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Emerging treatments for postmenopausal osteoporosis - focus on denosumab.

Geusens P - Clin Interv Aging (2009)

Bottom Line: The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease).The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study.In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Subdivision of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands. piet.geusens@scarlet.be

ABSTRACT
The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease). Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in increase in bone mineral density (BMD) in post-menopausal women with low BMD, and has the potential to prevent progression of erosions in RA and of skeletal-related events in metastatic bone disease. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study. In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

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Related in: MedlinePlus

Free RANKL (ie, not bound by osteoprotegerin [OPG]) binds to the transmembrane RANK receptor, which upregulates intracellular signal transducers which are involved in cytoskeletal organization, cell motility, growth and survival, and some also bind NF κB. After ubiquitination, signal transducers are released from NF κB and degraded by proteasomes. NF κB can than migrate to the nucleus, were it upregulates transcriptional regulators that start osteoclastogenic gene transcription.2
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f1-cia-4-241: Free RANKL (ie, not bound by osteoprotegerin [OPG]) binds to the transmembrane RANK receptor, which upregulates intracellular signal transducers which are involved in cytoskeletal organization, cell motility, growth and survival, and some also bind NF κB. After ubiquitination, signal transducers are released from NF κB and degraded by proteasomes. NF κB can than migrate to the nucleus, were it upregulates transcriptional regulators that start osteoclastogenic gene transcription.2

Mentions: The activation of RANK in osteoclasts results in activation of several intracellular signal transduction pathways, which bind the nuclear factor κB (NF κB). After ubiquitination of signal transducers (which results in their degradation by proteasomes), NF κB is released, so that it can translocate to the nucleus, where it upregulates cofactors that induce osteoclastogenic gene transcription (Figure 1).


Emerging treatments for postmenopausal osteoporosis - focus on denosumab.

Geusens P - Clin Interv Aging (2009)

Free RANKL (ie, not bound by osteoprotegerin [OPG]) binds to the transmembrane RANK receptor, which upregulates intracellular signal transducers which are involved in cytoskeletal organization, cell motility, growth and survival, and some also bind NF κB. After ubiquitination, signal transducers are released from NF κB and degraded by proteasomes. NF κB can than migrate to the nucleus, were it upregulates transcriptional regulators that start osteoclastogenic gene transcription.2
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697589&req=5

f1-cia-4-241: Free RANKL (ie, not bound by osteoprotegerin [OPG]) binds to the transmembrane RANK receptor, which upregulates intracellular signal transducers which are involved in cytoskeletal organization, cell motility, growth and survival, and some also bind NF κB. After ubiquitination, signal transducers are released from NF κB and degraded by proteasomes. NF κB can than migrate to the nucleus, were it upregulates transcriptional regulators that start osteoclastogenic gene transcription.2
Mentions: The activation of RANK in osteoclasts results in activation of several intracellular signal transduction pathways, which bind the nuclear factor κB (NF κB). After ubiquitination of signal transducers (which results in their degradation by proteasomes), NF κB is released, so that it can translocate to the nucleus, where it upregulates cofactors that induce osteoclastogenic gene transcription (Figure 1).

Bottom Line: The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease).The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study.In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Subdivision of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands. piet.geusens@scarlet.be

ABSTRACT
The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease). Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in increase in bone mineral density (BMD) in post-menopausal women with low BMD, and has the potential to prevent progression of erosions in RA and of skeletal-related events in metastatic bone disease. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study. In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

Show MeSH
Related in: MedlinePlus