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Areal bone mineral density (aBMD) currently represents the clinical gold standard for hip fracture risk assessment. Nevertheless, it is characterised by a limited prediction accuracy, as about half of the people experiencing a fracture are not classified as at being at risk by aBMD. In the context of a progressively ageing population, the identification of accurate predictive tools would be pivotal to implement preventive actions. In this study, DXA-based statistical models of the proximal femur shape, intensity (i.e., density) and their combination were developed and employed to predict hip fracture on a retrospective cohort of post-menopausal women. Proximal femur shape and pixel-by-pixel aBMD values were extracted from DXA images and partial least square (PLS) algorithm adopted to extract corresponding modes and components. Subsequently, logistic regression models were built employing the first three shape, intensity and shape-intensity PLS components, and their ability to predict hip fracture tested according to a 10-fold cross-validation procedure. The area under the ROC curves (AUC) for the shape, intensity, and shape-intensity-based predictive models were 0.59 (95%CI 0.47-0.69), 0.80 (95%CI 0.70-0.90) and 0.83 (95%CI 0.73-0.90), with the first being significantly lower than the latter two. aBMD yielded an AUC of 0.72 (95%CI 0.59-0.82), found to be significantly lower than the shape-intensity-based predictive model. In conclusion, a methodology to assess hip fracture risk uniquely based on the clinically available imaging technique, DXA, is proposed. Our study results show that hip fracture risk prediction could be enhanced by taking advantage of the full set of information DXA contains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Type 1 diabetes mellitus (T1DM) has been linked to increased osteocyte apoptosis, local accumulation of mineralized lacunar spaces, and microdamage suggesting an impairment of the mechanoregulation network in affected individuals. Diabetic neuropathy might exacerbate this dysfunction through direct effects on bone turnover, and indirect effects on balance, muscle strength, and gait. However, the in vivo effects of impaired bone mechanoregulation on bone remodeling in humans remain underexplored. This longitudinal cohort study assessed consenting participants with T1DM and varying degree of distal symmetric sensorimotor polyneuropathy (T1DM, n = 20, median age 46.5 yr, eight female) and controls (CTRL; n = 9, median age 59.0 yr, four female) at baseline and 4-yr follow-up. Nerve conduction in participants with T1DM was tested using DPNCheck and bone remodeling was quantified with longitudinal high-resolution peripheral quantitative-computed tomography (HR-pQCT, 82 μm) at the standard distal sites. Local trabecular bone formation (Tb.F) and resorption (Tb.R) sites were captured by implementing 3D rigid image registration of HR-pQCT images, and the mechanical environment across the bone microarchitecture at these sites was simulated using micro-finite element analysis. We calculated odds ratios to determine the likelihood of bone formation (ORF) and resorption (ORR) with increasing/decreasing strain in percent as markers for mechanoregulation. At the distal radius, Tb.F was 47% lower and Tb.R was 59% lower in T1DM participants compared with CTRL (P < .05). Tb.F correlated positively with nerve conduction amplitude (R = 0.69, P < .05) in participants with T1DM and negatively with glycated hemoglobin (HbA1c) (R = -0.45, P < .05). Additionally, ORF was 34% lower and ORR was 18% lower in T1DM compared with CTRL (P < .05). Our findings represent in vivo evidence suggesting that bone remodeling in individuals with T1DM is in a state of low responsiveness to mechanical stimuli, resulting in impaired bone formation and resorption rates; these correlate to the degree of neuropathy and level of diabetes control., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Passive soft tissues surrounding the trochanteric region attenuate fall impact forces and thereby control hip fracture risk. The degree of attenuation is related to Soft Tissue Thickness (STT). STT at the neutral hip impact orientation, estimated using a regression relation in body mass index (BMI), was previously shown to influence the current absolute risk of hip fracture (ARF0) and its fracture classification accuracy. The present study investigates whether fracture classification using ARF0 improves when STT is determined from the subject's Computed-Tomography (CT) scans (i.e. personalised) in an orientation-specific (i.e. 3D) manner. STT is calculated as the shortest distance along any impact orientation between a semi-automatically segmented femur surface and an automatically segmented soft tissue/air boundary. For any subject, STT along any of the 33 impact orientations analysed always exceeds the value estimated using BMI. Accuracy of fracture classification using ARF0 improves when using personalised 3D STT estimates (AUC = 0.87) instead of the BMI-based STT estimate (AUC = 0.85). The improvement is smaller (AUC = 0.86) when orientation-specificity of CT-based STT is suppressed and is nil when personalisation is suppressed instead. Thus, fracture classification using ARF0 improves when CT is used to personalise STT estimates and improves further when, in addition, the estimates are orientation specific., (© 2022. The Author(s).)

Severe predictions have been made regarding osteoporotic fracture incidence for the next years, with major economic and social impacts in a worldwide greying society. However, the performance of the currently adopted gold standard for fracture risk prediction, the areal Bone Mineral Density (aBMD), remains moderate. To overcome current limitations, the construction of statistical models of the proximal femur, based on three-dimensional shape and intensity (a hallmark of bone density), is here proposed for predicting hip fracture in a Caucasian postmenopausal cohort. Partial Least Square (PLS)-based statistical models of the shape, intensity and their combination were developed, and the corresponding modes and components were identified. Logistic regression models using the first two shape, intensity and shape-intensity PLS components were implemented and tested within a 10-fold cross-validation procedure as predictors of hip fracture. It emerged that (1) intensity components were superior to shape components in stratifying patients according to their fracture status, and that (2) a combination of intensity and shape improved patients risk stratification. The area under the ROC curve was 0.64, 0.85 and 0.92 for the models based on shape, intensity and shape-intensity combination respectively, against a 0.72 value for the aBMD standard approach. Based on these findings, the presented methodology turns out to be promising in tackling the need for an enhanced fracture risk assessment., (© 2022. The Author(s).)

Fracture risk is increased in type 1 diabetes (T1D). Diabetic neuropathy might contribute to this increased risk directly through effects on bone turnover and indirectly through effects on balance, muscle strength, and gait. We compared patients with T1D with (T1DN+, n = 20) and without (T1DN-, n = 20) distal symmetric sensorimotor polyneuropathy and controls (n = 20). We assessed areal bone mineral density (aBMD) and appendicular muscle mass by dual-energy X-ray absorptiometry, microarchitecture by high-resolution peripheral quantitative tomography at the standard ultra-distal site and at an exploratory 14% bone length site at the tibia and radius, bone turnover markers, and muscle strength, gait, and balance by Short Physical Performance Battery (SPPB). At the standard ultra-distal site, tibial cortical porosity was 56% higher in T1DN+ compared with T1DN- (p = .009) and correlated positively with the severity of neuropathy (Toronto Clinical Neuropathy Score; r = 0.347, p = .028) and negatively with nerve conduction amplitude and velocity (r = -0.386, p = .015 and r = -0.358, p = .025, respectively). Similar negative correlations were also observed at the radius (r = -0.484, p = .006 and r = -0.446, p = .012, respectively). At the exploratory 14% offset site (less distal), we found higher trabecular volumetric BMD (tibia 25%, p = .024; radius 46%, p = .017), trabecular bone volume (tibia 25%, p = .023; radius 46%, p = .017), and trabecular number (tibia 22%, p = .014; radius 30%, p = .010) in T1DN- compared with controls. Both CTX and PINP were lower in participants with TD1 compared with controls. No difference was found in aBMD and appendicular muscle mass. T1DN+ had worse performance in the SPPB compared with T1DN- and control. In summary, neuropathy was associated with cortical porosity and worse performance in physical tests. Our findings suggest that bone structure does not fully explain the rate of fractures in T1D. We conclude that the increase in the risk of fractures in T1D is multifactorial with both skeletal and non-skeletal contributions. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Background: Vascular calcification (VC) and renal osteodystrophy are important complications of advanced chronic kidney disease (CKD). High resolution peripheral quantitative computed tomography (HRpQCT) is able to assess bone microstructure in renal osteodystrophy and lower leg arterial calcification (LLAC) is usually seen as an incidental finding. LLAC can be a useful quantitative assessment of VC in CKD but the relationship between LLAC and vascular biomarkers and bone is unknown. We aimed to assess the relationship between LLAC and biomarkers, bone turnover and microstructure., Methods: In this cross-sectional study, fasting blood samples were taken from 69 CKD stages 4-5D patients and 68 healthy controls. HRpQCT of distal tibia and radius were performed. 43 CKD patients had trans-iliac bone biopsy after tetracycline labelling., Results: LLAC was more severe in CKD than controls (median [IQR] 1.043 [0.05-16.52] vs 0 [0-0.55] mgHA, p < 0.001). CKD patients with diabetes (28%) had significantly higher LLAC compared to non-diabetic CKD (median [IQR] 24.07 [3.42-61.30] vs 0.23 [0-3.78] mgHA, p < 0.001). LLAC mass in CKD correlated with serum phosphate (rho = 0.29, p < 0.05), calcium x phosphate product (rho = 0.31, p < 0.05), intact parathyroid hormone (rho = 0.38, p < 0.01), intact fibroblast growth factor-23 (iFGF23) (rho = 0.40, p = 0.001), total alkaline phosphatase (rho = 0.41, p < 0.001), bone alkaline phosphatase (rho = 0.29, p < 0.05), osteocalcin (rho = 0.32, p < 0.05), osteoprotegerin (rho = 0.40, p = 0.001) and dephosphorylated-uncarboxylated matrix Gla protein (rho = 0.31, p < 0.05). LLAC in CKD also correlated with worse distal tibia cortical bone mineral density, thickness and porosity. No association was found between LLAC and bone turnover, mineralization or volume on biopsy in CKD. In multivariate analysis, only age, diabetes, iPTH and iFGF23 were independently associated with LLAC in CKD., Conclusions: High levels of PTH and FGF23, along with older age and the presence of diabetes may all play independent roles in the development of LLAC in advanced CKD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recently, coupled musculoskeletal-finite element modelling approaches have emerged as a way to investigate femoral neck loading during various daily activities. Combining personalised gait data with finite element models will not only allow us to study changes in motion/movement, but also their effects on critical internal structures, such as the femur. However, previous studies have been hampered by the small sample size and the lack of fully personalised data in order to construct the coupled model. Therefore, the aim of this study was to build a pipeline for a fully personalised multiscale (body-organ level) model to investigate the strain levels at the femoral neck during a normal gait cycle. Five postmenopausal women were included in this study. The CT and MRI scans of the lower limb, and gait data were collected for all participants. Muscle forces derived from the body level musculoskeletal models were used as boundary constraints on the finite element femur models. Principal strains were estimated at the femoral neck region during a full gait cycle. Considerable variation was found in the predicted peak strain among individuals with mean peak first principal strain of 0.24% ± 0.11% and mean third principal strain of -0.29% ± 0.24%. For four individuals, two overall peaks of the maximum strains were found to occur when both feet were in contact with the floor, while one individual had one peak at the toe-off phase. Both the joint contact forces and the muscular forces were found to substantially influence the loading at the femoral neck. A higher correlation was found between the predicted peak strains and the gluteus medius (R2 ranged between 0.95 and 0.99) than the hip joint contact forces (R2 ranged between 0.63 and 0.96). Therefore, the current findings suggest that personal variations are substantial, and hence it is important to consider multiple subjects before deriving general conclusions for a target population., Competing Interests: The authors have declared that no competing interests exist.

Adults with type 1 diabetes mellitus (T1DM) are at risk of premature osteoporosis and fractures. The onset of T1DM typically starts during childhood and adolescence. Thus, the effects of DM on the skeleton may be established during this period. Studies in children with T1DM primarily use DXA with conflicting results. We present the first study in adolescents assessing the impact of T1DM on skeletal microstructure and strength using HRpQCT. We recruited 22 patients aged 12 to 16 years with T1DM who were matched by age, gender, and pubertal stage with healthy controls. Paired t tests were applied to assess differences in cortical and trabecular microarchitecture measurements from HRpQCT, and skeletal strength from HRpQCT-derived microfinite element analysis. Subtotal body, lumbar, and pelvic parameters were assessed using DXA. There was no significant difference in subtotal body, lumbar spine, and pelvic BMD between T1DM and control pairs. However, tibial trabecular thickness was lower (-0.005 mm; 95% CI, -0.01 to -0.001; p = 0.029) and trabecular loading was lower at the distal radius (ratio of the load taken by the trabecular bone in relation to the total load at the distal end (Tb.F/TF) distal: -6.2; 95% CI, -12.4 to -0.03; p = 0.049), and distal and proximal tibia (Tb.F/TF distal: -5.2, 95% CI, -9.2 to -1.2; p = 0.013; and Tb.F/TF proximal: -5.0, 95% CI, -9.8 to -0.1; p = 0.047) in T1DM patients. A subanalysis of radial data of participants with duration of T1DM of at least 2 years and their matched controls demonstrated a reduced trabecular bone number (-0.15, 95% CI, -0.26 to -0.04; p = 0.012), increased trabecular separation (0.041 mm, 95% CI, 0.009-0.072; p = 0.015), an increased trabecular inhomogeneity (0.018, 95% CI, 0.003-0.034; p = 0.021). Regression models demonstrated a reduction in tibial stiffness (-0.877 kN/mm; p = 0.03) and tibial failure load (-0.044 kN; p = 0.03) with higher HbA1C. Thus, in adolescents with T1DM, detrimental changes are seen in tibial and radial microarchitecture and tibial and radial strength before changes in DXA occur and may result from poor diabetic control. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Bone health in children with osteogenesis imperfecta is monitored using radiographs and dual-energy X-ray absorptiometry, which have limitations. High-resolution peripheral quantitative CT can non-invasively derive bone microarchitectural data. Children with severe osteogenesis imperfecta have fragile deformed bones, and positioning for this scan can be difficult. We assessed the feasibility of high-resolution peripheral quantitative CT in nine children aged 9-15 years with osteogenesis imperfecta and compared results with dual-energy X-ray absorptiometry and with healthy controls. All nine recruited children were successfully scanned and showed no preference for either modality. It therefore appears feasible to perform high-resolution peripheral quantitative CT in children with osteogenesis imperfecta aged 9 years and older. Future studies should focus on understanding the clinical implications of the technology in this patient cohort.

Postmenopausal osteoporosis is characterised by increased bone turnover and an imbalance between bone resorption and formation. Bisphosphonate treatment reduces bone turnover but their effect on bone balance is yet to be fully investigated. Using the T-score approach our aims were to: i) investigate the effects of oral nitrogen-containing bisphosphonates on bone balance and turnover in postmenopausal women with osteoporosis and ii) determine the relationship of the change in bone balance and turnover with the change in BMD at the lumbar spine and total hip. Women were recruited, mean age 67 years, and randomised to receive: ibandronate (n = 55, 150 mg/month), alendronate (n = 54, 70 mg/week) or risedronate (n = 56, 35 mg/week). They also received calcium and vitamin D daily. A fasting serum sample was collected at baseline and weeks 1, 2, 4, 12, 13, 48 and 96. The control group were 226 healthy premenopausal women receiving no treatments. PINP and CTX were measured using the iSYSIDS analyser and BMD (in g/cm2) of the lumbar spine and total hip were measured by DXA (Hologic Inc). PINP and CTX values were log10-transformed and normalised. T-scores were calculated using the mean and standard deviation from the premenopausal group. Bone turnover and bone balance were calculated from the T-scores. Mean levels (95% CI) of balance and turnover are shown in the table. The change in turnover at weeks 4, 12 and 48 was inversely correlated with the change in lumbar spine and total hip BMD at weeks 48 and 96, (p < .01 to p < .001). The change in balance at week 4 positively correlated with the change in total hip BMD at weeks 48, (p < .01). Bisphosphonates resulted in an initial positive balance and a reduction in turnover. Some of these changes were associated with increases in BMD. Bone turnover is a better predictor of BMD than bone balance., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Bone markers may be useful to monitor response to treatment withdrawal in osteoporosis. We used two criteria for investigating the change in BTMs after withdrawal of bisphosphonate treatment. A larger increase in BTMs was associated with greater bone loss. Bone markers may be useful in monitoring of patients taking a pause from treatment., Introduction: Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD)., Methods: We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2 years of treatment, participants with BMD T-score > - 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value., Results: Fifty women completed the study. At 48 weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was - 2.98%, 95%CI - 4.75 to - 1.22, P < 0.001, PINP - 2.25%, 95% CI - 4.46 to - 0.032, P = 0.046)., Conclusion: The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.

Background Renal osteodystrophy is common in advanced CKD, but characterization of bone turnover status can only be achieved by histomorphometric analysis of bone biopsy specimens (gold standard test). We tested whether bone biomarkers and high-resolution peripheral computed tomography (HR-pQCT) parameters can predict bone turnover status determined by histomorphometry. Methods We obtained fasting blood samples from 69 patients with CKD stages 4-5, including patients on dialysis, and 68 controls for biomarker analysis (intact parathyroid hormone [iPTH], procollagen type 1 N-terminal propeptide [PINP], bone alkaline phosphatase [bALP], collagen type 1 crosslinked C-telopeptide [CTX], and tartrate-resistant acid phosphatase 5b [TRAP5b]) and scanned the distal radius and tibia of participants by HR-pQCT. We used histomorphometry to evaluate bone biopsy specimens from 43 patients with CKD. Results Levels of all biomarkers tested were significantly higher in CKD samples than control samples. For discriminating low bone turnover, bALP, intact PINP, and TRAP5b had an areas under the receiver operating characteristic curve (AUCs) of 0.82, 0.79, and 0.80, respectively, each significantly better than the iPTH AUC of 0.61. Furthermore, radius HR-pQCT total volumetric bone mineral density and cortical bone volume had AUCs of 0.81 and 0.80, respectively. For discriminating high bone turnover, iPTH had an AUC of 0.76, similar to that of all other biomarkers tested. Conclusions The biomarkers bALP, intact PINP, and TRAP5b and radius HR-pQCT parameters can discriminate low from nonlow bone turnover. Despite poor diagnostic accuracy for low bone turnover, iPTH can discriminate high bone turnover with accuracy similar to that of the other biomarkers, including CTX., (Copyright © 2018 by the American Society of Nephrology.)

There is evidence to suggest accelerated bone loss following estrogen cessation. The effect of cessation of raloxifene therapy on bone turnover is unknown. Our aim was to determine the effect of cessation of raloxifene treatment on bone turnover and bone mineral density (BMD) in postmenopausal, osteopenic women. Women aged 50 to 80 years received raloxifene for 96 weeks and were then randomized to continue raloxifene (group 1, n=20) or placebo (group 2, n=20) for a further 96 weeks. A third group (group 3, n=14) received no treatment. Bone turnover markers and bone density (BMD) were measured throughout the study. Raloxifene treatment for 96 weeks resulted in a decrease in bone turnover (PINP by 31%) and an increase in spine BMD (by 2%) but no change in hip BMD for groups 1 and 2. Continuation of raloxifene (group 1) maintained these changes. Following cessation of raloxifene (group 2), bone markers returned to baseline levels (by 120 weeks). Hip BMD was decreased by 2% at 192 weeks compared to baseline. Bone markers in the controls (group 3) remained at the upper limit of the reference range throughout, with decreases in BMD of 2.3% (spine) and 2.8% (hip). Bone loss following cessation of raloxifene therapy at 96 weeks was greater than in the control group, suggesting accelerated bone loss. The beneficial effect on bone turnover of 96 weeks of raloxifene was lost 6 months after cessation of treatment.