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Shin SH, Chae HD, Suprana A, Jerban S, Chang EY, Shi L, Sah RL, Pettus JH, Woods GN, Du J. UTE MRI technical developments and applications in osteoporosis: a review. Front Endocrinol (Lausanne) 2025; 16:1510010. [PMID: 39980853 PMCID: PMC11839439 DOI: 10.3389/fendo.2025.1510010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 01/15/2025] [Indexed: 02/22/2025] Open
Abstract
Osteoporosis (OP) is a metabolic bone disease that affects more than 10 million people in the USA and leads to over two million fractures every year. The disease results in serious long-term disability and death in a large number of patients. Bone mineral density (BMD) measurement is the current standard in assessing fracture risk; however, the majority of fractures cannot be explained by BMD alone. Bone is a composite material of mineral, organic matrix, and water. While bone mineral provides stiffness and strength, collagen provides ductility and the ability to absorb energy before fracturing, and water provides viscoelasticity and poroelasticity. These bone components are arranged in a complex hierarchical structure. Both material composition and physical structure contribute to the unique strength of bone. The contribution of mineral to bone's mechanical properties has dominated scientific thinking for decades, partly because collagen and water are inaccessible using X-ray based techniques. Accurate evaluation of bone requires information about its components (mineral, collagen, water) and structure (cortical porosity, trabecular microstructure), which are all important in maintaining the mechanical integrity of bone. Magnetic resonance imaging (MRI) is routinely used to diagnose soft tissue diseases, but bone is "invisible" with clinical MRI due to its short transverse relaxation time. This review article discusses using ultrashort echo time (UTE) sequences to evaluate bone composition and structure. Both morphological and quantitative UTE MRI techniques are introduced. Their applications in osteoporosis are also briefly discussed. These UTE-MRI advancements hold great potential for improving the diagnosis and management of osteoporosis and other metabolic bone diseases by providing a more comprehensive assessment of bone quantity and quality.
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Affiliation(s)
- Soo Hyun Shin
- Department of Radiology, University of California, San Diego, San Diego, CA, United States
| | - Hee Dong Chae
- Department of Radiology, University of California, San Diego, San Diego, CA, United States
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Arya Suprana
- Department of Radiology, University of California, San Diego, San Diego, CA, United States
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States
| | - Saeed Jerban
- Department of Radiology, University of California, San Diego, San Diego, CA, United States
| | - Eric Y. Chang
- Department of Radiology, University of California, San Diego, San Diego, CA, United States
- Radiology Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
| | - Lingyan Shi
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States
| | - Robert L. Sah
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States
| | - Jeremy H. Pettus
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Gina N. Woods
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Jiang Du
- Department of Radiology, University of California, San Diego, San Diego, CA, United States
- Department of Bioengineering, University of California, San Diego, San Diego, CA, United States
- Radiology Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
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Zhou W, Ås J, Shore-Lorenti C, Nguyen HH, van de Laarschot DM, Sztal-Mazer S, Grill V, Girgis CM, Stricker BHC, van der Eerden BCJ, Thakker RV, Appelman-Dijkstra NM, Wadelius M, Clifton-Bligh RJ, Hallberg P, Verkerk AJMH, van Rooij JGJ, Ebeling PR, Zillikens MC. Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures. J Bone Miner Res 2024; 39:1315-1326. [PMID: 39126371 PMCID: PMC11371903 DOI: 10.1093/jbmr/zjae122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 06/18/2024] [Accepted: 07/08/2024] [Indexed: 08/12/2024]
Abstract
Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF.
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Affiliation(s)
- Wei Zhou
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Joel Ås
- Department of Medical Sciences, Uppsala University Hospital, Uppsala 75185, Sweden
| | - Catherine Shore-Lorenti
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton VIC 3168, Australia
| | - Hanh H Nguyen
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton VIC 3168, Australia
| | - Denise M van de Laarschot
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Shoshana Sztal-Mazer
- Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne VIC 3004, Australia
- Department of Public Health and Preventative Medicine, Monash University, Melbourne VIC 3004, Australia
| | - Vivian Grill
- Department of Endocrinology and Diabetes, Western Health, Melbourne VIC 3011, Australia
| | - Christian M Girgis
- Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, The Sydney University, Camperdown NSW 2050, Australia
| | - Bruno H Ch Stricker
- Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
| | - Bram C J van der Eerden
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Rajesh V Thakker
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom
- National Institute for Health Research Oxford Biomedical Research Centre, Oxford OX3 9DU, United Kingdom
| | - Natasha M Appelman-Dijkstra
- Department of Internal Medicine, division endocrinology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
| | - Mia Wadelius
- Department of Medical Sciences, Uppsala University Hospital, Uppsala 75185, Sweden
| | | | - Pär Hallberg
- Department of Medical Sciences, Uppsala University Hospital, Uppsala 75185, Sweden
| | - Annemieke J M H Verkerk
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Jeroen G J van Rooij
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Peter R Ebeling
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton VIC 3168, Australia
| | - M Carola Zillikens
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
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Zaki MK, Abed MN, Alassaf FA. Antidiabetic Agents and Bone Quality: A Focus on Glycation End Products and Incretin Pathway Modulations. J Bone Metab 2024; 31:169-181. [PMID: 39307518 PMCID: PMC11416877 DOI: 10.11005/jbm.2024.31.3.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/01/2024] [Accepted: 05/18/2024] [Indexed: 09/26/2024] Open
Abstract
Diabetes mellitus is associated with inadequate bone health and quality and heightened susceptibility to fractures, even in patients with normal or elevated bone mineral density. Elevated advanced glycation end-products (AGEs) and a suppressed incretin pathway are among the mechanisms through which diabetes affects the bone. Accordingly, the present review aimed to investigate the effects of antidiabetic medications on bone quality, primarily through AGEs and the incretin pathway. Google Scholar, Cochrane Library, and PubMed were used to examine related studies until February 2024. Antidiabetic medications influence AGEs and the incretin pathway directly or indirectly. Certain antidiabetic drugs including metformin, glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl-peptidase-4 (DDP-4) inhibitors, α-glucosidase inhibitors (AGIs), sodium-glucose co-transporter-2 inhibitors, and thiazolidinediones (TZDs), directly affect AGEs through multiple mechanisms. These mechanisms include decreasing the formation of AGEs and the expression of AGEs receptor (RAGE) in tissue and increasing serum soluble RAGE levels, resulting in the reduced action of AGEs. Similarly, metformin, GLP-1RA, DDP-4 inhibitors, AGIs, and TZDs may enhance incretin hormones directly by increasing their production or suppressing their metabolism. Additionally, these medications could influence AGEs and the incretin pathway indirectly by enhancing glycemic control. In contrast, sulfonylureas have not demonstrated any obvious effects on AGEs or the incretin pathway. Considering their favorable effects on AGEs and the incretin pathway, a suitable selection of antidiabetic drugs may facilitate more protective effects on the bone in diabetic patients.
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Affiliation(s)
- Muthanna K. Zaki
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul,
Iraq
| | - Mohammed N. Abed
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul,
Iraq
| | - Fawaz A. Alassaf
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul,
Iraq
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Maghami E, Sadighi A, Najafi AR. Fracture behavior of human cortical bone with high glycation content under dynamic loading. J Mech Behav Biomed Mater 2024; 155:106577. [PMID: 38759587 DOI: 10.1016/j.jmbbm.2024.106577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/29/2024] [Accepted: 05/08/2024] [Indexed: 05/19/2024]
Abstract
The present study simulates the fracture behavior of diabetic cortical bone with high levels of advanced glycation end-products (AGEs) under dynamic loading. We consider that the increased AGEs in diabetic cortical bone degrade the materials heterogeneity of cortical bone through a reduction in critical energy release rates of the microstructural features. To simulate the initiation and propagation of cracks, we implement a phase field fracture framework on 2D models of human tibia cortical microstructure. The simulations show that the mismatch between the fracture properties (e.g., critical energy release rate) of osteons and interstitial tissue due to high AGEs contents can change crack growth trajectories. The results show crack branching in the cortical microstructure under dynamic loading is affected by the mismatches related to AGEs. In addition, we observe cortical features such as osteons and cement lines can prevent multiple cracking under dynamic loading even with changing the mismatches due to high AGEs. Furthermore, under dynamic loading, some toughening mechanisms can be activated and deactivated with different AGEs contents. In conclusion, the current findings present that the combination of the loading type and materials heterogeneity of microstructural features can change the fracture response of diabetic cortical bone and its fragility.
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Affiliation(s)
- Ebrahim Maghami
- Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19104, USA
| | - Amirreza Sadighi
- Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19104, USA
| | - Ahmad R Najafi
- Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19104, USA.
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5
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Chavarry NGM, Abreu PVB, Feres-Filho EJ, Pereira DMT, Maia LC, Molon RSD. The effects of sodium alendronate on socket healing after tooth extraction: a systematic review of animal studies. Braz Oral Res 2024; 38:e038. [PMID: 38747825 PMCID: PMC11376628 DOI: 10.1590/1807-3107bor-2024.vol38.0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 11/07/2023] [Indexed: 05/25/2024] Open
Abstract
The aim of this systematic review was to answer the following question: "Does alendronate, a nitrogen-containing bisphosphonate, improve or impair alveolar socket healing after tooth extraction in animal models"? To this end, a systematic review of the literature was carried out in PubMed, Scopus, LILACS, Web of Science, as well as in the gray literature up to May 2023. Preclinical studies that evaluated alveolar healing after tooth extraction and the intake of sodium alendronate compared with placebo were included. Two investigators were responsible for screening the articles independently, extracting the data, and assessing their quality through the SYRCLE's RoB tool for randomized trials in animal studies. The study selection process, study characteristics, risk of bias in studies, impact of alendronate on bone healing, and certainty of evidence were described in text and table formats. Methodological differences among the studies were restricted to the synthesis methods. The synthesis of qualitative results followed the Synthesis Without Meta-analysis (SWiM) reporting guideline. From the 19 included studies, five were considered to have low risk, three were of unclear risk, and eleven presented a high risk of bias. The studies were considered heterogeneous regarding alendronate posology, including its dosage and route of administration. Furthermore, a variety of animal species, different age ranges, diverse teeth extracted, and exposure or not to ovariectomy contributed to the lack of parity of the selected studies. Our results indicated that alendronate monotherapy negatively affects the early phase of wound healing after tooth extraction in preclinical studies, suggesting that the bone resorption process after tooth extraction in animals treated with alendronate might impair the bone healing process of the extraction socket. In conclusion, alendronate administration restrains bone resorption, thereby delaying alveolar socket healing . Future studies should be conducted to validate these findings and to better understand the effects of alendronate therapy on oral tissues.
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Affiliation(s)
- Nilo Guliberto Martins Chavarry
- Universidade Federal do Rio de Janeiro - UFRJ, School of Dentistry, Department of Periodontology, Rio de Janeiro, RJ, Brazil
| | - Pedro Villas Boas Abreu
- Universidade Federal do Rio de Janeiro - UFRJ, School of Dentistry, Department of Periodontology, Rio de Janeiro, RJ, Brazil
| | - Eduardo Jorge Feres-Filho
- Universidade Federal do Rio de Janeiro - UFRJ, School of Dentistry, Department of Periodontology, Rio de Janeiro, RJ, Brazil
| | | | - Lucianne Cople Maia
- Universidade Federal do Rio de Janeiro - UFRJ, School of Dentistry, Department of Orthodontic and Pediatric Dentistry, Rio de Janeiro, RJ, Brazil
| | - Rafael Scaf De Molon
- Universidade Estadual Paulista - Unesp, School of Dentistry at Araçatuba, Department of Diagnosis and Surgery, Araçatuba, SP, Brazil
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6
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Maghami E, Najafi A. Microstructural fatigue fracture behavior of glycated cortical bone. Med Biol Eng Comput 2023; 61:3021-3034. [PMID: 37582979 DOI: 10.1007/s11517-023-02901-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 07/29/2023] [Indexed: 08/17/2023]
Abstract
The current study aims to simulate fatigue microdamage accumulation in glycated cortical bone with increased advanced glycation end-products (AGEs) using a phase field fatigue framework. We link the material degradation in the fracture toughness of cortical bone to the high levels of AGEs in this tissue. We simulate fatigue fracture in 2D models of cortical bone microstructure extracted from human tibias. The results present that the mismatch between the critical energy release rate of microstructural features (e.g., osteons and interstitial tissue) can alter crack initiation and propagation patterns. Moreover, the high AGEs content through the increased mismatch ratio can cause the activation or deactivation of bone toughening mechanisms under cyclic loading. The fatigue fracture simulations also show that the lifetime of diabetic cortical bone samples can be dependent on the geometry of microstructural features and the mismatch ratio between the features. Additionally, the results indicate that the trapped cracks in cement lines in the diabetic cortical microstructure can prevent further crack growth under cyclic loading. The present findings show that alterations in the materials heterogeneity of microstructural features can change the fatigue fracture response, lifetime, and fragility of cortical bone with high AGEs contents. Cortical bone models are created from microscopy images taken from the cortical cross-section of human tibias. Increased glycation contents in the cortical bone sample can change the crack growth trajectories.
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7
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Akasaka D, Iguchi S, Kaneko R, Yoshiga Y, Kajiwara D, Nakachi Y, Noma N, Tanaka K, Shimizu A, Hosoi F. Novel Bruton's tyrosine kinase inhibitor TAS5315 suppresses the progression of inflammation and joint destruction in rodent collagen-induced arthritis. PLoS One 2023; 18:e0282117. [PMID: 36821545 PMCID: PMC9949657 DOI: 10.1371/journal.pone.0282117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by autoantibody production, synovial inflammation, and joint destruction. Its pathogenesis is due to environmental factors and genetic backgrounds. Bruton's tyrosine kinase is a cytoplasmic non-receptor tyrosine kinase, expressed in most hematopoietic cell lineages, except T cells and plasma cells, and regulates various immune-related signaling pathways, thereby playing a crucial role in pathogenesis. Thus, inhibiting Bruton's tyrosine kinase may prove beneficial in treating autoimmune diseases. In the present study, we characterized Bruton's tyrosine kinase inhibitor, TAS5315, in vitro and evaluated its therapeutic effects in experimental arthritis models. TAS5315 markedly inhibited Bruton's tyrosine kinase enzyme activity and suppressed the B-cell receptor signaling pathway in Ramos cells. Moreover, it suppressed the expression of CD69, CD86, and MHC class II in mouse B lymphocytes and the production of TNF-α and MIP-1α in mouse macrophages and decreased bone resorption activity in mouse osteoclasts. Furthermore, it ameliorated the pathological changes in two rodent models of collagen-induced arthritis in vivo. TAS5315 improved bone mineral density and bone intensity. Thus, these results suggest that TAS5315 could be a promising therapeutic option for the treatment of rheumatoid arthritis.
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Affiliation(s)
- Daichi Akasaka
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
- * E-mail:
| | - Satoru Iguchi
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Ryusuke Kaneko
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Yohei Yoshiga
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Daisuke Kajiwara
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Yoshinori Nakachi
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Naruto Noma
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Kenji Tanaka
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Atsushi Shimizu
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Fumihito Hosoi
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
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Xu Z, Qi X, Bao M, Zhou T, Shi J, Xu Z, Zhou M, Boccaccini AR, Zheng K, Jiang X. Biomineralization inspired 3D printed bioactive glass nanocomposite scaffolds orchestrate diabetic bone regeneration by remodeling micromilieu. Bioact Mater 2023; 25:239-255. [PMID: 36817824 PMCID: PMC9929491 DOI: 10.1016/j.bioactmat.2023.01.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/10/2023] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Type II diabetes mellitus (TIIDM) remains a challenging clinical issue for both dentists and orthopedists. By virtue of persistent hyperglycemia and altered host metabolism, the pathologic diabetic micromilieu with chronic inflammation, advanced glycation end products accumulation, and attenuated biomineralization severely impairs bone regeneration efficiency. Aiming to "remodel" the pathologic diabetic micromilieu, we 3D-printed bioscaffolds composed of Sr-containing mesoporous bioactive glass nanoparticles (Sr-MBGNs) and gelatin methacrylate (GelMA). Sr-MBGNs act as a biomineralization precursor embedded in the GelMA-simulated extracellular matrix and release Sr, Ca, and Si ions enhancing osteogenic, angiogenic, and immunomodulatory properties. In addition to angiogenic and anti-inflammatory outcomes, this innovative design reveals that the nanocomposites can modulate extracellular matrix reconstruction and simulate biomineralization by activating lysyl oxidase to form healthy enzymatic crosslinked collagen, promoting cell focal adhesion, modulating osteoblast differentiation, and boosting the release of OCN, the noncollagenous proteins (intrafibrillar mineralization dependent), and thus orchestrating osteogenesis through the Kindlin-2/PTH1R/OCN axis. This 3D-printed bioscaffold provides a multifunctional biomineralization-inspired system that remodels the "barren" diabetic microenvironment and sheds light on the new bone regeneration approaches for TIIDM.
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Affiliation(s)
- Zeqian Xu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,College of Stomatology, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Center for Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Key Laboratory of Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China
| | - Xuanyu Qi
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,College of Stomatology, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Center for Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Key Laboratory of Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China
| | - Minyue Bao
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,College of Stomatology, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Center for Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Key Laboratory of Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China
| | - Tian Zhou
- National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200023, People's Republic of China
| | - Junfeng Shi
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,College of Stomatology, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Center for Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Key Laboratory of Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China
| | - Zhiyan Xu
- Institute of Biomaterials, University of Erlangen-Nuremberg, Cauerstrasse 6, 91058, Erlangen, Germany
| | - Mingliang Zhou
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,College of Stomatology, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Center for Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Key Laboratory of Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China
| | - Aldo R. Boccaccini
- Institute of Biomaterials, University of Erlangen-Nuremberg, Cauerstrasse 6, 91058, Erlangen, Germany
| | - Kai Zheng
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, People's Republic of China,Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, People's Republic of China,Corresponding author. Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
| | - Xinquan Jiang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,College of Stomatology, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Center for Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,National Clinical Research Center for Oral Diseases, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Key Laboratory of Stomatology, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China,Corresponding author. Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.
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Bonicelli A, Tay T, Cobb JP, Boughton OR, Hansen U, Abel RL, Zioupos P. Association between nanoscale strains and tissue level nanoindentation properties in age-related hip-fractures. J Mech Behav Biomed Mater 2023; 138:105573. [PMID: 36525874 DOI: 10.1016/j.jmbbm.2022.105573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/21/2022] [Accepted: 11/15/2022] [Indexed: 11/24/2022]
Abstract
Measurement of the properties of bone as a material can happen in various length scales in its hierarchical and composite structure. The aim of this study was to test the tissue level properties of clinically-relevant human bone samples which were collected from donors belonging to three groups: ageing donors who suffered no fractures (Control); untreated fracture patients (Fx-Untreated) and patient who experienced hip fracture despite being treated with bisphosphonates (Fx-BisTreated). Tissue level properties were assessed by (a) nanoindentation and (b) synchrotron tensile tests (STT) where strains were measured at the 'tissue', 'fibril' and 'mineral' levels by using simultaneous Wide-angle - (WAXD) and Small angle- X-ray diffraction (SAXD). The composition was analysed by thermogravimetric analysis and material level endo- and exo-thermic reactions by differential scanning calorimetry (TGA/DSC3+). Irrespective of treatment fracture donors exhibited significantly lower tissue, fibril and mineral strain at the micro and nanoscale respectively and had a higher mineral content than controls. In nanoindentation only nanohardness was significantly greater for Controls and Fx-BisTreated versus Fx-Untreated. The other nanoindentation parameters did not vary significantly across the three groups. There was a highly significant positive correlation (p < 0.001) between organic content and tissue level strain behaviour. Overall hip-fractures were associated with lower STT nanostrains and it was behaviour measured by STT which proved to be a more effective approach for predicting fracture risk because evidently it was able to demonstrate the mechanical deficit for the bone tissue of the donors who had experienced fractures.
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Affiliation(s)
- Andrea Bonicelli
- School of Natural Sciences, University of Central Lancashire, Preston, PR1 2HE, UK; Musculoskeletal & Medicolegal Research Group, Cranfield Forensic Institute, Defence Academy of the UK, Shrivenham, Swindon, SN6 8LA, UK
| | - Tabitha Tay
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - Justin P Cobb
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - Oliver R Boughton
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - Ulrich Hansen
- The Biomechanics Group, Department of Mechanical Engineering, Faculty of Engineering, London, SW7 2AZ, Imperial College London, London, UK
| | - Richard L Abel
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - Peter Zioupos
- Musculoskeletal & Medicolegal Research Group, Cranfield Forensic Institute, Defence Academy of the UK, Shrivenham, Swindon, SN6 8LA, UK.
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10
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Hussain M, Khan F, Al Hadidi S. The use of bone-modifying agents in multiple myeloma. Blood Rev 2023; 57:100999. [PMID: 36050125 DOI: 10.1016/j.blre.2022.100999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 01/28/2023]
Abstract
Multiple myeloma is a hematological neoplasm characterized by abnormal proliferation of plasma cells in the bone marrow and is usually associated with increased bone pain and skeletal-related events such as pathological fracture and/or spinal cord compression. Myeloma bone disease results in changes in the bone-marrow microenvironment evidenced by increased osteoclastic activity and/or decreased osteoblastic activity, which negatively affect quality of life. Treatment of myeloma bone disease includes bisphosphonates or denosumab (bone-modifying agents). These agents do not induce the formation of new bone or repair existing bone damage, but they can decrease bone pain and the risk of pathological fracture. While these agents improve quality of life, it is not known whether they improve overall survival. This review focuses on different classes of bone-modifying agents, their mechanisms of action, time of initiation, duration of therapy, and potential survival benefits.
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Affiliation(s)
- Munawwar Hussain
- Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Fatima Khan
- Department of Hematology Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Samer Al Hadidi
- Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
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11
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Brandt IAG, Jessen MH, Rimestad DE, Højgaard MKF, Vestergaard P. Advanced glycation end products and bone - How do we measure them and how do they correlate with bone mineral density and fractures? A systematic review and evaluation of precision of measures. Bone 2022; 165:116569. [PMID: 36174927 DOI: 10.1016/j.bone.2022.116569] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 08/20/2022] [Accepted: 09/21/2022] [Indexed: 11/24/2022]
Abstract
The role of advanced glycation end products (AGEs) in bone fragility especially in diabetic bone disease is increasingly recognized and researched. As skeletal frailty in diabetes does not correlate to bone mineral density (BMD) in the same way as in postmenopausal osteoporosis, BMD may not be a suitable measure of bone quality in persons with diabetes. Abundant research exists upon the effect of AGEs on bone, and though full understanding of the mechanisms of actions does not yet exist, there is little doubt of the clinical relevance. Thus, the measurement of AGEs as well as possible treatment effects on AGEs have become issues of interest. The aim of this report is to summarize results of measurements of AGEs. It consists of a systematic review of the existing literature on AGE measurements in clinical research, an evaluation of the precision of skin autofluorescence (SAF) measurement by AGE Reader® (Diagnoptics), and a short commentary on treatment of osteoporosis in patients with and without diabetes with respects to AGEs. We conclude that various AGE measures correlate well, both fluorescent and non-fluorescent and in different tissues, and that more than one target of measure may be used. However, pentosidine has shown good correlation with both bone measures and fracture risk in existing literature and results on SAF as a surrogate measurement is promising as some corresponding associations with fracture risk and bone measures are reported. As SAF measurements performed with the AGE Reader® display high precision and allow for a totally noninvasive procedure, conducting AGE measurements using this method has great potential and further research of its applicability is encouraged.
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12
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Ding Y, Cui Y, Yang X, Wang X, Tian G, Peng J, Wu B, Tang L, Cui CP, Zhang L. Anti-RANKL monoclonal antibody and bortezomib prevent mechanical unloading-induced bone loss. J Bone Miner Metab 2021; 39:974-983. [PMID: 34212247 DOI: 10.1007/s00774-021-01246-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 06/14/2021] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Bone loss is a major health concern for astronauts during long-term spaceflight and for patients during prolonged bed rest or paralysis. It is essential to develop therapeutic strategies to combat the bone loss occurring in people afflicted with disuse atrophy on earth as well as in astronauts in space, especially during prolonged missions. Although several drugs have been demonstrated for treating postmenopausal osteoporosis or bone-related diseases, their effects on microgravity-induced bone loss are still unclear. MATERIALS AND METHODS Here, we employed the hindlimb-unloading (HLU) tail suspension model and compared the preventive efficiencies of five agents including alendronate (ALN), raloxifene (Rox), teriparatide (TPTD), anti-murine RANKL monoclonal antibody (anti-RANKL) and proteasome inhibitor bortezomib (Bzb) on mechanical unloading-induced bone loss. Bone mineral density (BMD) was measured by quantitative computed tomography. The osteoblastic and osteoclastic activity were measured by serum ELISA, histology analysis, and histomorphometric analysis. RESULTS Compared to the control, ALN and anti-RANKL antibody could restore bone mass close to sham levels by inhibiting bone resorption. Bzb could increase the whole bone mass and strength by inhibiting bone resorption and promoting bone formation simultaneously. Meanwhile, Rox did not affect bone loss caused by HLU. TPTD stimulated cortical bone formation but the total bone mass was not increased significantly. CONCLUSIONS We demonstrated for the first time that anti-RANKL antibody and Bzb had a positive effect on preventing mechanical unloading-induced bone loss. This finding puts forward the potential use of anti-RANKL and Bzb on bone loss therapies or prophylaxis of astronauts in spaceflight.
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Affiliation(s)
- Yi Ding
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China
| | - Yu Cui
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China
| | - Xi Yang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China
- General Hospital of Xinjiang Military Command, Urumqi, 830000, Xinjiang, China
| | - Xiaolu Wang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China
| | - Guangzhao Tian
- Lab of Orthopaedics of Department of Orthopaedics, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jiang Peng
- Lab of Orthopaedics of Department of Orthopaedics, Chinese PLA General Hospital, Beijing, 100853, China
| | - Bo Wu
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China
| | - Li Tang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China
| | - Chun-Ping Cui
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.
| | - Lingqiang Zhang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.
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13
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Karim L, Kwaczala A, Vashishth D, Judex S. Dose-dependent effects of pharmaceutical treatments on bone matrix properties in ovariectomized rats. Bone Rep 2021; 15:101137. [PMID: 34660852 PMCID: PMC8503587 DOI: 10.1016/j.bonr.2021.101137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/23/2021] [Accepted: 09/28/2021] [Indexed: 01/22/2023] Open
Abstract
As both anabolic and anti-catabolic osteoporosis drugs affect bone formation and resorption processes, they may contribute to bone's overall mechanical behavior by altering the quality of the bone matrix. We used an ovariectomized rat model and a novel fracture mechanics approach to investigate whether treatment with an anabolic (parathyroid hormone) or anti-catabolic (alendronate) osteoporosis drugs will alter the organic and mineral matrix components and consequently cortical bone fracture toughness. Ovariectomized (at 5 months age) rats were treated with either parathyroid hormone or alendronate at low and high doses for 6 months (age 6–12 months). Specifically, treatment groups included untreated ovariectomized controls (n = 9), high-dose alendronate (n = 10), low-dose alendronate (n = 9), high-dose parathyroid hormone (n = 10), and low-dose parathyroid hormone (n = 9). After euthanasia, cortical microbeams from the lateral quadrant were extracted, notched, and tested in 3-point bending to measure fracture toughness. Portions of the bone were used to measure changes in the 1) organic matrix through quantification of advanced glycation end-products (AGEs) and non-collagenous proteins, and 2) mineral matrix through assessment of mineral crystallinity. Compared to the ovariectomized group, rats treated with high doses of parathyroid hormone and alendronate had significantly increased cortical bone fracture toughness, which corresponded primarily to increased non-collagenous proteins while there was no change in AGEs. Additionally, low-dose PTH treatment increased matrix crystallinity and decreased AGE levels. In summary, ovariectomized rats treated with pharmaceutical drugs had increased non-collagenous matrix proteins and improved fracture toughness compared to controls. Further investigation is required for different doses and longer treatment periods.
Alendronate increases non-collagenous proteins and improves fracture toughness. Parathyroid hormone also increases collagen maturity and mineral crystallinity. Both treatments minimize accumulation of advanced glycation end-products.
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Affiliation(s)
- Lamya Karim
- Department of Bioengineering, University of Massachusetts Dartmouth, Dartmouth, MA, USA
| | - Andrea Kwaczala
- Department of Biomedical Engineering, Western New England University, Springfield, MA, USA
| | - Deepak Vashishth
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Stefan Judex
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
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14
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Vancea A, Serban O, Fodor D. Relationship between Osteopontin and Bone Mineral Density. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2021; 17:509-516. [PMID: 35747863 DOI: 10.4183/aeb.2021.509] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Recent studies suggest that osteopontin (OPN) could be used as an early marker for the diagnosis of bone disorders. Considering the contradictory opinions in the literature, the objective of this systematic review is to analyse the current information regarding the relationship between OPN and bone mineral density (BMD), which represents an important process in the development of osteoporosis. We performed a literature search of clinical trials using the PubMed database, published between 1999-2020, and identified 7 studies that were eligible for analysis. The eligibility criteria were based on studies that analysed the relationship between osteopontin and bone mineral density on human subjects. Conclusion: serum OPN levels might be used as a biomarker of the early diagnosis of osteoporosis in postmenopausal women, with or without osteoporotic vertebral fractures.
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Affiliation(s)
- A Vancea
- "Iuliu Hațieganu" University of Medicine and Pharmacy, 2 Internal Medicine Department, Cluj-Napoca, Romania
| | - O Serban
- "Iuliu Hațieganu" University of Medicine and Pharmacy, 2 Internal Medicine Department, Cluj-Napoca, Romania
| | - D Fodor
- "Iuliu Hațieganu" University of Medicine and Pharmacy, 2 Internal Medicine Department, Cluj-Napoca, Romania
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15
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Frank M, Grabos A, Reisinger AG, Burr DB, Pahr DH, Allen MR, Thurner PJ. Effects of anti-resorptive treatment on the material properties of individual canine trabeculae in cyclic tensile tests. Bone 2021; 150:115995. [PMID: 33940224 DOI: 10.1016/j.bone.2021.115995] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/25/2021] [Accepted: 04/28/2021] [Indexed: 01/22/2023]
Abstract
Osteoporosis is defined as a decrease of bone mass and strength, as well as an increase in fracture risk. It is conventionally treated with antiresorptive drugs, such as bisphosphonates (BPs) and selective estrogen receptor modulators (SERMs). Although both drug types successfully decrease the risk of bone fractures, their effect on bone mass and strength is different. For instance, BP treatment causes an increase of bone mass, stiffness and strength of whole bones, whereas SERM treatment causes only small (4%) increases of bone mass, but increased bone toughness. Such improved mechanical behavior of whole bones can be potentially related to the bone mass, bone structure or material changes. While bone mass and architecture have already been investigated previously, little is known about the mechanical behavior at the tissue/material level, especially of trabecular bone. As such, the goal of the work presented here was to fill this gap by performing cyclic tensile tests in a wet, close to physiologic environment of individual trabeculae retrieved from the vertebrae of beagle dogs treated with alendronate (a BP), raloxifene (a SERM) or without treatments. Identification of material properties was performed with a previously developed rheological model and of mechanical properties via fitting of envelope curves. Additionally, tissue mineral density (TMD) and microdamage formation were analyzed. Alendronate treatment resulted in a higher trabecular tissue stiffness and strength, associated with higher levels of TMD. In contrast, raloxifene treatment caused a higher trabecular toughness, pre-dominantly in the post-yield region. Microdamage formation during testing was not affected by either anti-resorptive treatment regimens. These findings highlight that the improved mechanical behavior of whole bones after anti-resorptive treatment is at least partly caused by improved material properties, with different mechanisms for alendronate and raloxifene. This study further shows the power of performing a mechanical characterization of trabecular bone at the level of individual trabeculae for better understanding of clinically relevant mechanical behavior of bone.
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Affiliation(s)
- Martin Frank
- Institute of Lightweight Design and Structural Biomechanics, TU Wien, Gumpendorfer Straße 7, 1060 Vienna, Austria.
| | - Andreas Grabos
- Institute of Lightweight Design and Structural Biomechanics, TU Wien, Gumpendorfer Straße 7, 1060 Vienna, Austria; Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, 340 West 10th Street Fairbanks Hall, Suite 6200, Indianapolis, USA
| | - Andreas G Reisinger
- Department of Anatomy and Biomechanics, Division Biomechanics, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria.
| | - David B Burr
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, 340 West 10th Street Fairbanks Hall, Suite 6200, Indianapolis, USA.
| | - Dieter H Pahr
- Institute of Lightweight Design and Structural Biomechanics, TU Wien, Gumpendorfer Straße 7, 1060 Vienna, Austria; Department of Anatomy and Biomechanics, Division Biomechanics, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria.
| | - Matthew R Allen
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, 340 West 10th Street Fairbanks Hall, Suite 6200, Indianapolis, USA.
| | - Philipp J Thurner
- Institute of Lightweight Design and Structural Biomechanics, TU Wien, Gumpendorfer Straße 7, 1060 Vienna, Austria.
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16
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Maghami E, Josephson TO, Moore JP, Rezaee T, Freeman TA, Karim L, Najafi AR. Fracture behavior of human cortical bone: Role of advanced glycation end-products and microstructural features. J Biomech 2021; 125:110600. [PMID: 34246065 DOI: 10.1016/j.jbiomech.2021.110600] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 06/21/2021] [Accepted: 06/24/2021] [Indexed: 01/22/2023]
Abstract
Diabetes is associated with increased fracture risk in human bone, especially in the elderly population. In the present study, we investigate how simulated advanced glycation end-products (AGEs) and materials heterogeneity affect crack growth trajectory in human cortical bone. We used a phase field fracture framework on 2D models of cortical microstructure created from human tibias to analyze crack propagation. The increased AGEs level results in a higher rate of crack formation. The simulations also indicate that the mismatch between the fracture properties (e.g., critical energy release rate) of osteons and interstitial tissue can alter the post-yielding behavior. The results show that if the critical energy release rate of cement lines is lower than that of osteons and the surrounding interstitial matrix, cracks can be arrested by cement lines. Additionally, activation of toughening mechanisms such as crack merging and branching depends on bone microstructural morphology (i.e., osteons geometrical parameters, canals, and lacunae porosities). In conclusion, the present findings suggest that materials heterogeneity of microstructural features and the crack-microstructure interactions can play important roles in bone fragility.
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Affiliation(s)
- Ebrahim Maghami
- Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19104, USA
| | - Timothy O Josephson
- Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19104, USA
| | - Jason P Moore
- Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19104, USA
| | - Taraneh Rezaee
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, Dartmouth, MA 02747, USA
| | - Theresa A Freeman
- Thomas Jefferson University Division of Orthopaedic Research, Philadelphia, PA 19107, USA
| | - Lamya Karim
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, Dartmouth, MA 02747, USA
| | - Ahmad R Najafi
- Department of Mechanical Engineering and Mechanics, Drexel University, Philadelphia, PA 19104, USA.
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17
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Zhou W, van Rooij JGJ, Ebeling PR, Verkerk AJMH, Zillikens MC. The Genetics of Atypical Femur Fractures-a Systematic Review. Curr Osteoporos Rep 2021; 19:123-130. [PMID: 33587247 PMCID: PMC8016774 DOI: 10.1007/s11914-021-00658-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Atypical femur fractures (AFFs) are rare subtrochanteric or diaphyseal fractures regarded as side effects of bisphosphonates (BPs), possibly with a genetic background. Here, we summarize the most recent knowledge about genetics of AFFs. RECENT FINDINGS AFF has been reported in 57 patients with seven different monogenic bone disorders including hypophosphatasia and osteogenesis imperfecta; 56.1% had never used BPs, while 17.5% were diagnosed with the disorder only after the AFF. Gene mutation finding in familial and sporadic cases identified possible AFF-related variants in the GGPS1 and ATRAID genes respectively. Functional follow-up studies of mutant proteins showed possible roles in AFF. A recent small genome-wide association study on 51 AFF cases did not identify significant hits associated with AFF. Recent findings have strengthened the hypothesis that AFFs have underlying genetic components but more studies are needed in AFF families and larger cohorts of sporadic cases to confirm previous results and/or find novel gene variants involved in the pathogenesis of AFFs.
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Affiliation(s)
- Wei Zhou
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jeroen G J van Rooij
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
- Department of Neurology & Alzheimer Center, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Peter R Ebeling
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia
| | - Annemieke J M H Verkerk
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - M Carola Zillikens
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
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18
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Kanazawa I, Inaba M, Inoue D, Uenishi K, Saito M, Shiraki M, Suzuki A, Takeuchi Y, Hagino H, Fujiwara S, Sugimoto T. Executive summary of clinical practice guide on fracture risk in lifestyle diseases. J Bone Miner Metab 2020; 38:746-758. [PMID: 32892240 DOI: 10.1007/s00774-020-01149-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/23/2020] [Indexed: 12/16/2022]
Abstract
Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.
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Affiliation(s)
- Ippei Kanazawa
- Kanazawa Diabetes and Osteoporosis Clinic, 990-2-1 Enya-cho, Izumo, Shimane, 693-0021, Japan.
| | - Masaaki Inaba
- Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Inoue
- Third Department of Medicine, Teikyo University Chiba Medical Center, Chiba, Japan
| | - Kazuhiro Uenishi
- Division of Nutritional Physiology, Kagawa Nutrition University, Saitama, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Masataka Shiraki
- Research Institute and Practice for Involutional Diseases, Nagano, Japan
| | - Atsushi Suzuki
- Department of Endocrinology and Metabolism, Fujita Health University, Aichi, Japan
| | - Yasuhiro Takeuchi
- Endocrine Center, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Hiroshi Hagino
- School of Health Science Faculty of Medicine, Tottori University, Tottori, Japan
| | - Saeko Fujiwara
- Department of Pharmacy, Yasuda Women's University, Hiroshima, Japan
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19
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Saeki C, Saito M, Oikawa T, Nakano M, Torisu Y, Saruta M, Tsubota A. Effects of denosumab treatment in chronic liver disease patients with osteoporosis. World J Gastroenterol 2020; 26:4960-4971. [PMID: 32952342 PMCID: PMC7476181 DOI: 10.3748/wjg.v26.i33.4960] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Effective treatment of osteoporosis is essential for improving morbidity and health-related quality of life in chronic liver disease (CLD) patients. Denosumab has been shown to increase bone mineral density (BMD) and decrease the risk of osteoporotic fracture in the general population. However, there are few reports evaluating the efficacy of denosumab in CLD patients.
AIM To investigated the effects and safety of denosumab in CLD patients with osteoporosis.
METHODS Sixty CLD patients with osteoporosis were subcutaneously administered denosumab once every 6 mo. The study period for evaluating efficacy and safety was 12 mo. Changes from baseline in BMD at the lumbar spine, femoral neck, and total hip were evaluated at 12 mo of denosumab treatment. Bone turnover and quality were assessed by measuring serum tartrate-resistant acid phosphatase-5b (bone resorption marker), serum total procollagen type I N-terminal propeptide (bone formation maker), and plasma pentosidine (bone quality marker).
RESULTS Among the 405 CLD patients, 138 (34.1%) patients were diagnosed with osteoporosis; among these, 78 patients met the exclusion criteria and thus 60 patients were finally included in the present study. The median percentage changes from baseline to 12 mo of denosumab treatment in BMD at the lumbar spine, femoral neck, and total hip were +4.44%, +3.71%, and +4.03%, respectively. Denosumab significantly improved BMD, regardless of sex, patient age, and presence of liver cirrhosis. Serum tartrate-resistant acid phosphatase-5b and procollagen type I N-terminal propeptide levels constantly and significantly declined after denosumab treatment (P < 0.001). Plasma pentosidine levels were also significantly lower at 12 mo of treatment (P = 0.010). No patients experienced fractures and moderate-to-severe adverse events, except for transient hypocalcemia.
CONCLUSION Denosumab treatment was safe and increased BMD, suppressed bone turnover, and improved bone quality marker levels in CLD patients with osteoporosis, irrespective of differences in baseline characteristics.
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Affiliation(s)
- Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 1058461, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo 1058461, Japan
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20
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Ma S, Goh EL, Tay T, Wiles CC, Boughton O, Churchwell JH, Wu Y, Karunaratne A, Bhattacharya R, Terrill N, Cobb JP, Hansen U, Abel RL. Nanoscale mechanisms in age-related hip-fractures. Sci Rep 2020; 10:14208. [PMID: 32848149 PMCID: PMC7450077 DOI: 10.1038/s41598-020-69783-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/13/2020] [Indexed: 01/12/2023] Open
Abstract
Nanoscale mineralized collagen fibrils may be important determinants of whole-bone mechanical properties and contribute to the risk of age-related fractures. In a cross-sectional study nano- and tissue-level mechanics were compared across trabecular sections from the proximal femora of three groups (n = 10 each): ageing non-fractured donors (Controls); untreated fracture patients (Fx-Untreated); bisphosphonate-treated fracture patients (Fx-BisTreated). Collagen fibril, mineral and tissue mechanics were measured using synchrotron X-Ray diffraction of bone sections under load. Mechanical data were compared across groups, and tissue-level data were regressed against nano. Compared to controls fracture patients exhibited significantly lower critical tissue strain, max strain and normalized strength, with lower peak fibril and mineral strain. Bisphosphonate-treated exhibited the lowest properties. In all three groups, peak mineral strain coincided with maximum tissue strength (i.e. ultimate stress), whilst peak fibril strain occurred afterwards (i.e. higher tissue strain). Tissue strain and strength were positively and strongly correlated with peak fibril and mineral strains. Age-related fractures were associated with lower peak fibril and mineral strain irrespective of treatment. Indicating earlier mineral disengagement and the subsequent onset of fibril sliding is one of the key mechanisms leading to fracture. Treatments for fragility should target collagen-mineral interactions to restore nano-scale strain to that of healthy bone.
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Affiliation(s)
- Shaocheng Ma
- Department of Mechanical Engineering, Faculty of Engineering, Imperial College London, London, SW7 2AZ, UK.,MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - En Lin Goh
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - Tabitha Tay
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - Crispin C Wiles
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK.,Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
| | - Oliver Boughton
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - John H Churchwell
- Department of Medical Physics and Biomedical Engineering, University College London, London, WCIE 6BT, UK
| | - Yong Wu
- Centre for Medicine, University of Leicester Medical School, Leicester, LE1 7HA, UK
| | - Angelo Karunaratne
- Department of Mechanical Engineering, Faculty of Engineering, University of Moratuwa, Moratuwa, 10400, Sri Lanka
| | - Rajarshi Bhattacharya
- St. Mary's Hospital, North West London Major Trauma Centre, Imperial College, London, W2 1NY, UK
| | - Nick Terrill
- Diamond Light Source, Diamond House, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
| | - Justin P Cobb
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK
| | - Ulrich Hansen
- Department of Mechanical Engineering, Faculty of Engineering, Imperial College London, London, SW7 2AZ, UK
| | - Richard L Abel
- MSk Laboratory, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W6 8PR, UK.
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21
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Otaka A, Yamaguchi T, Saisho R, Hiraga T, Iwasaki Y. Bone-targeting phospholipid polymers to solubilize the lipophilic anticancer drug. J Biomed Mater Res A 2020; 108:2090-2099. [PMID: 32323471 DOI: 10.1002/jbm.a.36968] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/19/2020] [Accepted: 03/28/2020] [Indexed: 12/31/2022]
Abstract
Current chemotherapy methods have limited effectiveness in eliminating bone metastasis, which leads to a poor prognosis associated with severe bone disorders. To provide regional chemotherapy for this metastatic tumor, a bone-targeting drug carrier was produced by introducing the osteotropic bisphosphonate alendronate (ALN) units into an amphiphilic phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate). The polymer can form nanoparticles with a diameter of less than 30 nm; ALN units were exposed to the outer layer of the particle. A simple mixing procedure was used to encapsulate a hydrophobic anticancer drug, known as docetaxel (DTX), in the polymer nanoparticle, providing a uniform solution of a polymer-DTX complex in the aqueous phase. The complex showed anticancer activities against several breast cancer cell lines, and the complex formation did not hamper the pharmacological effect of DTX. The fluorescence observations evaluated by an in vivo imaging system and fluorescence microscopy showed that the addition of ALN to the polymer-DTX complex enhanced bone accumulation. Bone-targeting phospholipid polymers are potential solubilizing excipients used to formulate DTX and deliver the hydrophobic drug to bone tissues by blood administration.
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Affiliation(s)
| | - Tomoki Yamaguchi
- Department of Chemistry and Materials Engineering Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka, Japan
| | - Ryoya Saisho
- Department of Chemistry and Materials Engineering Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka, Japan
| | - Toru Hiraga
- Department of Histology and Cell Biology, Matsumoto Dental University, Nagano, Japan
| | - Yasuhiko Iwasaki
- ORDIST, Kansai University, Osaka, Japan.,Department of Chemistry and Materials Engineering Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka, Japan
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22
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Ramchand SK, Seeman E. Reduced Bone Modeling and Unbalanced Bone Remodeling: Targets for Antiresorptive and Anabolic Therapy. Handb Exp Pharmacol 2020; 262:423-450. [PMID: 32232792 DOI: 10.1007/164_2020_354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bone loss during advancing age is the net result of reduced modeling-based bone formation upon the outer (periosteal) envelope and unbalanced remodeling by basic multicellular units (BMUs) upon the three (intracortical, endocortical, and trabecular) components of the inner (endosteal) bone envelope. Each BMU deposits less bone than resorbed, reducing total bone volume and deteriorating the microstructure of the diminished residual bone volume.Antiresorptive agents like bisphosphonates reduce, but do not abolish, the rate of bone remodeling - fewer BMUs remodel, "turn over," the volume of bone. Residual unbalanced remodeling continues to slowly reduce total bone volume and deteriorate bone microstructure. By contrast, denosumab virtually abolishes remodeling so the decrease in bone volume and the deterioration in microstructure cease. The less remodeled matrix remains, leaving more time to complete the slow process of secondary mineralization which reduces the heterogeneity of matrix mineralization and allows it to become glycosylated, changes that may make the smaller and microstructurally deteriorated bone volume more brittle. Neither class of antiresorptive restores bone volume or its microstructure, despite increases in bone mineral density misleadingly suggesting otherwise. Nevertheless, these agents reduce vertebral and hip fractures by 50-60% but only reduce nonvertebral fractures by 20-30%.Restoring bone volume, microstructure, and material composition, "curing" bone fragility, may be partly achieved using anabolic therapy. Teriparatide, and probably abaloparatide, produce mainly remodeling-based bone formation by acting on BMUs existing in their resorption, reversal, or formation phase at the time of treatment and by promoting bone formation in newly initiated BMUs. Romosozumab produces modeling-based bone formation almost exclusively and decreases the surface extent of bone resorption. All three anabolic agents reduce vertebral fracture risk relative to untreated controls; parathyroid hormone 1-34 and romosozumab reduce vertebral fracture risk more greatly than risedronate or alendronate, respectively. Evidence for nonvertebral or hip fracture risk reduction relative to untreated or antiresorptive-treated controls is lacking or inconsistent. Only one study suggests sequential romosozumab followed by alendronate reduces vertebral, nonvertebral, and hip fracture risk compared to continuous alendronate alone. Whether combined antiresorptive and anabolic therapy result in superior fracture risk reduction than monotherapy is untested.
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Affiliation(s)
- Sabashini K Ramchand
- Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Harvard University, Boston, MA, USA.
- Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Melbourne, VIC, Australia.
| | - Ego Seeman
- Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Melbourne, VIC, Australia
- Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, VIC, Australia
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23
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Atypical femoral fractures from bisphosphonate in cancer patients - Review. J Bone Oncol 2019; 18:100259. [PMID: 31497503 PMCID: PMC6722257 DOI: 10.1016/j.jbo.2019.100259] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/13/2019] [Accepted: 08/21/2019] [Indexed: 02/08/2023] Open
Abstract
Bisphosphonates are commonly used in patients with metastatic bone disease to prevent skeletal related events. Atypical femur fracture is a known complication of long-term bisphosphonate use but the incidence in cancer patients and pathogenesis are not well known. Several mechanisms of pathogenesis have been proposed including altered angiogenesis, altered bone mechanical properties, micro damage and bone remodeling suppression. Atypical femur fractures are atraumatic or minimally traumatic fractures in the sub trochanteric region or the femoral shaft. Awareness of atypical femur fractures is critical to diagnose and treat them in a timely manner. There is a paucity of data regarding the management of atypical femur fracture in patients with malignancy. Management options of atypical femur fractures include stopping bisphosphonates, initiating calcium/vitamin D supplementation and either surgery with internal fixation or conservative management. In the future, it will be important to explore the effect of continuous vs. intermittent exposure, cumulative dose and length of exposure on the incidence of this complication. Herein, we review the epidemiology, risk factors, management options and proposed mechanisms of pathogenesis of atypical femur fractures.
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Key Words
- AFF, atypical femur fracture
- AGE, advanced glycation end products
- ASBMR, American Society of Bone and Mineral Research
- Atypical femur fracture
- BP, bisphosphonate
- Bisphosphonates
- Bone metastasis
- Bone remodeling
- CI, confidence interval
- CT, computed tomography
- Denosumab
- GGPPS, geranyl geranyl pyrophosphate synthase Her2, human epidermal growth factor receptor
- IM, intramedullary
- IV, intravenous
- MGUS, monoclonal gammopathy of unknown significance
- MRI, magnetic resonance imaging
- ONJ, osteonecrosis of the jaw
- OR, odds ratio
- ORIF, open reduction internal fixation
- RCT, randomized clinical trial
- VEGF, vascular endothelial growth factor
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24
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Ohishi T, Fujita T, Suzuki D, Nishida T, Asukai M, Matsuyama Y. Serum homocysteine levels are affected by renal function during a 3-year period of minodronate therapy in female osteoporotic patients. J Bone Miner Metab 2019; 37:319-326. [PMID: 29603071 DOI: 10.1007/s00774-018-0920-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 03/04/2018] [Indexed: 01/22/2023]
Abstract
Serum homocysteine is a possible marker to indicate bone quality. However, it is not clear whether changes are seen in serum homocysteine levels with long-term bisphosphonate therapy. We aimed to investigate the factors affecting serum homocysteine levels during a 3-year period of monthly minodronate therapy in osteoporotic women, and to examine if the serum homocysteine levels could reflect some aspects of bone metabolism. The study included 43 patients (age 72.3 ± 7.0 years) undergoing treatment for osteoporosis for the first time (New group) and 35 patients (age 74.4 ± 8.2 years) who switched from alendronate or risedronate to minodronate (Switch group). Minodronate (50 mg/every 4 weeks) was administered for 36 months. Lumbar, femoral neck, and total hip bone mineral densities (BMD), and serum homocysteine levels were monitored at baseline and after 9, 18, 27, and 36 months of treatment. Lumbar BMD increased significantly in both groups (New group 11.4%, Switch group 6.2%). However, femoral neck and total hip BMDs increased only in the New group (femoral neck 3.6%, total hip 4.1%). Serum homocysteine levels increased significantly at 18 and 27 months in all subjects. Multiple linear regression analysis revealed that changes in homocysteine levels during 18, 27, and 36 months significantly correlated with changes in creatinine clearance during the same corresponding periods (18 months: B = - 0.472, p = 0.003; 27 months: B = - 0.375, p = 0.021; 36 months: B = - 0.445, p = 0.012). Thus, serum homocysteine levels possibly reflect renal function instead of bone metabolism during minodronate therapy.
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Affiliation(s)
- Tsuyoshi Ohishi
- Department of Orthopedic Surgery, Enshu Hospital, 1-1-1 Chuo, Naka-ku, Hamamatsu, Shizuoka, 430-0929, Japan.
| | - Tomotada Fujita
- Department of Orthopedic Surgery, Enshu Hospital, 1-1-1 Chuo, Naka-ku, Hamamatsu, Shizuoka, 430-0929, Japan
| | - Daisuke Suzuki
- Department of Orthopedic Surgery, Enshu Hospital, 1-1-1 Chuo, Naka-ku, Hamamatsu, Shizuoka, 430-0929, Japan
| | - Tatsuya Nishida
- Department of Orthopedic Surgery, Enshu Hospital, 1-1-1 Chuo, Naka-ku, Hamamatsu, Shizuoka, 430-0929, Japan
| | - Mitsuru Asukai
- Department of Orthopedic Surgery, Enshu Hospital, 1-1-1 Chuo, Naka-ku, Hamamatsu, Shizuoka, 430-0929, Japan
| | - Yukihiro Matsuyama
- Department of Orthopedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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25
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Picke AK, Campbell G, Napoli N, Hofbauer LC, Rauner M. Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties. Endocr Connect 2019; 8:R55-R70. [PMID: 30772871 PMCID: PMC6391903 DOI: 10.1530/ec-18-0456] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 01/24/2019] [Indexed: 11/23/2022]
Abstract
The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide, especially as a result of our aging society, high caloric intake and sedentary lifestyle. Besides the well-known complications of T2DM on the cardiovascular system, the eyes, kidneys and nerves, bone strength is also impaired in diabetic patients. Patients with T2DM have a 40-70% increased risk for fractures, despite having a normal to increased bone mineral density, suggesting that other factors besides bone quantity must account for increased bone fragility. This review summarizes the current knowledge on the complex effects of T2DM on bone including effects on bone cells, bone material properties and other endocrine systems that subsequently affect bone, discusses the effects of T2DM medications on bone and concludes with a model identifying factors that may contribute to poor bone quality and increased bone fragility in T2DM.
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Affiliation(s)
- Ann-Kristin Picke
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany
| | - Graeme Campbell
- Institute of Biomechanics, TUHH Hamburg University of Technology, Hamburg, Germany
| | - Nicola Napoli
- Diabetes and Bone Network, Department Endocrinology and Diabetes, University Campus Bio-Medico of Rome, Rome, Italy
- Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, Missouri, USA
| | - Lorenz C Hofbauer
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
- Correspondence should be addressed to M Rauner:
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26
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Chavarry NGM, Perrone D, Farias MLF, Dos Santos BC, Domingos AC, Schanaider A, Feres-Filho EJ. Alendronate improves bone density and type I collagen accumulation but increases the amount of pentosidine in the healing dental alveolus of ovariectomized rabbits. Bone 2019; 120:9-19. [PMID: 30282057 DOI: 10.1016/j.bone.2018.09.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 09/23/2018] [Accepted: 09/24/2018] [Indexed: 01/22/2023]
Abstract
BACKGROUND It has been shown that the oral aminobisphosphonate sodium alendronate (ALN) therapy reduces the risk of main fractures in osteoporotic women, but its effect on the jaw bones is poorly known. Here, we hypothesized that ALN affects the newly formed alveolar bone, particularly the quality of the type I collagen cross-linking. METHODS Osteoporosis was induced by ovariectomy (OVX) in 6-month old rabbits. Six weeks following surgery, eight animals were treated by oral gavage with ALN (OVX + ALN) and ten received placebo (OVX + Pbo). Another six rabbits which were sham operated also received placebo (SHAM + Pbo). One month following the beginning of treatment, the upper and lower left first premolars were removed. Six weeks later, the upper and the lower right first premolars were also extracted. One month after the second extraction, biopsies were collected from the maxillary extraction sites and collagen crosslinks were analyzed in the newly formed bone tissue by HPLC. Also, at this time, mandibular bone segments were subjected to μCT. RESULTS Animals treated with ALN achieved a roughly 2-time greater bone volume fraction value at a late healing period than animals in the other groups (p < 0.05). Collagen mean results were 2- to 4-times superior in the OVX + ALN group than in the control groups (p < 0.05). ALN-treated animals presented higher amounts of the non-enzymatic collagen cross-link pentosidine (PEN) than the sham-operated rabbits (p < 0.05), whereas the OVX + Pbo group presented the highest amount of PEN (p < 0.05). CONCLUSION Alendronate increases bone volume and collagen accumulation, but does not fully rescue the non-osteoporotic alveolar tissue quality as is evident from the increased quantity of pentosidine.
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Affiliation(s)
| | - Daniel Perrone
- Laboratory of Nutritional Biochemistry and Food, Chemistry Institute, Federal University of Rio de Janeiro, RJ CEP 21941-909, Brazil
| | - Maria Lucia Fleiuss Farias
- Division of Endocrinology, School of Medicine, Federal University of Rio de Janeiro, RJ CEP 21941-913, Brazil
| | - Bernardo Camargo Dos Santos
- Department of Nuclear Engineering (COPPE), School of Engineering, Federal University of Rio de Janeiro, RJ CEP 21941-972, Brazil
| | - Andrea Castro Domingos
- Department of Oral Pathology, Oral Radiology and Oral Diagnosis, School of Dentistry, Federal University of Rio de Janeiro, RJ CEP 21941-971, Brazil
| | - Alberto Schanaider
- Department of Surgery, School of Medicine, Federal University of Rio de Janeiro, RJ CEP 21941-913, Brazil
| | - Eduardo Jorge Feres-Filho
- Division of Graduate Periodontics, School of Dentistry, Federal University of Rio de Janeiro, RJ CEP 21941-971, Brazil.
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Abstract
PURPOSE OF REVIEW Homocystinuria is a congenital metabolic disorder in which cystathionine β-synthase deficiency results in a prominent increase in homocysteine (serum levels > 100 μM), causing mental retardation, atherosclerotic cerebral infarction, and osteoporosis accompanied by fragility fractures. Encountering a case with excessive homocysteinemia such as that seen in hereditary homocystinuria is unlikely during usual medical examinations. However, in individuals who have vitamin B or folate deficiency, serum homocysteine concentrations are known to increase. These individuals may also have a polymorphism in methylenetetrahydrofolate reductase, MTHFR (C677T: TT type), which regulates homocysteine metabolism. These changes in homocysteine levels may elicit symptoms resembling those of homocystinuria (e.g., Alzheimer's disease, atherosclerosis, osteoporosis). RECENT FINDINGS High serum homocysteine has been shown to have detrimental effects on neural cells, vascular endothelial cells, osteoblasts, and osteoclasts. Homocysteine is also known to increase oxidative stress, disrupt cross-linking of collagen molecules, and increase levels of advanced glycation end products, which results in reduced bone strength through a mechanism that goes beyond low bone density and increased bone resorption. Therefore, high serum homocysteine may be regarded as a factor that can reduce both bone mass and impair bone quality. In this review, we outline the epidemiology and pathophysiology of osteoporosis associated with hyperhomocysteinemia.
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Affiliation(s)
- Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
| | - Keishi Marumo
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
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28
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Nakamura M, Inaba M, Yamada S, Ozaki E, Maruo S, Okuno S, Imanishi Y, Kuriyama N, Watanabe Y, Emoto M, Motoyama K. Association of Decreased Handgrip Strength with Reduced Cortical Thickness in Japanese Female Patients with Type 2 Diabetes Mellitus. Sci Rep 2018; 8:10767. [PMID: 30018407 PMCID: PMC6050319 DOI: 10.1038/s41598-018-29061-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 06/29/2018] [Indexed: 12/25/2022] Open
Abstract
LD-100, a quantitative ultrasonic device, allows us to measure cortical thickness (CoTh). Patients with type 2 diabetes mellitus (T2DM) show high prevalence of sarcopenia. This study aimed to clarify the association of handgrip strength (HGS) with cortical porosis, a major risk for fracture of DM. CoTh and trabecular bone mineral density (TrBMD) at the 5.5% distal radius were assessed in T2DM female patients (n = 122) and non-DM female controls (n = 704) by LD-100. T2DM patients aged older 40 years showed significantly lower HGS and CoTh, but not TrBMD, than non-DM counterparts. Although HGS was significantly and positively correlated with CoTh and TrBMD in T2DM patients, multivariate analysis revealed HGS as an independent factor positively associated with CoTh, but not TrBMD, in T2DM patients, suggesting the preferential association of HGS with cortical, but not trabecular, bone component in T2DM female patients. In conclusion, the present study demonstrated an early decline of HGS in T2DM female patients as compared with non-DM healthy controls after the age of 40 years, which is independently associated with thinner CoTh, but not TrBMD in T2DM patients, and thus suggested that reduced muscle strength associated with DM might be a major factor for cortical porosis development in DM patients.
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Affiliation(s)
- Miyuki Nakamura
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaaki Inaba
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | - Shinsuke Yamada
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsuko Ozaki
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Saori Maruo
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Senji Okuno
- Department of Nephrology, Shirasagi Hosiptal, Osaka, Japan
| | - Yasuo Imanishi
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Nagato Kuriyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshiyuki Watanabe
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masanori Emoto
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koka Motoyama
- Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
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29
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Tsuburai T, Nakamura T, Yoshikata H, Miyagi E, Sakakibara H. Eldecalcitol increases bone mass in patients with Turner syndrome who have insufficient bone mass acquisition after estrogen replacement therapy. Endocr J 2018; 65:629-638. [PMID: 29607913 DOI: 10.1507/endocrj.ej17-0498] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Most patients with Turner syndrome (TS) exhibit amenorrhea due to premature ovarian failure. Therefore, estrogen replacement therapy (ERT) is required; however, even after undergoing ERT, it is not rare for bone mass acquisition to be insufficient. This study was conducted in two stages, involving a cross-sectional and a prospective interventional study. We recruited 52 TS patients undergoing ERT due to amenorrhea (categorized into low (LB group; n = 23), and normal (NB group; n = 29) bone mass groups) and 7 TS patients who maintained ovarian function (spontaneous menstrual cycle group (MC group)) as controls. We compared bone associated markers between the three groups (LB, NB, and MC). Furthermore, the LB group had concomitant treatment with eldecalcitol (ELD) and ERT for 12 months. The bone mineral density (BMD) of the lumber spine (L2-4) and the bone metabolism markers were then compared before and after the treatment. The bone metabolism markers were significantly higher in the LB group than the NB and MC groups. Furthermore, with the concomitant use of ELD and ERT in the LB group, BMD increased significantly (pre-treatment 0.710 ± 0.056 g/cm2 vs. 0.736 ± 0.062 g/cm2 after 12 months; p < 0.001). TS patients with insufficient bone mass acquisition even after ERT were characterized by a higher turnover in bone metabolism. Therefore, the concomitant use of ELD was considered an effective adjuvant therapy for increasing bone mass.
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Affiliation(s)
- Taku Tsuburai
- Department of Gynecology, Yokohama City University Medical Center, Yokohama, Japan
| | - Tomomi Nakamura
- Department of Obstetrics and Gynecology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Hiromi Yoshikata
- Department of Gynecology, Yokohama City University Medical Center, Yokohama, Japan
| | - Etsuko Miyagi
- Department of Obstetrics and Gynecology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Hideya Sakakibara
- Department of Gynecology, Yokohama City University Medical Center, Yokohama, Japan
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30
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Abstract
PURPOSE OF THE REVIEW Bisphosphonates have well-established effects on suppressing bone resorption and slowing bone loss, yet the effects on bone mechanical properties are less clear. We review recent data from pre-clinical and clinical experiments that assessed mechanical properties of bisphosphonate-treated specimens. RECENT FINDINGS Pre-clinical work has utilized new techniques to show reduced fatigue life and transfer of stress from the mineral to collagen. Several notable studies have examined mechanical properties of tissue from patients treated with bisphosphonates with mixed results. Pre-clinical data suggest effects on mechanics may be independent of remodeling suppression. The direct effect of bisphosphonates on bone mechanics remains unclear but recent work has set a solid foundation for the coming years.
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Affiliation(s)
- Matthew R Allen
- Departments of Anatomy and Cell Biology, Medicine-Nephrology and Orthopaedic Surgery, Indiana University School of Medicine, 635 Barnhill Dr., MS 5035, Indianapolis, IN, 46202, USA.
- Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, USA.
- Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
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Ohishi T, Fujita T, Suzuki D, Nishida T, Yamamoto K, Okabayashi R, Ushirozako H, Banno T, Matsuyama Y. Changes of bone mineral density and serum pentosidine during a 27-month follow-up of monthly minodronate in osteoporotic patients. Endocr Res 2017; 42:232-240. [PMID: 28318330 DOI: 10.1080/07435800.2017.1292527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE Monthly regimen of minodronate for osteoporosis more than two years has not been reported yet. The aim of this study is to elucidate the effect of monthly minodronate (M-MIN) on bone mineral density (BMD) and serum pentosidine (Pen) during 27 months. MATERIALS AND METHODS The study consisted of 52 newly treated patients (73.3 ± 8.8 years) (new group) and 47 patients (75.9 ± 9.5 years) who were switched from either alendronate or risedronate (switch group). Monthly minodronate (50 mg/every 4 weeks) was administered for 27 months. Lumbar, femoral neck, and total hip BMDs and serum pentosidine were monitored at baseline and after 9, 18, and 27 months of treatment. RESULTS In the new condition, lumbar, neck, and total hip BMDs increased significantly by 9.07%, 3.15%, and 3.06%, respectively. Only the lumbar BMD significantly increased in the switch condition. Serum Pen increased in both groups in a time-dependent manner. In the group switch, multivariate logistic regression analysis revealed that the initial change in serum intact procollagen type I N-terminal propeptide (P1NP) at 9 months was an independent predictor of changes in neck and total hip BMDs at 27 months (OR = 1.039, 95% CI 1.003-1.077, p = 0.032 for neck and OR = 1.055, 95% CI 1.009-1.104, p = 0.020 for total hip). CONCLUSIONS Monthly minodronate treatment increased BMDs in newly treated patients over 27 months. Serum Pen increased with M-MIN therapy, possibly indicating prolonged bone turnover. The initial 9-month changes in serum P1NP predicted the 27-month changes in hip BMDs when M-MIN replaced alendronate or risedronate.
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Affiliation(s)
- Tsuyoshi Ohishi
- a Department of Orthopaedic Surgery , Enshu Hospital , Hamamatsu , Japan
| | - Tomotada Fujita
- a Department of Orthopaedic Surgery , Enshu Hospital , Hamamatsu , Japan
| | - Daisuke Suzuki
- a Department of Orthopaedic Surgery , Enshu Hospital , Hamamatsu , Japan
| | - Tatsuya Nishida
- a Department of Orthopaedic Surgery , Enshu Hospital , Hamamatsu , Japan
| | - Kazufumi Yamamoto
- b Department of Orthopaedic Surgery , Shintoshi Hospital , Iwata , Japan
| | - Ryo Okabayashi
- c Department of Orthopaedic Surgery , Iwata Municipal Hospital , Iwata , Japan
| | - Hiroki Ushirozako
- d Department of Orthopaedic Surgery , Fujinomiya City Hospital , Fujinomiya , Japan
| | - Tomohiro Banno
- e Department of Orthopaedic Surgery , Hamamatsu University School of Medicine , Hamamatsu , Japan
| | - Yukihiro Matsuyama
- e Department of Orthopaedic Surgery , Hamamatsu University School of Medicine , Hamamatsu , Japan
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Sato H, Kondo N, Nakatsue T, Wada Y, Fujisawa J, Kazama JJ, Kuroda T, Suzuki Y, Nakano M, Endo N, Narita I. High and pointed type of femoral localized reaction frequently extends to complete and incomplete atypical femoral fracture in patients with autoimmune diseases on long-term glucocorticoids and bisphosphonates. Osteoporos Int 2017; 28:2367-2376. [PMID: 28409215 DOI: 10.1007/s00198-017-4038-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 04/03/2017] [Indexed: 01/22/2023]
Abstract
UNLABELLED Once a localized reaction (beaking) was detected, discontinuation of bisphosphonates (BPs) and switching to vitamin D supplementation or teriparatide therapy effectively improved its shape. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete atypical femoral fracture increased and consideration of prophylactic fixation for such patients was required. INTRODUCTION Femoral localized reaction (localized periosteal thickening of the lateral cortex, beaking) is reported to precede atypical femoral fractures (AFFs) and to develop in 8-10% of patients with autoimmune diseases taking BPs and glucocorticoids. The aims of the present study were to retrospectively investigate the shapes of localized reaction to consider how to manage the condition. METHODS Twenty femora of 12 patients with autoimmune diseases who were on BPs and glucocorticoids exhibited femoral localized reaction. The heights of localized reaction were measured and the shapes classified as pointed, arched, and other. Localized reaction changes were divided into three categories: deterioration, no change, and improvement. A severe form of localized reaction was defined; this was associated with prodromal pain, de novo complete AFF, or incomplete AFF with a fracture line at the localized reaction. RESULTS The mean height of localized reaction was 2.3 ± 0.8 mm (range, 1.0-3.7 mm) and the pointed type was 35%. Localized reaction was significantly higher (3.3 ± 0.8 vs. 2.1 ± 0.7 mm; p = 0.003) and the pointed type more common (78 vs. 27%; p = 0.035) in those with the severe form of localized reaction. Seven patients with localized reactions discontinued BPs just after localized reaction was detected, but five continued on BPs for 2 years. Localized reaction deterioration was more common in patients who continued than discontinued BPs (100 vs. 29%; p = 0.027). After 2 years, all patients had discontinued BPs and localized reaction did not deteriorate further in any patient. CONCLUSIONS Once a localized reaction was detected, discontinuation of BPs and switching to vitamin D supplementation or teriparatide therapy effectively improved it. When the localized reaction was high, of the pointed type, and/or accompanied by prodromal pain, the risks of complete and incomplete AFF increased and consideration of prophylactic fixation for such patients was required.
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Affiliation(s)
- H Sato
- Health Administration Center, Niigata University, 2-8050 Ikarashi, Nishiku, Niigata City, 950-2181, Japan.
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuoku, Niigata City, 951-8510, Japan.
| | - N Kondo
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuoku, Niigata City, 951-8510, Japan
| | - T Nakatsue
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuoku, Niigata City, 951-8510, Japan
| | - Y Wada
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuoku, Niigata City, 951-8510, Japan
| | - J Fujisawa
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuoku, Niigata City, 951-8510, Japan
| | - J J Kazama
- Department of Nephrology and Hypertention, Fukushima Medical University, 1 Hikariga-oka, Fukushima City, 960-1295, Japan
| | - T Kuroda
- Health Administration Center, Niigata University, 2-8050 Ikarashi, Nishiku, Niigata City, 950-2181, Japan
| | - Y Suzuki
- Health Administration Center, Niigata University, 2-8050 Ikarashi, Nishiku, Niigata City, 950-2181, Japan
| | - M Nakano
- Department of Medical Technology, School of Health Sciences, Faculty of Medicine, Niigata University, 2-746 Asahimachi-Dori, Chuoku, Niigata City, 951-8518, Japan
| | - N Endo
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuoku, Niigata City, 951-8510, Japan
| | - I Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Chuoku, Niigata City, 951-8510, Japan
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Mashiba T, Saito M, Yamagami Y, Tanaka M, Iwata K, Yamamoto T. Effects of suppressed bone remodeling by minodronic acid and alendronate on bone mass, microdamage accumulation, collagen crosslinks and bone mechanical properties in the lumbar vertebra of ovariectomized cynomolgus monkeys. Bone 2017; 97:184-191. [PMID: 28082077 DOI: 10.1016/j.bone.2017.01.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 12/16/2016] [Accepted: 01/06/2017] [Indexed: 01/22/2023]
Abstract
Collagen crosslinking is an important determinant of the quality of bone material. We have previously shown that suppressed bone turnover by high doses of minodronic acid and alendronate increases compressive strength of vertebra, but also increases microdamage accumulation, in monkey bone. The aim of this study is to examine the effects of these bisphosphonates on collagen crosslinks and intrinsic material properties, in addition to microdamage accumulation, in vertebral cancellous bone in ovariectomized cynomolgus monkeys. Sixty female monkeys aged 9-17years were divided into five groups: sham and ovariectomized groups were treated daily for 17months with lactose vehicle, and the other three groups were given minodronic acid daily at 0.015 or 0.15mg/kg or alendronate daily at 0.5mg/kg orally. After sacrifice, lumbar vertebrae were subjected to histomorphometry, microdamage measurement, analysis of collagen crosslinking and compressive mechanical tests. Minodronic acid caused dose-dependent suppression of increased bone remodeling due to ovariectomy, and low-dose minodronic acid suppressed remodeling same level as alendronate. However, low-dose minodronic acid did not change microdamage accumulation, collagen maturity and the pentosidine level, whereas high-dose minodronic acid and alendronate increased these parameters. Compressive ultimate load was increased following high-dose minodronic acid and alendronate, but no treatment altered the reduction in intrinsic material properties caused by ovariectomy. These findings suggest that deterioration of bone material and formation of pentosidine and microdamage induced by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate, but this was not reflected in any significant change of mechanical properties.
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Affiliation(s)
- Tasuku Mashiba
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan.
| | - Mitsuru Saito
- Department of Orthopedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Yoshiki Yamagami
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Makoto Tanaka
- Research Promotion, Ono Pharmaceutical Co., Ltd., Osaka, Japan
| | - Ken Iwata
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Tetsuji Yamamoto
- Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan
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Kamimura M, Uchiyama S, Nakamura Y, Ikegami S, Mukaiyama K, Kato H. Short-term bisphosphonate treatment reduces serum 25(OH) vitamin D 3 and alters values of parathyroid hormone, pentosidine, and bone metabolic markers. Ther Clin Risk Manag 2017; 13:161-168. [PMID: 28243105 PMCID: PMC5315201 DOI: 10.2147/tcrm.s120749] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
This study aimed to clarify the effects of short-term bisphosphonate (BP) administration in Japanese osteoporotic patients retrospectively. Daily minodronate (MIN) at 1 mg/day (MIN group) or weekly risedronate (RIS) at 17.5 mg/week (RIS group) was primarily prescribed for each patient. We analyzed the laboratory data of 35 cases (18 of MIN and 17 of RIS) before the start of treatment and at 4 months afterward. The changes in 25(OH)D3, whole parathyroid hormone (PTH), serum pentosidine, and the bone turnover markers urinary cross-linked N-telopeptide of type I collagen (NTX), serum tartrate-resistant acid phosphatase (TRACP)-5b, bone-specific alkaline phosphatase (BAP), and undercarboxylated osteocalcin were evaluated. Overall, serum 25(OH)D3 was significantly decreased from 21.8 to 18.4 ng/mL at 4 months, with a percent change of −14.7%. Whole PTH increased significantly from 23.4 to 30.0 pg/mL, with a percent change of 32.1%. Serum pentosidine rose from 0.0306 to 0.0337 μg/mL, with a percent change of 15.2%. In group comparisons, 25(OH)D3 and pentosidine showed comparable changes in both groups after 4 months of treatment, whereas whole PTH became significantly more increased in the MIN group. All bone turnover markers were significantly decreased at 4 months in both groups. Compared with the RIS group, the MIN group exhibited significantly larger value changes for urinary NTX, serum TRACP-5b, and BAP at the study end point. This study demonstrated that serum 25(OH)D3 became significantly decreased after only 4 months of BP treatment in Japanese osteoporotic patients and confirmed that MIN more strongly inhibited bone turnover as compared with RIS.
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Affiliation(s)
- Mikio Kamimura
- Center for Osteoporosis and Spinal Disorders, Kamimura Orthopaedic Clinic, Matsumoto, Japan
| | - Shigeharu Uchiyama
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yukio Nakamura
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan; Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, Japan
| | - Shota Ikegami
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Keijiro Mukaiyama
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroyuki Kato
- Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan
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Abstract
OBJECTIVES Bisphosphonates are widely used as first-line treatment for primary and secondary prevention of fragility fractures. Whilst they have proved effective in this role, there is growing concern over their long-term use, with much evidence linking bisphosphonate-related suppression of bone remodelling to an increased risk of atypical subtrochanteric fractures of the femur (AFFs). The objective of this article is to review this evidence, while presenting the current available strategies for the management of AFFs. METHODS We present an evaluation of current literature relating to the pathogenesis and treatment of AFFs in the context of bisphosphonate use. RESULTS Six broad themes relating to the pathogenesis and management of bisphosphonate-related AFFs are presented. The key themes in fracture pathogenesis are: bone microdamage accumulation; altered bone mineralisation and altered collagen formation. The key themes in fracture management are: medical therapy and surgical therapy. In addition, primary prevention strategies for AFFs are discussed. CONCLUSIONS This article presents current knowledge about the relationship between bisphosphonates and the development of AFFs, and highlights key areas for future research. In particular, studies aimed at identifying at-risk subpopulations and organising surveillance for those on long-term therapy will be crucial in both increasing our understanding of the condition, and improving population outcomes.Cite this article: N. Kharwadkar, B. Mayne, J. E. Lawrence, V. Khanduja. Bisphosphonates and atypical subtrochanteric fractures of the femur. Bone Joint Res 2017;6:144-153. DOI: 10.1302/2046-3758.63.BJR-2016-0125.R1.
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Affiliation(s)
- N Kharwadkar
- The Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham B9 5SS, UK
| | - B Mayne
- F2, James Cook University Hospital, Marton Rd, Middlesbrough TS4 3BW, UK
| | - J E Lawrence
- Junior Clinical Fellow, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
| | - V Khanduja
- Department of Trauma and Orthopaedics, Addenbrooke's Hospital, Box 37, Hills Road, Cambridge CB2 0QQ, UK
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Abstract
Diabetic patients have a higher fracture risk than expected by their bone mineral density (BMD). Poor bone quality is the most suitable and explainable cause for the elevated fracture risk in this population. Advanced glycation end products (AGEs), which are diverse compounds generated via a non-enzymatic reaction between reducing sugars and amine residues, physically affect the properties of the bone material, one of a component of bone quality, through their accumulation in the bone collagen fibers. On the other hand, these compounds biologically act as agonists for these receptors for AGEs (RAGE) and suppress bone metabolism. The concentrations of AGEs and endogenous secretory RAGE, which acts as a "decoy receptor" that inhibits the AGEs-RAGE signaling axis, are associated with fracture risk in a BMD-independent manner. AGEs are closely associated with the pathogenesis of this unique clinical manifestation through physical and biological mechanisms in patients with diabetes mellitus.
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Affiliation(s)
- Masahiro Yamamoto
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501 Japan
| | - Toshitsugu Sugimoto
- Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501 Japan
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Olejnik C, Falgayrac G, During A, Cortet B, Penel G. Doses effects of zoledronic acid on mineral apatite and collagen quality of newly-formed bone in the rat's calvaria defect. Bone 2016; 89:32-39. [PMID: 27168397 DOI: 10.1016/j.bone.2016.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 04/18/2016] [Accepted: 05/05/2016] [Indexed: 01/12/2023]
Abstract
Due to their inhibitory effects on resorption, bisphosphonates are widely used in the treatment of diseases associated to an extensive bone loss. Yet, little is known about bisphosphonates effects on newly-formed bone quality. In the present study, adult male Sprague-Dawley rats (n=80) with a bone defect calvaria area were used and short-term effects of zoledronic acid (ZA) were studied on the healing bone area. Three ZA treatments were tested by using either: 1°) a low single dose (120μgZA/kg, n=10; equivalent to human osteoporosis treatment), 2°) a low fractionated doses (20μgZA/kg daily for 6days either a total of 120μg/kg, n=15), and 3°) a high fractionated doses, (100μgZA/kg weekly for 6weeks, n=15; equivalent to 6months of human bone metastasis treatment). For each treatment, a control "vehicle" treatment was performed (with an identical number of rats). After ZA administration, the intrinsic bone material properties were evaluated by quantitative backscattered electron imaging (qBEI) and Raman microspectroscopy. Neither single nor fractionated low ZA doses modify the intrinsic bone material properties of the newly-formed bone compared to their respective control animals. On the opposite, the high ZA treatment resulted in a significant decrease of the crystallinity (-25%, P< 0.05) and of the hydroxyproline-to-proline ratio (-30%, P<0.05) in newly-formed bones. Moreover, with the high ZA treatment, the crystallinity was positively correlated with the hydroxyproline-to-proline ratio (ρ=0.78, P<0.0001). The present data highlight new properties for ZA on bone formation in a craniofacial defect model. As such, ZA at high doses disrupted the apatite crystal organization. In addition, we report here for the first time that high ZA doses decreased the hydroxyproline-to-proline ratio suggesting that ZA may affect the early collagen organization during the bone healing.
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Affiliation(s)
- Cécile Olejnik
- Université de Lille, EA 4490 PMOI, F-59000 Lille, France; Faculté de Chirurgie Dentaire, Place de Verdun, F-59000 Lille, France; Service d'Odontologie, Centre Abel Caumartin, CHRU de Lille, F-59000 Lille, France.
| | - Guillaume Falgayrac
- Université de Lille, EA 4490 PMOI, F-59000 Lille, France; Faculté de Chirurgie Dentaire, Place de Verdun, F-59000 Lille, France
| | - Alexandrine During
- Université de Lille, EA 4490 PMOI, F-59000 Lille, France; Faculté de Chirurgie Dentaire, Place de Verdun, F-59000 Lille, France
| | - Bernard Cortet
- Université de Lille, EA 4490 PMOI, F-59000 Lille, France; Service de Rhumatologie, Hôpital Roger Salengro, CHRU de Lille, F-59000 Lille, France
| | - Guillaume Penel
- Université de Lille, EA 4490 PMOI, F-59000 Lille, France; Faculté de Chirurgie Dentaire, Place de Verdun, F-59000 Lille, France; Service d'Odontologie, Centre Abel Caumartin, CHRU de Lille, F-59000 Lille, France
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Kaneko T, Otani T, Kono N, Mochizuki Y, Mori T, Nango N, Ikegami H, Musha Y. Weekly injection of teriparatide for bone ingrowth after cementless total knee arthroplasty. J Orthop Surg (Hong Kong) 2016; 24:16-21. [PMID: 27122506 DOI: 10.1177/230949901602400106] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
PURPOSE To compare bone mineral density (BMD) in patients with or without weekly injection of teriparatide to promote bone ingrowth after cementless total knee arthroplasty (TKA). METHODS Records of 8 men and 32 women (mean age, 75.6 years) who underwent cementless TKA for medial knee osteoarthritis with (n=20) or without (n=20) once-weekly subcutaneous/hypodermic injection of teriparatide for 48 weeks were reviewed. BMD and bone volume/total volume (BV/TV) of the bone-prosthesis interface of the proximal tibia in 6 regions of interest (ROI) were assessed at 3, 6, 9, and 12 months using multi-detector computed tomography. RESULTS Patients with or without weekly injection of teriparatide after cementless TKA were comparable in terms of baseline characteristics and pre- and post-operative knee range of motion and Knee Society knee and function scores. In ROI 1 (medial), ROI 3 (anteromedial), and ROI 4 (posteromedial), the BV/TV increased throughout the postoperative period in patients with weekly injection of teriparatide and declined after 6 months in patients without weekly injection of teriparatide. These 3 ROIs of the 2 groups differed significantly only in BMD at 6, 9, and 12 months. In ROI 2 (lateral), ROI 5 (anterolateral), and ROI 6 (posterolateral), both BV/TV and BMD showed a decreasing trend, and these 3 ROIs of the 2 groups did not differ significantly. CONCLUSION Weekly injection of teriparatide after cementless TKA promoted bone ingrowth mostly in the medial aspect of the bone-prosthesis interface.
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Affiliation(s)
- T Kaneko
- Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan
| | - T Otani
- Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan
| | - N Kono
- Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan
| | - Y Mochizuki
- Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan
| | - T Mori
- Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan
| | - N Nango
- Ratoc System Engineering Co. Ltd., Tokyo, Japan
| | - H Ikegami
- Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan
| | - Y Musha
- Department of Orthopaedic Surgery, Toho University School of Medicine, Tokyo, Japan
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Bishop N. Bone Material Properties in Osteogenesis Imperfecta. J Bone Miner Res 2016; 31:699-708. [PMID: 26987995 DOI: 10.1002/jbmr.2835] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 03/08/2016] [Accepted: 03/10/2016] [Indexed: 12/29/2022]
Abstract
Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between collagen fibrils to the macroarchitecture of the whole skeleton. Investigations using an array of sophisticated instruments at multiple scale levels have now determined many aspects of the effect of the disease on the material properties of bone tissue. The brittle nature of bone in osteogenesis imperfecta reflects both increased bone mineralization density-the quantity of mineral in relation to the quantity of matrix within a specific bone volume-and altered matrix-matrix and matrix mineral interactions. Contributions to fracture resistance at multiple scale lengths are discussed, comparing normal and brittle bone. Integrating the available information provides both a better understanding of the effect of current approaches to treatment-largely improved architecture and possibly some macroscale toughening-and indicates potential opportunities for alternative strategies that can influence fracture resistance at longer-length scales.
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Affiliation(s)
- Nick Bishop
- University of Sheffield and Sheffield Children's NHS Foundation Trust, Sheffield, UK
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40
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Wang ZX, Lloyd AA, Burket JC, Gourion-Arsiquaud S, Donnelly E. Altered distributions of bone tissue mineral and collagen properties in women with fragility fractures. Bone 2016; 84:237-244. [PMID: 26780445 DOI: 10.1016/j.bone.2016.01.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 12/25/2015] [Accepted: 01/13/2016] [Indexed: 01/22/2023]
Abstract
Heterogeneity of bone tissue properties is emerging as a potential indicator of altered bone quality in pathologic tissue. The objective of this study was to compare the distributions of tissue properties in women with and without histories of fragility fractures using Fourier transform infrared (FTIR) imaging. We extended a prior study that examined the relationship of the mean FTIR properties to fracture risk by analyzing in detail the widths and the tails of the distributions of FTIR properties in biopsies from fracture and non-fracture cohorts. The mineral and matrix properties of cortical and trabecular iliac crest tissue were compared in biopsies from women with a history of fragility fracture (+Fx; n=21, age: mean 54±SD 15y) and with no history of fragility fracture (-Fx; n=12, age: 57±5y). A subset of the patients included in the -Fx group were taking estrogen-plus-progestin hormone replacement therapy (HRT) (-Fx+HRT n=8, age: 58±5y) and were analyzed separately from patients with no history of HRT (-Fx-HRT n=4, age: 56±7y). When the FTIR parameter mean values were examined by treatment group, the trabecular tissue of -Fx-HRT patients had a lower mineral:matrix ratio (M:M) and collagen maturity (XLR) than that of -Fx+HRT patients (-22% M:M, -18% XLR) and +Fx patients (-17% M:M, -18% XLR). Across multiple FTIR parameters, tissue from the -Fx-HRT group had smaller low-tail (5th percentile) values than that from the -Fx+HRT or +Fx groups. In trabecular collagen maturity and crystallinity (XST), the -Fx-HRT group had smaller low-tail values than those in the -Fx+HRT group (-16% XLR, -5% XST) and the +Fx group (-17% XLR, -7% XST). The relatively low values of trabecular mineral:matrix ratio and collagen maturity and smaller low-tail values of collagen maturity and crystallinity observed in the -Fx-HRT group are characteristic of younger tissue. Taken together, our data suggest that the presence of newly formed tissue that includes small/imperfect crystals and immature crosslinks, as well as moderately mature tissue, is an important characteristic of healthy, fracture-resistant bone. Finally, the larger mean and low-tail values of mineral:matrix ratio and collagen maturity noted in our -Fx+HRT vs. -Fx-HRT biopsies are consistent with greater tissue age and greater BMD arising from decreased osteoclastic resorption in HRT-treated patients.
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Affiliation(s)
- Zhen Xiang Wang
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY, United States
| | - Ashley A Lloyd
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY, United States
| | - Jayme C Burket
- Hospital for Special Surgery, New York, NY, United States
| | | | - Eve Donnelly
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY, United States; Hospital for Special Surgery, New York, NY, United States.
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Shinno Y, Ishimoto T, Saito M, Uemura R, Arino M, Marumo K, Nakano T, Hayashi M. Comprehensive analyses of how tubule occlusion and advanced glycation end-products diminish strength of aged dentin. Sci Rep 2016; 6:19849. [PMID: 26797297 PMCID: PMC4726429 DOI: 10.1038/srep19849] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 12/18/2015] [Indexed: 01/22/2023] Open
Abstract
In clinical dentistry, since fracture is a major cause of tooth loss, better understanding of mechanical properties of teeth structures is important. Dentin, the major hard tissue of teeth, has similar composition to bone. In this study, we investigated the mechanical properties of human dentin not only in terms of mineral density but also using structural and quality parameters as recently accepted in evaluating bone strength. Aged crown and root dentin (age ≥ 40) exhibited significantly lower flexural strength and toughness than young dentin (age < 40). Aged dentin, in which the dentinal tubules were occluded with calcified material, recorded the highest mineral density; but showed significantly lower flexural strength than young dentin. Dentin with strong alignment of the c-axis in hydroxyapatite exhibited high fracture strength, possibly because the aligned apatite along the collagen fibrils may reinforce the intertubular dentin. Aged dentin, showing a high advanced glycation end-products (AGEs) level in its collagen, recorded low flexural strength. We first comprehensively identified significant factors, which affected the inferior mechanical properties of aged dentin. The low mechanical strength of aged dentin is caused by the high mineral density resulting from occlusion of dentinal tubules and accumulation of AGEs in dentin collagen.
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Affiliation(s)
- Yuko Shinno
- Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan
| | - Takuya Ishimoto
- Division of Materials and Manufacturing Science, Osaka University Graduate School of Engineering, 1-2 Yamadaoka, Suita 565-0871, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minatoku, Tokyo 105-0003, Japan
| | - Reo Uemura
- Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan
| | - Masumi Arino
- Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan
| | - Keishi Marumo
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minatoku, Tokyo 105-0003, Japan
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Osaka University Graduate School of Engineering, 1-2 Yamadaoka, Suita 565-0871, Japan
| | - Mikako Hayashi
- Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita 565-0871, Japan
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Abstract
There is clear evidence that patients with type 2 diabetes mellitus (T2D) have increased fracture risk, despite having high bone mineral density (BMD) and body mass index (BMI). Thus, poor bone quality has been implicated as a mechanism contributing to diabetic skeletal fragility. Poor bone quality in T2D may result from the accumulation of advanced glycation end-products (AGEs), which are post-translational modifications of collagen resulting from a spontaneous reaction between extracellular sugars and amino acid residues on collagen fibers. This review discusses what is known and what is not known regarding AGE accumulation and diabetic skeletal fragility, examining evidence from in vitro experiments to simulate a diabetic state, ex vivo studies in normal and diabetic human bone, and diabetic animal models. Key findings in the literature are that AGEs increase with age, affect bone cell behavior, and are altered with changes in bone turnover. Further, they affect bone mechanical properties and microdamage accumulation, and can be inhibited in vitro by various inhibitors and breakers (e.g. aminoguanidine, N-Phenacylthiazolium Bromide, vitamin B6). While a few studies report higher AGEs in diabetic animal models, there is little evidence of AGE accumulation in bone from diabetic patients. There are several limitations and inconsistencies in the literature that should be noted and studied in greater depth including understanding the discrepancies between glycation levels across reported studies, clarifying differences in AGEs in cortical versus cancellous bone, and improving the very limited data available regarding glycation content in diabetic animal and human bone, and its corresponding effect on bone material properties in T2D.
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Affiliation(s)
- Lamya Karim
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02215 USA.
| | - Mary L Bouxsein
- Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02215 USA.
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The atypical femoral fracture. CURRENT ORTHOPAEDIC PRACTICE 2016. [DOI: 10.1097/bco.0000000000000326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Arakawa S, Saito M, Kubota M, Suzuki H, Tsuchida S, Hashimoto K, Marumo K. Applying low-intensity pulsed ultrasounds (LIPUS) to a zoledronate-associated atypical femoral shaft fracture without cessation of zoledronate therapy for 3 years follow up: a case report. CLINICAL CASES IN MINERAL AND BONE METABOLISM 2015; 12:269-72. [PMID: 26811711 DOI: 10.11138/ccmbm/2015.12.3.269] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Reports are increasing regarding atypical femoral fractures (AFFs) caused by minor trauma in patients using bisphosphonates (BPs) for long periods. Patients with malignant skeletal metastases potentially are at greater risk for these AFFs, especially considering the high dose and the duration of treatment with BPs. We evaluated a case of atypical femoral shaft fracture treated with an intramedullary nail in a patient treated for five years with zoledronate who had breast cancer with metastases to bone. Although bone union was achieved without cessation of zoledronate therapy by applying low-intensity pulsed ultrasounds (LIPUS), the remodeling phase of the fracture healing process was delayed. For BPs-associated AFFs, LIPUS is an alternative to parathyroid hormone (PTH) analogs such as teriparatide that are contraindicated in patients with malignant skeletal metastases. LIPUS is an effective treatment for fracture healing and may avoid the necessity to discontinue BP therapy.
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Affiliation(s)
- Shoutaro Arakawa
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Makoto Kubota
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Hidehiko Suzuki
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Shigeki Tsuchida
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Kurando Hashimoto
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
| | - Keishi Marumo
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Tokyo, Japan
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Iwasaki Y, Kazama JJ, Yamato H, Matsugaki A, Nakano T, Fukagawa M. Altered material properties are responsible for bone fragility in rats with chronic kidney injury. Bone 2015; 81:247-254. [PMID: 26187196 DOI: 10.1016/j.bone.2015.07.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 07/02/2015] [Accepted: 07/13/2015] [Indexed: 01/22/2023]
Abstract
Chronic kidney disease (CKD) is associated with an increased risk of fragility fractures, but the underlying pathophysiological mechanism remains obscure. We performed an in vivo experimental study to examine the roles of uremia and abnormal mineral/parathyroid metabolism in the development of bone metabolic abnormalities in uremic rats. Male Sprague-Dawley rats were divided into four groups, comprising sham operation (high turnover bone control=HTB-Cont), 5/6-nephrectomy (high turnover bone nephrectomized=HTB-Nx), thyroparathyroidectomy (low turnover bone control=LTB-Cont), and thyroparathyroidectomy plus 5/6 nephrectomy (low turnover bone nephrectomized=LTB-Nx), and maintained for 16 weeks. Uremia was successfully created in the LTB-Nx and HTB-Nx groups, while hyperparathyroidism was only found in the HTB-Nx group. Cancellous bone histomorphometry revealed significantly higher bone turnover in the HTB-Nx group than in the LTB-Nx group. Storage modulus at 1 Hz and tan delta in cortical bone of the femur, which represent the viscoelastic mechanical properties, were significantly lower in both Nx groups than in the Cont groups regardless of bone metabolism. Pentosidine-to-matrix ratio was increased and crystallinity was decreased in both Nx groups regardless of bone turnover. Mineral-to-matrix ratio was significantly decreased in the HTB-Nx group, but increased in the LTB-Nx group. Enzymatic collagen crosslinks were decreased in the HTB-Nx group. The degree of orientation of the c-axis in carbonated hydroxyapatite (biological apatite=BAp) crystallites was decreased in both Nx groups regardless of bone metabolism. Stepwise multivariate regression revealed that pentosodine-to-matrix ratio and BAp preferential c-axis orientation were significantly associated with storage modulus and tan delta. In conclusion, bone elastic mechanical properties deteriorated regardless of bone metabolism or bone mass in rats with chronic kidney injury. Various changes in bone mineral properties were associated with CKD, including abnormal parathyroid function, impaired bone turnover, and uremia associated with the accumulation of uremic toxins, were responsible for these changes. Pentosidine-to-matrix ratio and BAp orientation at position 5 were the two meaningful determinants of elastic bone mechanical strength, and both factors were associated with the severity of uremia, but not parathyroid function or bone metabolism. These two factors may account for the increased bone fragility among CKD patients.
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Affiliation(s)
- Yoshiko Iwasaki
- Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita, Japan
| | - Junichiro J Kazama
- Division of Blood Purification Therapy, Niigata University Medical and Dental Hospital, Niigata, Japan.
| | - Hideyuki Yamato
- Responsible Care Planning Division, Kureha Corporation, Iwaki, Japan
| | - Aira Matsugaki
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Masafumi Fukagawa
- Division of Nephrology and Metabolism, Tokai University School of Medicine, Isehara, Japan
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Saito M, Kida Y, Nishizawa T, Arakawa S, Okabe H, Seki A, Marumo K. Effects of 18-month treatment with bazedoxifene on enzymatic immature and mature cross-links and non-enzymatic advanced glycation end products, mineralization, and trabecular microarchitecture of vertebra in ovariectomized monkeys. Bone 2015; 81:573-580. [PMID: 26385255 DOI: 10.1016/j.bone.2015.09.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 08/26/2015] [Accepted: 09/14/2015] [Indexed: 01/22/2023]
Abstract
Bazedoxifene (BZA) is used for the treatment of post-menopausal osteoporosis. To elucidate changes in collagen, mineralization, and structural properties and their relationship to bone strength after treatment with BZA in ovariectomized (OVX) monkeys, the levels of collagen and enzymatic immature, mature, and non-enzymatic cross-links were simultaneously examined, as well as trabecular architecture and mineralization of vertebrae. Adult female cynomolgus monkeys were divided into 4 groups (n=18 each) as follows: Sham group, OVX group, and OVX monkeys given either 0.2 or 0.5mg/kg BZA for 18 months. Collagen concentration, enzymatic and non-enzymatic pentosidine cross-links, whole fluorescent advanced glycation end products (AGEs), trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed. The levels of enzymatic immature and mature cross-links, bone volume (BV/TV), and trabecular thickness (Tb.Th) in BZA-treated groups were significantly higher than those in the OVX control group. In contrast, the trabecular bone pattern factor (TBPf), the structure model index (SMI), the enzymatic cross-link ratio, and the levels of pentosidine and whole AGEs in BZA-treated groups were significantly lower than those in the OVX control group. Stepwise logistic regression analysis revealed that BV/TV, Tb.Th, TbPf, and pentosidine or whole AGEs independently affected ultimate load (model R(2)=0.748, p<0.001) and breaking energy (model R(2)=0.702). Stiffness was affected by Tb.Th, enzymatic immature cross-link levels and their ratio (model R(2)=0.400). Treatment with BZA prevented OVX-induced deterioration in the total levels of immature enzymatic cross-links and AGEs accumulation and structural properties such as BV/TV, Tb.Th, and TbPf, which contribute significantly to vertebral cancellous bone strength.
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Affiliation(s)
- Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan
| | - Yoshikuni Kida
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan
| | - Tetsuro Nishizawa
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan
| | - Shotaro Arakawa
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan
| | - Hinako Okabe
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan
| | - Azusa Seki
- Tsukuba Research Center, HAMRI Co., Ltd., Ibaraki, Japan
| | - Keishi Marumo
- Department of Orthopaedic Surgery, Jikei University School of Medicine, Japan
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47
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Toledano M, Aguilera FS, Osorio E, Cabello I, Toledano-Osorio M, Osorio R. Functional and molecular structural analysis of dentine interfaces promoted by a Zn-doped self-etching adhesive and an in vitro load cycling model. J Mech Behav Biomed Mater 2015; 50:131-49. [DOI: 10.1016/j.jmbbm.2015.05.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 05/20/2015] [Accepted: 05/22/2015] [Indexed: 01/22/2023]
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Bala Y, Seeman E. Bone's Material Constituents and their Contribution to Bone Strength in Health, Disease, and Treatment. Calcif Tissue Int 2015; 97:308-26. [PMID: 25712256 DOI: 10.1007/s00223-015-9971-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 02/11/2015] [Indexed: 12/24/2022]
Abstract
Type 1 collagen matrix volume, its degree of completeness of its mineralization, the extent of collagen crosslinking and water content, and the non-collagenous proteins like osteopontin and osteocalcin comprise the main constituents of bone's material composition. Each influences material strength and change in different ways during advancing age, health, disease, and drug therapy. These traits are not quantifiable using bone densitometry and their plurality is better captured by the term bone 'qualities' than 'quality'. These qualities are the subject of this manuscript.
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Affiliation(s)
- Y Bala
- Laboratoire Vibrations Acoustique, Institut National des Sciences Appliquées de Lyon, Campus LyonTech la Doua, Villeurbanne, France
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49
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Saito M, Marumo K. Effects of Collagen Crosslinking on Bone Material Properties in Health and Disease. Calcif Tissue Int 2015; 97:242-61. [PMID: 25791570 DOI: 10.1007/s00223-015-9985-5] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 03/09/2015] [Indexed: 12/18/2022]
Abstract
Data have accumulated to show that various types of collagen crosslinking are implicated in the health of individuals, as well as in a number of disease states, such as osteoporosis, diabetes mellitus, chronic kidney disease, inflammatory bowel disease, or in conditions of mild hyperhomocysteinemia, or when glucocorticoid use is indicated. Collagen crosslinking is a posttranslational modification of collagen molecules and plays important roles in tissue differentiation and in the mechanical properties of collagenous tissue. The crosslinking of collagen in the body can form via two mechanisms: one is enzymatic crosslinking and the other is nonenzymatic crosslinking. Lysyl hydroxylases and lysyl oxidases regulate tissue-specific crosslinking patterns and quantities. Enzymatic crosslinks initially form via immature divalent crosslinking, and a portion of them convert into mature trivalent forms such as pyridinoline and pyrrole crosslinks. Nonenzymatic crosslinks form as a result of reactions which create advanced glycation end products (AGEs), such as pentosidine and glucosepane. These types of crosslinks differ in terms of their mechanisms of formation and function. Impaired enzymatic crosslinking and/or an increase of AGEs have been proposed as a major cause of bone fragility associated with aging and numerous disease states. This review focuses on the effects of collagen crosslinking on bone material properties in health and disease.
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Affiliation(s)
- Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan,
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50
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Self-etching zinc-doped adhesives improve the potential of caries-affected dentin to be functionally remineralized. Biointerphases 2015; 10:031002. [DOI: 10.1116/1.4926442] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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