302 results on '"Socrates E. Papapoulos"'
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2. Increased Bone Resorption during Lactation in Pycnodysostosis
- Author
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Ineke D.C. Jansen, Socrates E. Papapoulos, Nathalie Bravenboer, Teun J. de Vries, and Natasha M. Appelman-Dijkstra
- Subjects
pycnodystostosis ,bone remodeling ,osteoclasts ,cathepsin K ,lactation ,osteocytes ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of multinucleated, but dysfunctional, osteoclasts. Cathepsin K degrades collagen type I and generates N-telopeptide (NTX) and the C-telopeptide (CTX) that can be quantified. Levels of these telopeptides are increased in lactating women and are associated with increased bone resorption. Nothing is known about the consequences of cathepsin K deficiency in lactating women. Here we present for the first time normalized blood and CTX measurements in a patient with pycnodysostosis, exclusively related to the lactation period. In vitro studies using osteoclasts derived from blood monocytes during lactation and after weaning further show consistent bone resorption before and after lactation. Increased expression of cathepsins L and S in osteoclasts derived from the lactating patient suggests that other proteinases could compensate for the lack of cathepsin K during the lactation period of pycnodysostosis patients.
- Published
- 2021
- Full Text
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3. Supplementary Table 2 from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
- Author
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Gabri van der Pluijm, Clemens W.G.M. Löwik, Marco G. Cecchini, Socrates E. Papapoulos, Philippe Clézardin, Slobodan Vukicevic, Richard Bachelier, Rosette Lidereau, Keltouma Driouch, Anne-Marie Cleton-Jansen, Peter ten Dijke, Cyrill Rentsch, Ruth Schwaninger, Ivo Que, Geertje van der Horst, Petra G.M. van Overveld, Nico V. Henriquez, and Jeroen T. Buijs
- Abstract
Supplementary Table 2 from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
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- 2023
4. Supplementary Table 1 from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
- Author
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Gabri van der Pluijm, Clemens W.G.M. Löwik, Marco G. Cecchini, Socrates E. Papapoulos, Philippe Clézardin, Slobodan Vukicevic, Richard Bachelier, Rosette Lidereau, Keltouma Driouch, Anne-Marie Cleton-Jansen, Peter ten Dijke, Cyrill Rentsch, Ruth Schwaninger, Ivo Que, Geertje van der Horst, Petra G.M. van Overveld, Nico V. Henriquez, and Jeroen T. Buijs
- Abstract
Supplementary Table 1 from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
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- 2023
5. Supplementary Methods and Materials from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
- Author
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Gabri van der Pluijm, Clemens W.G.M. Löwik, Marco G. Cecchini, Socrates E. Papapoulos, Philippe Clézardin, Slobodan Vukicevic, Richard Bachelier, Rosette Lidereau, Keltouma Driouch, Anne-Marie Cleton-Jansen, Peter ten Dijke, Cyrill Rentsch, Ruth Schwaninger, Ivo Que, Geertje van der Horst, Petra G.M. van Overveld, Nico V. Henriquez, and Jeroen T. Buijs
- Abstract
Supplementary Methods and Materials from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
- Published
- 2023
6. Data from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
- Author
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Gabri van der Pluijm, Clemens W.G.M. Löwik, Marco G. Cecchini, Socrates E. Papapoulos, Philippe Clézardin, Slobodan Vukicevic, Richard Bachelier, Rosette Lidereau, Keltouma Driouch, Anne-Marie Cleton-Jansen, Peter ten Dijke, Cyrill Rentsch, Ruth Schwaninger, Ivo Que, Geertje van der Horst, Petra G.M. van Overveld, Nico V. Henriquez, and Jeroen T. Buijs
- Abstract
Bone morphogenetic protein 7 (BMP7) counteracts the physiological epithelial-to-mesenchymal transition (EMT), a process that is indicative of epithelial plasticity. Because EMT is involved in cancer, we investigated whether BMP7 plays a role in breast cancer growth and metastasis. In this study, we show that decreased BMP7 expression in primary breast cancer is significantly associated with the formation of clinically overt bone metastases in patients with ≥10 years of follow-up. In line with these clinical observations, BMP7 expression is inversely related to tumorigenicity and invasive behavior of human breast cancer cell lines. Moreover, BMP7 decreased the expression of vimentin, a mesenchymal marker associated with invasiveness and poor prognosis, in human MDA-MB-231 (MDA-231)-B/Luc+ breast cancer cells under basal and transforming growth factor-β (TGF-β)–stimulated conditions. In addition, exogenous addition of BMP7 to TGF-β–stimulated MDA-231 cells inhibited Smad-mediated TGF-β signaling. Furthermore, in a well-established bone metastasis model using whole-body bioluminescent reporter imaging, stable overexpression of BMP7 in MDA-231 cells inhibited de novo formation and progression of osteolytic bone metastases and, hence, their metastatic capability. In line with these observations, daily i.v. administration of BMP7 (100 μg/kg/d) significantly inhibited orthotopic and intrabone growth of MDA-231-B/Luc+ cells in nude mice. Our data suggest that decreased BMP7 expression during carcinogenesis in the human breast contributes to the acquisition of a bone metastatic phenotype. Because exogenous BMP7 can still counteract the breast cancer growth at the primary site and in bone, BMP7 may represent a novel therapeutic molecule for repression of local and bone metastatic growth of breast cancer. [Cancer Res 2007;67(18):8742–51]
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- 2023
7. Supplementary Figure 1 from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
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Gabri van der Pluijm, Clemens W.G.M. Löwik, Marco G. Cecchini, Socrates E. Papapoulos, Philippe Clézardin, Slobodan Vukicevic, Richard Bachelier, Rosette Lidereau, Keltouma Driouch, Anne-Marie Cleton-Jansen, Peter ten Dijke, Cyrill Rentsch, Ruth Schwaninger, Ivo Que, Geertje van der Horst, Petra G.M. van Overveld, Nico V. Henriquez, and Jeroen T. Buijs
- Abstract
Supplementary Figure 1 from Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer
- Published
- 2023
8. Denosumab for the treatment of primary pediatric osteoporosis
- Author
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Polyzois Makras, A. D. Anastasilakis, V. Guarnieri, Stergios A. Polyzos, Socrates E. Papapoulos, and A. Doulgeraki
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musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,Pediatric Osteoporosis ,Vertebral reshaping ,Endocrinology, Diabetes and Metabolism ,Urology ,030209 endocrinology & metabolism ,Bone remodeling ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Back pain ,medicine ,Femoral neck ,Off-label ,business.industry ,Pediatric osteoporosis ,medicine.disease ,Rheumatology ,Denosumab ,medicine.anatomical_structure ,Osteogenesis imperfecta ,Hypercalcemia ,030101 anatomy & morphology ,Secondary osteoporosis ,medicine.symptom ,business ,medicine.drug - Abstract
Primary osteoporosis is rare in children and adolescents and its optimal pharmacological management is uncertain. Bisphosphonates are commonly used while denosumab has only been administered to a few children with osteogenesis imperfecta. We studied a treatment-naive 13.5-year-old boy with severe osteoporosis and multiple vertebral deformities who presented with back pain and difficulty in walking. Causes of secondary osteoporosis were excluded and there were no abnormalities in genes known to cause bone fragility. He was treated with denosumab 60 mg subcutaneously every 3 months for 30 months, and he was pain-free within 6 weeks after the first injection. Lumbar spine BMD and femoral neck BMD increased with treatment by 65.6% and 25.3%, respectively, and deformed vertebrae regained their normal shape; linear growth was not impaired. During the second year of treatment, transient hypercalcemia (maximum 3.09 mmol/l) before the denosumab injection was observed. In conclusion, denosumab was highly effective in this case of primary pediatric osteoporosis, with remarkable clinical and radiological response. Transient hypercalcemia was probably due to amplification of the effect of growth spurt and puberty on bone remodeling by the transient, short-term discontinuation of the drug. Furthermore, our data suggest that mobilization of calcium from treatment-induced sclerotic transverse lines in bone metaphyses may contribute to the development of hypercalcemia.
- Published
- 2021
9. The Duration of Denosumab Treatment and the Efficacy of Zoledronate to Preserve Bone Mineral Density After Its Discontinuation
- Author
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Sandra van Wissen, Natasha M. Appelman-Dijkstra, Elizabeth M. Winter, Athanasios D. Anastasilakis, Polyzois Makras, Stergios A. Polyzos, Socrates E. Papapoulos, and Maria P. Yavropoulou
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Urology ,Context (language use) ,Zoledronic Acid ,Biochemistry ,Drug Administration Schedule ,Bone remodeling ,postmenopausal osteoporosis ,Endocrinology ,Bone Density ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Infusions, Intravenous ,Prospective cohort study ,Osteoporosis, Postmenopausal ,Aged ,Retrospective Studies ,Femoral neck ,Bone mineral ,Lumbar Vertebrae ,Bone Density Conservation Agents ,business.industry ,Biochemistry (medical) ,zoledronate ,denosumab ,Middle Aged ,Discontinuation ,Treatment Outcome ,Denosumab ,medicine.anatomical_structure ,Withholding Treatment ,Cohort ,Female ,Bone Remodeling ,business ,bone mineral density ,bone turnover markers ,Follow-Up Studies ,medicine.drug - Abstract
Context Zoledronate is used to prevent bone loss following denosumab discontinuation but its efficacy differs among studies. Objective To test if the duration of denosumab treatment affects the efficacy of subsequent zoledronate infusion. Methods This multicenter, prospective cohort study, conducted at 2 Greek and 1 Dutch bone centers, included 47 postmenopausal women (n = 47) who received a single zoledronate infusion 6 months after the last denosumab injection and then were followed for 1 year. Twenty-seven women received ≤ 6 denosumab injections (≤ 6 Group) and 20 received > 6 denosumab injections (> 6 Group). The main outcome measure was changes in lumbar spine (LS) bone mineral density (BMD). Results At 12 months LS-BMD values were maintained in the ≤ 6 Group (0.98 ± 0.10 to 0.99 ± 0.9 g/cm2, P = 0.409) but decreased significantly in the > 6 Group (1.0 ± 0.11 to 0.93 ± 0.12 g/cm2, P 6 Group (−7.0%). In the whole cohort, the duration of denosumab treatment was negatively correlated with the percentage change of LS-BMD (rs = −0.669, P Conclusion The duration of denosumab treatment significantly affects the efficacy of subsequent zoledronate infusion to maintain BMD gains. Frequent follow-up of patients treated with denosumab longer than 3 years is advisable as additional therapeutic interventions may be needed.
- Published
- 2021
10. Paget’s Disease of Bone
- Author
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Socrates E. Papapoulos
- Abstract
Paget’s disease of bone is a focal disorder of bone remodelling that progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular, and vascular complications. Paget’s disease affects typically older people, slightly more men than women, and seldom presents before the age of 35 years. Its prevalence increases with age and it affects 1 to 5% of those above 50 years of age. However, only a small proportion of individuals with Paget’s disease comes to clinical attention, most commonly these with symptomatic or severe disease. In some parts of the world it is the second most common bone disorder after osteoporosis, although in recent years its prevalence and severity appeared to decrease. The disease is easily diagnosed and effectively treated but its pathogenesis remains incompletely understood.
- Published
- 2021
11. Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates
- Author
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Neveen A. T. Hamdy, Natasha M. Appelman-Dijkstra, P. D. Sander Dijkstra, B.C.J. Majoor, Marta Fiocco, and Socrates E. Papapoulos
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Urology ,030209 endocrinology & metabolism ,Biochemistry ,Bone remodeling ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Bone pain ,business.industry ,Fibrous dysplasia ,Biochemistry (medical) ,Retrospective cohort study ,medicine.disease ,Procollagen peptidase ,030104 developmental biology ,Denosumab ,Tolerability ,medicine.symptom ,business ,Cohort study ,medicine.drug - Abstract
Context Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete. Objective To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy. Design Case series. Setting Academic center of expertise for rare bone diseases. Patients Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months. Main outcome(s) Sustained reduction of BTMs and bone pain. Results A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated. Conclusion Our results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.
- Published
- 2019
12. Diagnostic et traitement de l’ostéoporose en médecine générale en France : comparaison avec 7 autres pays européens
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J. O’Kelly, Bernard Cortet, Socrates E. Papapoulos, P. Samama, and E. Mac Closkey
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Rheumatology - Published
- 2021
13. Increased bone resorption during lactation in pycnodysostosis
- Author
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Socrates E. Papapoulos, Ineke D. C. Jansen, Natasha M. Appelman-Dijkstra, Teun J. de Vries, Nathalie Bravenboer, and Periodontology
- Subjects
Adult ,0301 basic medicine ,medicine.medical_specialty ,Cathepsin L ,Pycnodysostosis ,030209 endocrinology & metabolism ,lactation ,cathepsin K ,Article ,Catalysis ,Bone resorption ,Bone remodeling ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Multinucleate ,SDG 3 - Good Health and Well-being ,Internal medicine ,Lactation ,medicine ,Cathepsin K ,Humans ,Bone Resorption ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,bone remodeling ,Cathepsin ,business.industry ,Organic Chemistry ,General Medicine ,medicine.disease ,Cathepsins ,Computer Science Applications ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,osteoclasts ,lcsh:Biology (General) ,lcsh:QD1-999 ,Dysplasia ,Female ,pycnodystostosis ,business ,osteocytes - Abstract
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of multinucleated, but dysfunctional, osteoclasts. Cathepsin K degrades collagen type I and generates N-telopeptide (NTX) and the C-telopeptide (CTX) that can be quantified. Levels of these telopeptides are increased in lactating women and are associated with increased bone resorption. Nothing is known about the consequences of cathepsin K deficiency in lactating women. Here we present for the first time normalized blood and CTX measurements in a patient with pycnodysostosis, exclusively related to the lactation period. In vitro studies using osteoclasts derived from blood monocytes during lactation and after weaning further show consistent bone resorption before and after lactation. Increased expression of cathepsins L and S in osteoclasts derived from the lactating patient suggests that other proteinases could compensate for the lack of cathepsin K during the lactation period of pycnodysostosis patients.
- Published
- 2021
14. The osteoporosis treatment gap in patients at risk of fracture in European primary care : a multi-country cross-sectional observational study
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J. O’Kelly, M. Blagden, Juraj Payer, S. Heijmans, Eugene V. McCloskey, Socrates E. Papapoulos, R. Stad, Peyman Hadji, Bernard Cortet, K. Palmer, Edward Czerwiński, and J. Rathi
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0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,FRAX ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,030209 endocrinology & metabolism ,Primary care ,Risk Assessment ,03 medical and health sciences ,Absorptiometry, Photon ,0302 clinical medicine ,Bone Density ,Risk Factors ,Germany ,Internal medicine ,Observational study ,Humans ,Medicine ,Aged ,Bone mineral ,Primary Health Care ,Treatment gap ,business.industry ,medicine.disease ,Fragility fracture ,Rheumatology ,Europe ,Cross-Sectional Studies ,Orthopedic surgery ,Fracture (geology) ,Original Article ,Female ,030101 anatomy & morphology ,business ,Osteoporotic Fractures - Abstract
Summary This study in 8 countries across Europe found that about 75% of elderly women seen in primary care who were at high risk of osteoporosis-related fractures were not receiving appropriate medication. Lack of osteoporosis diagnosis appeared to be an important contributing factor. Introduction Treatment rates in osteoporosis are documented to be low. We wished to assess the osteoporosis treatment gap in women ≥ 70 years in routine primary care across Europe. Methods This cross-sectional observational study in 8 European countries collected data from women 70 years or older visiting their general practitioner. The primary outcome was treatment gap: the proportion who were not receiving any osteoporosis medication among those at increased risk of fragility fracture (using history of fracture, 10-year probability of fracture above country-specific Fracture Risk Assessment Tool [FRAX] thresholds, T-score ≤ − 2.5). Results Median 10-year probability of fracture (without bone mineral density [BMD]) for the 3798 enrolled patients was 7.2% (hip) and 16.6% (major osteoporotic). Overall, 2077 women (55%) met one or more definitions for increased risk of fragility fracture: 1200 had a prior fracture, 1814 exceeded the FRAX threshold, and 318 had a T-score ≤ − 2.5 (only 944 received a dual-energy x-ray absorptiometry [DXA] scan). In those at increased fracture risk, the median 10-year probability of hip and major osteoporotic fracture was 11.2% and 22.8%, vs 4.1% and 11.5% in those deemed not at risk. An osteoporosis diagnosis was recorded in 804 patients (21.2%); most (79.7%) of these were at increased fracture risk. The treatment gap was 74.6%, varying from 53% in Ireland to 91% in Germany. Patients with an osteoporosis diagnosis were found to have a lower treatment gap than those without a diagnosis, with an absolute reduction of 63%. Conclusions There is a large treatment gap in women aged ≥ 70 years at increased risk of fragility fracture in routine primary care across Europe. The gap appears to be related to a low rate of osteoporosis diagnosis. Electronic supplementary material The online version of this article (10.1007/s00198-020-05557-z) contains supplementary material, which is available to authorized users.
- Published
- 2021
15. Incidence of hip and subtrochanteric/femoral shaft fractures in postmenopausal women with osteoporosis in the phase 3 long-term odanacatib fracture trial
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José Fernando Molina Restrepo, Socrates E. Papapoulos, Arthur C. Santora, Rachid Massaad, Anne E. de Papp, Toshitaka Nakamura, Michael R. McClung, D Cohn, Henry G. Bone, David W. Dempster, Mary L. Bouxsein, and Felicia Cosman
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,030209 endocrinology & metabolism ,biochemical markers of bone turnover ,Placebo ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Bone Density ,medicine ,therapeutics ,Humans ,Orthopedics and Sports Medicine ,Femur ,Cumulative incidence ,Osteoporosis, Postmenopausal ,Aged ,Femoral neck ,Bone mineral ,clinical trials ,Bone Density Conservation Agents ,Femur Neck ,Hip Fractures ,business.industry ,Incidence ,Biphenyl Compounds ,Hazard ratio ,medicine.disease ,osteoporosis ,Surgery ,Postmenopause ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Female ,business ,Odanacatib - Abstract
We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged >= 65 years with a bone mineral density (BMD) T-score
- Published
- 2021
16. Impact microindentation assesses cortical bone material properties in humans
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Stamatia Rokidi, Socrates E. Papapoulos, Natalie Bravenboer, Natasha M. Appelman-Dijkstra, Jochen Zwerina, Sonja Gamsjaeger, Eleftherios P. Paschalis, and Pascale Chavassieux
- Subjects
Materials science ,medicine.anatomical_structure ,lcsh:Diseases of the musculoskeletal system ,Endocrinology, Diabetes and Metabolism ,medicine ,Orthopedics and Sports Medicine ,Cortical bone ,lcsh:RC925-935 ,Material properties ,Biomedical engineering - Published
- 2020
17. Impact microindentation measurements correlate with cortical bone material properties measured by Fourier transform infrared imaging in humans
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Sonja Gamsjaeger, Socrates E. Papapoulos, Stamatia Rokidi, Natalie Bravenboer, Eleftherios P. Paschalis, Natasha M. Appelman-Dijkstra, Pascale Chavassieux, and Jochen Zwerina
- Subjects
0301 basic medicine ,Histology ,Bone matrix ,Physiology ,Infrared ,Endocrinology, Diabetes and Metabolism ,FTIR imaging analysis ,030209 endocrinology & metabolism ,Impact micro indentation ,Mineral to matrix content ,Iliac crest ,Material properties ,03 medical and health sciences ,symbols.namesake ,chemistry.chemical_compound ,Fractures, Bone ,0302 clinical medicine ,Bone Density ,Spectroscopy, Fourier Transform Infrared ,medicine ,Cortical Bone ,Humans ,Organic matrix ,Bone mineral strength index ,Pyridinoline ,Fourier Analysis ,Chemistry ,Iliac crest biopsies ,030104 developmental biology ,medicine.anatomical_structure ,Fourier transform ,Correlation analysis ,symbols ,Cortical bone ,Collagen ,Fractures ,Biomedical engineering - Abstract
Bone Material Strength index (BMSi) measured by Impact Microindentation is generally lower in subjects with fragility fractures independently of BMD values. We recently reported that in humans, BMSi values are strongly associated with material properties of subperiosteal mineralized bone surface (local mineral content, nanoporosity, pyridinoline content). In the present study we investigated the relationship of BMSi with material properties of the whole bone cortex, by analyzing thin sections of iliac crest biopsies (N = 12) from patients with different skeletal disorders and a wide range of BMD with or without fractures, by Fourier transform infrared imaging (FTIRI). The calculated parameters were: i) mineral and organic matrix content and their ratio (MM), ii) mineral maturity/crystallinity (MMC) and iii) the ratio of pyridinoline (Pyd) and divalent collagen cross-links (XLR). Results were expressed as images, which were converted to histogram distributions. For each histogram the characteristics recorded were: mean value, mode (most often occurring value), skewness, and kurtosis and their association with BMSi values was examined by correlation analysis. BMSi values were significantly correlated only with MM mean and mode values (r = 0.736, p = 0.0063, and r = 0.855, p = 0.0004, respectively), and with XLR mode values (r = −0.632, p = 0.0274). The results of the present study demonstrate that BMSi values are strongly associated with MM, a metric that corrects the mineral content for the organic matrix content, and may also depend on organic matrix quality. These and our previous observations strongly suggest that BMSi assesses material properties of cortical bone.
- Published
- 2020
18. Pamidronate
- Author
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Socrates E. Papapoulos
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Histology ,Physiology ,Nitrogen ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Osteoporosis ,Pamidronate ,030209 endocrinology & metabolism ,Bone resorption ,Academic institution ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Pharmacokinetics ,Diphosphonates ,business.industry ,Pagers disease ,Bisphosphonate ,medicine.disease ,Paget s disease ,030104 developmental biology ,Nitrogen atom ,Hypercalcemia ,business - Abstract
Pamidronate [3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD)] was the first nitrogen-containing bisphosphonate (N-BP) investigated in clinical studies. In contrast to other clinically used bisphosphonates, pamidronate was discovered and its properties were initially studied in an Academic Institution. On the occasion of the 50th Anniversary of the first publications on the biological effects of bisphosphonates, I review in this article the contribution of Leiden investigators to the development of pamidronate that led to the recognition of the significance of the Nitrogen atom in the side chain of bisphosphonates for their action on bone resorption and to the formulation of principles for the use of N-BPs in the management of patients with different skeletal disorders.
- Published
- 2020
19. Bisphosphonates for Postmenopausal Osteoporosis
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Andrea Giusti and Socrates E. Papapoulos
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0301 basic medicine ,Bone mineral ,medicine.medical_specialty ,Postmenopausal women ,business.industry ,Osteoporosis ,030209 endocrinology & metabolism ,Bone fragility ,Postmenopausal osteoporosis ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,medicine ,business - Published
- 2018
20. Osteoporosis
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Socrates E. Papapoulos, Michael R. McClung, and Paul D. Miller
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medicine.medical_specialty ,Postmenopausal women ,Pharmacological therapy ,business.industry ,Abaloparatide ,Osteoporosis ,Romosozumab ,030209 endocrinology & metabolism ,medicine.disease ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Clinical research ,Physical therapy ,Medicine ,030212 general & internal medicine ,Secondary osteoporosis ,business - Abstract
This chapter focuses on the clinical aspects and management of osteoporosis in postmenopausal women, men, young women, and various forms of secondary osteoporosis. Dual energy X‐ray absorptiometry is an important tool for clinical research, including clinical trials of bisphosphonates and other drugs. There is strong consensus, based on solid clinical trial evidence, that postmenopausal women, and probably older men, who have experienced fragility fractures of the spine and hip are definite candidates for pharmacological therapy, irrespective of other risk factors. Patients with nonhip, nonspine fractures are also at higher risk for fracture and deserve, at least, to be evaluated for other risk factors and as potential candidates for therapy. Finite element analysis of routine CT scans of the hip and spine provides accurate in vivo measurement of skeletal strength. The anticipated availability of abaloparatide and romosozumab will be the first new treatments for osteoporosis.
- Published
- 2018
21. Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway
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Socrates E. Papapoulos and Natasha M. Appelman-Dijkstra
- Subjects
Male ,0301 basic medicine ,Anabolism ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Regulator ,030209 endocrinology & metabolism ,Translational research ,Bioinformatics ,Severity of Illness Index ,Bone and Bones ,Bone remodeling ,03 medical and health sciences ,chemistry.chemical_compound ,Anabolic Agents ,0302 clinical medicine ,Endocrinology ,Osteogenesis ,Bone cell ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Wnt Signaling Pathway ,Aged ,business.industry ,Wnt signaling pathway ,Haplorhini ,Middle Aged ,Prognosis ,medicine.disease ,Rats ,Wnt Proteins ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Sclerostin ,Female ,Bone Remodeling ,business - Abstract
The WNT signalling pathway is a key regulator of bone metabolism, particularly bone formation, which has helped to define the role of osteocytes — the most abundant bone cells — as orchestrators of bone remodelling. Several molecules involved in the control of the WNT signalling pathway have been identified as potential targets for the development of bone-building therapeutics for patients with osteoporosis. Several of these molecules have been investigated in animal models, but only inhibitors of sclerostin (which is produced by osteocytes) have been investigated in phase III clinical studies. Here, we review the rationale for these developments and the specificity and potential off-target actions of WNT-based therapeutics. We also describe the available preclinical and clinical studies and discuss the benefits and risks of using sclerostin inhibitors for the management of patients with osteoporosis. The WNT signalling pathway has been identified as a potential target for the development of therapeutics for osteoporosis. This Review discusses the specificity and potential off-target actions of WNT-based therapeutics and describes the available preclinical and clinical studies.
- Published
- 2018
22. Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study
- Author
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Michael R McClung, Michelle L O'Donoghue, Socrates E Papapoulos, Henry Bone, Bente Langdahl, Kenneth G Saag, Ian R Reid, Douglas P Kiel, Ilaria Cavallari, Marc P Bonaca, Stephen D Wiviott, Tobias de Villiers, Xu Ling, Kurt Lippuner, Toshitaka Nakamura, Jean-Yves Reginster, Jose Adolfo Rodriguez-Portales, Christian Roux, José Zanchetta, Cristiano A F Zerbini, Jeong-Gun Park, KyungAh Im, Abby Cange, Laura T Grip, Norman Heyden, Carolyn DaSilva, Dosinda Cohn, Rachid Massaad, Boyd B Scott, Nadia Verbruggen, Deborah Gurner, Deborah L Miller, Micki L Blair, Adam B Polis, S Aubrey Stoch, Arthur Santora, Antonio Lombardi, Albert T Leung, Keith D Kaufman, Marc S Sabatine, Carlos Alfredo Mautalén, Zulema Man, Jose Ruben Zanchetta, Clelia Haydee Magaril, Philip Sambrook, Piet Geusens, Stefan Goemaere, Ben Hur Albergaria, Cristiano Augusto de Freitas Zerbini, Marise Lazaretti Castro, Luiz Henrique Gregorio, Rumen Stoilov, Anna-Maria I Borissova, Kiril Hristov Hristozov, Nataliya L Temelkova, Ivona Kirilova Daskalova, Stefka Ivanova Kuzmanova, Daniela Yaneva-Bichovska, Anastas Zgurov Batalov, Pablo Riedemann, José Adolfo Rodriguez Portales, Hai Tang, hanmin Zhu, Zhenlin Zhang, Aijun Chao, Yali Hu, Zhiming Liu, Juming Lu, Mingcai Qiu, Xin Gao, Shaofen Zhang, Ling Xu, Weibo Xia, Eryuan Liao, Wenying Yang, Wen Wu, Kerong Dai, Renming Hu, Juan Jose Jaller, Francisco Cabal, José Fernando Molina, Carlos A Cure Cure, Hernan Yupanqui-Lozno, Philippe Chalem, John Londono, Mauricio Abello, Edgardo D Tobias, William Otero, Tatjana Nikolic, Blazenka Miskic, Jan Stepan, Vaclav Vyskocil, Libor Novosad, Jan Slesinger, Pavel Novosad, Erika Vlckova, Ladislav Bortlik, Eva Dokoupilova, Tomas Hala, Jens-Erik Beck Jensen, Kim Torsten Brixen, Bente Lomholt Langdahl, Peter Schwarz, Peter Claes Eskildsen, Pia Agnete Eiken, Anne Pernille Hermann, Jeppe Gram, Maiken Brix Schou, Peter Alexandersen, Bettina Nedergaard, Dolores Magdalena Mejía, Lourdes Estrella De Henriquez, Norka Páez, Casimiro Velazco, Ivo Valter, Kadri-Liina Vahula, Ingrid Kull, Katre Maasalu, Roland Chapurlat, Patrice Fardellone, Claude Laurent Benhamou, Georges Weryha, Volkmar Herkt, Rene Martz, Ruth Nischik, Wolfgang Spieler, Christel Contzen, Dieter Felsenberg, Isolde Frieling, Eike Frahm, Henry Briones, Boris Sandoval, Patricia Barrios, Abraham García, Carlos Avendaño, Magdalena González, Jeremías Guerra, Maria Tuna, Olga Marina Díaz, Eduardo Samayoa, Edgar López, José Raúl Barrera, Mainor Palencia, Mayra Cifuentes, Georgina Alvarado, Miriam López, Nilmo Chavez, Franklin Haase, Ruddy Rivera, Claudio González, Kathryn Tan, Ping Chung Leung, Sheshadri Mandalam, Shailesh Umakant Pitale, Ganapathi Bantwal, Ariachery Chinamma Ammini, Shehla Sajid Akhta Shaikh, Prasanna Kumar Kanakatte Mylariah, Mala Dharmalingam, Satinath Mukhopadhyay, Arpit Jain, Parminder Singh, Naresh Shetty, Srikanta Shamanna Sathyanarayana, Nalini Shah, Manoj Dharam Chadha, Rajendra Bhandankar, Kumaravel Velayutham, Sudha Marwah, Mathew John, Rakesh Kumar Sahay, Silvano Adami, Ranuccio Nuti, Gerolamo Bianchi, Maria Luisa Brandi, Salvatore Minisola, Carmelo Erio Fiore, Alessandro Rubinacci, Hisayuki Miyajima, Hiroo Yamane, Yuji Nakatani, Sumiaki Okamoto, Koji Kuroda, Motoaki Fujimori, Akira Itabashi, Kuniaki Katayama, Satoru Nakajo, Yoshiaki Somekawa, Yoshimitsu Ohsawa, Wataru Tajima, Katsunori Mizuno, Shigeru Mori, Takato Kanabuchi, Hiroyuki Hashizume, Nobuyuki Oka, Kazutoshi Hamada, Motoi Yamaguchi, Fumiki Hirahara, Masaaki Atobe, Yoshiharu Ohtake, Shuichi Ichikawa, Tomoyuki Onishi, Kou Matsumoto, Tetsuro Nakamura, Eishi Shirasawa, Ko Katayama, Mitsugu Takahashi, Tadanori Oguma, Hideo Matsui, Yoshiharu Katoh, Keiichi Shigenobu, Tsutomu Onishi, Masato Shibukawa, Satoshi Ikeda, Kazuhiro Osaka, Ryosuke Kanda, Yoshito Inobe, Masaharu Shigenobu, Morimasa Hasegawa, Tetsuo Yamaji, Yu Miyazaki, Takayasu Ito, Eisuke Nakamura, Shinji Nagai, Sung-Kil Lim, Yoon-Sok Chung, Chan-Soo Shin, Yong-Ki Min, Ghi Su Kim, Hyun Koo Yoon, Moo-Il Kang, Kyu-Hyun Yang, Hyoung Moo Park, In Joo Kim, Dong Jin Chung, Ho Yeon Chung, Sandra Jaundzeikare, Dace Andersone, Agita Medne, Yasser Yaghi, Vidmantas Alekna, Vytautas Kasiulevicius, Irina Purtokaite - Labutiniene, Aurelija Krasauskiene, Jurate Varanaviciene, Vida Basijokiene, Agne Abraitiene, Lina Radzeviciene, Jesus Walliser, Pedro Alberto García Hernández, Maria Frida Araujo, Hilario Ernesto Avila Armengol, Pilar De la Peña, Juan Tamayo, Beatriz Zazueta, Fidencio Cons, Nigel Leslie Gilchrist, Ian Reginald Reid, Robert Leikis, Peter Jones, Joe Gragrath Pradeep Singh, Johan Inge Halse, Unni Syversen, Hans Olav Høivik, Erik Snorre Øfjord, Hans Christian Gulseth, Sigbjørn Elle, Paal Dag Norheim, Armando A. Calvo Quiroz, Pastor A. Cesar Augusto, Manuel Gustavo León Portocarrero, Luis Fernando Vidal Neira, Jose Chavez, Boris Garro Barrera, Rita Kuroiwa Sampei, Bellatín V. Luis Fernando, Rogger Oquelis Cabredo, Sonia Castillo, Agustin Miguel G Morales, Perry Pua Tan, Liberato Antonio C Leagogo, Edward HM Wang, Julie T Li-Yu, Andrzej Z Sawicki, Barbara Stasiuk, Grzegorz Kania, Roman Lorenc, Anna Sidorowicz-Bialynicka, Leszek Szczepanski, Edward Franek, Rafal Filip, Jan Sekula, Tomasz Blicharski, Piotr Leszczynski, Ewa Sewerynek, Tomasz Miazgowski, Andrzej Milewicz, Magda Dabrowska, Jerzy Romaszko, Wojciech Pluskiewicz, Lukasz Wojnowski, Catalin Codreanu, Horatiu Bolosiu, Ruxandra Ionescu, Ioana Zosin, Liviu Macovei, Mihai Bojinca, Florin Radulescu, Simona Pop, Adrian Sarbu, Lidia I Benevolenskaya, Evgeny L Nasonov, Lyudmila Ya Rozhinskaya, Raphael G Oganov, Svetlana S Rodionova, Eugeny Vladimirovich Shlyakhto, Vasiliy Trofimov, Eugeny G Zotkin, Irina E Zazerskaya, Elena N Grineva, Olga Ershova, Olga Lesnyak, Olga D Ostroumova, Svetlana B Malichenko, Eduard G Pikhlak, Valery G Pilyaev, Tatiana Raskina, Elena V Zonova, Valery S Shirinsky, Aleksandar N Dimic, Goran Cobeljic, Svetlana Vujovic, Graham Charlston Ellis, Stanley Lipschitz, Tobias Johannes De Villiers, Albert Jan De Weerd, Tasneem Vally, Yvonne Trinder, Jacobus Ludewikus Coetsee, Charles Pierre Davis, Savithree Nayiager, Frans Stephanus Hough, Louis F Oelofse, Eugene van der Walt, Johannes Jurgens Lombaard, Suzanne Blignaut, Uttam Govind, Leon Frederik Fouche, Dawid Stephanus Kruger, Johannes Paul Dalmeyer, Mada M Ferreira, Alejandro Escudero-Contreras, Manuel Muñoz Torres, Federico Hawkins Carranza, Jose Luis Perez Castrillon, Juan Antonio García Meijide, Esteban Jodar Gimeno, Santiago Palacios Gil-Antuñana, Luis de Teresa Parreno, Emilio Martín Mola, Carmen Alvarez Sanchez, Keh-Sung Tsai, Shih-Te Tu, Jung-Fu Chen, Oscar Kuang-Sheng Lee, Wen-Wei Hsu, Natalia Viktorivna Grygorieva, Vladyslav Volodymyrovych Povoroznyuk, Mykola Oleksiiovych Korzh, Oleksandr Levgeniiovych Loskutov, Andriy Borysovych Chukov, Rex Sarmiento, Hawys Thomas, Hugh Donnachie, Irina Pavel-Knox, Hilary Shaw, Hana Hassanin, Essam Eldin Ahmed Abdulhakim, Naren Savani, Gloria A Bachmann, Elizabeth Barrett-Connor, Neil C Binkley, Henry G Bone, Donald M Brandon, Darin David Checketts, Neil J Fraser, Nelson B Watts, Steven A Geller, Joseph S Gimbel, Maria White Greenwald, Peter A Holt, Cyrus Conrad Johnston, Chien Fang, David J Klashman, E. Michael Lewiecki, Mitchell B Lowenstein, Michael Roy McClung, Susan M Nattrass, Alberto Odio, Julie Levengood, Josefina Romaguera, Mohamed Bassam Sebai, Brian Snyder, Mark Eliot Kutner, Dan Streja, Elliott P Schwartz, and Mark G Christiansen
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cathepsin-k inhibitor ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Placebo-controlled study ,law.invention ,Fractures, Bone ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Randomized controlled trial ,Bone Density ,law ,Outpatient clinic ,030212 general & internal medicine ,Osteoporosis, Postmenopausal ,Aged, 80 and over ,density ,Hip fracture ,Bone Density Conservation Agents ,odanacatib, postmenopausal osteoporosis, LOFT, extension study ,Treatment Outcome ,medicine.anatomical_structure ,Spinal Fractures ,Female ,women ,strength ,Odanacatib ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Placebo ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,Internal Medicine ,medicine ,Humans ,bone mass ,fracture ,mortality ,denosumab ,turnover ,therapy ,Aged ,Femoral neck ,Hip Fractures ,business.industry ,Biphenyl Compounds ,medicine.disease ,chemistry ,business ,Osteoporotic Fractures - Abstract
Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p
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- 2019
23. Sclerostin deficiency in humans
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Socrates E. Papapoulos, Natasha M. Appelman-Dijkstra, and Antoon H van Lierop
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Genetic Markers ,0301 basic medicine ,Sclerosteosis ,Pathology ,medicine.medical_specialty ,Histology ,VAN BUCHEM DISEASE ,Sclerostin ,Physiology ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Bone resorption ,030209 endocrinology & metabolism ,Osteochondrodysplasias ,Bone and Bones ,Bone remodeling ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Bone Density ,medicine ,Humans ,Bone formation ,Adaptor Proteins, Signal Transducing ,Van Buchem disease ,business.industry ,Hyperostosis ,medicine.disease ,030104 developmental biology ,chemistry ,Bone Morphogenetic Proteins ,Syndactyly ,business ,Biomarkers - Abstract
Sclerosteosis and van Buchem disease are two rare bone sclerosing dysplasias caused by genetic defects in the synthesis of sclerostin. In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis.
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- 2017
24. Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial
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Polyzois Makras, Natasha M. Appelman-Dijkstra, Stergios A. Polyzos, Socrates E. Papapoulos, and Athanasios D. Anastasilakis
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0301 basic medicine ,medicine.medical_specialty ,VERTEBRAL FRACTURES ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Urology ,DISCONTINUATION ,030209 endocrinology & metabolism ,OSTEOPOROSIS ,Bone remodeling ,Fractures, Bone ,03 medical and health sciences ,0302 clinical medicine ,N-terminal telopeptide ,Bone Density ,medicine ,Clinical endpoint ,Humans ,Orthopedics and Sports Medicine ,Bone Resorption ,Aged ,Femoral neck ,DENOSUMAB ,Femur Neck ,business.industry ,Middle Aged ,medicine.disease ,Osteopenia ,030104 developmental biology ,medicine.anatomical_structure ,Zoledronic acid ,Denosumab ,Withholding Treatment ,ZOLEDRONIC ACID ,Female ,Bone Remodeling ,business ,Biomarkers ,BONE MINERAL DENSITY ,medicine.drug - Abstract
Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5-mg infusion of zoledronate (ZOL) (n = 27) or two additional 60-mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine-bone mineral density (LS-BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean +/- SD) 4.82% +/- 0.7% (p < 0.001) from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)-BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. (c) 2019 American Society for Bone and Mineral Research.
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- 2019
25. Abaloparatide in patients with mild or moderate renal impairment: results from the ACTIVE phase 3 trial
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Gary Hattersley, Ming-yi Hu, Bruce H. Mitlak, C. Dabrowski, Socrates E. Papapoulos, John P. Bilezikian, Lorraine A. Fitzpatrick, and Paul D. Miller
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medicine.medical_specialty ,Post hoc ,Abaloparatide ,Osteoporosis ,Urology ,030204 cardiovascular system & hematology ,Kidney ,Degree (temperature) ,03 medical and health sciences ,Fractures, Bone ,0302 clinical medicine ,bone regeneration ,Double-Blind Method ,Active phase ,Teriparatide ,medicine ,Humans ,In patient ,030212 general & internal medicine ,abaloparatide ,Renal Insufficiency ,Bone regeneration ,Osteoporosis, Postmenopausal ,Aged ,postmenopausal ,Bone Density Conservation Agents ,business.industry ,Parathyroid Hormone-Related Protein ,General Medicine ,Middle Aged ,medicine.disease ,Treatment Outcome ,Female ,Drug Monitoring ,business ,Tomography, X-Ray Computed ,Glomerular Filtration Rate - Abstract
Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment. Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80 mu g, placebo, or open-label teriparatide 20 mu g daily. Patients with serum creatinine >2.0 mg/dL or 1.5-2.0 mg/dL with an estimated glomerular filtration rate (eGFR) = 90 mL/min, 1276 had 60 to
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- 2019
26. Impact microindentation assesses subperiosteal bone material properties in humans
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Pascale Chavassieux, Natalie Bravenboer, Stéphane Blouin, Sonja Gamsjaeger, Natasha M. Appelman-Dijkstra, Klaus Klaushofer, Barbara M. Misof, Socrates E. Papapoulos, Stamatia Rokidi, and Eleftherios P. Paschalis
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0301 basic medicine ,Adult ,Male ,Histology ,Bone matrix ,Adolescent ,Physiology ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Bone tissue ,Apatite ,Bone and Bones ,03 medical and health sciences ,chemistry.chemical_compound ,Fractures, Bone ,Young Adult ,0302 clinical medicine ,MicroIndentation ,Bone Density ,medicine ,Cortical Bone ,Humans ,Noncollagenous proteins ,Tibia ,Bone mineral ,Pyridinoline ,Raman analysis ,Chemistry ,Bone material properties ,Fracture risk assessment ,Iliac crest biopsies ,Middle Aged ,030104 developmental biology ,medicine.anatomical_structure ,visual_art ,visual_art.visual_art_medium ,Cortical bone ,Female ,Collagen ,Biomedical engineering - Abstract
Impact microindentation (IMI) is a Reference Point Indentation technique measuring tissue-level properties of cortical bone in humans in vivo. The nature, however, of the properties that can affect bone strength is incompletely understood. In the present study we examined bone material properties in transiliac bone biopsies obtained concurrently with measurements of Bone Material Strength index (BMSi) by IMI in 12 patients with different skeletal disorders and a wide range of BMD, with or without fractures (8 males, 4 females, mean age 48 ± 12.2 (SD) years, range 15–60 years). IMI was performed in the mid-shaft of the right tibia with a hand‐held microindenter (OsteoProbe). Cancellous and cortical bone mineralization density distributions (BMDD) were measured in the entire biopsy bone area by quantitative backscattered electron imaging. Raman measurements were obtained right at the outer edge of the cortex, and 5, 50, 100, 500 μm inwards. The calculated parameters were: i) Mineral and organic matrix content as well as the mineral / matrix ratio. ii) Nanoporosity. iii) Glycosaminoglycan content. iv) Pyridinoline content. v) Maturity/crystallinity of the apatite crystallites. There was no relationship between BMSi values with any measurement of mineral content of whole bone tissue (BMD, BMDD) or maturity/crystallinity of bone mineral. On the other hand, a positive correlation between BMSi and local mineral content, and an inverse correlation between BMSi and nanoporosity at the mineralized subperiosteal edge of the sample and at 5 μm inwards was found. A positive correlation was also observed between BMSi and pyridinoline content at the same locations. These results indicate that local mineral content, nanoporosity and pyridinoline content at the subperiosteal site in the transiliac bone biopsy are linked to the BMSi values measured in the tibia. As both high porosity at the nano level and low pyridinoline content of the bone matrix can negatively impact bone strength, our findings suggest that BMSi most likely assesses subperiosteal bone material properties.
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- 2019
27. Targeting the Wnt signaling pathway for the development of novel therapies for osteoporosis
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Maria P. Yavropoulou and Socrates E. Papapoulos
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medicine.medical_specialty ,Animal Genetics ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Wnt signaling pathway ,Disease ,medicine.disease ,Bioinformatics ,Bone resorption ,Unmet needs ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,medicine ,Sclerostin ,Bone formation ,business - Abstract
A number of anti-osteoporotic drugs, predominantly inhibitors of bone resorption, are currently used in the management of patients with osteoporosis to reduce the risk of fractures. While the management of the disease has improved significantly, there are still unmet needs, mainly due to a lack of agents able to replace bone that has already been lost. Human and animal genetics have identified the pivotal role of the Wnt signaling pathway in the regulation of bone formation by the osteoblasts and have made it a very attractive target for the development of novel treatments for osteoporosis. In this article, we review evidence that supports the targeting of components of the Wnt signaling pathway for the design of bone-forming treatments for osteoporosis.
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- 2019
28. FRI0480 CHANGES IN CIRCULATING SCTLA-4 FOLLOWING ZOLEDRONIC ACID INFUSION
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Dario Camellino, Gerolamo Bianchi, G. Girasole, Erika Iervasi, Socrates E. Papapoulos, Daniele Saverino, and Andrea Giusti
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,T cell ,Osteoporosis ,Acute-phase protein ,Renal function ,Bisphosphonate ,medicine.disease ,Gastroenterology ,Zoledronic acid ,Cytokine ,medicine.anatomical_structure ,Internal medicine ,medicine ,Cytotoxic T cell ,business ,medicine.drug - Abstract
Background Acute phase response (APR) is a transient, flu-like reaction to first exposure to intravenous nitrogen-containing bisphosphonate (NBP). APR is characterised by a strong inflammatory response, associated with increases in circulating levels of IL-6 and TNF-, that is thought to be due to activation and increased proliferation of γδ T cells related to the molecular mechanism of action of NBP. Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), in both its soluble (s) and membrane-bound forms, is involved in the downregulation of T cell proliferation, cell cycle progression and cytokine production. High levels of serum sCTLA-4 have been reported in several autoimmune diseases, and its role as both inhibitor and enhancer of the immune response has been proposed. Objectives To evaluate the potential relationship between sCTLA-4 and the development of APR in patients treated with zoledronic acid (ZOL). Methods Included in the study were patients treated with a single intravenous ZOL infusion 5 mg. Exclusion criteria were previous treatment with ZOL, treatments interfering with CTLA-4, and estimated glomerular filtration rate Results Ten female patients (mean age 73-10 years) were included (2 had vertebral fractures and the remaining had osteoporosis), 5 of whom experienced APR (APR+) associated with the expected increases in serum CRP and IL-6. Baseline levels of sCTLA-4 did not differ between APR+ and APR- patients and decreased significantly in all from 32-9 ng/ml to 24-9 ng/ml (p=0.007) at 24 hr, 16-8 ng/ml (p=0.004) at 48 hr and 7-6 ng/ml (p Conclusion Contrary to our hypothesis, sCTLA-4 was not related to the occurrence of APR after ZOL. The significance of the substantial decrease of circulating levels of sCTLA-4 after ZOL in all studied patients warrants further investigation. Disclosure of Interests Gerolamo Bianchi Consultant for: Alfa-Sigma, Amgen, BMS, Celgene, Medac, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Daniele Saverino: None declared, Dario Camellino Consultant for: Janssen-Cilag, Novartis, AbbVie, Sanofi, Paid instructor for: Mylan, Andrea Giusti Grant/research support from: Abiogen Pharma, Consultant for: EffRx, Speakers bureau: Abiogen Pharma, Eli Lilly, AMGEN, Erika Iervasi: None declared, Giuseppe Girasole: None declared, Socrates Papapoulos Grant/research support from: No in the last 3 years, Consultant for: Amgen, Axsome, Gador, Radius Health, UCB, Speakers bureau: Amgen, UCB
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- 2019
29. Familial Paget's disease of bone : long-term follow-up of unaffected relatives with and without Sequestosome 1 mutations
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Socrates E. Papapoulos, Raphaël De Ridder, Wim Van Hul, Frits Smit, Esther C. Hamoen, Joséphine J.M. Peeters, Eveline Boudin, E. Marelise W. Eekhoff, Natasha M. Appelman-Dijkstra, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, and Amsterdam Movement Sciences - Rehabilitation & Development
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Physical examination ,Disease ,Asymptomatic ,03 medical and health sciences ,0302 clinical medicine ,Sequestosome 1 ,Familial ,Internal medicine ,Sequestosome-1 Protein ,medicine ,Humans ,Medical history ,SQSTM1 ,education ,Radionuclide Imaging ,Aged ,Aged, 80 and over ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,Follow-up ,Exons ,Middle Aged ,medicine.disease ,Alkaline Phosphatase ,Osteitis Deformans ,Natural history ,030104 developmental biology ,Paget's disease of bone ,Mutation ,Female ,Bone Remodeling ,Human medicine ,medicine.symptom ,business - Abstract
Objective Familial Paget's disease of bone is inherited as an autosomal-dominant trait and mutations in the sequestosome 1 (SQSTM1) gene have been reported with variable frequency in patients with familial disease. The natural history, however, of the disease in family members with or without SQSTM1 mutations is unknown. Methods To address this question, we investigated members of families with Paget's disease identified and genotyped in 2000 in The Netherlands without clinical, biochemical or radiological signs of Paget's disease. Seventy-five subjects, median age 56 years (range 44–93), with or without SQSTM1 mutations participated in the present study. Medical history was obtained and clinical examination and laboratory investigations were performed in all. When serum biochemical markers of bone turnover were increased, skeletal scintigraphy with SPECT-CT was performed. Results After a mean period of 15.9 ± 0.32 (SD) years no subject without SQSTM1 mutations (either from positive or negative families) developed Paget's disease. Of 14 carriers of SQSTM1 mutations, Paget's disease of the pelvis was diagnosed in a 74-year old asymptomatic woman. Conclusion The incidence of new Paget's disease in SQSTM1 positive subjects was 7.1% and no mutation-negative subject developed the disease within 16 years of follow-up. Subjects without SQSTM1 mutations can be reassured whereas mutation carriers should consider screening. Our findings should be confirmed in other populations as currently unknown environmental factors that might be involved in the development of the disease may differ.
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- 2019
30. New Bone-Forming Agents
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Socrates E. Papapoulos
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medicine.medical_specialty ,business.industry ,Osteoporosis ,Romosozumab ,Disease ,medicine.disease ,Bone resorption ,Pharmacological interventions ,medicine ,Bone formation ,Bone forming ,business ,Intensive care medicine ,Fracture reduction - Abstract
Pharmacological interventions for patients with osteoporosis aim at decreasing the risk of fractures and associated clinical consequences by correcting the imbalance between bone resorption and bone formation that constitutes the pathophysiological basis of the disease. Despite the availability of efficacious treatments for fracture reduction, there are still unmet needs requiring a broader range of therapeutics. In particular, there is a need for agents capable of replacing already lost bone and of drastically reducing the risk of non-vertebral fractures, the most frequent fragility fractures. In recent years, new molecules and therapeutic targets have been identified, and many were investigated as potential treatments for osteoporosis. This chapter briefly reviews newly developed bone-forming agents.
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- 2018
31. The three-year effect of a single zoledronate infusion on bone mineral density and bone turnover markers following denosumab discontinuation in women with postmenopausal osteoporosis
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Stergios A. Polyzos, Athanasios D. Anastasilakis, Socrates E. Papapoulos, Natasha M. Appelman-Dijkstra, and Polyzois Makras
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Urology ,030209 endocrinology & metabolism ,Postmenopausal osteoporosis ,Zoledronic Acid ,Bone remodeling ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Bone Density ,law ,Bone mineral density ,medicine ,Clinical endpoint ,Humans ,Prospective Studies ,Osteoporosis, Postmenopausal ,Femoral neck ,Bone mineral ,Bone Density Conservation Agents ,business.industry ,Discontinuation ,030104 developmental biology ,medicine.anatomical_structure ,Denosumab ,Female ,Bone Remodeling ,Bone turnover markers ,business ,Zoledronate ,medicine.drug - Abstract
Introduction In women with postmenopausal osteoporosis denosumab discontinuation is associated with rapid bone loss that could be potentially prevented by a single zoledronate infusion for two years. The longer-term effects, however, of zoledronate treatment are unknown. We aimed to study the effect of a single zoledronate infusion during the third year following denosumab discontinuation, in initially treatment-naive postmenopausal women who became osteopenic after 2.4 ± 0.2 years of denosumab therapy. Methods We report the 1-year follow-up results of a single arm observational extension of a previously reported 2-year multicenter prospective randomized clinical trial. The primary endpoint of this extension was the change in lumbar spine bone mineral density (LS-BMD); secondary endpoints were changes in femoral neck (FN)-BMD and markers of bone turnover (BTM) during the 3rd year from the zoledronate infusion. Changes are presented as mean and SEM. Results LS-BMD did not change significantly at year 3 compared to year 2 (−1.35 ± 1.1%, p = 1.00) and compared to baseline (−1.96 ± 1.44%, p = 1.00). FN-BMD values did not change while serum P1NP values decreased and CTX values remained unchanged during the third-year of the follow-up. In 4 of the 23 studied women BMD values returned to the osteoporotic range at 3 years. Conclusions A single i.v. infusion of zoledronate 5 mg, given 6 months after the last injection of denosumab therapy maintains for three years BMD gains in the majority of patients previously treated with denosumab for an approximate period of 2.5 years. Follow-up of patients is, however, recommended because about one-fifth of treated women will require additional antiosteoporotic treatment.
- Published
- 2020
32. Paget's disease of bone
- Author
-
Socrates E. Papapoulos and Natasha M. Appelman-Dijkstra
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,bone turnover ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,030209 endocrinology & metabolism ,Disease ,Bone and Bones ,Bone remodeling ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine ,Prevalence ,Humans ,genetics ,SQSTM1 ,business.industry ,zoledronate ,Paget's disease ,medicine.disease ,Osteitis Deformans ,Paget s disease ,030104 developmental biology ,Paget's disease of bone ,business - Abstract
Paget's disease of bone is a focal disorder of bone remodelling that progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular and vascular complications. In some parts of the world it is the second most common bone disorder after osteoporosis though in recent years its prevalence and severity appear to decrease. The disease is easily diagnosed and effectively treated but its pathogenesis remains incompletely understood.
- Published
- 2018
33. Implications for Fracture Healing of Current and New Osteoporosis Treatments: An ESCEO Consensus Paper
- Author
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Socrates E. Papapoulos, Willard H. Dere, Yannis Tsouderos, René Rizzoli, Jean-Marc Feron, Jörg Goldhahn, Jean-Yves Reginster, Steven Boonen, Bruce H. Mitlak, and John A. Kanis
- Subjects
Callus formation ,Healing ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Osteoporosis ,Dentistry ,Bone healing ,Antibodies, Monoclonal, Humanized ,Fractures, Bone ,Endocrinology ,Strontium ranelate ,Teriparatide ,medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,Fracture Healing ,Bone Density Conservation Agents ,business.industry ,Bisphosphonate ,medicine.disease ,Fractures ,Bone formation ,Treatment ,Denosumab ,ddc:618.97 ,business ,medicine.drug - Abstract
Calcified Tissue International, 90 (5), ISSN:0171-967X, ISSN:1432-0827
- Published
- 2018
34. Bone material strength index as measured by impact microindentation is low in patients with fractures irrespective of fracture site
- Author
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F. Malgo, Socrates E. Papapoulos, Neveen A. T. Hamdy, and Natasha M. Appelman-Dijkstra
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Reference point indentation ,Endocrinology, Diabetes and Metabolism ,Low bone mass ,Dentistry ,Fracture site ,030209 endocrinology & metabolism ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Bone Density ,Bone material ,Humans ,Medicine ,In patient ,Impact microindentation ,Aged ,Fragility fracture ,Femur Neck ,business.industry ,Middle Aged ,Cross-Sectional Studies ,030104 developmental biology ,Orthopedic surgery ,Fracture (geology) ,Osteoporosis ,Spinal Fractures ,Original Article ,Female ,Stress, Mechanical ,Vertebral fracture ,business ,Osteoporotic Fractures - Abstract
We evaluated the relationship between bone material strength index (BMSi) and fragility fractures, including vertebral fractures. Our data showed that BMSi is low in all fracture patients with low bone mass, independently of whether patients sustained a vertebral or a non-vertebral fracture.INTRODUCTION: Impact microindentation (IMI) is a new technique for the measurement of tissue level properties of cortical bone in vivo. Previous studies showed an association between BMSi and non-vertebral fractures, but an association with vertebral fractures is still being debated. The objective of this paper was to evaluate the relationship between BMSi and different types of fragility fractures, including vertebral fractures.METHODS: In this cross-sectional study, we measured BMSi in patients of both sexes with different types of fragility fractures and low bone mass with the IMI method using the Osteoprobe®. Vertebral fractures were diagnosed and graded on lateral spine radiographs.RESULTS: A total of 132 patients were included in the study, of whom 101 patients (65 women) had sustained a low energy fracture and 31 (mean age 57.7 ± 9.9 years) had no history or radiological evidence for a fracture. Of the fracture patients, 53 (mean age 62.8 ± 8.3 years) had only non-vertebral fractures (VF-/Fx+), 34 (mean age 62.8 ± 9.9 years) had vertebral and non-vertebral fractures (VF+/Fx+), and 14 (mean age 64.7 ± 9.3 years) had only vertebral fractures (VF+/Fx-). BMSi values, adjusted for age and BMD, were similar for all three groups of fracture patients (78.9 ± 0.7, 78.3 ± 0.9, and 78.4 ± 1.4, respectively; p = 0.866). BMSi values were not associated with number or severity of vertebral fractures.CONCLUSION: Our data demonstrate that BMSi is low in fracture patients with low bone mass, irrespective of whether they sustained a vertebral fracture or a non-vertebral fracture.
- Published
- 2017
35. Impact Microindentation: Consistency of Serial Measurements and Alterations in Patients With Paget's Disease of the Tibia
- Author
-
Frank, Malgo, Neveen At, Hamdy, Socrates E, Papapoulos, and Natasha M, Appelman-Dijkstra
- Subjects
Male ,Tibia ,Humans ,Female ,Middle Aged ,Osteitis Deformans ,Aged - Abstract
Impact microindentation (IMI) is a new technique for the in vivo measurement of tissue-level properties of cortical bone in humans. To address issues related to the proper application of IMI in clinical practice and to directly examine cortical bone properties in patients with tibia pathology, we studied 11 subjects without tibia pathology and nine patients with Paget's disease of the tibia in biochemical remission after bisphosphonate treatment. Serial indentations in the tibias of both legs were performed in all subjects by a single operator until 10 adequate measurements were obtained in each tibia. In patients without Paget's disease (7 men and 4 women; mean age, 61.9 years; range, 51 to 72 years), there was no difference in mean bone material strength index (BMSi) between the dominant and nondominant leg (82.1 ± 1.3 and 81.4 ± 1.3, respectively; p = 0.606). In each individual subject studied, sequential indentations in both legs showed no trends for higher or lower values with time. The standard deviation of unnormalized bone material strength (BMSu) was also comparable between the dominant and nondominant tibia (5.3 and 4.5, respectively; p = 0.657). In patients with Paget's disease (4 men and 5 women; mean age, 69.5 years; range, 55 to 87 years), mean BMSi of the Pagetic tibia was lower, albeit nonsignificantly, than that of the contralateral nonaffected tibia (74.7 ± 1.7 and 78.7 ± 1.3, respectively; p = 0.120). In contrast to subjects without Paget's disease, the SD of adequate BMSu values was significantly larger in the Pagetic tibia compared to that of the non-Pagetic tibia (7.6 versus 5.0, respectively, p = 0.008). These results highlight the consistency of serial IMI measurements as performed by a single operator in the presence as well as absence of tibia pathology and illustrate that the method is able to capture alterations of tissue-level cortical bone properties in patients with Paget's disease of the tibia. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
- Published
- 2017
36. Sclerostin: From bedside to bench, and back to bedside
- Author
-
Alexander G. Robling, Socrates E. Papapoulos, and Matthew T. Drake
- Subjects
medicine.medical_specialty ,Histology ,Physiology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Publications ,MEDLINE ,030209 endocrinology & metabolism ,Hyperostosis ,01 natural sciences ,Translational Research, Biomedical ,010101 applied mathematics ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Bone Morphogenetic Proteins ,Animals ,Humans ,Medicine ,Sclerostin ,Syndactyly ,0101 mathematics ,business ,Intensive care medicine - Published
- 2017
37. Circulating Sclerostin in Bone Sclerosing Disorders
- Author
-
Antoon H. van Lierop and Socrates E. Papapoulos
- Published
- 2017
38. Impact microindentation: Consistency of serial measurements and alterations in patients with Paget's disease of the tibia
- Author
-
F. Malgo, Socrates E. Papapoulos, Natasha M. Appelman-Dijkstra, and Neveen A. T. Hamdy
- Subjects
0301 basic medicine ,musculoskeletal diseases ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Mean age ,medicine.disease ,Surgery ,Paget s disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Paget's disease of bone ,Consistency (statistics) ,Bone material ,medicine ,Orthopedics and Sports Medicine ,Cortical bone ,In patient ,Tibia ,Nuclear medicine ,business - Abstract
Impact microindentation is a new technique for the in vivo measurement of tissue-level properties of cortical bone in humans. To address issues related to the proper application of IMI in clinical practice and to directly examine cortical bone properties in patients with tibia pathology, we studied 11 subjects without tibia pathology and 9 patients with Paget's disease of the tibia in biochemical remission after bisphosphonate treatment. Serial indentations in the tibiae of both legs were performed in all subjects by a single operator until 10 adequate measurements were obtained in each tibia. In patients without Paget's disease [7 men and 4 women; mean age 61.9 years (range 51 - 72 years)], there was no difference in mean Bone Material Strength index (BMSi) between the dominant and non-dominant leg (82.1 ± 1.3 and 81.4 ± 1.3, respectively; p = 0.606). In each individual subject studied, sequential indentations in both legs showed no trends for higher or lower values with time. The standard deviation of unnormalized Bone Material Strength (BMSu) was also comparable between the dominant and non-dominant tibia (5.3 and 4.5, respectively; p = 0.657). In patients with Paget's disease [4 men and 5 women; mean age 69.5 years (range 55 - 87 years)], mean BMSi of the Pagetic tibia was lower, albeit non-significantly, than that of the contralateral non-affected tibia (74.7 ± 1.7 and 78.7 ± 1.3, respectively; p = 0.120). In contrast to subjects without Paget's disease, the SD of adequate BMSu values was significantly larger in the Pagetic tibia compared to that of the non-Pagetic tibia (7.6 vs. 5.0, respectively, p = 0.008). These results highlight the consistency of serial IMI measurements as performed by a single operator in the presence as well as absence of tibia pathology and illustrate that the method is able to capture alterations of tissue-level cortical bone properties in patients with Paget's disease of the tibia. This article is protected by copyright. All rights reserved
- Published
- 2017
39. Sclerostin Deficiency Is Linked to Altered Bone Composition
- Author
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Paul Roschger, Eleftherios P. Paschalis, Sonja Lueger, Antoon van Lierop, Michaela Kneissel, Sonja Gamsjaeger, Andreas Roschger, Socrates E. Papapoulos, Klaus Klaushofer, Norbert Hassler, and Ina Kramer
- Subjects
Bone mineral ,medicine.medical_specialty ,biology ,Endocrinology, Diabetes and Metabolism ,Anatomy ,Bone tissue ,Mineralization (biology) ,Raman microspectroscopy ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,Proteoglycan ,chemistry ,Density distribution ,Internal medicine ,medicine ,biology.protein ,Sclerostin ,Orthopedics and Sports Medicine ,Cortical bone - Abstract
High bone mass in animals and humans with sclerostin deficiency is associated with increased bone strength, which is not the case for all disorders with high bone mineral density, some of which are even associated with fragility fractures owing to unfavorable bone composition. In the current study we investigated whether alterations in bone composition may contribute to the bone strength characteristics associated with lack of sclerostin. We examined cortical bone of Sost-knockout (KO) mice (n = 9, 16 weeks old) and sclerosteosis patients (young [4 to 14 years], n = 4 and adults [24 and 43 years], n = 2) by quantitative backscattered electron imaging and Raman microspectroscopy and compared it to bone from wild-type mice and healthy subjects, respectively. In Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged. When comparing endocortical bone tissue of identical tissue age as defined by sequential dual fluorochrome labeling the average bone matrix mineralization was reduced -1.9% (p < 0.0001, younger tissue age) and -1.5% (p < 0.05, older tissue age), and the relative proteoglycan content was significantly increased. Similarly, bone matrix mineralization density distribution was also shifted toward lower matrix mineralization in surgical samples of compact bone of sclerosteosis patients. This was associated with an increase in mineralization heterogeneity in the young population. In addition, and consistently, the relative proteoglycan content was increased. In conclusion, we observed decreased matrix mineralization and increased relative proteoglycan content in bone subcompartments of Sost-KO mice-a finding that translated into sclerosteosis patients. We hypothesize that the altered bone composition contributes to the increased bone strength of patients with sclerostin deficiency.
- Published
- 2014
40. Bone: Romosozumab - getting there but not quite yet
- Author
-
Socrates E, Papapoulos
- Subjects
Antibodies, Monoclonal ,Humans ,Bone and Bones ,Osteoporosis, Postmenopausal - Published
- 2016
41. Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Second Report of a Task Force of the American Society for Bone and Mineral Research
- Author
-
Thomas A. Einhorn, Bo Abrahamsen, David W. Dempster, Angela M. Cheung, Michael P. Whyte, Richard M. Dell, Fergus McKiernan, Howe Tet Sen, Marjolein C. H. van der Meulen, Peter R. Ebeling, Jeffrey R. Curtis, Felicia Cosman, David B. Burr, Harry K. Genant, Ross E. McKinney, Thomas D. Brown, Kenneth J. Koval, Joseph M. Lane, Klaus Klaushofer, Regis J. O'Keefe, Robert A. Adler, Alvin Choong Meng Ng, Elizabeth Shane, Socrates E. Papapoulos, Piet Geusens, Jeri W. Nieves, and Robert S. Weinstein
- Subjects
medicine.medical_specialty ,Pediatrics ,business.industry ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Periosteal reaction ,Femoral fracture ,medicine.disease ,Surgery ,Diaphysis ,medicine.anatomical_structure ,Denosumab ,Orthopedic surgery ,Insufficiency fracture ,Medicine ,Orthopedics and Sports Medicine ,Femur ,business ,medicine.drug - Abstract
Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. © 2010 American Society for Bone and Mineral Research.
- Published
- 2013
42. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation
- Author
-
Clemens W.G.M. Löwik, Herman Hamersma, Jonathan Reeve, Nigel Loveridge, Kenneth E. S. Poole, Rutger L. van Bezooijen, and Socrates E. Papapoulos
- Subjects
Genetic Markers ,Male ,Bone remodeling period ,medicine.medical_specialty ,Time Factors ,Biopsy ,Romosozumab ,Bone canaliculus ,Models, Biological ,Osteocytes ,Biochemistry ,Bone and Bones ,Bone resorption ,Bone remodeling ,chemistry.chemical_compound ,Osteogenesis ,Internal medicine ,Bone cell ,Image Processing, Computer-Assisted ,Genetics ,medicine ,Humans ,RNA, Messenger ,Tolonium Chloride ,Bone Resorption ,Coloring Agents ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Aged ,Bone Diseases, Developmental ,Bone Development ,Osteoblasts ,Antibodies, Monoclonal ,Cell Differentiation ,Middle Aged ,Alkaline Phosphatase ,Immunohistochemistry ,medicine.anatomical_structure ,Endocrinology ,Microscopy, Fluorescence ,chemistry ,Osteocyte ,Bone Morphogenetic Proteins ,Sclerostin ,Female ,Bone Remodeling ,Signal Transduction ,Biotechnology - Abstract
Osteocytes are the most abundant cells in bone and are ideally located to influence bone turnover through their syncytial relationship with surface bone cells. Osteocyte-derived signals have remained largely enigmatic, but it was recently reported that human osteocytes secrete sclerostin, an inhibitor of bone formation. Absent sclerostin protein results in the high bone mass clinical disorder sclerosteosis. Here we report that within adult iliac bone, newly embedded osteocytes were negative for sclerostin staining but became positive at or after primary mineralization. The majority of mature osteocytes in mineralized cortical and cancellous bone was positive for sclerostin with diffuse staining along dendrites in the osteocyte canaliculi. These findings provide for the first time in vivo evidence to support the concept that osteocytes secrete sclerostin after they become embedded in a mineralized matrix to limit further bone formation by osteoblasts. Sclerostin did not appear to influence the formation of osteocytes. We propose that sclerostin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces. In doing so, sclerostin may act as a key inhibitory signal governing skeletal microarchitecture.
- Published
- 2016
43. Ibandronate for the prevention of nonvertebral fractures: a pooled analysis of individual patient data
- Author
-
S. Adami, George A. Wells, Paul D. Miller, Ethel S. Siris, Jean-Yves Reginster, Jonathan D. Adachi, Cyrus Cooper, Ann Cranney, E. Yetisir, Socrates E. Papapoulos, Pierre D. Delmas, S. Silverman, and Philip N. Sambrook
- Subjects
ibandronate ,medicine.medical_specialty ,Bone density ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Urology ,Drug Administration Schedule ,law.invention ,Fractures, Bone ,Pharmacotherapy ,Randomized controlled trial ,Bone Density ,law ,medicine ,Humans ,Ibandronic Acid ,Osteoporosis, Postmenopausal ,Aged ,Proportional Hazards Models ,Randomized Controlled Trials as Topic ,"nonvertebral" ,Bone Density Conservation Agents ,Diphosphonates ,Proportional hazards model ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Surgery ,Menopause ,Treatment Outcome ,Pharmacodynamics ,Female ,business - Abstract
UNLABELLED: This analysis was conducted to assess the effect of high versus lower doses of ibandronate on nonvertebral fractures. The results were adjusted for clinical fracture, age, and bone density. The treatment effect was dose-dependent. Higher doses of ibandronate significantly reduced the risk of nonvertebral fractures more effectively compared with lower doses. INTRODUCTION: The objective of this study was to assess the efficacy of different doses of ibandronate on nonvertebral fractures in a pooled analysis. METHODS: Eight randomized trials of ibandronate were reviewed for inclusion. Alternative definitions of high versus low doses based on annual cumulative exposure (ACE) were explored. A time-to-event analysis was conducted using Kaplan-Meier methodology. Hazard ratios (HR) were derived using Cox regression and adjusted for covariates. RESULTS: Combining higher ACE doses of > or = 10.8 mg (150 mg once monthly, 3 mg i.v. quarterly, and 2 mg i.v. every 2 months) versus ACE doses of 5.5 mg, from two trials, resulted in an HR 0.62 (95% CI 0.396-0.974, p = 0.038). There was a dose-response trend with increasing ACE doses (7.2-12 mg) versus ACE of 5.5 mg. CONCLUSIONS: A dose-response effect on nonvertebral fractures was observed when comparing high with low ACE doses. A significant reduction in nonvertebral fractures was noted when pooling data from trials using ACE doses of > or = 10.8 mg versus ACE < or = 7.2 mg; and with ACE > or = 10.8 mg versus ACE of 5.5 mg (38% reduction). Higher ibandronate dose levels (150 mg monthly or 3 mg i.v. quarterly) significantly reduced nonvertebral fracture risk in postmenopausal women.
- Published
- 2016
44. Sclerostin Inhibition in the Management of Osteoporosis
- Author
-
Natasha M. Appelman-Dijkstra and Socrates E. Papapoulos
- Subjects
Genetic Markers ,0301 basic medicine ,medicine.medical_specialty ,Blosozumab ,Sclerostin ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Building agent ,Romosozumab ,030209 endocrinology & metabolism ,Review ,Antibodies, Monoclonal, Humanized ,Bioinformatics ,Bone morphogenetic protein ,Bone remodeling ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,Adaptor Proteins, Signal Transducing ,Bone modeling ,business.industry ,Antibodies, Monoclonal ,medicine.disease ,030104 developmental biology ,Tolerability ,chemistry ,Bone Morphogenetic Proteins ,business - Abstract
The recognition of the importance of the Wnt-signaling pathway in bone metabolism and studies of patients with rare skeletal disorders characterized by high bone mass identified sclerostin as target for the development of new therapeutics for osteoporosis. Findings in animals and humans with sclerostin deficiency as well as results of preclinical and early clinical studies with sclerostin inhibitors demonstrated a new treatment paradigm with a bone building agent for the management of patients with osteoporosis, the antifracture efficacy, and long-term tolerability of which remain to be established in on-going phase III clinical studies. In this article we review the currently available preclinical and clinical evidence supporting the use of sclerostin inhibitors in osteoporosis.
- Published
- 2016
45. Long-Term Efficacy and Safety of Treatments for Osteoporosis
- Author
-
Socrates E. Papapoulos
- Subjects
medicine.medical_specialty ,Denosumab ,Increased risk ,business.industry ,Osteoporosis ,Medicine ,business ,Intensive care medicine ,medicine.disease ,Term (time) ,medicine.drug - Abstract
Pharmacological agents used in the management of patients with osteoporosis are generally efficacious and well tolerated, but there are differences among them. Agents that reduce the risk of all osteoporotic fractures, including those of the hip, have a favorable benefit-to-harm profile especially when given to patients at increased risk of fractures. Knowledge of the mechanism of action, efficacy, and potential short- and long-term risks of every treatment prescribed is essential for proper care of patients with osteoporosis.
- Published
- 2016
46. Circulating Sclerostin in Bone Sclerosing Disorders
- Author
-
Antoon van Lierop and Socrates E. Papapoulos
- Subjects
chemistry.chemical_compound ,medicine.medical_specialty ,Endocrinology ,chemistry ,business.industry ,Internal medicine ,medicine ,Sclerostin ,business - Published
- 2016
47. Acute phase response following intravenous zoledronate in postmenopausal women with low bone mass
- Author
-
Athina Gkiomisi, Grigorios T. Sakellariou, Socrates E. Papapoulos, Ilias Bisbinas, Athanasios D. Anastasilakis, Dimitrios Oikonomou, Iris Ballaouri, Stergios A. Polyzos, Polyzois Makras, Spyridon Gerou, and Sideris Delaroudis
- Subjects
medicine.medical_specialty ,animal structures ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,Lymphocyte ,medicine.medical_treatment ,Osteoporosis ,Acute phase response ,Parathyroid hormone ,Zoledronic Acid ,Gastroenterology ,Bone and Bones ,White blood cell ,Internal medicine ,Humans ,Medicine ,Lymphocytes ,Acute-Phase Reaction ,Bone Density Conservation Agents ,Diphosphonates ,business.industry ,Imidazoles ,Acute-phase protein ,Organ Size ,Bisphosphonates ,Middle Aged ,Bisphosphonate ,medicine.disease ,Postmenopause ,Logistic Models ,medicine.anatomical_structure ,Zoledronic acid ,Injections, Intravenous ,Immunology ,Female ,Tumor necrosis factor alpha ,business ,Zoledronate ,medicine.drug - Abstract
An acute phase response (APR) is frequently observed in patients treated with intravenous (i.v.) zoledronate (ZOL). We aimed to define clinical and laboratory parameters that may predict ZOL-induced APR in women with low bone mass. Fifty-one postmenopausal women with low bone mass were given a single i.v. infusion of ZOL 5mg. APR was clinically defined by the visual analog pain scale (VAS) for the musculoskeletal symptoms and body temperature. White blood cell count (WBC), leucocyte subpopulations, C-reactive protein (CRP), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], interleukins (IL)-1b and -6, tumor necrosis factor (TNF)α and interferon (IFN)γ were measured before and 48 h following the infusion. Subsequently, patients were divided into those experiencing APR (APR+) or not (APR-). WBC, granulocytes, CRP, IL-1b and IL-6 were significantly increased, whereas lymphocytes, eosinophils, calcium, phosphate and 25(OH)D decreased 48h after ZOL infusion. Twenty-eight of the 51 patients (54.9%) experienced an APR. APR+ patients were younger and had higher baseline lymphocytes compared to APR- patients. There was no difference (p=0.405) in the development of APR between treatment-naive patients (19/32, 59.4%) and patients previously treated with another oral nitrogen-containing bisphosphonate (9/19, 47.4%). In conclusion, our data suggest that pre-treatment higher lymphocyte number increases the risk of APR while previous treatment with another nitrogen-containing bisphosphonate does not significantly reduce the risk. Serum 25(OH)D concentrations decrease significantly after the infusion, possibly as part of the inflammatory response to ZOL.
- Published
- 2012
48. Five years of denosumab exposure in women with postmenopausal osteoporosis: Results from the first two years of the FREEDOM extension
- Author
-
Cesar Libanati, Michelle N. Bradley, Nadia Daizadeh, Dan Mellström, Marc-Antoine Krieg, Heinrich Resch, José Andrés Román Ivorra, Eric Vittinghoff, M. Austin, Maria Luisa Brandi, Z. Man, Socrates E. Papapoulos, Christian Roux, Steven R. Cummings, Sebastião Cezar Radominski, Roland Chapurlat, Andreas Grauer, Edward Czerwiński, Henry G. Bone, Jean-Yves Reginster, and Jacques P. Brown
- Subjects
medicine.medical_specialty ,BONE TURNOVER MARKERS ,Bone density ,Endocrinology, Diabetes and Metabolism ,PIVOTAL FRACTURE TRIAL EXTENSION ,Osteoporosis ,Antibodies, Monoclonal, Humanized ,law.invention ,Bone remodeling ,Placebos ,Double-Blind Method ,Randomized controlled trial ,Bone Density ,law ,Internal medicine ,medicine ,Humans ,Orthopedics and Sports Medicine ,Aged ,Bone mineral ,DENOSUMAB ,Cross-Over Studies ,Bone Density Conservation Agents ,business.industry ,Antibodies, Monoclonal ,medicine.disease ,FRACTURE ,Surgery ,Postmenopause ,Antibodies, Monoclonal/adverse effects ,Antibodies, Monoclonal/therapeutic use ,Biological Markers/blood ,Bone Density Conservation Agents/adverse effects ,Bone Density Conservation Agents/therapeutic use ,Female ,Osteoporosis/drug therapy ,Denosumab ,Cohort ,Original Article ,business ,Osteonecrosis of the jaw ,Biomarkers ,BONE MINERAL DENSITY ,medicine.drug - Abstract
The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a “virtual untreated twin” cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile. © 2012 American Society for Bone and Mineral Research
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- 2012
49. Circulating sclerostin levels are decreased in patients with endogenous hypercortisolism and increase after treatment
- Author
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A. H. van Lierop, A. W. van der Eerden, Socrates E. Papapoulos, Neveen A. T. Hamdy, Ad R. M. M. Hermus, M. den Heijer, Internal medicine, EMGO - Musculoskeletal health, and ICaR - Circulation and metabolism
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Fibroblast growth factor 23 ,Male ,Hydrocortisone ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,Aetiology, screening and detection [ONCOL 5] ,Biochemistry ,Bone remodeling ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Endocrinology ,Cushing Syndrome ,0303 health sciences ,Adrenalectomy ,Middle Aged ,3. Good health ,Bone Morphogenetic Proteins ,Female ,Bone Remodeling ,Procollagen ,medicine.drug ,Adult ,Genetic Markers ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Context (language use) ,Osteocytes ,Collagen Type I ,Molecular epidemiology [NCEBP 1] ,03 medical and health sciences ,N-terminal telopeptide ,Internal medicine ,medicine ,Animals ,Humans ,Health aging / healthy living Cardiovascular diseases [IGMD 5] ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,business.industry ,Biochemistry (medical) ,Hormonal regulation [IGMD 6] ,JCEM Online: Brief Reports ,Peptide Fragments ,Fibroblast Growth Factors ,Procollagen peptidase ,Fibroblast Growth Factor-23 ,chemistry ,Sclerostin ,business ,Peptides - Abstract
Item does not contain fulltext CONTEXT: Increased bone fragility is a frequent complication of hypercortisolism due predominantly to suppression of bone formation. Sclerostin is an osteocyte-produced negative regulator of bone formation, which is up-regulated by glucocorticoids in mice. OBJECTIVE: Our objective was to assess the effect of endogenous hypercortisolism on circulating sclerostin and bone turnover in humans. DESIGN: We measured sclerostin, beta-C-terminal telopeptide, amino-terminal propeptide of type 1 procollagen, and fibroblast growth factor 23 in blood samples of 21 patients with endogenous hypercortisolism and 21 age- and gender-matched controls. In 12 patients, measurements were repeated at various time intervals after successful surgical treatment (transsphenoidal surgery or adrenalectomy). RESULTS: Plasma sclerostin levels were significantly decreased in patients compared with controls (112+/-49 vs. 207+/-48 pg/ml, P
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- 2012
50. Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism?
- Author
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Janneke E Witteveen, Antoon H van Lierop, Socrates E. Papapoulos, and Neveen A. T. Hamdy
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Adult ,Male ,Fibroblast growth factor 23 ,Parathyroidectomy ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Parathyroid hormone ,Renal function ,Bone remodeling ,Endocrinology ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Cholecalciferol ,Hyperparathyroidism ,business.industry ,General Medicine ,Middle Aged ,Hyperparathyroidism, Primary ,medicine.disease ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,Parathyroid Hormone ,Female ,business ,Primary hyperparathyroidism - Abstract
IntroductionFibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are major players in the bone–parathyroid–kidney axis controlling phosphate homeostasis. In patients with primary hyperparathyroidism (PHPT), data on the relationship between PTH and FGF23 are scarce and not always concordant.ObjectiveThe aim of our study was to evaluate the relationship between PTH and FGF23 in patients with PHPT and in euparathyroid patients cured after successful parathyroidectomy (PTx).Patients and methodsTwenty-one patients with PHPT and 24 patients in long-term cure after successful PTx (EuPTH) were studied. All patients underwent biochemical evaluation of renal function, parathyroid status, vitamin D status, bone turnover markers, and serum intact FGF23 levels.ResultsMean serum FGF23 concentration was significantly higher in PHPT than in EuPTH patients (50.8±6.1 vs 33.1±2.6 pg/ml,P=0.01). FGF23 levels significantly correlated with PTH levels (r=0.361,P=0.02), also after correction for 1,25(OH)2D levels (r=0.419,P=0.01). FGF23 levels showed a significant negative correlation with 1,25(OH)2D, which was more pronounced in PHPT than in EuPTH patients (r=−0.674,P=0.001, vsr=−0.509,P=0.01).ConclusionOur findings suggest that in PHPT, FGF23 levels are increased independent of 1,25(OH)2D levels. The more pronounced negative relationship between FGF23 and 1,25(OH)2D in the presence of high circulating PTH levels suggests that the increase in FGF23 levels may be an adaptive mechanism to counteract the PTH-induced increase in 1,25(OH)2D levels, although not completely overriding it.
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- 2012
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