Super-resolution of clinical CT: Revealing microarchitecture in whole bone clinical CT image data.

Osteoporotic fractures, prevalent in the elderly, pose a significant health and economic burden. Current methods for predicting fracture risk, primarily relying on bone mineral density, provide only modest accuracy. If better spatial resolution of trabecular bone in a clinical scan were available, a more complete assessment of fracture risk would be obtained using microarchitectural measures of bone (i.e. trabecular thickness, trabecular spacing, bone volume fraction, etc.). However, increased resolution comes at the cost of increased radiation or can only be applied at small volumes of distal skeletal locations. This study explores super-resolution (SR) technology to enhance clinical CT scans of proximal femurs and better reveal the trabecular microarchitecture of bone. Using a deep-learning-based (i.e. subset of artificial intelligence) SR approach, low-resolution clinical CT images were upscaled to higher resolution and compared to corresponding MicroCT-derived images. SR-derived 2-dimensional microarchitectural measurements, such as degree of anisotropy, bone volume fraction, trabecular spacing, and trabecular thickness were within 16 % error compared to MicroCT data, whereas connectivity density exhibited larger error (as high as 1094 %). SR-derived 3-dimensional microarchitectural metrics exhibited errors <18 %. This work showcases the potential of SR technology to enhance clinical bone imaging and holds promise for improving fracture risk assessments and osteoporosis detection. Further research, including larger datasets and refined techniques, can advance SR's clinical utility, enabling comprehensive microstructural assessment across whole bones, thereby improving fracture risk predictions and patient-specific treatment strategies.

The I-PREDICT 50th Percentile Male Warfighter Finite Element Model: Development and Validation of the Thoracolumbar Spine.

Military personnel are commonly at risk of lower back pain and thoracolumbar spine injury. Human volunteers and postmortem human subjects have been used to understand the scenarios where injury can occur and the tolerance of the warfighter to these loading regimes. Finite element human body models (HBMs) can accurately simulate the mechanics of the human body and are a useful tool for understanding injury. In this study, a HBM thoracolumbar spine was developed and hierarchically ï»¿validated as part of the Incapacitation Prediction for Readiness in Expeditionary Domains: an Integrated Computational Tool (I-PREDICT) program. Constitutive material models were sourced from literature and the vertebrae and intervertebral discs were hexahedrally meshed from a 50th percentile male CAD dataset. Ligaments were modeled through attaching beam elements at the appropriate anatomical insertion sites. 94 simulations were replicated from experimental PMHS tests at the vertebral body, functional spinal unit (FSU), and regional lumbar spine levels. The BioRank (BRS) biofidelity ranking system was used to assess the response of the I-PREDICT model. At the vertebral body level, the I-PREDICT model showed good agreement with experimental results. The I-PREDICT FSUs showed good agreement in tension and compression and had comparable stiffness values in flexion, extension, and axial rotation. The regional lumbar spine exhibited "good" biofidelity when tested in tension, compression, extension, flexion, posterior shear, and anterior shear (BRS regional average = 1.05). The validated thoracolumbar spine of the I-PREDICT model can be used to better understand and mitigate injury risk to the warfighter.

Mobility Solutions After a Lower Extremity Fracture and Applicability to Battlefield and Wilderness Medicine.

The potential for delayed evacuation of injured Service members from austere environments highlights the need to develop solutions that can stabilize a wound and enable mobility during these prolonged casualty care (PCC) scenarios. Lower extremity fractures have traditionally been treated by immobilization (splinting) followed by air evacuation - a paradigm not practical in PCC scenarios. In the civilian sector, treatment of extremity injuries sustained during remote recreational activities have similar challenges, particularly when adverse weather or terrain precludes early ground or air rescue. This review examines currently available fracture treatment solutions to include splinting, orthotic devices, and biological interventions and evaluates their feasibility: 1) for prolonged use in austere environments and 2) to enable patient mobilization. This review returned three common types of splints to include: a simple box splint, pneumatic splints, and traction splints. None of these splinting techniques allowed for ambulation. However, fixed facility-based orthotic interventions that include weight-bearing features may be combined with common splinting techniques to improve mobility. Biologically-focused technologies to stabilize a long bone fracture are still in their infancy. Integrating design features across these technologies could generate advanced treatments which would enable mobility, thus maximizing survivability until patient evacuation is feasible.

Biomechanical characteristics of proficient free-throw shooters-markerless motion capture analysis.

The winning game outcome in basketball is partially contingent on the team's ability to secure and make more free-throw shooting attempts, especially close to the end of the game. Thus, the purpose of the present study was to perform a comprehensive biomechanical analysis of the free-throw shooting motion to examine differences between (a) proficient (≥70%) and non-proficient shooters (<70%) and (b) made and missed free-throw shoots within the proficient group of shooters. Thirty-four recreationally active males with previous basketball playing experience attempted ten consecutive free-throw shots (4.57 m), with a 10-15 s rest interval between each shot. An innovative three-dimensional markerless motion capture system (SwRI Enable, San Antonio, TX, USA) composed of nine high-definition cameras recording at 120 Hz was used to capture and analyze the biomechanical parameters of interest. Independent t-tests and Mann-Whitney U tests were used to examine a presence of statistically significant differences. The findings of the present study reveal that proficient free-throw shooters performed the shooting motion in a more controlled manner by having significantly lower knee and center of mass peak and mean angular velocities. Also, proficient shooters attained a significantly greater release height and had less forward trunk lean when compared to non-proficient shooters at the time point of the ball release. Moreover, despite being beneficial for improvements in shooting accuracy, our findings suggest that overemphasizing the release height may be in certain instances counterproductive, as it may lead to more missed than made free-throw shots within the proficient group of shooters.

A comparative analysis of dimensionality reduction surrogate modeling techniques for full human body finite element impact simulations.

Fast-running surrogate computational models (simpler computational models) have been successfully used to replace time-intensive finite element models. However, it is unclear how well they perform in accurately and efficiently replicating complex, full human body finite element models. Here we survey several surrogate modeling techniques and assess their accuracy in predicting full strain fields of tissues of interest during a highly dynamic behind armor blunt trauma impact to the liver. We found that coupling dimensionality reduction on the high-dimensional output space (principal component analysis or autoencoders) with machine learning techniques (Gaussian Process Regression or multi-output neural networks) provides a framework capable of accurately and efficiently replacing complex full human body models. It was found that these surrogate models can successfully predict the strain fields (<10% average strain error) of select tissues during a nonlinear impact event but careful consideration should be given to element parsing and modeling technique.

Response of Thoraco-Abdominal Tissue in High-Rate Compression.

Body armor is used to protect the human from penetrating injuries, however, in the process of defeating a projectile, the back face of the armor can deform into the wearer at extremely high rates. This deformation can cause a variety of soft and hard tissue injuries. Finite element modeling (FEM) represents one of the best tools to predict injuries from this high-rate compression mechanism. However, the validity of a model is reliant on accurate material properties for biological tissues. In this study, we measured the stress-strain response of thoraco-abdominal tissue during high-rate compression (1000 and 1900 s-1) using a split Hopkinson pressure bar (SHPB). High-rate material properties of porcine adipose, heart, spleen, and stomach tissue were characterized. At a strain rate of 1000 s-1, adipose (E = 4.7 MPa) had the most compliant stress-strain response, followed by spleen (E = 9.6 MPa), and then heart tissue (E = 13.6 MPa). At a strain rate of 1900 s-1, adipose (E = 7.3 MPa) had the most compliant stress-strain response, followed by spleen (E = 10.7 MPa), heart (E = 14.1 MPa), and stomach (E = 32.6 MPa) tissue. Only adipose tissue demonstrated a consistent rate dependence for these high strain rates, with a stiffer response at 1900 s-1 compared to 1000 s-1. However, comparison of all these tissues to previously published quasi-static and intermediate dynamic experiments revealed a strong rate dependence with increasing stress response from quasi-static to dynamic to high strain rates. Together, these findings can be used to develop a more accurate finite element model of high-rate compression injuries.

Biglycan and chondroitin sulfate play pivotal roles in bone toughness via retaining bound water in bone mineral matrix.

Recent in vitro evidence shows that glycosaminoglycans (GAGs) and proteoglycans (PGs) in bone matrix may functionally be involved in the tissue-level toughness of bone. In this study, we showed the effect of biglycan (Bgn), a small leucine-rich proteoglycan enriched in extracellular matrix of bone and the associated GAG subtype, chondroitin sulfate (CS), on the toughness of bone in vivo, using wild-type (WT) and Bgn deficient mice. The amount of total GAGs and CS in the mineralized compartment of Bgn KO mouse bone matrix decreased significantly, associated with the reduction of the toughness of bone, in comparison with those of WT mice. However, such differences between WT and Bgn KO mice diminished once the bound water was removed from bone matrix. In addition, CS was identified as the major subtype in bone matrix. We then supplemented CS to both WT and Bgn KO mice to test whether supplemental GAGs could improve the tissue-level toughness of bone. After intradermal administration of CS, the toughness of WT bone was greatly improved, with the GAGs and bound water amount in the bone matrix increased, while such improvement was not observed in Bgn KO mice or with supplementation of dermatan sulfate (DS). Moreover, CS supplemented WT mice exhibited higher bone mineral density and reduced osteoclastogenesis. Interestingly, Bgn KO bone did not show such differences irrespective of the intradermal administration of CS. In summary, the results of this study suggest that Bgn and CS in bone matrix play a pivotal role in imparting the toughness to bone most likely via retaining bound water in bone matrix. Moreover, supplementation of CS improves the toughness of bone in mouse models.

Hip load capacity cut-points for Astronaut Skeletal Health NASA Finite Element Strength Task Group Recommendations.

Concerns raised at a 2010 Bone Summit held for National Aeronautics and Space Administration Johnson Space Center led experts in finite element (FE) modeling for hip fracture prediction to propose including hip load capacity in the standards for astronaut skeletal health. The current standards for bone are based upon areal bone mineral density (aBMD) measurements by dual X-ray absorptiometry (DXA) and an adaptation of aBMD cut-points for fragility fractures. Task Group members recommended (i) a minimum permissible outcome limit (POL) for post-mission hip bone load capacity, (ii) use of FE hip load capacity to further screen applicants to astronaut corps, (iii) a minimum pre-flight standard for a second long-duration mission, and (iv) a method for assessing which post-mission physical activities might increase an astronaut's risk for fracture after return. QCT-FE models of eight astronaut were analyzed using nonlinear single-limb stance (NLS) and posterolateral fall (NLF) loading configurations. QCT data from the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort and the Rochester Epidemiology Project were analyzed using identical modeling procedures. The 75th percentile of NLS hip load capacity for fractured elderly males of the AGES cohort (9537N) was selected as a post-mission POL. The NLF model, in combination with a Probabilistic Risk Assessment tool, was used to assess the likelihood of exceeding the hip load capacity during post-flight activities. There was no recommendation to replace the current DXA-based standards. However, FE estimation of hip load capacity appeared more meaningful for younger, physically active astronauts and was recommended to supplement aBMD cut-points.

Validity and reliability of an accelerometer-based player tracking device.

This study aimed to determine the intra- and inter-device accuracy and reliability of wearable athletic tracking devices, under controlled laboratory conditions. A total of nineteen portable accelerometers (Catapult OptimEye S5) were mounted to an aluminum bracket, bolted directly to an Unholtz Dickie 20K electrodynamic shaker table, and subjected to a series of oscillations in each of three orthogonal directions (front-back, side to side, and up-down), at four levels of peak acceleration (0.1g, 0.5g, 1.0g, and 3.0g), each repeated five times resulting in a total of 60 tests per unit, for a total of 1140 records. Data from each accelerometer was recorded at a sampling frequency of 100Hz. Peak accelerations recorded by the devices, Catapult PlayerLoad™, and calculated player load (using Catapult's Cartesian formula) were used for the analysis. The devices demonstrated excellent intradevice reliability and mixed interdevice reliability. Differences were found between devices for mean peak accelerations and PlayerLoad™ for each direction and level of acceleration. Interdevice effect sizes ranged from a mean of 0.54 (95% CI: 0.34-0.74) (small) to 1.20 (95% CI: 1.08-1.30) (large) and ICCs ranged from 0.77 (95% CI: 0.62-0.89) (very large) to 1.0 (95% CI: 0.99-1.0) (nearly perfect) depending upon the magnitude and direction of the applied motion. When compared to the player load determined using the Cartesian formula, the Catapult reported PlayerLoad™ was consistently lower by approximately 15%. These results emphasize the need for industry wide standards in reporting validity, reliability and the magnitude of measurement errors. It is recommended that device reliability and accuracy are periodically quantified.

Determination of sex differences of human cadaveric mandibular condyles using statistical shape and trait modeling.

The objective of this study was to elucidate sex differences in the anatomy of human temporomandibular joint mandibular condyles using a statistical shape and trait model (SSTM). Mandibles were obtained from 16 human cadavers (79±13years). The condyles were scanned using micro-computed tomography with 27µm resolution. An image processing algorithm was used to segment the bone, determine the border of the entire mandibular condyle and trabecular bone compartments, and create triangulated meshes of the compartments. One subject was chosen as the template and was registered to the other individuals using a coherence point drift algorithm. This process positioned all vertices at corresponding anatomic locations. For the trabecular bone region, around each vertex position, the average bone image intensity, which is proportional to bone density, and microstructural traits, including trabecular bone volume fraction, thickness, separation, connectivity, and connectivity density were calculated. For the entire mandibular condyle mesh, the surface vertices were extracted to represent the overall anatomy of the condyle. Using a SSTM, the shape and trait information was reduced to a small set of independent and uncorrelated variables for each individual. Wilcoxon rank sum tests were used to test for differences in the variables between sexes. A lasso approach was used to determine a set of variables that differentiate between sexes. Male condyles were on average larger than female condyles, with complex differences in the microstructural traits. Two out of 15 principal components were statistically different between males and females (p<0.1). The lasso approach determined a set of 7 principal components that fully described the complex shape and trait differences between males and females. A SSTM was able to determine sex-dependent differences in the shape of the mandibular condyle. These differences may alter the biomechanics of the joint and contribute to the development of temporomandibular joint disease.

Sex dependent mechanical properties of the human mandibular condyle.

The mandibular condyle consists of articular cartilage and subchondral bone that play an important role in bearing loads at the temporomandibular joint (TMJ) during static occlusion and dynamic mastication. The objective of the current study was to examine effects of sex and cartilage on 1) static and dynamic mechanical analysis (DMA) based dynamic energy storage and dissipation for the cartilage-subchondral bone construct of the human mandibular condyle, and 2) their correlations with the tissue mineral density and trabecular morphological parameters of subchondral bone. Cartilage-subchondral bone constructs were obtained from 16 individual human cadavers (9 males, 7 females, 79.00±13.10 years). After scanning with micro-computed tomography, the specimens were subjected to a non-destructive compressive static loading up to 7N and DMA using a cyclic loading profile (-5±2N at 2Hz). After removing the cartilage from the same specimen, the series of loading experiments were repeated. Static stiffness (K) and energy dissipation (W), and dynamic storage (K'), loss (K'') stiffness, and energy dissipation (tan δ) were assessed. Gray values, which are proportional to degree of bone mineralization, and trabecular morphological parameters of the subchondral bone were also measured. After removal of the cartilage, static energy dissipation significantly decreased (p<0.009) but dynamic energy dissipation was not influenced (p>0.064). Many subchondral bone properties were significantly correlated with the overall mechanical behavior of the cartilage-subchondral bone constructs for males (p<0.047) but not females (p>0.054). However, after removal of cartilage from the constructs, all of the significant correlations were no longer found (p>0.057). The current findings indicate that the subchondral bone is responsible for bearing static and dynamic loading in males but not in females. This result indicates that the female condyle may have a mechanically disadvantageous TMJ loading environment.

Finite Element Study of a Lumbar Intervertebral Disc Nucleus Replacement Device.

Nucleus replacement technologies are a minimally invasive alternative to spinal fusion and total disc replacement that have the potential to reduce pain and restore motion for patients with degenerative disc disease. Finite element modeling can be used to determine the biomechanics associated with nucleus replacement technologies. The current study focuses on a new nucleus replacement device designed as a conforming silicone implant with an internal void. A validated finite element model of the human lumbar L3-L4 motion segment was developed and used to investigate the influence of the nucleus replacement device on spine biomechanics. In addition, the effect of device design changes on biomechanics was determined. A 3D, L3-L4 finite element model was constructed from medical imaging data. Models were created with the normal intact nucleus, the nucleus replacement device, and a solid silicone implant. Probabilistic analysis was performed on the normal model to provide quantitative validation metrics. Sensitivity analysis was performed on the silicone Shore A durometer of the device. Models were loaded under axial compression followed by flexion/extension, lateral bending, or axial rotation. Compressive displacement, endplate stresses, reaction moment, and annulus stresses were determined and compared between the different models. The novel nucleus replacement device resulted in similar compressive displacement, endplate stress, and annulus stress and slightly higher reaction moment compared with the normal nucleus. The solid implant resulted in decreased displacement, increased endplate stress, decreased annulus stress, and decreased reaction moment compared with the novel device. With increasing silicone durometer, compressive displacement decreased, endplate stress increased, reaction moment increased, and annulus stress decreased. Finite element analysis was used to show that the novel nucleus replacement device results in similar biomechanics compared with the normal intact nucleus.

Development and validation of a statistical shape modeling-based finite element model of the cervical spine under low-level multiple direction loading conditions.

Cervical spinal injuries are a significant concern in all trauma injuries. Recent military conflicts have demonstrated the substantial risk of spinal injury for the modern warfighter. Finite element models used to investigate injury mechanisms often fail to examine the effects of variation in geometry or material properties on mechanical behavior. The goals of this study were to model geometric variation for a set of cervical spines, to extend this model to a parametric finite element model, and, as a first step, to validate the parametric model against experimental data for low-loading conditions. Individual finite element models were created using cervical spine (C3-T1) computed tomography data for five male cadavers. Statistical shape modeling (SSM) was used to generate a parametric finite element model incorporating variability of spine geometry, and soft-tissue material property variation was also included. The probabilistic loading response of the parametric model was determined under flexion-extension, axial rotation, and lateral bending and validated by comparison to experimental data. Based on qualitative and quantitative comparison of the experimental loading response and model simulations, we suggest that the model performs adequately under relatively low-level loading conditions in multiple loading directions. In conclusion, SSM methods coupled with finite element analyses within a probabilistic framework, along with the ability to statistically validate the overall model performance, provide innovative and important steps toward describing the differences in vertebral morphology, spinal curvature, and variation in material properties. We suggest that these methods, with additional investigation and validation under injurious loading conditions, will lead to understanding and mitigating the risks of injury in the spine and other musculoskeletal structures.

Fracture risk predictions based on statistical shape and density modeling of the proximal femur.

Increased risk of skeletal fractures due to bone mass loss is a major public health problem resulting in significant morbidity and mortality, particularly in the case of hip fractures. Current clinical methods based on two-dimensional measures of bone mineral density (areal BMD or aBMD) are often unable to identify individuals at risk of fracture. We investigated predictions of fracture risk based on statistical shape and density modeling (SSDM) methods using a case-cohort sample of individuals from the Osteoporotic Fractures in Men (MrOS) study. Baseline quantitative computed tomography (QCT) data of the right femur were obtained for 513 individuals, including 45 who fractured a hip during follow-up (mean 6.9 year observation, validated by physician review). QCT data were processed for 450 individuals (including 40 fracture cases) to develop individual models describing three-dimensional bone geometry and density distribution. Comparison of mean fracture and non-case models indicated complex structural differences that appear to be responsible for resistance to hip fracture. Logistic regressions were used to model the relation of baseline hip BMD and SSDM weighting factors to the occurrence of hip fracture. Area under the receiver operating characteristic (ROC) curve (AUC) for a prediction model based on weighting factors and adjusted by age was significantly greater than AUC for a prediction model based on aBMD and age (0.94 versus 0.83, respectively). The SSDM-based prediction model adjusted by age correctly identified 55% of the fracture cases (and 94.7% of the non-cases), whereas the clinical standard aBMD correctly identified 10% of the fracture cases (and 91.3% of the non-cases). SSDM identifies subtle changes in combinations of structural bone traits (eg, geometric and BMD distribution traits) that appear to indicate fracture risk. Investigation of important structural differences in the proximal femur between fracture and no-fracture cases may lead to improved prediction of those at risk for future hip fracture.

Platelet-derived growth-factor-releasing aligned collagen-nanoparticle fibers promote the proliferation and tenogenic differentiation of adipose-derived stem cells.

In order to enhance the healing potential of an injured tendon, we have prepared a novel biomimetic aligned collagen-nanoparticle (NP) composite fiber using an electrochemical process. The aligned collagen-NP composite fiber is designed to affect the cellular activity of adipose-derived stem cells (ADSCs) through two different ways: (i) topographic cues from the alignment of collagen fibril and (ii) controlled release of platelet-derived growth factors (PDGFs) from the NPs. PDGF released from collagen-NP fibers significantly enhanced the proliferation of ADSCs when tested for up to 7 days. Moreover, compared to random collagen fibers with PDGFs, aligned collagen-NP fibers significantly promoted the desirable tenogenic differentiation of ADSCs, as evidenced by an increased level of tendon markers such as tenomodulin and scleraxis. On the other hand, no undesirable osteogenic differentiation, as measured by the unchanged level of alkaline phosphatase and osteocalcin, was observed. Together, these results indicate that the aligned collagen-NP composite fiber induced the tenogenic differentiation of ADSCs through both a topographic cue (aligned collagen fibril) and a chemical cue (PDGF released from NPs). Thus, our novel aligned collagen-NP composite fiber has a significant potential to be used for tendon tissue engineering and regeneration.

Implementation and validation of probabilistic models of the anterior longitudinal ligament and posterior longitudinal ligament of the cervical spine.

The objective of this investigation was to develop probabilistic finite element (FE) models of the anterior longitudinal ligament (ALL) and posterior longitudinal ligament (PLL) of the cervical spine that incorporate the natural variability of biological specimens. In addition to the model development, a rigorous validation methodology was developed to quantify model performance. Experimental data for the geometry and dynamic properties of the ALL and PLL were used to create probabilistic FE models capable of predicting not only the mean dynamic relaxation response but also the observed experimental variation of that response. The probabilistic FE model uses a quasilinear viscoelastic material constitutive model to capture the time-dependent behaviour of the ligaments. The probabilistic analysis approach yields a statistical distribution for the model-predicted response at each time point rather than a single deterministic quantity (e.g. ligament force) and that response can be statistically compared to experimental data for validation. A quantitative metric that compares the cumulative distribution functions of the experimental data and model response is computed for both the ALL and PLL throughout the time histories and is used to quantify model performance.

Baboons as a model to study genetics and epigenetics of human disease.

A major challenge for understanding susceptibility to common human diseases is determining genetic and environmental factors that influence mechanisms underlying variation in disease-related traits. The most common diseases afflicting the US population are complex diseases that develop as a result of defects in multiple genetically controlled systems in response to environmental challenges. Unraveling the etiology of these diseases is exceedingly difficult because of the many genetic and environmental factors involved. Studies of complex disease genetics in humans are challenging because it is not possible to control pedigree structure and often not practical to control environmental conditions over an extended period of time. Furthermore, access to tissues relevant to many diseases from healthy individuals is quite limited. The baboon is a well-established research model for the study of a wide array of common complex diseases, including dyslipidemia, hypertension, obesity, and osteoporosis. It is possible to acquire tissues from healthy, genetically characterized baboons that have been exposed to defined environmental stimuli. In this review, we describe the genetic and physiologic similarity of baboons with humans, the ability and usefulness of controlling environment and breeding, and current genetic and genomic resources. We discuss studies on genetics of heart disease, obesity, diabetes, metabolic syndrome, hypertension, osteoporosis, osteoarthritis, and intrauterine growth restriction using the baboon as a model for human disease. We also summarize new studies and resources under development, providing examples of potential translational studies for targeted interventions and therapies for human disease.

Computational anatomy in the study of bone structure.

Osteoporosis is a major public health threat for millions of Americans with billions of dollars per year of national direct costs for osteoporotic fractures. Osteoporosis results in a decrease in overall bone mass and subsequent increase in the risk of bone fracture. Bone strength arises from the combination of bone size and shape, the distribution of bone mass throughout the structure, and the quality of the bone material. Advances in medical imaging have enabled a comprehensive assessment of bone structure through the analysis of high-resolution scans of relevant anatomical sites, eg, the proximal femur. However, conventional imaging analysis techniques use predefined regions of interest that do not take full advantage of such scans. Recently, computational anatomy, a set of imaging-based analysis algorithms, has emerged as a promising technique in studies of osteoporosis. Computational anatomy enables analyses that are not biased to one particular region and provide a more complete assessment of the whole structure. In this article, we review studies that have used computational anatomy to investigate the structure of the proximal femur in relation to age, fracture, osteoporotic treatment, and spaceflight effects.

Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee.

Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.

Addressing the gaps: sex differences in osteoarthritis of the knee.

An introduction to the accompanying three papers.