A bright μm-sized source of hard synchrotron x-rays (critical energy Ecrit > 30 keV) based on the betatron oscillations of laser wakefield accelerated electrons has been developed. The potential of this source for medical imaging was demonstrated by performing micro-computed tomography of a human femoral trabecular bone sample, allowing full 3D reconstruction to a resolution below 50 μm. The use of a 1 cm long wakefield accelerator means that the length of the beamline (excluding the laser) is dominated by the x-ray imaging distances rather than the electron acceleration distances. The source possesses high peak brightness, which allows each image to be recorded with a single exposure and reduces the time required for a full tomographic scan. These properties make this an interesting laboratory source for many tomographic imaging applications.

Osteoporosis is characterised by trabecular bone loss resulting from increased osteoclast activation and unbalanced coupling between resorption and formation, which induces a thinning of trabeculae and trabecular perforations. Bisphosphonates are the frontline therapy for osteoporosis, which act by reducing bone remodelling, and are thought to prevent perforations and maintain microstructure. However, bisphosphonates may oversuppress remodelling resulting in accumulation of microcracks. This paper aims to investigate the effect of bisphosphonate treatment on microstructure and mechanical strength. Assessment of microdamage within the trabecular bone core was performed using synchrotron X-ray micro-CT linked to image analysis software. Bone from bisphosphonate-treated fracture patients exhibited fewer perforations but more numerous and larger microcracks than both fracture and non-fracture controls. Furthermore, bisphosphonate-treated bone demonstrated reduced tensile strength and Young’s Modulus. These findings suggest that bisphosphonate therapy is effective at reducing perforations but may also cause microcrack accumulation, leading to a loss of microstructural integrity and consequently, reduced mechanical strength.

ObjectivesBisphosphonates (BP) are the first-line treatment for preventing fragility fractures. However, concern regarding their efficacy is growing because bisphosphonate is associated with over-suppression of remodelling and accumulation of microcracks. While dual-energy X-ray absorptiometry (DXA) scanning may show a gain in bone density, the impact of this class of drug on mechanical properties remains unclear. We therefore sought to quantify the mechanical strength of bone treated with BP (oral alendronate), and correlate data with the microarchitecture and density of microcracks in comparison with untreated controls.MethodsTrabecular bone from hip fracture patients treated with BP (n = 10) was compared with naïve fractured (n = 14) and non-fractured controls (n = 6). Trabecular cores were synchrotron scanned and micro-CT scanned for microstructural analysis, including quantification of bone volume fraction, microarchitecture and microcracks. The specimens were then mechanically tested in compression.ResultsBP bone was 28% lower in strength than untreated hip fracture bone, and 48% lower in strength than non-fractured control bone (4.6 MPa vs 6.4 MPa vs 8.9 MPa). BP-treated bone had 24% more microcracks than naïve fractured bone and 51% more than non-fractured control (8.12/cm2 vs 6.55/cm2 vs 5.25/cm2). BP and naïve fracture bone exhibited similar trabecular microarchitecture, with significantly lower bone volume fraction and connectivity than non-fractured controls.ConclusionBP therapy had no detectable mechanical benefit in the specimens examined. Instead, its use was associated with substantially reduced bone strength. This low strength may be due to the greater accumulation of microcracks and a lack of any discernible improvement in bone volume or microarchitecture. This preliminary study suggests that the clinical impact of BP-induced microcrack accumulation may be significant.Cite this article: A. Jin, J. Cobb, U. Hansen, R. Bhattacharya, C. Reinhard, N. Vo, R. Atwood, J. Li, A. Karunaratne, C. Wiles, R. Abel. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res 2017;6:602–609. DOI: 10.1302/2046-3758.610.BJR-2016-0321.R1.

Bone is a complex hierarchical structure, and its principal function is to resist mechanical forces and fracture. Bone strength depends not only on the quantity of bone tissue but also on the shape and hierarchical structure. The hierarchical levels are interrelated, especially the micro-architecture, collagen and mineral components; hence, analysis of their specific roles in bone strength and stiffness is difficult. Synchrotron imaging technologies including micro-CT and small/wide angle X-ray scattering/diffraction are becoming increasingly popular for studying bone because the images can resolve deformations in the micro-architecture and collagen–mineral matrix under in situ mechanical loading. Synchrotron cannot be directly applied in vivo due to the high radiation dose but will allow researchers to carry out systematic multifaceted studies of bone ex vivo. Identifying characteristics of aging and disease will underpin future efforts to generate novel devices and interventional therapies for assessing and promoting healthy aging. With our own research work as examples, this paper introduces how synchrotron imaging technology can be used with in situ testing in bone research.

IntroductionMeasuring the health of bone is important for understanding the pathogenesis, progression, diagnosis and treatment outcomes for fragility. At present the most common method for measuring bone health in a clinical setting is to assess skeletal mass. The current gold standard is dualenergy X-ray absorptiometry (DXA) which models bones as 2D objects and measures areal bone mineral density (BMD). However, BMD only accounts for 50% of bone strength and the technique ignores other important factors such as cortical geometry and trabecular architecture, which are also significant contributors. Consequently a new concept of 'bone quality' has developed the material and structural basis of bone strength and fragility. As yet though, a suitable non-invasive method has not been developed for measuring quality in living patients. The aim of this paper is to discuss how bone quality might be visualised, quantified and applied in a clinical setting. Discussion The most useful imaging techniques are likely to be clinical-CT and MRI. Both modalities have been used successfully to characterise bone macro-structure in 3D e.g. volume fraction and orientation. More recently in vivo systems with high

Abstract. A laser-wakefield driven x-ray source is used for the radiography of human bone. The betatron motion of accelerated electrons generates x-rays which are hard (critical energy E crit > 30 keV), have small source size (< 3µm) and high average brightness. The x-rays are generated from a helium gas cell which is near-instantly replenishable, and thus the average photon flux is limited by the repetition rate of the driving laser rather than the breakdown of the x-ray source. A tomograph of a human bone sample was recorded with a resolution down to 50 µm. The photon flux was sufficiently high that a radiograph could be taken with each laser shot, and the fact that x-ray beams were produced on 97% of shots minimised failed shots and facilitated full micro-computed tomography in a reasonable time scale of several hours, limited only by the laser repetition rate. The x-ray imaging beamline length (not including the laser) is shorter than that of a synchrotron source due to the high accelerating fields and small source size. Hence this interesting laboratory-based source may one day bridge the gap between small microfocus x-ray tubes and large synchrotron facilities.

Osteoporosis with resultant fractures is a major global health problem with huge socioeconomic implications for patients, families and healthcare services. Areal (2D bone mineral density (BMD) assessment is commonly used for predicting such fracture risk, but is unreliable, estimating only about 50% of bone strength. By contrast, computed tomography (CT) based techniques could provide improved metrics for estimating bone strength such as bone volume fraction (BVF; a 3D volumetric measure of mineralised bone), enabling cheap, safe and reliable strategies for clinical application, and to help divert resources to patients identified as most likely to benefit, meeting an unmet need. Here we describe a novel method for measuring BVF at clinical-CT like low-resolution (550µm voxel size). Femoral heads (n=8) were micro-CT scanned ex-vivo. Micro-CT data were downgraded in resolution from 30µm to 550µm voxel size and BVF calculated at high and low resolution. Experimental mechanical testing was applied to measure ex vivo bone strength of samples. BVF measures collected at high-resolution showed high correlation (correlation coefficient r 2 =0.95) with low-resolution data. Low-resolution BVF metrics showed high correlation (r 2 =0.96) with calculated sample strength. These results demonstrate that measuring BVF at low resolution is feasible, which also predicts bone strength. Measures of BVF should be useful for 214