Article Published in the Author Account of

E. Michael Lewiecki

Sclerostin: A Novel Target for Intervention in the Treatment of Osteoporosis

Abstract: Bone remodeling is the process by which the adult skeleton is continually renewed through the highly coordinated activity of three types of cells -- osteoclasts, osteoblasts, and osteocytes. Disruptions in signaling among these cells and alterations in their activity have been associated with skeletal diseases. In a rare accident of nature, some families have been found to have dense and strong bones due to a recessive loss of function mutation in the SOST gene that encodes for sclerostin, a protein expressed by osteocytes that downregulates osteoblastic bone formation. Individuals who are homozygous for this mutation have sclerosteosis, a disease with no detectable circulating sclerostin, resulting in generalized osteosclerosis with skeletal deformities, cranial nerve compression, and increased intracranial pressure due to boney overgrowth in the skull, and premature death. However, family members who are heterozygous carriers for the mutation have normal phenotype and normal lifespan, with dense bones and low risk of fracture. This observation has led to the concept that compounds that reduce sclerostin levels might mimic the heterozygous carrier state and be effective in the treatment of osteoporosis. To this end, monoclonal antibodies to sclerostin have been developed. Preclinical and early clinical studies of sclerostin inhibitors have shown robust stimulation of osteoblastic bone formation. The investigational compound that has advanced the furthest in development is AMG 785 (CDP7851), a humanized monoclonal antibody to sclerostin. Monoclonal antibodies to sclerostin represent a class of compounds with potential benefit in the treatment of osteoporosis and other skeletal disorders.


Osteoporosis is a disease characterized by low bone mineral density (BMD) and poor bone quality resulting in reduced bone strength and increased risk of fractures (Klibanski et al., 2001). It is a major public health concern that affects more than 75 million people in the United States (U.S.), Europe, and Japan, with over 8.9 million low trauma fractures annually (Kanis and on behalf of the World Health Organization Scientific Group, 2007). In the U.S., an estimated 44 million people have osteoporosis or low bone mass (osteopenia) leading to increased risk of fractures (National Osteoporosis Foundation, 2002). The lifetime risk of an osteoporotic fracture is about 50% for Caucasian women and 20% for men (U.S. Department of Health and Human Services, 2004). Fractures of the spine and hip are associated with acute and chronic pain, deformity, depression, disability, and increased risk of death (Kanis and on behalf of the World Health Organization Scientific Group, 2007), representing a substantial burden to the limited resources of healthcare systems (Burge et al., 2007; Kanis and Johnell, 2005).

The prevention and treatment of osteoporosis include a lifelong effort to maintain good nutrition, particularly with regard to adequacy of calcium and vitamin D intake, as well as regular physical activity and avoidance of cigarette smoking, excess alcohol, and drugs known to have adverse skeletal effects (e.g., glucocorticoids, anticonvulsants, aromatase inhibitors, androgen deprivation therapy). In patients at high risk for fracture, pharmacological agents have been proven effective to reduce fracture risk, with generally favorable safety profiles. These drugs include estrogen with or without medroxyprogesterone (Writing Group for the Women’s Health Initiative Investigators, 2002; Anderson et al., 2004), alendronate (Black et al., 1996; Cummings et al., 1998), risedronate (McClung et al., 2001; Reginster et al., 2000; Harris et al., 1999), ibandronate (Chesnut III et al., 2004), zoledronate (Black et al., 2007; Lyles et al., 2007), denosumab (Cummings et al., 2009), salmon calcitonin (Chesnut et al., 2000), raloxifene (Ettinger et al., 1999), bazedoxifene (Silverman et al., 2008), lasofoxifene (Cummings et al., 2008), teriparatide (Neer et al., 2001), recombinant human parathyroid hormone (PTH, 1-84) (Greenspan et al., 2007), and strontium ranelate (Reginster et al., 2005; Meunier et al., 2004). However, osteoporosis remains under-diagnosed (Curtis et al., 2008) and under-treated (Panneman et al., 2004); when treatment is prescribed, adherence to therapy is often poor (Cramer et al., 2007). The poor clinical outcomes (i.e., greater risk of fractures) due to suboptimal osteoporosis care have led to efforts to enhance the use of the clinical tools and drugs that are currently available and to develop new treatments with more convenient dosing and improved benefit/risk ratio (U.S. Department of Health and Human Services, 2004). Great effort has been expended toward better understanding of genetic determinants of skeletal health and the regulators and mediators of bone metabolism in order to identify new targets for therapeutic intervention. The Wnt signaling pathway is now recognized as playing an important role in the regulation of bone formation (Wagner et al., 2011). This is the story of a rare genetic disease involving Wnt signaling, the discovery of an endogenous antagonist to Wnt signaling, and a promising investigational agent for the treatment of osteoporosis that inhibits this antagonist.

Bone Remodeling

Figure 1. Modulation of Wnt signaling by sclerostin. The binding of Wnt proteins to the LRP5/6-Frizzled co-receptor on the cell membrane of osteoblasts leads to stabilization of intracellular β-catenin and regulation of gene transcription that promotes osteoblastic bone formation. Sclerostin is a naturally occurring modulator of osteoblast function; by binding to LRP5/6 it antagonizes Wnt signaling and inhibits osteoblastic bone formation. Monoclonal antibodies that block sclerostin enhance Wnt signaling and increase osteoblastic bone formation.

Figure 1. Modulation of Wnt signaling by sclerostin. The binding of Wnt proteins to the LRP5/6-Frizzled co-receptor on the cell membrane of osteoblasts leads to stabilization of intracellular β-catenin and regulation of gene transcription that promotes osteoblastic bone formation. Sclerostin is a naturally occurring modulator of osteoblast function; by binding to LRP5/6 it antagonizes Wnt signaling and inhibits osteoblastic bone formation. Monoclonal antibodies that block sclerostin enhance Wnt signaling and increase osteoblastic bone formation.

Bone remodeling is the physiological process by which small discreet packets of bone are continually removed and replaced on the surface of trabecular bone and in Haversian systems within cortical bone. This requires the coordinated activity of three types of cells — osteoclasts (bone resorbing cells), osteoblasts (bone forming cells), and osteocytes (cells that detect loads applied to bone). Osteocytes are former osteoblasts that have become embedded in the bone matrix, communicating with one another and with bone lining cells through a network of cytoplasmic connections, similar to what is seen with nerve cells (Bonewald, 2008). After sensing a load or stress applied to bone, a signal(s) appears to be generated that serves to modulate bone remodeling. The presence of this mechanoregulatory system was suggested many years ago (Cowin et al., 1991; Lanyon, 1993), but it is only recently that sclerostin has been identified as a molecule expressed by osteocytes with an important role in regulating osteoblastic bone formation (Figure 1).

In a healthy young adult, the bone remodeling rate is generally low, with bone resorption being approximately equal to bone formation (Figure 2). This is associated with a steady-state of bone mass and good bone strength. In an estrogen deficient postmenopausal woman, the rate of bone remodeling is high, with an imbalance of bone resorption greater than bone formation. With the high rate of bone remodeling, bone resorption units become more numerous and larger, with each representing a “stress riser” or weakened portion of the bone that may be a focal point for microfractures. If this continues unabated, measurable bone loss occurs, with a high likelihood of osteoporosis developing.

All of the drugs currently used for the treatment of postmenopausal osteoporosis have effects on bone remodeling (Riggs and Parfitt, 2005). Antiresorptive drugs primarily work by reducing bone resorption, while osteoanabolic drugs primarily work by increasing bone formation. Antiresorptive agents strengthen bone and reduce fracture risk by decreasing bone turnover. This reduces the bone remodeling space and stabilizes or increases BMD through prolongation of secondary mineralization, with preservation of bone microarchitecture, reduction in trabecular perforation, and a decrease in cortical porosity. However, lost bone is not replaced and degraded bone microarchitectural elements are not restored. Osteoanabolic drugs strengthen bone and reduce fracture risk by increasing bone formation. They are associated with an increase in bone size and restoration or formation of new trabecular microarchitectural elements. The rebuilding of bone with this class of agents, alone or perhaps in combination with antiresorptive drugs, offers the potential of “curing” osteoporosis (Lane and Kelman, 2003) and enhancing healing of bone following fractures and orthopedic procedures.

Figure 2. Conceptualization of bone remodeling and bone modeling on the surface of trabecular bone in health and disease.

Figure 2. Conceptualization of bone remodeling and bone modeling on the surface of trabecular bone in health and disease.

Sclerostin, a protein encoded by the SOST gene in osteocytes, inhibits osteoblastic bone formation (Poole et al., 2005; van Bezooijen et al., 2004). Compounds that reduce the production, increase the breakdown, or inhibit the activity of sclerostin might be expected to increase osteoblastic bone formation and thereby have an osteoanabolic effect. Preclinical studies of sclerostin inhibition with monoclonal antibodies have shown an increase in bone formation without the increase in bone resorption that is seen in osteoanabolic therapy with teriparatide and PTH(1-84) (Ominsky et al., 2010; Li et al., 2010). This is suggestive of uncoupling of formation and resorption that may represent bone modeling (direct activation of bone formation on quiescent surfaces) occurring independently of bone resorption. AMG 785 (CDP-7851; co-developed by Amgen, Thousand Oaks, CA, USA, and UCB, Belgium) is an investigational humanized sclerostin monoclonal antibody that is now in phase 2 clinical trials.

Sclerosteosis and van Buchem Disease

Sclerosteosis is a rare autosomal recessive disorder initially described in the 1950s (TRUSWELL, 1958) and identified by that name (”sklerosteose” in German) in 1967 (Hausen, 1967). It is characterized by progressive bone thickening and sclerosis that is particularly evident in the skull, leading to enlargement of the jaw and facial bones that can cause facial nerve palsies (Figure 3) due to entrapment of cranial nerves and increases in intracranial pressure that may result in sudden death due to impaction of the brainstem in the foramen magnum (Gardner et al., 2005; Hamersma et al., 2003). Although sporadic cases have been reported in many world regions (Tacconi et al., 1998; Bueno et al., 1994; Stein et al., 1983; Sugiura and Yasuhara, 1975), sclerosteosis is principally a disease of Afrikaners — white settlers in South Africa of Dutch origin. In this population, the carrier rate for the mutant SOST gene is about 1 in every 100 (Gardner et al., 2005). Sclerosteosis is caused by one of at least 6 types of loss of function mutations (Papapoulos, 2011) of SOST, a gene located on the chromosomal region 17q12-21, resulting in decreased production of sclerostin by osteocytes. This leads to an increase in osteoblastic bone formation and the typical bone phenotype. Few, if any, patients with sclerosteosis have fractures (Hamersma et al., 2003). Heterozygous carriers of this disorder are clinically normal, although some may develop age-related radiographic evidence of skull thickening (Beighton et al., 1977). In a study of 18 heterozygous carriers of sclerosteosis, BMD values were found to be consistently higher than normal subjects, without the complications encountered in homozygotes (Gardner et al., 2005). Bone biopsies performed in a limited number of patients with sclerosteosis have shown increased bone formation, no consistent pattern of osteoclast activity, and no evidence of poor quality woven bone (Moester et al., 2010).

Figure 3. Patient with sclerosteosis. A. This man has the typical manifestations of mandibular overgrowth, facial palsy, and deafness. B. The skull X-ray of an affected patient shows hyperostosis of the calverium and base of the skull. Heterozygous carriers of the SOST mutation causing sclerosteosis are phenotypically normal with dense strong bones.  Used with permission from American Journal of Human Genetics (Brunkow et al., 2001).

Figure 3. Patient with sclerosteosis. A. This man has the typical manifestations of mandibular overgrowth, facial palsy, and deafness. B. The skull X-ray of an affected patient shows hyperostosis of the calverium and base of the skull. Heterozygous carriers of the SOST mutation causing sclerosteosis are phenotypically normal with dense strong bones. Used with permission from American Journal of Human Genetics (Brunkow et al., 2001).

Van Buchem disease is a related rare autosomal recessive disorder, reported mostly in the Netherlands, with skeletal manifestations similar to sclerosteosis, without the findings of tall stature and syndactyly (fusion of two or more digits) that are often seen with sclerosteosis (Wergedal et al., 2003). Van Buchem disease is caused by a 52-kb deletion in the same 17q12-21 chromosomal region as SOST, resulting in downstream impairment of SOST function leading to defective sclerostin production (Staehling-Hampton et al., 2002).


Sclerostin is a monomeric glycoprotein containing a cystine knot-like domain with homology to the Cerebrus/DAN family of bone morphogenetic protein (BMP) antagonists (Balemans et al., 2001; Brunkow et al., 2001; Veverka et al., 2009). It antagonizes Wnt/β-catenin signaling (Li et al., 2005) in osteoblasts by binding to low-density lipoprotein (LDL) receptor-related proteins 5 and 6 (LRP6 and LRP6), thereby inhibiting osteoblast differentiation, activity, and survival (Baron and Rawadi, 2007; Li et al., 2008). Sclerostin is expressed by osteocytes (van Bezooijen et al., 2004) and other terminally differentiated cells within the bone matrix (e.g., mineralized hypertropic chondrocytes, cementocytes). The finding of SOST mRNA expression in off-target tissues, such as kidney, heart, and liver (Brunkow et al., 2001) suggests the possibility of unintended non-skeletal effects with anti-sclerostin therapy; however, it is reassuring that sclerostin protein has not been detected postnatally in any of these organs.

The concept that osteocytes have a mechanosensing role with sclerostin as a key signaling protein for osteoblasts is supported by preclinical studies. SOST knockout mice, an animal model for sclerosteosis and van Buchem disease, have high bone mass (Li et al., 2008). Ulnar loading in rodents is associated with decreased expression of sclerostin by osteocytes, with bone histomorphometry showing an increase in bone formation (Robling et al., 2008). Hindlimb unloading in mice is associated with an increase in SOST transcription (Robling et al., 2008), upregulation of sclerostin, and a decrease in Wnt/β-catenin signaling (Lin et al., 2009), suggesting that disuse osteoporosis (e.g., osteoporosis in the lower extremities of a paralyzed spinal cord injury patient) may in part be mediated by sclerostin-related inhibition of osteoblastic bone formation. The totality of observations with human disease and experiments in animals has led to the investigation of sclerostin inhibition as a potential method of treating osteoporosis.

Preclinical Studies of Sclerostin Inhibition

Scl-AbI is an anti-sclerostin monoclonal antibody that has been shown to stimulate Wnt/β-catenin signaling in cell culture and increase BMD in mice (Veverka et al., 2009). Scl-AbII is another anti-sclerostin monoclonal antibody tested in ovariectomized (OVX) rats (Li et al., 2009c), an animal model for evaluating candidate compounds for the treatment of postmenopausal osteoporosis (Thompson et al., 1995). It was found to have osteoanabolic properties, with increases in bone formation on trabecular, periosteal, endocortical, and intracortical bone surfaces, as well as increases in bone mass and bone strength compared with non-OVX control rats. Interestingly, there was a decrease in osteoclast surface area consistent with uncoupling of resorption and formation.

Humanized sclerostin monoclonal antibody (Scl-AbIV) has been evaluated in non-human primates. Healthy adolescent gonad-intact female cynomolgus age 3-5 years were given 2 subcutaneous (SC) doses of Scl-AbIV 3 mg/kg (n = 2), 10 mg/kg (n = 3), 30 mg/kg (n =3), or vehicle (n = 4) 1 month apart (Ominsky et al., 2010). On day 61, the study was terminated and the bones analyzed. There was a significant increase followed by a decline in markers of bone formation (osteocalcin, N-terminal propeptide of type I procollagen [P1NP]) after each dose of Scl-AbIV, with no clear change in the bone resorption marker C-telopeptide (CTX). There was an increase in bone mineral content (BMC) and/or BMD at the femoral neck, radial metaphysis, and tibial metaphysis. Bone histomorphometry showed marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces, consistent with increased recruitment, activation, and/or survival of osteoblasts. The pattern of bone marker and histomorphometric changes was consistent with uncoupling of bone resorption and formation in favor of formation, with at least some bone formation occurring on bone surfaces without prior resorption.

Anti-sclerostin therapy has also been shown to enhance fracture healing and bone repair, with increased callus density, increased bone strength at the fracture site, and accelerated bone repair in rodent studies (Agholme et al., 2010; Li et al., 2009a) and improved bone healing (increased callus area, increased callus BMC, and increased torsional stiffness) in cynomolgus monkeys after bilateral fibular osteotomies compared to vehicle (Ominsky et al., 2009).

The osteoanabolic effect of anti-sclerostin therapy in these preclinical studies has led to further investigation of sclerostin inhibition in humans. The compound with the most published data is AMG 785.

Phase 1 Clinical Trial of AMG 785 in Healthy Men and Postmenopausal Women

AMG 785, a humanized sclerostin monoclonal antibody, was first studied in humans in a phase 1 randomized, double-blind, placebo-controlled, ascending single-dose study in 72 healthy men and postmenopausal women (Padhi et al., 2011). This study evaluated its safety, tolerability, pharmacodynamics (PD), pharmacokinetics (PK), and response of BMD and bone turnover markers (Table 1). Study subjects were randomized to receive AMG 785 or placebo in a 3:1 ratio, with 56 receiving SC AMG 785 in a range of 6 doses or SC placebo, and 16 receiving 1 of 2 doses of intravenous (IV) AMG or IV placebo. Follow-up was for up to 85 days, depending on dose. The SC cohorts were dosed sequentially, beginning with the lowest dose, with a decision to proceed to a higher dose made after subjects were monitored for safety for at least 6 days. After SC and IV dosing of AMG 785, a greater than dose-proportional increase in serum concentrations was observed, with clearance or apparent clearance decreasing as the dose increased. Peak AMG 785 serum concentrations were observed within one week of SC administration. In the highest SC and IV dose groups, serum concentrations of AMG 785 decreased in a biphasic pattern with beta half-lives of 11 to 18 days and gamma half-lives of 6 to 7 days. Although there are no published data on distribution, metabolism, excretion, or drug interactions of AMG 785, these are probably similar to other therapeutic monoclonal antibodies (Wang et al., 2008). Renal elimination is insignificant for monoclonal antibodies, since the molecules are too large for glomerular filtration.

The rate of bone formation was assessed by measurement of serum P1NP, bone specific alkaline phosphatase (BSAP), and osteocalcin; bone resorption was assessed by measurement of serum CTX. Following a single dose of AMG 785, there was a dose-dependent increase in the serum levels of P1NP, BSAP, and osteocalcin compared to baseline. The maximum increases from baseline for P1NP, BSAP, and osteocalcin were 184%, 126%, and 176% for the 10.0 mg/kg SC dose and 167%, 125%, and 143% for the 5.0 mg/kg IV dose, respectively (p < 0.01 compared with placebo). Serum CTX levels decreased in an approximately dose-dependent manner after a single dose of AMG 785. The maximum significant decreases from baseline for CTX were 54% for the 10.0 mg/kg SC dose and 49% for the 5.0 mg/kg IV dose, respectively (p < 0.01 compared with placebo).

BMD was measured by dual-energy X-ray absorptiometry (DXA) at baseline and approximately days 29 and 57 for all groups except those receiving 0.1 and 0.3 mg/kg SC. There was an additional BMD measurement on approximately day 85 for the 5.0 and 10.0 mg/kg groups. The mean baseline T-score for each cohort ranged from -1.09 to -0.17 at the lumbar spine and -0.57 to 0.27 at the total hip. Compared to placebo, a single SC dose of AMG 785 increased lumbar spine and total hip BMD in all cohorts that were measured at days 29 (except for total hip BMD with 5.0 mg/kg), 57, and 85, in an approximately dose-dependent manner. The largest significant increase in lumbar spine (5.3%) and total hip (2.8%) BMD was observed on day 85 with a SC dose of 10.0 mg/kg (p < 0.01 compared with placebo). In the IV cohorts, the largest increase in lumbar spine (5.2%) and total hip (1.1%) BMD was also observed on day 85 with a dose of 5.0 mg/kg (p < 0.01 for lumbar spine; p > 0.05 for total hip).

AMG 785 was generally well tolerated with all administered doses. At least 1 adverse event (AE) was reported by 64% or 60% of the subjects who received SC placebo or AMG 785, respectively, and 50% or 25% of the subjects who received IV placebo or AMG 785, respectively. Most AEs were considered mild by the investigator, and none resulted in study discontinuation or death. The most commonly reported AEs with SC administration of either placebo or AMG 785 were injection site erythema, back pain, headache, constipation, injection site hemorrhage, arthralgia, and dizziness, all of which were considered mild and not serious. One serious AE was reported in a subject who received 10 mg/kg SC AMG 785: severe non-specific hepatitis, with an elevated liver function test beginning 1 day after dosing and liver enzymes peaking at levels of 6-13 times the upper limit of normal. Six to 8 days after dosing, abdominal ultrasound tests and hepatitis panels were normal; resolution of the serious AE occurred on day 26. No additional information was provided on confounding variables that might have contributed to the risk of hepatitis. In study subjects who received IV dosing of placebo or AMG 785, none reported more than 1 mild AE, and there were no serious AEs. Mild, transient asymptomatic decreases in mean serum ionized calcium levels (about 4% below baseline) were reported after SC and IV dosing of AMG 785, with values returning to baseline during the course of the study or follow-up period. In association with the decreased serum calcium levels, there was a transient increase in serum intact PTH levels that returned to baseline levels by the end of the study. Some subjects who received higher doses of AMG 785 were reported to have increased total serum alkaline phosphatase levels, probably a consequence of osteoanabolic activity increasing the BSAP. Six (11%) of the 54 subjects receiving AMG 785 tested positive for binding anti-AMG 785 antibodies; of these who tested positive, 1 subject receiving the 10.0 mg/kg SC dose tested positive for AMG 785 neutralizing antibodies at study end and up to day 283, and 1 subject receiving 5.0 mg/kg IV tested positive for neutralizing antibodies during follow-up on day 132 and up to day 252. The finding of neutralizing antibodies was not associated with any AEs or abnormalities of other laboratory tests, vital signs, or electrocardiogram. The effects of neutralizing antibody formation on the PK and PD of AMG 785 could not be definitively determined in this study due to the timing of antibody formation relative to when serum concentrations of AMG 785 and bone turnover markers began to return to baseline.

Phase 2 Clinical Trial of AMG 785 in Postmenopausal Women with Low BMD

A fully enrolled phase 2 randomized, placebo-controlled, multi-dose study is evaluating the efficacy, safety and tolerability of AMG 785 in 419 postmenopausal women with low BMD. The primary outcome measure is percentage change from baseline at month 12 in BMD at the lumbar spine for the individual AMG 785 groups and pooled placebo arms. Secondary outcome measures include percentage change from baseline of total hip, femoral neck and distal radius BMD at month 12 and percentage change from baseline of bone turnover makers at month 1, 3, 6, 9, and 12. The study started in June 2009 with an estimated completion date of August 2012. There are four study arms: monthly SC dosing of AMG 785 70 mg, 140 mg, 210 mg, or placebo; 3-monthly SC dosing of AMG 785 140 mg, 210 mg, or placebo; an active comparator group receiving teriparatide 20 mcg SC daily; and an active comparator group receiving alendronate 70 mg orally once weekly. Preliminary 12 month data, first publically presented as a press release on April 21, 2011, stated that the study met its primary endpoint, with significant increases in lumbar spine BMD at month 12 for the AMG 785 active arms compared to the placebo arm. AMG 785 compared “positively” with the two active comparators, teriparatide and alendronate. The overall incidence of AEs was generally balanced between groups. Injection site reactions were more common with AMG 785 (Amgen and UCB, 2011).


It is intriguing to consider the osteoanabolic properties of AMG 785 in comparison with teriparatide, the only osteoanabolic drug currently approved by the US Food and Drug Administration (FDA) for the treatment of osteoporosis. The BMD response at the lumbar spine and hip 3 months after a single dose of AMG 785 10/mg/kg SC (Padhi et al., 2011) was similar to or greater than what was seen after 6 months of daily teriparatide (McClung et al., 2005). The increase in bone formation markers 1 month after receiving AMG 785 in the phase 1 clinical trial (Padhi et al., 2011) was similar to that seen with teriparatide at 6 months (Chen et al., 2005), suggesting a more rapid onset of osteoanabolic effect with AMG 785 compared to teriparatide. The sustained decrease in serum CTX with AMG 785 during the period of observation in the same phase 1 study suggests that the osteoanabolic effect of AMG 785 may be more prolonged than with teriparatide, a drug characterized by an increase in bone resorption with prolonged use (Rubin and Bilezikian, 2003; Canalis et al., 2007). The duration of the osteoanabolic effect with long-term use of AMG 785 is not yet known. The pattern of an increase in bone formation markers with a decrease in bone resorption marker with sclerostin inhibition are consistent with observations in preclinical studies in SOST knockout mice (Li et al., 2008), ovariectomized rats (Li et al., 2009b), and primates (Ominsky et al., 2010). If there is indeed an uncoupling of bone formation and resorption, this could lead to large increases in BMD with improvements in bone quality and enhanced therapeutic benefit compared to currently approved agents (Lewiecki, 2011). Teriparatide has been shown to reduce the risk of vertebral and nonvertebral fractures, but not hip fractures (Neer et al., 2001). Its use is limited due to the inconvenience of daily self-administered SC dosing, the requirement for refrigeration, and high cost. It is restricted to no more than 24 months of lifetime exposure due to concern of osteosarcoma in rats receiving high doses and limited evidence of efficacy beyond that period of time.

If AMG 785 is ultimately shown to reduce fracture risk, especially at the hip as well as other skeletal sites, with a favorable safety profile, it will be a welcome addition to the current options for treating patients at high risk for fracture. Studies with human osteosarcoma cell lines have shown activation of Wnt signaling with loss of Wnt inhibitory factor 1 (Kansara et al., 2009), suggesting the possibility that sclerostin inhibition could increase the risk of osteosarcoma. Although there is no evidence that AMG 785 increases the risk of osteosarcoma, further study is needed to assess this potential safety concern.


Preclinical studies of sclerostin monoclonal antibodies have demonstrated a robust osteoanabolic effect with increases in bone formation, bone mass, and bone strength. The first clinical trial of sclerostin inhibition with AMG 785 showed a significant increase in bone formation markers, a significant decrease in bone resorption markers, and significant increases in BMD in healthy men and postmenopausal women. Treatment with AMG 785 was well tolerated with a generally favorable safety profile. Preliminary findings in a phase 2 clinical trial of AMG 785 in postmenopausal women with low BMD show an increase in BMD after 12 months of treatment, again with a generally favorable safety profile. More study is needed to determine its efficacy in reducing fracture risk. AMG 785 is a promising investigational compound for the treatment of osteoporosis.


The author has received grant/research support from Amgen, Merck, Eli Lilly, Novartis, Warner Chilcott, and Genentech. He has served as a consultant, advisory board member, speakers’ bureau participant, or given presentations at sponsored speaking events for Amgen, Merck, Eli Lilly, Novartis, Warner Chilcott, and Genentech.


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[Discovery Medicine; ISSN: 1539-6509; Discov Med 12(65):263-273, October 2011. Copyright © Discovery Medicine. All rights reserved.]

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