Person: Bouxsein, Mary
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Bouxsein
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Bouxsein, Mary
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Publication Evaluation of a new approach to compute intervertebral disc height measurements from lateral radiographic views of the spine(Springer Nature, 2016) Allaire, Brett T.; DePaolis Kaluza, M. Clara; Bruno, Alexander G.; Samelson, Elizabeth; Kiel, Douglas; Anderson, Dennis; Bouxsein, MaryPurpose Current standard methods to quantify disc height, namely distortion compensated Roentgen analysis (DCRA), have been mostly utilized in the lumbar and cervical spine and have strict exclusion criteria. Specifically, discs adjacent to a vertebral fracture are excluded from measurement, thus limiting the use of DCRA in studies that include older populations with a high prevalence of vertebral fractures. Thus, we developed and tested a modified DCRA algorithm that does not depend on vertebral shape. Methods Participants included 1186 men and women from the Framingham Heart Study Offspring and Third Generation Multidetector CT Study. Lateral CT scout images were used to place 6 morphometry points around each vertebra at 13 vertebral levels in each participant. Disc heights were calculated utilizing these morphometry points using DCRA methodology and our modified version of DCRA, which requires information from fewer morphometry points than the standard DCRA. Results Modified DCRA and standard DCRA measures of disc height are highly correlated, with concordance correlation coefficients above 0.999. Both measures demonstrate good inter- and intra-operator reproducibility. 13.9 % of available disc heights were not evaluable or excluded using the standard DCRA algorithm, while only 3.3 % of disc heights were not evaluable using our modified DCRA algorithm. Conclusions Using our modified DCRA algorithm, it is not necessary to exclude vertebrae with fracture or other deformity from disc height measurements as in the standard DCRA. Modified DCRA also yields identical measurements to the standard DCRA. Thus, the use of modified DCRA for quantitative assessment of disc height will lead to less missing data without any loss of accuracy, making it a preferred alternative to the current standard methodology.Publication Heritability of Thoracic Spine Curvature and Genetic Correlations With Other Spine Traits: The Framingham Study(Wiley, 2016) Yau, Michelle; Demissie, Serkalem; Zhou, Yanhua; Anderson, Dennis; Lorbergs, Amanda L; Kiel, Douglas; Allaire, Brett T; Yang, Laiji; Cupples, L Adrienne; Travison, Thomas; Bouxsein, Mary; Karasik, David; Samelson, ElizabethHyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co-occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T4–T12 kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (math formulaG, –0.46; 95% CI, –0.67 to –0.26), vertebral fracture (math formulaG, 0.39; 95% CI, 0.18 to 0.61), vBMD (math formulaG, –0.23; 95% CI, –0.41 to –0.04), and paraspinal muscle density (math formulaG, –0.22; 95% CI, –0.48 to 0.03). Genetic correlations between kyphosis angle and disc height narrowing (math formulaG, 0.17; 95% CI, –0.05 to 0.38) and facet joint OA (math formulaG, 0.05; 95% CI, –0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age-related spine traits including trunk muscle size, vertebral fracture, and bone mineral density.Publication Effect of follower load on motion and stiffness of the human thoracic spine with intact rib cage(Elsevier BV, 2016) Sis, Hadley L.; Mannen, Erin M.; Wong, Benjamin M.; Cadel, Eileen S.; Bouxsein, Mary; Anderson, Dennis; Friis, Elizabeth A.Researchers have reported on the importance of the rib cage in maintaining mechanical stability in the thoracic spine and on the validity of a compressive follower preload. However, dynamic mechanical testing using both the rib cage and follower load has never been studied. An in vitro biomechanical study of human cadaveric thoracic specimens with rib cage intact in lateral bending, flexion/extension, and axial rotation under varying compressive follower preloads was performed. The objective was to characterize the motion and stiffness of the thoracic spine with intact rib cage and follower preload. The hypotheses tested for all modes of bending were (i) range of motion, elastic zone, and neutral zone will be reduced with a follower load, and (ii) neutral and elastic zone stiffness will be increased with a follower load. Eight human cadaveric thoracic spine specimen (T1–T12) with intact rib cage were subjected to 5 Nm pure moments in lateral bending, flexion/extension, and axial rotation under follower loads of 0–400 N. Range of motion, elastic and neutral zones, and elastic and neutral zone stiffness values were calculated for functional spinal units and segments within the entire thoracic section. Combined segmental range of motion decreased by an average of 34% with follower load for every mode. Application of a follower load with intact rib cage impacts the motion and stiffness of the human cadaveric thoracic spine. Researchers should consider including both aspects to better represent the physiologic implications of human motion and improve clinically relevant biomechanical thoracic spine testing.Publication The effect of thoracic kyphosis and sagittal plane alignment on vertebral compressive loading(Wiley, 2012) Bruno, Alexander G; Anderson, Dennis; D'Agostino, John; Bouxsein, MaryTo better understand the biomechanical mechanisms underlying the association between hyperkyphosis of the thoracic spine and risk of vertebral fracture and other degenerative spinal pathology, we used a previously validated musculoskeletal model of the spine to determine how thoracic kyphosis angle and spinal posture affect vertebral compressive loading. We simulated an age-related increase in thoracic kyphosis (T1-T12 Cobb angle 50° to 75°) during two different activities (relaxed standing and standing with 5 kg weights in the hands) and three different posture conditions: 1) an increase in thoracic kyphosis with no postural adjustment (uncompensated posture), 2) an increase in thoracic kyphosis with a concomitant increase in pelvic tilt that maintains a stable center of mass and horizontal eye gaze (compensated posture), and 3) an increase in thoracic kyphosis with a concomitant increase in lumbar lordosis that also maintains a stable center of mass and horizontal eye gaze (congruent posture). For all posture conditions, compressive loading increased with increasing thoracic kyphosis, with loading increasing more in the thoracolumbar and lumbar regions than in the mid-thoracic region. Loading increased the most for the uncompensated posture, followed by the compensated posture, with the congruent posture almost completely mitigating any increases in loading with increased thoracic kyphosis. These findings indicate that thoracic kyphosis and spinal posture both influence vertebral loading during daily activities, implying that thoracic kyphosis measurements alone are not sufficient to characterize the impact of spinal curvature on vertebral loading.Publication Regressions for estimating muscle parameters in the thoracic and lumbar trunk for use in musculoskeletal modeling(Elsevier BV, 2012) Anderson, Dennis; D, John M.; Bruno, Alexander G.; Manoharan, Rajaram K.; Bouxsein, MaryMusculoskeletal modeling requires information on muscle parameters such as cross-sectional area (CSA) and moment arms. A variety of previous studies have reported muscle parameters in the trunk based on in vivo imaging, but there remain gaps in the available data as well as limitations in the generalizability of such data. Specifically, available trunk muscle CSA data is very limited for older adults, lacking entirely in the thoracic region. In addition, previous studies have made measurements in groups of healthy volunteers or hospital patients who may not be representative of the population in general. Finally, such studies have not reported data for the major muscles connecting the upper limb to the thoracic trunk. In this study, muscle morphology measurements were made for major muscles present in the trunk between vertebral levels T6 and L5 using quantitative computed tomography scans from a community-based sample of 100 men and women aged 36–87. We present regression equations to predict trunk muscle CSA and position relative to the vertebral body in the transverse plane from sex, age, height and weight at vertebral levels T6 to L5. Regressions were also developed for predicting anatomical CSA and muscle moment arms, which were estimated using literature data on muscle line of action. This work thus provides a resource for estimating muscle parameters in the general population for musculoskeletal modeling of the thoraco-lumbar trunk.Publication Effects of follower load and rib cage on intervertebral disc pressure and sagittal plane curvature in static tests of cadaveric thoracic spines(Elsevier BV, 2016) Anderson, Dennis; Mannen, Erin M.; Sis, Hadley L.; Wong, Benjamin M.; Cadel, Eileen S.; Friis, Elizabeth A.; Bouxsein, MaryThe clinical relevance of mechanical testing studies of cadaveric human thoracic spines could be enhanced by using follower preload techniques, by including the intact rib cage, and by measuring thoracic intervertebral disc pressures, but studies to date have not incorporated all of these components simultaneously. Thus, this study aimed to implement a follower preload in the thoracic spine with intact rib cage, and examine the effects of follower load, rib cage stiffening and rib cage removal on intervertebral disc pressures and sagittal plane curvatures in unconstrained static conditions. Intervertebral disc pressures increased linearly with follower load magnitude. The effect of the rib cage on disc pressures in static conditions remains unclear because testing order likely confounded the results. Disc pressures compared well with previous reports in vitro, and comparison with in vivo values suggests the use of a follower load of about 400 N to approximate loading in upright standing. Follower load had no effect on sagittal plane spine curvature overall, suggesting successful application of the technique, although increased flexion in the upper spine and reduced flexion in the lower spine suggest that the follower load path was not optimized. Rib cage stiffening and removal both increased overall spine flexion slightly, although with differing effects at specific spinal locations. Overall, the approaches demonstrated here will support the use of follower preloads, intact rib cage, and disc pressure measurements to enhance the clinical relevance of future studies of the thoracic spine.Publication Computed Tomography-Based Muscle Attenuation and Electrical Impedance Myography as Indicators of Trunk Muscle Strength Independent of Muscle Size in Older Adults(Ovid Technologies (Wolters Kluwer Health), 2014) Anderson, Dennis; Bean, Jonathan; Holt, Nicole E.; Keel, John C.; Bouxsein, MaryObjective—To examine the associations of computed tomography (CT) -based x-ray attenuation and paraspinal electrical impedance myography (EIM) measures of trunk muscles with absolute and relative (normalized by body weight) trunk extension strength, independent of muscle cross- sectional area (CSA). Design—A cross-sectional study of mobility-limited community dwelling older adults (34 women, 15 men, mean age 78.2±7.2 years) recruited from within an existing prospective research cohort. Trunk extension strength, CT-based trunk muscle CSA and attenuation at L4 level, and paraspinal EIM measures were collected. Results—Attenuation was positively correlated with absolute and relative strength for multiple muscle groups (r = 0.32 to 0.61, p < 0.05). Paraspinal EIM phase was positively correlated with paraspinal attenuation (r = 0.30, p = 0.039) and with relative strength (r = 0.30, p = 0.042). In multivariable linear regressions adjusting for sex and CSA, attenuations of the anterior abdominal muscles (semipartial r2 = 0.11, p = 0.013) and combined muscles (semipartial r2 = 0.07, p = 0.046) were associated with relative strength. Conclusions—While attenuation was associated with relative strength, small effect sizes indicate limited usefulness as clinical measures of muscle strength independent of muscle size. However, there remains a need for additional studies in larger and more diverse groups of subjects.Publication The associations between QCT-based vertebral bone measurements and prevalent vertebral fractures depend on the spinal locations of both bone measurement and fracture(Springer Nature, 2013) Anderson, Dennis; Demissie, S.; Allaire, B. T.; Bruno, A. G.; Kopperdahl, D. L.; Keaveny, T. M.; Kiel, Douglas; Bouxsein, MarySummary—We examined how spinal location affects the relationships between quantitative computed tomography (QCT)-based bone measurements and prevalent vertebral fractures. Upper spine (T4–T10) fractures appear to be more strongly related to bone measures than lower spine (T11–L4) fractures, while lower spine measurements are at least as strongly related to fractures as upper spine measurements. Introduction—Vertebral fracture (VF), a common injury in older adults, is most prevalent in the mid-thoracic (T7–T8) and thoracolumbar (T12–L1) areas of the spine. However, measurements of bone mineral density (BMD) are typically made in the lumbar spine. It is not clear how the associations between bone measurements and VFs are affected by the spinal locations of both bone measurements and VF. Methods—A community-based case–control study includes 40 cases with moderate or severe prevalent VF and 80 age- and sex-matched controls. Measures of vertebral BMD, strength (estimated by finite element analysis), and factor of risk (load:strength ratio) were determined based on QCT scans at the L3 and T10 vertebrae. Associations were determined between bone measures and prevalent VF occurring at any location, in the upper spine (T4–T10), or in the lower spine (T11–L4). Results—Prevalent VF at any location was significantly associated with bone measures, with odds ratios (ORs) generally higher for measurements made at L3 (ORs=1.9–3.9) than at T10 (ORs=1.5–2.4). Upper spine fracture was associated with these measures at both T10 and L3 (ORs=1.9–8.2), while lower spine fracture was less strongly associated (ORs=1.0–2.4) and only reached significance for volumetric BMD measures at L3. Conclusions—Closer proximity between the locations of bone measures and prevalent VF does not strengthen associations between bone measures and fracture. Furthermore, VF etiology may vary by region, with VFs in the upper spine more strongly related to skeletal fragility.Publication Irisin Levels Are Lower in Young Amenorrheic Athletes Compared with Eumenorrheic Athletes and Non-Athletes and Are Associated with Bone Density and Strength Estimates(Public Library of Science, 2014) Singhal, Vibha; Lawson, Elizabeth; Ackerman, Kathryn; Fazeli, Pouneh; Clarke, Hannah; Lee, Hang; Eddy, Kamryn; Marengi, Dean A.; Derrico, Nicholas P.; Bouxsein, Mary; Misra, MadhusmitaIrisin and FGF21 are novel hormones implicated in the “browning” of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14–21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes.Publication SIKs control osteocyte responses to parathyroid hormone(Nature Publishing Group, 2016) Wein, Marc; Liang, Yanke; Goransson, Olga; Sundberg, Thomas B.; Wang, Jinhua; Williams, Elizabeth A.; O'Meara, Maureen J.; Govea, Nicolas; Beqo, Belinda; Nishimori, Shigeki; Nagano, Kenichi; Brooks, Daniel J.; Martins, Janaina S.; Corbin, Braden; Anselmo, Anthony; Sadreyev, Ruslan; Wu, Joy Y.; Sakamoto, Kei; Foretz, Marc; Xavier, Ramnik; Baron, Roland; Bouxsein, Mary; Gardella, Thomas; Divieti-Pajevic, Paola; Gray, Nathanael; Kronenberg, HenryParathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.