- Email: [email protected]
Cathepsin K inhibitors
Abstracts / Bone 48 (2011) S50–S60 survival. Interestingly, RANKL is essential for lactation suggesting that this system evolved to mobilize calcium from the skeleton to provide milk for newborns. Denosumab, a fully human monoclonal antibody to RANKL, inhibits the differentiation, activity, and survival of osteoclasts and thereby rapidly and potently decreasing bone resorption. Within 1 month, denosumab decreases average bone resorption (by serum CTX), by about 90%. This effect is faster and greater than seen with alendronate. Three years of denosumab every 6 months increases spine BMD about 9% and total hip BMD by about 6%. It increases BMD about 1% more than alendronate and increases BMD in women who switch to denosumab after treatment with alendronate. Unlike bisphosphonates therapy, the effect of denosumab is fully reversible: after discontinuation bone resorption increases above baseline levels and BMD decreases. Resumption of treatment restores BMD within 1 year. In the FREEDOM trial, denosumab reduced the risk of vertebral fractures 68%, hip fractures 40%, and nonvertebral fractures 20%. The reduction in risk of nonvertebral fractures was significantly greater (35% decreased risk) in those with FN BMD ≤−2.5 than women with higher BMD. No cases of ONJ or atypical femoral fractures were observed during about 10,000 woman-years of treatment. Analyses from FREEDOM suggest that denosumab does not interfere with fracture healing, remains effective and safe in patients with decreased renal function. In an extension of FREEDOM, the efficacy and safety of denosumab appears to continue at least 5 years. Denosumab has also been estimated to be cost-effective for women with osteoporosis. Every 6 monthly subcutaneous treatment with denosumab might improve the poor compliance observed for pills. Denosumab also prevents bone loss and reduces the risk of vertebral in men undergoing androgen deprivation for prostate cancer and prevents bone loss from treatment with aromatase inhibitors. Trials found that it reduces the risk of skeletal ‘events’ patients with breast or prostate cancer to a greater degree than zoledronate. At these high doses, both zoledronate and denosumab occasionally caused ONJ. By acting on the fundamental pathways that control osteoclasts, denosumab has taken treatment of osteoporosis to the limit achievable by inhibiting bone resorption. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: S. Cummings Grant / Research Support from Amgen, Consultant for Amgen, Lilly, Novartis, Merck. doi:10.1016/j.bone.2011.03.015
IS12 Cathepsin K inhibitors M. McClung Oregon Osteoporosis Center, Portland, OR, USA Among the various specialized steps of osteoclast-mediated bone resorption, the activity of cathepsin K is an attractive target as a potential treatment for osteoporosis. Cathepsin K, the collagenase in osteoclasts whose activity is required for effective bone resorption, is a member of the family of cysteine proteases. Deficiency of cathepsin K in transgenic rodents and humans (pycnodysostosis) is associated with decreased bone resorption and high bone mass. In preclinical studies, inhibitors of cathepsin K reduce bone resorption but do not decrease osteoclast number or activity. Bone formation on trabecular surfaces may be reduced, but periosteal bone formation is enhanced, increasing cortical thickness and long bone strength. Several cathepsin K inhibitors have been developed with high specificity in vitro, and some of these have come to clinical evaluation. Balicatib therapy decreased bone resorption and improved bone density but was associated with morphea-like skin lesions that could be a clinical manifestation of off-target cathepsin inhibition. Further clinical development of balicatib was halted. Early results of a Phase II study with ONO-5334 were recently reported, demonstrating decreased bone resorption, increased bone mineral density, and good short-term tolerability. Odanacatib is a non-basic molecule that does not accumulate in lysosomes, retaining its enzymatic specificity in vivo. In postmenopausal women with low bone mass, odanacatib treatment reduced bone resorption and increased bone mineral density in a dose-dependent manner. Therapy for four years resulted in persistent inhibition of bone resorption while biochemical markers of bone formation were relatively unaffected. Progressive increases were noted in the bone mineral density in both the lumbar spine and proximal femur, and the drug was well-tolerated. No offtarget side effects have been observed. As expected, discontinuation of therapy was associated with a rebound in bone resorption and bone loss back toward baseline levels within two years. A large Phase III fracture endpoint study is now fully enrolled. By virtue of a unique mechanism of action that inhibits bone resorption without decreasing osteoclast number or activity, cathepsin K inhibitors provide a novel strategy for treating osteoporosis. These agents have the potential to be an even more effective treatment to reduce the risk of nonvertebral fractures than current antiresorptive agents. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: M. Mcclung Grant / Research Support from Amgen, Lilly, Merck, Consultant for Amgen, Lilly, Merck, Novartis, Warner-Chilcott, Speaker Bureau with Amgen. Lilly, Novartis. doi:10.1016/j.bone.2011.03.016
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IS13 Association studies in bone genetics A. Uitterlinden Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Many -if not all- common traits and diseases, including height and diseases of the skeleton such as osteoporosis and osteoarthritis, have moderate to strong genetic influences and therefore intense efforts are ongoing to identify the underlying genetic variants. Knowledge of these variants can help in understanding the disease process and might benefit development of interventions and diagnostics. Previously, genome wide linkage searches and candidate gene studies have been pursued to this end, but not without controversy. Genome-Wide Association studies (GWAS) have now become the standard approach to uncover the genetic effects of (very) common variants on a genome-wide hypothesis-free scale. The GWAS approach builds upon the availability of extensive data on human genetic variation, novel genotyping technology such as very high-density single nucleotide polymorphism (SNP) arrays), accessibility to biobanks of large population cohorts and case-control series with DNA and phenotype information, and a collaborative spirit among researchers. An important part of the process of GWAS analysis is the testing of identified variants in international consortia with very large collections of DNA samples with a certain phenotype. The GIANT consortium is playing such a role in the analysis of height genes, while the GEFOS/ GENOMOS consortium is doing that for osteoporosis, and the TREAT-OA consortium for osteoarthritis. In the past few years GWAS has proven to be widely successful for almost all complex traits and diseases in discovering novel and common risk genes, although mainly in Caucasian populations and mostly with modest effect size. For example, for height, osteoporosis, and osteoarthritis several large GWAS have been published, while also for other bone phenotypes such as seen in Paget's disease. For example, 80 loci have been identified for bone mineral density (BMD), ~ 200 loci for height, and a few loci for OA. Interestingly, experience so far has shown that a) GWAS in general- identifies DNA variants rather than genes, and b) that the effects seen for the common variants are modest, e.g., with Odds Ratios ranging from 1.1 –1.7, and explained variance of combined common variants, e.g., for height being 10-15% and for BMD being 3–7%. On the one hand this sheds interesting light on how human genes are regulated and what common genetic variation is tolerated throughout evolution, but on the other hand also pose serious challenges in translating the results of GWAS to clinical practice. Efforts are therefore also focussed on selecting the underlying genes and to establish biological mechanisms. Pharmaco-genetic studies of osteoporosis have been scarce, but for some other disease-treatments has resulted in identification of sometimes substantial genetic influences on the response-to-treatment. Together with genetic studies on more rare genetic syndromes, the GWAS approach is clarifying part of the genetic architecture of complex traits and diseases, including aspects of the skeleton. GWAS techniques using SNP arrays are assessing only a small part, 0.1-0.2%, of the base pairs constituting the human genome. Newly developed high throughout sequencing technology allows to assess all coding parts of the genome (~ 1% of bp) and even the majority of bp by full-genome sequencing. These approaches are now underway and will again also be based on association approaches in large consortia, and will likely contribute to a further understanding of the genetics of bone. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.
doi:10.1016/j.bone.2011.03.017
IS14 Deep resequencing of promising osteoporosis loci from gwas D.P. Kiel Institute for Aging Research, Hebrew Seniorlife, Boston, MA, USA Genome-wide association studies (GWAS) such as those conducted by the Genetics Factors for Osteoporosis (GEFOS) consortium have identified disease-related genomic regions; however, the majority of identified common SNPs that achieved genome-wide significance may not causally link to diseases and have no functional implication. These observations are not unexpected because of the fundamental limitation of GWAS that feature predominantly common and/or tag SNPs in the genotyping arrays or imputation reference panel. Extensive deep re-sequencing of an associated locus may identify additional, previously unknown and rare variants with a possible biological role. The identification of causal genetic variants may lead to more individualized approaches to treatment and prevention of osteoporosis and will add genetic risk profiles to existing lifestyle factors in the prediction of fracture. Based on our past GWAS efforts in GEFOS, we have identified more than 30 genome-wide significant (5 × 10-8) loci associated with BMD. Among them, 15 loci map to new regions. We are carrying out targeted next generation sequencing of three of these 15 loci (WLS, MEF2C, JAG1) for the identification of rare or low-frequency variants associated in the GEFOS GWAS with BMD). From the Framingham Osteoporosis Study
IS12 Cathepsin K inhibitors M. McClung Oregon Osteoporosis Center, Portland, OR, USA Among the various specialized steps of osteoclast-mediated bone resorption, the activity of cathepsin K is an attractive target as a potential treatment for osteoporosis. Cathepsin K, the collagenase in osteoclasts whose activity is required for effective bone resorption, is a member of the family of cysteine proteases. Deficiency of cathepsin K in transgenic rodents and humans (pycnodysostosis) is associated with decreased bone resorption and high bone mass. In preclinical studies, inhibitors of cathepsin K reduce bone resorption but do not decrease osteoclast number or activity. Bone formation on trabecular surfaces may be reduced, but periosteal bone formation is enhanced, increasing cortical thickness and long bone strength. Several cathepsin K inhibitors have been developed with high specificity in vitro, and some of these have come to clinical evaluation. Balicatib therapy decreased bone resorption and improved bone density but was associated with morphea-like skin lesions that could be a clinical manifestation of off-target cathepsin inhibition. Further clinical development of balicatib was halted. Early results of a Phase II study with ONO-5334 were recently reported, demonstrating decreased bone resorption, increased bone mineral density, and good short-term tolerability. Odanacatib is a non-basic molecule that does not accumulate in lysosomes, retaining its enzymatic specificity in vivo. In postmenopausal women with low bone mass, odanacatib treatment reduced bone resorption and increased bone mineral density in a dose-dependent manner. Therapy for four years resulted in persistent inhibition of bone resorption while biochemical markers of bone formation were relatively unaffected. Progressive increases were noted in the bone mineral density in both the lumbar spine and proximal femur, and the drug was well-tolerated. No offtarget side effects have been observed. As expected, discontinuation of therapy was associated with a rebound in bone resorption and bone loss back toward baseline levels within two years. A large Phase III fracture endpoint study is now fully enrolled. By virtue of a unique mechanism of action that inhibits bone resorption without decreasing osteoclast number or activity, cathepsin K inhibitors provide a novel strategy for treating osteoporosis. These agents have the potential to be an even more effective treatment to reduce the risk of nonvertebral fractures than current antiresorptive agents. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: M. Mcclung Grant / Research Support from Amgen, Lilly, Merck, Consultant for Amgen, Lilly, Merck, Novartis, Warner-Chilcott, Speaker Bureau with Amgen. Lilly, Novartis. doi:10.1016/j.bone.2011.03.016
S53
IS13 Association studies in bone genetics A. Uitterlinden Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands Many -if not all- common traits and diseases, including height and diseases of the skeleton such as osteoporosis and osteoarthritis, have moderate to strong genetic influences and therefore intense efforts are ongoing to identify the underlying genetic variants. Knowledge of these variants can help in understanding the disease process and might benefit development of interventions and diagnostics. Previously, genome wide linkage searches and candidate gene studies have been pursued to this end, but not without controversy. Genome-Wide Association studies (GWAS) have now become the standard approach to uncover the genetic effects of (very) common variants on a genome-wide hypothesis-free scale. The GWAS approach builds upon the availability of extensive data on human genetic variation, novel genotyping technology such as very high-density single nucleotide polymorphism (SNP) arrays), accessibility to biobanks of large population cohorts and case-control series with DNA and phenotype information, and a collaborative spirit among researchers. An important part of the process of GWAS analysis is the testing of identified variants in international consortia with very large collections of DNA samples with a certain phenotype. The GIANT consortium is playing such a role in the analysis of height genes, while the GEFOS/ GENOMOS consortium is doing that for osteoporosis, and the TREAT-OA consortium for osteoarthritis. In the past few years GWAS has proven to be widely successful for almost all complex traits and diseases in discovering novel and common risk genes, although mainly in Caucasian populations and mostly with modest effect size. For example, for height, osteoporosis, and osteoarthritis several large GWAS have been published, while also for other bone phenotypes such as seen in Paget's disease. For example, 80 loci have been identified for bone mineral density (BMD), ~ 200 loci for height, and a few loci for OA. Interestingly, experience so far has shown that a) GWAS in general- identifies DNA variants rather than genes, and b) that the effects seen for the common variants are modest, e.g., with Odds Ratios ranging from 1.1 –1.7, and explained variance of combined common variants, e.g., for height being 10-15% and for BMD being 3–7%. On the one hand this sheds interesting light on how human genes are regulated and what common genetic variation is tolerated throughout evolution, but on the other hand also pose serious challenges in translating the results of GWAS to clinical practice. Efforts are therefore also focussed on selecting the underlying genes and to establish biological mechanisms. Pharmaco-genetic studies of osteoporosis have been scarce, but for some other disease-treatments has resulted in identification of sometimes substantial genetic influences on the response-to-treatment. Together with genetic studies on more rare genetic syndromes, the GWAS approach is clarifying part of the genetic architecture of complex traits and diseases, including aspects of the skeleton. GWAS techniques using SNP arrays are assessing only a small part, 0.1-0.2%, of the base pairs constituting the human genome. Newly developed high throughout sequencing technology allows to assess all coding parts of the genome (~ 1% of bp) and even the majority of bp by full-genome sequencing. These approaches are now underway and will again also be based on association approaches in large consortia, and will likely contribute to a further understanding of the genetics of bone. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.
doi:10.1016/j.bone.2011.03.017
IS14 Deep resequencing of promising osteoporosis loci from gwas D.P. Kiel Institute for Aging Research, Hebrew Seniorlife, Boston, MA, USA Genome-wide association studies (GWAS) such as those conducted by the Genetics Factors for Osteoporosis (GEFOS) consortium have identified disease-related genomic regions; however, the majority of identified common SNPs that achieved genome-wide significance may not causally link to diseases and have no functional implication. These observations are not unexpected because of the fundamental limitation of GWAS that feature predominantly common and/or tag SNPs in the genotyping arrays or imputation reference panel. Extensive deep re-sequencing of an associated locus may identify additional, previously unknown and rare variants with a possible biological role. The identification of causal genetic variants may lead to more individualized approaches to treatment and prevention of osteoporosis and will add genetic risk profiles to existing lifestyle factors in the prediction of fracture. Based on our past GWAS efforts in GEFOS, we have identified more than 30 genome-wide significant (5 × 10-8) loci associated with BMD. Among them, 15 loci map to new regions. We are carrying out targeted next generation sequencing of three of these 15 loci (WLS, MEF2C, JAG1) for the identification of rare or low-frequency variants associated in the GEFOS GWAS with BMD). From the Framingham Osteoporosis Study