Nuevos Targets en Osteoporosis

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20 nature clinical practice RHEUMATOLOGY jAnUARY 2009 vOL 5 nO 1

www.nature.com/clinicalpractice/rheum

Potential new drug targets for osteoporosisChad Deal

INTRODUCTION

Osteoporosis is a worldwide health problem thataffects as many as 75 million people in the US,Japan and Europe. Fracture is the most commoncomplication of osteoporosisit is estimatedthat 3050% of women and 1530% of menwith this disease have a fracture during their life-time. Osteoporosis accounts for more hospitaldays than diabetes, breast cancer or myocardial

infarction.

1

Bone remodeling facilitates repair ofmicrodamage and provides calcium from bonestores for cellular functions (Figure 1). The meta-bolic component of bone is made up of boneremodeling units (BRUs), over 1 million ofwhich are active at any given time in a healthyadult woman.It is estimated that complete turn-over of the skeleton occurs every 10 years. Boneremodeling is, however, accelerated in post-menopausal women, in whom estrogen defi-ciency results in increased bone turnover withan excess of resorption over formation. The factthat bone remodeling is an active and dynamicprocess enables the use of interventions in thetreatment of osteoporosis that limit resorption(antiresorptive therapy) or augment formation(anabolic therapy).2

The activity of BRUs follows a well choreo-graphed sequence of events. In the initial step,osteoclasts reabsorb bone over a period of about3 weeks to create resorption cavities, whichare collectively termed the remodeling space.Resorption is followed by osteoblast activationand formation of osteoid, which fills the resorp-tion cavities over a period of about 3 months.

When this active matrix synthesis is finished,osteoblasts become embedded in the matrixand function as osteocytes. These cells remainactive in bone remodeling by maintainingconnections to the bone surface, the BRUs andother osteocytes via an extensive canalicularnetwork. Fluid flows through this network andis thought to induce signaling, thus permittingosteocytes to function as mechanoreceptors.Osteocytes are able to direct remodeling toareas that require repair.3

SuMMarY

Osteoporosis is a worldwide health problem with a high prevalence. Agentsfor the treatment of osteoporosis are classified as either antiresorptive oranabolic. Antiresorptive agents work by inhibiting the activity of osteoclastsand, therefore, reducing bone resorption. Currently available antiresorptiveagents include bisphosphonates, selective estrogen-receptor modulators,calcitonin and estrogen. Various novel antiresorptive agents are indevelopment. Receptor activator of nuclear factor B ligand is an importantcytokine involved in osteoclast activation; denosumab, a fully human

monoclonal antibody to this molecule, has finished a major fracture trial.Assessment is underway of odanacatiban inhibitor of cathepsin K, whichis an osteoclast enzyme required for resorption of bone matrix. Glucagon-like peptide 2 is being evaluated for the prevention of the nocturnal risein bone resorption without affecting bone formation. Anabolic agents act

by stimulating formation of new bone. The only anabolic agent currentlyavailable in the US is teriparatiderecombinant human parathyroidhormone (PTH)134and recombinant human PTH184 is available inEurope. PTH stimulates osteoblast function and bone formation. Novelanabolic agents in development include: antibodies such as sclerostin anddickkopf-1 that target molecules involved in Wnt signaling, a pathway thatregulates gene transcription of proteins that are important for osteoblastfunction; an antagonist to the calcium-sensing receptor; and an activinreceptor fusion protein, which functions as an activin antagonist and hasshown promise as an anabolic agent in early human trials.

Keywords anablic agnt, antiptiv agnt, calcium-ning cpt,tpi, wnt ignaling

C Deal is Head of the Center for Osteoporosis and Metabolic Bone Diseaseat the Orthopedic and Rheumatology Institute, Cleveland Clinic, Cleveland,OH, USA.

CorrspondncCenter for Osteoporosis and Metabolic Bone Disease, Orthopedic and Rheumatologic

Institute (A50), Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA

[email protected]

Rcid 6 May 2008 Accptd 12 November 2008

www.nature.com/clinicalpractice

doi:10.1038/ncprheum0977

RevIew CRITeRIAA review of the literature was performed by searching PubMed using thefollowing search terms antiresorptive agents, anabolic agents, Wnt signaling,calcium sensing receptor and novel osteoporosis therapies. Abstracts andfull-text papers published between 2000 and 2008 were reviewed.

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jAnUARY 2009 vOL 5 nO 1 DEAL nature clinical practice RHEUMATOLOGY 21


The therapies currently available to modifybone remodeling and, therefore, treat osteo-porosis all have limitations. Treatment withantiresorptive agents, for example, eventuallyleads to a decrease in osteoblast function. Theinitial increase in bone mass that results fromthe use of this type of therapy is due to inhibi-tion of bone resorption by osteoclasts, whileosteoblasts continue to function and fill in theremodeling space. This uncoupling of formationand resorption, however, lasts for only a shorttime (about 2 years) before osteoblast func-tion decreases and accumulation of bone massbegins to slow. Increases in bone mass after thistime point are largely related to an increase inmineralization densitya result of reducedbone turnover. Bisphosphonatesa type ofantiresorptive agenthave a long half life inbone; after discontinuation of therapy a residualamount of drug remains in bone and is availableto osteoclasts in the future when further BMUsare activated. In rare cases, long-term therapymight lead to turnover being inadequate to repairmicrodamage, at which point bone is referred

to as being adynamic.4 This low turnover stateis thought to result in the accumulation andcoalescence of microcracks, which results in frac-tures.4 For the anabolic agent teriparatide, use islimited to 24 months in the US and 18 monthsin Europe, as the clinical trial of this agent wasdiscontinued after a mean treatment duration of19 months because an animal toxicology studyshowed an increased incidence of osteosarcoma.5Evidence from more than 6 years of clinical use,however, indicates that the development of

osteosarcoma does not seem to be increased withthe use of teriparatide.

Research is currently focusing on drugs thattarget the remodeling cycle by affecting osteo-blasts, osteoclasts and osteocytes, and/or mole-cules that control signaling pathways importantfor cell function and gene transcription. Thegoal of this article is to review the types andmodes of action of therapies that are currentlyavailable and those that are in development forthe treatment of patients with low bone mass.

ANTIReSORPTIve AGeNTS

Bisphosphonates are the most frequently usedtype of antiresorptive agent. These drugs bindavidly to hydroxyapatite and work by inhibitingfarnesyl pyrophosphate synthase, an enzymein the mevalonate pathway (Box 1).6,7 Thispathway is important for protein prenylationthe attachment of lipids to proteinswhich iscritical for cytoskeletal organization in osteo-clasts. Inhibition of the mevalonate pathwaydisrupts cytoskeletal structure, which preventsosteoclasts from forming a ruffled border on

the bone during the remodeling process, genera-ting a proton gradient, and resorbing mineralsand matrix.

Bone resorption and formation are tightlycoupled. As described above, inhibition ofresorption eventually results in inhibition of for-mation. An agent that inhibits bone resorptionbut allows bone formation to continue would,therefore, have a greater effect on bone massand quality than currently available agents. Micethat lack the chloride channel CLC-7 have no

Resting

bonesurface Resorption

Activation

Reversal

OCprecursor

OBprecursor

Mononuclearcells

~3 weeks ~3 months

OC OB

Bone formation Mineralization

BRUOSCL

LC

Figur 1 The sequence of bone remodeling in healthy individuals. Remodeling is initiated when osteoclasts

are activated, resorb bone and create resorption cavities. Resorption is followed by osteoblast activation

and formation of osteoid, which then fills in the resorption cavity. This active process is the target of

pharmaceutical agents that affect bone resorption and formation. Abbreviations: BRU, bone remodeling unit;

CL, cement line; LC, lining cells; OB, osteoblast; OC, osteoclast; OS, osteoid.

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22 nature clinical practice RHEUMATOLOGY DEAL jAnUARY 2009 vOL 5 nO 1


functional osteoclasts and thus have reducedbone resorption, but do have ongoing boneformation. This finding suggests that the develop-ment of an agent that inhibits bone resorptionbut permits bone formation could be possible.8

Glucagon-like peptide 2

Glucagon-like peptide 2 (GLP-2) is a polypeptide

hormone released from the intestinal mucosa inresponse to food intake. Bone remodeling occursaccording to a circadian rhythm, with bone resorp-tion rising in the night.9 The rhythm is affected bythe rate of food intake, for example by nocturnalfasting. Treatment with GLP-2 at bedtime resultsin a substantial reduction in the bone resorptionthat normally occurs overnight. GLP-2 does notseem to reduce bone formation, as evidenced bystable levels of osteocalcina marker of boneformationduring treatment.10,11 A 120-day

phase II trial of GLP-2 in 160 postmenopausalwomen demonstrated an increase in hip bonemineral density (BMD) and a reduction inthe nocturnal rise in the concentration of C-telopeptidea marker of bone resorptionwithno effect on osteocalcin.10,11 If this pattern could

be sustained in the long term, GLP-2 would have anadvantage over currently available antiresorptiveagents, which decrease bone formation.

Cathepsin K inhibitors

Cathepsin K is a cysteine protease that is selec-tively expressed by osteoclasts and can degradekey bone matrix proteins, including collagen.12Elimination of cathepsin K in osteoclasts resultsin inhibition of bone resorption. Inhibitors of cat-hepsin K are suggested to have less of an effect onosteoclastosteoblast interaction than available

bisphosphonate antiresorptive agents, resultingin less inhibition of bone formation.The first demonstration of the effect of cat-

hepsin K inhibitors on BMD in humans wasin a 12-month trial of balicatib in 675 post-menopausal women with BMD T scores of lessthan 2.0.13 In this study, markers of bone resorp-tion declined by 5561%, with no decline inmarkers of bone formation. BMD in the lumbarspine increased by 4.4% and in the hip by 2.2%.Skin reactions, including pruritis and morphea-like changes, were noted in a small number ofpatients. In addition, balicatib increased intactparathyroid hormone (PTH) levels by 50% in asmall Japanese trial.14

Owing to adverse effects, especially skinreactions, drug development of all cathepsin Kinhibitors except for odanacatib (formerly MK-0822) has been suspended. Cathepsin inhibi-tors other than odanacatib seem less specific forcathepsin K, which may account for the apparentdifferences in toxicity. Inhibition of cathepsin Kin humans by orally bioavailable odanacatib isbeing evaluated in several ongoing trials. The 24-month results of a randomized controlled trial

evaluating four doses of odanacatib given as adaily oral dose showed increases in spine andhip density (5.5% and 3.2%, respectively). UrineN-telopeptide of type I collagen (uNTX) andbone-specific alkaline phosphatase (BSAP)decreased 52% and 13%, respectively, in patientson odanacatib, whereas uNTX decreased by 5%and BSAP increased by 3% with placebo. Thesefindings suggest that odanacatib produces lessinhibition of bone formation than seen withcurrent antiresorptive therapies.15

Box 1 Mechanism of action of nitrogen-

containing bisphosphonates.

Nitrogen-containing bisphosphonatessuch as

risedronate sodium, zoledronic acid, disodium

pamidronate, alendronic acid and ibandronic

acidwork predominantly by inhibiting the enzyme

FPPS, which catalyzes a step in the mevalonate

pathway and inhibits protein prenylation.

Protein prenylation involves the transfer of a

farnesyl or geranylgeranyl isoprenoid lipid group

onto the C-terminus of small GTPases. The

GTPases are critical for osteoclast proliferation,

apoptosis, membrane ruffling and membrane

trafficking. Loss of these prenylated proteins

in cell membranes results in loss of osteoclast

function. Abbreviations: HMG-CoA, hydroxy-

3-methylglutaryl coenzyme A; FPP, farnesyl

pyrophosphate; FPPS, farnesyl pyrophosphate

synthase; GGPP, geranylgeranyl diphosphate;

GTP, guanine triphosphate.

Nitrogen-containingbiophosphonates inhibitFPPS

RhoGGPP

FPP

Cholesterol

Squalene

Mevalonate

HMG-CoA

Rab

C20

Ras

C15

Rac

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Denosumab

Receptor activator of nuclear factor B ligand(RANKL), a member of the TNF receptor family,is an important mediator of bone remodelingand is expressed by various cell types, includingosteoblasts, synovial fibroblasts and activatedT cells. RANKL binds to receptor activator ofnuclear factor B (RANK) on osteoclast mem-branes and induces differentiation, activationand survival of these cells.16,17 A regulatorof RANKRANKL interaction is the solublecytokine osteoprotegerin, which is a naturallyoccurring member of the TNF receptor familythat acts as a decoy receptor by competing withRANKL for the bind sites of RANK (Figure 2).Denosumab is a human monoclonal IgG2 anti-body that binds selectively and with high affinityto RANKL and pharmacologically mimics theeffect of osteoprotegerin on RANKL. The results

of a phase II randomized dose-ranging trialevaluating denosumab have been reported.18At 24 months, increases in lumbar spine densityranging from 4.1% to 8.9% were observed.BMD gains at cortical sites, such as the hip andforearm, were greater with denosumab than withalendronic acid. No patient developed neutraliz-ing antibodies during the trial. A 3-year phase IIIfracture trial examining denosumab administeredsubcutaneously in 60 mg doses every 6 monthsdemonstrated 68%, 41% and 20% reductions

in vertebral, hip and nonvertebral fractures,respectively, compared with placebo.19

Denosumab differs from bisphosphonatesin several ways. First, levels of bone turnovermarkers nadir more rapidly, within a few days ofinjection, after denosumab treatment than follow-ing bisphosphonate therapy; after discontinu-ation, bone markers recover to normal levelsmore rapidly than with oral bisphosphonates.Second, there is no accumulation of denosumabin the bone, as there is with bisphosphonates.A third potential difference is that combiningdenosumab with PTH therapy could, in theory,have an additive effect on BMD. This effect isseen in animal models when osteoprotegerinis added to PTH therapy and is in contrast to theeffect seen with the addition of bisphosphonates,which blunts the PTH response.

ANABOLIC AGeNTS

Anabolic agents have the capacity to increasebone mass to a greater degree than antiresorptiveagents. Not only are anabolic agents able toincrease bone mass, but they also have thecapacity to improve bone quality and increasebone strengthin part by affecting micro-architectural features such as connectivity, densityand geometric features. These changes in qualitycannot, however, be detected by current clinicalmeasures of drug response, such as assessment

Osteoblastlineage

Growth factors,hormones,cytokines

RANKL

RANKL

RANK

OPG

Denosumab

Colony-formingunit macrophage

Prefusionosteoclast

Multinucleated

osteoclast

Bone

OC

Figur 2 Proposed mechanism of action for denosumab. Denosumab is an investigational, fully human

monoclonal antibody that binds with high affinity to and inhibits the activity of human RANKL, a key

mediator of osteoclast activity. RANKL is an essential mediator of the formation, activation and survival

of osteoclasts. Denosumab does not bind to other TNF receptors, including TRAIL. Abbreviations:OPG, osteoprotegerin; RANK, receptor activator of nuclear factor B; RANKL, receptor activatorof nuclear factor B ligand; TRAIL, TNF-related apoptosis-inducing ligand.

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of levels of bone turnover markers and dualX-ray absorptiometry. When quantitative CT,a volumetric measure of bone mass, is used tomeasure change in BMD during PTH treatment,the increases observed are substantially greaterthan those seen with dual X-ray absorptio-metry, an area measure of bone mass. The useof quantitative CT to measure drug response inclinical practice is, however, prevented by the costof this technique and the concern regarding theintensity of radiation required.

Parathyroid hormone

The recombinant human PTH134 teriparatide isthe only anabolic agent currently available in theUS for the treatment of patients with low bonemass, and recombinant human PTH1-84 is avail-able in Europe.20 The mechanism of action ofrecombinant human PTH is still under investi-gation, but the drug probably affects multiplepathways and alters the activity of osteoblasts,

bone lining cells, osteoclasts and osteocytes.PTH stimulates bone formation by increasingthe number of osteoblasts, partly by delayingosteoblast apoptosis.21 Transient exposure tothis hormone, by injection of a short-half-life(13 h) preparation, results in distinct anaboliceffects. Continuous elevation of PTH levels,as seen in patients with hyperparathyroidism,usually results in catabolic effects and boneloss. The effects of PTH are mediated by aG-protein-coupled receptor, PTH receptor 1.

Different amino-terminal fragments of PTH,such as PTH131, could have a different ana-bolic effect to that of PTH134. Cyclic PTH131has been hypothesized to produce a more ana-bolic profile than PTH134 or PTH184 becausethe PTH131 doses that provide a robust bone-

formation response decrease bone resorption.A 12-month phase II dose-ranging trial in post-menopausal women demonstrated an increasein lumbar spine BMD of 11%.22 Selected aminoacid substitutions at various positions in PTH128have been shown to increase the activity of thishormone, suggesting that more-potent PTHligands might be available.23 Given that the dura-tion of PTH treatment is limited to 2 years in theUS and 18 months in Europe, there is an unmetneed for additional anabolic agents.

Modulators of calcium-sensing receptors

The calcium-sensing receptor is a G-protein-coupled, seven-pass transmembrane moleculepresent in the parathyroid gland (and kidney),whose function is to coordinate calcium homeo-stasis by regulating the release of PTH.24Manipulation of this receptor by small-moleculeallosteric modulators can affect PTH secre-tion. Positive allosteric modulatorscalcium-sensing-receptor agonists termed calcimimet-ics, such as cinacalcetare used to lessen PTHsecretion in patients with renal disease and hyper-parathyroidism. Negative allosteric modulatorscalcium-sensing-receptor antagonists termedcalcilyticsare in development for the treatmentof osteoporosis. These agents block the function ofcalcium-sensing receptors, resulting in a PTHpulse with each dose (Figure 3). Calcilytics canbe administered orally and would, therefore,remove the need for daily injections associatedwith teriparatide administration.

Calcilytics must meet several importantrequirements before they can be useful as ana-bolic agents. First, they must stimulate the releaseof sufficient PTH. Second, anabolic action

requires a short half-life and transient activa-tion of the receptor, since in the case of calcilyticssustained activation would result in prolongedPTH secretion and a catabolic state, such ashyperparathyroidism. Third, the moleculeshould not exhaust the parathyroid gland, whichwould result in hyperplasia. A proof of conceptstudy in rats with the calcilytic ronacaleret hasshown that this PTH agent has a short half-lifeand produces a robust PTH response, increasesboth cortical and trabecular bone formation,

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Parathyroid cell

Calcium-sensing

receptor

Antagonist

PTH

Figur 3 Therapeutic manipulation of the calcium-

sensing receptor. The calcium-sensing receptor is

a G-coupled receptor that has an important role in

calcium homeostasis because of its expression on

parathyroid and kidney cells. Antagonism of the

receptor prevents binding of calcium and results in

the release of parathyroid hormone. Abbreviation:

PTH, parathyroid hormone.

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and generates notable increases in markersof osteoblast functionsuch as propeptide oftype I procollagen, osteocalcin and bone-specificalkaline phosphataseequivalent to those seenwith teriparatide. A dose-ranging clinical trialof ronacaleret in humans was discontinued,however, due to a poor effect on BMD.

Modulation of wnt signaling

Wnt proteins form a large family of extracellularcysteine-rich glycoproteins that help regulateembryogenetic bone remodeling and are involvedin many additional cellular processes.2527Wnt proteins activate an intracellular pathwaythat results in accumulation of beta-catenin.

Wnt permits association of the membrane recep-tors frizzled and lipoprotein-receptor-relatedprotein 5/6 (LRP5/6) and activation of a proteincomplex consisting of axin, adenomatous poly-posis coli and glycogen synthase kinase 3, whichactivates an intracellular pathway (Figure 4). Inthe absence of Wnt, glycogen synthase kinase 3phosphorylates beta-catenin, which is thendegraded via the ubiquitinproteosome pathway.In the presence of Wnt, the protein complex isdisrupted and phosphorylation of beta-catenin

does not occur, so beta-catenin accumulates,translocates to the cell nucleus and binds totranscription factors that affect transcription ofWnt-responsive genes, which are important inbone formation.

Inhibitors of Wnt signaling can bind to friz-zled (serum frizzled-related proteins), Wnt(Wnt inhibitory factors) or LRP5/6 (sclerostinand dickkopf-1). These agonist proteins preventWnt from activating the signaling pathwaymediated by frizzled and LRP5/6 receptor,leading to a decrease in signaling and a conse-quent reduction in bone formation. By contrast,deficiencies in these inhibitors or antibodiesresult in increased Wnt signaling and, therefore,

increased bone formation.Sclerosteosis, a human disease of high bone

mass, is the result of a homozygous mutationin the SOSTgene, which encodes sclerostin.28A deficiency of sclerostin results in increasedWnt signaling and high bone mass, and, in theskull, causes entrapment of cranial nerves andincreased intracranial pressure, which can subse-quently lead to stroke. Heterozygous mutations inthe SOST gene result in moderate increasesin bone mass and fewer skeletal complications.

Apc

Apc

A Without Wnt

-TRCP

Wnt

Axin

Gsk3

Ck1-Cat

Wnt-responsive gene

Fz

Lrp5/Lrp6

P P

TCF

B With Wnt

Axin

Gk3 -Cat

-Cat

-Cat

-Cat

Wnt-responsive gene

Fz

Lrp5/Lrp6

TCF

Dvl

Ck1

Figur 4 Simplified view or Wnt and beta-catenin signaling. (A) Without Wnt, the scaffolding protein

axin assembles a protein complex, beta-catenin is phosphorylated, ubiquitinated and degraded by the

proteosome. (B) With Wnt, beta-catenin is not phosphorylated, and is instead translocated to the nucleuswhere it binds to the TCF transcription factor, activating Wnt-responsive genes. Two membrane proteins,

Fz and LRP5/6, can associate in the presence of Wnt, which leads to formation of the protein scaffolding

complex, accumulation or degradation of -catenin, and gene transduction. Abbreviations:Apc, antigen presenting cell; -Cat, beta-catenin; -TRCP, transducin repeat-containing protein;Ck1, casein kinase 1; Dvl, disheveled; Fz, frizzled protein; GsK3, glycogen synthase kinase 3; LRP,

lipoprotein-receptor-related protein; TCF, T-cell factor. Reproduced with permission of the Company

of Biologists.

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Given that sclerostin is almost exclusively aproduct of osteocytes, the development of anti-bodies to this protein offers a way to specificallytarget bone formation. Antibodies to sclerostinincrease bone formation in osteopenic estrogen-deficient rats.29 In postmenopausal women, a

single subcutaneous dose of an antibody tosclerostin resulted in a 60100% increase inthe levels of propeptide of type I procollagenat day 84 of treatment, no increase in serumC-telopeptides, and a 6% increase in lumbarspine BMD.29

Gain of function mutations in the gene encod-ing LRP5/6 lead to increased bone mass. Thesemutations impair binding of dickkopf-1 toLRP5/6 and permit increased Wnt signaling andbone formation. Antibodies against dickkopf-1prevent binding of dickkopf-1 to LRP5/6 and

increase bone mass, volume and formationin rodents. Antibodies to dickkopf-1 could beused as an anabolic agent for the treatment ofpatients with low bone mass.

Activin inhibitors

A key signaling component in bone forma-tion is bone morphogenic protein (BMP), amember of the transforming growth factor superfamily.30 BMPs signal via SMADs, whichare nuclear transcription factors that regulatethe activity of transforming growth factor betaligands and specific genes involved in osteo-genesis. Fibrodysplasia ossificans progressivea genetic disorder of progressive heterotopicossificationis caused by missense mutations inactivin receptor IA, a BMP type I receptor, andleads to increased BMP signaling.31 This signal-ing promotes osteoblast maturation and functionby binding to two distinct activin receptorsIand IIon the cell membrane. Activin binds toactivin receptor IIA and is a negative regulatorof bone mass, acting as an essential cofactor forosteoclastogenesis.

A fusion protein comprising the extracellular

domain of human activin receptor IIA andthe Fc portion of human IgG1 (ACE-011) hasthe capacity to bind to activin and preventreceptor binding. This antibody has beenshown to increase bone mass in cynomologusmonkeys (>70% increase in trabecular bonemass, as determined by quantitative CT).32Administration of a single dose of the fusionprotein to 48 postmenopausal women resultedin an increase in levels of bone-specific alkalinephosphatase and a decrease in C-telopeptides.33

The BMP pathway is a promising new area totarget therapeutic agents for the treatment oflow bone mass.

CONCLUSIONS

Notable advances in the treatment of low bone

mass seem to be on the horizon and are a resultof increased understanding of the mechanismsunderlying bone formation and resorption.New anabolic agents affecting the calcium-sensing receptor and Wnt signaling, and newantiresorptive agents that might have less of aneffect on bone formation than currently availabletherapies, offer promise for the treatment of lowbone mass. Additional therapies, especially thosethat can be used to treat patients with estab-lished fractures, are needed to reduce the burdenof osteoporosis.

KeY POINTS

Drugs that influence bone mass do so

by acting directly on cells that are integral to

the bone remodeling unit

Antiresorptive agents inhibit osteoclasts

and prevent bone resorption

Anabolic agents stimulate osteoblasts

and, therefore, bone formation

Potential new therapeutic agents include

denosumab, an antibody to receptor activator

of nuclear factor B ligand, and odanacatib,

a cathepsin K inhibitor

Potential new anabolic agents include those

that target the calcium-sensing receptor and

proteins in the Wnt signaling pathway

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Compting intrstsC Deal has declared

associations with the

following companies:

Amgen, GSK, Lilly, Novartis,

Proctor & Gamble and

Roche. See the article

online for full details

of the relationships.

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