Osteoporosis New drugs Review
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Osteoporosis New drugs Review
Denosumab is a breakthrough fully human monoclonal antibody approved by both the FDA and EMA in 2010. It had been fast tracked by FDA for treatment and prevention of postmenopausal osteoporosis, treatment and prevention of bone loss in hormone treated prostate and breast cancer patients. The FDA advisory committee (August 13, 2009) to review the safety and efficacy had recommend approval for treatment of high risk bone loss postmenopausal osteoporosis in women and hormone ablation treated men with prostate cancer, with black box warnings for serious side effects and under REMS program. Denosumab may have peak sales in the range of $5 billion within 5 years after approval in US, Europe, Japan and other major markets. New additional indications may follow and it may cross sales of $1 billion in 2012 due to unmet medical need from patients and healthcare providers. Clinical data published and in public domain indicates a superior safety and efficacy profile. FDA has asked for modifications and details of the REMS for treatment of osteoporosis. Denosumab (Prolia, Amgen) after FDA Review was approved under REMS on 1 June 2010. For prevention of osteoporosis and cancer indications, FDA has asked for new studies to show that there was no incidence of increased cancer. Amgen has submitted the BLA for prevention of bone loss in cancer patients on 14 June 2010. FDA had granted it the priority review status and approved the use for reducing fractures and other bone problems in cancer patients on 18 November, 2010. The European Committee for Human Medicinal Products CHMP recommended its approval in December 2009. It was approved by the EMA on 28 may 2010 and was launched there in the 3Q2010. Data presented at the ASCO and ESMO 2010 meetings has been added. The UK cost control agency NICE has recommended the clinical use of Prolia in osteoporosis. Data presented at EULAR showed increased bone density in women taking denosumab for 6 years and significantly reduced risk of fractures in elderly patients. The drug is approved in Switzerland for the prevention of bone loss in breast and prostate cancer patients undergoing hormone therapy besides osteoporosis. Sales of the drug were $33 million in 2010 and peak potential sales of over $ 5 billion per year.
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Denosumab (Prolia, Amgen) FDA Review & Approval - Krishan Maggon

Denosumab (Prolia, Amgen) FDA Review & Approval - Krishan Maggon | Osteoporosis New drugs Review | Scoop.it
Denosumab is a breakthrough fully human monoclonal antibody approved by both the FDA and EMA in 2010. It had been fast...
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Trends in clinical trials for articular cartilage repair by cell therapy

Trends in clinical trials for articular cartilage repair by cell therapy | Osteoporosis New drugs Review | Scoop.it
Abstract
Focal and degenerative lesions of articular cartilage greatly reduce the patient’s quality of life. Various therapies including surgical treatment have been developed, but a definitive therapy is not yet known. Several cell therapy products have already been developed and are available in the market. In this study, we examined the clinical research trends related to cell therapy products in the cartilage repair field based on data obtained from the ClinicalTrial.gov website. Although this website does not provide comprehensive results of clinical trials, it offers information on prospective clinical trials, including work in progress, and thus allows for chronological analysis of the data. We selected 203 studies related to the field of cartilage regeneration from ClinicalTrial.gov. The results showed a shift in the clinical translational trend in utilized cells from cartilage- and bone marrow- to adipose tissue-based cells. Whereas the studies that used cartilage as the cell source included many phase III trials, fewer studies using bone marrow and adipose tissue cells progressed to phase III, suggesting that most clinical developments using the latter sources have not been successful so far. One product covered the entire period from the start of phase I to the completion of phase III, with a time to completion of more than 100 months. Translational trends in autologous chondrocyte implantation were also discussed. The use of ClinicalTrials.gov as the sole data source can yield a perspective view of the global clinical translational trends, which has been difficult to observe up to this point.
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The convergence of regenerative medicine and rehabilitation: federal perspectives

The convergence of regenerative medicine and rehabilitation: federal perspectives | Osteoporosis New drugs Review | Scoop.it
Perspective...

 

rehabilitation technique might involve the pairing of an articular cartilage regeneration therapy with a rehabilitation therapy to yield synergistic improvements over either therapy alone [...] This “pathway” to successful translation of cell t

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Osteogenesis from Dental Pulp Derived Stem Cells: A Novel Conditioned Medium Including Melatonin within a Mixture of Hyaluronic, Butyric, and Retinoic Acids

Osteogenesis from Dental Pulp Derived Stem Cells: A Novel Conditioned Medium Including Melatonin within a Mixture of Hyaluronic, Butyric, and Retinoic Acids | Osteoporosis New drugs Review | Scoop.it
Stem Cells International is a peer-reviewed, Open Access journal that publishes original research articles, review articles, and clinical studies in all areas of stem cell biology and applications. The journal will consider basic, translational, and clinical research, including animal models and...
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Reconstruction of Beagle Hemi-Mandibular Defects with Allogenic Mandibular Scaffolds and Autologous Mesenchymal Stem Cells

Reconstruction of Beagle Hemi-Mandibular Defects with Allogenic Mandibular Scaffolds and Autologous Mesenchymal Stem Cells | Osteoporosis New drugs Review | Scoop.it
Objective Massive bone allografts are frequently used in orthopedic reconstructive surgery, but carry a high failure rate of approximately 25%. We tested whether treatment of graft with mesenchymal stem cells (MSCs) can increase the integration of massive allografts (hemi-mandible) in a large...
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Make No Bones About It: Human skeletal stem cells discovered for first time

Make No Bones About It: Human skeletal stem cells discovered for first time | Osteoporosis New drugs Review | Scoop.it
Human stem cells are specialized cells that can be harvested from the body and engineered to turn into various tissues and organs. Perhaps the greatest potential use of stem cells is the generation of new tissues for organ transplants.
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Engineering functional BMP-2 expressing teratoma-derived fibroblasts for enhancing osteogenesis

Engineering functional BMP-2 expressing teratoma-derived fibroblasts for enhancing osteogenesis | Osteoporosis New drugs Review | Scoop.it
Bone morphogenetic protein 2 (BMP-2) is considered an effective growth factor for bone formation, and is used for making osteo-inductive scaffolds, but the related clinical investigations have shown low success rates. In this study, we genetically manipulated teratoma-derived fibroblast (TDF) cells by simultaneous introduction of BMP-2 and herpes simplex virus-thymidine kinase (HSV-tk) encoding genes. Self-production of BMP-2 in TDF cells strongly enhanced the alkaline phosphatase (ALP) activity, calcium content, and elevated the mRNA expression of osteogenic marker genes during in vitro osteogenesis. The bone formation volume was also remarkably enhanced in calvarial and femoral critical-size defect models. Ganciclovir (GCV) treatment induced apoptosis in TDF cells co-expressing HSV-tk and BMP-2, implying that HSV-tk suicide gene can modulate the side-effects of stem cell therapy, e.g., development of uncontrollable teratoma and tumor formation. Altogether, our findings revealed a safe and highly efficient technique with potential therapeutic applications for bone regeneration.
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Discovery of a periosteal stem cell mediating intramembranous bone formation

Discovery of a periosteal stem cell mediating intramembranous bone formation | Osteoporosis New drugs Review | Scoop.it
A periosteal stem cell specialized in intramembranous bone formation has been identified and was found to be essential for normal bone development and fracture healing.
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Inflammatory-Driven Angiogenesis in Bone Augmentation with Bovine Hydroxyapatite, B-Tricalcium Phosphate, and Bioglasses: A Comparative Study

Inflammatory-Driven Angiogenesis in Bone Augmentation with Bovine Hydroxyapatite, B-Tricalcium Phosphate, and Bioglasses: A Comparative Study | Osteoporosis New drugs Review | Scoop.it
Journal of Immunology Research is a peer-reviewed, Open Access journal that provides a platform for scientists and clinicians working in different areas of immunology and therapy. The journal publishes research articles, review articles, as well as clinical studies related to classical immunology,...
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New Approaches to Treat Osteoarthritis with Mesenchymal Stem Cells

New Approaches to Treat Osteoarthritis with Mesenchymal Stem Cells | Osteoporosis New drugs Review | Scoop.it
Stem Cells International is a peer-reviewed, Open Access journal that publishes original research articles, review articles, and clinical studies in all areas of stem cell biology and applications. The journal will consider basic, translational, and clinical research, including animal models and...
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Hyperbranched poly(ϵ-lysine) substrate presenting the laminin sequence YIGSR induces the formation of spheroids in adult bone marrow stem cells

Hyperbranched poly(ϵ-lysine) substrate presenting the laminin sequence YIGSR induces the formation of spheroids in adult bone marrow stem cells | Osteoporosis New drugs Review | Scoop.it
Unlike the fibroblast-like cells formed upon monolayer culture of human mesenchymal stem cells, the natural stem cell niche of the bone marrow and other types of tissues favours the formation of 3-dimensional (3D) cell clusters.
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The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling | Osteoporosis New drugs Review | Scoop.it
Skeletal dysplasias are rare genetic disorders affecting bone and cartilage growth during development. Csukasi et al . identified two patients with developmental delay and a skeletal phenotype similar to Jansen metaphyseal chondrodysplasia, a disorder caused by altered parathyroid hormone signaling. They identified a genetic mutation in SIK3 as the cause of the of the patients’ dysplasia. The SIK3 mutation altered mTOR signaling, and parathyroid hormone signaling was found to regulate SIK3 activity. This study identifies a common signaling pathway underlying two distinct skeletal disorders, suggesting it plays an important role during skeletal development.

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)–salt-inducible kinase 3 (SIK3)–mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.
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Required growth facilitators propel axon regeneration across complete spinal cord injury

Required growth facilitators propel axon regeneration across complete spinal cord injury | Osteoporosis New drugs Review | Scoop.it
Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
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Site-specific differences in osteoblast phenotype, mechanical loading response and estrogen receptor-related gene expression - ScienceDirect

Site-specific differences in osteoblast phenotype, mechanical loading response and estrogen receptor-related gene expression - ScienceDirect | Osteoporosis New drugs Review | Scoop.it
Highlights

Adult-derived skull and limb osteoblasts exhibit phenotypic heterogeneity.


Skull osteoblasts have reduced mineralisation capacity and loading responsiveness.


Estrogen responsive gene Rerg selectively highly expressed in skull osteoblasts.


Rerg gene silencing reduced estrogen pathway signalling in skull osteoblasts only.
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IJMS |  3D Bone Biomimetic Scaffolds for Basic and Translational Studies with Mesenchymal Stem Cells

IJMS |  3D Bone Biomimetic Scaffolds for Basic and Translational Studies with Mesenchymal Stem Cells | Osteoporosis New drugs Review | Scoop.it
Mesenchymal stem cells (MSCs) are recognized as an attractive tool owing to their self-renewal and differentiation capacity, and their ability to secrete bioactive molecules and to regulate the behavior of neighboring cells within different tissues.
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Bone-eating giant cell provides clues to brittle bones and other disorders

Bone-eating giant cell provides clues to brittle bones and other disorders | Osteoporosis New drugs Review | Scoop.it
Bone-related diseases are the most common cause of severe long-term pain and reduced quality of life for millions of people. They include osteoporosis, periodontitis and rheumatoid arthritis – the number of people suffering ...
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Caution: Cartilage under reconstruction

Caution: Cartilage under reconstruction | Osteoporosis New drugs Review | Scoop.it
A bioactive 3D-printed scaffold combined with microfracture surgery promotes cartilage tissue regeneration.
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Bio-artificial bone formation model with a radial-flow bioreactor for implant therapy—comparison between two cell culture carriers: porous hydroxyapatite and β-tricalcium phosphate beads

Bio-artificial bone formation model with a radial-flow bioreactor for implant therapy—comparison between two cell culture carriers: porous hydroxyapatite and β-tricalcium phosphate beads | Osteoporosis New drugs Review | Scoop.it
Abstract
Bone grafting is necessary before dental implant treatment in patients with jaw bone defects. Currently, autologous bone grafting is a major burden on the patient. However, it is impossible to form a sufficient foundation for the implant with a bone-filling agent alone. It is, therefore, necessary to prepare hybrid artificial bone tissue containing osteoblasts and osteoclasts. In this study, mouse MC3T3-E1 pre-osteoblast cells and human embryonic-derived osteoblastic cell line hFOB1.19 were cultured in radial-flow bioreactors (RFB) to form three-dimensional artificial bone filled with porous beads of β-tricalcium phosphate (β-TCP) or hydroxyapatite (HA)—which are clinically used as bone-filling agents—as cell culture carriers. When circulation culturing was performed in the growth medium for the first 10–12 days, glucose consumption was increased in the cultures with HA beads in comparison to the cultures with β-TCP beads. When cultured in the differentiation culture medium during the second half of the culture period, the glucose consumption decreased in the culture with HA beads. A DNA microarray analysis suggested that osteogenesis progressed fast in three-dimensional culture filled with HA beads and that partly differentiation into osteoblasts was prominent in cultures with β-TCP beads. In the growth process of MC3T3-E1 cells, the vitamin A metabolism was also activated, the synthesis and degradation of retinoic acid was enhanced, and the metabolism of the same process decreased at the end of differentiation in three-dimensional cultures. Three-dimensional circulation culture in RFB is considered to be useful for the formation of hybrid bio-artificial bone tissue.

Keywords
Bio-artificial bone Bioreactor β-Tricalcium phosphate (β-TCP) Hydroxyapatite (HA) Implant Glucose metabolism 13CO2 exhaust test Sulfotransferase (SULT) 1 Vitamin A metabolism 
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Researchers Discover Stem Cells Responsible for Growing and Healing Bone

Researchers Discover Stem Cells Responsible for Growing and Healing Bone | Osteoporosis New drugs Review | Scoop.it
A type of stem cell newly discovered by Weill Cornell Medicine and NewYork-Presbyterian investigators is responsible for growing and healing the hard, outer surface of bone, according to a study...
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Identification of the Human Skeletal Stem

Identification of the Human Skeletal Stem | Osteoporosis New drugs Review | Scoop.it
Highlights
PDPN+CD146−CD73+CD164+ marks a self-renewing, multipotent human skeletal stem cell
hSSCs can be isolated from fetal, adult, BMP2-treated human adipose stroma, and iPSCs
hSSCs undergo local expansion in response to acute skeletal injury
Comparison of mouse and human SSCs reveals evolutionary differences in skeletogenesis
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eCM Journal -The functional role of chondrogenic stem/progenitor cells: novel evidence for immunomodulatory properties and regenerative potential after cartilage injury-True Open Access

eCM Journal -The functional role of chondrogenic stem/progenitor cells: novel evidence for immunomodulatory properties and regenerative potential after cartilage injury-True Open Access | Osteoporosis New drugs Review | Scoop.it
Abstract: Split-thickness skin autografts (AGs) are the standard surgical treatment for severe burn injuries. However, the treatment of patients with substantial skin loss is limited by the availability of donor sites for skin harvesting. As an alternative to skin autografts, our research group developed autologous self-assembled skin substitutes (SASSs), allowing the replacement of both dermis and epidermis in a single surgical procedure. The aim of the study was to assess the clinical outcome of the SASSs as a permanent coverage for full-thickness burn wounds. Patients were recruited through the Health Canada’s Special Access Program. SASSs were grafted on debrided full-thickness wounds according to similar protocols used for AGs. The graft-take and the persistence of the SASS epithelium over time were evaluated. 14 patients received surgical care with SASSs. The mean percentage of the SASS graft-take was 98 % (standard deviation = 5) at 5 to 7 d after surgery. SASS integrity persisted over time (average follow-up time: 3.2 years), without noticeable deficiency in epidermal regeneration. Assessment of scar quality (skin elasticity, erythema, thickness) was performed on a subset of patients. Non-homogeneous pigmentation was noticed in several patients. These results indicated that the SASS allowed the successful coverage of full-thickness burns given its high graft-take, aesthetic outcome equivalent to autografting and the promotion of long-term tissue regeneration. When skin donor sites are in short supply, SASSs could be a valuable alternative to treat patients with full-thickness burns covering more than 50 % of their total body surface area.

Key Words: Autologous, burn, culture techniques, connective tissue, regenerative medicine, skin, skin grafts, tissue culture, tissue engineering, tissue therapy.

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Comparative analysis of gene expression identifies distinct molecular signatures of bone marrow- and periosteal-skeletal stem/progenitor cells

Comparative analysis of gene expression identifies distinct molecular signatures of bone marrow- and periosteal-skeletal stem/progenitor cells | Osteoporosis New drugs Review | Scoop.it
Periosteum and bone marrow (BM) both contain skeletal stem/progenitor cells (SSCs) that participate in fracture repair. However, the functional difference and selective regulatory mechanisms of SSCs in different locations are unknown due to the lack of specific markers.
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Human skeletal stem cell can generate cartilage, bone

Human skeletal stem cell can generate cartilage, bone | Osteoporosis New drugs Review | Scoop.it
Discovery of the human skeletal stem cell opens the way to regenerate cartilage and bone to repair damaged tissues, say Stanford scientists.
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Skeletal stem cells found in humans for first time, promising new treatments for fractures and osteoporosis

Skeletal stem cells found in humans for first time, promising new treatments for fractures and osteoporosis | Osteoporosis New drugs Review | Scoop.it
Team also discovers a way to turn fat into bone...
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Bone and plasma citrate is reduced in osteoporosis - ScienceDirect

Bone and plasma citrate is reduced in osteoporosis - ScienceDirect | Osteoporosis New drugs Review | Scoop.it
Highlights

Citrate content of bone is reduced in osteoporotic and aged mice and rats.


Plasma citrate level is reduced in osteoporotic and aged mice and rats.


Plasma citrate level is reduced in senile osteoporotic patients.


Osteoblasts are highly specialized cells that produce citrate.
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