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  • Finite element analysis of bone strength in osteogenesis imperfecta
    Bone (IF 4.360) Pub Date : 2020-01-22
    Peter Varga; Bettina M. Willie; Chris Stephan; Kenneth M. Kozloff; Philippe K. Zysset

    As a dedicated experimentalist, John Currey praised the high potential of finite element (FE) analysis but also recognized its critical limitations. The application of the FE methodology to bone tissue is reviewed in the light of his enthusiastic and colorful statements. In the past decades, FE analysis contributed substantially to the understanding of structure-function properties in the hierarchical organization of bone and to the simulation of bone adaptation. The systematic experimental validation of FE analysis of bone strength in anatomical locations at risk of fracture led to its application in clinical studies to evaluate efficacy of antiresorptive or anabolic treatment of bone fragility. Beyond the successful analyses of healthy or osteoporotic bone, FE analysis becomes increasingly involved in the investigation of other fragility-related bone diseases. The case of osteogenesis imperfecta (OI) is exposed, the multiscale alterations of the bone tissue and the effect of treatment summarized. A few FE analyses attempting to answer open questions in OI are then reported. An original study is finally presented that explored the structural properties of the Brtl/+ murine model of OI type IV subjected to sclerostin neutralizing antibody treatment using microFE analysis. The use of identical material properties in the four-point bending FE simulations of the femora reproduced not only the experimental values but also the statistical comparisons examining the effect of disease and treatment. Further efforts are needed to build upon the extraordinary legacy of John Currey and clarify the impact of different bone diseases on the hierarchical mechanical properties of bone.

  • Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells
    Bone (IF 4.360) Pub Date : 2020-01-21
    Dalia Ali; Li Chen; Justyna M. Kowal; Meshail Okla; Muthurangan Manikandan; Moayad AlShehri; Yousef AlMana; Reham AlObaidan; Najd AlOtaibi; Rimi Hamam; Nehad M. Alajez; Abdullah Aldahmash; Moustapha Kassem; Musaad Alfayez
  • Intravital optoacoustic and ultrasound bio-microscopy reveal radiation-inhibited skull angiogenesis
    Bone (IF 4.360) Pub Date : 2020-01-21
    Héctor Estrada; Johannes Rebling; Wolfgang Sievert; Daniela Hladik; Urs Hofmann; Sven Gottschalk; Soile Tapio; Gabriele Multhoff; Daniel Razansky
  • Diagnostic performance of morphometric vertebral fracture analysis (MXA) in children using a 33-point software program
    Bone (IF 4.360) Pub Date : 2020-01-21
    Fawaz F. Alqahtani; Nicola J. Crabtree; Paul A. Bromiley; Timothy Cootes; Penny Broadley; Isla Lang; Amaka C. Offiah

    Background There is significant inter and intraobserver variability in diagnosing vertebral fractures in children. Purpose We aimed to evaluate the diagnostic accuracy of morphometric vertebral fracture analysis (MXA) using a 33-point software program designed for adults, on dual-energy x-ray absorptiometry (DXA) images of children. Materials and methods Lateral spine DXA images of 420 children aged between 5 and 18 years were retrospectively reviewed. Vertebral fracture assessment (VFA) by an expert pediatric radiologist using Genant's semiquantitative scoring system served as the gold standard. All 420 DXA scans were analyzed by a trained radiographer, using semi-automated software (33-point morphometry). VFA of a random sample of 100 DXA was performed by an experienced pediatric clinical scientist. MXA of a random sample of 30 DXA images were analyzed by three pediatric radiologists and the pediatric clinical scientist. Diagnostic accuracy and inter and intraobserver agreement (kappa statistics) were calculated. Results Overall sensitivity, specificity, false positive (FP) and false negative (FN) rates for the radiographer using the MXA software were 80%, 90%, 10%, and 20% respectively and for mild fractures alone were 46%, 92%, 8%, and 54% respectively. Overall sensitivity, specificity, FP, and FN rates for the four additional observers using MXA were 89%, 79%, 21%, and 11% respectively and for mild fractures alone were 36%, 86%, 14%, and 64% respectively. Agreement between two expert observers was fair to good for VFA and MXA [kappa = 0·29 to 0·76 (95% CI: 0·17–0·88) and 0·29 to 0·69 (95% CI: 0·17–0·83)] respectively. Conclusion MXA using a 33-point technique developed for adults is not a reliable method for the identification of mild vertebral fractures in children. A pediatric standard is required which not only incorporates specific vertebral body height ratios but also the age-related physiological changes in vertebral shape that occur throughout childhood.

  • Identification of PIEZO1 polymorphisms for human bone mineral density
    Bone (IF 4.360) Pub Date : 2020-01-20
    Wei-Yang Bai; Lijun Wang; Zhi-Min Ying; Bin Hu; Lin Xu; Guo-Qing Zhang; Pei-Kuan Cong; Xiaofeng Zhu; Weiguo Zou; Hou-Feng Zheng

    Bone mineral density (BMD) is a key indicator for diagnosis and treatment for osteoporosis; the reduction of BMD could increase the risk of osteoporotic fracture. It was very recently found that Piezo1 mediated mechanically evoked responses in bone and further participated in bone formation in mice. Here, we performed cross phenotype meta-analysis for human BMD at lumbar spine (LS), femoral neck (FN), distal radius/forearm (FA) and heel and screened out 14 top SNPs for PIEZO1, these SNPs were overlapped with putative enhancers, DNase-I hypersensitive sites and active promoter flanking regions. We found that the signal of the best SNP rs62048221 was mainly from heel ultrasound estimated BMD (−0.02 SD per T allele, P = 8.50E-09), where calcaneus supported most of the mechanical force of body when standing, walking and doing physical exercises. Each copy of the effect allele T of SNP rs62048221 was associated with a decrease of 0.0035 g/cm2 BMD (P = 4.6E-27, SE = 0.0003) in UK Biobank data within 477,760 samples. SNP rs62048221 was located at the enhancer region (HEDD enhancer ID 2331049) of gene PIEZO1, site-directed ChIP assays in human mesenchymal stem cells (hMSCs) showed significant enrichment of H3K4me1 and H3K27ac in this region, luciferase assays showed that rs62048221 could significantly affect the activity of the enhancer where it resides. Our results first suggested that SNP rs62048221 might mediate the PIEZO1 expression level via modulating the activity of cis-regulatory elements and then further affect the BMD.

  • Spatial and biochemical interactions between bone marrow adipose tissue and hematopoietic stem and progenitor cells in rhesus macaques
    Bone (IF 4.360) Pub Date : 2020-01-20
    Jacob J. Robino; Nathalie Pamir; Sara Rosario; Lindsey B. Crawford; Benjamin J. Burwitz; Charles T. Roberts; Peter Kurre; Oleg Varlamov

    Recent developments in in situ microscopy have enabled unparalleled resolution of the architecture of the bone marrow (BM) niche for murine hematopoietic stem and progenitor cells (HSPCs). However, the extent to which these observations can be extrapolated to human BM remains unknown. In humans, adipose tissue occupies a significant portion of the BM medullary cavity, making quantitative immunofluorescent analysis difficult due to lipid-mediated light scattering. In this study, we employed optical clearing, confocal microscopy and the nearest neighbor analysis to determine the spatial distribution of CD34+ HSPCs in the BM in a translationally relevant rhesus macaque model. Immunofluorescent analysis revealed that femoral BM adipocytes are associated with the branches of vascular sinusoids, with half of HSPCs localizing in close proximity of the nearest BM adipocyte. Immunofluorescent microscopy and flow cytometry analysis demonstrate that BM adipose tissue exists as a multicellular niche consisted of adipocytes, endothelial cells, granulocytes, and macrophages. Analysis of the BM adipose tissue conditioned media using liquid chromatography-tandem mass spectrometry revealed the presence of multiple bioactive proteins involved in regulation of hematopoiesis, inflammation and bone development with many predicted to reside inside microvesicles. Pretreatment of purified HSPCs with BM adipose tissue-conditioned media, comprising soluble and exosomal/microvesicle-derived factors, led to enhanced proliferation and an increase in granulocyte-monocyte differentiation potential ex vivo. Our work translationally extends extensive studies in murine models, indicating that BM adipose tissue is a central paracrine regulator of hematopoiesis and in nonhuman primates and possibly in humans.

  • Evaluation of the effectiveness of prophylactic oral vitamin D (cholecalciferol) in children with sickle cell disease
    Bone (IF 4.360) Pub Date : 2020-01-20
    Carmen Garrido; Eduardo J. Bardón-Cancho; Verónica de los Ángeles Fajardo-Sánchez; María Elena Cascón-Pérez-Teijón; Marina García-Morín; Elena Cela

    Background Vitamin D (25(OH)D) deficiency has become an emerging public health problem due to its influence on skeletal and extraskeletal diseases. Bone health in patients with sickle cell disease (SCD) is especially compromised and they are more likely to have 25(OH)D deficiency than the general population. Despite this, there is little information on the efficacy of vitamin D3 (vitD3) prophylaxis and its role in improving bone mineral density (BMD) in this population. Procedures A prospective, longitudinal, single-center study was conducted with 136 children with SCD monitored at a tertiary referral hospital for SCD. Demographic, clinical and management data, 25(OH)D levels and bone densitometries (DXA) were collected. Results Eighty patients were included. There are significant differences between the means of each of 25(OH)D levels as a function of whether the patient started prophylactic treatment as an infant or not (35.71 vs. 27.89 ng/ml, respectively [p = .014]). In multivariate analysis, 800 IU daily dose was shown as a protective factor (p = .044) to reach optimal blood levels (≥30 ng/ml). According to Kaplan-Meier curves, patients younger than 10 years reached optimal levels earlier than older (p = .002), as well as those who were not being treated with hydroxyurea (p = .039). Conclusions VitD3 prophylaxis is a safe practice in SCD. It is important to start this prophylactic treatment when the child is an infant. The daily regimen with 800 IU could be more effective for reaching levels ≥30 ng/ml, and, especially in preadolescent and adolescent patients, we should raise awareness about the importance of good bone health.

  • Subchondral bone dysplasia partly participates in prenatal dexamethasone induced-osteoarthritis susceptibility in female offspring rats
    Bone (IF 4.360) Pub Date : 2020-01-18
    Hao Xiao; Xingkui Xie; Yinxian Wen; Yang Tan; Yangfan Shangguan; Bin Li; Jacques Magdalou; Hui Wang; Liaobin Chen

    Prenatal 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.

  • Major fractures after initiation of dialysis: Incidence, predictors and association with mortality
    Bone (IF 4.360) Pub Date : 2020-01-17
    Ken Iseri; Juan Jesús Carrero; Marie Evans; Li Felländer-Tsai; Hans Berg; Björn Runesson; Peter Stenvinkel; Bengt Lindholm; Abdul Rashid Qureshi

    Background Major fractures (MF) are common in dialysis patients. We investigated incidence, predictors and clinical outcomes associated with first MF occurring after initiation of dialysis (MFfirst). Methods In Swedish Renal Registry of 9714 incident (2005–2016) dialysis patients (age 68 years, 67% men), we identified all MFfirst in hip, spine, humerus and forearm. Using flexible parametric hazard models and Fine-Gray analysis, we estimated incidence, mortality rates and predictors of MFfirst, and, in time-dependent analysis, risk of all-cause and cardiovascular disease (CVD) mortality following MFfirst. Results During median follow-up of 2.2 years, the crude incidence rate of MFfirst (n = 835) was 23.7/1000 patient-years and that of hip fractures (n = 470) 13.3/1000 patient-years. The multivariate-adjusted fracture incidence rates increased gradually after dialysis initiation and were 47% higher among women. Female sex, higher age, comorbidity, and previous history of MF (MFprevious) were associated with increased risk for MFfirst, whereas peritoneal dialysis as compared to hemodialysis was associated with decreased risk. The adjusted fracture incidence rate of MFfirst during the first 90 days following dialysis initiation was higher in patients with MFprevious than in those without MFprevious. MFfirst independently predicted increased all-cause (sub-distribution hazard ratio, SHR, 1.67(95%CI 1.47–1.91)) and CVD (SHR 1.49 (95%CI 1.22–1.84)) mortality. Adjusted mortality rate following hip fractures was higher than for other types of MF. Spline curves showed that mortality following MFfirst was highest during the first 6 months of follow-up. Conclusions MF are common and associated with increased mortality in incident dialysis patients.

  • Pamidronate: A model compound of the pharmacology of nitrogen-containing bisphosphonates; A Leiden historical perspective
    Bone (IF 4.360) Pub Date : 2020-01-17
    Socrates E. Papapoulos

    Pamidronate [3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD)] was the first nitrogen-containing bisphosphonate (N-BP) investigated in clinical studies. In contrast to other clinically used bisphosphonates, pamidronate was discovered and its properties were initially studied in an Academic Institution. On the occasion of the 50th Anniversary of the first publications on the biological effects of bisphosphonates, I review in this article the contribution of Leiden investigators to the development of pamidronate that led to the recognition of the significance of the Nitrogen atom in the side chain of bisphosphonates for their action on bone resorption and to the formulation of principles for the use of N-BPs in the management of patients with different skeletal disorders.

  • Extracellular pyrophosphate: The body's “water softener”
    Bone (IF 4.360) Pub Date : 2020-01-16
    Isabel R. Orriss

    Extracellular 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.

  • Bone material strength index is associated with prior fracture in men with and without moderate chronic kidney disease
    Bone (IF 4.360) Pub Date : 2020-01-16
    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. Pasco

    Background Patients 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. Methods Men (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<60 mL/min/1.73m2 (n = 53). Prior low trauma fractures (n = 37) were ascertained from radiological reports. Associations were examined using binary logistic regression, adjusting for potential confounders. Interaction terms were tested in all models. Results Men with CKD tended to have a higher likelihood of prior fracture (adjusted OR 2.27, 95%CI 1.02–5.01). Higher BMSi was associated with a lower likelihood of prior fracture (adjusted OR for 1SD increase: 0.70; 95%CI 0.51–0.97). This association was sustained after adjustment for FNBMD (OR 0.68; 95%CI 0.49–0.96) or LSBMD (OR 0.69; 95%CI 0.49–0.95). No interaction was detected between BMSi and CKD (p = 0.898). No associations were detected between FNBMD, LSBMD or TBS and prior fracture in either population and there were no interactions with CKD for FNBMD, LSBMD or TBS. Conclusions BMSi was associated with prior fracture in men with and without CKD, however, FNBMD, LSBMD and TBS were not. Lack of an interaction term suggests that BMSi performed similarly in identifying the likelihood of prior fracture, regardless of CKD status. IMI may have clinical utility for assessing fracture risk in patients with CKD.

  • Consumption of nutrients and insulin resistance suppress markers of bone turnover in subjects with abdominal obesity
    Bone (IF 4.360) Pub Date : 2020-01-15
    Rasmus Fuglsang-Nielsen; Elin Rakvaag; Peter Vestergaard; Bolette Hartmann; Jens Juul Holst; Kjeld Hermansen; Søren Gregersen; Jakob Starup-Linde

    Objective Abdominal 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. Methods We 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. Results CTX, 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. Conclusion The 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 osteoporosis
    Bone (IF 4.360) Pub Date : 2020-01-13
    Maki Yokomoto-Umakoshi; Hironobu Umakoshi; Tazuru Fukumoto; Yayoi Matsuda; Hiromi Nagata; Masatoshi Ogata; Hisaya Kawate; Takashi Miyazawa; Ryuichi Sakamoto; Yoshihiro Ogawa

    Context Pheochromocytoma (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. Objective To evaluate the risk of vertebral fracture (VF) in PPGLs and the improvement of BMD after surgery. Design and settings A retrospective cross-sectional study in a single referral center. Participants This 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. Intervention 1) The prevalence of VF was evaluated between PPGLs and non-functional AT. 2) In PPGLs, BMD was evaluated at baseline and after surgery. Results PPGLs 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. Conclusion This 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.

  • Relationship of volumetric bone mineral density by quantitative computed tomography with abdominal aortic calcification
    Bone (IF 4.360) Pub Date : 2020-01-13
    Sidong Li; Lu Yin; Kai Li; Bo Hu; Ling Wang; Yang Wang; Ning Li; Kai You; Yu Liu; Guoqin Liu; Shaoqi Xu; Lei Zhu; Jiman Shao; Xiaoguang Hao; Jun Zhou; Xiaoguang Cheng; Wei Li

    Objective This multicenter study aimed to evaluate the association between volumetric bone mineral density (vBMD) and abdominal aortic calcification (AAC) in a Chinese population. Methods Quantitative computed tomography (QCT) and Agatston score (AS) were used to measure vBMD and AAC, respectively, in 3457 participants during 2013–2017. The association between vBMD and AAC was assessed using multivariate regression analysis, adjusted for age, residence, education, body mass index, and other cardiovascular risk factors. Results The mean age of women and men was 61.4 and 62.7 years, respectively. In total, 30.4% of women and 37.7% of men were found to have AAC. After full adjustment, higher vBMD was associated with lower AAC score (β, −0.095; 95% confidence interval [CI], −0.167 to −0.024; P = 0.0087) and lower AAC prevalence (odds ratio [OR], 0.873; 95% CI, 0.824 to 0.924; P < 0.0001) in men. Inverse trends were also observed in the association of vBMD quartile with AAC severity (lowest vs highest quartile; β = 0.235; 95% CI, 0.011 to 0.459; Ptrend < 0.0001) and AAC prevalence (lowest vs highest quartile; OR = 1.329; 95% CI, 1.087 to 1.625; Ptrend < 0.0001) in men. However, no significant result was obtained in women, except for the association between quartiles of vBMD and AAC score. Conclusions In our study, vBMD was inversely associated with AAC among men independent of age and shared risk factors. However, the association was not significant among women.

  • Assessment of romosozumab efficacy in the treatment of postmenopausal osteoporosis: results from a mechanistic PK-PD mechanostat model of bone remodeling
    Bone (IF 4.360) Pub Date : 2020-01-11
    Madge Martin; Vittorio Sansalone; David M.L. Cooper; Mark R. Forwood; Peter Pivonka

    This 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
    Bone (IF 4.360) Pub Date : 2020-01-09
    Jin-long Sun; Jian-fei Yan; Jing Li; Wan-rong Wang; Shi-bin Yu; Hong-yun Zhang; Fei Huang; Li-na Niu; Kai Jiao

    β2-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 testing
    Bone (IF 4.360) Pub Date : 2020-01-09
    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 Chang

    Half 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 < 0.0001), and failure force (r = 0.92, p < 0.0001). The anisotropic sequence showed similar trends for stiffness, plastic deformation point, and failure force (r = 0.68, 0.70, 0.84; p = 0.02, 0.01, 0.0006, respectively). Surface strain-gauge measurements showed moderate to strong agreement with simulated magnitude strain values at the greater trochanter, superior neck, and inferior neck (r = −0.97, −0.86, 0.80; p ≤0.0001, 0.003, 0.03, respectively). The findings from this study support the use of MRI-based FE analysis of the hip to reliably predict the mechanical competence of the human femur in clinical settings.

  • Early-onset Paget's disease of bone in a Mexican family caused by a novel tandem duplication (77dup27) in TNFRSF11A that encodes RANK
    Bone (IF 4.360) Pub Date : 2020-01-08
    Sean J. Iwamoto; Micol S. Rothman; Shenghui Duan; Jonathan C. Baker; Steven Mumm; Michael P. Whyte
  • Sensory neuropeptides are required for bone and cartilage homeostasis in a murine destabilization-induced osteoarthritis model
    Bone (IF 4.360) Pub Date : 2020-01-08
    Dominique Muschter; Lutz Fleischhauer; Shahed Taheri; Arndt F. Schilling; Hauke Clausen-Schaumann; Susanne Grässel
  • Myelination during fracture healing in vivo in myelin protein zero (p0) transgenic medaka line
    Bone (IF 4.360) Pub Date : 2020-01-07
    Yusuke Dodo; Masahiro Chatani; Yuki Azetsu; Masahiro Hosonuma; Akiko Karakawa; Nobuhiro Sakai; Takako Negishi-Koga; Mayumi Tsuji; Katsunori Inagaki; Yuji Kiuchi; Masamichi Takami

    During 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
    Bone (IF 4.360) Pub Date : 2020-01-07
    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; Carlos R. Ferreira

    Catel-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.

  • History of etidronate
    Bone (IF 4.360) Pub Date : 2020-01-03
    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 Valent

    Etidronate 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
    Bone (IF 4.360) Pub Date : 2020-01-02
    Ruben Aquino-Martinez; Jennifer L. Rowsey; Daniel G. Fraser; Brittany A. Eckhardt; Sundeep Khosla; Joshua N. Farr; David G. Monroe

    Cellular 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
    Bone (IF 4.360) Pub Date : 2019-12-31
    Risa Sugisaki; Yoichi Miyamoto; Kentaro Yoshimura; Kiyohito Sasa; Kotaro Kaneko; Motohiro Tanaka; Masakatsu Itose; Sakie Inoue; Kazuyoshi Baba; Tatsuo Shirota; Daichi Chikazu; Ryutaro Kamijo

    Neutrophils 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
    Bone (IF 4.360) Pub Date : 2019-12-30
    Marie Cottard; Emmanuelle Vignot; Elisabeth Fontanges; Blandine Merle; Corinne Collet; Roland Chapurlat

    Summary We 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. Introduction OPT, 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. Methods We 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. Results These 3 cases of limited phenotypes were associated with unknown or poorly described variants of 3 rare bone genetic diseases. Conclusions Genetic tests proved useful to establish the diagnosis and manage the condition of adults with rare bone sclerosing GD.

  • Persistent low-normal bone mineral density in adolescent idiopathic scoliosis with different curve severity: A longitudinal study from presentation to beyond skeletal maturity and peak bone mass
    Bone (IF 4.360) Pub Date : 2019-12-28
    Xue Li; Vivian Wing Yin Hung; Fiona Wai Ping Yu; Alec Lik Hang Hung; Bobby Kin Wah Ng; Jack Chun Yiu Cheng; Tsz Ping Lam; Benjamin Hon Kei Yip

    Objectives Low bone mineral status has been reported in patients first presented with adolescent idiopathic scoliosis (AIS). We aimed to study whether low-normal bone mineral density (BMD) is persistent among AIS girls during puberty and at peak bone mass, and whether if such persistence is associated with curve severity and differed from healthy controls. Method This prospective longitudinal study comprised 550 AIS girls and 194 healthy control subjects followed from 1997 till 2016. Low-normal BMD was defined as z-standardized bone mineral density (z-BMD) of bilateral femoral neck ≤ −1. Markov Chain 2-stages analysis was conducted to investigate the low-normal BMD transition rate. Linear mixed-effects model and Bland-Altman plot were used to investigate whether low-normal BMD is persistent among a subgroup of AIS patients that reached peak bone mass. Results The average z-BMD were comparable between AIS cohort and controls at 11 years old (−0.532 vs −0.602), but at 19 years old z-BMD worsened among AIS subjects (−0.860) while controls z-BMD improved (−0.455). During growth period until skeletal maturity, persistence of low-normal BMD was high in both cohorts (>80%) and the AIS group with severe curve presented 100% persistence. Subgroup analysis revealed that z-BMD of AIS patients at skeletal maturity and peak bone mass were highly correlated (r2 = 0.905) and with good agreement. Conclusion AIS patients had poorer BMD that is associated with curve severity and more likely to persist beyond peripubertal period and at peak bone mass when compared to controls.

  • Biomechanics of callus in the bone healing process, determined by specimen-specific finite element analysis
    Bone (IF 4.360) Pub Date : 2019-12-28
    Takane Suzuki; Yusuke Matsuura; Takahiro Yamazaki; Tomoyo Akasaka; Ei Ozone; Yoshiyuki Matsuyama; Michiaki Mukai; Takeru Ohara; Hiromasa Wakita; Shinji Taniguchi; Seiji Ohtori

    As 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
    Bone (IF 4.360) Pub Date : 2019-12-27
    Jonathan M. LaCombe; Randall J. Roper

    Individuals 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.

  • Effect of inducible bone morphogenetic protein 2 expression on the osteogenic differentiation of dental pulp stem cells in vitro
    Bone (IF 4.360) Pub Date : 2019-12-26
    Ferenc Tóth; József M. Gáll; József Tőzsér; Csaba Hegedűs

    Bone 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.

  • Factors associated with bone microstructural alterations assessed by HR-pQCT in long-term HIV-infected individuals
    Bone (IF 4.360) Pub Date : 2019-12-23
    Sarah C. Foreman; Po Hung Wu; Ruby Kuang; Malcolm D. John; Phyllis C. Tien; Thomas M. Link; Roland Krug; Galateia J. Kazakia

    Purpose In 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. Methods Forty-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. Results In 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. Conclusions In 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.

  • Abnormal microarchitecture and stiffness in postmenopausal women with isolated osteoporosis at the 1/3 radius
    Bone (IF 4.360) Pub Date : 2019-12-20
    Alexander S. Dash; Sanchita Agarwal; Donald J. McMahon; Felicia Cosman; Jeri Nieves; Mariana Bucovsky; X. Edward Guo; Elizabeth Shane; Emily M. Stein

    Background Postmenopausal 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. Methods This 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. Results Mean 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. Conclusions Although 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.

  • Plectin stabilizes microtubules during osteoclastic bone resorption by acting as a scaffold for Src and Pyk2
    Bone (IF 4.360) Pub Date : 2019-12-20
    Takuma Matsubara; Tatsuki Yaginuma; William N. Addison; Yuko Fujita; Kouji Watanabe; Izumi Yoshioka; Hisako Hikiji; Kenshi Maki; Roland Baron; Shoichiro Kokabu

    Osteoclasts 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.

  • Bone resorption is unchanged by liraglutide in type 2 diabetes patients: A randomised controlled trial
    Bone (IF 4.360) Pub Date : 2019-12-20
    Katrine Hygum; Torben Harsløf; Niklas Rye Jørgensen; Jørgen Rungby; Steen B. Pedersen; Bente L. Langdahl

    Background Liraglutide, 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. Methods The 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). Results P-CTX increased in patients treated with liraglutide by 0.07 (0.03; 0.10) μg/l (p < 0.001) and in patients treated with placebo by 0.03 (0.00; 0.06) μg/l (p = 0.04), however, changes were not different between the groups (p = 0.16). Weight decreased in patients treated with liraglutide from baseline to week four (p < 0.001) and remained stable thereafter. P-procollagen type 1 N-terminal propeptide (P1NP) decreased in patients treated with liraglutide from baseline to week four (p < 0.01), increased between weeks 4 and 13 (p = 0.03), and remained elevated thereafter. Weight and p-P1NP did not change in patients treated with placebo. Hip bone mineral density (BMD) decreased in placebo treated patients from baseline to end of study, whereas no changes were seen in patients treated with liraglutide (p = 0.01 difference between groups). Conclusion Liraglutide treatment for 26 weeks did not affect bone resorption and preserved hip BMD despite weight loss in patients with T2D, suggesting that liraglutide has some antiresorptive effect.

  • Objective measures of moderate to vigorous physical activity are associated with higher distal limb bone strength among elderly men
    Bone (IF 4.360) Pub Date : 2019-12-20
    Lisa Langsetmo; Andrew J. Burghardt; John T. Schousboe; Peggy M. Cawthon; Jane A. Cauley; Nancy E. Lane; Eric S. Orwoll; Kristine E. Ensrud

    Our 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, <1.5 metabolic equivalents of task [METs]), light (1.5 to <3 METs), or moderate to vigorous physical activity(MVPA: ≥3 METs) were calculated as mean over the two time points. Estimated failure load was determined from HR-pQCT data using finite element analysis. We used standardized variables and adjusted for potential confounders using linear regression. The means ±SDs for daily activity were: 2338 ± 356 kcal/d [TEE]; 5739 ± 2696 steps/day [step count], 60 ± 20 cpm [peak cadence], 67 ± 28 min/d [light activity], and 85 ± 52 min/d [MVPA]. Higher TEE, step count, and peak cadence were each associated with higher failure load of the distal radius (effect sizes respectively: 0.13 [95% CI: 0.05, 0.20], 0.11 [95% CI: 0.04, 0.18], and 0.08 [95% CI: 0.01, 0.15]) and higher failure load of the distal tibia (effect sizes respectively 0.21 [95% CI: 0.13, 0.28], 0.19 [95% CI: 0.13, 0.26], 0.19 [95% CI, 0.13, 0.25]). Time spent in MVPA vs. time sedentary was related to bone strength at both sites after adjustment, whereas time spent in light activity vs. time sedentary was not. TEE was associated with compartmental area and BMD parameters at distal tibia, but only area parameters at the distal radius. In summary, MVPA over a 7-year period of time may have a modest association with bone strength and geometry among older men.

  • Conditional knockout of ephrinB1 in osteogenic progenitors delays the process of endochondral ossification during fracture repair
    Bone (IF 4.360) Pub Date : 2019-12-19
    Agnieszka Arthur; Sharon Paton; Andrew C.W. Zannettino; Stan Gronthos

    The 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 structures
    Bone (IF 4.360) Pub Date : 2019-12-19
    Chenlin Dai; Junjing Jia; Alexander Kot; Xueping Liu; Lixian Liu; Min Jiang; Nancy E. Lane; Barton L. Wise; Wei Yao

    Objective The 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. Methods We 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. Results Compared 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. Conclusion These 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.

  • Burn injury and restoration of muscle function
    Bone (IF 4.360) Pub Date : 2019-12-19
    Gordon L. Klein

    Burn 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.

  • Cell cycle progression is disrupted in murine MPS VII growth plate leading to reduced chondrocyte proliferation and transition to hypertrophy
    Bone (IF 4.360) Pub Date : 2019-12-18
    Zhirui Jiang; Ainslie L.K. Derrick-Roberts; Clare Reichstein; Sharon Byers

    Endochondral 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.

  • Skeletal effects of plyometric exercise and metformin in ovariectomized rats
    Bone (IF 4.360) Pub Date : 2019-12-17
    A.K. Stunes; R.G. Erben; C. Schüler; E.F. Eriksen; M. Tice; D. Vashishth; U. Syversen; M.P. Mosti

    Estrogen 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 < .01). The combined intervention also resulted in a higher gain in femoral and spine BMD compared to OVX-Met (p < .01). Both exercise groups displayed improved microarchitecture, including both cortical and trabecular parameters (p < .05). This was most evident in the OVX-MetEx group where several indices were at sham level or superior to OVX-Ctr (p < .05). The OVX-MetEx group also exhibited an enhanced toughening effect compared to the other OVX groups (p < .05). The beneficial skeletal effects seemed to be mediated by inhibition of bone resorption and stimulation of bone formation. The training response (i.e. jumping height) was also greater in the metformin treated rats compared to OVX-Ex (p < .01), indicating a performance-enhancing effect of metformin. Both exercise groups displayed higher lean mass than OVX-Ctr (p < .05). In conclusion, the combination of plyometric exercise and metformin improved trabecular microarchitecture and bone material properties relative to OVX controls. However, no additive effect of the combined intervention was observed compared to exercise alone.

  • Regional changes in indices of bone strength of upper and lower limbs in response to high-intensity impact loading or high-intensity resistance training
    Bone (IF 4.360) Pub Date : 2019-12-15
    Conor Lambert; Belinda R. Beck; Amy T. Harding; Steven L. Watson; Benjamin K. Weeks

    It 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.

  • Tibial speed of sound changes in preterm infants during the first year of life
    Bone (IF 4.360) Pub Date : 2019-12-14
    Zuzana Korčeková; Peter Korček; Václav Čunát; Zuzana Staníčková; Patrícia Zemanová; Zbyněk Straňák

    Introduction Metabolic 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. Objective To 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. Methods QUS 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). Results Overall, 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. Conclusions Tibial 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.

  • FRAX prognostic and intervention thresholds in the management of major bone fractures in hemodialysis patients: A two-year prospective multicenter cohort study
    Bone (IF 4.360) Pub Date : 2019-12-13
    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; Joanna Matuszkiewicz-Rowińska

    Purpose The 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. Methods The 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. Results The 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. Conclusions We 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 osteopathy?
    Bone (IF 4.360) Pub Date : 2019-12-13
    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 Mumm

    The 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.

  • 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
    Bone (IF 4.360) Pub Date : 2019-12-09
    M. Geserick, M. Vogel, F. Eckelt, M. Schlingmann, A. Hiemisch, R. Baber, J. Thiery, A. Körner, W. Kiess, J. Kratzsch

    Background We 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. Methods 2416 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. Results OC, 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. Conclusions OC, 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.

  • Breaking crown dentine in whole teeth: 3D observations of prevalent fracture patterns following overload
    Bone (IF 4.360) Pub Date : 2019-12-06
    Claudia Fleck, Martin Burke, Gregor Ganzosch, Cecilia Müller, John D. Currey, Paul Zaslansky

    Teeth 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 consequently it is not much more massive or stronger than it needs to be. To answer 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.

  • Serum periostin is associated with cancer mortality but not cancer risk in older home-dwelling men: A 8-year prospective analysis of the STRAMBO study
    Bone (IF 4.360) Pub Date : 2019-12-05
    Jean-Charles Rousseau, Cindy Bertholon, Roland Chapurlat, Pawel Szulc

    Background Periostin (POSTN) regulates multiple biological behaviors of tumor cells. We studied the association of serum POSTN with mortality in home-dwelling men. Methods POSTN was measured at baseline using immunoassay (USCN life science, China) in 815 home-dwelling men aged 60–87 followed-up for 8 years. Results In 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 < .001] after adjustment for potential confounders. In a similar model, cancer mortality (n = 69) increased with POSTN levels (HR = 1.44 per SD, 95%CI: 1.16–1.78, p < .001). Cardiovascular mortality (n = 55) and non-cardiovascular-non-cancer mortality (n = 44) was not associated with POSTN levels (p = .28 and p = .94 respectively). In 107 men with prevalent cancer, all-cause mortality (HR = 1.93 per SD, 95%CI: 1.30–2.87, p < .005) and cancer mortality (HR = 2.07 per SD, 95%CI: 1.23–3.47, p < .01) increased with the increasing POSTN concentrations. In 613 men with incident cancer, higher POSTN concentrations were associated with higher cancer mortality (HR = 1.40 per SD, 95%CI: 1.12–1.76, p < .005) but not with the risk of cancer (HR = 1.16 per SD, 95%CI: 0.89–1.46, p = .21). Conclusions Higher serum POSTN is associated with higher cancer mortality, but not with the cancer risk in older home-dwelling men.

  • Differences in geometric strength at the contralateral hip between men with hip fracture and non-fractured comparators
    Bone (IF 4.360) Pub Date : 2019-12-05
    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. Hochberg

    Older 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 (−0.884%; 95% CI: −0.889%, −0.088%) 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.

  • Ageing bone fractures: The case of a ductile to brittle transition that shifts with age
    Bone (IF 4.360) Pub Date : 2019-12-03
    Peter Zioupos, Helmut O.K. Kirchner, Herwig Peterlik

    Human bone becomes increasingly brittle with ageing. Bones also fracture differently under slow and fast loadings, being ductile and brittle, respectively. The effects of a combination of these two factors have never been examined before. Here we show that cortical bone is most fracture-resistant at the physiologically prevalent intermediate strain rates of 10−3 s−1 to 10−2 s−1 such as they occur in walking or running, slightly weaker at slower quasistatic and much weaker at fast impact loading rates. In young cortical bone (15 years of age) the ductile-to-brittle transition (DBT) occurs at strain rates of 10−2 s−1, in old cortical bone (85 yrs) at speeds lower by a factor of 10 to 40. Other research has shown that the energy required to break bone (per unit of fracture surface) drops as much as 60% between these two ages. Therefore, DBT seems to compound the well-known phenomenon of ‘brittle old bones’. Old bones can only cope with slow movement, young ones with both slow and fast movement. These observed material characteristics of (i) a shift of the DBT and (ii) a reduced energy absorption capacity appear to contribute at least as much to the loss of bone quality as the various quantity based (lowered bone density and mineral content) explanations of the past. They also provide a new powerful paradigm, which allows us to demonstrate mechanically, and uniquely, how human bone becomes increasingly brittle with age.

  • Muscle contraction induces osteogenic levels of cortical bone strain despite muscle weakness in a mouse model of Osteogenesis Imperfecta
    Bone (IF 4.360) Pub Date : 2019-12-02
    Alycia G. Berman, Jason M. Organ, Matthew R. Allen, Joseph M. Wallace

    Mechanical 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.

  • Disuse-induced loss of bone mineral density and bone strength is attenuated by post-lactational bone gain in NMRI mice
    Bone (IF 4.360) Pub Date : 2019-11-30
    Thomas Givskov Sørensen, Mikkel Bo Brent, Jesper Skovhus Thomsen, Annemarie Brüel

    Lactation in mice is associated with a substantial bone loss, which almost completely recovers within four weeks after weaning. The post-lactational recovery mechanism is considered one of the most potent physiological bone anabolic responses in adult life. The aim of the study was to investigate whether the post-lactational bone anabolic response could attenuate or prevent a disuse bone loss induced by botulinum toxin (BTX) in mice. Eighty-one 10-week-old female NMRI mice were divided into the following groups: Pregnant, Lactation, Recovery + Vehicle, Recovery + BTX, No Lactation, No Lactation + Vehicle, No Lactation + BTX, and Virgin Control. The mice lactated for 12 days before weaning followed by 21 days of recovery. On the last day of lactation, disuse was induced by injecting 2 IU of BTX per 100 g body weight into the right hind limb. Mechanical testing, μCT, and dynamic bone histomorphometry were performed on the right femur. Lactation induced a loss of aBMD and of vBMD, Tb.Th, and MS/BS at the distal femoral metaphysis, Ct.Th and bone strength at the femoral mid-diaphysis, and femoral neck bone strength compared to pregnant mice. This bone loss was partly or fully reversed after 21 days of recovery from lactation. In non-lactating mice, BTX resulted in a loss of aBMD and of vBMD, BV/TV, Tb.Th, MS/BS, and BFR/BS at the distal femoral metaphysis, Ct.Th at the femoral mid-diaphysis, and femoral neck bone strength compared to ambulating non-lactating mice. The post-lactational response attenuated the BTX-induced loss of aBMD, Tb.Th, Ct.Th, trabecular MS/BS and BFR/BS, and femoral neck bone strength indicating that the recovery after lactation had reduced the negative effects of BTX on these parameters. In contrast, it was unable to counteract the loss of BV/TV and vBMD at the distal femoral metaphysis. In conclusion, the post-lactational response attenuated disuse-induced decrease of femoral aBMD, femoral neck bone strength, trabecular and cortical thickness, and trabecular MS/BS, BFR/BS, while it could not counteract the disuse-induced loss of BV/TV and vBMD.

  • The effect of pubertal timing, as reflected by height tempo, on proximal femur shape: Findings from a population-based study in adolescents
    Bone (IF 4.360) Pub Date : 2019-11-30
    Monika Frysz, Jennifer S. Gregory, Richard M. Aspden, Lavinia Paternoster, Jonathan H. Tobias

    Objective To examine the relationship between pubertal timing (using measures of height tempo) and proximal femur shape in a large adolescent cohort. Methods Hip DXA scans were obtained in offspring from the Avon Longitudinal Study of Parents and Children. To quantify hip morphology, the images were analyzed using Shape software based on a 53-point statistical shape model and independent modes of variation (hip shape mode (HSM) scores) for each image were generated. Height tempo (which corresponds to age at peak height velocity (aPHV)) was estimated from serial height measurements collected between age 5–20 years. Multivariable linear regression was used to examine cross-sectional associations between height tempo and the top ten HSMs at age 14 and 18, adjusting for sex and fat mass index (FMI). Results Complete outcome and covariate data were available from 3827 and 3507 participants at age 14 and 18 years, respectively. Mean aPHV was 13.5 and 11.8 years for males and females, respectively. At age 14, height tempo was associated with a majority of modes, except for HSM4 and there was strong evidence of interaction by sex. In males, all modes showed evidence of an association with tempo, independent of FMI, with the strongest observed for HSM8 (adjusted β 0.38 (0.33, 0.43) p = 4.1 × 10−50). Compared with males, the associations were generally weaker in females, with the strongest effect observed for HSM8 (adjusted β 0.10 (0.05, 0.14) p = 1.6 × 10−5). The overall effect of later pubertal timing on proximal femur shape in males was a narrower femoral neck and larger superolateral head, whereas in females these changes were hard to discern. When assessed at age 18, there was little relationship between tempo and proximal femur shape in either sex. Conclusion Our results indicate that significant changes in hip shape occur during puberty, including aspects of shape which may be related to future risk of hip OA and/or fracture. However, puberty timing per se does not appear to exert long lasting effects on proximal femur shape.

  • The risk of hip and non-vertebral fractures in patients with Parkinson's disease and parkinsonism: A systematic review and meta-analysis
    Bone (IF 4.360) Pub Date : 2019-11-29
    Marian Schini, Tatiane Vilaca, Edith Poku, Susan Harnan, Anthea Sutton, Isabel Elaine Allen, Steve R. Cummings, Richard Eastell

    Parkinson'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
    Bone (IF 4.360) Pub Date : 2019-11-29
    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 Voruganti

    Context Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied. Objective We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children. Methods We 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. Results Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 × 10−9). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score > 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 < 9 × 10−7). Conclusions We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. The findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.

  • Skeletal maturation in relation to ethnic background in children of school age: The Generation R Study
    Bone (IF 4.360) Pub Date : 2019-11-28
    Olja Grgic, Enisa Shevroja, Brunilda Dhamo, Andre G. Uitterlinden, Eppo B. Wolvius, Fernando Rivadeneira, Carolina Medina-Gomez

    Ethnicity 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 < 0.0001) and African boys 0.36 years (95% CI 0.20–0.53, p-value < 0.0001) older SA as compared to European boys. Similarly, Asian girls showed 0.64 (95% CI 0.51–0.77, p-value < 0.0001) and African girls 0.38 years (95% CI 0.27–0.48, p-value < 0.0001) older SA as compared to European girls. A similar pattern was observed in the analysis with genetically-defined ancestry. Furthermore, an increase in the proportion of Asian or African component was associated with older SA in both boys (log[Non-European/European]proportion = 0.10, 95% CI 0.06–0.13, p-value < 0.0001) and girls (log[Non-European/European]proportion = 0.06, 95% CI 0.04–0.08, p-value < 0.0001). In summary, children of Asian and African backgrounds have on average older SA as compared to children of European descent, partially explained by a genetic component.

  • Are blood lipids risk factors for fracture? Integrative evidence from instrumental variable causal inference and mediation analysis using genetic data
    Bone (IF 4.360) Pub Date : 2019-11-27
    Haimiao Chen, Zhonghe Shao, Yixin Gao, Xinghao Yu, Shuiping Huang, Ping Zeng

    Background The relationship between lipids and the risk of fracture is currently controversial and whether such association is causal remains elusive. Methods We performed two-sample inverse variance weighted (IVW) Mendelian randomization (MR) analyses to evaluate causal effects of four lipids (i.e. high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol [LDL], total cholesterol [TC] and triglyceride [TG]) on fracture or bone mineral density (BMD) with summary statistics from large scale genome-wide association studies (up to ~190,000 for lipids, ~66,628 for BMD and ~53,000 for fracture). We validated our MR results with extensive sensitive analyses including MR-PRESSO and MR-Egger regression. Multivariable analyses were implemented to investigate whether other lipids (i.e. LDL and TG) may confound the causal effect of HDL on fracture and mediation analyses were conducted to assess indirect effects of lipids on fracture mediated by BMD. Results The IVW MR showed there existed a statistically significant association between HDL and fracture, with the odd ratio (OR) per standard deviation change of HDL on fracture being 1.12 (95% CI: 1.02–1.22, p = 1.20E-02). HDL was also detected to be causally associated with BMD (beta = −0.116; 95% CI: −0.182 ~ −0.050, p = 5.47E-04). These associations were further confirmed by the weighted median and maximum likelihood methods, with the MR-Egger regression removing the possibility of pleiotropy and the multivariable analysis excluding the confounding effect of other lipids on HDL. Negative associations of HDL with BMD among the elderly and with BMD at the lumbar spine were also discovered. However, no causal associations were detected between other lipids (OR = 0.87, 95% CI: 0.74–1.03, p = .107 for LDL; OR = 1.03; 95% CI: 0.88–1.21, p = .696 for TC and OR = 1.04; 95% CI: 0.90–1.20, p = .610 for TG) and fracture; whereas TG was positively associated BMD (beta = 0.184; 95% CI: 0.048–0.319, p = 7.93E−03). Finally, the mediation effect of BMD was estimated to be −0.116 (95% CI: −0.182 to −0.05, p = 5.47E−04) for HDL or 0.184 (95% CI: 0.048–0.319, p = 7.93E−03) for TG, implying HDL and TG could be indirectly associated with fracture risk via the pathway of BMD. Conclusion Our study is supportive of the causal relationship between HDL and fracture but offers little direct evidence for causal associations between other lipids and fracture, and further reveals HDL and TG may have an indirect influence on fracture mediated by BMD.

  • Overexpression of Pitx1 attenuates the senescence of chondrocytes from osteoarthritis degeneration cartilage–A self-controlled model for studying the etiology and treatment of osteoarthritis
    Bone (IF 4.360) Pub Date : 2019-11-27
    Xiang Zhao, Ping Huang, Gen Li, Yu Feng, Lv Zhendong, Chun Zhou, Guangyu Hu, Qingrong Xu

    To explore the role of low expression of Pitx1 in degenerative cartilage tissue. A cartilage injury model was established by using the cartilage scratch method. The newly generated tissue by BrdU labeled in injured cartilage region expressed SOX-9 and Col2A1 in 5-week-old rats. Compared with that, the number of BrdU-positive cells was lower in 4-month-old cartilage injury model rats. Compared with that in lateral cartilage, the expression of Pitx1 was lower in medial cartilage. Compared with chondrocytes derived from the lateral cartilage, chondrocytes derived from the medial cartilage exhibited significantly increased cell aging, as determined by SA-β-GAL staining; downregulated Pitx1 expression; reduced autophagy levels; and decreased Col2A1 expression in a chondrogenic differentiation assay. Inhibition of Pitx1 expression in chondrocytes from the lateral cartilage significantly increased the ratio of cell senescence. Overexpression of Pitx1 in chondrocytes derived from the medial cartilage decreased the cell senescence ratio. In a luciferase assay, Pitx1 was found to promote Sirt1 gene transcription. Decreased Pitx1 expression is an essential cause of cartilage degeneration in the medial tibial plateau. The described self-controlled model is an excellent way to study OA etiology and screen therapeutic drugs for OA.

  • Bone density status in a large population of patients with anorexia nervosa
    Bone (IF 4.360) Pub Date : 2019-11-23
    Cassandra Workman, Dan V. Blalock, Philip S. Mehler

    Anorexia nervosa (AN) is associated with multiple medical complications. One of the rare permanent complications of AN is the deleterious effect that it has on a patient's bone mineral density (BMD). We report on the Dual-Energy X-ray Absorptiometry (DXA) findings of 336 consecutive patients with AN. Also, we investigated the effects of different factors on these DXA results. These factors included age, body mass index (BMI), percentage of ideal body weight (IBW), duration of illness, duration of amenorrhea, medications such as proton pump inhibitors (PPI) or selective serotonin reuptake inhibitors (SSRI), tobacco use and 25-hydroxy vitamin D levels. This study demonstrated a concerning high prevalence of reduced bone mineral density in patients with AN. Thus, the implication being that those involved in the care of patients with AN need to be cognizant of this serious complication and not be assuaged by the young age of this patient population.

  • Age at attainment of peak bone mineral density and its associated factors: The National Health and Nutrition Examination Survey 2005–2014
    Bone (IF 4.360) Pub Date : 2019-11-21
    Shanshan Xue, Oumer Kemal, Meihan Lu, Lisa M. Lix, William D. Leslie, Shuman Yang

    Osteoporosis is a major public health problem worldwide. Lower peak bone mineral density (BMD) in youth may be the single most important factor leading to the development of osteoporosis in the elderly. Using cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2005–2014, we included 18,713 individuals with complete and valid data on femoral neck, total hip and lumbar spine BMD. Generalized additive models were used to estimate the age at attainment of peak BMD and 95% confidence intervals (95%Cls); model covariates were sex, race, body mass index (BMI) and we also examine factors potentially affecting age at attainment of peak BMD. This study clearly stated that age at attainment of peak femoral neck, total hip and lumbar spine BMD were 20.5 years, 21.2 years and 23.6 years in males, and 18.7 years, 19.0 years and 20.1 years in females, respectively and age at attainment of peak BMD varied by skeletal sites and sex. The study also found that females achieved peak femoral neck, total hip and lumbar spine BMD earlier than males (all P < 0.001); race and BMI were not associated with the age at attainment of peak BMD (all P > 0.05). These results suggested that improving bone health among individuals before 20 years old may be useful for reducing future risk of osteoporosis and osteoporotic fractures.

  • Sex differences in the longitudinal associations between body composition and bone stiffness index in European children and adolescents
    Bone (IF 4.360) Pub Date : 2019-11-21
    Lan Cheng, Hermann Pohlabeln, Wolfgang Ahrens, Paola Russo, Toomas Veidebaum, Charalambos Chadjigeorgiou, Dénes Molnár, Gabriele Eiben, Stefaan De Henauw, Luis Moreno, Angie Page, Antje Hebestreit

    Fat mass (FM) and fat free mass (FFM) may influence bone health differentially. However, existing evidences on associations between FM, FFM and bone health are inconsistent and vary according to sex and maturity. The present study aims to evaluate longitudinal associations between FM, FFM and bone stiffness index (SI) among European children and adolescents with 6 years follow-up. A sample of 2468 children from the IDEFICS/I.Family was included, with repeated measurements of SI using calcaneal quantitative ultrasound, body composition using skinfold thickness, sedentary behaviors and physical activity using self-administrated questionnaires. Regression coefficients (β) and 99%-confidence intervals (99% CI) were calculated by sex-specified generalized linear mixed effects models to analyze the longitudinal associations between FM and FFM z-scores (zFM and zFFM) and SI percentiles, and to explore the possible interactions between zFM, zFFM and maturity. Baseline zFFM was observed to predict the change in SI percentiles in both boys (β = 4.57, 99% CI: 1.36, 7.78) and girls (β = 3.42, 99% CI: 0.05, 6.79) after 2 years. Moreover, baseline zFFM (β = 8.72, 99% CI: 3.18, 14.27 in boys and β = 5.89, 99% CI: 0.34, 11.44 in girls) and the change in zFFM (β = 6.58, 99% CI: 0.83, 12.34 in boys and β = 4.81, 99% CI: −0.41, 10.02 in girls) were positively associated with the change in SI percentiles after 6 years. In contrast, a negative association was observed between the change in zFM and SI percentiles in boys after 6 years (β = −3.70, 99% CI: −6.99, −0.42). Besides, an interaction was observed between the change in zFM and menarche on the change in SI percentiles in girls at 6 years follow-up (p = .009), suggesting a negative association before menarche while a positive association after menarche. Our findings support the existing evidences for a positive relationship between FFM and SI during growth. Furthermore, long-term FM gain was inversely associated with SI in boys, whereas opposing associations were observed across menarche in girls.

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上海纽约大学William Glover