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ScienceDirect New therapeutics for osteoporosis Kong Wah Ng and T John Martin Two new approaches for the treatment of osteoporosis are summarized, each having arisen out of important new discoveries in bone biology. Odanacatib (ODN) inhibits the enzyme, cathepsin K, that is essential for the resorbing activity of osteoclasts. It is effective in preventing ovariectomy-induced bone loss in preclinical studies, and a phase II clinical study has shown inhibition of resorption sustained over five years. Outcome of a phase III study is awaited. The finding from mouse and human genetics that Wnt signaling is a powerful inducer of bone formation led to developments aimed at enhancing this pathway. Of the several approaches towards this, the most advanced is with a neutralizing antibody against sclerostin, the osteocyte-derived inhibitor of Wnt signaling. Preclinical studies show a powerful bone anabolic effect, and a clinical phase II study shows dose-dependent increases in bone formation and decreases in bone resorption markers. Addresses University of Melbourne, Department of Medicine, St. Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy 3065, Victoria, Australia Corresponding author: Martin, T John ([email protected])
Current Opinion in Pharmacology 2013, 16:58–63 This review comes from a themed issue on Musculoskeletal Edited by Alison Gartland and Lynne J Hocking
1471-4892/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coph.2014.03.004
Introduction Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches for prevention and treatment of bone fragility. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. Means are now available to promote the formation of new bone, and recent discoveries in bone biology show promise of new molecular targets for anabolic therapies. In this article we will discuss a novel resorption inhibitor, Odanacatib (ODN), and the application of neutralizing antibodies to sclerostin as an anabolic therapy. Remodelling of bone consists of a strict coupling of bone resorption and formation that continues throughout life and is necessary for the removal of damaged and old bone Current Opinion in Pharmacology 2014, 16:58–63
and to maintain normal bone structure [1–4,5]. The process begins with resorption of a volume of bone by osteoclasts, followed by new bone formation by osteoblasts. This process takes place in ‘bone multicellular units’ (BMUs) asynchronously throughout the skeleton. If the volume of bone resorbed exceeds the volume formed, bone loss results, leading to bone fragility and susceptibility to fracture. Intercellular communication processes are crucial in ensuring the balance that is achieved within BMUs throughout the skeleton. These communication pathways favour resorption by promoting osteoclast formation from haemopoietic precursors, or formation by promoting osteoblast differentiation from mesenchymal precursors. The latter activity within the BMU is referred to as the coupling of bone formation to resorption, and the development of the cathepsin K inhibitor, ODN, arose out of this concept of coupling.
ODN — a selective cathepsin K inhibitor Of the eleven different types of cathepsins [6], cathepsin K is the most important in the bone. It is predominantly expressed in osteoclasts and in actively resorbing osteoclasts, is localized at the ruffled border and discharged into the extracellular space when the lysosomal vesicles fuse with the cell membrane. It degrades the two main types of collagen I and II within the acidic microenvironment of resorption lacunae [7–9]. Cathepsin K cleaves the N-telopeptide of collagen to generate NTx and also degrades serum C-terminal telopeptide of type I collagen (1CTP), to generate CTx [10]. The inhibition of bone resorption observed in human and animal models deficient for cathepsin K [11,12,13,14,15,16] identified this enzyme as a suitable target for intervention by small molecules that might be used as therapeutic agents in osteoporosis [17,18,19]. With cathepsin K as target, the aim was direct inhibition of matrix degradation by osteoclasts without affecting either cell formation or survival. Indeed, in cathepsin K null mice the number of osteoclasts tends to be increased [17]. ODN (MK-0822, Merck) is a non-basic and nonlysosomotropic nitrile-based molecule displaying high potency for cathepsin K (IC50 = 0.2 nM). In studies of cathepsin K ( / ) mice or human osteoclast progenitors treated with ODN, loss of cathepsin K causes them to make small shallow resorption lacunae in contrast to untreated osteoclasts, which generate typical deep traillike resorption lacunae. While their resorption efficiency is reduced, ODN-treated osteoclasts can nonetheless continue to release osteogenic factors derived from the viable osteoclasts [17,20,21]. Of particular interest was the finding that in resorption-deficient cathepsin K / mice, www.sciencedirect.com
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bone formation was high in both trabecular and cortical bone [16]. In preclinical studies, ODN presented good pharmacokinetic parameters such as minimal in vitro metabolism, a long half-life, and oral bioavailability [22,23]. In ovariectomized rabbits, ODN was an effective inhibitor of resorption without inhibiting bone formation [B Pennybacker et al., abstract 1030, Annual Meeting of American Society for Bone and Mineral Research, San Diego, September 2011]. Osteoclast numbers on bone increased, but their resorption capacity was disabled, with shallow resorption pits evident. Monkey treatment studies show that ODN is an effective resorption inhibitor, which is dose-dependent [24,25]. Unlike conventional antiresorptives however, ODN treatment in the monkey resulted in a compartmentspecific increase in bone formation, with increased periosteal bone formation and cortical thickness whereas trabecular bone formation was reduced, alongside reduced bone resorption. Thus the drug did not reproduce the preservation of bone formation as seen in the cathepsin K / mice or in the ODN-treated rabbits, and currently the increased periosteal bone formation in the monkey study has no ready explanation.
Clinical studies of ODN Phase I studies indicated safety of ODN, and a once-daily regimen showed no obvious advantage over a once-weekly regimen [26,27]. In phase II studies, when analysed for up to five years [28–30], subjects showed almost linear increases in bone mineral density (BMD) from baseline at the lumbar spine (11.9%), femoral neck (9.8%) and total hip (8.5%). The bone resorption effect was maintained through five years of treatment, while bone formation was only slightly reduced relative to baseline. Reversibility of ODN effect after stopping treatment was striking. After ODN discontinuation at month 24, bone turnover markers increased transiently before returning to baseline by month 36 [30]. Such rapid reversibility observed upon stopping treatment was similar to that seen with estrogens, selective estrogen receptor modulators (SERMs) and denosumab, but not oral or intravenous bisphosphonates [31–35]. There is as yet, no published fracture data for ODN. An international multicentre placebo-controlled phase III fracture outcome trial that enrolled more than 16,000 postmenopausal women taking 50 mg ODN once weekly in a double-blind treatment (ClinicalTrials.gov registration number: NCT00529373) is completed and the results are anticipated in 2014. The large phase III placebo-controlled study with ODN will also provide important insight regarding safety and tolerability. There are two other ongoing phase III studies with ODN, one in www.sciencedirect.com
postmenopausal women (ClinicalTrials.gov registration number: NCT00729183) and the other in men (NCT0112600). These ongoing fracture outcome studies are necessary to determine whether the increased bone mass demonstrated in the phase II studies is translated into better fracture risk reduction [17,36]. If cathepsin K inhibitors are safe and at least as effective in fracture reduction as other inhibitors, they could offer theoretical advantages over bisphosphonates. For instance, ODN and other selective cathepsin K inhibitors might be more effectively combined with anabolic therapy such as parathyroid hormone (PTH), than resorption inhibitors that lead to inhibition of bone formation [B Pennybacker et al., abstract 1030, Annual Meeting of American Society for Bone and Mineral Research, San Diego, September 2011]. While cathepsin K is highly expressed in osteoclasts, very low levels exist in other adult tissues, including the heart, liver, skeletal muscle, placenta, ovary, testis, small intestine, colon as well as embryonic lung and neonatal dermal fibroblasts. It is also expressed in synovial fibroblasts and macrophages of rheumatoid arthritic joints, breast and prostate tumors. Therefore inhibition of cathepsin K could affect the turnover of type I collagen in organs other than bone [18]. While there is good potential for ODN to be a useful treatment for osteoporosis, rheumatoid arthritis and metastatic bone disease, the clinician will need to be vigilant for potential off-target effects.
Anabolic therapy The first opportunity to restore bone after it had been lost came with the development of PTH as a highly effective anabolic therapy for the skeleton, despite its betterknown action as a resorptive hormone. The approved therapies in several countries are PTH(1–34) and PTH(1–84). The anabolic effectiveness of PTH requires that it be administered intermittently, with daily injections that rapidly achieve a peak level in blood, which is not maintained [37,38]. Studies of PTH pre-treatment and post-treatment bone biopsies in women indicated that the predominant PTH effect was to increase remodelling, with some lesser effect on modelling [39,40]. Current views on the anabolic action of PTH are that it increases the activation of the BMUs in remodelling, that it acts on committed osteoblast precursors to promote their differentiation, inhibits osteoblast and osteocyte apoptosis [41], and inhibits the production of the bone formation inhibitor, sclerostin [42]. Special attention is being paid to activation of the Wnt signaling pathway to achieve an anabolic effect in bone. The first link between Wnt signaling and human bone disease came from observations that inactivating mutations in the low density lipoprotein receptor-related protein 5 (LRP5) cause the osteoporosis-pseudoglioma syndrome (OPPG, OMIM 259770) characterized by Current Opinion in Pharmacology 2014, 16:58–63
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severely decreased bone mass [43]. Conversely, a syndrome of high bone mass was found to be caused by a gain-of-function mutation of LRP5 (OMIM 601884) [44]. These genetic syndromes were reproduced with the appropriate genetic manipulations in mice [45,46]. The Wnt/b-catenin signaling pathway offers several targets that may be suitable for pharmacological intervention at a number of specific points. These include extracellular agonists and the points of interaction of antagonists. The primary aim of these interventions is to increase Wnt/b-catenin canonical signaling (see http:// www.stanford.edu/group/nusselab/cgi-bin/wnt/) in order to increase bone mass. This has been achieved in animal models with the inhibition of dickkopf-1 (DKK-1), glycogen synthase kinase-3b (GSK-3b), or of sclerostin, as described below. Inhibition of DKK-1
LRP5 can form a ternary complex with DKK-1 and Kremen (a receptor for DKK), which triggers rapid internalization and depletion of LRP5, leading to inhibition of the canonical Wnt signaling pathway. Inhibition of the interactions between DKK-1 and LRP5 would release LRP5 to activate the Wnt pathway. Genetic studies with mice lacking a single allele of DKK-1 showed a markedly increased trabecular bone volume and elevated trabecular bone formation rate [47]. The production of DKK-1 by multiple myeloma cells has been invoked as a contributing factor to the reduced bone formation in the lytic bone lesions of myeloma [48]. A study using antibodies raised against DKK-1 in the treatment of a mouse model of multiple myeloma showed increased numbers of osteoblasts, reduced number of osteoclasts, and reduced myeloma burden in the antibody-treated mice [49]. Initial drug development attempts in osteoporosis also use monoclonal anti-DKK-1 reagents, but the possibility of directing small molecules to prevent the DKK-1–LRP5 interaction is being explored. Inhibition of GSK-3
Inhibition of GSK-3 would prevent the phosphorylation of b-catenin, leading to stabilization of b-catenin independently of Wnt interactions with the receptor complex. Mice treated with lithium chloride as a GSK-3 inhibitor showed increased bone formation and bone mass [50]. Treatment of ovariectomized rats with an orally active dual GSK a/b inhibitor, LY603281-31-8, for two months resulted in an increase in the number of trabeculae and connectivity as well as trabecular area and thickness. BMD at cancellous and cortical sites was increased, and this was associated with increased bone formation on histomorphometry and increased strength [51]. Inhibition of sclerostin
Sclerostin, the protein product of SOST, is produced in bone exclusively by osteocytes and is a circulating inhibitor Current Opinion in Pharmacology 2014, 16:58–63
of the Wnt-signaling pathway that achieves this by binding to LRP5 and LRP6 [52]. High bone density in sclerosteosis is caused by an inactivating mutation in SOST gene (OMIM 607363) [53]. Inhibition of production or action of sclerostin resulting in enhanced Wnt canonical signaling was predicted to lead to increased bone mass, and did so with impressive effect in preclinical studies, where monoclonal antibody against sclerostin has been shown to promote bone formation rapidly in monkeys and ovariectomized rats. Considerable increases in bone formation rates and in the amounts of trabecular bone took place rapidly without increases in resorption parameters [54]. At the time of writing, a phase I study of anti-sclerostin (AMG 785, Amgen) had been published [55], in which healthy men and women were treated for up to 85 days with escalating doses of AMG 785, resulting in doserelated increases in bone formation markers and a decrease in the resorption marker, serum CTx. The latter observation might relate to changes in osteoblast differentiation, with less cells of the osteoblast lineage available for presentation of the critical osteoclast differentiation factor, Receptor Activator of Nuclear Factor kB Ligand (RANKL), to osteoclast precursors. In this short study, BMD increased significantly at the spine (5.3%) and hip (2.8%), with five subjects at the highest dose developing detectable antibodies, two of which were neutralizing. The treatment with AMG 785 was generally well tolerated, and further clinical studies will be expected with what appears to be a most promising way of increasing the amount of bone. Of particular interest is the fact that PTH rapidly reduces sclerostin mRNA and protein production by osteoblasts in vitro and in bone in vivo [42,56] raising the possibility that transient reduction of sclerostin output by osteocytes in response to intermittent PTH could mediate enhanced osteoblast differentiation and bone formation [57] and reduced osteoblast apoptosis [58]. Such a mechanism would offer real possibilities as a drug target, and the mechanism of this inhibition is all the more interesting with the recent finding [59] that the cyclic AMPmediated effect of PTH to diminish sclerostin production operates through a long range enhancer, MEF2, the discovery of which came from the pursuit of the nature of the van Buchem’s disease mutation. There may be small molecule approaches amenable to sclerostin regulation, in addition to antibody neutralization of its activity. Safety and specificity
Any manipulation of the Wnt canonical signaling pathway will need to be shown to be safe, and that its action can be targeted specifically to bone. Wnt proteins are critical signaling proteins involved in developmental biology, with roles in early axis specification, brain patterning, intestinal development, and limb development. In adults, Wnt proteins play a vital role in tissue maintenance, with www.sciencedirect.com
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aberrations in Wnt signaling leading to diseases such as adenomatous polyposis [60]. Inhibition of GSK-3 results in increased cyclin D1, cyclin E, and c-Myc, and overexpression of these cell cycle regulators has been linked to tumor formation [61]. All relevant possibilities of side effects of enhanced Wnt signaling need to be kept in mind throughout preclinical studies. Exciting possibilities of new anabolic therapies are becoming more evident. The early evidence that it might be possible to develop resorption inhibitors that can uncouple bone resorption from bone formation is exciting, potentially offering an advantage over currently available antiresorptive agents. Nonetheless, all these predictions are based largely on preclinical data, and it is hoped that properly conducted clinical trials in the coming years will see the emergence of new therapies that are effective, durable, and safe, at an affordable cost.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
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ScienceDirect New therapeutics for osteoporosis Kong Wah Ng and T John Martin Two new approaches for the treatment of osteoporosis are summarized, each having arisen out of important new discoveries in bone biology. Odanacatib (ODN) inhibits the enzyme, cathepsin K, that is essential for the resorbing activity of osteoclasts. It is effective in preventing ovariectomy-induced bone loss in preclinical studies, and a phase II clinical study has shown inhibition of resorption sustained over five years. Outcome of a phase III study is awaited. The finding from mouse and human genetics that Wnt signaling is a powerful inducer of bone formation led to developments aimed at enhancing this pathway. Of the several approaches towards this, the most advanced is with a neutralizing antibody against sclerostin, the osteocyte-derived inhibitor of Wnt signaling. Preclinical studies show a powerful bone anabolic effect, and a clinical phase II study shows dose-dependent increases in bone formation and decreases in bone resorption markers. Addresses University of Melbourne, Department of Medicine, St. Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy 3065, Victoria, Australia Corresponding author: Martin, T John ([email protected])
Current Opinion in Pharmacology 2013, 16:58–63 This review comes from a themed issue on Musculoskeletal Edited by Alison Gartland and Lynne J Hocking
1471-4892/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coph.2014.03.004
Introduction Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches for prevention and treatment of bone fragility. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. Means are now available to promote the formation of new bone, and recent discoveries in bone biology show promise of new molecular targets for anabolic therapies. In this article we will discuss a novel resorption inhibitor, Odanacatib (ODN), and the application of neutralizing antibodies to sclerostin as an anabolic therapy. Remodelling of bone consists of a strict coupling of bone resorption and formation that continues throughout life and is necessary for the removal of damaged and old bone Current Opinion in Pharmacology 2014, 16:58–63
and to maintain normal bone structure [1–4,5]. The process begins with resorption of a volume of bone by osteoclasts, followed by new bone formation by osteoblasts. This process takes place in ‘bone multicellular units’ (BMUs) asynchronously throughout the skeleton. If the volume of bone resorbed exceeds the volume formed, bone loss results, leading to bone fragility and susceptibility to fracture. Intercellular communication processes are crucial in ensuring the balance that is achieved within BMUs throughout the skeleton. These communication pathways favour resorption by promoting osteoclast formation from haemopoietic precursors, or formation by promoting osteoblast differentiation from mesenchymal precursors. The latter activity within the BMU is referred to as the coupling of bone formation to resorption, and the development of the cathepsin K inhibitor, ODN, arose out of this concept of coupling.
ODN — a selective cathepsin K inhibitor Of the eleven different types of cathepsins [6], cathepsin K is the most important in the bone. It is predominantly expressed in osteoclasts and in actively resorbing osteoclasts, is localized at the ruffled border and discharged into the extracellular space when the lysosomal vesicles fuse with the cell membrane. It degrades the two main types of collagen I and II within the acidic microenvironment of resorption lacunae [7–9]. Cathepsin K cleaves the N-telopeptide of collagen to generate NTx and also degrades serum C-terminal telopeptide of type I collagen (1CTP), to generate CTx [10]. The inhibition of bone resorption observed in human and animal models deficient for cathepsin K [11,12,13,14,15,16] identified this enzyme as a suitable target for intervention by small molecules that might be used as therapeutic agents in osteoporosis [17,18,19]. With cathepsin K as target, the aim was direct inhibition of matrix degradation by osteoclasts without affecting either cell formation or survival. Indeed, in cathepsin K null mice the number of osteoclasts tends to be increased [17]. ODN (MK-0822, Merck) is a non-basic and nonlysosomotropic nitrile-based molecule displaying high potency for cathepsin K (IC50 = 0.2 nM). In studies of cathepsin K ( / ) mice or human osteoclast progenitors treated with ODN, loss of cathepsin K causes them to make small shallow resorption lacunae in contrast to untreated osteoclasts, which generate typical deep traillike resorption lacunae. While their resorption efficiency is reduced, ODN-treated osteoclasts can nonetheless continue to release osteogenic factors derived from the viable osteoclasts [17,20,21]. Of particular interest was the finding that in resorption-deficient cathepsin K / mice, www.sciencedirect.com
New therapeutics for osteoporosis Ng and Martin 59
bone formation was high in both trabecular and cortical bone [16]. In preclinical studies, ODN presented good pharmacokinetic parameters such as minimal in vitro metabolism, a long half-life, and oral bioavailability [22,23]. In ovariectomized rabbits, ODN was an effective inhibitor of resorption without inhibiting bone formation [B Pennybacker et al., abstract 1030, Annual Meeting of American Society for Bone and Mineral Research, San Diego, September 2011]. Osteoclast numbers on bone increased, but their resorption capacity was disabled, with shallow resorption pits evident. Monkey treatment studies show that ODN is an effective resorption inhibitor, which is dose-dependent [24,25]. Unlike conventional antiresorptives however, ODN treatment in the monkey resulted in a compartmentspecific increase in bone formation, with increased periosteal bone formation and cortical thickness whereas trabecular bone formation was reduced, alongside reduced bone resorption. Thus the drug did not reproduce the preservation of bone formation as seen in the cathepsin K / mice or in the ODN-treated rabbits, and currently the increased periosteal bone formation in the monkey study has no ready explanation.
Clinical studies of ODN Phase I studies indicated safety of ODN, and a once-daily regimen showed no obvious advantage over a once-weekly regimen [26,27]. In phase II studies, when analysed for up to five years [28–30], subjects showed almost linear increases in bone mineral density (BMD) from baseline at the lumbar spine (11.9%), femoral neck (9.8%) and total hip (8.5%). The bone resorption effect was maintained through five years of treatment, while bone formation was only slightly reduced relative to baseline. Reversibility of ODN effect after stopping treatment was striking. After ODN discontinuation at month 24, bone turnover markers increased transiently before returning to baseline by month 36 [30]. Such rapid reversibility observed upon stopping treatment was similar to that seen with estrogens, selective estrogen receptor modulators (SERMs) and denosumab, but not oral or intravenous bisphosphonates [31–35]. There is as yet, no published fracture data for ODN. An international multicentre placebo-controlled phase III fracture outcome trial that enrolled more than 16,000 postmenopausal women taking 50 mg ODN once weekly in a double-blind treatment (ClinicalTrials.gov registration number: NCT00529373) is completed and the results are anticipated in 2014. The large phase III placebo-controlled study with ODN will also provide important insight regarding safety and tolerability. There are two other ongoing phase III studies with ODN, one in www.sciencedirect.com
postmenopausal women (ClinicalTrials.gov registration number: NCT00729183) and the other in men (NCT0112600). These ongoing fracture outcome studies are necessary to determine whether the increased bone mass demonstrated in the phase II studies is translated into better fracture risk reduction [17,36]. If cathepsin K inhibitors are safe and at least as effective in fracture reduction as other inhibitors, they could offer theoretical advantages over bisphosphonates. For instance, ODN and other selective cathepsin K inhibitors might be more effectively combined with anabolic therapy such as parathyroid hormone (PTH), than resorption inhibitors that lead to inhibition of bone formation [B Pennybacker et al., abstract 1030, Annual Meeting of American Society for Bone and Mineral Research, San Diego, September 2011]. While cathepsin K is highly expressed in osteoclasts, very low levels exist in other adult tissues, including the heart, liver, skeletal muscle, placenta, ovary, testis, small intestine, colon as well as embryonic lung and neonatal dermal fibroblasts. It is also expressed in synovial fibroblasts and macrophages of rheumatoid arthritic joints, breast and prostate tumors. Therefore inhibition of cathepsin K could affect the turnover of type I collagen in organs other than bone [18]. While there is good potential for ODN to be a useful treatment for osteoporosis, rheumatoid arthritis and metastatic bone disease, the clinician will need to be vigilant for potential off-target effects.
Anabolic therapy The first opportunity to restore bone after it had been lost came with the development of PTH as a highly effective anabolic therapy for the skeleton, despite its betterknown action as a resorptive hormone. The approved therapies in several countries are PTH(1–34) and PTH(1–84). The anabolic effectiveness of PTH requires that it be administered intermittently, with daily injections that rapidly achieve a peak level in blood, which is not maintained [37,38]. Studies of PTH pre-treatment and post-treatment bone biopsies in women indicated that the predominant PTH effect was to increase remodelling, with some lesser effect on modelling [39,40]. Current views on the anabolic action of PTH are that it increases the activation of the BMUs in remodelling, that it acts on committed osteoblast precursors to promote their differentiation, inhibits osteoblast and osteocyte apoptosis [41], and inhibits the production of the bone formation inhibitor, sclerostin [42]. Special attention is being paid to activation of the Wnt signaling pathway to achieve an anabolic effect in bone. The first link between Wnt signaling and human bone disease came from observations that inactivating mutations in the low density lipoprotein receptor-related protein 5 (LRP5) cause the osteoporosis-pseudoglioma syndrome (OPPG, OMIM 259770) characterized by Current Opinion in Pharmacology 2014, 16:58–63
60 Musculoskeletal
severely decreased bone mass [43]. Conversely, a syndrome of high bone mass was found to be caused by a gain-of-function mutation of LRP5 (OMIM 601884) [44]. These genetic syndromes were reproduced with the appropriate genetic manipulations in mice [45,46]. The Wnt/b-catenin signaling pathway offers several targets that may be suitable for pharmacological intervention at a number of specific points. These include extracellular agonists and the points of interaction of antagonists. The primary aim of these interventions is to increase Wnt/b-catenin canonical signaling (see http:// www.stanford.edu/group/nusselab/cgi-bin/wnt/) in order to increase bone mass. This has been achieved in animal models with the inhibition of dickkopf-1 (DKK-1), glycogen synthase kinase-3b (GSK-3b), or of sclerostin, as described below. Inhibition of DKK-1
LRP5 can form a ternary complex with DKK-1 and Kremen (a receptor for DKK), which triggers rapid internalization and depletion of LRP5, leading to inhibition of the canonical Wnt signaling pathway. Inhibition of the interactions between DKK-1 and LRP5 would release LRP5 to activate the Wnt pathway. Genetic studies with mice lacking a single allele of DKK-1 showed a markedly increased trabecular bone volume and elevated trabecular bone formation rate [47]. The production of DKK-1 by multiple myeloma cells has been invoked as a contributing factor to the reduced bone formation in the lytic bone lesions of myeloma [48]. A study using antibodies raised against DKK-1 in the treatment of a mouse model of multiple myeloma showed increased numbers of osteoblasts, reduced number of osteoclasts, and reduced myeloma burden in the antibody-treated mice [49]. Initial drug development attempts in osteoporosis also use monoclonal anti-DKK-1 reagents, but the possibility of directing small molecules to prevent the DKK-1–LRP5 interaction is being explored. Inhibition of GSK-3
Inhibition of GSK-3 would prevent the phosphorylation of b-catenin, leading to stabilization of b-catenin independently of Wnt interactions with the receptor complex. Mice treated with lithium chloride as a GSK-3 inhibitor showed increased bone formation and bone mass [50]. Treatment of ovariectomized rats with an orally active dual GSK a/b inhibitor, LY603281-31-8, for two months resulted in an increase in the number of trabeculae and connectivity as well as trabecular area and thickness. BMD at cancellous and cortical sites was increased, and this was associated with increased bone formation on histomorphometry and increased strength [51]. Inhibition of sclerostin
Sclerostin, the protein product of SOST, is produced in bone exclusively by osteocytes and is a circulating inhibitor Current Opinion in Pharmacology 2014, 16:58–63
of the Wnt-signaling pathway that achieves this by binding to LRP5 and LRP6 [52]. High bone density in sclerosteosis is caused by an inactivating mutation in SOST gene (OMIM 607363) [53]. Inhibition of production or action of sclerostin resulting in enhanced Wnt canonical signaling was predicted to lead to increased bone mass, and did so with impressive effect in preclinical studies, where monoclonal antibody against sclerostin has been shown to promote bone formation rapidly in monkeys and ovariectomized rats. Considerable increases in bone formation rates and in the amounts of trabecular bone took place rapidly without increases in resorption parameters [54]. At the time of writing, a phase I study of anti-sclerostin (AMG 785, Amgen) had been published [55], in which healthy men and women were treated for up to 85 days with escalating doses of AMG 785, resulting in doserelated increases in bone formation markers and a decrease in the resorption marker, serum CTx. The latter observation might relate to changes in osteoblast differentiation, with less cells of the osteoblast lineage available for presentation of the critical osteoclast differentiation factor, Receptor Activator of Nuclear Factor kB Ligand (RANKL), to osteoclast precursors. In this short study, BMD increased significantly at the spine (5.3%) and hip (2.8%), with five subjects at the highest dose developing detectable antibodies, two of which were neutralizing. The treatment with AMG 785 was generally well tolerated, and further clinical studies will be expected with what appears to be a most promising way of increasing the amount of bone. Of particular interest is the fact that PTH rapidly reduces sclerostin mRNA and protein production by osteoblasts in vitro and in bone in vivo [42,56] raising the possibility that transient reduction of sclerostin output by osteocytes in response to intermittent PTH could mediate enhanced osteoblast differentiation and bone formation [57] and reduced osteoblast apoptosis [58]. Such a mechanism would offer real possibilities as a drug target, and the mechanism of this inhibition is all the more interesting with the recent finding [59] that the cyclic AMPmediated effect of PTH to diminish sclerostin production operates through a long range enhancer, MEF2, the discovery of which came from the pursuit of the nature of the van Buchem’s disease mutation. There may be small molecule approaches amenable to sclerostin regulation, in addition to antibody neutralization of its activity. Safety and specificity
Any manipulation of the Wnt canonical signaling pathway will need to be shown to be safe, and that its action can be targeted specifically to bone. Wnt proteins are critical signaling proteins involved in developmental biology, with roles in early axis specification, brain patterning, intestinal development, and limb development. In adults, Wnt proteins play a vital role in tissue maintenance, with www.sciencedirect.com
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aberrations in Wnt signaling leading to diseases such as adenomatous polyposis [60]. Inhibition of GSK-3 results in increased cyclin D1, cyclin E, and c-Myc, and overexpression of these cell cycle regulators has been linked to tumor formation [61]. All relevant possibilities of side effects of enhanced Wnt signaling need to be kept in mind throughout preclinical studies. Exciting possibilities of new anabolic therapies are becoming more evident. The early evidence that it might be possible to develop resorption inhibitors that can uncouple bone resorption from bone formation is exciting, potentially offering an advantage over currently available antiresorptive agents. Nonetheless, all these predictions are based largely on preclinical data, and it is hoped that properly conducted clinical trials in the coming years will see the emergence of new therapies that are effective, durable, and safe, at an affordable cost.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
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