Heterogenous bone response to biologic DMARD therapies in rheumatoid arthritis patients and their relationship to functional indices.

Objectives: Previous studies of high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging of hand joints in patients with rheumatoid arthritis (RA) have suggested that erosion healing may occur. Our objective was to examine changes in erosion volume, joint space width (JSW), bone mineral density (BMD), and bone remodelling, and their association with clinical outcomes and measures of patient hand function.Method: We examined 48 patients who achieved a good response to a newly initiated biologic therapy. HR-pQCT images of the dominant hands' second and third metacarpophalangeal joints were obtained 3 and 12 months after therapy initiation. Bone erosion volume, JSW, BMD, and bone remodelling were quantified from HR-pQCT images, with improvement, no change (unchanged), or progression in these measures determined by least significant change. Disease activity and hand function measures were collected.Results: There were no significant group changes in HR-pQCT outcomes over the 9 month period. Twenty-two patients had total erosion volumes that remained unchanged, nine showed improvement, and two progressed. The majority of JSW and BMD measures remained unchanged. There was a significant association between the baseline Health Assessment Questionnaire score and the change in minimum JSW, but no other significant associations between HR-pQCT outcomes and function were observed.Conclusions: The vast majority of patients maintained unchanged JSW and BMD over the course of follow-up. Significant improvements in total erosion volume occurred in 27% of patients, suggesting that biologic therapies may lead to erosion healing in some patients, although this did not have an impact on self-reported and demonstrated hand function.

Opportunistic CT screening predicts individuals at risk of major osteoporotic fracture.

Millions of CT scans are performed annually and could be also used to opportunistically assess musculoskeletal health; however, it is unknown how well this secondary assessment relates to osteoporotic fracture. This study demonstrates that opportunistic CT screening is a promising tool to predict individuals with previous osteoporotic fracture. INTRODUCTION: Opportunistic computed tomography (oCT) screening for osteoporosis and fracture risk determination complements current dual X-ray absorptiometry (DXA) diagnosis. This study determined major osteoporotic fracture prediction by oCT at the spine and hip from abdominal CT scans. METHODS: Initial 1158 clinical abdominal CT scans were identified from administrative databases and were the basis to generate a cohort of 490 men and women with suitable abdominal CT scans. Participant CT scans met the following criteria: over 50 years of age, the scan had no image artifacts, and the field-of-view included the L4 vertebra and proximal femur. A total of 123 participants were identified as having previously suffered a fracture within 5 years of CT scan date. Fracture cause was identified from clinical data and used to create a low-energy fracture sub-cohort. At each skeletal site, bone mineral density (BMD) and finite element (FE)-estimated bone strength were determined. Logistic regression predicted fracture and receiver-operator characteristic curves analyzed prediction capabilities. RESULTS: In participants with a fracture, low-energy fractures occurred in 88% of women and 79% of men. Fracture prediction by combining both BMD and FE-estimated bone strength was not statistically different than using either BMD or FE-estimated bone strength alone. Predicting low-energy fractures in women determined the greatest AUC of 0.710 by using both BMD and FE-estimated bone strength. CONCLUSIONS: oCT screening using abdominal CT scans is effective at predicting individuals with previous fracture at major osteoporotic sites and offers a promising screening tool for skeletal health assessment.

Using 3D image registration to maximize the reproducibility of longitudinal bone strength assessment by HR-pQCT and finite element analysis.

We developed and validated a finite element (FE) approach for longitudinal high-resolution peripheral quantitative computed tomography (HR-pQCT) studies using 3D image registration to account for misalignment between images. This reduced variability in longitudinal FE estimates and improved our ability to measure in vivo changes in HR-pQCT studies of bone strength. INTRODUCTION: We developed and validated a finite element (FE) approach for longitudinal high-resolution peripheral quantitative computed tomography (HR-pQCT) studies using 3D rigid-body registration (3DR) to maximize reproducibility by accounting for misalignment between images. METHODS: In our proposed approach, we used the full common bone volume defined by 3DR to estimate standard FE parameters. Using standard HR-pQCT imaging protocols, we validated the 3DR approach with ex vivo samples of the distal radius (n = 10, four repeat scans) by assessing whether 3DR can reduce measurement variability from repositioning error. We used in vivo data (n = 40, five longitudinal scans) to assess the sensitivity of 3DR to detect changes in bone strength at the distal radius by the standard deviation of the rate of change (σ), where the ideal value of σ is minimized to define true change. FE estimates by 3DR were compared to estimates by no registration (NR) and slice-matching (SM). RESULTS: Group-wise comparisons of ex vivo variation (CVRMS, %) found that FE measurement precision was improved by SM (CVRMS < 0.80%) and 3DR (CVRMS < 0.62%) compared to NR (CVRMS~2%), and 3DR was advantageous as repositioning error increased. Longitudinal in vivo reproducibility was minimized by 3DR for failure load estimates (σ = 0.008 kN/month). CONCLUSION: Although 3D registration cannot negate motion artifacts, it plays an important role in detecting and reducing variability in FE estimates for longitudinal HR-pQCT data and is well suited for estimating effects of interventions in in vivo longitudinal studies of bone strength.

Differences in fracture prevalence and in bone mineral density between Chinese and White Canadians: the Canadian Multicentre Osteoporosis Study (CaMos).

Fracture determinants differ between Canadians of Chinese and White descent, the former constituting the second largest visible minority group in Canada. The results of this study support the importance of characterizing bone health predictors in Canadians of different ethnicity to improve population-specific fracture prevention and treatment strategies. PURPOSE: We aimed to compare clinical risk factors, bone mineral density, prevalence of osteoporosis, and fractures between Chinese and White Canadians to identify ethnicity-specific risks. METHODS: We studied 236 Chinese and 8945 White Canadians aged 25+ years from the Canadian Multicentre Osteoporosis Study (CaMos). The prevalence of osteoporosis using ethnicity-specific peak bone mass (PBM), and of prior and incident low trauma fractures were assessed and compared between groups. Linear regressions, adjusting for age and anthropometric measures, were used to examine the association between baseline and 5-year changes in BMD and ethnicity. RESULTS: Chinese participants had shorter stature, lower BMI, and lower rate of falls than White participants. Adjusted models showed no significant differences in baseline BMD between ethnic groups except in younger men where total hip BMD was 0.059 g/cm2 (0.009; 0.108) lower in Chinese. Adjusted 5-year BMD change at lumbar spine was higher in older Chinese women and men compared with Whites. When using Chinese-specific PBM, the prevalence of osteoporosis in Chinese women was 2-fold lower than when using that of White women The prevalence of fractures was higher in White women compared with Chinese with differences up to 14.5% (95% CI 9.2; 19.7) and 10.5% (95% CI 4.5-16.4) in older White men. Incident fractures were rare in young Chinese compared with White participants and not different in the older groups. CONCLUSION: Our results support the importance of characterizing bone strength predictors in Chinese Canadians and the development of ethnicity-specific fracture prediction and prevention strategies.

Effect of high-dose vitamin D supplementation on peripheral arterial calcification: secondary analysis of a randomized controlled trial.

Although high-dose vitamin D supplementation is common, effects on arterial calcification remain unexplored. Tibial artery calcification was identified and quantified over 3 years in participants randomized to 400, 4000, or 10,000 IU vitamin D3 daily. High-dose vitamin D supplementation did not affect the development or progression of arterial calcification. INTRODUCTION: To determine whether vitamin D supplementation has a dose-dependent effect on development and progression of arterial calcification. METHODS: This was a secondary analysis of the Calgary Vitamin D Study, a 3-year, double-blind, randomized controlled trial conducted at a single-center in Calgary, Canada. Participants were community-dwelling adults aged 55-70 years with serum 25-hydroxyvitamin D 30-125 nmol/L. Participants were randomized 1:1:1 to receive vitamin D3 400, 4000, or 10,000 IU/day for 3 years. Tibial artery calcification was identified and quantified (in milligrams of hydroxyapatite, mgHA) using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6, 12, 24, and 36 months. Changes in calcification over time and treatment group interaction were evaluated using a constrained linear mixed effects model. RESULTS: Of 311 randomized participants, 302 (400: 105, 4000: 96, 10,000: 101) were eligible for analysis of arterial calcification (54% male, mean (SD) age 62 (4) years, mean (SD) 25-hydroxyvitamin D 78.9 (19.9) nmol/L). At baseline, 85 (28%) had tibial artery calcification, and mean (95% CI) calcification quantity was 2.8 mgHA (95% CI 1.7-3.9). In these 85 participants, calcification quantity increased linearly by 0.020 mgHA/month (95% CI 0.012-0.029) throughout the study, with no evidence of a treatment-group effect (p = 0.645 for interaction). No participants developed new arterial calcifications during the study. CONCLUSIONS: In this population of community-dwelling adults who were vitamin D replete at baseline, supplementation with vitamin D 400, 4000, or 10,000 IU/day did not have differential effects on the development or progression of arterial calcification over 3 years. TRIAL REGISTRATION: clinicaltrials.gov (NCT01900860).

Longitudinal bone microarchitectural changes are best detected using image registration.

Longitudinal studies of bone using high-resolution medical imaging may result in non-physiological measurements of longitudinal changes. In this study, we determined that three-dimensional image processing techniques best capture realistic longitudinal changes in bone density and should therefore be used with high-resolution imaging when studying bone changes over time. INTRODUCTION: The purpose of this study was to determine which longitudinal analysis technique (no registration (NR), slice-match (SM) registration, or three-dimensional registration (3DR)) produced the most realistic longitudinal changes in a 3-year study of bone density and structure using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: We assessed HR-pQCT scans of the distal radius and tibia for men and women (N = 40) aged 55-70 years at baseline and 6, 12, 24, and 36 months. To evaluate which longitudinal analysis technique (NR, SM, or 3DR) best captured physiologically reasonable 3-year changes, we calculated the standard deviation of the absolute rate of change in each bone parameter. The data were compared between longitudinal analysis techniques using repeated measures ANOVA and post hoc analysis. RESULTS: As expected, both SM and 3DR better captured physiological longitudinal changes than NR. At the tibia, there were no differences between SM and 3DR; however, at the radius where precision was lower, 3DR produced better results for total bone mineral density. CONCLUSIONS: At least SM or 3DR should be implemented in longitudinal studies using HR-pQCT. 3DR is preferable, particularly at the radius, to ensure that physiological changes in bone density are observed.

Guidelines for the assessment of bone density and microarchitecture in vivo using high-resolution peripheral quantitative computed tomography.

INTRODUCTION: The application of high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess bone microarchitecture has grown rapidly since its introduction in 2005. As the use of HR-pQCT for clinical research continues to grow, there is an urgent need to form a consensus on imaging and analysis methodologies so that studies can be appropriately compared. In addition, with the recent introduction of the second-generation HrpQCT, which differs from the first-generation HR-pQCT in scan region, resolution, and morphological measurement techniques, there is a need for guidelines on appropriate reporting of results and considerations as the field adopts newer systems. METHODS: A joint working group between the International Osteoporosis Foundation, American Society of Bone and Mineral Research, and European Calcified Tissue Society convened in person and by teleconference over several years to produce the guidelines and recommendations presented in this document. RESULTS: An overview and discussion is provided for (1) standardized protocol for imaging distal radius and tibia sites using HR-pQCT, with the importance of quality control and operator training discussed; (2) standardized terminology and recommendations on reporting results; (3) factors influencing accuracy and precision error, with considerations for longitudinal and multi-center study designs; and finally (4) comparison between scanner generations and other high-resolution CT systems. CONCLUSION: This article addresses the need for standardization of HR-pQCT imaging techniques and terminology, provides guidance on interpretation and reporting of results, and discusses unresolved issues in the field.

Optimizing HR-pQCT workflow: a comparison of bias and precision error for quantitative bone analysis.

Manual correction of automatically generated contours for high-resolution peripheral quantitative computed tomography can be time consuming and introduces precision error. However, bias related to the automated protocol is unknown. This study provides insight into error bias that is present when using uncorrected contours and inter-operator precision error based on operator training. INTRODUCTION: High-resolution peripheral quantitative computed tomography workflow includes manually correcting contours generated by the manufacturer's automated protocol. There is interest in minimizing corrections to save time and reduce precision error; however, bias related to the automated protocol is unknown. This study quantifies error bias when contours are uncorrected and identifies the impact of operator training on bias and precision error. METHODS: Forty-five radii and tibiae scans across a representative range of bone density were analyzed using the automated and manually corrected contours of three operators, with training ranging from beginner to expert, and compared with a "ground truth" to estimate bias. Inter-operator precision was measured across operators. RESULTS: The tibia had greater error bias than the radius when contours were uncorrected, with compartmental bone mineral densities and cortical microarchitecture having greatest biases, which could have significant implications for interpretation of studies using this skeletal site. Bias and precision error were greatest when contours were corrected by the beginner operator; however, when this operator was removed, bias was no longer present and inter-operator precision was between 0.01 and 3.74% for all parameters except cortical porosity. CONCLUSION: These findings establish the need for manual correction and provide guidance on operator training needed to maximize workflow efficiency.

An automated algorithm for the detection of cortical interruptions and its underlying loss of trabecular bone; a reproducibility study.

BACKGROUND: We developed a semi-automated algorithm that detects cortical interruptions in finger joints using high-resolution peripheral quantitative computed tomography (HR-pQCT), and extended it with trabecular void volume measurement. In this study we tested the reproducibility of the algorithm using scan/re-scan data. METHODS: Second and third metacarpophalangeal joints of 21 subjects (mean age 49 (SD 11) years, 17 early rheumatoid arthritis and 4 undifferentiated arthritis, all diagnosed < 1 year ago) were imaged twice by HR-pQCT on the same day with repositioning between scans. The images were analyzed twice by one operator (OP1) and once by an additional operator (OP2), who independently corrected the bone contours when necessary. The number, surface and volume of interruptions per joint were obtained. Intra- and inter-operator reliability and intra-operator reproducibility were determined by intra-class correlation coefficients (ICC). Intra-operator reproducibility errors were determined as the least significant change (LSCSD). RESULTS: Per joint, the mean number of interruptions was 3.1 (SD 3.6), mean interruption surface 4.2 (SD 7.2) mm2, and mean interruption volume 3.5 (SD 10.6) mm3 for OP1. Intra- and inter-operator reliability was excellent for the cortical interruption parameters (ICC ≥0.91), except good for the inter-operator reliability of the interruption surface (ICC = 0.70). The LSCSD per joint was 4.2 for the number of interruptions, 5.8 mm2 for interruption surface, and 3.2 mm3 for interruption volume. CONCLUSIONS: The algorithm was highly reproducible in the detection of cortical interruptions and their volume. Based on the LSC findings, the potential value of this algorithm for monitoring structural damage in the joints in early arthritis patients needs to be tested in clinical studies.

Differences in subchondral bone plate and cartilage thickness between women with anterior cruciate ligament reconstructions and uninjured controls.

OBJECTIVE: Anterior cruciate ligament (ACL) tears increase early onset osteoarthritis (OA) risk leading to cartilage and bone degradation. While the contribution of bone in OA development is unclear, evidence suggests that bone changes accompany cartilage degradation. This study aims to assess if regions with differences in subchondral bone plate thickness have differences in cartilage thickness when comparing ACL reconstructed (ACLR) knees of women ≥5 years post-injury to contralateral and controls with uninjured knees. DESIGN: Magnetic resonance imaging (MRI) assessed cartilage and high resolution peripheral quantitative computed tomography (HR-pQCT) assessed subchondral bone in both knees. Multimodal 3D image registration aligned anatomy. Maps of the spatial distribution of thickness on the articular surfaces were generated to compare women with ACL reconstructions to contralateral and controls with uninjured knees. RESULTS: ACLR knees had a thicker subchondral bone plate in the posterior and central lateral femur compared to contralateral knees (10.4% and 4.2% thicker, P = 0.032 and 0.032, W = 108 and 107, respectively) and in the posterior lateral femur compared to control knees (17.1% thicker, P = 0.014, W = 177). Cartilage differences were not detected (P > 0.05) in these regions. CONCLUSIONS: This study demonstrates that subchondral bone plate thickness differences are prominent following knee injury, as measured by HR-pQCT, but no statistically significant differences in cartilage morphology, measured by MRI, were found between ACLR knees compared to contralateral and control knees. These data provide novel insight into post-traumatic knee injuries that may be signs of early OA pathogenesis.

Cortical porosity exhibits accelerated rate of change in peri- compared with post-menopausal women.

The rate of change in bone density was not different between peri- and post-menopausal women. Differences in rate of change were observed in bone microarchitecture, specifically cortical porosity (Ct.Po), where peri-menopausal women increased +9% per year compared with the +6% per year for post-menopausal women. INTRODUCTION: The purpose of this study was to compare changes in bone density and microarchitecture in peri- and post-menopausal women over 6 years. METHODS: Peri- (n = 26) and post- (n = 65) menopausal women were selected from the Canadian Multicenter Osteoporosis Study. Caucasian women were scanned on dual x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and follow-up, an average 6 years later. To compare repeat scans, automated 3D image registration was conducted. At the radius and tibia, total volumetric BMD (Tt.BMD), total bone area (Tt.Ar) and cortical porosity (Ct.Po) were assessed, and finite element analysis estimated apparent bone strength. RESULTS: At the tibia, the rate of change for Ct.Po and Tt.Ar was different between groups. Peri-menopausal women had a + 9% per year increase in Ct.Po, but this increase was slower for post-menopausal women at +6% per year (p = 0.049). In addition, post-menopausal women had an increase in Tt.Ar of +0.13% per year compared with a slower increase of +0.06% per year for peri-menopausal women (p = 0.017). The rate of change of density between groups was not significantly different and was approximately -1% per year at the hip by DXA, and -1% per year at the radius and -0.5% per year tibia by HR-pQCT. CONCLUSION: This is a 6-year prospective HR-pQCT study exploring rate of change in Caucasian peri- and post-menopausal women. The microarchitectural features represented by Ct.Po and Tt.Ar changed at a significantly different rate between groups, but group differences were not detected by density measures.

Operator variability in scan positioning is a major component of HR-pQCT precision error and is reduced by standardized training.

In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter-operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection ("scout view image") and define the region to be scanned by positioning a "reference line" on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanner's software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter-operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p < 0.001). New trained operators achieved comparable intra-operator reproducibility to experienced operators and lower inter-operator reproducibility (p < 0.001). Precision errors were significantly greater for the radius than for the tibia. CONCLUSION: Operator reference line positioning contributes significantly to in vivo measurement precision and is significantly greater for multi-operator datasets. Inter-operator variability can be significantly reduced using a systematic training platform, now available online ( http://webapps.radiology.ucsf.edu/refline/ ).

Morphology based anisotropic finite element models of the proximal femur validated with experimental data.

Finite element analysis (FEA) of bones scanned with Quantitative Computed Tomography (QCT) can improve early detection of osteoporosis. The accuracy of these models partially depends on the assigned material properties, but anisotropy of the trabecular bone cannot be fully captured due to insufficient resolution of QCT. The inclusion of anisotropy measured from high resolution peripheral QCT (HR-pQCT) could potentially improve QCT-based FEA of the femur, although no improvements have yet been demonstrated in previous experimental studies. This study analyzed the effects of adding anisotropy to clinical resolution femur models by constructing six sets of FE models (two isotropic and four anisotropic) for each specimen from a set of sixteen femurs that were experimentally tested in sideways fall loading with a strain gauge on the superior femoral neck. Two different modulus-density relationships were tested, both with and without anisotropy derived from mean intercept length analysis of HR-pQCT scans. Comparing iso- and anisotropic models to the experimental data resulted in nearly identical correlation and highly similar linear regressions for both whole bone stiffness and strain gauge measurements. Anisotropic models contained consistently greater principal compressive strains, approximately 14% in magnitude, in certain internal elements located in the femoral neck, greater trochanter, and femoral head. In summary, anisotropy had minimal impact on macroscopic measurements, but did alter internal strain behavior. This suggests that organ level QCT-based FE models measuring femoral stiffness have little to gain from the addition of anisotropy, but studies considering failure of internal structures should consider including anisotropy to their models.

Integrin α1ß1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor signalling.

OBJECTIVE: To investigate the role of integrin α1ß1 in the progression of post-traumatic osteoarthritis (PTOA), and elucidate the contribution of epidermal growth factor receptor (EGFR) signalling to the mechanism by which integrin α1ß1 might control PTOA. We hypothesised that integrin α1ß1 plays a protective role in the course of PTOA and that the effect of PTOA (e.g., synovitis, loss of cartilage and growth of osteophytes) would be exacerbated in mice lacking integrin α1ß1 at every time point post destabilisation of medial meniscus (DMM). METHODS: DMM or sham surgery was performed on integrin α1-null and wild type (WT) mice and the progression of PTOA analysed at 2, 4, 8 and 12 weeks post-surgery (PS) using micro-computed tomography (microCT), histology, and immunohistochemistry. In addition, the effects of EGFR blockade were examined by treating the mice with the EGFR inhibitor erlotinib. RESULTS: Integrin α1-null female, but not male, mice showed earlier cartilage degradation post DMM surgery compared to WT controls. Furthermore, erlotinib treatment resulted in significantly less cartilage damage in integrin α1-null but not WT mice. Independent of genotype, erlotinib treatment significantly mitigated the effects of PTOA on many tissues of female mice including meniscal and fabella bone volume, subchondral bone thickness and density and cartilage degradation. In contrast, reduced EGFR signalling had little effect on signs of PTOA in male mice. CONCLUSION: Integrin α1ß1 protects against PTOA-induced cartilage degradation in female mice partially via the reduction of EGFR signalling. Furthermore, reduction of EGFR signalling protects against the development of PTOA in female, but not male mice.

Bone micro-architecture of elite alpine skiers is not reflected by bone mineral density.

UNLABELLED: Bone quality is affected by muscle forces and external forces. We investigated how micro-architecture is influenced in elite alpine skiers who have received high loading levels throughout their adolescent bone development. Bone strength was higher in skiers, likely due to external forces, but muscle forces may also be a significant contributor. INTRODUCTION: Impact loading and muscle forces affect bone quality, but little is known about how they influence 3 dimensional aspects of bone structure. This study investigated bone quality in female and male elite alpine skiers using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: HR-pQCT at the distal radius and tibia, whole-body lean mass, and muscle strength were assessed in 10 female (22.7 ± 3.9 years) and 12 male (25.5 ± 3.3 years) Canadian national alpine team athletes and compared to recreationally active female (N = 10, 23.8 ± 3.2 years) and male (N = 12; 23.7 ± 3.6 years) control subjects. HR-pQCT standard parameters and customized cortical and finite element (FE) analyses were performed and analyzed using one-way ANOVA and Pearson's correlation. RESULTS: Male and female skiers had stronger bones than controls at radius (38-49 %, p < 0.001) and tibia (24-28 %, p < 0.001). This result was not consistently reflected by total bone mineral density (BMD) because higher trabecular BMD occurred in parallel with lower cortical BMD, which was due to a redistribution of mineral leading to a shift of the endocortical margin toward a thicker cortex. The endocortical regional adaptation was likely responsible for the greater strength of the athletes' bones. Lean mass and muscle strength was 29 to 90 % greater (p < 0.001) in athletes compared to controls. Good associations between muscle strength and FE-estimated bone strength were found (r = 0.63 to 0.80; p < 0.001), although micro-architecture was more strongly associated with muscle outcomes in females than males. CONCLUSIONS: Higher bone strength in elite alpine skiers is achieved through micro-architectural adaptation that is not apparent by BMD measurements alone. The improved micro-architecture at radius and tibia suggests that muscle forces may play an important role in bone adaptation.

The relationship between serum 25(OH)D and bone density and microarchitecture as measured by HR-pQCT.

UNLABELLED: The relation between serum 25-hydroxy vitamin D [25(OH)D] and bone quality is not well understood, particularly for high levels. We measured bone microarchitecture in three groups of people stratified by their serum 25(OH)D. There was a weak association of serum 25(OH)D and microarchitecture for this cross-sectional population, suggesting possible benefits to bone quality. INTRODUCTION: Vitamin D plays an important role in bone and mineral metabolism, but the relation between serum 25(OH)D and bone quality is not well understood. Here, we present a cross-sectional study that investigated a convenience group of participants from an ongoing health initiative in Alberta, Canada, who have been receiving daily vitamin D supplementation. METHODS: A total of 105 participants were organized into three groups based on their serum 25(OH)D levels: low (<75 nmol/L), medium (75-175 nmol/L), and high (>175 nmol/L). They were also assessed with 25(OH)D as a continuous variable. Average daily supplementation was 7670 ± 438 IU, and the change in 25(OH)D ranged from 22 to 33 % during the period of receiving supplements. We used high-resolution peripheral quantitative computed tomography measurements at the radius and tibia to assess bone microarchitecture. RESULTS: Microarchitectural parameters were not strongly associated with serum 25(OH)D. In the tibia, there were fewer trabeculae (TbN; p = 0.015) and a non-significant trend toward thicker trabeculae (p = 0.067) of the high group. Body mass index (BMI) was negatively associated with serum 25(OH)D levels (p < 0.001) and PTH levels (p < 0.001). There was no clinically significant relationship detected between high serum 25(OH)D and high serum calcium. CONCLUSION: These data suggest a weak relationship between serum 25(OH)D and bone microarchitecture in this population of mostly vitamin-D-sufficient participants, and there were no indications of negative effects related to the high supplementation levels. These data provided a basis to design and implement our 3-year dose-dependent randomized controlled trial investigating the effects of vitamin D supplementation on bone health outcomes.

Bone quality in osteopenic postmenopausal women is not improved after 12 months of whole-body vibration training.

UNLABELLED: Whole-body vibration training may improve bone quality through structural adaptation. We tested if 12 months of training affects bone structure in osteopenic postmenopausal women by using advanced 3-dimensional high-resolution imaging techniques. We found that whole-body vibration training did not improve bone structure compared to inactive controls. INTRODUCTION: Whole-body vibration training (WBVT) has been suggested as a preventive measure against bone loss. Contradicting results of previous studies may be confounded by insufficiently sensitive bone density measures to detect relevant bone changes. WBVT may improve bone quality through structural adaptations, without increasing bone mineral density (BMD). We hypothesized that 12 months of WBVT will improve or maintain bone microarchitecture and bone strength in osteopenic postmenopausal women. METHODS: Twenty-two women received WBVT for 2-3 sessions/week and were compared with 20 controls. Bone outcomes were measured by high-resolution peripheral quantitative CT (HR-pQCT, XtremeCT, Scanco Medical) and finite element estimated bone strength. Balance and jump performance and maximum voluntary contraction (MVC) of knee flexor and extensor muscles were recorded. All measurements were taken at baseline, 4, 8, and 12 months and a reduced data set at 4 and 8 months follow-up and compared using a mixed model repeated measures ANOVA. RESULTS: Thirty-one women completed the study with 90 % compliance (WBVT: n = 17, control n = 14). Total BMD (p < 0.001), cortical area*(p = 0.004), cortical thickness (p = 0.011), and cortical porosity (p = 0.024) all significantly decreased over time in both groups; WBVT did not affect the response. All other bone outcomes were not affected by WBVT or time. No difference in measures of balance, jump height, and MVC due to WBVT were detected. CONCLUSION: In our cohort, WBVT did not lead to improved bone quality in postmenopausal osteopenic women after 12 months of training compared to controls, and there were no detected benefits related to balance and muscle strength outcomes.

Proximal femur elastic behaviour is the same in impact and constant displacement rate fall simulation.

Understanding proximal femur fracture may yield new targets for fracture prevention screening and treatment. The goal of this study was to characterize force-displacement and failure behaviours in the proximal femur between displacement control and impact loading fall simulations. Twenty-one human proximal femurs were tested in two ways, first to a sub-failure load at a constant displacement rate, then to fracture in an impact fall simulator. Comparisons of sub-failure energy and stiffness were made between the tests at the same compressive force. Additionally, the impact failure tests were compared with previous, constant displacement rate failure tests (at 2 and 100mm/s) in terms of energy, yield force, and stiffness. Loading and displacement rates were characterized and related to specimen stiffness in the impact tests. No differences were observed between the sub-failure constant displacement and impact tests in the aforementioned metrics. Comparisons between failure tests showed that the impact group had the lowest absorbed energy, 24% lower maximum force and 160% higher stiffness than the 100mm/s group (p<0.01 for all), but suffered from low statistical power to differentiate the donor age and specimen BMD. Loading and displacement rates for the specimens tested using impact varied during each test and between specimens and did not show appreciable viscoelasticity. These results indicate that constant displacement rate testing may help understand sub-failure mechanical behaviour, but may not elucidate failure behaviours. The differences between the impact and constant displacement rate fall simulations have important ramifications for interpreting the results of previous experiments.

Embryonic stem cell therapy improves bone quality in a model of impaired fracture healing in the mouse; tracked temporally using in vivo micro-CT.

In the current study, we used an estrogen-deficient mouse model of osteoporosis to test the efficacy of a cell-generated bone tissue construct for bone augmentation of an impaired healing fracture. A reduction in new bone formation at the defect site was observed in ovariectomized fractures compared to the control group using repeated measures in vivo micro-computed tomography (µCT) imaging over 4 weeks. A significant increase in the bone mineral density (BMD), trabecular bone volume ratio, and trabecular number, thickness and connectivity were associated with fracture repair in the control group, whereas the fractured bones of the ovariectomized mice exhibited a loss in all of these parameters (p<0.001). In a separate group, ovariectomized fractures were treated with murine embryonic stem (ES) cell-derived osteoblasts loaded in a three-dimensional collagen I gel and recovery of the bone at the defect site was observed. A significant increase in the trabecular bone volume ratio (p<0.001) and trabecular number (p<0.01) was observed by 4 weeks in the fractures treated with cell-loaded collagen matrix compared to those treated with collagen I alone. The stem cell-derived osteoblasts were identified at the fracture site at 4 weeks post-implantation through in situ hybridization histochemistry. Although this cell tracking method was effective, the formation of an ectopic cellular nodule adjacent to the knee joints of two mice suggested that alternative in vivo cell tracking methods should be employed in order to definitively assess migration of the implanted cells. To our knowledge, this study is the first of its kind to examine the efficacy of stem cell therapy for fracture repair in an osteoporosis-related fracture model in vivo. The findings presented provide novel insight into the use of stem cell therapies for bone injuries.

Classification of women with and without hip fracture based on quantitative computed tomography and finite element analysis.

UNLABELLED: We used quantitative computed tomography and finite element analysis to classify women with and without hip fracture. Highly accurate classifications were achieved indicating the potential for these methods to be used for subject-specific assessment of fracture risk. INTRODUCTION: Areal bone mineral density (aBMD) is the current clinical diagnostic standard for assessing fracture risk; however, many fractures occur in people not defined as osteoporotic by aBMD. Finite element (FE) analysis based on quantitative computed tomography (QCT) images takes into account both bone material and structural properties to provide subject-specific estimates of bone strength. Thus, our objective was to determine if FE estimates of bone strength could classify women with and without hip fracture. METHODS: Twenty women with femoral neck fracture and 15 women with trochanteric fractures along with 35 age-matched controls were scanned with QCT at the hip. Since it is unknown how a specific subject will fall, FE analysis was used to estimate bone stiffness and bone failure load under loading configurations with femoral neck internal rotation angles ranging from -30° to 45° with 15° intervals. Support vector machine (SVM) models and a tenfold cross-validation scheme were used to classify the subjects with and without fracture. RESULTS: High accuracy was achieved when using only FE analysis for classifying the women with and without fracture both when the fracture types were pooled (82.9 %) and when analyzed separately by femoral neck fracture (87.5 %) and trochanteric fracture (80.0 %). The accuracy was further increased when FE analysis was combined with volumetric BMD (pooled fractures accuracy, 91.4 %) CONCLUSIONS: While larger prospective studies are needed, these results demonstrate that FE analysis using multiple loading configurations together with SVM models can accurately classify individuals with previous hip fracture.