An in silico approach to elucidate the pathways leading to primary osteoporosis: age-related vs. postmenopausal.

Numerical models of bone remodelling have traditionally been used to perform in silico tests of bone loss in postmenopausal women and also to simulate the response to different drug treatments. These models simulate the menopausal oestrogen decline by altering certain signalling pathways. However, they do not consider the simultaneous effect that ageing can have on cell function and bone remodelling, and thus on bone loss. Considering ageing and oestrogen decline together is important for designing osteoporosis treatments that can selectively counteract one or the other disease mechanism. A previously developed bone cell population model was adapted to consider the effect of ageing through: (1) the decrease of TGF- ß contained in the bone matrix and (2) an increased production of sclerostin by non-skeletal cells. Oestrogen deficiency is simulated in three different ways: (a) an increase in RANKL expression, (b) a decrease in OPG production, and (c) an increase in the responsiveness of osteoclasts to RANKL. The effect of ageing was validated using the cross-sectional study of (Riggs et al. in J Bone Miner Res 19: 1945-1954, 2004) on BMD of trabecular bone of the vertebral body of men. The joint effect of ageing and oestrogen deficiency was validated using these same clinical results but in women. In ageing, the effect of the increasing production of sclerostin is more important than the decrease of TGF- ß , while the three mechanisms used to simulate the effect of oestrogen deficiency produce almost identical responses. The results show that an early menopause leads to a lower average density in the fifth decade, but after the sixth decade the average density is independent of the age at menopause. Treatment of osteoporosis with denosumab was also simulated to conclude that the drug is not very effective if started before 10 years after menopause or before age 60.

The loading direction dramatically affects the mechanical properties of the mouse tibia.

Introduction: The in vivo tibial loading mouse model has been extensively used to evaluate bone adaptation in the tibia after mechanical loading treatment. However, there is a prevailing assumption that the load is applied axially to the tibia. The aim of this in silico study was to evaluate how much the apparent mechanical properties of the mouse tibia are affected by the loading direction, by using a validated micro-finite element (micro-FE) model of mice which have been ovariectomized and exposed to external mechanical loading over a two-week period. Methods: Longitudinal micro-computed tomography (micro-CT) images were taken of the tibiae of eleven ovariectomized mice at ages 18 and 20 weeks. Six of the mice underwent a mechanical loading treatment at age 19 weeks. Micro-FE models were generated, based on the segmented micro-CT images. Three models using unitary loads were linearly combined to simulate a range of loading directions, generated as a function of the angle from the inferior-superior axis (θ, 0°-30° range, 5° steps) and the angle from the anterior-posterior axis (ϕ, 0°: anterior axis, positive anticlockwise, 0°-355° range, 5° steps). The minimum principal strain was calculated and used to estimate the failure load, by linearly scaling the strain until 10% of the nodes reached the critical strain level of -14,420 µÎµ. The apparent bone stiffness was calculated as the ratio between the axial applied force and the average displacement along the longitudinal direction, for the loaded nodes. Results: The results demonstrated a high sensitivity of the mouse tibia to the loading direction across all groups and time points. Higher failure loads were found for several loading directions (θ = 10°, ϕ 205°-210°) than for the nominal axial case (θ = 0°, ϕ = 0°), highlighting adaptation of the bone for loading directions far from the nominal axial one. Conclusion: These results suggest that in studies which use mouse tibia, the loading direction can significantly impact the failure load. Thus, the magnitude and direction of the applied load should be well controlled during the experiments.

Bone turnover and mineralisation kinetics control trabecular BMDD and apparent bone density: insights from a discrete statistical bone remodelling model.

The mechanical quality of trabecular bone is influenced by its mineral content and spatial distribution, which is controlled by bone remodelling and mineralisation. Mineralisation kinetics occur in two phases: a fast primary mineralisation and a secondary mineralisation that can last from several months to years. Variations in bone turnover and mineralisation kinetics can be observed in the bone mineral density distribution (BMDD). Here, we propose a statistical spatio-temporal bone remodelling model to study the effects of bone turnover (associated with the activation frequency Ac . f ) and mineralisation kinetics (associated with secondary mineralisation T sec ) on BMDD. In this model, individual basic multicellular units (BMUs) are activated discretely on trabecular surfaces that undergo typical bone remodelling periods. Our results highlight that trabecular BMDD is strongly regulated by Ac . f and T sec in a coupled way. Ca wt% increases with lower Ac . f and short T sec . For example, a Ac . f = 4 BMU/year/mm 3 and T sec = 8 years result in a mean Ca wt% of 25, which is in accordance with Ca wt% values reported in quantitative backscattered electron imaging (qBEI) experiments. However, for lower Ac . f and shorter T sec (from 0.5 to 4 years) one obtains a high Ca wt% and a very narrow skew BMDD to the right. This close link between Ac . f and T sec highlights the importance of considering both characteristics to draw meaningful conclusion about bone quality. Overall, this model represents a new approach to modelling healthy and diseased bone and can aid in developing deeper insights into disease states like osteoporosis.

Cortical bone adaptation response is region specific, but not peak load dependent: insights from µ CT image analysis and mechanostat simulations of the mouse tibia loading model.

The two major aims of the present study were: (i) quantify localised cortical bone adaptation at the surface level using contralateral endpoint imaging data and image analysis techniques, and (ii) investigate whether cortical bone adaptation responses are universal or region specific and dependent on the respective peak load. For this purpose, we re-analyse previously published µ CT data of the mouse tibia loading model that investigated bone adaptation in response to sciatic neurectomy and various peak load magnitudes (F = 0, 2, 4, 6, 8, 10, 12 N). A beam theory-based approach was developed to simulate cortical bone adaptation in different sections of the tibia, using longitudinal strains as the adaptive stimuli. We developed four mechanostat models: universal, surface-based, strain directional-based, and combined surface and strain direction-based. Rates of bone adaptation in these mechanostat models were computed using an optimisation procedure (131,606 total simulations), performed on a single load case (F = 10 N). Subsequently, the models were validated against the remaining six peak loads. Our findings indicate that local bone adaptation responses are quasi-linear and bone region specific. The mechanostat model which accounted for differences in endosteal and periosteal regions and strain directions (i.e. tensile versus compressive) produced the lowest root mean squared error between simulated and experimental data for all loads, with a combined prediction accuracy of 76.6, 55.0 and 80.7% for periosteal, endosteal, and cortical thickness measurements (in the midshaft of the tibia). The largest root mean squared errors were observed in the transitional loads, i.e. F = 2 to 6 N, where inter-animal variability was highest. Finally, while endpoint imaging studies provide great insights into organ level bone adaptation responses, the between animal and loaded versus control limb variability make simulations of local surface-based adaptation responses challenging.

Cortical thickness adaptation to combined mechanical loading and parathyroid hormone treatments is site specific and synergistic in the mouse tibia model.

In this study, we aimed to quantify the localised effects of mechanical loading (ML), low (20 µg/kg/day), moderate (40 µg/kg/day) or high (80 µg/kg/day) dosages of parathyroid hormone (PTH), and combined (PTHML) treatments on cortical bone adaptation in healthy 19-week old female C57BL/6 mice. To this end, we utilise a previously reported image analysis algorithm on µCT data of the mouse tibia published by Sugiyama et al. (2008) to measure changes in cortical area, marrow cavity area and local cortical thickness measures (ΔCt.Ar, ΔMa.Ar, ΔCt.Th respectively), evaluated at two cross-sections within the mouse tibia (proximal-middle (37 %) and middle (50 %)), and are compared to a superposed summation (P + M) of individual treatments to determine the effectiveness of combining treatments in vivo. ΔCt.Ar analysis revealed a non-linear, synergistic interactions between PTH and ML in the 37 % cross-section that saturates at higher PTH dosages, whereas the 50 % cross-section experiences an approximately linear, additive adaptation response. This coincided with an increase in ΔMa.Ar (indicating resorption of the endosteal surface), which was only counteracted by combined high dose PTH with ML in the middle cross-section. Regional analysis of ΔCt.Th changes reveal localised cortical thinning in response to low dose PTH treatment in the posteromedial region of the middle cross-section, signifying that PTH does not provide a homogeneous adaptation response around the cortical perimeter. We observe a synergistic response in the proximal-middle cross-section, with regions of compressive strain experiencing the greatest adaptation response to PTHML treatments, (peak ΔCt.Th of 189.32, 213.78 and 239.30 µm for low, moderate and high PTHML groups respectively). In contrast, PTHML treatments in the middle cross-section show a similar response to the superposed P + M group, with the exception of the combined high dose PTHML treatment which shows a synergistic interaction. These analyses suggest that, in mice, adding mechanical loading to PTH treatments leads to region specific bone responses; synergism of PTHML is only achieved in some regions experiencing high loading, while other regions respond additively to this combined treatment.

Engineering the perfect mattress: The influence of substrate mechanics on deep tissue stresses in supine.

BACKGROUND: With increasing global interest in sleep hygiene, sleep ergonomics is an area that has been largely understudied. During sleep individuals turn over during the night to restore blood flow in occluded blood vessels, indicating that control of local tissue pressure may play a role in improving sleep comfort. This study investigates the influence of mattress stiffness on tissue compressive stresses during supine lying. METHODS: A subject-specific 3D finite element (FE) model of the pelvis area has been developed to simulate supine lying on substrates of varying firmness. Constitutive parameters for the adipose-skin tissue and muscle-organ tissue were calibrated using a novel application of the inverse finite element method. FINDINGS: The compressive stress was consistently greatest in the muscle interfacing the sacrum at 18.5 kPa on the soft foam, and 30.9 kPa on the firm foam. From soft to firm, the compressive stress increased by 67% at the sacrum, 20% at the ischium, 42% at the lesser trochanter, and 50% at the skin. INTERPRETATION: The non-linearity of the foam substrate had a pressure distributing effect, relieving the peak compressive stresses at the sacrum, indicating that it may be possible to design arrays of foam substrates that can provide most efficient pressure relief.

Daily administration of parathyroid hormone slows the progression of basic multicellular units in the cortical bone of the rabbit distal tibia.

Basic Multicellular Units (BMUs) conduct bone remodeling, a critical process of tissue turnover which, if imbalanced, can lead to disease, including osteoporosis. Parathyroid hormone (PTH 1-34; Teriparatide) is an osteoanabolic treatment for osteoporosis; however, it elevates the rate of intra-cortical remodeling (activation frequency) leading, at least transiently, to increased porosity. The purpose of this study was to test the hypothesis that PTH not only increases the rate at which cortical BMUs are initiated but also increases their progression (Longitudinal Erosion Rate; LER). Two groups (n = 7 each) of six-month old female New Zealand white rabbits were both administered 30 µg/kg of PTH once daily for a period of two weeks to induce remodeling. Their distal right tibiae were then imaged in vivo by in-line phase contrast micro-CT at the Canadian Light Source synchrotron. Over the following two weeks the first group (PTH) received continued daily PTH while the second withdrawal group (PTHW) was administrated 0.9 % saline. At four weeks all animals were euthanized, their distal tibiae were imaged by conventional micro-CT ex vivo and histomorphometry was performed. Matching micro-CT datasets (in vivo and ex vivo) were co-registered in 3D and LER was measured from 612 BMUs. Counter to our hypothesis, mean LER was lower (p < 0.001) in the PTH group (30.19 ± 3.01 µm/day) versus the PTHW group (37.20 ± 2.77 µm/day). Despite the difference in LER, osteonal mineral apposition rate (On.MAR) did not differ between groups indicating the anabolic effect of PTH was sustained after withdrawal. The slowing of BMU progression by PTH warrants further investigation; slowed resorption combined with elevated bone formation rate, may play an important role in how PTH enhances coupling between resorption and formation within the BMU. Finally, the prolonged anabolic response following withdrawal may have utility in terms of optimizing clinical dosing regimens.

Quantifying Muscle Size Asymmetry in Adolescent Idiopathic Scoliosis Using Three-dimensional Magnetic Resonance Imaging.

STUDY DESIGN: This is a case-control study of prospectively collected data. OBJECTIVE: To quantify paraspinal muscle size asymmetry in adolescent idiopathic scoliosis (AIS) and determine if this asymmetry is (i) greater than observed in adolescent controls with symmetrical spines; and (ii) positively associated with skeletal maturity using Risser grade, scoliosis severity using the Cobb angle, and chronological age in years. SUMMARY OF BACKGROUND DATA: AIS is a three-dimensional deformity of the spine which occurs in 2.5% to 3.7% of the Australian population. There is some evidence of asymmetry in paraspinal muscle activation and morphology in AIS. Asymmetric paraspinal muscle forces may facilitate asymmetric vertebral growth during adolescence. METHODS: An asymmetry index [Ln(concave/convex volume)] of deep and superficial paraspinal muscle volumes, at the level of the major curve apex (Thoracic 8-9 th vertebral level) and lower-end vertebrae ( LEV , Thoracic 10-12 th vertebral level), was determined from three-dimensional Magnetic Resonance Imaging of 25 adolescents with AIS (all right thoracic curves), and 22 healthy controls (convex=left); all female, 10 to 16 years. RESULTS: Asymmetry index of deep paraspinal muscle volumes was greater in AIS (0.16±0.20) than healthy spine controls (-0.06±0.13) at the level of the apex ( P <0.01, linear mixed-effects analysis) but not LEV ( P >0.05). Asymmetry index was positively correlated with Risser grade ( r =0.50, P <0.05) and scoliosis Cobb angle ( r =0.45, P <0.05), but not age ( r =0.34, P >0.05). There was no difference in the asymmetry index of superficial paraspinal muscle volumes between AIS and controls ( P >0.05). CONCLUSIONS: The asymmetry of deep apical paraspinal muscle volume in AIS at the scoliosis apex is greater than that observed at equivalent vertebral levels in controls and may play a role in the pathogenesis of AIS.

Effect of neglecting passive spinal structures: a quantitative investigation using the forward-dynamics and inverse-dynamics musculoskeletal approach.

Purpose: Inverse-dynamics (ID) analysis is an approach widely used for studying spine biomechanics and the estimation of muscle forces. Despite the increasing structural complexity of spine models, ID analysis results substantially rely on accurate kinematic data that most of the current technologies are not capable to provide. For this reason, the model complexity is drastically reduced by assuming three degrees of freedom spherical joints and generic kinematic coupling constraints. Moreover, the majority of current ID spine models neglect the contribution of passive structures. The aim of this ID analysis study was to determine the impact of modelled passive structures (i.e., ligaments and intervertebral discs) on remaining joint forces and torques that muscles must balance in the functional spinal unit. Methods: For this purpose, an existing generic spine model developed for the use in the demoa software environment was transferred into the musculoskeletal modelling platform OpenSim. The thoracolumbar spine model previously used in forward-dynamics (FD) simulations provided a full kinematic description of a flexion-extension movement. By using the obtained in silico kinematics, ID analysis was performed. The individual contribution of passive elements to the generalised net joint forces and torques was evaluated in a step-wise approach increasing the model complexity by adding individual biological structures of the spine. Results: The implementation of intervertebral discs and ligaments has significantly reduced compressive loading and anterior torque that is attributed to the acting net muscle forces by -200% and -75%, respectively. The ID model kinematics and kinetics were cross-validated against the FD simulation results. Conclusion: This study clearly shows the importance of incorporating passive spinal structures on the accurate computation of remaining joint loads. Furthermore, for the first time, a generic spine model was used and cross-validated in two different musculoskeletal modelling platforms, i.e., demoa and OpenSim, respectively. In future, a comparison of neuromuscular control strategies for spinal movement can be investigated using both approaches.

Latarjet's muscular alterations increase glenohumeral joint stability: A theoretical study.

The surgical Latarjet procedure aims to stabilise the glenohumeral joint following anterior dislocations. Despite restoring joint stability, the procedure introduces alterations of muscle paths which likely modify the shoulder dynamics. Currently, these altered muscular functions and their implications are unclear. Hence, this work aims to predict changes in muscle lever arms, muscle and joint forces following a Latarjet procedure by using a computational approach. Planar shoulder movements of ten participants were experimentally assessed. A validated upper-limb musculoskeletal model was utilised in two configurations, i.e., a baseline model, simulating normal joint, and a Latarjet model simulating its related muscular alterations. Muscle lever arms and differences in muscle and joint forces between models were derived from the experimental marker data and static optimisation technique. Lever arms of most altered muscles, hence their role, were substantially changed after Latarjet. Altered muscle forces varied by up to 15% of the body weight. Total glenohumeral joint force increased by up to 14% of the body weight after Latarjet, mostly due to increase in compression force. Our simulation indicated that the Latarjet muscular alterations lead to changes in the muscular recruitment and contribute to the stability of the glenohumeral joint by increasing compression force during planar motions.

Effects of PTH glandular and external dosing patterns on bone cell activity using a two-state receptor model-Implications for bone disease progression and treatment.

Temporal aspects of ligand specificity have been shown to play a significant role in the case of pulsatile hormone secretion, as exemplified by parathyroid hormone (PTH) binding to its receptor (PTH1R), a G-protein-coupled receptor expressed on surfaces of osteoblasts and osteocytes. The latter binding reaction regulates intracellular signalling and subsequently modulates skeletal homeostasis via bone remodelling. PTH glandular secretion patterns dictate bone cellular activity. In healthy humans, 70% of PTH is secreted in a tonic fashion, whereas 30% is secreted in low-amplitude and high-frequency bursts occurring every 10-20 min, superimposed on the tonic secretion. Changes in the PTH secretion patterns have been associated with various bone diseases. In this paper, we analyse PTH glandular secretion patterns for healthy and pathological states and their link to bone cellular responsiveness (αR). We utilise a two-state receptor ligand binding model of PTH to PTH1R together with a cellular activity function which is able to distinguish various aspects of the stimulation signal including peak dose, time of ligand exposure, and exposure period. Formulating and solving several constrained optimisation problems, we investigate the potential of pharmacological manipulation of the diseased glandular secretion and via clinical approved external PTH injections to restore healthy bone cellular responsiveness. Based on the mean experimentally reported data, our simulation results indicate cellular responsiveness in healthy subjects is sensitive to the tonic baseline stimulus and it is 28% of the computed maximum responsiveness. Simulation results for pathological cases of glucocorticoid-induced osteoporosis, hyperparathyroidism, initial and steady state hypocalcemia clamp tests indicate αR values significantly larger than the healthy baseline (1.7, 2.2, 4.9 and 1.9-times, respectively). Manipulation of the pulsatile glandular secretion pattern, while keeping the mean PTH concentration constant, allowed restoration of healthy baseline values from these catabolic bone diseases. Conversely, PTH glandular diseases that led to maximum bone cellular responsiveness below the healthy baseline value can't be restored to baseline via glandular manipulation. However, external PTH injections allowed restoration of these latter cases.

Spatio-temporal simulations of bone remodelling using a bone cell population model based on cell availability.

Here we developed a spatio-temporal bone remodeling model to simulate the action of Basic Multicelluar Units (BMUs). This model is based on two major extensions of a temporal-only bone cell population model (BCPM). First, the differentiation into mature resorbing osteoclasts and mature forming osteoblasts from their respective precursor cells was modelled as an intermittent process based on precursor cells availability. Second, the interaction between neighbouring BMUs was considered based on a "metabolic cost" argument which warrants that no new BMU will be activated in the neighbourhood of an existing BMU. With the proposed model we have simulated the phases of the remodelling process obtaining average periods similar to those found in the literature: resorption ( ∼ 22 days)-reversal (∼8 days)-formation (∼65 days)-quiescence (560-600 days) and an average BMU activation frequency of ∼1.6 BMUs/year/mm3. We further show here that the resorption and formation phases of the BMU become coordinated only by the presence of TGF-ß (transforming growth factor ß), i.e., a major coupling factor stored in the bone matrix. TGF-ß is released through resorption so upregulating osteoclast apoptosis and accumulation of osteoblast precursors, i.e., facilitating the transition from the resorption to the formation phase at a given remodelling site. Finally, we demonstrate that this model can explain targeted bone remodelling as the BMUs are steered towards damaged bone areas in order to commence bone matrix repair.

A biomechanical analysis of double-screw, double-button, and screw-button fixation constructs in patient-specific instrument-guided Latarjet procedure.

BACKGROUND: The Latarjet coracoid transfer procedure reliably stabilizes the glenohumeral joint for shoulder instability. However, complications such as graft osteolysis, nonunion and fracture continue to affect patient clinical outcomes. The double-screw (SS) construct is regarded as the gold standard method of fixation. SS constructs are associated with graft osteolysis. More recently, a double-button technique (BB) has been suggested to minimize graft-related complications. However, BB constructs are associated with fibrous nonunion. To mitigate this risk, a single screw combined with a single button (SB) construct has been proposed. It is thought that this technique incorporates the strength of the SS construct and allows micromotion superiorly to mitigate stress shielding-related graft osteolysis. AIMS: The primary aim of this study was to compare the failure load of SS, BB, and SB constructs under a standardized biomechanical loading protocol. The secondary aim was to characterize the displacement of each construct throughout testing. METHODS: Computed tomography scans of 20 matched-pair cadaveric scapulae were performed. Specimens were harvested and dissected free of soft tissue. SS and BB techniques were randomly assigned to specimens for matched-pair comparison with SB trials. A patient-specific instrument (PSI)-guided Latarjet procedure was performed on each scapula. Specimens were tested using a uniaxial mechanical testing device under cyclic loading (100 cycles, 1 Hz, 200 N/s) followed by a load-to-failure protocol (0.5 mm/s). Construct failure was defined by graft fracture, screw avulsion, and/or graft displacement of more than 5 mm. RESULTS: Forty scapulae from 20 fresh frozen cadavers with a mean age of 69.3 years underwent testing. On average, SS constructs failed at 537.8 N (SD 296.8), whereas BB constructs failed at 135.1 N (SD 71.4). SB constructs required a significantly greater load to fail compared with BB constructs (283.5 N, SD 162.8, P = .039). Additionally, SS (1.9 mm, IQR 0.87) had a significantly lower maximum total graft displacement during the cyclic loading protocol compared with SB (3.8 mm, IQR 2.4, P = .007) and BB (7.4 mm, IQR 3.1, P < .001) constructs. CONCLUSION: These findings support the potential of the SB fixation technique as a viable alternative to SS and BB constructs. Clinically, the SB technique could reduce the incidence of loading-related graft complications seen in the first 3 months of BB Latarjet cases. The study is limited to time-specific results and does not account for bone union or osteolysis.

Anterior deltoid muscle reflection using a deltopectoral approach is safe and does not influence outcome of reverse shoulder arthroplasty.

BACKGROUND: The deltopectoral approach is well accepted for shoulder arthroplasty procedures. The extended deltopectoral approach with detachment of the anterior deltoid from the clavicle allows increased joint exposure and can protect the anterior deltoid from traction injury. The efficacy of this extended approach has been demonstrated in anatomic total shoulder replacement surgery. However, this has not been shown in reverse shoulder arthroplasty (RSA). The primary aim of this study was to evaluate the safety of the extended deltopectoral approach in RSA. The secondary aim was to evaluate the performance of the deltoid reflection approach in terms of complications and surgical, functional, and radiologic outcomes up to 24 months after surgery. METHODS: A prospective, nonrandomized comparative study was performed between January 2012 and October 2020 including 77 patients in the deltoid reflection group and 73 patients in the comparative group. The decision for inclusion was based on patient and surgeon factors. Complications were recorded. Patients were followed up for ≥24 months to evaluate their shoulder function and undergo ultrasound evaluation. Functional outcome measures included the Oxford Shoulder Score, Disabilities of the Arm, Shoulder and Hand score, American Shoulder and Elbow Surgeons score, pain intensity (rated on visual analog scale [VAS] from 0 to 100), and range of motion (forward flexion, abduction, and external rotation). A regression analysis was performed to evaluate any factors of influence on the VAS score. RESULTS: There were no significant differences in the complication rate between the 2 groups (14.5% in deltoid reflection group and 13.8% in comparative group, P = .915). Ultrasound evaluation was available in 64 patients (83.1%), and no proximal detachment was observed. In addition, there were no significant differences in functional outcome measures both preoperatively and at 24 months after surgery between the groups assessed based on the mean VAS pain score, Oxford Shoulder Score, Disabilities of the Arm, Shoulder and Hand score, American Shoulder and Elbow Surgeons score, forward flexion, abduction, and external rotation. Adjustment for possible confounders in a regression model indicated that only prior surgery significantly influenced the VAS pain score after surgery (P = .031; 95% confidence interval, 0.574-11.67). Deltoid reflection (P = .068), age (P = .466), sex (P = .936), use of glenoid graft (P = .091), prosthesis manufacturer (P = .382), and preoperative VAS score (P = .362) were not of influence. DISCUSSION: The results of this study show that an extended deltopectoral approach for RSA is safe. Selected reflection of the anterior deltoid muscle improved exposure and prevented anterior deltoid muscle injury followed by reattachment. Patients had similar functional scores preoperatively and at 24 months postoperatively compared with a comparative group. Furthermore, ultrasound evaluation showed intact reattachments.

Assessment of thoracic spinal curvatures in static postures using spatially tracked 3D ultrasound volumes: a proof-of-concept study.

The assessment of spinal posture is a difficult endeavour given the lack of identifiable bony landmarks for placement of skin markers. Moreover, potentially significant soft tissue artefacts along the spine further affect the accuracy of marker-based approaches. The objective of this proof-of-concept study was to develop an experimental framework to assess spinal postures by using three-dimensional (3D) ultrasound (US) imaging. A phantom spine model immersed in water was scanned using 3D US in a neutral and two curved postures mimicking a forward flexion in the sagittal plane while the US probe was localised by three electromagnetic tracking sensors attached to the probe head. The obtained anatomical 'coarse' registrations were further refined using an automatic registration algorithm and validated by an experienced sonographer. Spinal landmarks were selected in the US images and validated against magnetic resonance imaging data of the same phantom through image registration. Their position was then related to the location of the tracking sensors identified in the acquired US volumes, enabling the localisation of landmarks in the global coordinate system of the tracking device. Results of this study show that localised 3D US enables US-based anatomical reconstructions comparable to clinical standards and the identification of spinal landmarks in different postures of the spine. The accuracy in sensor identification was 0.49 mm on average while the intra- and inter-observer reliability in sensor identification was strongly correlated with a maximum deviation of 0.8 mm. Mapping of landmarks had a small relative distance error of 0.21 mm (SD = ± 0.16) on average. This study implies that localised 3D US holds the potential for the assessment of full spinal posture by accurately and non-invasively localising vertebrae in space.

Effects of geometric individualisation of a human spine model on load sharing: neuro-musculoskeletal simulation reveals significant differences in ligament and muscle contribution.

In spine research, two possibilities to generate models exist: generic (population-based) models representing the average human and subject-specific representations of individuals. Despite the increasing interest in subject specificity, individualisation of spine models remains challenging. Neuro-musculoskeletal (NMS) models enable the analysis and prediction of dynamic motions by incorporating active muscles attaching to bones that are connected using articulating joints under the assumption of rigid body dynamics. In this study, we used forward-dynamic simulations to compare a generic NMS multibody model of the thoracolumbar spine including fully articulated vertebrae, detailed musculature, passive ligaments and linear intervertebral disc (IVD) models with an individualised model to assess the contribution of individual biological structures. Individualisation was achieved by integrating skeletal geometry from computed tomography and custom-selected muscle and ligament paths. Both models underwent a gravitational settling process and a forward flexion-to-extension movement. The model-specific load distribution in an equilibrated upright position and local stiffness in the L4/5 functional spinal unit (FSU) is compared. Load sharing between occurring internal forces generated by individual biological structures and their contribution to the FSU stiffness was computed. The main finding of our simulations is an apparent shift in load sharing with individualisation from an equally distributed element contribution of IVD, ligaments and muscles in the generic spine model to a predominant muscle contribution in the individualised model depending on the analysed spine level.

Geometry and bone mineral density determinants of femoral neck strength changes following exercise.

Physical exercise induces spatially heterogeneous adaptation in bone. However, it remains unclear where the changes in BMD and geometry have the greatest impact on femoral neck strength. The aim of this study was to determine the principal BMD-and-geometry changes induced by exercise that have the greatest effect on femoral neck strength. Pre- and post-exercise 3D-DXA images of the proximal femur were collected of male participants from the LIFTMOR-M exercise intervention trial. Meshes with element-by-element correspondence were generated by morphing a template mesh to each bone to calculate changes in BMD and geometry. Finite element (FE) models predicted femoral neck strength changes under single-leg stance and sideways fall load. Partial least squares regression (PLSR) models were developed with BMD-only, geometry-only, and BMD-and-geometry changes to determine the principal modes that explained the greatest variation in neck strength changes. The PLSR models explained over 90% of the strength variation with 3 PLS components using BMD-only (R2 > 0.92, RMSE < 0.06 N) and 8 PLS components with geometry-only (R2 > 0.93, RMSE < 0.06 N). Changes in the superior neck and distal cortex were most important during single-leg stance while the superior neck, medial head, and lateral trochanter were most important during a sideways fall. Local changes in femoral neck and head geometry could differentiate the exercise groups from the control group. Exercise interventions may target BMD changes in the superior neck, inferior neck, and greater trochanter for improved femoral neck strength in single-leg stance and sideways fall.

Mechanistic PK-PD model of alendronate treatment of postmenopausal osteoporosis predicts bone site-specific response.

Alendronate is the most widely used drug for postmenopausal osteoporosis (PMO). It inhibits bone resorption, affecting osteoclasts. Pharmacokinetics (PK) and pharmacodynamics (PD) of alendronate have been widely studied, but few mathematical models exist to simulate its effect. In this work, we have developed a PK model for alendronate, valid for short- and long-term treatments, and a mechanistic PK-PD model for the treatment of PMO to predict bone density gain (BDG) at the hip and lumbar spine. According to our results, at least three compartments are required in the PK model to predict the effect of alendronate in both the short and long terms. Clinical data of a 2-year treatment of alendronate, reproduced by our PK-PD model, demonstrate that bone response is site specific (hip: 7% BDG, lumbar spine: 4% BDG). We identified that this BDG is mainly due to an increase in tissue mineralization and a decrease in porosity. The difference in BDG between sites is linked to the different loading and dependence of the released alendronate on the bone-specific surface and porosity. Osteoclast population diminishes quickly within the first month of alendronate treatment. Osteoblast population lags behind but also falls due to coupling of resorption and formation. Two dosing regimens were studied (70 mg weekly and 10 mg daily), and both showed very similar BDG evolution, indicating that alendronate accumulates quickly in bone and saturates. The proposed PK-PD model could provide a valuable tool to analyze the effect of alendronate and to design patient-specific treatments, including drug combinations.

Direct Assessment of Rabbit Cortical Bone Basic Multicellular Unit Longitudinal Erosion Rate: A 4D Synchrotron-Based Approach.

Cortical bone remodeling is carried out by basic multicellular units (BMUs), which couple resorption to formation. Although fluorochrome labeling has facilitated study of BMU formative parameters since the 1960s, some resorptive parameters, including the longitudinal erosion rate (LER), have remained beyond reach of direct measurement. Indeed, our only insights into this spatiotemporal parameter of BMU behavior come from classical studies that indirectly inferred LER. Here, we demonstrate a 4D in vivo method to directly measure LER through in-line phase contrast synchrotron imaging. The tibias of rabbits (n = 15) dosed daily with parathyroid hormone were first imaged in vivo (synchrotron micro-CT; day 15) and then ex vivo 14 days later (conventional micro-CT; day 29). Mean LER assessed by landmarking the co-registered scans was 23.69 ± 1.73 µm/d. This novel approach holds great promise for the direct study of the spatiotemporal coordination of bone remodeling, its role in diseases such as osteoporosis, as well as related treatments. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).