Higher fracture prevalence and smaller bone size in patients with hEDS/HSD-a prospective cohort study

Increased fracture risk in patients with Ehlers-Danlos syndromes has been reported, but the reasons for it are incompletely understood. We aimed to investigate possible determinants of this increased risk and found that hEDS/HSD patients present with a cortical bone size deficit compared with control subjects, possibly related to lower mechanical loading. Introduction The Ehlers-Danlos syndromes (EDS) comprise a group of heritable connective tissue disorders caused by defects in the biosynthesis, secretion, and/or organization of fibrillar collagens which might impair bone strength. Our aim was to compare fracture prevalence, volumetric and areal bone mineral density (BMD), bone geometry, muscle size and the muscle-bone interaction, body composition and longitudinal changes therein between patients with hypermobile EDS (hEDS) or hypermobility spectrum disorder (HSD), and healthy control subjects. Methods Cross-sectional data comprised 39 female hEDS/HSD patients (age 41 +/- 11 years) and 43 age-matched controls. After 8 years, 27 hEDS/HSD and 17 control subjects were re-evaluated. Tibial trabecular and cortical volumetric BMD, bone mineral content (BMC), cortical bone geometry, and lower leg muscle cross-sectional area (CSA) were measured using pQCT. Body composition, areal BMD, and BMC were determined by DXA. Results At baseline, patients with hEDS/HSD presented with a smaller cortical bone area, smaller cortical thickness and muscle CSA, and a higher fracture prevalence than control subjects (all p < 0.05). No differences in areal or volumetric BMD were found. Longitudinally, muscle CSA decreased in both groups and muscle density decreased in the hEDS/HSD group (p < 0.001) whereas all bone parameters remained unchanged. Conclusion hEDS/HSD patients have a cortical bone size deficit compared with controls, possibly contributing to their increased fracture risk. They presented with decreased muscle CSA but normal bone/muscle area ratio, suggesting that this bone size deficit is likely secondary to decreased mechanical loading. Further, there were no arguments for accelerated bone loss in hEDS/HSD subjects

Endocortical bone loss in osteoporosis: The role of bone surface availability

Age-related bone loss and postmenopausal osteoporosis are disorders of bone remodelling, in which less bone is reformed than resorbed. Yet, this dysregulation of bone remodelling does not occur equally in all bone regions. Loss of bone is more pronounced near and at the endocortex, leading to cortical wall thinning and medullary cavity expansion, a process sometimes referred to as "trabecularisation" or "cancellisation". Cortical wall thinning is of primary concern in osteoporosis due to the strong deterioration of bone mechanical properties that it is associated with. In this paper, we examine the possibility that the non-uniformity of microscopic bone surface availability could explain the non-uniformity of bone loss in osteoporosis. We use a computational model of bone remodelling in which microscopic bone surface availability influences bone turnover rate and simulate the evolution of the bone volume fraction profile across the midshaft of a long bone. We find that bone loss is accelerated near the endocortical wall where the specific surface is highest. Over time, this leads to a substantial reduction of cortical wall thickness from the endosteum. The associated expansion of the medullary cavity can be made to match experimentally observed cross-sectional data from the Melbourne Femur Collection. Finally, we calculate the redistribution of the mechanical stresses in this evolving bone structure and show that mechanical load becomes critically transferred to the periosteal cortical bone.Comment: 13 pages, 3 figures. V2: minor stylistic improvements in text/figures; more accurately referenced subsection "Internal mechanical stress distribution"; some improved remarks in the Discussion sectio

Regional diversity in the murine cortical vascular network is revealed by synchrotron X-ray tomography and is amplified with age

Cortical bone is permeated by a system of pores, occupied by the blood supply and osteocytes. With ageing, bone mass reduction and disruption of the microstructure are associated with reduced vascular supply. Insight into the regulation of the blood supply to the bone could enhance the understanding of bone strength determinants and fracture healing. Using synchrotron radiation-based computed tomography, the distribution of vascular canals and osteocyte lacunae was assessed in murine cortical bone and the influence of age on these parameters was investigated. The tibiofibular junction from 15-week- and 10-month-old female C57BL/6J mice were imaged post-mortem. Vascular canals and three-dimensional spatial relationships between osteocyte lacunae and bone surfaces were computed for both age groups. At 15 weeks, the posterior region of the tibiofibular junction had a higher vascular canal volume density than the anterior, lateral and medial regions. Intracortical vascular networks in anterior and posterior regions were also different, with connectedness in the posterior higher than the anterior at 15 weeks. By 10 months, cortices were thinner, with cortical area fraction and vascular density reduced, but only in the posterior cortex. This provided the first evidence of age-related effects on murine bone porosity due to the location of the intracortical vasculature. Targeting the vasculature to modulate bone porosity could provide an effective way to treat degenerative bone diseases, such as osteoporosis

3D Micron-scale Imaging of the Cortical Bone Canal Network in Human Osteogenesis Imperfecta (OI)

Osteogenesis imperfecta (OI) is a genetic disorder leading to increased bone fragility. Recent work has shown that the hierarchical structure of bone plays an important role in determining its mechanical properties and resistance to fracture. The current study represents one of the first attempts to characterize the 3D structure and composition of cortical bone in OI at the micron-scale. A total of 26 pediatric bone fragments from 18 individuals were collected during autopsy (Nc=5) or routing orthopaedic procedures (NOI=13) and imaged by microtomography with a synchrotron light source (SRµCT) for several microstructural parameters including cortical porosity (Ca.V/TV), canal surface to tissue volume (Ca.S/TV), canal diameter (Ca.Dm), canal separation (Ca.Sp), canal connectivity density (Ca.ConnD), and volumetric tissue mineral density (TMD). Results indicated significant differences in all imaging parameters between pediatric controls and OI tissue, with OI bone showing drastically increased cortical porosity, canal diameter, and connectivity. Preliminary mechanical testing revealed a possible link between cortical porosity and strength. Together these results suggest that the pore network in OI contributes greatly to its reduced mechanical properties

Excessive growth hormone expression in male GH transgenic mice adversely alters bone architecture and mechanical strength

Patients with acromegaly have a higher prevalence of vertebral fractures despite normal bone mineral density (BMD), suggesting that GH overexpression has adverse effects on skeletal architecture and strength. We used giant bovine GH (bGH) transgenic mice to analyze the effects of high serum GH levels on BMD, architecture, and mechanical strength. Five-month-old hemizygous male bGH mice were compared with age- and sex-matched nontransgenic littermates controls (NT; n=16/group). Bone architecture and BMD were analyzed in tibia and lumbar vertebrae using microcomputed tomography. Femora were tested to failure using three-point bending and bone cellular activity determined by bone histomorphometry. bGH transgenic mice displayed significant increases in body weight and bone lengths. bGH tibia showed decreases in trabecular bone volume fraction, thickness, and number compared with NT ones, whereas trabecular pattern factor and structure model index were significantly increased, indicating deterioration in bone structure. Although cortical tissue perimeter was increased in transgenic mice, cortical thickness was reduced. bGH mice showed similar trabecular BMD but reduced trabecular thickness in lumbar vertebra relative to controls. Cortical BMD and thickness were significantly reduced in bGH lumbar vertebra. Mechanical testing of femora confirmed that bGH femora have decreased intrinsic mechanical properties compared with NT ones. Bone turnover is increased in favor of bone resorption in bGH tibia and vertebra compared with controls, and serum PTH levels is also enhanced in bGH mice. These data collectively suggest that high serum GH levels negatively affect bone architecture and quality at multiple skeletal sites

In vivo assessment of the mechanical properties of the child cortical bone using quantitative computed tomography

The mechanical properties of the rib cortical bone are extremely rare on children due to difficulties to obtain specimens to perform conventional tests. Some recent studies used cadaveric bones or bone tissues collected during surgery but are limited by the number of samples that could be collected. A non-invasive technique could be extremely valuable to overcome this limitation. It has been shown that a relationship exists between the mechanical properties (apparent Young’s modulus and ultimate strength) and the bone mineral density (assessed using Quantitative Computed Tomography, QCT), for the femur and recently by our group for the adult ribs ex vivo. Thus the aim of this study was to assess the mechanical properties of the child rib cortical bone using both QCT images in vivo and the previous relationship between bone mineral density and mechanical properties of the rib cortical bone. Twenty-eight children were included in this study. Seven age-groups have been considered (1, 1.5, 3, 6, 10, 15, 18 years old). The QCT images were prescribed for various thoracic pathologies at the pediatric hospital in Lyon. A calibration phantom was added to the clinical protocol without any modifications for the patient. The protocol was approved by the ethical committee. A 3D reconstruction of each thorax was performed using the QCT images. A custom software was then used to obtain cross-sections to the rib midline. The mean bone mineral density was then computed by averaging the Hounsfield Units in a specific cross-section and by converting the mean value (Hounsfield Units) in bone mineral density using the calibration phantom. This bone mineral density was assessed for the 6th rib of each subject. Our relationship between the bone mineral density and the mechanical properties of the rib cortical bone was used to derive the mechanical properties of the child ribs in vivo. The results give values for the apparent Young’s modulus and the ultimate strength. The mechanical properties increase along growth. As an example the apparent Young’s modulus in the lateral region ranges from 7 GPa +/-3 at 1 year old up to 13 GPa +/- 2 at 18 years old. These data are in agreement with the few previous values obtained from child tissues. This methodology opens the way to in vivo measurement of the mechanical properties of the child cortical bone based on calibrated QCT images

Identification of anisotropic tensile strength of cortical bone using Brazilian test.

For a proper analysis of cortical bone behaviour, it is essential to take into account both the elastic stiffness and the failure criteria. While ultrasound methods allow complete identification of the elastic orthotropic coefficients, tests used to characterise the various failure mechanisms and to identify the brittle tensile strength in all directions are currently inadequate. In the present work we propose the Brazilian test as a complement to conventional tensile tests. In fact, this experimental technique, rarely employed in the biomechanics field, has the potential to provide an accurate description of the anisotropic strength of cortical bone. Additionally, it allows us to assess the scale influence on failure behaviour which may be attributed to an intrinsic length in correlation with the cortical bone microstructure. In order to correctly set up the Brazilian test, several aspects such as the machining, the geometrical parameters of the specimen and the loading conditions were determined. The finite element method was used to evaluate the maximal tensile stress at the centre of a 2D anisotropic elastic specimen as a simple function of the loading. To validate the protocol, the Brazilian test was carried out on 29 cortical bovine cylindrical specimens with diameters ranging from 10mm to 4mm

The effect of advanced glycation endproduct accumulation on bone

Diabetes is associated with increased fracture risk, which leads to increased morbidity and eventual mortality with a substantial financial burden. Type 2 Diabetics also have increased fracture risk, despite having the same or higher BMD as non-diabetics with a low fracture risk. One hypothesis for this is increased modifications made to the extra-cellular matrix via non-enzymatic glycation (NEG) that can occur in a hyperglycemic environment, such as with diabetes. The accumulation of NEG products, known as advanced glycation endproducts (AGEs) can possibly lead to microdamage and eventual weakening of the bone itself. We developed a time-response model in order to induce a wide range of AGEs in a manner that would sustain the mineral integrity of the bone and could be applied to a variety of bone sample types. This was performed on 65 rat tibias, distributed amongst 8 groups (3,7,10, & 14 days) for both ribose and control. Secondly, the protocol was performed on human cortical beam samples cut from 10 donor tibias with 3,5 and 7 day time points for ribose and control groups. All samples were incubated in a 0.6 M ribose solution or 0.0 M ribose control solution. There was a 7, 4, and 5-fold increase in AGEs at the 7, 10, and 14 day time points respectively over controls in the rat tibia study. There was no significant variation in cortical porosity, however TTMD was significantly less dense in the 14-day ribose treated groups. There was a trend toward higher AGEs with time in the human cortical beam specimens, but no significant increase. The AGEs values in the human cortical beam specimens were much lower than expected based on previous trials and reports in the literature. We were able to establish a time-response model for AGE accumulation in bone. However, the effects of AGEs on bone material properties remains inconclusive

Analysis of locking self-taping bone screws for angularly stable plates

Paper focuses on biomechanics, specifically on locking cortical bone screws in angularly stable plates used for the treatment of bone fractures in the medical fields of traumatology and orthopaedics. During extraction of titanium-alloy implants, problems are encountered in an effort to loosen some locking bone screws from the locking holes of an angularly stable plate and the subsequent stripping of the internal hexagon of the screw head. The self-locking of the screw-plate threaded joint was verified by calculation and the effect of the angle of the thread on the head of the locking cortical bone screw on self-locking was evaluated. The magnitude of the torque, causing the stripping of the internal hexagon (the Inbus type head) of a locking cortical bone screw with a shank diameter of 3.5 mm from Ti6Al4 V titanium alloy to ISO 5832-3, was determined experimentally. Also, it was experimentally found that the rotation of the screwdriver end with a hexagonal tip inside the locking cortical bone screw head during stripping of the internal hexagon causes strain of the screw head perimeter and thereby an increase of thread friction. The effect of tightening torque on the possibility of loosening of the locking cortical bone screw from the locking hole of an angularly stable plate was assessed experimentally. From the evaluation of five alternative shapes of locking cortical bone screw heads in terms of the acting stress and generated strains, it follows that the best screw is the screw with the Torx type head, which demonstrates the lowest values of reduced stress and equivalent plastic strain. Based on experiments and simulations the authors recommend that all global producers of locking cortical bone screws for locking holes of angularly stable plates use the Torx type heads, and not heads of the Inbus type or the Square, PH, PZ types.Web of Science37462561

Predicting cortical bone adaptation to axial loading in the mouse tibia

The development of predictive mathematical models can contribute to a deeper understanding of the specific stages of bone mechanobiology and the process by which bone adapts to mechanical forces. The objective of this work was to predict, with spatial accuracy, cortical bone adaptation to mechanical load, in order to better understand the mechanical cues that might be driving adaptation. The axial tibial loading model was used to trigger cortical bone adaptation in C57BL/6 mice and provide relevant biological and biomechanical information. A method for mapping cortical thickness in the mouse tibia diaphysis was developed, allowing for a thorough spatial description of where bone adaptation occurs. Poroelastic finite-element (FE) models were used to determine the structural response of the tibia upon axial loading and interstitial fluid velocity as the mechanical stimulus. FE models were coupled with mechanobiological governing equations, which accounted for non-static loads and assumed that bone responds instantly to local mechanical cues in an on–off manner. The presented formulation was able to simulate the areas of adaptation and accurately reproduce the distributions of cortical thickening observed in the experimental data with a statistically significant positive correlation (Kendall's τ rank coefficient τ = 0.51, p < 0.001). This work demonstrates that computational models can spatially predict cortical bone mechanoadaptation to a time variant stimulus. Such models could be used in the design of more efficient loading protocols and drug therapies that target the relevant physiological mechanisms