Sclerostin: A gem from the genome leads to bone-building antibodies


Discovery of Sclerostin

Genomics technologies and DNA sequencing have had a transformative impact on biological research, giving us unprecedented access to the genomes of numerous organisms and ushering in such new fields as systems biology1 and, more recently, synthetic biology.2, 3 In the 1990s, the advent of high-throughput sequencing spurred application of this powerful new technology to the challenging endeavor of trying to understand the genetic basis of various inherited human diseases. One such disease was sclerosteosis, a very rare, recessively inherited high-bone-mass disorder that was thought to be caused primarily by excessive osteoblast-mediated bone formation rather than by defective osteoclast-mediated bone resorption.4, 5 Within the realm of inherited high-bone-mass disorders,6 it was the hope for a discovery in the area of osteoblast biology that made sclerosteosis particularly interesting.

Indeed, the identification of new bone-building pathways that might yield novel anabolic agents had been a long-standing goal in bone biology, with hopes for therapeutic application in fracture healing, orthopedic procedures, and low-bone-mass conditions such as osteoporosis. Against this backdrop came the exciting news, independently from Mary Brunkow's group at Celltech R&D, Inc.,7, 8 and from Wim Van Hul's group at the University of Antwerp,9 that sclerosteosis was caused by mutations in a single gene (SOST) encoding a novel secreted protein. Because these were inactivating mutations, it was clear that this protein, aptly given the name sclerostin, functioned either directly or indirectly as an inhibitor of bone formation. During this same general time period, large-scale cDNA/expressed sequence tag (EST)10–12 and genomic DNA sequencing efforts were being made in academia and industry to rapidly identify new human genes. A novel secreted protein of unknown function, which turned out to be sclerostin, was discovered by computational mining of large DNA sequence databases using either homology-based programs (eg, BLAST)13, 14 or a special CxGxC-class cystine-knot search pattern (C Paszty, unpublished)15 designed to identify new families of cystine-knot proteins.16, 17 Thus sclerostin emerged during an exciting era of gene discovery that was fueled, in part, by the development of important genomics technologies and the advent of high-throughput DNA sequencing.

Similar to sclerostin inactivation in humans, mice with a targeted deletion of the sclerostin gene (SOST knockout mice) were found to have high bone mass, demonstrating evolutionary conservation of sclerostin's function as a negative regulator of bone formation.18 Analysis of bones from these mice revealed that bone formation was markedly increased on each of the key skeletal surfaces where new bone is normally formed (surface of trabecular bone and internal and external surfaces of cortical bone). Consistent with the increases in bone formation and bone mass, robust increases in bone strength also were found in these animals. These data from SOST knockout mice further highlighted sclerostin's critical role as an inhibitor of bone formation throughout the skeleton and its potential as a pharmacologic target for increasing bone mass and bone strength.

Molecular Interactions and Signaling Pathways

Efforts to understand the genetic control of bone mass were, of course, not restricted to studying sclerosteosis. Van Buchem disease, another very rare, recessively inherited high-bone-mass disorder, was determined to be caused by a 52-kb deletion 35 kb downstream of SOST,19, 20 resulting in absence of postnatal sclerostin expression.21, 22 For osteoporosis pseudoglioma syndrome (OPPG), a recessively inherited low-bone-mass disease, loss-of-function mutations were found in a Wnt signaling coreceptor, the low-density lipoprotein receptor–related protein 5 (LRP5).23 This important result provided the first evidence that Wnt signaling played a critical role in the control of bone mass. Elegant support for LRP5's key role in bone biology came from the discovery that single-point mutations in the first propeller region of the LRP5 extracellular domain were responsible for causing dominantly inherited high bone mass (HBM) in several human kindreds.24–26 The HBM phenotype indicated that the specific amino acid substitutions caused by these point mutations had somehow resulted in a gain-of-function LRP5 protein.

The bone phenotypes in individuals with LRP5 HBM alleles were similar in nature but generally milder than the range of phenotypes in individuals with sclerosteosis and Van Buchem disease. Despite reports of cases of LRP5 HBM that fell within the range of sclerosteosis and Van Buchem disease phenotypes,27, 28 the first clue linking sclerostin and LRP5 did not come from molecular studies in bone but came instead from a study investigating anteroposterior patterning in Xenopus (African clawed frog). The Xenopus publication described a context-dependent activator and inhibitor of Wnt signaling (given the name Wise) that acted by binding to LRP6, a protein closely related to LRP5.29 Wise, also known as ectodin,30 USAG-1,31 and SOSTDC1, is most closely related to sclerostin, and together they make up the two-member sclerostin family. These interesting findings in Xenopus, coupled with the sclerostin and LRP5 genetic data, strongly suggested that sclerostin acted at the molecular level, at least in part, by binding to LRP5. Several groups subsequently confirmed that sclerostin did indeed bind LRP5 and inhibit Wnt signaling in vitro.32–34 Additionally, it was shown that both sclerostin and another Wnt signaling antagonist, Dickkopf1 (DKK1), had decreased binding affinity to HBM LRP5 and reduced ability to inhibit HBM LRP5-mediated Wnt signaling.34–38 As such, the gain of function for HBM LRP5 appeared to be primarily from enhanced resistance to inhibition by sclerostin and/or DKK1. Thus the totality of genetic and in vitro data indicated that, in vivo, sclerostin very likely did bind to the extracellular domain of LRP5 on cells of the osteoblast lineage and inhibit Wnt signaling.

In addition to these Wnt pathway findings, sclerostin had been reported to regulate the bone morphogenetic protein (BMP) pathway by binding to and antagonizing the activity of BMPs, 39, 40 as well as Noggin,41 itself a well-known BMP antagonist. Subsequent reports questioned the ability of sclerostin to act as a direct antagonist of BMPs.42, 43 Above and beyond the reported associations with LRP5 and BMPs, hints that sclerostin's mechanism of action at the molecular level might contain additional complexity came from the observation that sclerostin's inhibitory activity was notably variable across different osteoblast-lineage cell-based assays, much more so than the Wnt signaling inhibitor DKK1 and the BMP signaling inhibitor Gremlin.44 With regard to other possible molecular interactions for sclerostin, data from in vitro experiments had shown that sclerostin could bind LRP6 and inhibit Wnt signaling,32–34 similar to the findings for LRP5. This, coupled with mouse genetic data showing that LRP6 appeared to play a role in achieving and/or maintaining normal bone mass,45–47 suggested that sclerostin also might interact with LRP6 in vivo. Recently, it has been reported that sclerostin binds to LRP4, a single-transmembrane protein related to LRP5 and LRP6, and, additionally, that LRP4 is expressed in bone by osteoblasts and osteocytes.48, 49 Knockdown of LRP4 expression in cell culture was found to block sclerostin's inhibitory activity on Wnt signaling and on in vitro mineralization.48 Thus in these in vitro systems, sclerostin's activity was shown to depend on the presence of LRP4. Analysis of hypomorphic (partial loss-of-function) LRP4 alleles in mice showed that LRP4 appears to play a role in achieving and/or maintaining normal bone mass.49 This, coupled with recent exciting data demonstrating that certain missense mutations in LRP4 cause increased bone mineral density in humans,50 strongly suggests that sclerostin interacts with LRP4 in vivo.

Of note, unlike the viability of mice (and humans) with complete loss of function for LRP5, mice with complete loss of function for LRP6 or LRP4 die perinatally. This early lethality makes it experimentally challenging to gain further insight into the roles of LRP6 and LRP4 in bone biology, particularly with respect to these two proteins possibly being in vivo binding partners for sclerostin. Clarification of this aspect of sclerostin biology will likely require sophisticated genetic manipulation of LRP6 and LRP4 in mice, such as the creation of osteoblast- and/or osteocyte-specific knockouts, as well as knockins of various LRP6 and LRP4 alleles.

Two NMR structures of sclerostin have been reported,51, 52 both revealing that the 190-amino-acid sclerostin polypeptide has highly flexible N- and C-terminal arms extending out from a three-loop structure containing a cross-linking cystine knot at its core. Loops 1 and 3 lie side by side and form a rigid finger-like structure made up of twisted antiparallel B strands joined at their tips by a noncystine knot disulfide bond. Loop 2 is distinct in that it extends out from the opposite side of the cystine knot and is relatively flexible, being able to adopt a diverse range of conformations. A patch of positively charged amino acid residues comprising most of one side of sclerostin was identified and shown to promote binding to heparin.51 Interestingly, specific amino acid mutations in this region resulted in reduced heparin binding but did not appear to reduce the ability of sclerostin to inhibit Wnt signaling in vitro. These mutations did, however, reduce the ability of sclerostin to associate with the cell surface of osteoblast-lineage cells. This type of interaction between sclerostin and negatively charged proteoglycans, such as heparan sulfate, may be important in vivo for retaining and concentrating sclerostin in the bone microenvironment to act on cells of the osteoblast lineage.

Although much remains to be learned about the spectrum of sclerostin binding partners, the effects of sclerostin on signaling, and the components of the higher-order molecular complexes that engage sclerostin in vivo, very significant progress has been made since the discovery of sclerostin more than 10 years ago.

Osteocytes, Mechanical Loading, and Interface with the PTH Pathway

The skeleton has many important structural and metabolic functions, with a critical role being mechanical support of the musculature for movement and locomotion. In response to increased mechanical loading or lack of loading (disuse), bone is known to undergo adaptive changes in mass and shape, thereby providing for dynamic adjustment of skeletal strength in the face of ongoing changing loading conditions experienced during life. Thus mechanical loading has an anabolic effect (stimulation of bone formation), whereas disuse causes bone loss.

Sclerostin is expressed almost exclusively in bone, specifically by osteocytes.39, 42, 53 These terminally differentiated cells of the osteoblast lineage are found embedded within bone matrix throughout the entire skeleton and are the most abundant cell type in bone. With their extensive cytoplasmic connections to one another and to osteoblasts and bone-lining cells located on bone surfaces, osteocytes form an interconnected network and had been postulated to act as bone mechanosensors.54, 55 Intriguingly, osteocytes were also predicted to emit a powerful but unknown inhibitory signal (or signals) as a means of controlling bone formation and bone mass.56, 57 In this scenario, osteocytes would sense mechanical load and actively modulate the strength of this inhibitory signal to transmit loading information to effector cells on the bone surface. Sclerostin's osteocyte-specific expression and its inhibitory effect on bone formation led to the view that it represented one such key inhibitory signal used by osteocytes to regulate bone mass.

Indeed, evidence for mechanoregulation of sclerostin expression, as assessed by probing bone tissue for protein and mRNA levels, was recently reported in mice and rats subjected to ulnar loading in vivo.58 Specifically, there was a significant reduction (up to about 70%) in sclerostin protein levels and in SOST transcripts in bones subjected to loading. Moreover, the regions of bone that endured the greatest strain energy were those which exhibited the greatest reductions in SOST/sclerostin and that had the greatest increases in bone formation.58 Others have subsequently replicated many of these initial results.59 In addition to decreased SOST/sclerostin, there also was a loading-induced significant reduction in another Wnt signaling antagonist, DKK1. Conversely, tail suspension, a rodent model for disuse-induced bone loss, resulted in an increase in SOST mRNA levels in the mouse tibia, suggesting that SOST expression is also modulated by mechanical unloading.58 Consistent with this, SOST knockout mice, when subjected to tail suspension, were found to not lose bone.60 Thus load-induced adjustment of sclerostin levels appears to be a finely tuned mechanism by which osteocytes coordinate regional and local osteogenesis in response to mechanical stimulation.

Mice engineered for a loss-of-function mutation in LRP5 have low bone mass, with the weight-bearing portions of the skeleton showing a greater deficit in bone mass than the non-weight-bearing portions. This observation in LRP5 knockout mice led to the hypothesis that LRP5 was important in mechanical signaling. In support of this notion, there was a greater than 85% reduction in in vivo load-induced bone formation in these knockout mice compared with wild-type controls.61 Additionally, in a large human genetic association study, several single-nucleotide polymorphisms (SNPs) were found in LRP5 that significantly affected the relationship between physical activity and bone mineral density, further supporting a function for LRP5 in mechanotransduction.62 Taken together, these data indicate that LRP5 plays a key role in translating mechanical signaling into the proper skeletal response.

Several experiments also have demonstrated the involvement of canonical Wnt signaling in mechanotransduction. Osteoblasts cultured from transgenic mice expressing a T-cell factor (TCF)/β-catenin transcription reporter (TopGal mice) exhibited activation of canonical Wnt signaling when subjected to mechanical strain induced by physical deformation.63 In another study, in vivo loading of the tibia was found to result in the upregulation of a host of Wnt pathway and Wnt/β-catenin target genes (eg, Wnt10b, sFrp1, Ccnd1, Cxn43, and Wisp2).64 More recently, loading experiments in TopGal mice revealed a rapid induction of canonical Wnt signaling in osteocytes that preceded, by at least 20 hours, the activation of canonical Wnt signaling in osteoblasts. This activation of osteoblasts was found to occur concurrent with a significant decrease in the number of osteocytes that stained positive for sclerostin or DKK1.65 The results from this temporal analysis of Wnt signaling in osteocytes and osteoblasts supports the view that the mechanosensory osteocyte network regulates and deploys sclerostin as a means of transmitting strain information to effector cells located on bone surfaces.

In addition to mechanical loading studies looking at changes in sclerostin expression and Wnt signaling, there has been considerable interest in assessing the effects of the parathyroid hormone (PTH) pathway on sclerostin expression levels. One of the goals of this line of investigation has been to determine whether sclerostin serves as a paracrine mediator of PTH actions. Both intermittent dosing (daily injection) and continuous infusion of PTH are known to increase osteoblast number. While intermittent PTH has a net anabolic effect, continuous PTH has a net catabolic effect owing to excessive stimulation of osteoclast-mediated bone resorption. In mice, intermittent PTH was found to decrease sclerostin expression in bone by about 50%.66-68 In the case of continuous PTH infusion67 or osteocyte-specific constitutively elevated PTH signaling,69 the effect was more pronounced, with sclerostin expression being decreased by more than 80%. Experiments using in vitro approaches have shown that PTH can downregulate sclerostin expression through the MEF2 transcription complex in a downstream enhancer region for the sclerostin gene.70 This work provides a possible molecular mechanism for the observations in mice of decreased sclerostin expression in bone following PTH administration. Alternatively, data from another in vitro study showed evidence for PTH-induced association of the PTH receptor with LRP6, leading to activation of LRP6 and canonical Wnt signaling.71 This report raises the possibility that PTH might act directly on the Wnt signaling pathway through LRP6, irrespective of any decreases in sclerostin expression. Interestingly, two studies demonstrated a normal anabolic response to intermittent PTH in LRP5-deficient mice (LRP5 knockouts), indicating that LRP5 is not needed for intermittent PTHs stimulatory effects on bone formation.61, 72 Finally, a recent study examined the effects of intermittent PTH in mice with either genetically increased bone formation owing to sclerostin deficiency (SOST knockouts) or genetically decreased bone formation owing to sclerostin overexpression (SOST transgenics). In both types of mice, there was a marked blunting of the anabolic effects of intermittent PTH compared with the level of anabolism obtained for intermittent PTH in the wild-type control mice.68 Taken together, the data obtained over the past few years from various PTH-sclerostin/SOST studies suggest that part of the anabolic effect of PTH in mice is mediated through a decrease in sclerostin expression, as measured directly in bone. Given the fact that intermittent PTH is currently the only approved anabolic therapy for bone, we can anticipate reports emerging in the near future describing the effects of intermittent PTH treatment on sclerostin levels in humans.

Pharmacology of Sclerostin Antibodies

Based on the increases in bone formation and bone mass in humans with genetic sclerostin deficiency, pharmacologic inhibition of sclerostin represented a therapeutic opportunity for the anabolic treatment of bone-related conditions (eg, bone loss, fracture healing, and orthopedic procedures).7–9 This was further highlighted by the high-bone-mass phenotype of SOST knockout mice and the substantial increases in bone formation and bone strength found in both the trabecular and cortical bone compartments of these animals.

With sclerostin being a secreted protein involved in protein-protein interactions, efforts to achieve pharmacologic inhibition of sclerostin focused around the development of sclerostin-neutralizing antibodies. Surprisingly, in standard osteoblast-lineage screening assays, the potency of sclerostin was low and notably context-dependent. From an expanded empirical search aimed at identifying a suitable antibody screening assay, it was found that mineralization of the MC3T3-E1 osteoblast-lineage cell line was particularly sensitive to inhibition by recombinant sclerostin.44 This relatively long 2-week assay was refined and adapted for use in an industrial-scale screening effort that culminated in the identification of numerous sclerostin-neutralizing antibodies (C Paszty, MK Robinson, et al., unpublished), thus setting the stage for in vivo studies.

The first report of pharmacologic inhibition of sclerostin described the effects of sclerostin antibody (Scl-Ab) administration in aged ovariectomized (OVX) rats, a widely used model for postmenopausal osteoporosis.44 In this study, short-term treatment with Scl-Ab not only resulted in complete reversal of the 1 year of estrogen-deficiency-induced bone loss but also further increased bone mass and bone strength to levels greater than sham controls. Bone volume was increased in both the cortical and trabecular bone compartments, and bone formation was increased markedly on trabecular, periosteal, and endocortical surfaces. This increase in bone formation was driven largely by substantial increases in bone-forming surface (mineralizing surface). The magnitude of the anabolic response obtained in these aged OVX rats clearly demonstrated that sclerostin functions as a pivotal negative regulator of bone formation, even in the aging skeleton. This has significant implications for the clinical potential of sclerostin inhibition because clinical situations where increases in bone formation might be therapeutically desirable are found much more frequently in older adults. Furthermore, this proof-of-concept study for pharmacologic blockade of sclerostin sparked considerable interest in the potential of antibody-mediated sclerostin inhibition for the anabolic treatment of bone-related disorders.73, 74

Despite the clear increase in osteoblast-mediated bone formation found in this OVX rat study, osteoclast surface was decreased, pointing toward an absence of the coupling that typically exists between osteoblasts and osteoclasts during bone remodeling. This apparent lack of coupling was also reported for SOST knockout mice18 and is consistent with the very limited (one patient) histomorphometric data available for sclerosteosis.75 Currently, it is unclear whether the reduction in osteoclast surface resulting from antibody-mediated sclerostin inhibition is from a direct impact on osteoclasts or secondary to the marked increase in bone-forming surface. Another interesting feature of pharmacologic sclerostin inhibition in OVX rats is that the strong anabolic effect comes largely from activation of bone formation on quiescent surfaces (bone modeling), with much smaller contributions coming from bone formation on remodeling surfaces.76 Further investigation into the effect of pharmacologic sclerostin inhibition on bone remodeling and modeling is warranted.

For anabolic agents, there is general interest in determining whether or not anabolic activity is blunted by cotreatment or pretreatment with antiresorptive agents such as bisphosphonates. The anabolism of sclerostin antibody (Scl-Ab) in OVX rats was found to not be blunted by cotreatment with alendronate, as determined by histomorphometric measurement of bone formation and by densitometric assessment of trabecular and cortical bone mass.77 Similarly, pretreatment of OVX rats with alendronate did not result in a blunting of subsequent Scl-Ab-mediated increases in bone formation and bone mass.78 Additionally, studies in OVX mice showed that increases in bone mass from Scl-Ab treatment could be maintained over time by follow-on administration of an antiresorptive agent such as zoledronic acid.79

Chronic inflammation has long been known to lead to bone loss in part owing to inflammation-induced increases in RANKL-mediated osteoclastogenesis.80, 81 Additionally, increased levels of tumor necrosis factor α (TNF-α) are known to have a key role in many inflammatory diseases, and TNF-related weak inducer of apoptosis (TWEAK) has been reported to have a role in inflammatory bone remodeling in mouse collagen-induced arthritis.82, 83 A recent report showed that both TNF-α and TWEAK can upregulate sclerostin expression and that they do so synergistically in certain settings.84 Conversely, in ankylosing spondylitis, a disease characterized by inflammation-associated bony proliferations, local sclerostin production appears to be downregulated.85 In mice, oncostatin M, a cytokine expressed by osteoblasts, osteocytes, and activated T cells, has been found to downregulate sclerostin expression by signaling through the leukemia inhibitory factor receptor (LIFR)–gp130 receptor complex.86 In a mouse model of chronic colitis, short-term treatment with Scl-Ab had no anti-inflammatory effects but increased bone formation and reversed both inflammation-induced bone loss and the inflammation-induced decline in bone mechanical properties.87 Circulating TRACP5b levels were decreased, suggesting that administration of Scl-Ab also reduced osteoclast-mediated bone resorption. Scl-Ab treatment also has been found to prevent the systemic bone loss seen in a mouse collagen-induced arthritis model (M Marenzana, personal communication). These interesting preclinical results suggest that antibody-mediated sclerostin inhibition may represent a potential anabolic bone therapy in the pathophysiologic setting of inflammation-induced bone loss.

In addition to postmenopausal osteoporosis and inflammatory disease, there are numerous other conditions that can lead to bone loss. These include limb immobilization/disuse (unloading) and normal skeletal aging. In this regard, Scl-Ab administration has been shown to have significant anabolic effects in a rat model of immobilization/disuse-induced bone loss88 and in aged male rats.89

Nonhuman primates are considered to be the most appropriate species to approximate human bone biology owing to similarities in cortical bone remodeling and response to estrogen withdrawal. In gonad-intact female cynomolgus monkeys, short-term dosing of Scl-Ab produced a strong anabolic response in both trabecular and cortical bone.90 In this study, a once-monthly administration of Scl-Ab for 2 months resulted in marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Significant increases in bone mineral content and/or bone mineral density were found at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline, were 11 to 29 percentage points higher than those found in the vehicle-treated group. Despite the short duration of this study, the increases in bone mass were large enough to be translated into significant increases in bone strength. These impressive results in nonhuman primates speak again to the therapeutic potential of sclerostin inhibition and highlight the powerful nature of the anabolic pathway that sclerostin controls.

In the realm of fracture healing, systemic administration of Scl-Ab (ie, not injected at the fracture site) has been shown to have beneficial effects in several types of rodent models of fracture healing and bone repair (eg, femoral osteotomy, femoral gap defect, femoral closed fracture, and tibial metaphyseal fracture).91–94 Positive effects include increased callus density, increased bone strength at the fracture/trauma site, and accelerated bone repair. In a nonhuman primate fibular osteotomy model, systemic administration of Scl-Ab was shown to increase callus area, callus bone mineral content, and fibular torsional stiffness, thereby accelerating fracture healing.95 For orthopedic implant procedures such as hip replacement surgery, the ability to increase bone formation is thought to have the potential to improve early implant fixation and reduce the extent of implant loosening that can occur over time. Scl-Ab was tested in rat models of implant fixation using titanium cylinder implants in the femur96 and stainless steel screws in the proximal tibia.94 Mechanical pull-out testing demonstrated functionally increased fixation of cylinder implants and screws by Scl-Ab in both these models.

Finally, in a phase 1 clinical study, single-dose administration of Scl-Ab in healthy men and postmenopausal women was found to increase several markers of bone formation, decrease a serum marker of bone resorption, and increase bone mineral density.97 These encouraging first-in-human data have led to expanded clinical efforts, with phase 2 trials currently under way in fracture healing and postmenopausal osteoporosis.


The ground-breaking discovery of sclerostin in the late 1990s raised hopes for the emergence of novel anabolic bone therapies targeting sclerostin and also helped open the door on a treasure trove of complex and fascinating biology. Although there has been significant progress in delineating the molecular and cellular details underlying sclerostin's pivotal role in negatively regulating bone formation and bone mass, much remains to be learned. The structural components and workings of the powerful anabolic pathway(s) that sclerostin antagonizes remain incompletely understood. In addition, sclerostin appears to have more than one binding partner and is likely to function by interacting with multiprotein signaling complexes, making research in this area experimentally challenging. Certainly, the fact that sclerostin is expressed primarily by osteocytes has helped point the illuminating beam of scientific enquiry into the shadowy realm of the entombed osteocyte network. With the relatively recent emergence of molecular and genetic data highlighting osteocytes as important orchestrators of key skeletal activities, many questions arise. Does sclerostin have autocrine action on osteocytes? Do osteocytes send other inhibitory signals, and perhaps stimulatory signals, to control the effector cell lineages that physically perform the acts of bone modeling and remodeling? What are the biochemical and biophysical signals influencing the amount of sclerostin that the osteocyte network deploys to do its bidding? These questions notwithstanding, what is clear is that sclerostin is a master regulatory molecule linking osteocyte biology to the anabolic output of the osteoblast lineage.

Bone-related conditions cause significant morbidity worldwide, particularly among the elderly. A vast amount of basic biology, drug development, and clinical work spanning many decades has resulted in significant advances in the treatment of bone-related disorders, such as the availability of antiresorptive agents for use in blocking bone destruction and bone loss. Nevertheless, there has been a long-standing effort aimed at discovering novel molecular pathways that could lead to the development of anabolic agents for rebuilding and repairing bone. In this regard, the marked anabolic effects achieved with pharmacologic inhibition of sclerostin in a wide range of preclinical models, coupled with positive data from an early clinical trial in men and women, are very encouraging. Taken in their totality, these exciting results suggest that inhibition of sclerostin represents a promising new anabolic treatment approach for bone-loss conditions, fracture healing, orthopedic procedures, and other bone-related disorders.


CP is an employee of Amgen, Inc., and has received stock and stock options from Amgen, Inc. CHT has no conflicts of interest. MKR is an employee of UCB-Celltech and has received stock and stock options from UCB-Celltech.