Metacarpal cortical bone loss and osteoporotic fractures in the Coimbra Identified Skeletal Collection

There has been considerable progress in recent years in our understanding of the patterns of cortical bone loss in the second metacarpal in archeological skeletal samples. Nevertheless, cortical data from reference skeletal collections are insufficient, and the possible connection of metacarpal cortical parameters with osteoporotic fractures has not been thoroughly addressed. As such, this article aims to identify and explain sex-specific and age-associated metacarpal cortical bone loss in a large sample (N = 302females: 154/males: 148) from the Coimbra Identified Skeletal Collection. Another objective is to evaluate the association of cortical and demographic features with osteoporotic fractures. Age-related endocortical bone loss is significant in women but not evident in men. Periosteal accretion of the bone is absent in both sexes. Overall, there is a net loss of the cortical bone in women, whereas cortical bone strength seems to be preserved in men. The prevalence of osteoporotic fractures is similar in both sexes, with age at death significantly influencing the probability of exhibiting a fracture. Metacarpal cortical index does not seem to be an independent risk factor for osteoporotic fractures in this sample.Fundacao para a Ciencia e a TecnologiaPortuguese Foundation for Science and Technology [SFRH/BPD/74015/2010

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Validation of Finite Element models of the Mouse Tibia using Digital Volume Correlation

The mouse tibia is a common site to investigate bone adaptation. Micro-Finite Element (microFE) models based on micro-Computed Tomography (microCT) images can estimate bone mechanical properties non-invasively but their outputs need to be validated with experiments. Digital Volume Correlation (DVC) can provide experimental measurements of displacements over the whole bone volume. In this study we applied DVC to validate the local predictions of microFE models of the mouse tibia in compression. Six mouse tibiae were stepwise compressed within a microCT system. MicroCT images were acquired in four configurations with applied compression of 0.5 N (preload), 6.5 N, 13.0 N and 19.5 N. Failure load was measured after the last scan. A global DVC algorithm was applied to the microCT images in order to obtain the displacement field over the bone volume. Homogeneous, isotropic linear hexahedral microFE models were generated from the images collected in the preload configuration with boundary conditions interpolated from the DVC displacements at the extremities of the tibia. Experimental displacements from DVC and numerical predictions were compared at corresponding locations in the middle of the bone. Stiffness and strength were also estimated from each model and compared with the experimental measurements. The magnitude of the displacement vectors predicted by microFE models was highly correlated with experimental measurements (R2 >0.82). Higher but still reasonable errors were found for the Cartesian components. The models tended to overestimate local displacements in the longitudinal direction (R2 = 0.69–0.90, slope of the regression line=0.50–0.97). Errors in the prediction of structural mechanical properties were 14% ± 11% for stiffness and 9% ± 9% for strength. In conclusion, the DVC approach has been applied to the validation of microFE models of the mouse tibia. The predictions of the models for both structural and local properties have been found reasonable for most preclinical applications

Effect of repeated in vivo microCT imaging on the properties of the mouse tibia

In longitudinal studies, in vivo micro-Computed Tomography (microCT) imaging is used to investigate bone changes over time due to interventions in mice. However, ionising radiation can provoke significant variations in bone morphometric parameters. In a previous study, we evaluated the effect of reducing the integration time on the properties of the mouse tibia measured from microCT images. A scanning procedure (100 ms integration time, 256 mGy nominal radiation dose) was selected as the best compromise between image quality and radiation dose induced on the animal. In this work, the effect of repeated in vivo scans has been evaluated using the selected procedure. The right tibia of twelve female C57BL/6 (six wild type, WT, six ovariectomised, OVX) and twelve BALB/c (six WT, six OVX) mice was scanned every two weeks, starting at week 14 of age. At week 24, mice were sacrificed and both tibiae were scanned. Standard trabecular and cortical morphometric parameters were calculated. The spatial distribution of densitometric parameters (e.g. bone mineral content) was obtained by dividing each tibia in 40 partitions. Stiffness and strength in compression were estimated using homogeneous linear elastic microCT-based micro-Finite Element models. Differences between right (irradiated) and left (non-irradiated control) tibiae were evaluated for each parameter. The irradiated tibiae had higher Tb.Th (+3.3%) and Tb.Sp (+11.6%), and lower Tb.N (-14.2%) compared to non-irradiated tibiae, consistently across both strains and intervention groups. A reduction in Tb.BV/TV (-14.9%) was also observed in the C57BL/6 strain. In the OVX group, a small reduction was also observed in Tt.Ar (-5.0%). In conclusion, repeated microCT scans (at 256 mGy, 5 scans, every two weeks) had limited effects on the mouse tibia, compared to the expected changes induced by bone treatments. Therefore, the selected scanning protocol is acceptable for measuring the effect of bone interventions in vivo

Non-invasive prediction of the mouse tibia mechanical properties from microCT images: comparison between different finite element models

New treatments for bone diseases require testing in animal models before clinical translation, and the mouse tibia is among the most common models. In vivo micro-Computed Tomography (microCT)-based micro-Finite Element (microFE) models can be used for predicting the bone strength non-invasively, after proper validation against experimental data. Different modelling techniques can be used to estimate the bone properties, and the accuracy associated with each is unclear. The aim of this study was to evaluate the ability of different microCT-based microFE models to predict the mechanical properties of the mouse tibia under compressive load. Twenty tibiae were microCT scanned at 10.4 µm voxel size and subsequently compressed at 0.03 mm/s until failure. Stiffness and failure load were measured from the load–displacement curves. Different microFE models were generated from each microCT image, with hexahedral or tetrahedral mesh, and homogeneous or heterogeneous material properties. Prediction accuracy was comparable among models. The best correlations between experimental and predicted mechanical properties, as well as lower errors, were obtained for hexahedral models with homogeneous material properties. Experimental stiffness and predicted stiffness were reasonably well correlated (R2 = 0.53–0.65, average error of 13–17%). A lower correlation was found for failure load (R2 = 0.21–0.48, average error of 9–15%). Experimental and predicted mechanical properties normalized by the total bone mass were strongly correlated (R2 = 0.75–0.80 for stiffness, R2 = 0.55–0.81 for failure load). In conclusion, hexahedral models with homogeneous material properties based on in vivo microCT images were shown to best predict the mechanical properties of the mouse tibia

Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children

BACKGROUND Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. METHODS We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. RESULTS The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture–confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. CONCLUSIONS Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture–confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426