Subjects -> MEDICAL SCIENCES (Total: 8359 journals)
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MEDICAL SCIENCES (2268 journals)            First | 1 2 3 4 5 6 7 8 | Last

Showing 201 - 400 of 3562 Journals sorted alphabetically
Audiology - Communication Research     Open Access   (Followers: 10)
Auris Nasus Larynx     Full-text available via subscription  
Australasian Journal of Ultrasound in Medicine (AJUM)     Hybrid Journal  
Australian Coeliac     Full-text available via subscription   (Followers: 1)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 2)
Autopsy and Case Reports     Open Access  
Avicenna     Open Access   (Followers: 3)
Avicenna Journal of Clinical Medicine     Open Access  
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 2)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 4)
Bangladesh Journal of Medical Education     Open Access   (Followers: 2)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 4)
Bangladesh Journal of Medical Physics     Open Access   (Followers: 1)
Bangladesh Journal of Medical Science     Open Access  
Bangladesh Journal of Medicine     Open Access   (Followers: 1)
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Bangladesh Medical Journal     Open Access  
Bangladesh Medical Journal Khulna     Open Access  
Basal Ganglia     Hybrid Journal  
Basic Sciences of Medicine     Open Access   (Followers: 2)
Batı Karadeniz Tıp Dergisi / Medical Journal of Western Black Sea     Open Access  
Baylor University Medical Center Proceedings     Hybrid Journal  
BBA Clinical     Open Access  
BC Medical Journal     Free  
Benha Medical Journal     Open Access  
Beni-Suef University Journal of Basic and Applied Sciences     Open Access   (Followers: 4)
Bijblijven     Hybrid Journal  
Bijzijn     Hybrid Journal   (Followers: 1)
Bijzijn XL     Hybrid Journal  
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 2)
BioDiscovery     Open Access   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 2)
Bioelectronic Medicine     Open Access   (Followers: 1)
Bioengineering & Translational Medicine     Open Access  
Bioethics     Hybrid Journal   (Followers: 17)
Bioethics Research Notes     Full-text available via subscription   (Followers: 14)
Biologics in Therapy     Open Access  
Biology of Sex Differences     Open Access   (Followers: 2)
Biomarker Research     Open Access   (Followers: 3)
Biomarkers in Medicine     Hybrid Journal   (Followers: 2)
BioMed Research International     Open Access   (Followers: 4)
Biomédica     Open Access  
Biomedical & Life Sciences Collection     Full-text available via subscription   (Followers: 3)
Biomedical and Biotechnology Research Journal     Open Access   (Followers: 1)
Biomedical Engineering     Hybrid Journal   (Followers: 17)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 13)
Biomedical Engineering Letters     Hybrid Journal   (Followers: 6)
Biomedical Engineering Research     Open Access   (Followers: 7)
Biomedical Informatics Insights     Open Access   (Followers: 8)
Biomedical Journal     Open Access   (Followers: 3)
Biomedical Materials     Hybrid Journal   (Followers: 7)
Biomedical Microdevices     Hybrid Journal   (Followers: 8)
Biomedical Optics Express     Open Access   (Followers: 6)
Biomedical Photonics     Open Access  
Biomedical Reports     Full-text available via subscription  
Biomedical Research Reports     Full-text available via subscription   (Followers: 2)
Biomedical Safety & Standards     Full-text available via subscription   (Followers: 8)
Biomedical Science and Engineering     Open Access   (Followers: 7)
BioMedicine     Open Access  
Biomedicine Hub     Open Access  
Biomedicines     Open Access   (Followers: 1)
Biomedika     Open Access  
Biomolecular and Health Science Journal     Open Access   (Followers: 1)
Biophysics Reports     Open Access  
BioPsychoSocial Medicine     Open Access   (Followers: 8)
Biosalud     Open Access   (Followers: 1)
Biostatistics & Epidemiology     Hybrid Journal   (Followers: 1)
Birat Journal of Health Sciences     Open Access  
BIRDEM Medical Journal     Open Access   (Followers: 1)
Birth Defects Research     Hybrid Journal  
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 3)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal  
BJR|Open     Open Access   (Followers: 1)
BJS Open     Open Access   (Followers: 1)
Black Sea Journal of Health Science     Open Access  
BLDE University Journal of Health Sciences     Open Access  
Blickpunkt Medizin     Hybrid Journal  
BMC Biomedical Engineering     Open Access  
BMC Medical Ethics     Open Access   (Followers: 21)
BMC Medical Research Methodology     Open Access   (Followers: 9)
BMC Medicine     Open Access   (Followers: 13)
BMC Obesity     Open Access   (Followers: 8)
BMC Proceedings     Full-text available via subscription   (Followers: 1)
BMC Research Notes     Open Access   (Followers: 4)
BMC Sports Science, Medicine and Rehabilitation     Open Access   (Followers: 34)
BMH Medical Journal     Open Access   (Followers: 2)
BMI Journal : Bariátrica & Metabólica Iberoamericana     Open Access  
BMJ     Hybrid Journal   (Followers: 1740)
BMJ Case Reports     Hybrid Journal   (Followers: 26)
BMJ Evidence-Based Medicine     Hybrid Journal   (Followers: 2)
BMJ Global Health     Open Access   (Followers: 3)
BMJ Innovations     Hybrid Journal   (Followers: 6)
BMJ Leader     Hybrid Journal  
BMJ Open     Open Access   (Followers: 42)
BMJ Open Quality     Open Access   (Followers: 19)
BMJ Open Science     Open Access   (Followers: 1)
BMJ Sexual & Reproductive Health     Hybrid Journal   (Followers: 2)
BMJ Surgery, Interventions, & Health Technologies     Open Access  
Bodine Journal     Open Access  
Boletín del Consejo Académico de Ética en Medicina     Open Access  
Boletín del ECEMC     Open Access  
Boletin Médico de Postgrado     Open Access  
Boletín Médico del Hospital Infantil de México     Open Access  
Bone     Hybrid Journal   (Followers: 18)
Bone and Tissue Regeneration Insights     Open Access   (Followers: 2)
Bone Marrow Research     Open Access   (Followers: 2)
Bone Reports     Open Access  
Bosnian Journal of Basic Medical Sciences     Open Access  
Bozok Tıp Dergisi / Bozok Medical Journal     Open Access  
Brachytherapy     Full-text available via subscription   (Followers: 6)
Brain and Development     Full-text available via subscription   (Followers: 5)
Brain Connectivity     Hybrid Journal   (Followers: 5)
Brain Impairment     Full-text available via subscription   (Followers: 2)
Brazilian Journal of Medical and Biological Research     Open Access  
Brazilian Journal of Medicine and Human Health     Open Access  
Brazilian Journal of Pain (BrJP)     Open Access  
Brazilian Journal of Physical Therapy     Open Access   (Followers: 1)
Breastfeeding Review     Full-text available via subscription   (Followers: 18)
British Journal of Biomedical Science     Full-text available via subscription   (Followers: 7)
British Journal of General Practice     Full-text available via subscription   (Followers: 38)
British Journal of Hospital Medicine     Full-text available via subscription   (Followers: 16)
British Medical Bulletin     Hybrid Journal   (Followers: 6)
Buddhachinaraj Medical Journal     Open Access  
Bulletin Amades     Open Access  
Bulletin de la Société de pathologie exotique     Hybrid Journal   (Followers: 1)
Bulletin of Legal Medicine     Open Access  
Bulletin of Medical Sciences     Open Access  
Bulletin of the History of Medicine     Full-text available via subscription   (Followers: 18)
Bulletin of the Menninger Clinic     Full-text available via subscription  
Bulletin of The Royal College of Surgeons of England     Free  
Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products     Open Access  
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz     Hybrid Journal   (Followers: 6)
Burapha Journal of Medicine     Open Access  
Burns     Hybrid Journal   (Followers: 10)
Cadernos de Naturologia e Terapias Complementares     Open Access   (Followers: 1)
Calcified Tissue International     Hybrid Journal   (Followers: 2)
Canadian Bulletin of Medical History     Hybrid Journal  
Canadian Family Physician     Partially Free   (Followers: 13)
Canadian Journal of Pain     Open Access   (Followers: 2)
Canadian Journal of Rural Medicine     Full-text available via subscription   (Followers: 1)
Canadian Medical Association Journal     Open Access   (Followers: 17)
Canadian Medical Education Journal     Open Access   (Followers: 10)
Canadian Prosthetics & Orthotics Journal     Open Access  
Cannabis and Cannabinoid Research     Hybrid Journal   (Followers: 1)
Cardiac Electrophysiology Clinics     Full-text available via subscription   (Followers: 1)
Care Management Journals     Hybrid Journal   (Followers: 5)
Case Reports     Open Access  
Case Reports in Acute Medicine     Open Access  
Case Reports in Clinical Medicine     Open Access   (Followers: 1)
Case Reports in Clinical Nutrition     Open Access   (Followers: 1)
Case Reports in Medicine     Open Access   (Followers: 2)
Case Reports in Transplantation     Open Access  
Case Reports in Vascular Medicine     Open Access  
Case Reports in Women's Health     Open Access   (Followers: 4)
Case Study and Case Report     Open Access   (Followers: 5)
CBU International Conference Proceedings     Open Access   (Followers: 3)
Cell & Bioscience     Open Access   (Followers: 6)
Cell Adhesion & Migration     Open Access   (Followers: 9)
Cell and Molecular Response to Stress     Full-text available via subscription   (Followers: 2)
Cell and Tissue Transplantation and Therapy     Open Access   (Followers: 2)
Cell Cycle     Full-text available via subscription   (Followers: 6)
Cell Death and Differentiation     Hybrid Journal   (Followers: 7)
Cell Death Discovery     Open Access   (Followers: 1)
Cell Health and Cytoskeleton     Open Access   (Followers: 1)
Cell Medicine     Open Access   (Followers: 6)
Cell Research     Hybrid Journal   (Followers: 8)
Cell Transplantation     Open Access   (Followers: 4)
CEN Case Reports     Hybrid Journal  
Central African Journal of Medicine     Full-text available via subscription  
Ceylon Journal of Medical Science     Open Access  
Ceylon Medical Journal     Open Access  
Chattagram Maa-O-Shishu Hospital Medical College Journal     Open Access  
Chiang Mai Medical Journal     Open Access  
ChiangRai Medical Journal     Open Access  
Chimerism     Full-text available via subscription  
Chinese Journal of Integrative Medicine     Hybrid Journal   (Followers: 3)
Chinese Journal of Natural Medicines     Full-text available via subscription   (Followers: 1)
Chinese Medical Journal     Open Access   (Followers: 10)
Chinese Medical Record English Edition     Hybrid Journal  
Chinese Medical Sciences Journal     Full-text available via subscription   (Followers: 2)
Chinese Medicine     Open Access   (Followers: 2)
Chinese Medicine     Open Access   (Followers: 4)
Chisholm Health Ethics Bulletin     Full-text available via subscription   (Followers: 1)
CHRISMED Journal of Health and Research     Open Access   (Followers: 2)
Christian Journal for Global Health     Open Access  
Chronic Diseases and Translational Medicine     Open Access  
Chronic Illness     Hybrid Journal   (Followers: 6)
Chronic Wound Care Management and Research     Open Access   (Followers: 4)
Chronobiology International     Hybrid Journal   (Followers: 3)
ChronoPhysiology and Therapy     Open Access  
Chulalongkorn Medical Bulletin     Open Access  
Chulalongkorn Medical Journal     Open Access  
Ciencia e Innovación en Salud     Open Access  
Ciencia e Investigación Medico Estudiantil Latinoamericana     Open Access  
Ciencias Clínicas     Open Access  

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Journal Cover
Journal Prestige (SJR): 1.652
Citation Impact (citeScore): 4
Number of Followers: 18  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 8756-3282 - ISSN (Online) 8756-3282
Published by Elsevier Homepage  [3161 journals]
  • Subchondral bone dysplasia partly participates in prenatal dexamethasone
           induced-osteoarthritis susceptibility in female offspring rats
    • Abstract: Publication date: Available online 18 January 2020Source: BoneAuthor(s): Hao Xiao, Xingkui Xie, Yinxian Wen, Yang Tan, Yangfan Shangguan, Bin Li, Jacques Magdalou, Hui Wang, Liaobin ChenAbstractPrenatal dexamethasone exposure (PDE) induces developmental toxicities of multi-organs and susceptibility to multi-diseases in offspring. However, the effects of PDE on osteoarthritis susceptibility in adult offspring and its mechanism have not been reported. In the present study, we treated pregnant Wistar rats with dexamethasone (0.2 mg/kg) daily on gestational days (GD) 9–20. Some pregnant rats were sacrificed on GD20, and the rest were delivered to obtain the postnatal offspring. The adult female offspring rats were performed with ovariectomy or sham operation during postnatal weeks 22–28. We found that PDE led to osteoarthritis phenotypes in articular cartilage and an increase in modified Mankin's score, but reduced the cartilage thickness in female adult offspring rats, which were more evident after ovariectomy. Moreover, PDE reduced the bone mass of subchondral bone in female adult offspring, which was aggravated by ovariectomy. The correlation analysis results indicated that the osteoarthritic phenotype and cartilage thickness were closely associated with the decreased bone mass of subchondral bone induced by PDE. Further, PDE retarded the development of primary and secondary ossification centers, then led to subchondral bone dysplasia, which could be partly mediated by the inhibited osteogenic function before and after birth. Collectively, the subchondral bone dysplasia partly participated in osteoarthritis susceptibility induced by PDE in female offspring rats.
  • Pamidronate: A model compound of the pharmacology of nitrogen-containing
           bisphosphonates; A Leiden historical perspective
    • Abstract: Publication date: Available online 17 January 2020Source: BoneAuthor(s): Socrates E. PapapoulosAbstractPamidronate [3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD)] was the first nitrogen-containing bisphosphonate (N-BP) investigated in clinical studies. In contrast to other clinically used bisphosphonates, pamidronate was discovered and its properties were initially studied in an Academic Institution. On the occasion of the 50th Anniversary of the first publications on the biological effects of bisphosphonates, I review in this article the contribution of Leiden investigators to the development of pamidronate that led to the recognition of the significance of the Nitrogen atom in the side chain of bisphosphonates for their action on bone resorption and to the formulation of principles for the use of N-BPs in the management of patients with different skeletal disorders.
  • Bone material strength index is associated with prior fracture in men with
           and without moderate chronic kidney disease
    • Abstract: Publication date: Available online 16 January 2020Source: BoneAuthor(s): Kara L. Holloway-Kew, Pamela Rufus-Membere, Kara B. Anderson, Amelia Betson, James Gaston, Mark A. Kotowicz, Adolfo Diez-Perez, Natalie K. Hyde, Julie A. PascoAbstractBackgroundPatients with chronic kidney disease (CKD) are at high risk for fracture. The ability of bone mineral density (BMD) to predict fractures in CKD patients has been inconsistent. Other measures such as trabecular bone score (TBS) and impact microindentation (IMI) may be more useful in this group. This study aimed to determine if TBS or IMI values differed between men with and without CKD and examine associations between prior fracture, TBS and IMI values.MethodsMen (n = 343, age 33–96 yr) from the Geelong Osteoporosis Study were included. Femoral neck (FNBMD) and lumbar spine BMD (LSBMD) were measured using DXA (Lunar ProdigyPro). TBS was determined from lumbar spine scans (TBS iNsight software Version 2.2). IMI values (bone material strength index; BMSi) were measured using an OsteoProbe. CKD was defined as an eGFR
  • Extracellular pyrophosphate: The body's “water softener”
    • Abstract: Publication date: Available online 16 January 2020Source: BoneAuthor(s): Isabel R. OrrissAbstractExtracellular pyrophosphate (ePPi) was first identified as a key endogenous inhibitor of mineralisation in the 1960's by Fleisch and colleagues. The main source of ePPi seems to be extracellular ATP which is continually released from cells in a controlled way. ATP is rapidly broken down by enzymes including ecto-nucleotide pyrophosphatase/phosphodiesterases to produce ePPi. The major function of ePPi is to directly inhibit hydroxyapatite formation and growth meaning that this simple molecule acts as the body's own “water softener”. However, studies have also shown that ePPi can influence gene expression and regulate its own production and breakdown. This review will summarise our current knowledge of ePPi metabolism and how it acts to prevent pathological soft tissue calcification and regulate physiological bone mineralisation.
  • Consumption of nutrients and insulin resistance suppress markers of bone
           turnover in subjects with abdominal obesity
    • Abstract: Publication date: Available online 15 January 2020Source: BoneAuthor(s): Rasmus Fuglsang-Nielsen, Elin Rakvaag, Peter Vestergaard, Bolette Hartmann, Jens Juul Holst, Kjeld Hermansen, Søren Gregersen, Jakob Starup-LindeAbstractObjectiveAbdominal obesity and type 2 diabetes are associated with insulin resistance and low bone turnover along with an increased fracture risk. The mode of action is poorly understood. The bone resorption marker, C-terminal telopeptide type 1 collagen (CTX), and to a lesser extent, the bone formation marker, Procollagen type 1 N-terminal propeptide (P1NP) appear to be inhibited by food consumption. The link between food consumption, insulin resistance and bone turnover remains to be clarified.Primarily we aimed to compare the postprandial CTX, P1NP and PTH responses by two frequently applied methods in assessing metabolic health; oral glucose tolerance test (OGTT) and mixed meal tolerance test. Secondly, we explored the effect of insulin resistance on bone marker responses.MethodsWe enrolled 64 subjects with abdominal obesity. Following 10 h of fasting, subjects initially underwent a standard OGTT (300 kcal) and approximately one week later a mixed meal tolerance test (1130 kcal). Circulating CTX, P1NP and PTH were assessed on both days at time = 0, after 30 min and after 90 min for comparison of the two interventions. We analyzed glucose and insulin levels for the assessment of insulin resistance. Additionally, we measured plasma calcium levels along with the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 2 (GLP-2) in an attempt to identify possible mediators of the postprandial bone response.ResultsCTX, P1NP and PTH were suppressed by OGTT and the mixed meal; the latter induced a more pronounced suppression after 90 min. Calcium levels were similar between OGTT and meal. GIP and GLP-2 levels increased after both interventions, although only the meal induced a sustained increase after 90 min. Fasting P1NP was inversely associated with insulin resistance. The meal-induced suppression of P1NP (but not CTX or PTH) was inversely associated with level of insulin resistance.ConclusionThe acute postprandial suppression of bone turnover markers is extended after ingestion of a mixed meal compared to an OGTT. The response appears to be independent of gender and prompted by a reduction in PTH. The study additionally indicates a possible link between the development of insulin resistance and low bone turnover — which may be of key essence in the development of the fragile bone structure and increased fracture risk demonstrated in subjects with abdominal obesity and T2D.
  • Pheochromocytoma and paraganglioma: An emerging cause of secondary
    • Abstract: Publication date: Available online 13 January 2020Source: BoneAuthor(s): Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Tazuru Fukumoto, Yayoi Matsuda, Hiromi Nagata, Masatoshi Ogata, Hisaya Kawate, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Q-AND-A study groupAbstractContextPheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs) are catecholamine-producing neuroendocrine tumors, which are known to be associated with low bone mineral density (BMD). However, it remains unknown whether PPGLs are associated with high prevalence of osteoporotic fracture and if so, whether their surgical resection improves BMD has been addressed.ObjectiveTo evaluate the risk of vertebral fracture (VF) in PPGLs and the improvement of BMD after surgery.Design and settingsA retrospective cross-sectional study in a single referral center.ParticipantsThis study included the following patients: 1) 49 patients with PPGLs and 61 patients with non-functional AT who were examined radiograph of the spine, 2) 23 patients with PPGLs who were examined BMD at follow-up.Intervention1) The prevalence of VF was evaluated between PPGLs and non-functional AT. 2) In PPGLs, BMD was evaluated at baseline and after surgery.ResultsPPGLs had a higher prevalence of VF (43% [21/49]) than non-functional AT (16% [10/61]; p = 0.002). PPGLs were associated with VF after adjusting for age and sex (odds ratio, 4.47; 95% confidence interval, 1.76–11.3; p = 0.001). In PPGLs, BMD at the lumber spine was improved (before: 0.855 ± 0.198 g/cm2, after: 0.888 ± 0.169 g/cm2, mean of the difference: 0.032 g/cm2, p = 0.026), with 3.8% increase.ConclusionThis study demonstrates that PPGLs was associated with VF and that their surgical resection contributes to the improvement of BMD in the trabecular bone. These observations support the notion that PPGLs are an emerging cause of secondary osteoporosis.
  • Assessment of romosozumab efficacy in the treatment of postmenopausal
           osteoporosis: results from a mechanistic PK-PD mechanostat model of bone
    • Abstract: Publication date: Available online 11 January 2020Source: BoneAuthor(s): Madge Martin, Vittorio Sansalone, David M.L. Cooper, Mark R. Forwood, Peter PivonkaAbstractThis paper introduces a theoretical framework for the study of the efficacy of romosozumab, a humanized monoclonal antibody targeting sclerostin for the treatment of osteoporosis. We developed a comprehensive mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model of the effect of drug treatment on bone remodeling in postmenopausal osteoporosis (PMO). We utilized a one-compartment PK model to represent subcutaneous injections of romosozumab and subsequent absorption into serum. The PD model is based on a recently-developed bone cell population model describing the bone remodeling process at the tissue scale. The latter accounts for mechanical feedback via incorporating nitric oxide (NO) and sclerostin (Scl) as biochemical feedback molecules. Utilizing a competitive binding model, where Wnt and Scl compete for binding to LRP5/6, allows to regulate anabolic bone remodeling responses. Here, we extended this model with respect to romosozumab binding to sclerostin. For the currently approved monthly injections of 210 mg, the model predicted a 6.59%, 10.38% and 15.25% increase in BMD at the lumbar spine after 6, 12 and 24 months, respectively. These results are in good agreement with the data reported in the literature. Our model is also able to distinguish the bone-site specific drug effects. For instance, at the femoral neck, our model predicts a BMD increase of 3.85% after 12 months of 210 mg injections, which is consistent with literature observations. Finally, our simulations indicate rapid bone loss after treatment discontinuation, indicating that some additional interventions such as use of bisphosphonates are required to maintain bone.
  • Conditional deletion of Adrb2 in mesenchymal stem cells attenuates
           osteoarthritis-like defects in temporomandibular joint
    • Abstract: Publication date: Available online 9 January 2020Source: BoneAuthor(s): Jin-long Sun, Jian-fei Yan, Jing Li, Wan-rong Wang, Shi-bin Yu, Hong-yun Zhang, Fei Huang, Li-na Niu, Kai JiaoAbstractβ2-adrenergic signal transduction in mesenchymal stem cells (MSCs) induces subchondral bone loss in osteoarthritis (OA) of temporomandibular joints (TMJs). However, whether conditional deletion of β2-adrenergic receptor (Adrb2) in nestin+ MSCs can alleviate TMJ-OA development remains unknown. In this study, nestin-Cre mice were crossed with Adrb2 flox mice to generate mice lacking Adrb2 expression specifically in the nestin+ MSCs (Adrb2−/−), and TMJ-OA development in such mice was investigated. Adrb2 flox mice (Adrb2+/+) and Adrb2−/− mice were subjected to unilateral anterior crossbite (UAC), while mice in the control group were subjected to sham operation. Adrb2+/+ and Adrb2−/− mice in the control group showed no distinguishable phenotypic changes in body weight and length, mandibular condylar size, and other histomorphological parameters of the condylar subchondral bone. A significant increase in subchondral bone loss and cartilage degradation was observed in Adrb2+/+ UAC mice; the former was characterized by decreased bone mineral density, bone volume fraction, and trabecular plate thickness, and increased trabecular separation, osteoclast number and osteoclast surface, and pro-osteoclastic factor expression; the latter was characterized by decreased cartilage thickness, chondrocyte density, proteoglycan area, and collagen II and aggrecan expression, but increased matrix metalloproteinase and alkaline phosphatase expression and percentage area of calcified cartilage. Adrb2 deletion in nestin+ MSCs largely attenuated UAC-induced increase in condylar subchondral bone loss, cartilage degradation, and aberrant calcification at the osteochondral interface. Thus, Adrb2-expressing MSCs in the condylar subchondral bone play an important role in TMJ-OA progression and may serve as novel therapeutic targets for TMJ-OA.
  • MRI-based assessment of proximal femur strength compared to mechanical
    • Abstract: Publication date: Available online 9 January 2020Source: BoneAuthor(s): Chamith S. Rajapakse, Alexander R. Farid, Daniel C. Kargilis, Brandon C. Jones, Jae S. Lee, Alyssa J. Johncola, Alexandra S. Batzdorf, Snehal S. Shetye, Michael W. Hast, Gregory ChangAbstractHalf of the women who sustain a hip fracture would not qualify for osteoporosis treatment based on current DXA-estimated bone mineral density criteria. Therefore, a better approach is needed to determine if an individual is at risk of hip fracture from a fall. The objective of this study was to determine the association between radiation-free MRI-derived bone strength and strain simulations compared to results from direct mechanical testing of cadaveric femora.Imaging was conducted on a 3-Tesla MRI scanner using two sequences: one balanced steady-state free precession sequence with 300 μm isotropic voxel size and one spoiled gradient echo with anisotropic voxel size of 234 × 234 × 1500 μm. Femora were dissected free of soft-tissue and 4350-ohm strain-gauges were securely applied to surfaces at the femoral shaft, inferior neck, greater trochanter, and superior neck. Cadavers were mechanically tested with a hydraulic universal test frame to simulate loading in a sideways fall orientation.Sideways fall forces were simulated on MRI-based finite element meshes and bone stiffness, failure force, and force for plastic deformation were computed. Simulated bone strength metrics from the 300 μm isotropic sequence showed strong agreement with experimentally obtained values of bone strength, with stiffness (r = 0.88, p = 0.0002), plastic deformation point (r = 0.89, p 
  • Sensory neuropeptides are required for bone and cartilage homeostasis in a
           murine destabilization-induced osteoarthritis model
    • Abstract: Publication date: Available online 8 January 2020Source: BoneAuthor(s): Dominique Muschter, Lutz Fleischhauer, Shahed Taheri, Arndt F. Schilling, Hauke Clausen-Schaumann, Susanne GrässelNumerous studies identified a role for the sensory neuropeptides substance P (SP) and alpha calcitonin gene-related peptide (αCGRP) in osteoarthritis (OA) pain behavior. Surprisingly, little attention has been paid on how their trophic effects on cartilage and bone cells might affect structural changes of bone and cartilage in OA pathology. Here, we sought to elucidate sensory neuropeptides influence on structural alterations of bone and cartilage during murine OA pathophysiology. OA was induced by destabilization of the medial meniscus (DMM) in the right knee joint of 12 weeks old male C57Bl/6J wildtype (WT) mice and mice either deficient for SP (tachykinin 1 (Tac1)−/−) or αCGRP. By OARSI histopathological grading we observed significant cartilage matrix degradation after DMM surgery in αCGRP-deficient mice after 4 weeks whereas Tac1−/− scores were not different to sham mice before 12 weeks after surgery. Indentation-type atomic force microscopy (IT-AFM) identified a strong superficial zone (SZ) cartilage phenotype in Tac1−/− Sham mice. Opposed to WT and αCGRP−/− mice, SZ cartilage of Tac1−/− mice softened 2 weeks after OA induction. In Tac1−/− DMM mice, bone volume to total volume ratio (BV/TV) increased significantly compared to the Tac1−/− Sham group, 2 weeks after surgery. WT mice had reduced BV/TV compared to αCGRP−/− and Tac1−/− mice after 12 weeks. Increased calcified cartilage thickness and medial condyle diameter were detected in the medial tibia of all groups 8 weeks after OA induction by nanoCT analysis. Meniscal ossification occurred in all OA groups, but was significantly stronger in the absence of neuropeptides. Increased serum concentration of the respective non-deleted neuropeptide was observed in both neuropeptide-deficient mice strains.Both neuropeptides protect from age-related bone structural changes under physiological conditions and SP additionally demonstrates an anabolic effect on bone structure preservation in a pathophysiological situation. Both neuropeptide deficient mice display an intrinsic structural cartilage matrix phenotype that might alter progression of cartilage degeneration in OA.Graphical abstractUnlabelled Image
  • Early-onset Paget's disease of bone in a Mexican family caused by a novel
           tandem duplication (77dup27) in TNFRSF11A that encodes RANK
    • Abstract: Publication date: Available online 8 January 2020Source: BoneAuthor(s): Sean J. Iwamoto, Micol S. Rothman, Shenghui Duan, Jonathan C. Baker, Steven Mumm, Michael P. WhyteFour heterozygous in-frame tandem duplications of different lengths in TNFRSF11A, the gene that encodes receptor activator of nuclear factor κB (RANK), constitutively activate RANK and lead to high turnover skeletal disease. Each duplication elongates the signal peptide of RANK. The 18-base pair (bp) duplication at position 84 (84dup18) causes familial expansile osteolysis (FEO), the 15-bp duplication at position 84 (84dup15) causes expansile skeletal hyperphosphatasia (ESH), the 12-bp duplication at position 90 (90dup12) causes panostotic expansile bone disease (PEBD), and the 27-bp duplication causes early-onset Paget's disease of bone (PDB2). The severity of the associated skeletal disease seems inversely related to the duplication's length. Additional 15- and 18-bp duplications of TNFRSF11A fit this pattern. Herein, we delineate the skeletal disease of a middle-aged man of Mexican descent who we found to harbor a novel 27-bp tandem duplication at position 77 (77dup27) of TNFRSF11A. His disorder shares features, particularly hand involvement, with the single Japanese (75dup27) and Chinese (78dup27) kindreds with PDB2. However, his distinct hearing loss developed later in adulthood compared to the other 27-bp families (PDB2Jpn and PDB2Chn). He reported no morbidities during childhood, but in his late 20s developed unexplained tooth loss, low-trauma fractures, post-operative hypercalcemia, and painless enlargement of his hands. Biochemical studies showed elevated serum alkaline phosphatase (ALP), bone-specific ALP, C-telopeptide, and osteocalcin consistent with rapid bone remodeling. Radiologic imaging revealed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. DXA showed extremely low bone mineral density. His disorder genetically and phenotypically fits best with PDB2 and can be called PDB2Mex.Graphical abstractUnlabelled Image
  • Myelination during fracture healing in vivo in myelin protein zero (p0)
           transgenic medaka line
    • Abstract: Publication date: Available online 7 January 2020Source: BoneAuthor(s): Yusuke Dodo, Masahiro Chatani, Yuki Azetsu, Masahiro Hosonuma, Akiko Karakawa, Nobuhiro Sakai, Takako Negishi-Koga, Mayumi Tsuji, Katsunori Inagaki, Yuji Kiuchi, Masamichi TakamiAbstractDuring the fracture healing process, osteoblasts and osteoclasts, as well as the nervous system are known to play important roles for signaling in the body. Glia cells contribute to the healing process by myelination, which can increase the speed of signals transmitted between neurons. However, the behavior of myelinating cells at a fracture site remains unclear. We developed a myelin protein zero (mpz)-EGFP transgenic medaka line for tracing myelinating cells. Mpz-enhanced green fluorescence protein (EGFP)-positive (mpz+) cells are driven by the 2.9-kb promoter of the medaka mpz gene, which is distributed throughout the nervous system, such as the brain, spinal cord, lateral line, and peripheral nerves. In the caudal fin region, mpz+ cells were found localized parallel with the fin ray (bone) in the adult stage. mpz+ cells were not distributed with fli-DsRed positive (fli+) blood vessels, but with some nerve fibers, and were dyed with the anti-acetylated tubulin antibody.We then fractured one side of the caudal lepidotrichia in a caudal fin of mpz-EGFP medaka and found a unique phenomenon, in that mpz+ cells were accumulated at 1 bone away from the fracture site. This mpz+ cell accumulation phenomenon started from 4 days after fracture of the proximal bone. Thereafter, mpz+ cells became elongated from the proximal bone to the distal bone and finally showed a crosslink connection crossing the fracture site to the distal bone at 28 days after fracture.Finally, the effects of rapamycin, known as a mTOR inhibitor, on myelination was examined. Rapamycin treatment of mpz-EGFP/osterix-DsRed double transgenic medaka inhibited not only the crosslink connection of mpz+ cells but also osterix+ osteoblast accumulation at the fracture site, accompanied with a fracture healing defect. These findings indicated that mTOR signaling plays important roles in bone formation and neural networking during fracture healing. Taken together, the present results are the first to show the dynamics of myelinating cells in vivo.
  • Biallelic variants in KYNU cause a multisystemic syndrome with
           hand hyperphalangism
    • Abstract: Publication date: Available online 7 January 2020Source: BoneAuthor(s): Nadja Ehmke, Kristina Cusmano-Ozog, Rainer Koenig, Manuel Holtgrewe, Banu Nur, Ercan Mihci, Holly Babcock, Claudia Gonzaga-Jauregui, John D. Overton, Jing Xiao, Ariel Martinez, Max Muenke, Alexander Balzer, Judith Jochim, Naji El Choubassi, Björn Fischer-Zirnsak, Céline Huber, Uwe Kornak, Sarah Elsea, Valérie Cormier-DaireAbstractCatel-Manzke syndrome is characterized by the combination of Pierre Robin sequence and radial deviation, shortening as well as clinodactyly of the index fingers, due to an accessory ossification center. Mutations in TGDS have been identified as one cause of Catel-Manzke syndrome, but cannot be found as causative in every patient with the clinical diagnosis. We performed a chromosome microarray and/or exome sequencing in three patients with hand hyperphalangism, heart defect, short stature, and mild to severe developmental delay, all of whom were initially given a clinical diagnosis of Catel-Manzke syndrome. In one patient, we detected a large deletion of exons 1–8 and the missense variant c.1282C > T (p.Arg428Trp) in KYNU (NM_003937.2), whereas homozygous missense variants in KYNU were found in the other two patients (c.989G > A (p.Arg330Gln) and c.326G > C (p.Trp109Ser)). Plasma and urine metabolomic analysis of two patients indicated a block along the tryptophan catabolic pathway and urine organic acid analysis showed excretion of xanthurenic acid. Biallelic loss-of-function mutations in KYNU were recently described as a cause of NAD deficiency with vertebral, cardiac, renal and limb defects; however, no hand hyperphalangism was described in those patients, and Catel-Manzke syndrome was not discussed as a differential diagnosis. In conclusion, we present unrelated patients identified with biallelic variants in KYNU leading to kynureninase deficiency and xanthurenic aciduria as a very likely cause of their hyperphalangism, heart defect, short stature, and developmental delay. We suggest performance of urine organic acid analysis in patients with suspected Catel-Manzke syndrome, particularly in those with cardiac or vertebral defects or without mutations in TGDS.
  • Cell cycle progression is disrupted in murine MPS VII growth plate leading
           to reduced chondrocyte proliferation and transition to hypertrophy
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Zhirui Jiang, Ainslie L.K. Derrick-Roberts, Clare Reichstein, Sharon ByersAbstractEndochondral bone growth is abnormal in 6 of the 11 types of mucopolysaccharidoses (MPS) disorders; resulting in short stature, reduced size of the thoracic cavity and compromised manual dexterity. Current therapies for MPS have had a limited effect on bone growth and to improve these therapies or develop adjunct approaches requires an understanding of the underlying basis of abnormal bone growth in MPS. The MPS VII mouse model replicates the reduction in long bone and vertebral length observed in human MPS. Using this model we have shown that the growth plate is elongated but contains fewer chondrocytes in the proliferative and hypertrophic zones. Endochondral bone growth is in part regulated by entry and exit from the cell cycle by growth plate chondrocytes. More MPS VII chondrocytes were positive for Ki67, a marker for active phases of the cell cycle, suggesting that more MPS VII chondrocytes were in the cell cycle. The number of cells positive for phosphorylated histone H3 was significantly reduced in MPS VII chondrocytes, suggesting fewer MPS VII chondrocytes progressed to mitotic division. While MPS VII HZ chondrocytes continued to express cyclin D1 and more cells were positive for E2F1 and phos pRb than normal, fewer MPS VII HZ chondrocytes were positive for p57kip2 a marker of terminal differentiation, suggesting fewer MPS VII chondrocytes were able to exit the cell cycle. In addition, multiple markers typical of PZ to HZ transition were not downregulated in MPS VII, in particular Sox9, Pthrpr and Wnt5a. These findings are consistent with MPS VII growth plates elongating at a slower rate than normal due to a delay in progression through the cell cycle, in particular the transition between G1 and S phases, leading to both reduced cell division and transition to the hypertrophic phenotype.
  • Corrigendum to “Peroxisomal dysfunction is associated with up-regulation
           of apoptotic cell death viamiR-223 induction in knee osteoarthritis
           patients with type 2 diabetes mellitus” [Bone 64 (2014) 124–131]
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Dongkyun Kim, Jinsoo Song, Chihyun Ahn, Yeonho Kang, Churl-Hong Chun, Eun-Jung Jin
  • Conditional knockout of ephrinB1 in osteogenic progenitors delays the
           process of endochondral ossification during fracture repair
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Agnieszka Arthur, Sharon Paton, Andrew C.W. Zannettino, Stan GronthosAbstractThe Eph receptor tyrosine kinase ligand, ephrinB1 (EfnB1) is important for correct skeletal and cartilage development, however, the role of EfnB1 in fracture repair is unknown. This study investigated the role of EfnB1 during fracture repair where EfnB1 expression increased significantly at 1 and 2 weeks post fracture in C57Bl/6 wildtype mice, coinciding with the haematoma, soft callus formation/remodelling stages, respectively. To investigate the specific role of EfnB1 within the osteogenic lineage during fracture repair, male mice with a conditional deletion of EfnB1 in the osteogenic lineage (EfnB1OBfl/O), driven by the Osterix (Osx) promoter, and their male Osx:Cre counterparts were subject to a femoral fracture with internal fixation. Two weeks post fracture micro computed tomography (μCT) analysis revealed that EfnB1OBfl/O mice displayed a significant decrease in bone volume relative to tissue volume within the fracture callus. This was attributed to an alteration in the distribution of osteoclasts within the fracture site, a significant elevation in cartilaginous tissue and reduction in the osteoprogenitor population and calcein labelled bone within the fracture site of EfnB1OBfl/O mice. Supportive in vitro studies demonstrated that under osteogenic conditions, cultured EfnB1OBfl/O stromal cells derived from the 2 week fracture site exhibited a reduced capacity to produce mineral and decreased expression of the osteogenic gene, Osterix, when compared to Osx:Cre controls. These findings suggest that the loss of EfnB1 delays the fracture repair process. The present study confirmed that EFNB1 activation in human BMSC, following stimulation with soluble-EphB2 resulted in de-phosphorylation of TAZ, demonstrating similarities in EfnB1 signalling between human and mouse stromal populations. Overall, the present study provides evidence that loss of EfnB1 in the osteo/chondrogenic lineages delays the soft callus formation/remodelling stages of the fracture repair process.
  • Selective inhibition of progesterone receptor in osteochondral progenitor
           cells, but not in mature chondrocytes, modulated subchondral bone
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Chenlin Dai, Junjing Jia, Alexander Kot, Xueping Liu, Lixian Liu, Min Jiang, Nancy E. Lane, Barton L. Wise, Wei YaoAbstractObjectiveThe presence or relative proportion of progesterone nuclear receptors (PR) in different tissues may contribute to sexual dimorphism in these tissues. PR is expressed in chondrocytes, but its function is mostly unknown. We hypothesized that the PR may regulate chondrocyte metabolism and affect subchondral bone structure.MethodsWe utilized genetic fate mapping and immunohistochemistry to elucidate PR expression in and effect on cartilage. To define sex-dependent and chondrocyte-specific effects of the PR on subchondral bone, we selectively deleted PR in osteochondrogenic progenitor cells marked by Prx1 (Prx1; PRcKO) and Collagen 2 (Col2; PRcKO), or in matured chondrocytes marked by aggrecan (Acan; PRcKO) and evaluated subchondral bone structure at 4 months of age. Chondrocyte aging was monitored by anti-senescence marker p16INK4a, and MMP13, one of the Senescence-Associated Secretary Phenotype (SASP) components.ResultsCompared to wild-type (WT) mice, the female Prx1; PRcKO and the Col2; PRcKO mice had greater total subchondral bone volume and greater subchondral cortical bone thickness, with increased estimated subchondral bone stiffness and failure load in both female and male Col2; PRcKO mice. Moreover, Col2; PRcKO mice from both sexes had greater bone formation and bone strength at the femurs. In contrast, we did not observe any subchondral bone changes in Acan; PRcKO mice other than higher work-to-failure observed in the male Acan; PRcKO mice. Despite no detected difference in articular cartilage between the WT and the PR; chondrocyte conditional deletion mice, there were greater numbers of senescent chondrocytes and increased MMP13 expression, especially in the male mutant mice.ConclusionThese findings suggest that selective inhibition of PR in osteoprogenitor cells, but not in terminally differentiated chondrocytes, induced an increased subchondral bone phenotype and high estimated subchondral bone strength, which might be associated with the development of osteoarthritis in older age.
  • Bone resorption is unchanged by liraglutide in type 2 diabetes patients: A
           randomised controlled trial
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Katrine Hygum, Torben Harsløf, Niklas Rye Jørgensen, Jørgen Rungby, Steen B. Pedersen, Bente L. LangdahlAbstractBackgroundLiraglutide, a glucagon-like peptide-1 receptor agonist, has well known beneficial effects on glucose metabolism, and animal studies indicate that liraglutide also affects bone turnover by decreasing bone resorption. The primary objective of the study was to investigate the effect of liraglutide on bone turnover in patients with T2D.MethodsThe study was a randomized, double-blinded, clinical trial. Sixty participants with T2D were randomized to treatment with liraglutide 1.8 mg daily or placebo for 26 weeks. The primary endpoint was change in p-collagen I cross-linked C-terminal telopeptide (p-CTX).ResultsP-CTX increased in patients treated with liraglutide by 0.07 (0.03; 0.10) μg/L (p 
  • Effect of inducible bone morphogenetic protein 2 expression on the
           osteogenic differentiation of dental pulp stem cells in vitro
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Ferenc Tóth, József M. Gáll, József Tőzsér, Csaba HegedűsAbstractBone morphogenetic protein 2 (BMP-2) is a member of the transforming growth factor-β superfamily, it is known to be a factor involved in skeletal development and capable of inducing in vitro osteogenic differentiation of mesenchymal stem cells (MSCs). Dental pulp stem cells (DPSCs) isolated from extracted third molar teeth are an ideal resource for bone tissue engineering and regeneration applications, due to their convenient isolation, safe cryopreservation, and easy maintenance in cell cultures. The aims of this study were to deliver BMP-2 under control of the tetracycline-inducible (tet-on) promoter into dental pulp stem cells and to examine whether these BMP-2 expressing cell lines are capable of promoting osteogenic differentiation in vitro. BMP-2 gene was cloned into the lentiviral transfer plasmid pTet-IRES-EGFP and used to establish the DPSC-BMP-2 cell line. DPSC, DPSC-GFP (mock) and DPSC-BMP-2 cell lines were cultured in growth medium or osteogenic medium in the presence or absence of 100 ng/ml doxycycline. To assess differentiation, alkaline phosphatase activity, calcium accumulation and gene transcription levels of different genes involved in osteogenic differentiation (BMP-2, Runx2, alkaline phosphatase, and noggin) were measured. Doxycycline-induced BMP-2 expression induced the differentiation of DPSCs into the preosteoblastic stage but could not favor the further maturation into osteoblasts and osteocytes. We found that while Runx2 gene transcription was continuously upregulated in doxycycline-treated DPSC-BMP-2 cells, the alkaline phosphatase activity and the accumulation of minerals were reduced. As a result of the increased BMP-2 expression, the transcription level of the BMP antagonist noggin was also upregulated, and probably caused the observed effects regarding alkaline phosphatase (ALP) activity and mineral deposition. Our study shows that this system is effective in controlling transgene expression in DPSC cell line. Exploration of all known factors affecting osteogenic differentiation and their interactions is of major importance for the field of regenerative medicine. As the metabolic reaction to the upregulated transgene transcription appears to be cell line-specific, a wrongly selected target gene and/or regulation system could have adverse effects on differentiation.
  • Children and adolescents with obesity have reduced serum bone turnover
           markers and 25-hydroxyvitamin D but increased parathyroid hormone
           concentrations – Results derived from new pediatric reference ranges
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): M. Geserick, M. Vogel, F. Eckelt, M. Schlingmann, A. Hiemisch, R. Baber, J. Thiery, A. Körner, W. Kiess, J. KratzschAbstractBackgroundWe aimed to establish age- and gender-specific reference ranges for concentrations of the bone markers osteocalcin (OC), procollagen type 1 N-propeptides (PINP) and carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX-I) as well as for the calciotropic hormones 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in healthy infants, children and adolescents. In addition, the effect of age, gender, puberty and body mass index (BMI) on bone markers was investigated.Methods2416 healthy subjects (5714 blood withdrawals), aged 3 months to 17 years, were included to estimate the age- and gender-dependence of reference ranges. Subsequently, measured values of the biomarkers were transformed to standard deviation scores (SDS) and their associations with age, gender and puberty were analyzed. Bone marker-SDS values of the reference cohort were compared with an obese cohort (n = 317 and 489 blood withdrawals) to analyze the effect of BMI.ResultsOC, PINP and CTX-I showed a distinct age- and gender-dependence with peak levels at 10 to 11 years (girls, Tanner 3) and 13 years (boys, Tanner 3–4). Children with obesity had significantly lower SDS levels for OC (−0.44), PINP (−0.27), CTX-I (−0.33), 25(OH)D (−0.43) and higher SDS levels for PTH (+0.44) than the reference cohort.ConclusionsOC, PINP and CTX-I vary with age, gender and pubertal stage. The body weight status has to be considered in the interpretation of pediatric OC, PINP, CTX-I, 25(OH)D and PTH levels. Consequences of childhood obesity on bone health should be carefully investigated in long-term studies.
  • Abnormal microarchitecture and stiffness in postmenopausal women with
           isolated osteoporosis at the 1/3 radius
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Alexander S. Dash, Sanchita Agarwal, Donald J. McMahon, Felicia Cosman, Jeri Nieves, Mariana Bucovsky, X. Edward Guo, Elizabeth Shane, Emily M. SteinAbstractBackgroundPostmenopausal women with isolated osteoporosis at the 1/3 radius (1/3RO) present a therapeutic dilemma. Little is known about whether these patients have generalized skeletal fragility, and whether this finding warrants treatment. The aim of this study was to investigate the biochemical and microarchitectural phenotype of women with 1/3RO compared to women with classic postmenopausal osteoporosis by DXA at the spine and hip (PMO), and controls without osteoporosis at any site.MethodsThis cross-sectional study enrolled 266 postmenopausal women, who were grouped according to densitometric pattern. Subjects had serum biochemistries, areal BMD (aBMD) measured by DXA, trabecular and cortical vBMD, microarchitecture, and stiffness by high resolution peripheral QCT (HR-pQCT, voxel size ~82 μm) of the distal radius and tibia.ResultsMean age was 68 ± 7 years. DXA T-Scores reflected study design. By HR-pQCT, 1/3RO had abnormalities at both radius and tibia compared to controls: lower total, cortical and trabecular vBMD, cortical thickness and trabecular number, higher trabecular separation and heterogeneity, and lower whole bone stiffness. In contrast, the magnitude and pattern of abnormalities in vBMD, microarchitecture and stiffness in 1/3RO were similar to those in PMO; the difference compared to controls was similar among the two groups. Serum calcium, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 24-hour urine calcium did not differ.ConclusionsAlthough aBMD appeared relatively preserved at the spine and hip by DXA, women with 1/3RO had significant microarchitectural and biomechanical deficits comparable to those in women with typical PMO. Further study is required to guide treatment decisions in this population.
  • Objective measures of moderate to vigorous physical activity are
           associated with higher distal limb bone strength among elderly men
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Lisa Langsetmo, Andrew J. Burghardt, John T. Schousboe, Peggy M. Cawthon, Jane A. Cauley, Nancy E. Lane, Eric S. Orwoll, Kristine E. Ensrud, Osteoporotic Fractures in Men (MrOS) Study GroupAbstractOur aim was to determine the association between objectively measured physical activity (PA) and bone strength of the distal limbs among older men. We studied 994 men from the MrOS cohort study (mean age 83.9) who had repeat (Year 7 and 14) 5-day activity assessment with at least 90% wear time (SenseWearPro3 Armband) and Year 14 measures using high resolution peripheral quantitative tomography (HR-pQCT) (Scanco). Total energy expenditure (TEE), total steps per day, peak cadence (mean of top 30 steps/min over 24 h) and time spent in a given level of activity: sedentary (reference,
  • Plectin stabilizes microtubules during osteoclastic bone resorption by
           acting as a scaffold for Src and Pyk2
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Takuma Matsubara, Tatsuki Yaginuma, William N. Addison, Yuko Fujita, Kouji Watanabe, Izumi Yoshioka, Hisako Hikiji, Kenshi Maki, Roland Baron, Shoichiro KokabuAbstractOsteoclasts are multinuclear cells which maintain bone homeostasis by resorbing bone. During bone resorption, osteoclasts attach to the bone matrix via a sealing zone formed by an actin ring. Rous sarcoma oncogene (Src) is essential for actin ring formation and bone resorption. Recently, we demonstrated that plectin, a cytolinker protein, is a Src-binding protein in osteoclasts. However, the function of plectin in osteoclasts remains unknown. In this study, we demonstrated that shRNA knockdown of plectin in RAW 264.7 cells resulted in tartrate resistant acid phosphatase positive multinuclear cells (TRAP (+) MNCs) with impaired actin ring formation and bone resorption activity. Moreover, we found that in plectin-silenced TRAP (+) MNCs, Src and protein tyrosine kinase 2 beta (Pyk2), two critical kinases in osteoclastic bone resorption, were inactivated and microtubule polarity was disturbed. These results suggest that plectin plays a critical role in osteoclast biology by acting as a scaffold to facilitate Src and Pyk2 activation during microtubule organization.
  • Breaking crown dentine in whole teeth: 3D observations of prevalent
           fracture patterns following overload
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Claudia Fleck, Martin Burke, Gregor Ganzosch, Cecilia Müller, John D. Currey, Paul ZaslanskyAbstractTeeth with intact crowns rarely split or fracture, despite decades of cyclic loading and occasional unexpected overload. This is largely attributed to the presence of dentine, since cracking and fracture of enamel have been frequently reported. Dentine is similar to bone, comprising mineralised collagen fibres as a main constituent. Unlike cortical bone, however, where microcracking and damage arrest are essential for re/modelling and healing, dentine can neither remodel nor regenerate. This raises questions regarding the evolutionary benefits of toughening, leading to uncertainty whether cracks actually appear in dentine in situ. Here we study the notion that circumpulpal dentine is usually protected against, rather than damaged by severe overloads, and that it is not much more massive or stronger than it needs to be. To address this, we examined hydrated teeth still within whole jawbones of freshly-slaughtered skeletally mature pigs, mechanically loaded until fracture. Force displacement curves, optical and electron microscopy combined with 3D microstructural analysis by conventional micro-computed tomography (μCT) revealed mostly brittle fracture paths in circumpulpal crown dentine. Once overload cracks reach this mass of dentine they propagate rapidly along straight paths often parallel to the enamel flanks of the oblong shovel shaped premolars. We find infrequent signs of active toughening mechanisms with minimal crack diversion, ligament bridging and microcracking. When such toughening is seen, it mainly appears in softer dentine in the root, or near the dentine-enamel-junction (DEJ) in mantle dentine. We observed shear bands in overloaded circumpulpal dentine, due to mutual gliding of large cracked segments. These shear bands are formed as periodic arrays of rotated dentine fragments. The 3D data consistently demonstrate the importance of the layered tooth structure, containing a stiff outer enamel shell, a soft sub-DEJ interlayer and a stiff circumpulpal dentine bulk, for deflecting cracks from splitting the tooth.
  • Skeletal effects of plyometric exercise and metformin in ovariectomized
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): A.K. Stunes, R.G. Erben, C. Schüler, E.F. Eriksen, M. Tice, D. Vashishth, U. Syversen, M.P. MostiAbstractEstrogen deficiency causes bone loss and skeletal muscle dysfunction, and attenuates the musculoskeletal effects of exercise. The anti-diabetic drug metformin has been suggested to promote beneficial skeletal effects. To explore whether metformin can improve musculoskeletal training response during estrogen deficiency, we investigated the skeletal effects of plyometric exercise and metformin, in an ovarectomized (OVX) rat model of osteoporosis. Female Sprague Dawley rats, 12 weeks of age, rats were allocated to a sham-operated group (Sham), and four OVX groups; metformin (OVX-Met), exercise (OVX-Ex), combined metformin and exercise (OVX-MetEx) and a control group (OVX-Ctr), n = 12/group. Dual X-ray absorptiometry, micro computed tomography, fracture toughness testing, histomorphometry and plasma analyses were performed to explore skeletal effects. All intervention groups exhibited a higher gain in femoral bone mineral density (BMD) than OVX-Ctr (p 
  • Tibial speed of sound changes in preterm infants during the first year of
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Zuzana Korčeková, Peter Korček, Václav Čunát, Zuzana Staníčková, Patrícia Zemanová, Zbyněk StraňákAbstractIntroductionMetabolic bone disease of prematurity (MBD) frequently affects preterm infants. The accurate diagnosis of the MBD remains a challenging issue despite characteristic clinical, laboratory and imaging features. Recently, non-invasive quantitative ultrasound (QUS) measuring speed of sound (SOS) has been applied to assess bone status. Limited data are available on comparison of QUS among preterm infants.ObjectiveTo evaluate development of tibial bone SOS values in preterm infants during the first year of life and compare the SOS values among different birth weight categories.MethodsQUS was used in 153 infants below 34 weeks of gestation. The study group was divided into 3 subgroups based on birth weight (BW): ≤1000 g, 1001–1500 g and>1500 g. SOS measurement was performed at 6 and 12 months of corrected age (CA).ResultsOverall, we found significant increase in mean tibial SOS between 6 and 12 months of CA (3004 ± 123 vs 3253 ± 109 m/s, p = 0.001). There were significant differences in SOS among birth weight categories at 6 months of CA (p = 0.045). However, these differences were not statistically significant at 12 months of CA (p = 0.289). The infants ≤ 1000 g scored the highest SOS values at both time points.ConclusionsTibial SOS significantly increases during infancy in preterm newborns. Significant variation exists in SOS at 6 months, but not at 12 months of corrected age according to BW. Moreover, inverse correlation between BW and SOS indicating better bone status was revealed in extremely low birth weight infants at both 6 or at 12 months of CA.
  • Differences in geometric strength at the contralateral hip between men
           with hip fracture and non-fractured comparators
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Alan M. Rathbun, Jay Magaziner, Michelle D. Shardell, Thomas J. Beck, Laura M. Yerges-Armstrong, Denise Orwig, Gregory E. Hicks, Alice S. Ryan, Marc C. HochbergAbstractOlder men sustain excess bone mineral density (BMD) declines after hip fracture; however, BMD provides no information on mechanical structure and strength. The aim was to assess whether changes in hip bone geometry in older men after hip fracture differ than that expected with aging. Two cohorts were used: Baltimore Hip Studies 7th cohort (BHS-7) and Baltimore Men's Osteoporosis Study (MOST). The sample (N = 170) included older Caucasian men with hip fracture that were propensity score matched (1:1) to community-dwelling non-fractured comparators. Hip Structural Analysis (HSA) calculated aerial BMD and metrics of bone structural strength: cross-sectional bone area (CSA), cortical outer diameter (OD), section modulus (SM), and centroid position (CP). Mixed-effect models estimated changes in HSA parameters and adjusted robust regression models evaluated between-cohort differences in annual percent change at the narrow neck (NN), intertrochanteric (IT), and femoral shaft (FS). Hip fracture was associated with statistically greater declines in NN CSA (β = −2.818; 95% CI: −3.300%, −2.336%), SM (β = −1.896%; 95% CI: −2.711%, −1.080%) and CP (β = −0.884%; 95% CI: −0.889%, −0.880%) and significantly larger increases in NN OD (β = 0.187%; 95% CI: 0.185%, 0.190%). Differences in IT HSA parameters were like the NN but larger in magnitude, while there were favorable changes in FS geometry where fragility fractures are rare. Findings indicate there are declines in bone structure and strength at the NN and IT regions of the proximal femur in older men during hip fracture recovery that far exceed what occurs during normal aging.
  • Serum periostin is associated with cancer mortality but not cancer risk in
           older home-dwelling men: A 8-year prospective analysis of the STRAMBO
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Jean-Charles Rousseau, Cindy Bertholon, Roland Chapurlat, Pawel SzulcAbstractBackgroundPeriostin (POSTN) regulates multiple biological behaviors of tumor cells. We studied the association of serum POSTN with mortality in home-dwelling men.MethodsPOSTN was measured at baseline using immunoassay (USCN life science, China) in 815 home-dwelling men aged 60–87 followed-up for 8 years.ResultsIn the entire cohort, higher serum POSTN was associated with higher all-cause mortality [Hazard Ratio (HR) = 1.30 per Standard Deviation (SD), 95% Confidence Interval (CI): 1.13–1.50, p 
  • Muscle contraction induces osteogenic levels of cortical bone strain
           despite muscle weakness in a mouse model of Osteogenesis Imperfecta
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Alycia G. Berman, Jason M. Organ, Matthew R. Allen, Joseph M. WallaceAbstractMechanical interactions between muscle and bone have long been recognized as integral to bone integrity. However, few studies have directly measured these interactions within the context of musculoskeletal disease. In this study, the osteogenesis imperfecta murine model (oim/oim) was utilized because it has both reduced bone and muscle properties, allowing direct assessment of whether weakened muscle is able to engender strain on weakened bone. To do so, a strain gauge was attached to the tibia of healthy and oim/oim mice, muscles within the posterior quadrant of the lower hind limb were stimulated, and bone strain during muscle contraction was measured. Results indicated that the relationship between maximum muscle torque and maximum engendered strain is altered in oim/oim bone, with less torque required to engender strain compare to wild-type and heterozygous mice. Maximum muscle torque at 150 Hz stimulation frequency was able to engender ~1500 μɛ in oim/oim animals. However, even though the strain engendered in the oim/oim mice was high relative to historical bone formation thresholds, the maximum strain values were still significantly lower than that of the wild-type mice. These results are promising in that they suggest that muscle stimulation may be a viable means of inducing bone formation in oim/oim and potentially other disease models where muscle weakness/atrophy exist.
  • Burn injury and restoration of muscle function
    • Abstract: Publication date: March 2020Source: Bone, Volume 132Author(s): Gordon L. KleinAbstractBurn injury in children results in a systemic inflammatory reaction as well as a stress response. Consequences of these non-specific adaptive responses include resorptive bone loss and muscle catabolism. These adverse events can result in a post-burn fracture rate of approximately 15% and long-term muscle weakness that prolongs recovery. A randomized controlled trial of a single dose of the bisphosphonate pamidronate within the first ten days of burn injury resulted in the prevention of resorptive bone loss and continuous bone accrual. Examining the muscle protein kinetics in pediatric burn patients enrolled in that randomized controlled trial revealed that those who had been given the single dose bisphosphonate experienced preservation of muscle mass and strength. An in vitro study of mouse myoblasts incubated with serum from patients who participated in the randomized controlled study demonstrated that mouse myoblasts exposed to serum from patients given the single dose bisphosphonate exhibited greater myotube diameter than those from burned children given placebo. Moreover, the serum from bisphosphonate treated patients stimulated the protein anabolic pathways and suppressed protein catabolic pathways in these cells. Inasmuch as incubation of the myotubes with an antibody to transforming growth factor beta (TGFβ) rescued myotube size in the cultures with serum from patients who received the placebo to the same magnitude as cultures with serum from patients treated with single dose bisphosphonate, we postulate that post-burn bone resorption liberates muscle catabolic factors which cause muscle wasting. Future uses of bisphosphonates could include studies designed to prevent short-term acute bone resorption in conditions that may result in muscle wasting as well as in short-term interventions in chronic inflammatory conditions which may flare and cause acute bone and muscle loss.
  • History of etidronate
    • Abstract: Publication date: Available online 3 January 2020Source: BoneAuthor(s): Nelson B. Watts, Charles H. Chesnut, Harry K. Genant, Steven T. Harris, Rebecca D. Jackson, Angelo A. Licata, Paul D. Miller, W. Jerry Mysiw, Bradford Richmond, David ValentAbstractEtidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in “hard” water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.
  • LPS-induced premature osteocyte senescence: Implications in inflammatory
           alveolar bone loss and periodontal disease pathogenesis
    • Abstract: Publication date: Available online 2 January 2020Source: BoneAuthor(s): Ruben Aquino-Martinez, Jennifer L. Rowsey, Daniel G. Fraser, Brittany A. Eckhardt, Sundeep Khosla, Joshua N. Farr, David G. MonroeAbstractCellular senescence is associated with inflammation and extracellular matrix tissue remodeling through the secretion of proteins termed the senescence-associated secretory phenotype (SASP). Although osteocyte senescence in older individuals in the skeleton is well recognized, whether young alveolar osteocytes can also become senescent is unknown. This is potentially important in the context of periodontal disease, which is an inflammatory condition caused by a gradual change from symbiotic to pathogenic oral microflora that can lead to tooth loss. Our aim was to identify whether senescent osteocytes accumulate in young alveolar bone and whether bacterial-derived lipopolysaccharide (LPS) can influence cellular senescence in alveolar bone. An osteocyte-enriched cell population isolated from alveolar bone expressed increased levels of the known senescence marker p16Ink4a, as well as select SASP markers known to be implicated alveolar bone resorption (Icam1, Il6, Il17, Mmp13 and Tnfα), compared to ramus control cells. Increased senescence of alveolar bone osteocytes was also observed in vivo using the senescence-associated distension of satellites (SADS) assay and increased γH2AX, a marker of DNA damage associated with senescent cells. To approximate a bacterial infection in vitro, alveolar osteocytes were treated with LPS. We found increased expression of various senescence and SASP markers, increased γH2AX staining, increased SA-β-Gal activity and the redistribution of F-actin leading to a larger and flattened cell morphology, all hallmarks of cellular senescence. In conclusion, our data suggests a model whereby bacterial-derived LPS stimulates premature alveolar osteocyte senescence, which in combination with the resultant SASP, could potentially contribute to the onset of alveolar bone loss.
  • Possible involvement of elastase in enhanced osteoclast differentiation by
           neutrophils through degradation of osteoprotegerin
    • Abstract: Publication date: Available online 31 December 2019Source: BoneAuthor(s): Risa Sugisaki, Yoichi Miyamoto, Kentaro Yoshimura, Kiyohito Sasa, Kotaro Kaneko, Motohiro Tanaka, Masakatsu Itose, Sakie Inoue, Kazuyoshi Baba, Tatsuo Shirota, Daichi Chikazu, Ryutaro KamijoAbstractNeutrophils are one of the most abundant leukocytes in the sites of lesion of inflammatory diseases such as periodontitis and rheumatoid arthritis. These diseases are accompanied by bone loss, which worsens the quality of life of the patients. However, the role of neutrophils in the inflammatory bone loss has not been fully investigated. In the present study, we found that human neutrophils enhanced osteoclast differentiation from mouse bone marrow cells co-cultured with mouse osteoblasts in the presence of active vitamin D3. The enhanced osteoclast differentiation was significantly suppressed by elastatinal, a synthetic inhibitor of neutrophil elastase. Also, we found that human neutrophils degraded human recombinant osteoprotegerin (OPG), a decoy receptor for nuclear factor κB (RANK) ligand (RANKL), the essential osteoclast differentiation-inducing factor, expressed by osteoblasts. Degradation of OPG by neutrophils was suppressed by human α1-protease inhibitor, the major endogenous inhibitor of neutrophil elastase. Recombinant human neutrophil elastase degraded human OPG in its death domain-like region. These results indicated that the degradation of OPG by elastase contributed at least in part to the enhanced osteoclast differentiation by neutrophils. There is a possibility that neutrophils play an important role in inflammatory bone loss.
  • Genetic testing is useful in adults with limited phenotypes of genetic
           skeletal conditions
    • Abstract: Publication date: Available online 30 December 2019Source: BoneAuthor(s): Marie Cottard, Emmanuelle Vignot, Elisabeth Fontanges, Blandine Merle, Corinne Collet, Roland ChapurlatAbstractSummaryWe show the value of genetic screening in 3 adults with limited phenotypes of three bone sclerosing genetic disease (GD): osteopetrosis (OPT), Camurati-Engelmann disease (CED) and pycnodysostosis.IntroductionOPT, CED and pycnodysostosis are three rare bone diseases often diagnosed in childhood. However, some atypical phenotypes raise the problem of delayed diagnosis in adults. Genetic tests may then be useful to establish a formal diagnosis.MethodsWe report 3 cases of adult patients with symptomatic or asymptomatic bone sclerosing lesions for whom the clinical, radiological and biological explorations were atypical and did not allow a formal diagnosis. These unusual descriptions led to the search for genetic mutations.ResultsThese 3 cases of limited phenotypes were associated with unknown or poorly described variants of 3 rare bone genetic diseases.ConclusionsGenetic tests proved useful to establish the diagnosis and manage the condition of adults with rare bone sclerosing GD.
  • Biomechanics of callus in the bone healing process, determined by
           specimen-specific finite element analysis
    • Abstract: Publication date: Available online 28 December 2019Source: BoneAuthor(s): Takane Suzuki, Yusuke Matsuura, Takahiro Yamazaki, Tomoyo Akasaka, Ei Ozone, Yoshiyuki Matsuyama, Michiaki Mukai, Takeru Ohara, Hiromasa Wakita, Shinji Taniguchi, Seiji OhtoriAbstractAs fractures heal, immature callus formed in the hematoma is calcified by osteoblasts and altered to mature bone. Although the bone strength in the fracture-healing process cannot be objectively measured in clinical settings, bone strength can be predicted by specimen-specific finite element modeling (FEM) of quantitative computed tomography (qCT) scans. FEM predictions of callus strength would enable an objective treatment plan. The present study establishes an equation that converts material properties to bone density and proposes a specimen-specific FEM. In 10 male New Zealand white rabbits, a 10-mm long bone defect was created in the center of the femur and fixed by an external fixator. The callus formed in the defect was extracted after 3–6 weeks, and formed into a (5 × 5 × 5 mm3) cube. The bone density measured by qCT was related to the Young's modulus and the yield stress measured with a mechanical tester. For validation, a 10-mm long bone defect was created in the central femurs of another six New Zealand white rabbits, and fixed by an external fixator. At 3, 4, and 5 weeks, the femur was removed and subjected to Computed tomography (CT) scanning and mechanical testing. A specimen-specific finite element model was created from the CT data. Finally, the bone strength was measured and compared with the experimental value. The bone mineral density σ was significantly and nonlinearly correlated with both the Young's modulus E and the yield stress σ. The material-property conversion equations were E = 0.2391e8.00ρ and ρ = 30.49σ2.41. Moreover, the experimental bone strength was significantly linearly correlated with the prospective FEM. We demonstrated the Young's moduli and yield stresses for different bone densities, enabling a FEM of the bone-healing process. An FEM based on these material properties is expected to yield objective clinical judgment criteria.
  • Skeletal dynamics of down syndrome: A developing perspective
    • Abstract: Publication date: Available online 27 December 2019Source: BoneAuthor(s): Jonathan M. LaCombe, Randall J. RoperAbstractIndividuals with Down syndrome (DS) display distinctive skeletal morphology compared to the general population, but disparate descriptions, methodologies, analyses, and populations sampled have led to diverging conclusions about this unique skeletal phenotype. As individuals with DS are living longer, they may be at a higher risk of aging disorders such as osteoporosis and increased fracture risk. Sexual dimorphism has been suggested between males and females with DS in which males, not females, experience an earlier decline in bone mineral density (BMD). Unfortunately, studies focusing on skeletal health related to Trisomy 21 (Ts21) are few in number and often too underpowered to answer questions about skeletal development, resultant osteoporosis, and sexual dimorphism, especially in stages of bone accrual. Further confounding the field are the varied methods of bone imaging, analysis, and data interpretation. This review takes a critical look at the current knowledge of DS skeletal phenotypes, both from human and mouse studies, and presents knowledge gaps that need to be addressed, differences in research methodologies and analyses that affect the interpretation of results, and proposes guidelines for overcoming obstacles to understand skeletal traits associated with DS. By examining our current knowledge of bone in individuals with Ts21, a trajectory for future studies may be established to provide meaningful solutions for understanding the development of and improving skeletal structures in individuals with and without DS.
  • Factors associated with bone microstructural alterations assessed by
           HR-pQCT in long-term HIV-infected individuals
    • Abstract: Publication date: Available online 23 December 2019Source: BoneAuthor(s): Sarah C. Foreman, Po Hung Wu, Ruby Kuang, Malcolm D. John, Phyllis C. Tien, Thomas M. Link, Roland Krug, Galateia J. KazakiaAbstractPurposeIn adults with long-term HIV infection, low bone density and increased fracture risk have emerged as significant comorbidities. Our aim was to assess the association of exercise, nutrition, and medications with bone quality in adults with long-term HIV infection.MethodsForty-three adults with HIV infection were enrolled (median BMI 25.7, range 18.2–35.6 kg/m2; median age 57, range 50–69 years). Participants underwent ultradistal radius and tibia high-resolution peripheral quantitative CT (HR-pQCT). Questionnaires included the revised Community Healthy Activities Model Program for Seniors (CHAMPS), the Mini Nutritional Assessment (MNA) as well as medication assessments. Multivariable linear regression models were used to evaluate the association of exercise, nutritional status, tenofovir disoproxil fumarate (TDF) and protease inhibitor (PI) use with bone density and microstructure, adjusting for demographic risk factors.ResultsIn regression models, higher nutrition scores were associated with higher tibia cortical thickness (R2 = 0.23; β = 0.03; p = 0.044) and higher radius cortical BMD (R2 = 0.43; β = 8.4; p = 0.026). Higher weekly frequency of all physical activities was significantly associated with higher radius trabecular BMD (R2 = 0.38; β = 0.96; p = 0.050), higher radius trabecular number (R2 = 0.31; β = 0.01; p = 0.026), lower tibia and radius trabecular separation (tibia: R2 = 0.30; β = −0.003; p = 0.038; radius: R2 = 0.35; β = −0.003; p = 0.021), and higher radius bone stiffness (R2 = 0.45; β = 0.38; p = 0.047). Higher frequency of bone loading physical activities was significantly associated with higher tibia trabecular density (R2 = 0.44; β = 4.06; p = 0.036), higher tibia bone stiffness (R2 = 0.46; β = 3.06; p = 0.050), and higher tibia estimated failure load (R2 = 0.46; β = 0.17; p = 0.049). TDF used in combination with a PI was associated with lower radius trabecular BMD (R2 = 0.39; β = −41.2; p = 0.042), lower radius trabecular number (R2 = 0.34; β = −0.44; p = 0.009) and greater radius trabecular separation (R2 = 0.42; β = 0.16; p = 0.002), while TDF use without a PI was not associated with reduced bone quality.ConclusionsIn adults with HIV infection, malnutrition is associated with poor cortical bone quality, while reduced frequency of physical activities and specifically reduced frequency of mechanical loading activities are associated with deficient trabecular bone structure and reduced estimates of bone strength. TDF use in combination with a PI is associated with deleterious effects on trabecular bone structure.
  • Regional changes in indices of bone strength of upper and lower limbs in
           response to high-intensity impact loading or high-intensity resistance
    • Abstract: Publication date: Available online 15 December 2019Source: BoneAuthor(s): Conor Lambert, Belinda R. Beck, Amy T. Harding, Steven L. Watson, Benjamin K. WeeksAbstractIt is well known that the bone response to physical activity is highly dependent on the nature of the loads imposed. Despite this, few direct comparisons of the effect of impact-style loading and resistance training on bone have been made. We therefore aimed to compare the effects of 10-month, twice-weekly, high-impact loading and 10-month, twice-weekly, high-intensity resistance training on indices of bone strength of both the upper and lower limbs of young adult women. Physically inactive, otherwise healthy, young adult women (18–30 years) with below average bone mass (T-score ≤ 0) were recruited as part of the OPTIMA-Ex trial. Testing included DXA- and pQCT-derived measures of bone mass and indices of bone strength and QUS-derived measures of bone quality of the dominant (D) and non-dominant (ND) upper (radius) and lower limbs (femoral neck, tibia, calcaneus). The present study examined those participants who completed the impact training (IT; n = 10) and resistance training (RT; n = 12) arms of the trial. Age differed between groups at baseline (IT = 23.2 ± 3.8 years, RT = 20.5 ± 1.8 years; p = 0.042). Compliance with the training programs did not differ (IT = 61.4 ± 15.1%, RT = 66.4 ± 11.2%, p = 0.381). Age and baseline differences in bone outcomes served as covariates for repeated measures and univariate ANCOVA conducted for dependent variables and percent change respectively. IT improved distal pQCT-derived bone mineral density (BMD) of the upper limb (ND radius: total BMD = 8.55 ± 2.26% versus 1.50 ± 2.04%, p = 0.040 and trabecular BMD = 1.86 ± 0.90% versus −1.30 ± 0.81%, p = 0.029) and lower limb (ND tibia trabecular BMD = 1.22 ± 0.55% versus −0.82 ± 0.50%, p = 0.017), more than RT. IT also improved upper limb bone strength index (BSI) (ND radius total BSI = 15.35 ± 2.83% versus 2.67 ± 2.55, p = 0.005) and lower limb BSI (D tibia total BSI = 5.16 ± 1.13% versus 0.37 ± 1.02%, p = 0.008; D tibia trabecular BSI = 3.93 ± 1.76% versus −2.84 ± 1.59, p = 0.014, ND tibia trabecular BSI = 3.57 ± 1.63% versus −3.15 ± 1.48%, p = 0.009) more than RT. Conversely, RT improved DXA-derived cortical volumetric BMD at the femoral neck more than IT (3.68 ± 1.99% versus −4.14 ± 2.20%, p = 0.021). Results suggest that IT and RT provide differing site-specific effects in both the upper and lower limbs, with superior bone responses observed at the distal segment from IT, while RT appeared to have greater effect on the shaft of the bone, on indices of bone-strength in young adult women.
  • FRAX prognostic and intervention thresholds in the management of major
           bone fractures in hemodialysis patients: A two-year prospective
           multicenter cohort study
    • Abstract: Publication date: Available online 13 December 2019Source: BoneAuthor(s): Jerzy Przedlacki, Jolanta Buczyńska-Chyl, Piotr Koźmiński, Ewa Niemczyk, Ewa Wojtaszek, Edyta Gieglis, Paweł Żebrowski, Andrzej Podgórzak, Jolanta Wściślak, Monika Wieliczko, Janusz Grochowski, Małgorzata Kędzierska, Bożenna Kaczanowska, Agnieszka Wyszyńska, Zofia Sitkowska-Kurzec, Wiesław Klatko, Ryszard Gellert, Dorota Daniewska, Dariusz Osuch, Dariusz StryjewskiAbstractPurposeThe usefulness of FRAX in predicting major bone fractures in patients with end-stage kidney disease on maintenance hemodialysis treatment has been confirmed in previous studies. For meaningful clinical use, the prognostic and intervention FRAX thresholds need to be established.MethodsThe primary aim of our study was to calculate the optimal cut-off point of FRAX for the best prediction of an increased bone fracture risk in dialysis patients and additionally, to propose its intervention threshold, indicating the need for antifracture pharmacological treatment. The study included 718 hemodialysis patients, who were followed up for two years. Thirty low-energy major bone fractures were diagnosed during the study period. We used the Polish version of FRAX (without the DXA examination) and some particular variables of the FRAX calculator. The optimal cut-off point for prediction of an increased major bone fracture risk was based on the analysis of the sensitivity and specificity curves of FRAX.ResultsThe analysis revealed FRAX>5% (sensitivity of 70.0%, specificity of 69.8%) as the prognostic threshold for major bone fractures. Its sensitivity for bone fracture prediction was significantly higher, but specificity lower than those of FRAX ≥10%, used in general Polish population. The reason for this can be an underestimation of bone fracture risk with FRAX in dialysis patients.ConclusionsWe conclude that the FRAX prognostic threshold for identification of an increased risk of major bone fractures in hemodialysis patients is>5%. We propose to use this specific value of FRAX as an intervention threshold for pharmacological antifracture treatment in hemodialysis patients.
  • Hypophosphatemic osteosclerosis, hyperostosis, and enthesopathy associated
           with novel homozygous mutations of DMP1 encoding dentin matrix protein 1
           and SPP1 encoding osteopontin: The first digenic SIBLING protein
    • Abstract: Publication date: Available online 13 December 2019Source: BoneAuthor(s): Michael P. Whyte, S. Deepak Amalnath, William H. McAlister, Marc D. McKee, Deborah J. Veis, Margaret Huskey, Shenghui Duan, Vinieth N. Bijanki, Suhas Alur, Steven MummAbstractThe SIBLINGs are a subfamily of the secreted calcium-binding phosphoproteins and comprise five small integrin-binding ligand N-linked glycoproteins [dentin matrix protein-1 (DMP1), secreted phosphoprotein-1 (SPP1) also called osteopontin (OPN), integrin-binding sialoprotein (IBSP) also called bone sialoprotein (BPS), matrix extracellular phosphoglycoprotein (MEPE), and dentin sialophosphoprotein (DSPP)]. Each SIBLING has at least one “acidic, serine- and aspartic acid-rich motif” (ASARM) and multiple Ser-x-Glu/pSer sequences that when phosphorylated promote binding of the protein to hydroxyapatite for regulation of biomineralization. Mendelian disorders from loss-of-function mutation(s) of the genes that encode the SIBLINGs thus far involve DSPP causing various autosomal dominant dysplasias of dentin but without skeletal disease, and DMP1 causing autosomal recessive hypophosphatemic rickets, type 1 (ARHR1). No diseases have been reported from gain-of-function mutation(s) of DSPP or DMP1 or from alterations of SPP1, IBSP, or MEPE.Herein, we describe severe hypophosphatemic osteosclerosis and hyperostosis associated with skeletal deformity, short stature, enthesopathy, tooth loss, and high circulating FGF23 levels in a middle-aged man and young woman from an endogamous family living in southern India. Both shared novel homozygous mutations within two genes that encode a SIBLING protein: stop-gain (“non-sense”) DMP1 (c.556G > T, p.Glu186Ter) and missense SPP1 (c.769C > T, p.Leu266Phe). The man alone also carried novel heterozygous missense variants within two additional genes that condition mineral homeostasis and are the basis for autosomal recessive disorders: CYP27B1 underlying vitamin D dependent rickets, type 1, and ABCC6 underlying both generalized arterial calcification of infancy, type 2 and pseudoxanthoma elasticum (PXE). By immunochemistry, his bone contained high amounts of OPN, particularly striking surrounding osteocytes. We review how our patients' disorder may represent the first digenic SIBLING protein osteopathy.
  • The risk of hip and non-vertebral fractures in patients with Parkinson's
           disease and parkinsonism: A systematic review and meta-analysis
    • Abstract: Publication date: Available online 29 November 2019Source: BoneAuthor(s): Marian Schini, Tatiane Vilaca, Edith Poku, Susan Harnan, Anthea Sutton, Isabel Elaine Allen, Steve R. Cummings, Richard EastellAbstractParkinson's disease (PD) is a neurodegenerative disorder that is common in older individuals. PD patients have an increased risk of fractures compared to the general population, perhaps due to multiple falls. However, the fracture risk has not been fully assessed. To assess the impact of PD on the risk of hip and non-vertebral fractures, we conducted a systematic review and meta-analysis.Comprehensive searches of three key bibliographic databases were conducted to identify reviews and primary studies relating to the risk of fractures in patients with PD. Search terms included all relevant terms for Parkinson's disease and for fractures. We selected observational studies with data on the risk of fractures in adults with PD compared to controls without the diagnosis. Study quality was assessed using the Newcastle Ottawa Scale. The random-effects model was used to pool the results.Eighteen studies were included in the review. Seventeen independent studies (14 cohort and 3 case-control studies) were included in the hip fracture analysis. Nine studies (all cohorts, no case-control studies) were included in the non-vertebral fracture analysis. Study quality was judged to be moderate to good. Overall, PD patients had an increased risk for both hip fractures (2.40, 95% CI 2.04 to 2.82) and non-vertebral fractures (1.80, 95% CI 1.60 to 2.01) compared to controls. The relative risk for hip fractures was higher in men (2.93, 95% CI 2.05 to 4.18) than in women (1.81, 95% CI 1.61 to 2.04). There were no effects of the study design, geographical region, or criteria for diagnosing Parkinson's disease on these estimates of fracture risk.There is an increase in the risk of hip and non-vertebral fractures in patients with Parkinson's disease and we recommend a re-evaluation of the clinical guidelines on bone health in patients with PD to address this.
  • Genetic variants affecting bone mineral density and bone mineral content
           at multiple skeletal sites in Hispanic children
    • Abstract: Publication date: Available online 29 November 2019Source: BoneAuthor(s): Ruixue Hou, Shelley A. Cole, Mariaelisa Graff, Karin Haack, Sandra Laston, Anthony G. Comuzzie, Nitesh R. Mehta, Kathleen Ryan, Diana L. Cousminer, Babette S. Zemel, Struan F.A. Grant, Braxton D. Mitchell, Roman J. Shypailo, Margaret L. Gourlay, Kari E. North, Nancy F. Butte, V. Saroja VorugantiAbstractContextOsteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied.ObjectiveWe aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children.MethodsWe conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4–19 years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry.ResultsSignificant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P  3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P = 4.6 × 10−8), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 × 10−8). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P 
  • Skeletal maturation in relation to ethnic background in children of school
           age: The Generation R Study
    • Abstract: Publication date: Available online 28 November 2019Source: BoneAuthor(s): Olja Grgic, Enisa Shevroja, Brunilda Dhamo, Andre G. Uitterlinden, Eppo B. Wolvius, Fernando Rivadeneira, Carolina Medina-GomezAbstractEthnicity is a well-established determinant of pediatric maturity, but the underlying genetic and environmental contributions to these ethnic differences are poorly comprehended. We aimed to evaluate the influence of ethnicity on skeletal age (SA), an assessment of pediatric maturation widely used in clinical settings. We included children from the Generation R Study, a multiethnic population-based pregnancy cohort, assessed at a mean age of 9.78 (±0.33) years. SA was evaluated by a trained observer on hand DXA scans using the Greulich and Pyle method. Ethnic background was defined as geographic ancestry (questionnaire-based assessment) (N = 5325) and genetic ancestry (based on admixture analysis) (N = 3413). Associations between the ethnic background and SA were investigated separately in boys and girls, using linear regression models adjusted for age, height and BMI. Based on geographic ancestry, 84% of the children were classified as European, 6% as Asian and 10% as African. Children of European background had on average younger SA than those of Asian or African descent. Asian boys had 0.46 (95% CI 0.26–0.66, p-value 
  • The effects of metastatic lesion on the structural determinants of bone:
           Current clinical and experimental approaches
    • Abstract: Publication date: Available online 21 November 2019Source: BoneAuthor(s): Stacyann Bailey, David Hackney, Deepak Vashishth, Ron N. AlkalayAbstractMetastatic bone disease is incurable with an associated increase in skeletal-related events, particularly a 17–50% risk of pathologic fractures. Current surgical and oncological treatments are palliative, do not reduce overall mortality, and therefore optimal management of adults at risk of pathologic fractures presents an unmet medical need. Plain radiography lacks specificity and may result in unnecessary prophylactic fixation. Radionuclide imaging techniques primarily supply information on the metabolic activity of the tumor or the bone itself. Magnetic resonance imaging and computed tomography provide excellent anatomical and structural information but do not quantitatively assess bone matrix. Research has now shifted to developing unbiased data-driven tools that can predict risk of impending fractures and guide individualized treatment decisions. This review discusses the state-of-the-art in clinical and experimental approaches for prediction of pathologic fractures with bone metastases. Alterations in bone matrix quality are associated with an age-related increase in skeletal fragility but the impact of metastases on the intrinsic material properties of bone is unclear. Engineering-based analyses are non-invasive with the capability to evaluate oncological treatments and predict failure due to the progression of metastasis. The combination of these approaches may improve our understanding of the underlying deterioration in mechanical performance.
  • MicroCT analyses of mouse femoral neck architecture
    • Abstract: Publication date: Available online 19 August 2019Source: BoneAuthor(s): Robert Brommage, Sabrina Jeter-Jones, Wendy Xiong, Jeff LiuAbstractHip fractures at the femoral neck are a major cause of morbidity and mortality, but aside from biomechanical strength testing, little is known about femoral neck architecture in mice. Procedures were optimized to analyze high-resolution (6 μm voxel size) microCT scans of the mouse femoral neck to provide bone mass and architectural information. Similar to histomorphometric observations in rats, the boundary between cortical and trabecular bone is difficult to identify in the mouse femoral mid-neck and these compartments were not analyzed separately. Analyses included total area, mineralized bone area, and bone volume fraction (BV/TV). Femoral neck architecture varies in C57BL6/J, 129SvEv and BALB/c mouse strains. Bone cross sectional area and BV/TV were low in Lrp5 but elevated in Sost gene knockout mice. Sfrp4 gene knockout resulted in high total area, normal bone area, low BV/TV and, as indicated by BS/BV values, greater trabecularization. Femoral neck BV/TV declined with age and ovariectomy, but increased with teriparatide treatment. These findings demonstrate that the architecture of the mouse femoral neck mimics phenotypes and treatment effects observed at other skeletal sites and is a relevant bone site for translational studies examining osteoporosis therapies.
  • In vivo analysis of subchondral trabecular bone in patients with
           osteoarthritis of the knee using second-generation high-resolution
           peripheral quantitative computed tomography (HR-pQCT)
    • Abstract: Publication date: Available online 14 November 2019Source: BoneAuthor(s): Kazuteru Shiraishi, Ko Chiba, Narihiro Okazaki, Kazuaki Yokota, Yusuke Nakazoe, Kenichi Kidera, Akihiko Yonekura, Masato Tomita, Makoto OsakiAbstractObjectiveSubchondral bone plays an important role in the pathological mechanisms of knee osteoarthritis (OA). High-resolution peripheral quantitative computed tomography (HR-pQCT) is an imaging modality allowing noninvasive microstructural analysis of human bone, and the second generation enables scanning of the knee.The purpose of this study was to perform in vivo analysis of subchondral trabecular bone in patients with medial knee OA, to elucidate features of bone microstructure in medial knee OA, and to investigate relationships between bone microstructure and both stage of disease and lower limb alignment.MethodsSubjects were 20 women, including both patients with medial knee OA (Kellgren-Lawrence (KL) grade 2, n = 5, KL grade 3, n = 7, and KL grade 4, n = 4; mean age: 63.0 years; body mass index (BMI): 23.8 kg/m2) and volunteers without knee OA (KL grade 1, n = 4, mean age: 66.0 years; BMI: 23.8 kg/m2). The proximal tibia (20-mm length) was scanned by second-generation HR-pQCT at a voxel size of 60.7 μm. A subchondral trabecular bone volume of 5 mm length was extracted from the medial and lateral plateaus. They were then divided into 4 regions: anterior, central, medial or lateral, and posterior. Finally, subchondral bone microstructure parameters were analyzed and compared, between each plateau and region. Relationships between microstructural parameters and disease stage (KL grade, minimum joint space width), and between those parameters and lower limb alignment (femorotibial angle: FTA, mechanical axis deviation: MAD) were also investigated.ResultsIn the medial plateau, volumetric bone mineral density (vBMD), bone volume fraction (BV/TV), and trabecular thickness were significantly higher and structure model index (SMI) was significantly lower than in the lateral plateau, particularly in the anterior, central, and medial regions (p 
  • PDGF-BB exhibited therapeutic effects on rat model of
           bisphosphonate-related osteonecrosis of the jaw by enhancing angiogenesis
           and osteogenesis
    • Abstract: Publication date: Available online 30 October 2019Source: BoneAuthor(s): Si-yong Gao, Rui-bang Lin, Si-hui Huang, Yu-jie Liang, Xiang Li, Si-en Zhang, Dai-qiao Ouyang, Kan Li, Guang-sen Zheng, Gui-qing LiaoAbstractThe mechanism and effective treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) are still uncertain. Our previous study revealed that zoledronate (ZOL) preferentially inhibited osteoclasts formation and platelet-derived growth factor-BB (PDGF-BB) secretion, causing suppression of angiogenesis and osteogenesis in vitro. The present study aimed to elucidate whether PDGF-BB had therapeutic effects on rat model of BRONJ by enhancing angiogenesis and angiogenesis. Firstly, rat model of BRONJ was established by ZOL and dexamethasone administration, followed by teeth extraction. The occurrence of BRONJ was confirmed and detected dead bone formation by maxillae examination, micro-CT scan and HE staining (10/10). Compared to control rats (0/10), both angiogenesis and mature bone formation were suppressed in BRONJ-like rats, evidenced by enzyme-linked immunosorbent assay (ELISA) for VEGF (P < 0.01), immunohistochemistry of CD31 (P < 0.05) and OCN (P < 0.01). Moreover, in the early stage of bone healing, the number of preosteoclasts (P < 0.001) and PDGF-BB secretion (P < 0.05) were significantly decreased in bisphosphonates-treated rats, along with the declined numbers of microvessels (P < 0.05) and osteoblasts (P < 0.05). In vitro study, CCK8 assay, alizarin red S staining and western blot assay showed that mandible-derived bone marrow mesenchymal stem cells (BMMSCs) in BRONJ-like rats presented suppressed functions of proliferation, osteogenesis and angiogenesis. Interestingly, recombinant PDGF-BB was able to rescue the impaired functions of BMMSCs derived from BRONJ-like rats at more than 10 ng/ml. Then fibrin sealant with or without recombinant PDGF-BB were tamped into the socket after debridement in BRONJ rats. After 8 weeks, fibrin sealant containing PDGF-BB showed significant therapeutic effects on BRONJ-like rats (bone healing: 8/10 vs 3/10, P < 0.05) with enhancing microvessels and mature bone formation. Our study suggested that the inhibition of angiogenesis and osteogenesis, the potential mechanisms of BRONJ, might partly result from suppression of PDGF-BB secretion in the early stage of bone healing. PDGF-BB local treatment after debridement might avail the healing of BRONJ by increasing angiogenesis and osteogenesis.
  • Mind the gap: Incidence of osteoporosis treatment after an osteoporotic
           fracture – Results of the Austrian branch of the International Costs and
           Utilities Related to Osteoporotic Fractures Study (ICUROS)
    • Abstract: Publication date: Available online 5 October 2019Source: BoneAuthor(s): O. Malle, F. Borgstroem, A. Fahrleitner-Pammer, A. Svedbom, S.V. Dimai, H.P. DimaiIntroductionDespite availability of effective treatment options proven to prevent osteoporotic fractures, a huge gap in osteoporosis treatment exists. The aim of the present study was to evaluate the treatment rate after a major osteoporotic fracture (MOF) in Austria, one of the 25 wealthiest countries worldwide.MethodsThis analysis is based on the data of the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS), a prospective observational study assessing data from patients who suffered a MOF. We stratified these patients by treatment status at time of fracture and compared treatment use following MOF by sex as well as by fracture sites at the time of the index fracture, and 4, 12, and 18 months thereafter. Descriptive statistics, t-tests for continuous variables and chi-squared tests for nominal variables, were performed to compare treatment groups.ResultsA total of 915 patients (78% female) were recruited at 8 different trauma centers throughout Austria. At the time of fracture, 731 patients (80%) did not receive osteoporosis treatment. In this group, follow-up analysis after 4, 12 and 18 months revealed a treatment rate of 18%, 16%, 15% in women, and 8%, 12%, 10% in men, respectively. In those who received osteoporosis medication at the time of fracture the treatment rate was 65%, 54% and 60% in women, and comparable results in men.ConclusionsOnly 1 in 10 men, and
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