the RANKL-RANK and osteoprotegerin pathway.
The main pathway involved in osteoclast formation and differentiation is composed
of receptor activator of NK-␬B ligand (RANKL) and its receptor RANK. RANKL is
a TNF superfamily protein that exists in both transmembrane and soluble form.
RANKL is expressed only in bone tissue (stromal cells and osteoblastic cells) and
lymphoid organs. Osteoprotegerin belongs to the TNF receptor family and is the soluble RANKL receptor. Osteotropic agents modulate the expression of RANKL and/or
osteoprotegerin [6] or affect the signaling process induced by RANKL binding to
RANK [58,59].
223
Fig. 3. Osteoblast signaling pathways.
The Wnt signaling pathway plays a particularly critical role in bone formation. The
Wnt proteins bind to a receptor complex composed of a frizzled receptor coupled to
a G protein and of the co-receptor LRP5/6. Activation of the Wnt-pathway induces a
cascade of intracellular events that stabilize ␤-catenin, which can then be more easily transferred to the nucleus, where it binds to transcription factors and modulates
the expression of genes that promote osteoblast expansion and function. Naturally
occurring Wnt antagonists include Dickkopf (DKK1), secreted frizzled-related proteins (sFRP1/2) and sclerostin. These antagonists interfere with the activation of the
complex, thereby inhibiting bone formation.
the activation or repression of multiple genes and the integration of biological signals from the BMP/TGF␤ pathway and Wnt
signaling pathway, whose role in bone formation is particularly
important (Fig. 3). The physiologic Wnt antagonists Dickkopf 1
(Dkk1), secreted frizzled-related proteins (sFRP1/2), and sclerostin
affect the activation of this complex, thereby inhibiting bone formation [7].
2. Implications for osteoporosis treatment
At the menopause, bone loss occurs, as a result of increased
bone remodeling with excessive bone resorption relative to the
small increase in bone formation. Bone formation is altered and
a resorption-formation imbalance sets in. Estrogens exert mainly
indirect effects on the osteoclasts via non-osteoclastic cells that
produce factors capable of stimulating bone resorption [8,9]. Thus,
estrogen deficiency leads to the production of factors that promote
osteoclast formation and activation and that activate RANKLmediated signaling [10–12]. The decrease in bone formation seen
in postmenopausal women may be related in part to decreased
growth factor expression [13].
Until now, osteoporosis prevention and treatment has relied on
anti-catabolic drugs, bone resorption inhibitors such as the bisphosphonates or hormonal treatments including estrogens and
selective estrogen-receptor modulators (SERMs). Anabolic agents
are undoubtedly of interest, given the decrease in bone formation.
PTH is the only anabolic agent used today for osteoporosis. Strontium ranelate both inhibits bone resorption and stimulates bone
formation. Recent insights gained into the physiology of bone tissue
suggest new approaches to osteoporosis treatment (Fig. 4).
3. New resorption inhibitors
3.1. Receptor activator of NK-kB ligand inhibitors
The identification of RANKL and osteoprotegerin as key players in the regulation of osteoclasts and bone resorption and in
the pathogenesis of postmenopausal bone loss has prompted the
224
S. Roux / Joint Bone Spine 77 (2010) 222–228
Fig. 4. Targeted treatments for osteoporosis.
Bisphosphonates are the most widely used anticatabolic agents. They act chiefly
by inducing the apoptosis of mature osteoclasts. RANKL inhibitors block the main
pathway involved in osteoclast formation and activation. Other inhibitors are being
developed, such as cathepsin K inhibitors and ␣v␤3 integrin antagonists. Other
potential treatment targets include the ATPase proton pump, tyrosine kinase c-Src
and the chloride channel ClC-7. Apart from parathyroid hormone, new anabolic
agents are being evaluated. Among them, calcilytic agents, Wnt-pathway inhibitors
and soluble activin receptors may be of interest.
development of RANKL inhibitors for osteoporosis. The RANKL
inhibitor that is being developed is the human anti-RANKL antibody denosumab (AMG 162). The effects of a single subcutaneous
injection of denosumab were evaluated in a Phase I study [14].
A Phase II randomized double-blind study was conducted in 332
postmenopausal women to compare denosumab 60 mg subcutaneously every 6 months for 2 years to a placebo [15]. At study
completion, denosumab was associated with significant increases
versus placebo in bone mineral density (BMD) at the lumbar spine
(+6%, P < 0.0001), total hip, and distal radius and with significant
decreases in the bone remodeling markers serum C-telopeptide
(CTx) and N-terminal propeptide of type 1 procollagen (P1NP). The
results of a Phase III multicenter randomized placebo-controlled
study of denosumab in 7868 patients with postmenopausal osteoporosis (mean age, 72 years) were recently reported [16]. This
3-year study evaluated the effects of denosumab in a dosage of
60 mg every 6 months on the rate of vertebral and non-vertebral
fractures (fracture reduction evaluation of denosumab in osteoporosis
every 6 months [FREEDOM] study). After 3 years, the denosumab
group had 68% fewer new vertebral fractures (P < 0.001), 20%
fewer non-vertebral fractures overall (P = 0.01), and 40% fewer hip
fractures (P = 0.046). Compared to the placebo, denosumab was
associated with significant BMD increases of 9.2% at the spine and
6% at the total hip (P < 0.001).
In the denosumab group, there was a 72% decrease in serum
CTx. Denosumab was well tolerated, with no significant betweengroup differences in rates of adverse events (serious adverse events,
cancer, infection, rhythm disturbances, stroke and time to fracture
healing).
Denosumab has been evaluated in a Phase II study comparatively to a placebo and to alendronate. The study patients were
postmenopausal women with low BMD values. Denosumab was
given in a dosage of 6 to 30 mg every 3 months or 14 to 210 mg
every 6 months; the alendronate dosage was 70 mg/week. 412
women have been included, 46 in the placebo group, 47 in the alendronate group, and 319 in the denosumab group. The 1-year and
2-year findings have been reported [17,18], as well as the 4-year
analysis [19]. At 2 years, the patients who continued denosumab
therapy switched to a regimen of 60 mg every 6 months continuously; the patients previously on 210 mg every 6 months switched
to the placebo (treatment discontinuation); and the patients previously on 30 mg every 3 months switched to the placebo for 12
months then to denosumab 60 mg every 6 months for 12 months
(re-treatment).
At 4 years, denosumab therapy was associated with BMD
increases versus baseline of 9.4 to 11.8% at the lumbar spine and
4 to 6.1% at the total hip (P < 0.001 versus placebo). In the group
that discontinued denosumab therapy, BMD decreased nearly to
the baseline values, and denosumab re-treatment produced similar BMD increases to the initial treatment. Continuous denosumab
therapy led to sustained decreases versus baseline in the serum
bone remodeling markers CTx and bone-specific alkaline phosphatase (BSAP) (CTx, 80% at 6 months and 60% at 48 months;
and BSAP, 60% at 6 months and 40% at 48 months). Both markers increased after denosumab discontinuation and decreased with
denosumab re-treatment (CTx, 70%; and BSAP, 50% at 4 years).
These results indicate sustained BMD gains and bone remodeling
suppression with denosumab for 4 years, compared to placebo.
Bone remodeling suppression is reversible at treatment discontinuation and recurs with re-treatment.
A Phase III study in patients with postmenopausal osteoporosis
compared denosumab to alendronate (determining efficacy: comparison of initiating denosumab versus alendronate: the DECIDE trial)
[20]. The outcome measures of this multicenter double-blind active
drug-controlled trial were BMD values and the bone remodeling
markers serum CTx and P1NP. The 1189 postmenopausal study
patients had a mean age of 64 years and lumbar spine or total
hip BMD T-scores less or equal to −2. Denosumab was used in a
dosage of 60 mg subcutaneously every 6 months and alendronate in
a dosage of 70 mg/week, for 1 year. With denosumab, the resorption
marker serum CTx decreased significantly, by 89% after 1 month,
77% after 6 months, and 74% after 12 months; these decreases
were significantly greater than those seen in the alendronate group
(61%, 73%, and 76%, respectively; P < 0.0001 after 1 and 6 months).
Denosumab was associated with significant decreases in the bone
formation marker serum P1NP, of 76% at 3 months, 78% at 9 months,
and 72% at 12 months, compared to alendronate (56%, 65% and
65%, respectively; P < 0.0001 at all three time points). At all measurement sites, the BMD increase was larger with denosumab than
with alendronate. The adverse event rates were not significantly
different between the two groups.
The effects of denosumab given after alendronate were assessed
in a randomized, controlled, double-blind trial (study of transitioning from alendronate to denosumab [STAND]) [21]. The 504 study
patients were postmenopausal women with lumbar spine or total
hip T-scores less than −2 who had been treated with alendronate.
Denosumab 60 mg subcutaneously every 6 months was compared
to continued alendronate therapy 70 mg/week. After 12 months,
the patients switched to denosumab had significantly higher BMD
values at the spine, total hip, and distal radius than did the patients
left on alendronate.
Both DECIDE and STAND indicate that denosumab is a valid
anticatabolic alternative to bisphosphonates both for the first-line
treatment of osteoporosis and after bisphosphonate therapy. The
FREEDOM trial demonstrated the efficacy of denosumab in decreasing the fracture rate versus a placebo. No studies have compared
fracture rates with denosumab and bisphosphonates.
3.2. Cathepsin K inhibitors
Cathepsin K is a cysteine protease that is strongly expressed in
osteoclasts and contributes to break down the bone matrix, being
capable of degrading type 1 collagen, osteopontin, and osteonectin.
Cathepsin K is expressed not only by osteoclasts, but also by the
S. Roux / Joint Bone Spine 77 (2010) 222–228
heart, lungs and liver [22]. Mutations in the cathepsin K gene cause
pycnodysostosis (also known as Toulouse-Lautrec syndrome), a
rare bone disease characterized by osteosclerosis and abnormalities of the head, face, and spine. Bone resorption markers are low
[23] and histomorphometry shows bone remodeling abnormalities
that contribute to the brittleness of the bones [24]. Mice lacking
cathepsin K have a bone disease that resembles pycnodysostosis,
with thickened bone trabeculae [25]. Thus, cathepsin K inhibition
may hold promise for the treatment of conditions characterized by
increased bone resorption.
At least two peptides capable of inhibiting cathepsin K have been
shown to decrease bone resorption markers and to increase BMD
values in humans, namely, odanacatib (MK-0822) and balicatib
(AAE581). The development of balicatib was stopped because of
major adverse events, most notably involving the skin, which were
ascribed to lack of specificity of the drug, which inhibited not only
cathepsin K, but also other cathepsins (B and L). Odanacatib may
show greater specificity for cathepsin K and a stronger resorptioninhibiting effect, according to several preclinical studies and one
Phase I study [26].
In a 2-year Phase II randomized double-blind placebocontrolled trial, 399 postmenopausal women with a mean age of
64.2 years and BMD T score values less or equal to −2 at one site
received 3 mg to 50 mg of oral odanacatib once a week or a placebo;
280 patients completed the 2-year treatment period [27]. At the
end of the 2-year treatment period, dose-dependent BMD increases
were seen in the odanacatib group. With 50 mg/week, the increases
were 5.5% at the spine and 3.2% at the femoral neck. Another effect
of odanacatib noted at the same 2-year time point was a decrease in
bone remodeling markers; with 50 mg/week, serum CTx was 40%
lower and P1NP 25% lower compared to the placebo. Odanacatib
was well tolerated.
3.3. ˛vˇ3 antagonists
Integrin ␣v␤3 is the main integrin found on osteoclasts. Interactions between integrin ␣v␤3 and bone matrix proteins anchor
the osteoclasts to the bone surface and allow the formation of
the resorptive cavity under the osteoclast. These interactions also
induce the transmission of anti-apoptotic signals, thereby promoting osteoclast survival [28,29]. All these effects are inhibited by
peptides that contain the RGD sequence [30] and by antibodies
to integrin ␣v␤3 [31]. Mice lacking ␤3 (␤3−/− ) have a high bone
mass as a result of abnormal osteoclast function [32]. Thus, integrin
␣v␤3 may hold promise as a target for bone resorption-inhibiting
treatments. In a 12-month multicenter study, 227 postmenopausal
women having a mean age of 63 years and low BMD values were
allocated at random to the oral nonpeptide integrin ␣v␤3 inhibitor
L-000845704 (100 or 400 mg once daily or 200 mg twice daily)
or to a placebo [33]. L-000845704 therapy increased BMD at the
lumbar spine (+3.5% with 200 mg twice daily, P < 0.01 vs. placebo).
The 200 mg twice daily dose, but neither of the other two doses,
significantly increased BMD at the total hip (+1.7%) and femoral
neck (+2.4%) (P < 0.05). All three L-000845704 doses decreased the
urinary bone resorption marker N-telopeptide of type I collagen
by about 42% versus baseline (P < 0.001). L-000845704 was well
tolerated; events with trends toward higher rates in the activetreatment groups were headache, dermatitis, pruritus, rash, and
urticaria [33].
3.4. Glucagon-like peptide 2 (GLP-2)
Glucagon-like peptide 2 (GLP-2) is a hormone produced by
intestinal endocrine cells in response to nutrients. In postmenopausal women, 14 days of subcutaneous GLP-2 therapy
significantly diminished bone resorption without affecting bone
225
formation or osteocalcin levels [34]. In a Phase II randomized placebo-controlled study, 160 postmenopausal women with
osteopenia received a daily subcutaneous injection of GLP-2 or
placebo at bedtime for 120 days [35]. The GLP-2 dose was 0.4 mg,
1.6 mg, or 3.2 mg. GLP-2 therapy produced dose-dependent BMD
increases at the total hip and trochanter, which were statistically
significant with the highest dose (3.2 mg/day). The nighttime serum
CTx elevation seen in the placebo group was rapidly and lastingly
suppressed by all three GLP-2 doses. GLP-2 had no effect on bone
formation, and serum osteocalcin levels were unaffected. These
results suggest that GLP-2 may dissociate bone resorption from
bone formation. The beneficial effects of GLP-2 on BMD values indicate that GLP-2 may hold promise for the treatment of osteoporosis.
3.5. Bone resorption inhibitors: future prospects
The quest for new bone resorption inhibitors is ongoing. Potential treatment targets include the ATPase proton pump, c-Src
tyrosine kinase, and ClC-7 chloride channel (Fig. 4). The protooncogene c-Src encodes a tyrosine kinase that is strongly expressed
by osteoclasts. Mice lacking p60c-Src develop osteopetrosis [36].
The c-Src kinase is involved in the development of the ruffled border at the bone side of resorptive osteoclasts and is also linked to
the PI3K/Akt pathway involved in osteoclast survival. Disruption
of this signaling pathway induces osteoclast apoptosis, as shown
with c-Src inhibitors [37]. To minimize adverse effects on tissues
other than bone, drugs that target osteoclast c-Src kinases are being
developed, for instance by coupling an inhibitor to a diphosphonate group [38] Vacuolar type H+ ATPases (V-ATPases) are proton
pumps expressed on the osteoclast ruffled border. V-ATPases acidify the resorptive cavity under the osteoclast [4,39]. Functional
V-ATPase deficiency causes severe osteopetrosis in mice and in
humans [40]. Research is ongoing to develop drugs that inhibit the
V-ATPases without affecting other ATP-dependent cation pumps
(P- and F-type ATPases) and to identify osteoclast-specific VATPase inhibitors. Chloride channels (ClC-7) contribute to acidify
the resorptive cavity via Cl-extrusion. ClC-7 is expressed in the
osteoclast endosomes, lysosomes, and ruffled border. Mutations
affecting the chloride channel gene CLCN7 have been identified in
patients with autosomal recessive osteopetrosis (ARO) or autosomal dominant osteopetrosis type II (ADO II). Furthermore, a study in
postmenopausal women showed that CLCN7 polymorphisms were
significantly associated with BMD variance and bone resorption
marker levels [41]. In a study of a rat model of ovariectomy-induced
osteoporosis, administration of a ClC-7 inhibitor increased bone
mass in vivo and inhibited osteoclastic resorption in vitro [42].
Thus, ClC-7 constitutes another target for treatments aimed at
inhibiting bone resorption.
4. New bone formation inducing agents
4.1. Calcilytic agents
Extracellular calcium regulates PTH secretion via a calcium surface receptor (CaR) coupled to a G protein. Calcimimetic agents
replicate the effects of high serum calcium levels on the CaR. Among
them, type II calcimimetics are positive allosteric modulators that
increase CaR sensitivity to calcium. Type II calcium mimetic agents
are used as therapeutic agents and can be given orally. Clinical
studies have established the efficacy of type II calcimimetic agents
in patients with primary or secondary hyperparathyroidism or
parathyroid cancer [43]. Calcilytic agents, in contrast, diminish the
sensitivity of the CaR, thereby increasing PTH production. Permanent PTH elevation, related for instance to hyperparathyroidism,
induces marked bone catabolism with increased bone resorption.
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S. Roux / Joint Bone Spine 77 (2010) 222–228
Intermittent PTH elevation, in contrast, exerts an anabolic effect on
bone with increased bone formation. This bimodal effect of PTH has
been put to advantage in clinical practice. Thus, intermittent PTH
therapy can be used to increase bone mass and to decrease the fracture rate in patients with osteoporosis [44]. Calcilytic agents may
produce similar benefits by intermittently increasing the release of
endogenous PTH.
Ronacaleret is an oral CaR antagonist and a candidate for
osteoporosis treatment. The safety, pharmacokinetics, and pharmacodynamics of Ronacaleret were assessed in a randomized
placebo-controlled trial in 65 postmenopausal women with a mean
age of 55 years [45]. Ronacaleret was given twice at an interval
of 28 days in a dose of 75 mg, 175 mg or 475 mg. Bone formation markers showed dose-dependent increases in the Ronacaleret
groups. With 475 mg, osteocalcin increased by 63%, P1NP by 79%,
and BSAP by 35% (P < 0.05 vs. placebo). The resorption marker serum
CTx showed no statistically significant changes. Ronacaleret had
a mean terminal half-life of 4 to 5 hours, and the post-dose PTH
peak increased in a dose- and concentration-dependent manner
(by 300% to 900%). Adverse effects were mild to moderate and
consisted chiefly of headaches and constipation or diarrhea. The
dose-dependent increases in endogenous PTH, calcium, and bone
formation markers indicate that Ronacaleret held promise as an
oral anabolic drug for osteoporosis. However, a Phase II study in
postmenopausal women with osteoporosis was stopped prematurely based on lack of efficacy.
4.2. Blocking the Wnt signaling pathway
4.2.1. Antibodies to sclerostin
Sclerosteosis is an autosomal recessive bone dysplasia characterized by hyperostosis and increased bone density that
predominate at the skull and long-bone diaphyses. The cause is
an inactivating mutation in the SOST gene. Sclerostin, the protein
product of the SOST gene, is expressed in various tissues but is
found chiefly on bone cells (osteocytes). Sclerostin is a circulating
inhibitor of the Wnt signaling pathway which acts by inactivating
LRP5. As Wnt signaling is involved in bone formation, sclerostin is a
physiological inhibitor of bone formation [46]. Transgenic mice that
overexpress human sclerostin have low bone mass and an increased
susceptibility to fractures [47], and mice lacking sclerostin (Sost−/− )
exhibit a diffuse increase in bone density [48]. These findings indicate that sclerostin inhibition exerts anabolic effects on bone and
may therefore hold promise for osteoporosis treatment. A study in
ovariectomized rats with osteopenia evaluated the effects on bone
mass and bone formation of various antisclerostin antibody doses
injected subcutaneously once a week for 5 months [49]. Histomorphometry showed a dose-dependent increase in bone formation
parameters with no increase in bone resorption.
A monoclonal antisclerostin antibody was evaluated in a Phase
I randomized double-blind placebo-controlled trial in 48 postmenopausal women [50]. The women were randomized in a 3:1
ratio to a single antibody dose (0.1 to 10 mg/kg) or to a placebo.
Compared to the placebo, antisclerostin therapy induced statistically significant dose-dependent increases in the bone formation
markers P1NP, osteocalcin, and BSAP (mean increase, 60% to 100%
with 3 mg/kg 21 days post-dose); as well as a trend toward a
decrease in the resorption marker serum CTx. The antibody was
well tolerated. These results invite further clinical studies on sclerostin inhibition for stimulating bone formation in diseases such as
osteoporosis.
4.2.2. Anti-Dkk1 antibody
DKK1, a naturally occurring Wnt-pathway antagonist, inhibits
interactions between the co-receptor LRP5/6 and the frizzled Wntpathway receptor involved in bone formation [51]. In mice, bone
mass correlates inversely with the Dkk1 expression level [52]. Dkk1
is expressed in adult bone, and interventions that inhibit the binding of LRP to Dkk1 may stimulate bone formation.
The development and the in vitro and in vivo characterization of
neutralizing monoclonal antibodies against Dkk1 in mice have been
described [53]. In vitro, anti-Dkk1 antibodies blocked Dkk1 function, so that Dkk1 no longer inhibited the Wnt-pathway, and they
also inhibited bone formation. In vivo, anti-Dkk1 antibodies had a
long half-life of 17 days in mice. Administration of anti-Dkk1 antibodies once or twice a week for 2 months significantly increased
serum P1NP and induced new bone formation on the endocortical surfaces and within the trabecular bone, thus ensuring partial
or complete resolution of ovariectomy-induced osteopenia at the
femur and spine. These findings establish the feasibility of modulating the Wnt-pathway by administering neutralizing anti-Dkk1
antibodies to animals and demonstrate the efficacy of anti-Dkk1
therapy in an animal model of bone loss induced by estrogen
deprivation. Thus, anti-DKK1 therapy may hold promise for the
treatment of bone diseases characterized by low BMD values, such
as osteoporosis.
4.3. Soluble activin receptor
Activin, a member of the TGF-␤ superfamily, stimulates FSH production by the pituitary gland. Until recently, the role for activin in
bone metabolism was unclear. Activin receptor type A (ACVR1) or
activin receptor-like kinase 2 (ALK2) is one of the BMP receptors.
The BMPs constitute a family of growth factors that play a crucial
role in bone formation. ACVR1 gene mutations cause fibrodysplasia ossificans progressiva (FOP), a rare dominant autosomal disease
whose features include skeletal birth defects and ectopic bone formation within muscles. These mutations lead to the production of
an active receptor that constitutively activates intracellular BMP
signaling [54]. The activin antagonist RAP-011 was developed by
fusing the extracellular domain of the activin receptor type IIA
to the Fc fragment of murine immunoglobulin. In both normal
mice and ovariectomized mice with established bone loss, RAP-011
increased bone formation, increased in vivo BMD values, improved
bone strength and architecture, and produced histomorphometric
evidence of bone anabolism [55].
ACE-011 is a fusion protein composed of the extracellular
domain of the human activin receptor type IIA and of the Fc
fragment of human IgG1. ACE-011 binds activin. In a Phase I
randomized, double-blind, placebo-controlled trial in 48 postmenopausal women, the effects of a single ACE-011 injection in
a dose of 0.01 to 3 mg/kg intravenously or 0.03 to 0.1 mg/kg subcutaneously were evaluated [56]. Follow-up was 120 days. No
serious adverse events were recorded. The main adverse events
were headaches, nausea and vomiting, and injection-site reactions. Blood levels were linearly related to the dose, and the
half-life was 25 to 32 days. ACE-011 injection was rapidly followed by a sustained dose-dependent increase in BSAP levels
and induced dose-dependent decreases in CTx and TRAP-5b levels. These changes persisted for at least 28 days with the highest
doses studied. A dose-dependent decrease in serum FSH levels reflecting activin inhibition was noted. The pharmacokinetics
and bone mass effects of ACE-011 were evaluated in Cynomolgus monkeys given ACE-011 (10 mg/kg subcutaneously twice a
week) or the vehicle for 3 months (n = 5/group) [57]. At treatment
completion, BMD was significantly higher in the ACE-011 group
than in the vehicle group (+13% at the spine, P < 0.01; and +15%
at the femur, P = 0.05). Microcomputed tomography showed that
ACE-011 increased trabecular bone volume (BV/TV, +16%, P < 0.01)
and trabecular number (+11%, P = 0.04) and improved the structural parameters. Thus, ACE-011 stimulates bone formation and
diminishes bone resorption, and the results obtained so far indi-
S. Roux / Joint Bone Spine 77 (2010) 222–228
cate that ACE-011 holds promise as a new anabolic treatment
of bone diseases characterized by an increased susceptibility to
fractures.
5. Conclusion
Postmenopausal osteoporosis is related to increased bone
remodeling with a predominance of bone resorption over bone formation. At present, the most widely used anticatabolic agents for
osteoporosis treatment are the bisphosphonates, which act chiefly
by inducing apoptosis of mature osteoclasts. RANKL inhibitors are
undergoing active development, but their place in the therapeutic armamentarium and their long-term safety profile remain to be
determined. Other bone resorption inhibitors that are being developed target the molecular mechanisms involved in bone resorption
(cathepsin K inhibitors and ␣v␤3 antagonists). It is too soon to
say whether these agents are useful. In particular, follow-ups are
too short to draw conclusions about safety, and no data are available regarding effects on fracture rates. Long-term studies and
investigations into the interactions of these drugs with other systems will provide crucial information on safety and therapeutic
usefulness. However, anticatabolic agents do not stimulate bone
formation. The identification of new pathways involved in bone
formation is prompting clinical researchers to focus on developing anabolic agents. New knowledge indicates that the signaling
pathways involved in bone formation, most notably the Wntpathway, hold considerable promise for the treatment of diseases
characterized by inadequate bone formation. However, the clinical
development of drugs targeting these pathways is still in its infancy.
Conflicts of interest
The authors have no conflicts of interest to declare.
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