This systematic literature review examined the efficacy and safety of denosumab for the treatment of osteoporosis based on 25 clinical trials. The review found that denosumab reduces the risk of new radiographic vertebral fractures by 68% compared to placebo, and increases bone mineral density more than alendronate and placebo. A single dose of denosumab resulted in a rapid, profound, and sustained decrease in bone turnover markers. Denosumab was generally well tolerated, but a meta-analysis showed an increased risk of urinary tract infections and eczema in patients treated with denosumab.
The Effect of Recombinant Bone Morphogenetic Protien-2 in Revison Tibiotaloca...skisnfeet
The document summarizes a study examining the effect of recombinant bone morphogenetic protein-2 (rhBMP-2) in revision tibiotalocalcaneal arthrodesis using an intramedullary nail. Twenty-three patients undergoing revision hindfoot and ankle arthrodesis were divided into those who received rhBMP-2 (BMP Group) and those who did not (NoBMP Group). The study found no statistically significant differences between the groups in time to partial or full weight bearing, or time to radiographic union. Both groups had high rates of fusion, with the NoBMP Group achieving union in 68.8% of cases and the BMP Group achieving union in 71.4% of cases.
Significance of Trace Element Quantities in Osteomyelitis and Osteosarcoma_Cr...CrimsonpublishersCancer
To clarify the role of trace elements (TE) in the etiology and the pathogenesis of osteomyelitis (OM) and osteosarcoma (OS), a nondestructive neutron activation analysis were performed. The Ag, Co, Cr, Fe, Hg, Rb, Sb, Se, and Zn contents were measured in three groups of samples: normal bone samples from 27 persons with intact bone, and also in samples, obtained from open biopsies or after operation of 10 patients with OM and 27 patients with OS. The difference in the results between TE contents in the three groups was evaluated by the parametric Student’s t-test and non-parametric Wilcoxon-Mann-Whitney U-test. In the OM tissue the mean contents of Co, Cr, Fe, Se, and Zn are respectively 1.8, 1.7, 1.8, 1.7, and 1.5 times higher than those in normal bone tissues In the OS tissue the mean mass fractions of Co, Cr, Fe, Sb, Se, and Zn are respectively 4.6, 2.0, 4.8 2.4, 11.0, and 2.4 times higher while the mean mass fraction of Rb is more than 40% lower than in normal bone tissues. In the OS tissue the mean mass fractions of Co, Fe, Se, and Zn are significantly higher (2.6, 2.6, 6.2, and 1.6 times, respectively) and the mean mass fraction of Rb is more than 2 times lower than in inflamed bone. In addition, many inter-correlations between TE contents found in the control group were no longer evident in the inflamed and tumor transformed bone. Thus, considerable changes in TE content and their relationships were found in OM and OS and possible causes and effects of these alterations are discussed.
The document describes a study that used whole-exome sequencing to identify novel genetic variations associated with osteoarthritis (OA) patients. Several variations were found in genes involved in cartilage development, extracellular matrix organization, and inflammatory/immune responses. Two novel mutations were validated by Sanger sequencing, including a mutation in the SELP gene and another in the COL6A6 gene. The approach identified variations in genes impacting pathways relevant to OA pathogenesis.
This study investigated the effects of heat from an arthroscope on human bone marrow-derived mesenchymal stem cells (hBMMSCs). hBMMSCs were isolated from osteoarthritis patients and exposed to heat from an illuminated arthroscope for various time periods as single cell suspensions or cell pellets. Cell suspensions exposed to heat showed decreased viability over time, while cell pellets maintained or increased viability. Gene expression analysis found increased expression of heat shock and inflammatory genes in cell suspensions compared to pellets after heat exposure. The results suggest that transplanting hBMMSCs as cell pellets may better protect them from heat effects during arthroscopic procedures and thus support cartilage regeneration.
This document discusses the use of adult stem cells, specifically mesenchymal stem cells (MSCs), in orthopedics. It provides several examples of how MSCs derived from bone marrow have been used to treat orthopedic injuries and conditions. These include using bone marrow concentrate to treat non-unions, avascular necrosis, and promote healing in ACL reconstruction, spinal fusions, and rotator cuff injuries. Studies show MSCs can reduce healing times and promote stronger tissue regeneration compared to other treatments like corticosteroids or autografts. The document also discusses how MSCs may help regenerate cartilage and treat osteoarthritis by reducing pain and slowing degeneration.
THE EFFECT OF CHEMICAL FIXATION ON THE STRUCTURAL PROPERTIES OF HUMAN COLLATE...Dr. Abdurahman Salem
Chemical fixation is commonly used to preserve soft tissues for mechanical testing, but it can alter tissue properties. This study compared the mechanical properties of human knee collateral ligaments that were chemically fixed versus non-fixed. The ultimate tensile strength and structural stiffness of the fixed ligaments were not significantly different than the fresh ligaments. Despite the cross-linking effect of common fixatives like formaldehyde and phenol-formaldehyde, fixation had a negligible impact on the strength and stiffness of the collateral ligaments based on testing of a small number of human specimens.
Stem cells show promise in treating orthopedic conditions like non-union fractures and avascular necrosis. For non-unions, stem cells from bone marrow can be injected to promote bone healing when other treatments fail. They may also help repair bone defects. For avascular necrosis, stem cell injections into the dead bone area have helped regrow bone in some cases. Further research is still needed but stem cells represent a potential alternative to bone grafts for filling bony voids from conditions like cysts.
This study investigated the relative influences of apatite crystal orientations and intracortical porosity on the elastic anisotropy of human cortical bone. Experimental measurements of elastic constants from human femoral bone specimens exhibited orthotropic elasticity. Predictions from a micromechanical model accounting for apatite crystal orientations accurately captured the transverse isotropy observed in the longitudinal-circumferential plane but underestimated orthotropy. A finite element model accounting for intracortical porosity predicted orthotropy but underestimated elastic anisotropy. Only a combined model accounting for both apatite crystal orientations and intracortical porosity provided predictions within 10% of experimental measurements, suggesting both microstructural features contribute significantly to cortical bone's elastic
The Effect of Recombinant Bone Morphogenetic Protien-2 in Revison Tibiotaloca...skisnfeet
The document summarizes a study examining the effect of recombinant bone morphogenetic protein-2 (rhBMP-2) in revision tibiotalocalcaneal arthrodesis using an intramedullary nail. Twenty-three patients undergoing revision hindfoot and ankle arthrodesis were divided into those who received rhBMP-2 (BMP Group) and those who did not (NoBMP Group). The study found no statistically significant differences between the groups in time to partial or full weight bearing, or time to radiographic union. Both groups had high rates of fusion, with the NoBMP Group achieving union in 68.8% of cases and the BMP Group achieving union in 71.4% of cases.
Significance of Trace Element Quantities in Osteomyelitis and Osteosarcoma_Cr...CrimsonpublishersCancer
To clarify the role of trace elements (TE) in the etiology and the pathogenesis of osteomyelitis (OM) and osteosarcoma (OS), a nondestructive neutron activation analysis were performed. The Ag, Co, Cr, Fe, Hg, Rb, Sb, Se, and Zn contents were measured in three groups of samples: normal bone samples from 27 persons with intact bone, and also in samples, obtained from open biopsies or after operation of 10 patients with OM and 27 patients with OS. The difference in the results between TE contents in the three groups was evaluated by the parametric Student’s t-test and non-parametric Wilcoxon-Mann-Whitney U-test. In the OM tissue the mean contents of Co, Cr, Fe, Se, and Zn are respectively 1.8, 1.7, 1.8, 1.7, and 1.5 times higher than those in normal bone tissues In the OS tissue the mean mass fractions of Co, Cr, Fe, Sb, Se, and Zn are respectively 4.6, 2.0, 4.8 2.4, 11.0, and 2.4 times higher while the mean mass fraction of Rb is more than 40% lower than in normal bone tissues. In the OS tissue the mean mass fractions of Co, Fe, Se, and Zn are significantly higher (2.6, 2.6, 6.2, and 1.6 times, respectively) and the mean mass fraction of Rb is more than 2 times lower than in inflamed bone. In addition, many inter-correlations between TE contents found in the control group were no longer evident in the inflamed and tumor transformed bone. Thus, considerable changes in TE content and their relationships were found in OM and OS and possible causes and effects of these alterations are discussed.
The document describes a study that used whole-exome sequencing to identify novel genetic variations associated with osteoarthritis (OA) patients. Several variations were found in genes involved in cartilage development, extracellular matrix organization, and inflammatory/immune responses. Two novel mutations were validated by Sanger sequencing, including a mutation in the SELP gene and another in the COL6A6 gene. The approach identified variations in genes impacting pathways relevant to OA pathogenesis.
This study investigated the effects of heat from an arthroscope on human bone marrow-derived mesenchymal stem cells (hBMMSCs). hBMMSCs were isolated from osteoarthritis patients and exposed to heat from an illuminated arthroscope for various time periods as single cell suspensions or cell pellets. Cell suspensions exposed to heat showed decreased viability over time, while cell pellets maintained or increased viability. Gene expression analysis found increased expression of heat shock and inflammatory genes in cell suspensions compared to pellets after heat exposure. The results suggest that transplanting hBMMSCs as cell pellets may better protect them from heat effects during arthroscopic procedures and thus support cartilage regeneration.
This document discusses the use of adult stem cells, specifically mesenchymal stem cells (MSCs), in orthopedics. It provides several examples of how MSCs derived from bone marrow have been used to treat orthopedic injuries and conditions. These include using bone marrow concentrate to treat non-unions, avascular necrosis, and promote healing in ACL reconstruction, spinal fusions, and rotator cuff injuries. Studies show MSCs can reduce healing times and promote stronger tissue regeneration compared to other treatments like corticosteroids or autografts. The document also discusses how MSCs may help regenerate cartilage and treat osteoarthritis by reducing pain and slowing degeneration.
THE EFFECT OF CHEMICAL FIXATION ON THE STRUCTURAL PROPERTIES OF HUMAN COLLATE...Dr. Abdurahman Salem
Chemical fixation is commonly used to preserve soft tissues for mechanical testing, but it can alter tissue properties. This study compared the mechanical properties of human knee collateral ligaments that were chemically fixed versus non-fixed. The ultimate tensile strength and structural stiffness of the fixed ligaments were not significantly different than the fresh ligaments. Despite the cross-linking effect of common fixatives like formaldehyde and phenol-formaldehyde, fixation had a negligible impact on the strength and stiffness of the collateral ligaments based on testing of a small number of human specimens.
Stem cells show promise in treating orthopedic conditions like non-union fractures and avascular necrosis. For non-unions, stem cells from bone marrow can be injected to promote bone healing when other treatments fail. They may also help repair bone defects. For avascular necrosis, stem cell injections into the dead bone area have helped regrow bone in some cases. Further research is still needed but stem cells represent a potential alternative to bone grafts for filling bony voids from conditions like cysts.
This study investigated the relative influences of apatite crystal orientations and intracortical porosity on the elastic anisotropy of human cortical bone. Experimental measurements of elastic constants from human femoral bone specimens exhibited orthotropic elasticity. Predictions from a micromechanical model accounting for apatite crystal orientations accurately captured the transverse isotropy observed in the longitudinal-circumferential plane but underestimated orthotropy. A finite element model accounting for intracortical porosity predicted orthotropy but underestimated elastic anisotropy. Only a combined model accounting for both apatite crystal orientations and intracortical porosity provided predictions within 10% of experimental measurements, suggesting both microstructural features contribute significantly to cortical bone's elastic
Abstract— Cerebral palsy (CP) is the most common physical disability of childhood. Children with CP frequently grow slowly and are more prone to fractures. So this study was aimed to explore relationship of bone mineral density (BMD) with cerebral palsy by case-control study. This study was conducted at Department of Physical Medicine and Rehabilitation of Sawai Man Singh Medical College, Jaipur. Hip bone and spine bone was used to assess BMD. Bone mineral density was measured by DEXA in both groups i.e. study group and control group after ensuring the comparability of both groups. Difference in means of BMD in both the groups was inferred by unpaired student's’ test of significance. It was found in this study that bone mineral density of hip well as spine was significantly lowered in cerebral palsy cases.
This document discusses treatment strategies for knee osteoarthritis, including regenerative therapy using mesenchymal stem cells (MSCs). It notes that while MSCs have properties making them preferable for osteoarthritis treatment, including ease of accessibility, anti-inflammatory effects, safety, and differentiation abilities, some studies have found MSCs reduce pain but not degenerative changes. Multiple injections of allogeneic bone marrow MSCs may be important to modulate the osteoarthritis joint environment and restore lost cells. Future developments hoped for include generation of commercial stem cell products at a reasonable cost.
Adult Stem cells in Orthopaedics present and future perspectives.
Παρουσίαση του Δρ. Σταύρου Αλευρογιάννη που έγινε στο ξενοδοχείο Χίλτον, στις 12/06/15 στα πλαίσια Ημερίδας της Ελληνικής Εταιρείας Αναγεννητικής Ιατρικής, Αντιγήρανσης και Βιοτεχνολογίας, στο 41ο Πανελλήνιο Ιατρικό Συνέδριο.
"H θέση της αναγεννητική Ιατρικής στις παθήσεις Οστών και Αρθρώσεων"
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading research programs in bone health, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published over 30 peer-reviewed papers and is an active reviewer for several academic journals.
This document summarizes a study on using cell therapy to assist in regenerating cartilage in cases of avascular bone necrosis. It discusses how mesenchymal stem cells derived from bone marrow were used in 15 patients with avascular bone necrosis of the femoral head. The stem cells were isolated from patients' bone marrow and fat tissue then reintroduced with platelet rich plasma. Follow-ups over a year found improved symptoms and radiological signs of new cartilage formation in the patients. The role of the stem cell microenvironment in differentiation is also discussed. The study suggests cell therapy is a promising alternative to traditional surgery for certain orthopedic conditions.
R3 stem cell treatment will help you recover from injuries and diseases without going into surgeries. When we talk about stem cell therapy, R3 is a pioneer of the stem cell industry. At present, Dr. Greene's R3 stem cell is the global leader in regenerative cell therapies.
Polymers have been widely evaluated for cartilage repair over the past two decades. The review discusses cartilage structure and repair mechanisms. It then provides an overview of polymer components used in commercially available cartilage repair constructs. These include natural polymers like collagen and hyaluronic acid, as well as synthetic polymers. The review discusses considerations for construct design, including degradation rates, mechanical properties, cell sources, and one versus two-stage repair techniques. Future directions are seen in optimizing degradable scaffolds, patient-specific non-degradable implants, and hybrid constructs combining degradable and non-degradable materials.
This review analyzes the current evidence on the biologic width around dental implants. The review summarizes 75 studies on this topic, including 2 clinical studies, 8 human histology studies, and 44 animal studies. The key findings are:
- Evidence from animal studies shows that the biologic width around implants consists of sulcular and junctional epithelium and an underlying connective tissue zone, similar to natural teeth.
- Human histology studies found the total height of peri-implant tissues to be 4-4.5mm, with the peri-implant sulcus ranging from 0.2-0.5mm and junctional epithelium limited to 1.4-2.9mm.
This research paper summarizes studies on using cell therapy and stem cells to regenerate cartilage in cases of avascular bone necrosis. It discusses how regenerative medicine using stem cells has potential to treat many orthopedic conditions. Specifically, it presents case studies where autologous transplantation of stem cells from bone marrow, adipose tissue or platelet rich plasma helped regenerate cartilage and bone in patients with avascular necrosis of the femoral head. The stem cells were able to differentiate into osteocytes and chondrocytes, integrating at the damaged site and promoting healing of fractures and cartilage defects.
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading multiple research programs investigating bone regeneration, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published extensively in peer-reviewed journals and serves as a reviewer for several orthopedic research publications.
The authors wrote a letter to the editor in response to an article on the learning curve associated with using a new cephalomedullary femoral nail. They note several factors that could impact the learning curve that were not addressed, such as using cerclage cables or open surgery for complex fractures. The authors also point out inconsistencies in the reported data on patient characteristics and medical histories, such as bisphosphonate use, that require clarification to properly evaluate the results. The letter aims to provide additional context and perspectives to more fully understand the learning curve analyzed in the original study.
Background: The spectrum of pathological bone lesions ranges from inflammatory to neoplastic conditions. Bone tumours are comparatively uncommon among wide array of lesions. The roentgenogram helps in defining exact location of lesion but becomes difficult to differentiate them. They often pose diagnostic problem as they constitute a small portion of diagnostic experience among pathologist.
Objective: To study histopathological spectrum of bone lesions & correlate them with age, gender and site of occurrence.
Results: All bone biopsies from January 2011 to December 2015 received at department of pathology, S.Nijalingappa Medical College, India. Total 121 cases of bone biopsies were analysed. They were decalcified & processed routinely. Out of 121 bone biopsies, 35 (28.9%) cases are non- neoplastic, 77 (63.6%) are neoplastic and 9 (7.4%) were inadequate for evaluation. The incidence of benign lesions are more than malignant with 51(66.2%) and 26(33.7%) cases respectively. Chronic osteomyelitis is the most common non-neoplastic lesion. Giant cell tumor and osteosarcoma are common benign and malignant lesions respectively. Femur is the common bone involved and metaphysis, the commonest site. The maximum numbers of cases are in the age group between 11-30 years with male preponderance.
Conclusion: Though bone lesions are less common, if viewed in perspective of clinico-radiology and histopathology, correct diagnosis can be reached.
Key-words- Bone lesions, Chronic osteomyelitis, Osteosarcoma, Giant cell tumor, Histopathology
This document summarizes a clinical trial that examined the effects of intra-articular injection of autologous microfragmented fat tissue on proteoglycan synthesis in patients with knee osteoarthritis. Seventeen patients with knee osteoarthritis received injections of microfragmented adipose tissue containing adipose-derived mesenchymal stem cells. Magnetic resonance imaging and biochemical analysis were used to assess proteoglycan content and glycosaminoglycan levels in cartilage at baseline and over 12 months following treatment. Results indicated that glycosaminoglycan content in hyaline cartilage increased following treatment, as measured by magnetic resonance imaging. This suggests the treatment increased proteoglycan synthesis in osteoarthritic cartilage. No evidence of chondrotoxicity from the treatment
This study investigated using microribbon (μRB) scaffolds to support chondrogenesis of adipose-derived stem cells (ADSCs) for cartilage regeneration. The μRB scaffolds were macroporous and gelatin-based, while conventional hydrogel (HG) scaffolds lacked macroporosity. ADSCs encapsulated in μRB scaffolds attached, spread, and proliferated more than in HG scaffolds. After 3 weeks of culture, ADSCs in μRB scaffolds deposited more interconnected type II collagen and sulfated glycosaminoglycans (sGAG), and the resulting neocartilage had a higher compressive modulus than ADSCs in HG scaffolds. The enhanced chondrogenesis and mechanical properties of
The document provides guidelines for non-clinical evaluation of osteoporosis drugs. It recommends conducting long-term bone quality studies in two animal species to evaluate effects on bone turnover, mass, density, structure, and strength. Studies should be designed to support clinical development and be submitted for FDA review. Bone quality cannot be directly assessed, but nonclinical studies provide indirect measures of strength determined by both bone mass and quality.
Intra-Articular Administration of Autologous Micro-Fragmented Adipose Tissue in Dogs with Spontaneous Osteoarthritis: Safety, Feasibility, and Clinical Outcomes
OFFER ZEIRA,a SIMONE SCACCIA,a LETIZIA PETTINARI,a ERICA GHEZZI,a NIMROD ASIAG,a LAURA MARTINELLI,a DANIELE ZAHIRPOUR,a MARIA P. DUMAS,a MARTIN KONAR,a DAVIDE M. LUPI,a LAURENCE FIETTE,b LUISA PASCUCCI,c LEONARDO LEONARDI,c ALISTAIR CLIFF,d GIULIO ALESSANDRI,e AUGUSTO PESSINA,f DANIELE SPAZIANTE,g MARINA ARALLAa
ABSTRACT Similar to the disease affecting humans, osteoarthritis (OA) is a painful musculoskeletal condition affecting 20% of the adult canine population. Several solutions have been proposed, but the results achieved to date are far from being satisfactory. New approaches, such as intra-articular delivery of cells (including mesenchymal stromal cells), have been proposed. Among the many sources, the adipose tissue is considered very promising. We evaluated the safety, feasibility, and efficacy of a single intra-articular injection of autologous and micro-fragmented adipose tissue (MFAT) in 130 dogs with spontaneous OA. MFAT was obtained using a minimally invasive technique in a closed system and injected in the intra- and/or peri-articular space. Clinical outcomes were determined using orthopedic examination and owners’ scores for up to 6 months. In 78% of the dogs, improvement in the orthopedic score was registered 1 month after treatment and continued gradually up to 6 months when 88% of the dogs improved, 11% did not change, and 1% worsened compared with baseline. Considering the owners’ scores at 6 months, 92% of the dogs significantly improved, 6% improved only slightly, and 2% worsened compared with baseline. No local or systemic major adverse effects were recorded. The results of this study suggest that MFAT injection in dogs with OA is safe, feasible, and beneficial. The procedure is time sparing and cost-effective. Post injection cytological investigation, together with the clinical evidence, suggests a long-term pain control role of this treatment. The spontaneous OA dog model has a key role in developing successful treatments for translational medicine. STEM CELLS TRANSLATIONAL MEDICINE 2018;00:1–10
This document discusses stem cells and their potential applications in orthopedics. It begins with an overview of stem cell classifications and sources, including embryonic stem cells, induced pluripotent stem cells, and adult stem cells like mesenchymal stem cells derived from bone marrow. The document then focuses on the properties and differentiation potential of mesenchymal stem cells, describing their use in treating conditions like osteonecrosis, cartilage defects, spinal cord injuries, and intervertebral disc regeneration. It presents several case studies on using bone marrow concentrate containing mesenchymal stem cells for avascular necrosis. In summary, the document reviews stem cell types and their emerging role in regenerative orthopedic therapies.
Bioactive Nanoparticle Materials for Bone Tissue RegenerationKathleen Broughton
The document discusses bioactive scaffolds for bone tissue regeneration using emerging nano-materials. It outlines that bone regeneration is a growing medical need and describes criteria for effective bone regeneration scaffolds. The focus is on comparing porous nano-materials in terms of porosity and mechanical strength. Formulas for calculating porosity, compressive strength, and degradation are provided to analyze scaffold materials.
This document discusses osteoporosis treatment in patients with chronic kidney disease (CKD). It notes that while CKD patients have a high risk of fracture similar to postmenopausal osteoporosis, CKD-mineral and bone disorder (CKD-MBD) is more complex. Evaluating fracture risk in CKD patients is challenging as laboratory tests, bone turnover markers, and imaging modalities all have limitations. Bone biopsy remains the gold standard but has limitations for use in clinical practice. Treatment should be based on the underlying pathophysiology and more research is needed on fracture outcomes in CKD-MBD patients.
A D I S D R U G E V A L U A T I O NDenosumab A Review of .docxransayo
A D I S D R U G E V A L U A T I O N
Denosumab: A Review of its Use in Postmenopausal Women
with Osteoporosis
Lesley J. Scott
Published online: 17 June 2014
� Springer International Publishing Switzerland 2014
Abstract Subcutaneous denosumab (Prolia� [USA,
Europe]; Pralia
�
[Japan]) once every 6 months is indi-
cated in several countries for the treatment of postmen-
opausal women with osteoporosis at increased or high
risk for fractures (featured indication). In some countries,
it is also indicated for use in postmenopausal women who
have failed or are intolerant to other osteoporosis treat-
ments. In several international, phase III trials (B3 years’
duration) involving more than 12,000 women with post-
menopausal osteoporosis or low bone mineral density
(BMD), including Asian studies, denosumab was an
effective and generally well tolerated treatment. Relative
to placebo, denosumab treatment significantly reduced the
risk of vertebral, nonvertebral and hip fractures and
increased BMD at all skeletal sites evaluated, including
the lumbar spine and total hip. Furthermore, the benefits
of denosumab treatment were generally evident after the
first dose and were maintained during up to 8 years of
treatment in an ongoing extension study. The tolerability
profile of denosumab during this extension phase was
consistent with that observed during the initial 3-year
FREEDOM trial. At 12 months, denosumab treatment
increased BMD at the total hip, lumbar spine and/or
femoral neck and reduced markers of bone turnover to a
significantly greater extent than oral bisphosphonates in
women who were essentially bisphosphonate-naive and in
those who had switched from alendronate to denosumab
treatment. Further clinical experience, including an
ongoing postmarketing safety study, will more fully
define the long-term safety of denosumab. In the mean-
time, denosumab is an important option for the treatment
of women with postmenopausal osteoporosis at increased
or high-risk of fractures, including in women at increased
risk of fracture who are unable to take other osteoporosis
treatments.
Denosumab in postmenopausal women with osteo-
porosis: a summary
Human monoclonal antibody targeting RANKL, a
key mediator of bone resorption
Relative to placebo, denosumab reduces the
incidence of vertebral, nonvertebral and hip fractures
Reduces bone resorption, increases bone mineral
content, bone mass and bone strength
Increases BMD to a significantly greater extent than
oral alendronate, ibandronate or risedronate
Generally well tolerated (B8 years treatment), with
most adverse events of mild to moderate severity;
long-term safety studies are ongoing
The manuscript was reviewed by: J-P. Devogelaer, Universite
Catholique de Lovain, Service de Rheumatologie, Cliniques
Universitaires Saint-Luc, Brussels, Belgium; M. Kleerekoper,
University of Toledo Medical School, Department of Internal
Medicine, Endocrinology Division, Ru.
In this study of 277 post-menopausal women, the researchers found:
1) Higher bone mineral density was associated with increased severity of disc space narrowing at both the lumbar spine and femoral sites.
2) There was no association found between bone mineral density and severity of osteophytes.
3) Biochemical markers of bone resorption (CTX levels) decreased with increased severity of disc space narrowing, but were not associated with osteophyte severity. This suggests disc space narrowing may have a protective effect against bone loss through decreased bone resorption.
Abstract— Cerebral palsy (CP) is the most common physical disability of childhood. Children with CP frequently grow slowly and are more prone to fractures. So this study was aimed to explore relationship of bone mineral density (BMD) with cerebral palsy by case-control study. This study was conducted at Department of Physical Medicine and Rehabilitation of Sawai Man Singh Medical College, Jaipur. Hip bone and spine bone was used to assess BMD. Bone mineral density was measured by DEXA in both groups i.e. study group and control group after ensuring the comparability of both groups. Difference in means of BMD in both the groups was inferred by unpaired student's’ test of significance. It was found in this study that bone mineral density of hip well as spine was significantly lowered in cerebral palsy cases.
This document discusses treatment strategies for knee osteoarthritis, including regenerative therapy using mesenchymal stem cells (MSCs). It notes that while MSCs have properties making them preferable for osteoarthritis treatment, including ease of accessibility, anti-inflammatory effects, safety, and differentiation abilities, some studies have found MSCs reduce pain but not degenerative changes. Multiple injections of allogeneic bone marrow MSCs may be important to modulate the osteoarthritis joint environment and restore lost cells. Future developments hoped for include generation of commercial stem cell products at a reasonable cost.
Adult Stem cells in Orthopaedics present and future perspectives.
Παρουσίαση του Δρ. Σταύρου Αλευρογιάννη που έγινε στο ξενοδοχείο Χίλτον, στις 12/06/15 στα πλαίσια Ημερίδας της Ελληνικής Εταιρείας Αναγεννητικής Ιατρικής, Αντιγήρανσης και Βιοτεχνολογίας, στο 41ο Πανελλήνιο Ιατρικό Συνέδριο.
"H θέση της αναγεννητική Ιατρικής στις παθήσεις Οστών και Αρθρώσεων"
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading research programs in bone health, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published over 30 peer-reviewed papers and is an active reviewer for several academic journals.
This document summarizes a study on using cell therapy to assist in regenerating cartilage in cases of avascular bone necrosis. It discusses how mesenchymal stem cells derived from bone marrow were used in 15 patients with avascular bone necrosis of the femoral head. The stem cells were isolated from patients' bone marrow and fat tissue then reintroduced with platelet rich plasma. Follow-ups over a year found improved symptoms and radiological signs of new cartilage formation in the patients. The role of the stem cell microenvironment in differentiation is also discussed. The study suggests cell therapy is a promising alternative to traditional surgery for certain orthopedic conditions.
R3 stem cell treatment will help you recover from injuries and diseases without going into surgeries. When we talk about stem cell therapy, R3 is a pioneer of the stem cell industry. At present, Dr. Greene's R3 stem cell is the global leader in regenerative cell therapies.
Polymers have been widely evaluated for cartilage repair over the past two decades. The review discusses cartilage structure and repair mechanisms. It then provides an overview of polymer components used in commercially available cartilage repair constructs. These include natural polymers like collagen and hyaluronic acid, as well as synthetic polymers. The review discusses considerations for construct design, including degradation rates, mechanical properties, cell sources, and one versus two-stage repair techniques. Future directions are seen in optimizing degradable scaffolds, patient-specific non-degradable implants, and hybrid constructs combining degradable and non-degradable materials.
This review analyzes the current evidence on the biologic width around dental implants. The review summarizes 75 studies on this topic, including 2 clinical studies, 8 human histology studies, and 44 animal studies. The key findings are:
- Evidence from animal studies shows that the biologic width around implants consists of sulcular and junctional epithelium and an underlying connective tissue zone, similar to natural teeth.
- Human histology studies found the total height of peri-implant tissues to be 4-4.5mm, with the peri-implant sulcus ranging from 0.2-0.5mm and junctional epithelium limited to 1.4-2.9mm.
This research paper summarizes studies on using cell therapy and stem cells to regenerate cartilage in cases of avascular bone necrosis. It discusses how regenerative medicine using stem cells has potential to treat many orthopedic conditions. Specifically, it presents case studies where autologous transplantation of stem cells from bone marrow, adipose tissue or platelet rich plasma helped regenerate cartilage and bone in patients with avascular necrosis of the femoral head. The stem cells were able to differentiate into osteocytes and chondrocytes, integrating at the damaged site and promoting healing of fractures and cartilage defects.
Xuhui Liu is an experienced physician-scientist specializing in biomedical research. He has over 20 years of experience conducting clinical and preclinical research focused on musculoskeletal and neurological diseases. Currently, he is an Associate Professor at UCSF leading multiple research programs investigating bone regeneration, rotator cuff injuries, and neuro-musculoskeletal trauma. He has published extensively in peer-reviewed journals and serves as a reviewer for several orthopedic research publications.
The authors wrote a letter to the editor in response to an article on the learning curve associated with using a new cephalomedullary femoral nail. They note several factors that could impact the learning curve that were not addressed, such as using cerclage cables or open surgery for complex fractures. The authors also point out inconsistencies in the reported data on patient characteristics and medical histories, such as bisphosphonate use, that require clarification to properly evaluate the results. The letter aims to provide additional context and perspectives to more fully understand the learning curve analyzed in the original study.
Background: The spectrum of pathological bone lesions ranges from inflammatory to neoplastic conditions. Bone tumours are comparatively uncommon among wide array of lesions. The roentgenogram helps in defining exact location of lesion but becomes difficult to differentiate them. They often pose diagnostic problem as they constitute a small portion of diagnostic experience among pathologist.
Objective: To study histopathological spectrum of bone lesions & correlate them with age, gender and site of occurrence.
Results: All bone biopsies from January 2011 to December 2015 received at department of pathology, S.Nijalingappa Medical College, India. Total 121 cases of bone biopsies were analysed. They were decalcified & processed routinely. Out of 121 bone biopsies, 35 (28.9%) cases are non- neoplastic, 77 (63.6%) are neoplastic and 9 (7.4%) were inadequate for evaluation. The incidence of benign lesions are more than malignant with 51(66.2%) and 26(33.7%) cases respectively. Chronic osteomyelitis is the most common non-neoplastic lesion. Giant cell tumor and osteosarcoma are common benign and malignant lesions respectively. Femur is the common bone involved and metaphysis, the commonest site. The maximum numbers of cases are in the age group between 11-30 years with male preponderance.
Conclusion: Though bone lesions are less common, if viewed in perspective of clinico-radiology and histopathology, correct diagnosis can be reached.
Key-words- Bone lesions, Chronic osteomyelitis, Osteosarcoma, Giant cell tumor, Histopathology
This document summarizes a clinical trial that examined the effects of intra-articular injection of autologous microfragmented fat tissue on proteoglycan synthesis in patients with knee osteoarthritis. Seventeen patients with knee osteoarthritis received injections of microfragmented adipose tissue containing adipose-derived mesenchymal stem cells. Magnetic resonance imaging and biochemical analysis were used to assess proteoglycan content and glycosaminoglycan levels in cartilage at baseline and over 12 months following treatment. Results indicated that glycosaminoglycan content in hyaline cartilage increased following treatment, as measured by magnetic resonance imaging. This suggests the treatment increased proteoglycan synthesis in osteoarthritic cartilage. No evidence of chondrotoxicity from the treatment
This study investigated using microribbon (μRB) scaffolds to support chondrogenesis of adipose-derived stem cells (ADSCs) for cartilage regeneration. The μRB scaffolds were macroporous and gelatin-based, while conventional hydrogel (HG) scaffolds lacked macroporosity. ADSCs encapsulated in μRB scaffolds attached, spread, and proliferated more than in HG scaffolds. After 3 weeks of culture, ADSCs in μRB scaffolds deposited more interconnected type II collagen and sulfated glycosaminoglycans (sGAG), and the resulting neocartilage had a higher compressive modulus than ADSCs in HG scaffolds. The enhanced chondrogenesis and mechanical properties of
The document provides guidelines for non-clinical evaluation of osteoporosis drugs. It recommends conducting long-term bone quality studies in two animal species to evaluate effects on bone turnover, mass, density, structure, and strength. Studies should be designed to support clinical development and be submitted for FDA review. Bone quality cannot be directly assessed, but nonclinical studies provide indirect measures of strength determined by both bone mass and quality.
Intra-Articular Administration of Autologous Micro-Fragmented Adipose Tissue in Dogs with Spontaneous Osteoarthritis: Safety, Feasibility, and Clinical Outcomes
OFFER ZEIRA,a SIMONE SCACCIA,a LETIZIA PETTINARI,a ERICA GHEZZI,a NIMROD ASIAG,a LAURA MARTINELLI,a DANIELE ZAHIRPOUR,a MARIA P. DUMAS,a MARTIN KONAR,a DAVIDE M. LUPI,a LAURENCE FIETTE,b LUISA PASCUCCI,c LEONARDO LEONARDI,c ALISTAIR CLIFF,d GIULIO ALESSANDRI,e AUGUSTO PESSINA,f DANIELE SPAZIANTE,g MARINA ARALLAa
ABSTRACT Similar to the disease affecting humans, osteoarthritis (OA) is a painful musculoskeletal condition affecting 20% of the adult canine population. Several solutions have been proposed, but the results achieved to date are far from being satisfactory. New approaches, such as intra-articular delivery of cells (including mesenchymal stromal cells), have been proposed. Among the many sources, the adipose tissue is considered very promising. We evaluated the safety, feasibility, and efficacy of a single intra-articular injection of autologous and micro-fragmented adipose tissue (MFAT) in 130 dogs with spontaneous OA. MFAT was obtained using a minimally invasive technique in a closed system and injected in the intra- and/or peri-articular space. Clinical outcomes were determined using orthopedic examination and owners’ scores for up to 6 months. In 78% of the dogs, improvement in the orthopedic score was registered 1 month after treatment and continued gradually up to 6 months when 88% of the dogs improved, 11% did not change, and 1% worsened compared with baseline. Considering the owners’ scores at 6 months, 92% of the dogs significantly improved, 6% improved only slightly, and 2% worsened compared with baseline. No local or systemic major adverse effects were recorded. The results of this study suggest that MFAT injection in dogs with OA is safe, feasible, and beneficial. The procedure is time sparing and cost-effective. Post injection cytological investigation, together with the clinical evidence, suggests a long-term pain control role of this treatment. The spontaneous OA dog model has a key role in developing successful treatments for translational medicine. STEM CELLS TRANSLATIONAL MEDICINE 2018;00:1–10
This document discusses stem cells and their potential applications in orthopedics. It begins with an overview of stem cell classifications and sources, including embryonic stem cells, induced pluripotent stem cells, and adult stem cells like mesenchymal stem cells derived from bone marrow. The document then focuses on the properties and differentiation potential of mesenchymal stem cells, describing their use in treating conditions like osteonecrosis, cartilage defects, spinal cord injuries, and intervertebral disc regeneration. It presents several case studies on using bone marrow concentrate containing mesenchymal stem cells for avascular necrosis. In summary, the document reviews stem cell types and their emerging role in regenerative orthopedic therapies.
Bioactive Nanoparticle Materials for Bone Tissue RegenerationKathleen Broughton
The document discusses bioactive scaffolds for bone tissue regeneration using emerging nano-materials. It outlines that bone regeneration is a growing medical need and describes criteria for effective bone regeneration scaffolds. The focus is on comparing porous nano-materials in terms of porosity and mechanical strength. Formulas for calculating porosity, compressive strength, and degradation are provided to analyze scaffold materials.
This document discusses osteoporosis treatment in patients with chronic kidney disease (CKD). It notes that while CKD patients have a high risk of fracture similar to postmenopausal osteoporosis, CKD-mineral and bone disorder (CKD-MBD) is more complex. Evaluating fracture risk in CKD patients is challenging as laboratory tests, bone turnover markers, and imaging modalities all have limitations. Bone biopsy remains the gold standard but has limitations for use in clinical practice. Treatment should be based on the underlying pathophysiology and more research is needed on fracture outcomes in CKD-MBD patients.
A D I S D R U G E V A L U A T I O NDenosumab A Review of .docxransayo
A D I S D R U G E V A L U A T I O N
Denosumab: A Review of its Use in Postmenopausal Women
with Osteoporosis
Lesley J. Scott
Published online: 17 June 2014
� Springer International Publishing Switzerland 2014
Abstract Subcutaneous denosumab (Prolia� [USA,
Europe]; Pralia
�
[Japan]) once every 6 months is indi-
cated in several countries for the treatment of postmen-
opausal women with osteoporosis at increased or high
risk for fractures (featured indication). In some countries,
it is also indicated for use in postmenopausal women who
have failed or are intolerant to other osteoporosis treat-
ments. In several international, phase III trials (B3 years’
duration) involving more than 12,000 women with post-
menopausal osteoporosis or low bone mineral density
(BMD), including Asian studies, denosumab was an
effective and generally well tolerated treatment. Relative
to placebo, denosumab treatment significantly reduced the
risk of vertebral, nonvertebral and hip fractures and
increased BMD at all skeletal sites evaluated, including
the lumbar spine and total hip. Furthermore, the benefits
of denosumab treatment were generally evident after the
first dose and were maintained during up to 8 years of
treatment in an ongoing extension study. The tolerability
profile of denosumab during this extension phase was
consistent with that observed during the initial 3-year
FREEDOM trial. At 12 months, denosumab treatment
increased BMD at the total hip, lumbar spine and/or
femoral neck and reduced markers of bone turnover to a
significantly greater extent than oral bisphosphonates in
women who were essentially bisphosphonate-naive and in
those who had switched from alendronate to denosumab
treatment. Further clinical experience, including an
ongoing postmarketing safety study, will more fully
define the long-term safety of denosumab. In the mean-
time, denosumab is an important option for the treatment
of women with postmenopausal osteoporosis at increased
or high-risk of fractures, including in women at increased
risk of fracture who are unable to take other osteoporosis
treatments.
Denosumab in postmenopausal women with osteo-
porosis: a summary
Human monoclonal antibody targeting RANKL, a
key mediator of bone resorption
Relative to placebo, denosumab reduces the
incidence of vertebral, nonvertebral and hip fractures
Reduces bone resorption, increases bone mineral
content, bone mass and bone strength
Increases BMD to a significantly greater extent than
oral alendronate, ibandronate or risedronate
Generally well tolerated (B8 years treatment), with
most adverse events of mild to moderate severity;
long-term safety studies are ongoing
The manuscript was reviewed by: J-P. Devogelaer, Universite
Catholique de Lovain, Service de Rheumatologie, Cliniques
Universitaires Saint-Luc, Brussels, Belgium; M. Kleerekoper,
University of Toledo Medical School, Department of Internal
Medicine, Endocrinology Division, Ru.
In this study of 277 post-menopausal women, the researchers found:
1) Higher bone mineral density was associated with increased severity of disc space narrowing at both the lumbar spine and femoral sites.
2) There was no association found between bone mineral density and severity of osteophytes.
3) Biochemical markers of bone resorption (CTX levels) decreased with increased severity of disc space narrowing, but were not associated with osteophyte severity. This suggests disc space narrowing may have a protective effect against bone loss through decreased bone resorption.
This study analyzed data from a clinical trial of once-weekly teriparatide therapy for osteoporosis. It found that two thresholds - the least significant change (LSC) criterion and achieving a bone mineral density above -2.5 standard deviations from the young adult mean - were useful indicators of treatment success. Using these thresholds, the study found treatment success rates of 79.2% for the lumbar spine and 44.1% for the femoral neck at 72 weeks of teriparatide therapy. Achieving the treatment success thresholds, especially at the femoral neck, was associated with a lower incidence of vertebral fractures.
This document provides an overview and highlights of trends in rheumatology from 2012. It discusses updated guidelines and recommendations for osteoporosis management, the approval and use of belimumab for systemic lupus erythematosus, rituximab for ANCA associated vasculitis, tocilizumab for rheumatoid arthritis, and collagenase clostridium histolyticum for Dupuytren's contracture. It also reviews musculoskeletal ultrasound, challenges with treatment adherence, and new data on bisphosphonates, denosumab, teriparatide, and other drugs.
Journal of Pediatrics & Child Health Care is an open access, peer reviewed, scholarly journal dedicated to publish articles covering all areas of Pediatrics & Child Health.
The journal aims to promote research communications and provide a forum for doctors, researchers, physicians and healthcare professionals to find most recent advances in all areas of Pediatrics. Journal of Pediatrics & Child Health Care accepts original research articles, reviews, mini reviews, case reports and rapid communication covering all aspects of pediatrics.
Journal of Pediatrics & Child Health Care strongly supports the scientific up gradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group also brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Derick Adams proposes individualizing dosing of the osteoporosis drug denosumab based on a patient's bone physiology rather than a standard every 6 months schedule. Individualizing dosing could reduce over-suppression of bone turnover and lower the risk of adverse effects like atypical fractures. A patient would receive another denosumab dose if bone turnover markers are not suppressed by 30-50% of baseline, BMD declines, or a fracture occurs. This approach could lower healthcare costs by avoiding unnecessary doses but would need to be tested in a clinical trial to evaluate outcomes like fractures and adverse events compared to standard dosing. Concerns include bone turnover increasing above baseline after stopping denosumab and variability in marker assays.
Denosumab is a potent monoclonal antibody which inactivates
the RANK ligand. Inactivation of RANK ligand leads to the
inhibition of osteoclast activity and maturation which decreases
bone resorption. Denosumab is a potent antiresorptive that has been shown to dramatically suppress bone turnover markers, maintain bone mineral density, and prevent fractures
This systematic review and meta-analysis investigated the rate of soft tissue complications following guided bone regeneration (GBR) for ridge augmentation. The overall weighted complication rate was 16.8% based on 15 studies included in the quantitative analysis. When considering membrane type, resorbable membranes had a weighted complication rate of 18.3% while nonresorbable membranes had a rate of 17.6%, indicating membrane type did not significantly affect the complication rate. Soft tissue lesions were reported from 1 week to 6 months post-operatively. The review concluded that soft tissue complications after GBR are common, occurring in around 16.8% of cases, and technique sensitivity in soft tissue management may be important to avoid complications and ensure bone regenerative
This document provides an updated definition and guidelines for medication-related osteonecrosis of the jaw (MRONJ) from the American Association of Oral and Maxillofacial Surgeons (AAOMS). It recommends changing the term from bisphosphonate-related osteonecrosis of the jaw (BRONJ) to MRONJ to include cases involving other antiresorptive and antiangiogenic medications. It defines MRONJ as exposed bone in the jaw for over 8 weeks in a patient taking these medications, without radiation or metastasis to the jaw. The document discusses risk factors, potential mechanisms including inhibited bone remodeling and inflammation/infection, and provides guidance on prevention and management based on disease stage.
Stem cell therapy was examined for early stage avascular necrosis of the femoral head in pre-clinical and clinical studies:
- Pre-clinical studies using animal models found stem cell therapy improved bone formation and angiogenesis compared to core decompression alone, based on histological and imaging analyses.
- Clinical studies including randomized controlled trials and case series found stem cell therapy improved patient reported outcomes compared to core decompression alone, but did not significantly impact time to hip replacement. However, studies had inconsistencies in stem cell dose and disease severity assessed.
- Routine use of stem cell therapy will require further research optimizing dose and quality of treatment, as well as confirming delays in hip replacement.
This document provides an introduction and methods section for a meta-analysis comparing the effectiveness of three treatments for myelodysplastic syndrome (MDS): epigenetic therapy, chemotherapy, and bone marrow transplant. The methods describe how studies were identified and selected for each treatment from various databases. Key criteria for study inclusion were described, such as median patient age, year of publication, and reporting of results in terms of remission rates. The selected studies for each treatment were then compiled into tables to analyze and compare the treatments' effectiveness based on outcomes like complete remission rates.
The effect of cigarette smoking and native bone heigthBerenice Gomes
This study examined the effect of cigarette smoking and residual native bone height on the survival of dental implants placed immediately in grafted sinuses. The study reviewed records of 75 patients who received 155 implants. Implant survival rates after 12 months were significantly lower for smokers (79%) compared to non-smokers (87%). Analysis also showed smoking had a more significant negative effect on implant survival when the preoperative bone height was less than 4 mm, with survival rates of 82.4% for non-smokers and 60% for smokers. The study concludes smoking should be considered a high risk factor for implants placed immediately in grafted sinuses, especially in areas of limited bone height.
CLINICAL EVALUATION OF THE EFFECT OF OMEGA-3 FATTY ACIDS ON OSTEOPOROTIC FEMA...Mohamed A. Galal
Mohamed A. Galal ; Mushira A. Dahaba, ; Basma M. Zaki
and Hanaa M. Elshenawy. CLINICAL EVALUATION OF THE EFFECT OF OMEGA-3 FATTY ACIDS ON OSTEOPOROTIC FEMALES HAVING CHRONIC PERIODONTITIS. Cairo Dental Journal (30)Number (1), 1:10January, 2014.
A randomized controlled_trial_of_four_doses_of_transdermal_estradiol_for_prev...manelle gutierrez
This randomized controlled trial tested the effects of four doses of transdermal estradiol (0.025 mg/day, 0.05 mg/day, 0.06 mg/day, and 0.1 mg/day) on preventing bone loss in postmenopausal women compared to a placebo. At 24 months, all doses of estradiol resulted in statistically significant increases in bone mineral density at the spine and hip compared to decreases seen with placebo. The lowest dose of 0.025 mg/day increased spine bone mineral density by 2.37% and hip bone mineral density by 0.26% compared to decreases of 2.49% and 2.04% respectively with placebo. This study demonstrates that even the
This document provides an overview of medication-related osteonecrosis of the jaw (MRONJ), including descriptions of antiresorptive and antiangiogenic medications, diagnostic criteria, theories of pathophysiology, risk estimates, and management strategies. It discusses bisphosphonates, denosumab, tyrosine kinase inhibitors, diagnostic criteria requiring exposed bone for over 8 weeks, and proposed mechanisms including inhibition of bone remodeling, inflammation, angiogenesis, and immune dysfunction. Risk factors include medication type/duration, dentoalveolar surgery, oral disease, anatomy, and systemic factors. Management involves preventive dental treatment and is based on clinical staging from asymptomatic exposed bone to extensive necrosis.
A comparative study on the clinical and functional outcome of limb salvage su...NAAR Journal
The aim of this study was to analyze the survival, recurrence, complications as well as the quality of life (QOL) in tibial osteosarcoma (OSA) patients managed by limb salvage surgery (LSS), either by a prosthesis, resection or graft or by amputation. 106 tibial osteosarcoma patients were enrolled where 39 had custom-designed endoprosthetic arthroplasty (LSS1), 36 underwent resection and bone graft (LSS2) while only 31 underwent amputation. A Comparison was done based on post-operative survival rates, postoperative recurrence, and complications. The impact of the patient’s QOL was also evaluated.
Everything you need to know about moa of bone targeted agents amgen 2017Mohamed Abdulla
This document summarizes key information about giant cell tumor of bone (GCTB) and a phase II study of the RANK ligand inhibitor denosumab for treatment of GCTB. The study showed that nearly all GCTB patients treated with denosumab had stable disease or an objective response, with few experiencing disease progression. Histological analysis found that denosumab significantly reduced or eliminated RANK-positive tumor giant cells in GCTB tissue specimens. These results suggest that denosumab is an effective treatment that stabilizes disease in the majority of GCTB patients.
The USPSTF guideline addresses screening for osteoporosis and vitamin D supplementation. For osteoporosis screening, there is convincing evidence that bone measurement tests accurately detect osteoporosis. Clinical risk assessment tools are moderately accurate in identifying risk. One study found screening reduced hip fractures but not other fractures. Drug therapies reduce fractures in women with osteoporosis, but evidence is lacking for men. Potential harms of screening are small. For vitamin D, evidence is insufficient on supplementation to prevent falls in adults, with potential harms including toxicity. More research is needed on screening men for osteoporosis and on vitamin D supplementation.
Joker Wigs has been a one-stop-shop for hair products for over 26 years. We provide high-quality hair wigs, hair extensions, hair toppers, hair patch, and more for both men and women.
Chandrima Spa Ajman is one of the leading Massage Center in Ajman, which is open 24 hours exclusively for men. Being one of the most affordable Spa in Ajman, we offer Body to Body massage, Kerala Massage, Malayali Massage, Indian Massage, Pakistani Massage Russian massage, Thai massage, Swedish massage, Hot Stone Massage, Deep Tissue Massage, and many more. Indulge in the ultimate massage experience and book your appointment today. We are confident that you will leave our Massage spa feeling refreshed, rejuvenated, and ready to take on the world.
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PET CT beginners Guide covers some of the underrepresented topics in PET CTMiadAlsulami
This lecture briefly covers some of the underrepresented topics in Molecular imaging with cases , such as:
- Primary pleural tumors and pleural metastases.
- Distinguishing between MPM and Talc Pleurodesis.
- Urological tumors.
- The role of FDG PET in NET.
Gemma Wean- Nutritional solution for Artemiasmuskaan0008
GEMMA Wean is a high end larval co-feeding and weaning diet aimed at Artemia optimisation and is fortified with a high level of proteins and phospholipids. GEMMA Wean provides the early weaned juveniles with dedicated fish nutrition and is an ideal follow on from GEMMA Micro or Artemia.
GEMMA Wean has an optimised nutritional balance and physical quality so that it flows more freely and spreads readily on the water surface. The balance of phospholipid classes to- gether with the production technology based on a low temperature extrusion process improve the physical aspect of the pellets while still retaining the high phospholipid content.
GEMMA Wean is available in 0.1mm, 0.2mm and 0.3mm. There is also a 0.5mm micro-pellet, GEMMA Wean Diamond, which covers the early nursery stage from post-weaning to pre-growing.
This particular slides consist of- what is Pneumothorax,what are it's causes and it's effect on body, risk factors, symptoms,complications, diagnosis and role of physiotherapy in it.
This slide is very helpful for physiotherapy students and also for other medical and healthcare students.
Here is a summary of Pneumothorax:
Pneumothorax, also known as a collapsed lung, is a condition that occurs when air leaks into the space between the lung and chest wall. This air buildup puts pressure on the lung, preventing it from expanding fully when you breathe. A pneumothorax can cause a complete or partial collapse of the lung.
Letter to MREC - application to conduct studyAzreen Aj
Application to conduct study on research title 'Awareness and knowledge of oral cancer and precancer among dental outpatient in Klinik Pergigian Merlimau, Melaka'
TEST BANK For Accounting Information Systems, 3rd Edition by Vernon Richardso...rightmanforbloodline
TEST BANK For Accounting Information Systems, 3rd Edition by Vernon Richardson, Verified Chapters 1 - 18, Complete Newest Version
TEST BANK For Accounting Information Systems, 3rd Edition by Vernon Richardson, Verified Chapters 1 - 18, Complete Newest Version
TEST BANK For Accounting Information Systems, 3rd Edition by Vernon Richardson, Verified Chapters 1 - 18, Complete Newest Version
Michigan HealthTech Market Map 2024. Includes 7 categories: Policy Makers, Academic Innovation Centers, Digital Health Providers, Healthcare Providers, Payers / Insurance, Device Companies, Life Science Companies, Innovation Accelerators. Developed by the Michigan-Israel Business Accelerator
Let's Talk About It: Breast Cancer (What is Mindset and Does it Really Matter?)bkling
Your mindset is the way you make sense of the world around you. This lens influences the way you think, the way you feel, and how you might behave in certain situations. Let's talk about mindset myths that can get us into trouble and ways to cultivate a mindset to support your cancer survivorship in authentic ways. Let’s Talk About It!
The facial nerve, also known as cranial nerve VII, is one of the 12 cranial nerves originating from the brain. It's a mixed nerve, meaning it contains both sensory and motor fibres, and it plays a crucial role in controlling various facial muscles, as well as conveying sensory information from the taste buds on the anterior two-thirds of the tongue.
Comprehensive Rainy Season Advisory: Safety and Preparedness Tips.pdfDr Rachana Gujar
The "Comprehensive Rainy Season Advisory: Safety and Preparedness Tips" offers essential guidance for navigating rainy weather conditions. It covers strategies for staying safe during storms, flood prevention measures, and advice on preparing for inclement weather. This advisory aims to ensure individuals are equipped with the knowledge and resources to handle the challenges of the rainy season effectively, emphasizing safety, preparedness, and resilience.
We are one of the top Massage Spa Ajman Our highly skilled, experienced, and certified massage therapists from different corners of the world are committed to serving you with a soothing and relaxing experience. Luxuriate yourself at our spas in Sharjah and Ajman, which are indeed enriched with an ambiance of relaxation and tranquility. We could confidently claim that we are one of the most affordable Spa Ajman and Sharjah as well, where you can book the massage session of your choice for just 99 AED at any time as we are open 24 hours a day, 7 days a week.
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International Cancer Survivors Day is celebrated during June, placing the spotlight not only on cancer survivors, but also their caregivers.
CANSA has compiled a list of tips and guidelines of support:
https://cansa.org.za/who-cares-for-cancer-patients-caregivers/
LGBTQ+ Adults: Unique Opportunities and Inclusive Approaches to CareVITASAuthor
This webinar helps clinicians understand the unique healthcare needs of the LGBTQ+ community, primarily in relation to end-of-life care. Topics include social and cultural background and challenges, healthcare disparities, advanced care planning, and strategies for reaching the community and improving quality of care.
About this webinar: This talk will introduce what cancer rehabilitation is, where it fits into the cancer trajectory, and who can benefit from it. In addition, the current landscape of cancer rehabilitation in Canada will be discussed and the need for advocacy to increase access to this essential component of cancer care.
3. 44 L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52
Table 1
Medline search strategy.
# Search strategy
1 (((((((((((“OP”[Mesh] OR Osteoporoses OR OP, Post-Traumatic OR OP, Post Traumatic OR Post-Traumatic Osteoporoses OR Post-Traumatic OP OR
OP, Senile OR Osteoporoses, Senile OR Senile Osteoporoses OR Senile OP OR OP, Age-Related OR OP, Age Related OR Bone Loss, Age-Related OR
Age-Related Bone Loss OR Age-Related Bone Losses OR Bone Loss, Age Related OR Bone Losses, Age-Related OR Age-Related OP OR Age Related OP
OR Age-Related Osteoporoses OR Osteoporoses, Age-Related)) OR (“OP, Postmenopausal”[Mesh] OR Perimenopausal Bone Loss OR Bone Loss,
Postmenopausal OR Bone Losses, Postmenopausal OR Postmenopausal Bone Losses OR OP, Post-Menopausal OR Osteoporoses, Post-Menopausal
OR OP, Post Menopausal OR Post-Menopausal Osteoporoses OR Post-Menopausal OP OR Postmenopausal OP OR Osteoporoses, Postmenopausal
OR Postmenopausal Osteoporoses OR Bone Loss, Perimenopausal OR Bone Losses, Perimenopausal OR Perimenopausal Bone Losses OR
Postmenopausal Bone Loss)) OR (“Female Athlete Triad Syndrome”[Mesh] OR Female Athlete Triad)) OR (“Decalcification, Pathologic”[Mesh] OR
Decalcification, Pathological OR Pathological Decalcification OR Pathologic Decalcification OR Corticosteroid Induced OP OR glucocorticoid
induced OP OR Idiopathic OP OR Involutional OP OR Juvenile OP OR Primary OP OR Secondary OP OR Bone Fragility Endocrine OP OR Osteoporotic
Decalcification)) OR (“Bone Density”[Mesh] OR Bone Densities OR Density, Bone OR Bone Mineral Density OR Bone Mineral Densities OR Density,
Bone Mineral OR Bone Mineral Content OR Bone Mineral Contents OR BMD)) OR (“Fractures, Bone”[Mesh] OR Broken Bones OR Bone, Broken OR
Bones, Broken OR Broken Bone OR Bone Fractures OR Bone Fracture OR Fracture, Bone)) OR (((((((((((((Bone mineral density[All Fields])) OR (low
bone mass)) OR (low bone mass density)) OR (low bone mineral density)) OR (low bone mass in premenopausal women with depression)) OR
(low bone mass premenopausal women)) OR (low bone)) OR (low bone density)) OR (postmenopausal bone loss)) OR (bone loss OP)) OR (bone
loss postmenopausal)) OR (bone loss))))
2 (((((“denosumab”[Substance Name] OR AMG 162 OR Prolia)) OR (“Antibodies, Monoclonal”[Mesh] OR Monoclonal Antibodies)) OR (“RANK
Ligand/adverse effects”[Mesh] OR “RANK Ligand/antagonists and inhibitors”[Mesh] OR “RANK Ligand/pharmacology”[Mesh] OR “RANK
Ligand/therapeutic use”[Mesh])) OR (“RANK Ligand”[Mesh] OR Osteoclast Differentiation Factor OR Differentiation Factor, Osteoclast OR
Osteoprotegerin Ligand OR RANKL Protein OR Receptor Activator of Nuclear Factor-kappa B Ligand OR Receptor Activator of Nuclear Factor kappa
B Ligand OR TNF Superfamily, Member 11 OR TRANCE Protein OR Tumor Necrosis Factor Ligand Superfamily Member 11 OR Tumor Necrosis
Factor-Related Activation-Induced Cytokine OR Tumor Necrosis Factor Related Activation Induced Cytokine OR OPGL Protein OR Receptor
Activator of Nuclear Factor-kappaB Ligand OR Receptor Activator of Nuclear Factor kappaB Ligand)))
3 (((((((((((((((((((((((“adverse effects”[Subheading] OR side effects OR undesirable effects OR injurious effects)) OR (“Safety”[Mesh] OR Safeties)) OR
(“Drug Toxicity”[Mesh] OR Drug Toxicities ORToxicities, Drug OR Toxicity, Drug OR Drug Safety OR Safety, Drug OR Adverse Drug Reaction OR
Adverse Drug Reactions OR Drug Reaction, Adverse OR Drug Reactions, Adverse OR Reaction, Adverse Drug OR Reactions, Adverse Drug OR
Adverse Drug Event OR Adverse Drug Events OR Drug Event, Adverse OR Drug Events, Adverse OR Event, Adverse Drug OR Events, Adverse Drug))
OR (“toxicity”[Subheading] OR toxic potential OR margin of safety)) OR (drug fatality)) OR (‘drug mortality’ OR ‘fatal adverse drug reaction’ OR
‘fatal adverse reaction’ OR ‘fatal side effect’)) OR (drug mortality OR fatal adverse drug reaction OR fatal adverse reaction OR fatal side effect)) OR
(“poisoning”[Subheading] OR poisonous effects)) OR (“Drug Hypersensitivity”[Mesh] OR Drug Hypersensitivities OR Hypersensitivities, Drug OR
Drug Allergy OR Allergies, Drug OR Drug Allergies OR Hypersensitivity, Drug OR Allergy, Drug)) OR (‘drug sensitivity’ OR ‘drug sensitivity test’ OR
‘drug subsensitivity’ OR ‘drug susceptibility’ OR ‘parasitic sensitivity tests’ OR ‘susceptibility, drug’)) OR (drug sensitivity OR drug sensitivity test
OR drug subsensitivity OR drug susceptibility OR parasitic sensitivity tests OR susceptibility, drug)) OR (sensitivity drug)) OR (“Drug
Interactions”[Mesh] OR Drug Interaction OR Interaction, Drug OR Interactions, Drug)) OR (“drug effects”[Subheading] OR pharmacologic effects
OR effect of drugs)) OR (“Adverse Drug Reaction Reporting Systems”[Mesh] OR Drug Reaction Reporting Systems, Adverse)) OR (’adverse drug
reaction’ OR ‘adverse drug effect’ OR ‘adverse drug eventor adverse effect’ OR ‘adverse reaction’ OR ‘adverse reaction, drug’ OR ‘drug adverse
effect’ OR ‘drug adverse reaction’ OR ‘drug reaction, adverse’ OR ‘drug side effect’)) OR (‘adverse drug reaction’ OR ‘adverse drug effect’ OR
“adverse drug eventor” OR “adverse effect” OR ‘adverse reaction’ OR ‘adverse reaction, drug’ OR ‘drug adverse effect’ OR ‘drug adverse reaction’ OR
‘drug reaction, adverse’ OR ‘drug side effect’)) OR (adverse drug reaction OR adverse drug effect OR “adverse drug eventor” OR “adverse effect” OR
adverse reaction OR adverse reaction, drug OR drug adverse effect OR drug adverse reaction OR drug reaction, adverse OR drug side effect)) OR
(“drug carcinogenicity” OR ‘carcinogenicity, drug induced’)) OR (“drug carcinogenicity” OR carcinogenicity, drug induced)) OR (“drug cytotoxicity”
OR “cytotoxicity, drug”)) OR (“Treatment Outcome”[Mesh] OR Outcome, Treatment OR Rehabilitation Outcome OR Outcome, Rehabilitation OR
Treatment Effectiveness OR Effectiveness, Treatment OR Treatment Efficacy OR Efficacy, Treatment)))
4 ((((((((((“Clinical Trial”[Publication Type] OR “Clinical Trial, Phase I”[Publication Type]) OR Clinical Trial, Phase 1 OR “Clinical Trial, Phase
II”[Publication Type]) AND Clinical Trial, Phase 2 OR “Clinical Trial, Phase III”[Publication Type]) OR Clinical Trial, Phase 3 OR “Clinical Trial, Phase
IV”[Publication Type]) OR Clinical Trial, Phase 4 OR “Controlled Clinical Trial”[Publication Type]) OR “Multicenter Study”[Publication Type]) OR
“Randomized Controlled Trial”[Publication Type])) OR ((((((((“Clinical Trials as Topic”[Mesh] OR Clinical Trial as Topic)) OR (“Clinical Trials, Phase I
as Topic”[Mesh] OR Clinical Trials, Phase I OR Phase 1 Clinical Trials OR Phase I Clinical Trials OR Clinical Trials, Phase 1 OR Evaluation Studies, FDA
Phase I OR Evaluation Studies, FDA Phase 1 OR Microdosing Trials, Human OR Human Microdosing Trial OR Microdosing Trial, Human OR Trial,
Human Microdosing OR Trials, Human Microdosing OR Human Microdosing Trials OR Drug Evaluation, FDA Phase I as Topic OR Drug Evaluation,
FDA Phase I OR Drug Evaluation, FDA Phase 1)) OR (“Clinical Trials, Phase II as Topic”[Mesh] AND *Drug Evaluation, FDA Phase II as Topic OR Drug
Evaluation, FDA Phase 2 as Topic OR Evaluation Studies, FDA Phase II as Topic OR Evaluation Studies, FDA Phase 2 as Topic)) OR (“Clinical Trials,
Phase III as Topic”[Mesh] OR Clinical Trials, Phase 3 as Topic OR Evaluation Studies, FDA Phase III as Topic OR Drug Evaluation, FDA Phase III as
Topic OR Drug Evaluation, FDA Phase 3 as Topic OR Evaluation Studies, FDA Phase 3 as Topic)) OR (“Clinical Trials, Phase IV as Topic”[Mesh] OR
Clinical Trials, Phase 4 as Topic OR Drug Evaluation, FDA Phase IV as Topic OR Evaluation Studies, FDA Phase 4 as Topic OR Drug Evaluation, FDA
Phase 4 as Topic OR Evaluation Studies, FDA Phase IV as Topic)) OR (“Randomized Controlled Trials as Topic”[Mesh] OR Controlled Clinical Trials,
Randomized OR Clinical Trials, Randomized OR Trials, Randomized Clinical)) OR (“Multicenter Studies as Topic”[Mesh] OR Multicentre Studies as
Topic OR Multicenter Trials OR Multicenter Trial OR Trial, Multicenter OR Trials, Multicenter OR Multicentre Trials OR Multicentre Trial OR Trial,
Multicentre OR Trials, Multicentre))) OR ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical
trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms]))
5 #1 AND #2 AND #3 AND #4
6 Limit #e to humans
Results
A flowchart summarizing the search results is exposed in
Fig. 1. The search strategy identified 518 potentially relevant arti-
cles of which 10 fulfilled the inclusion criteria.8–17 The excluded
articles18–24 and the reasons for exclusion are depicted in Table 2. In
addition, 7 additional articles were identified by hand search,25–31
as well as 8 congresses abstracts.32–39 Table 3 shows the main
characteristics of the 25 included studies.8–17,25–39 Most of them
were high quality RCT, which included more than 10,000 post-
menopausal women, with a mean age range from 59 years to
72 years. Only 1 RCT14 evaluated the efficacy of denosumab in terms
of reduction of risk of new fractures and the rest evaluated changes
in BTMs or BMD. All the studies had been supported by Amgen.
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4. L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52 45
Medline
n=264
Embase
n=231
Cochrane Library
n=23
n=518
Duplicates
n=46
Congresses Abstracts( n=49)
• ECCEO (n=15)
• ASBMR (n=22)
• ACR (n=6)
• EULAR (n=6)
n=472 Excluded by title/abstract (n=455)
• Population (n=319)
• Intervention (n=69)
• Outcome (n=4)
• Design (n=63)
n=17 Excluded (detailed review) n=7
n=10 Hand search n=7
Included n=25
n=8
Fig. 1. Articles retrieved by the search strategies and result of selection and appraisal process. Abbreviations: American College of Rheumatology (ACR), the American Society
for Bone and Mineral Research (ASBMR), the European Congress on Osteoporosis and Osteoarthritis (ECCEO), the International Osteoporosis Foundation (IOF) and the
European League against Rheumatism (EULAR).
Efficacy of denosumab
Bekker9 in a double-blind, placebo-controlled RCT, analyzed the
effect of single dose escalation effect of denosumab, up to 3.0 mg/kg,
which resulted in a dose-dependent, rapid (within 12 h), profound
(up to 84%), and sustained (up to 6 months) decrease in urinary
N-telopeptide (uNTX). At 6 months, denosumab compared with
placebo, showed a greater decrease in the urinary NTX/creatinine
(81% vs 10%) and in serum NTX (56% vs 2%). Bone-specific alka-
line phosphatase (BALP) levels decreased remarkably after the first
month, and intact parathyroid hormone (iPTH) levels increased up
to 3-fold after 4 days in denosumab group, but returned to baseline
levels during the follow-up.
A 2-year double blind, placebo-controlled, dose-ranging
RCT with an open-label arm compared in 412 postmenopausal
women with low BMD, the efficacy and safety of denosumab 14, or
30 mg/ 3 months or denosumab 14, 60, 100, or 210 mg/6 months,
with alendronate 70 mg/week and placebo.10 The first year deno-
sumab increased BMD at the lumbar spine of 3–6.7% (4.6% with
alendronate, −0.8% with placebo), at the total hip of 1.9–3.6% (2.1%
with alendronate, −0.6% with placebo), and at the distal third of
the radius of 0.4–1.3% (−0.5% with alendronate, −2% with placebo).
Reductions in serum C-telopeptide (sCTX) were higher compared
with placebo (p < 0.001). At 24 months, compared with placebo,
all doses of denosumab significantly increased BMD at all skeletal
sites, and compared with alendronate, denosumab was associated
with similar or greater increases in BMD, with the exception of the
14 mg/6 months dose, in which the change in lumbar spine BMD
Table 2
Excluded studies and reason for exclusion.
Article Reason for exclusion
No authors listed 2006 (24) Editorial
No authors listed 2008 (25) Treatment guideline
No authors listed 2009 (26) Editorial
Cummings 2009 (27) Editorial
Ecker-Sclipf 2010 (28) Editorial
Favus 2006 (29) Editorial
Lewiecki 2009 (30) Review
was less (p = 0.020). Compared with placebo, significant reduc-
tions (p < 0.001) in sCTX and urine N-telopeptide/creatinine were
observed for all doses of denosumab except the 14 mg/6 months
group, and reductions in BALP levels were also higher (p < 0.002).
Moreover, reductions in sCTX by alendronate were less than those
observed with the higher doses of denosumab, whereas reduc-
tions in BALP were similar with alendronate and denosumab.15 In a
post hoc analysis, hip scans were performed using dual-energy X-
ray absorptiometry (DEXA) at baseline, 12, and 24 months in 116
patients to evaluate BMD and cross-sectional geometry parameters
at the narrowest segment of the femoral neck, the intertrochanter,
and the proximal shaft. These analyses showed that at 12 and 24
months, denosumab and alendronate improved these parameters
compared with placebo. Denosumab effects were greater than alen-
dronate at the intertrochanteric and shaft sites.8 After that, a 2-year
extension study16 which included 307 patients showed that con-
tinuous denosumab treatment for 4 years, compared with placebo,
was associated with significant increases in BMD at all skeletal sites
(0.001), at the lumbar spine (9.4–11.8%), at total hip (4–6.1%), and
with a sustained reduction of BTMs. Discontinuation of denosumab
led to a BMD decrease of 6.6% (lumbar spine), 5.3% (total hip) within
the first 12 months. Retreatment increased lumbar spine BMD by
9% from original baseline values. Levels of BTM increased upon dis-
continuation and decreased with retreatment. Those on continuous
denosumab followed 2 additional years of treatment that led to
further gains in BMD interval.29 From the extension study base-
line, mean BMD increased at the lumbar spine by 2.9%, total hip by
1.1%, 1/3 radius by 1%, and femoral neck by 1.2%. Six years of con-
tinuous treatment was associated with mean BMD changes from
parent study baseline of 13.3, 6.1, and 1.9% for the lumbar spine,
total hip, and 1/3 radius, respectively, and 5.6% for femoral neck. At
year 6, sCTX remained below parent study baseline with a median
reduction of 54.8% compared with baseline.
In the DEFEND trial, a 2-year double-blind, placebo-controlled
RCT11 332 postmenopausal women with osteopenia received
denosumab 60 mg/6 months or placebo. Compared with placebo,
denosumab significantly increased BMD at lumbar spine (6.5 vs
−0.6%), at the hip, 1/3 radius, and total body (p < 0.001), increased
distal radius volumetric BMD (p < 0.010), improved hip structural
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5. 46 L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52
Table 3
Characteristics of the included studies.
Study Participants Intervention Outcomes Qualitya
Bekker (2004)9
Phase I double blind placebo
controlled RCT
6–9 m follow-up
n = 49 healthy
postmenopausal women,
mean age range 54–63 yr
• Denosumab 0.01 mg/kg →
0.03 mg/kg → 0.1 mg/kg →
0.3 mg/kg → 1 mg/kg → 3 mg/kg
• Placebo
• % change in urinary NTX
• % change in serum NTX
• % change in BALP
• Adverse events
Oxford 1b
Jadad 5
McClung (2006)10
Phase II double blind placebo
controlled RCT with an
open-label arm
1 yr follow-up
n = 412 postmenopausal
women, mean age 62 yr,
with low BMD (T-score
−1.8 to −4 at lumbar spine
or −1.8 to −3.5 at proximal
femur)
• Denosumab 6 mg/3 m;
14 mg/3 m; 30 mg/3 m;
60 mg/6 m; 100 mg/6 m;
210 mg/6 m
• Alendronate 70 mg/w
• Placebo
• % change in BMD at lumbar
spine, femoral neck, total hip,
1/3 radius, and total body
(minus head)
• % change in BTMs
• Adverse events
Oxford 2b
Lewiecki (2007)15
Phase II double blind placebo
controlled RCT with an open
label arm
2 yr follow-up
n = 412 postmenopausal
women, mean age 62 yr,
with low BMD (T-score
−1.8 to −4 at lumbar spine
or −1.8 to −3.5 at proximal
femur)
• Denosumab 6 mg/3 m;
14 mg/3 m; 30 mg/3 m;
60 mg/6 m; 100 mg/6 m;
210 mg/6 m
• Alendronate 70 mg/w
• Placebo
% change in BMD at lumbar
spine, total hip, 1/3 radius, and
total body (minus head)
% change in BTMs
Adverse events
Oxford 2b
Beck (2008)8
Post hoc analysis of phase II
RCT15
1 yr follow-up
n = 116 postmenopausal
women, mean age 62 yr,
with low BMD (lumbar
spine T score −1.8 to −4 or
−1.8 to −3.5 proximal
femur)
• Denosumab 60 mg/6 m
• Alendronate 70 mg/w
• Placebo
% change in hip BMD
cross-sectional geometry
parameters
Oxford 2b
Miller (2008)16
Phase III extension study15
2 yr follow-up
n = 307 postmenopausal
women, mean age 62 yr,
with low BMD (T-score
−1.8 to −4.0 at lumbar
spine or −1.8 to −3.5 at
proximal femur)
• Denosumab 6 mg/6 m
• Denosumab cessation
1st yr→denosumab 6 mg/6 m
the 2nd yr
• Placebo
% change in BMD at lumbar
spine, total hip, 1/3 radius, and
total body
% change in BTMs
Adverse events
Oxford 2b
Miller (2011)29
Ongoing 4-yr, open-label,
extension study of a phase II
RCT15
6 yr follow-up
n = 178 postmenopausal
women with low BMD
(T-score −1.8 to −4.0 at
lumbar spine or −1.8 to
−3.5 at proximal femur)
• Denosumab 60 mg/6 m % change in lumbar spine, hip
and 1/3 radius BMD
% change in BTMs
Adverse events
Oxford 2b
Bone (2008)11
DEFEND study
Phase III double blind
placebo controlled RCT
2 yr follow-up
n = 332 postmenopausal
women, mean age 59 yr,
with lumbar spine BMD
T-scores between −1
and −2.5
• Denosumab 60 mg/6 m
• Placebo
% change in lumbar spine BMD
by DEXA
% change in volumetric BMD of
the distal radius by QCT
% change in total hip, 1/3
radius, total body BMD by
DEXA
Hip structural analysis
% change in BTMs
Adverse events
Oxford 1b
Jadad 4
Genant (2010)26
Post hoc analysis of DEFEND
study
2 yr follow-up
n = 332 postmenopausal
women, mean age 59 yr,
with BMD T-scores
between −1 and −2.5
• Denosumab 60 mg/6 m
• Placebo
% change in volumetric BMD,
volumetric bone mineral
content, cortical thickness,
volume, circumference, and
density-weighted PMI along
distal radius
Adverse events
Oxford 1b
Jadad 4
Bone (2011)31
Off-treatment extension
of DEFEND study
2 yr follow-up
n = 256 postmenopausal
women, mean age 59 yr
with a mean lumbar spine
T score of −1.61
• No treatment • % change in lumbar spine, hip
and 1/3 radius BMD
• % change in BTMs
• Adverse events
Oxford 2b
Brown (2009)12
DECIDE study
Phase III double blind RCT
1 yr follow-up
n = 1189 postmenopausal
women, mean age 64 yr,
with a T-score ≤−2 at the
lumbar spine or total hip
• Denosumab 60 mg/6 m
• Alendronate
70 mg/w + subcutaneous
placebo injections/6 m
% change in BMD in lumbar
spine, total hip, femoral neck,
throcanter, 1/3 radius
% change in BTMs
Adverse events
Oxford 1b
Jadad 5
Kendler (2010)13
STAND study
Phase III double-blind,
double-dummy RCT
1 yr follow-up
n = 504 postmenopausal
women, mean age 67 yr,
with a BMD T-score
between −2 and −4
on alendronate therapy
for at least 6 m
• Denosumab 60 mg/6 m
• Alendronate 70 mg/w
• % change in BMD at lumbar
spine and hip
• Change in BTMs
• Adverse events
Oxford 1b
Jadad 5
Kendler (2011)27
DAPS study
Randomized, open-label,
crossover study
2 yr follow-up
n = 250 postmenopausal
women, mean age 65 yr,
with low BMD
• Denosumab 60 mg/6 m
• Alendronate 70 mg/w
• Treatment adherence
• Preference and satisfaction
with treatment regimen
• Adverse events
Oxford 2a
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6. L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52 47
Table 3 (Continued)
Study Participants Intervention Outcomes Qualitya
Cummings (2009)14
FREEDOM study
Phase III placebo controlled
RCT
3 yr follow-up
n = 7808 women, mean age
72 yr, with BMD T-score
<−2.5 but not <−4 at the
lumbar spine
or total hip
• Denosumab 60 mg/6 m
• Placebo
• New vertebral fracture
• Nonvertebral and hip
fractures
• Adverse events
Oxford 1b
Jadad 4
Eastell (2010)25
FREEDOM subgroup analysis
3 yr follow-up
n = 160 women, mean age
59 yr, with BMD T-score
between −2.5 and −4 at
the lumbar spine or total
hip
• Denosumab 60 mg/6 m
• Placebo
• % patients with BTMs (CTX,
P1NP, TACP-5b and BALP)
below the premenopausal
reference interval
• Adverse events
Oxford 1b
Jadad 4
Rizzoli (2010)33
FREEDOM subgroup analysis
3 yr follow-up
Subgroups of age, race,
body mass index,
creatinine clearance,
region, prior use of
osteoporosis medication,
femoral neck T score,
prevalent vertebral
fracture and prior
nonvertebral fracture
• Denosumab 60 mg/6 m
• Placebo
• New and worsening vertebral
fracture
• Severe and moderate new
vertebral fracture
Oxford 1b
Jadad 4
Boonen (2010)34
FREEDOM subgroup analysis
n = 5667 women at a higher
risk for fracture at the hip
(age ≥75 yr) or vertebrae
(≥2 prevalent vertebral
fractures, moderate/severe
prevalent vertebral
fractures, or both)
• Denosumab 60 mg/6 m
• Placebo
• New vertebral fracture
• Nonvertebral and hip
fractures
Oxford 1b
Jadad 4
Boonen (2011)30
FREEDOM subgroup analysis
3 yr follow-up
Women with multiple
and/or moderate or severe
prevalent vertebral
fractures (n = 759), aged
≥75 yr (n = 2471), and/or
femoral neck BMD T-score
≤−2.5 (n = 2790)
• Denosumab 60 mg/6 m
• Placebo
• New vertebral fracture
• Hip fractures
Oxford 1b
Jadad 4
Keaveney (2010)36
FREEDOM pos hoc analysis
3 yr follow-up
n = 99 women with BMD
T-score <−2.5 but not <−4
at the lumbar spine
or total hip
• Denosumab 60 mg/6 m
• Placebo
• Femoral strength
• L2 vertebral strength
Oxford 1b
Jadad 4
Silverman (2010)32
FREEDOM study
3 yr follow-up
n = 7808 women, mean age
72 yr, with BMD T-score
<−2.5 but not <−4 at the
lumbar spine or total hip
• Denosumab 60 mg/6 m
• Placebo
• Health related quality of life Oxford 1b
Jadad 4
Genant (2010)38
FREEDOM study
3 yr follow-up
n = 81 women, mean age
75 yr, mean BMD T-score
of the total hip −1.85
• Denosumab 60 mg/6 m
• Placebo
• Integral, cortical, subcortical
and trabecular BMD
• Integral, cortical, subcortical
and trabecular BMC
Oxford 1b
Jadad 4
Reid (2010)28
Substudy of STAND
and FREEDOM trials
1–3 yr follow-up
Patients from:
• STAND study (n = 39
women)
• FREEDOM study (n = 103
women)
• STAND (12 m):
◦ Denosumab
◦ Alendronate
• FREEDOM (36 m):
◦ Denosumab
◦ Placebo
• Bone histomorphometry Oxford 2b
Papapoulus (2010)37
FREEDOM extension study
1 yr follow-up
n = 4550 women • Denosumab 60 mg/6 m • % change in BMD at lumbar
spine and hip
• Change in BTMs
• Adverse events
Oxford 2b
Seeman (2010)17
XTREME-CT study
Phase II double blind RCT
1 yr follow-up
n = 247 postmenopausal
women, mean age 60 yr
• Denosumab 60 mg/6 m
• Alendronate 70 mg/w
• Placebo
• Morphologic changes
(HR-pQCT at the distal radius
and distal tibia, QCT at the
distal radius)
• Change in BTMs
Oxford 1b
Jadad 4
Wagman (2010)39
Substudy of DEFEND
and XTREME-CT trials
3 yr follow-up
n = 5 women, mean age
59 yr
• No treatment • Bone histomorphometry
• Change in BTMs
Oxford 4
Abbreviations: mg, milligram; m, month; yr, year; BMD, bone mineral density; m, month; w, week; BALP, bone specific alkaline phosphatase; BMD, bone mineral density; BTMs,
bone turnover markers; DEXA, dual-energy X-ray absorptiometry; CTX, C-telopeptide; NTX, N-telopeptide; PINP, N-terminal propeptide of type 1 procollagen; PMI, polar
moment of inertia; QCT, quantitative computed tomography; TRAP-5b, tartrate-resistant acid phosphatase-5b; HR-pQCT, high-resolution peripheral quantitative computed
tomography.
a
Quality was assessed according to the modification of the Oxford Centre for Evidence-based Medicine Levels of Evidence (March 2009 Update) and Jadad scale when
possible.
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7. 48 L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52
analysis parameters, and significantly suppressed sCTX, tartrate-
resistant acid phosphatase-5b (TRAP-5b), and intact N-terminal
propeptide of type 1 procollagen (PINP). Besides, denosumab sig-
nificantly increased volumetric bone mineral content (BMC) along
the radius (proximal, distal, and ultradistal sections) and bone
strength.26 In a 2 year off-treatment period of DEFEND study,31
BMD decreased at all sites, but those patients who previously had
received denosumab maintained a higher BMD compared with
those on placebo. After denosumab discontinuation, BTM increased
above baseline within 3 months (sCTX) or 6 months (PINP), peaked
at 30 months (sCTX) or 36 months (PINP), and returned to base-
line by month 48. BTM did not significantly change in the placebo
group.
The DECIDE trial, a phase III, 1 year double-blind RCT, compared
denosumab (60 mg/6 months) with oral alendronate (70 mg/week)
in postmenopausal women with low BMD. Denosumab, at the total
hip, significantly increased BMD compared with alendronate (3.5%
vs 2.6%, p < 0.001). Furthermore, significantly greater increases
in BMD were observed with denosumab treatment at all mea-
sured skeletal sites (treatment difference: 0.6% femoral neck; 1.0%
trochanter; 1.1% lumbar spine; 0.6%1/3 radius). Denosumab also
led to significantly greater reduction of BTM.12
The STAND study was a 1-year double-blind, double-dummy
RCT that included 504 postmenopausal women (BMD T-score
between −2.0 and −4.0) who had been on alendronate for at least
6 months. Subjects received alendronate 70 mg/week for 1 month
and then were randomly assigned to continue on alendronate or
denosumab 60 mg/6 months. In denosumab group, total hip BMD
increased by 1.90% vs 1.05% in the alendronate group (p < 0.001).
Similar results were found at the lumbar spine, femoral neck, and
1/3 radius (all p < 0.0130). Median sCTX levels remained close to
baseline in the alendronate group and significantly decreased in
denosumab patients.13
In a 2-year, randomized, crossover study,27 DAPS study, adher-
ence, preference, and satisfaction in 250 patients on denosumab
60 mg/6 months or alendronate 70 mg/week were analyzed. Adher-
ence in the first 12 months was 76.6% for alendronate and 87.3% for
denosumab. Significantly more patients preferred and were more
satisfied with the 6-month injection than with the weekly tablet
(p < 0.001).
The FREEDOM study, a 3-year phase III placebo controlled
RCT14 enrolled 7868 women with osteoporosis and evaluated the
effect of denosumab 60 mg/6 months. As compared with placebo,
denosumab reduced the risk of new radiographic vertebral frac-
ture, cumulative incidence of 2.3% (7.2% placebo), RR = 0.32 (95%
CI 0.26–0.41), a relative decrease of 68%; reduced the risk of
hip fracture, cumulative incidence of 0.7% (1.2% with placebo),
HR = 0.60 (95% CI 0.37–0.97), a relative decrease of 40%; reduced
the risk of nonvertebral fracture, cumulative incidence of 6.5% (8%
with placebo), HR = 0.80 (95% CI 0.67–0.95), a relative decrease of
20%. Denosumab was also associated with a relative increase in
BMD of 9.2% at the lumbar spine and 6% at the total hip, and a
decreased in sCTX levels by 72%. Levels of PINP were also lower
compared with placebo. The estimated number needed to treat
(NNT) to prevent a clinical vertebral fracture with denosumab was
62 (95% CI 46.3–93.8) and for a radiologic vertebral fracture was 22
(95% CI 18.3–27.5), 230 for hip fracture.
A substudy25 of the FREEDOM trial evaluated 160 women in
whom 1 month post-injection, sCTX levels in denosumab group
decreased to levels below the premenopausal reference interval.
The percentage of subjects with sCTX below this interval before
each subsequent injection decreased from 79% to 51%. Besides,
sCTX and PINP remained below the premenopausal reference inter-
val at all time points in 46% and 31% denosumab subjects. With
denosumab, but not placebo, there were significant correlations
between sCTX reduction and BMD increase (r-value: −0.24 to
−0.44). Another subanalysis by subgroups of age, race, body mass
index, creatinine clearance, region, prior use of osteoporosis medi-
cation, femoral neck T score, prevalent vertebral fracture, and prior
nonvertebral fracture found, compared with placebo a reduced
risk of new and worsening vertebral fractures as well as severe
and moderate new vertebral fractures but did not find differences
between subgroups in the efficacy of denosumab in reducing new
vertebral fractures,33 neither in a subgroup of patients at higher
fracture risk.34
Similarly, in another post hoc analysis,30 denosumab, compared
with placebo significantly reduced the risk of new vertebral frac-
tures in women with multiple and/or severe prevalent vertebral
fractures (16.6% placebo vs 7.5% denosumab), the risk of hip frac-
tures in subjects aged ≥75 years (2.3% vs 0.9%) or with a baseline
femoral neck BMD T-score ≤−2.5 (2.8% vs 1.4%).
More subanalyses showed that denosumab significantly
increased femoral strength compared with baseline by 5.4% at
12 months, which continued over time reaching 8.4% at 36 months.
In contrast, placebo decreased femoral strength at 36 months
(−5.4%). The same trends were seen at the spine but changes were
superior: at 36 months, vertebral strength increased by 18.1% with
denosumab and decreased by −4.1% with placebo.36 With regard to
the health-related quality of life, statistically significant differences
between groups were not found.32 An exploratory analysis38 eval-
uated the magnitude of changes from baseline and from placebo in
denosumab subjects with hip Quantitative Computed Tomography
in 81 patients. Over 36 months, the improvements from baseline in
integral hip BMD reached 6.3% and 4.8% for BMC with denosumab,
but decreased with placebo. The differences between groups were
highly significant (p < 0.001) at 12, 24, and 36 months for integral,
cortical, and trabecular BMD and BMC, except for cortical BMD at
12 months (p = 0.066). Along with patients from the STAND study,
142 Iliac crest bone biopsies were collected at 24 and/or 36
months.28 In the FREEDOM study, median eroded surface was
reduced by >80% and osteoclasts were absent from >50% of biopsies
in the denosumab group. Double labeling in trabecular bone was
observed in 94% of placebo bones, and in 19% of those treated with
denosumab. Median bone formation rate was reduced by 97%. In
the STAND trial, indices of bone turnover tended to be lower in the
denosumab group, compared with alendronate. Double labeling in
trabecular bone was seen in 20% of the denosumab biopsies and in
90% of alendronate samples.
The open-label extension of FREEDOM is evaluating the
long-term (10 years) efficacy and safety of denosumab in
4550 patients.37 During the first year, in the denosumab group
lumbar spine BMD increased an extra 2% to a total of 12.1%, and
total hip BMD an additional 0.8% to a total of 6.5%. Reductions in
BTM continued, and 31 osteoporotic nonvertebral fractures were
reported.
The XTREME-CT study17 was a phase II double-blind RCT which
compared morphologic changes of denosumab 60 mg/6 months,
alendronate 70 mg/week and or placebo for 12 months. Mor-
phologic changes were assessed using high-resolution peripheral
quantitative computed tomography at the distal radius and distal
tibia. Alendronate prevented the decline (−0.6% to 2.4%, p = 0.051
to <0.001 vs placebo), and denosumab prevented the decline or
improved these variables (0.3–3.4%, p < 0.001 vs placebo). Changes
in total and cortical BMD were greater with denosumab than with
alendronate (p ≤ 0.024). Similar changes in these parameters were
observed at the tibia.
A small cohort of patients from the DEFEND and XTREME-CT
studies discontinued denosumab treatment for 12–36 months.39
Bone histomorphometry results were compared with results from
placebo-treated subjects in the bone biopsy substudy. BTMs were
similar to pretreatment values, and 100% of biopsy specimens had
evidence of tetracycline labels.
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8. L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52 49
Table 4
Safety of denosumab. Results of the meta-analysis.
RR 95% CI p value I2
(%), p value Studies
All infections 0.97 0.89–1.05 0.441 0%, 0.429 18–20,22
Upper respiratory infections 0.11 0.83–1.49 0.472 0%, 0.860 16,17,21,22
Urinary infections 1.73 1.13–2.64 0.012 17%, 0.298 16,17,21,22
Severe infections 1.26 1.01–1.58 0.041 0%, 0.676 16,17,19–22
Cancer 1.15 0.93–1.41 0.190 0%, 0.920 16,17,19–21
Cardiovascular events 1.01 0.82–1.23 0.982 34%, 0.198 16,20,21
Eczema 1.91 1.43–2.55 <0.001 0%, 0.661 16,17,20
Pain in extremity 1.01 0.76–1.32 0.991 0%, 0.930 16,17,19–23
Abbreviations: RR, risk ratio; CI, confidence interval; I2
, heterogeneity statistic.
Safety of denosumab
Denosumab was in general safe and well tolerated. The most
common adverse events with denosumab were urinary tract infec-
tion, upper respiratory tract infection, and sciatica.
As exposed in the methods section, when possible meta-
analyses were performed (Table 4). We did not find differences
in the risk of any type infections between denosumab (6 mg/
6 months) and alendronate/placebo (irrespectively of the follow-
up). There was no heterogeneity either.12–14,16 The same results
were obtained when data regarding 12-month follow-up were
analyzed [RR = 1.13 (95% CI 0.93–1.38)] (I2 = 0%, p = 0.329),12,13
in a direct comparison between denosumab and alendronate
[RR = 1.11 (95% CI 0.92–1.34)] (I2 = 0%, p = 0.461),12,13,16 and specif-
ically for upper respiratory infections.10,11,15,16 On the other hand,
we detected a significant increase in the risk of urinary infections
in patients treated with denosumab (Fig. 2). However, hetero-
geneity among studies was also found (17%) not statistically
significant though.10,11,15,16 Moreover, there was a slight increase
in the risk of severe infections with denosumab (Fig. 3) and no
heterogeneity.10,11,13–16 But when we performed a meta-analysis
of severe infections during the first 12 months of follow-up, these
differences disappeared [RR = 0.59 (95% CI 0.14–2.40)] (I2 = 0%,
p = 0.761).10,13
Regarding the risk of cancer, cardiovascular events, and pain
in an extremity when we compared denosumab with alen-
dronate/placebo (independently of the time of follow-up) we did
not find differences,10,11,13–17 see Table 4.
And finally, a significant increase in the risk of eczema was
found when we compared denosumab (6 mg/6 months) with
alendronate/placebo (irrespectively of the follow-up) without het-
erogeneity among the included studies (I2 = 0%, p = 0.661).10,11,14
Discussion
Denosumab is a new drug in the treatment of osteoporo-
sis. The rationale of denosumab emerges from recent research
on the pivotal role of RANKL and osteoprotegrin in the control
of osteoclastic proliferation and differentiation.3 Denosumab is
a human monoclonal antibody that binds to RANKL with high
affinity and specificity, and thereby mimics the action of osteo-
protegrin through neutralization of RANKL and the inhibition
of the osteoclastogenesis.23 According to recent clinical studies,
denosumab seems to be effective and safe in the treatment of post-
menopausal osteoporosis.
Therefore, the aim of this systematic literature review was
to analyze the efficacy and safety of denosumab in osteoporo-
sis. For the purpose of this review we included RCT in which the
ID
Study
WeightOR (95% CI)
%%
3
1
2
11.07 (0.67. 183.76)
12.04 (0.65. 224.22)
1.71 (0.38. 7.60)
2.17
1.25
7.56
4
6
5
1.68 (0.49. 5.73)
3.30 (0.77. 14.15)
13.07
25.39
8.46
Overall (I-squared = 17.2%. p = 0.298)
7
(1.73 (1.13. 2.64)
1.07 (0.53. 2.16)
100.0
42.10
(1.00 (0.40. 2.51)
1.00446 1 224
Fig. 2. Comparison of urinary infections between denosumab and placebo/alendronate.
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9. 50 L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52
Study %
1
ID
1.04 (0.05. 20.56)
OR (95% CI)
0.63
Weight
4
3
2
1.96 (0.11. 35.36)
1.96 (0.11. 35.36)
1.04 (0.05. 20.56)
0.62
0.62
0.63
6
7
5
3.21 (0.18. 55.65)
8.41 (1.04. 68.02)
3.21 (0.18. 55.65)
0.61
0.69
0.61
Overall (I-squared = 0.0%. p = 0.676)
10
9
1.26 (1.01. 1.58)
0.33 (0.03. 3.15)
1.20 (0.95. 1.52)
100.00
2.20
93.37
1.0147 1 68
Fig. 3. Comparison of severe infections between denosumab and placebo/alendronate.
comparator was placebo or alendronate as we considered this as
the best way to perform the review.
Overall, denosumab was effective and safe in the treatment of
osteoporosis. It decreased BTMs and increased BMD in both lumbar
spine and hip.
But, interestingly, only one of the selected studies considered
the incidence of new vertebral fractures as its primary endpoint.14
The rest considered fractures as an adverse event or did not eval-
uate this outcome. In recent years, the use of surrogate end points
for antifracture efficacy of new treatments has clearly increased.
Given the availability of effective drugs for osteoporosis, new
placebo-controlled trials for new therapies that enroll moderate to
high-risk patients are sometimes perceived as unethical in many
countries. Alternatives to the current paradigm for establishing
antifracture efficacy of a new drug include the design of placebo-
controlled trials in subjects with low fracture risk, assuming that
the results could be extrapolatedto patients at high risk for fracture;
or RCTs that compare the new drug with an alternative that has
already demonstrated consistent and robust anti fracture efficacy.
This could be achieved with either a non-inferiority or superior-
ity design, in patients with moderate to high fracture risk. In both
cases, the primary endpoint would be new fracture incidence, but
the required sample sizes would be extremely large. This implies
significant costs that may jeopardize the development of new ther-
apeutic agents in osteoporosis.40
Only the FREEDOM trial fulfilled these conditions.14 In this
study, denosumab reduced the risk of new radiographic verte-
bral fractures and also hip and other nonvertebral fractures. The
estimated NNT to prevent a clinical vertebral fracture with deno-
sumab was 62 (95% CI 46.32–93.85) and for a radiologic vertebral
fracture was 22 (95% CI 18.29–27.45),14 quite similar to those
reported for bisphosphonates and other antiosteoporotic drugs.
On the other hand, denosumab NNT to prevent a hip fracture
was higher compared to the registered for other drugs as bis-
phosphonates. This finding could be explained at least in part due
to population differences and fracture risk factors. We could not
calculate the NNT for age subgroups although in the FREEDOM
study it was communicated that its efficacy is similar in higher
fracture risk subgroups.
However, as mentioned above, the efficacy of denosumab
increasing BMD was demonstrated in several trials,8,10–13,15,16,26
which was higher compared with alendronate and placebo. Results
were presented as a percentage of change in the BMD or, in some
cases, as the difference in the percentage of change between the
study groups. This prevented us for performing a meta-analysis.
BMD is the most frequently used intermediate outcome in osteo-
porosis. Prospective studies have shown that women with low BMD
are at an increased risk of clinical fractures.41,42 Some other studies
with denosumab43,44 have concluded that relatively large gains in
total hip BMD might indicate a greater reduction in risk of nonver-
tebral fracture. However, from a clinical perspective, this outcome
is an imperfect proxy for true clinical endpoint. Furthermore, the
benefit of treatment with different agents correlates with different
degrees of differences in BMD.45
Denosumab also reduced bone biomarkers very effectively,
which is dose-dependent and higher compared with other
therapies.9,10,12,25 The assessment of biochemical markers is the
most sensitive method for monitoring acute changes in bone
metabolism. Several studies have shown a good correlation46,47
between predicted and measured BMD for different groups of
patients. Although the role of bone biomarkers in the follow-
up of osteoporotic patients has not fully established yet, they
are extensively used. However, the variability is large and the
predictive ability of markers is not as certain for individual
patients.
With regard to safety issues, denosumab was safe and well
tolerated. The most common adverse events were urinary tract
infection, upper respiratory tract infection, and sciatica. According
to our meta-analysis, there was a slightly increased risk of urinary
infection and eczema. There was also an increased risk of severe
infections, but disappeared when we performed a meta-analysis
during the first 12 months of follow-up. Averse events are probably
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10. L. Silva-Fernández et al. / Reumatol Clin. 2013;9(1):42–52 51
related to the RANKL inhibition, which could affect the immune
response. It is thought that CD4+ T helper cells require RANKL
signaling for activation and priming, an important aspect of cell-
mediated immunity.48 Because of the importance of RANK/RANKL
in immunity, inhibition of this system could potentially make
patients susceptible to infections and cancer. Although we found
only a small and unclear increase of the risk of infections, particu-
lar attention should be given to any effects on the immune system
in patients treated with long-term RANKL inhibition.
Osteonecrosis of the jaw (ONJ) has recently emerged as a serious
adverse event of osteoporosis drugs.49 To date, no ONJ cases with
denosumab have been communicated. Whether ONJ will compli-
cate long-term RANKL inhibition is unknown, but since denosumab
deeply suppresses bone turnover, this issue should be considered
in its post-approval long-term use.
Another consequence of a profound inhibition of bone remod-
eling is the ‘frozen bone’. It leads to an increase of microfractures
and bone fragility. A number of reports of unusual fragility
fractures because of a dynamic bone disease after prolonged alen-
dronate therapy have been published.50,51 Therefore, caution with
prolonged RANKL inhibition should also be taken, although prelim-
inary results are not alarming.35
Other issues like adherence and compliance are also impor-
tant, since they are often low for chronic conditions, especially if
they are asymptomatic like osteoporosis. Among patients receiving
treatment for osteoporosis, approximately half discontinue therapy
within the first six months.52 Analyses of administrative data sug-
gest that more adherence and compliance are required to achieve
antifracture efficacy.53 In the present systematic review, we have
found that, after 12 months of treatment significantly more patients
preferred and were more satisfied with the six-month injection
than with weekly tablets. In case of elderly patients or individuals
with relevant comorbidities and/or patients who require multiple
medications, a twice-yearly subcutaneous injection seems appro-
priate.
In conclusion, denosumab has demonstrated to reduce the inci-
dence of vertebral and nonvertebral fractures in women with
osteoporosis and profoundly inhibits bone metabolism. An increase
in the incidence of urinary infections and eczema has also been
found. The role of this new drug in the therapeutic arsenal for
osteoporosis will be fully established in the coming years.
Responsabilidades éticas
Protección de personas y animales. Los autores declaran que
para esta investigación no se han realizado experimentos en seres
humanos ni en animales.
Confidencialidad de los datos. Los autores declaran que en este
artículo no aparecen datos de pacientes.
Derecho a la privacidad y consentimiento informado. Los
autores declaran que en este artículo no aparecen datos de
pacientes.
Funding
Spanish Society of Rheumatology.
Conflicts of interest
The authors have no conflicts of interest to declare.
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