Impact of Type 1 diabetes mellitus on skeletal integrity and strength in adolescents as assessed by HRpQCT

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

Effect of age and gender on serum periostin: Relationship to cortical measures, bone turnover and hormones

Periostin is an extracellular matrix protein, and in bone is expressed most highly in the periosteum. It increases bone formation through osteoblast differentiation, cell adhesion, Wnt signalling and collagen cross-linking. We hypothesised that serum periostin would be high at times of life when cortical modeling is active, in early adulthood and in older age, and that it would correlate with cortical bone measures, bone turnover and hormones that regulate cortical modeling. We conducted a cross-sectional observational study of 166 healthy men and women at three skeletal stages; the end of longitudinal growth (16–18 years), peak bone mass (30–32 years) and older age (over 70 years). We measured serum periostin with a new ELISA optimised for human serum and plasma which recognises all known splice variants (Biomedica). We measured the distal radius and distal tibia with HR-pQCT, and measured serum PINP, CTX, sclerostin, PTH, IGF-1, estradiol and testosterone. Periostin was higher at age 16–18 than age 30–32 (1253 vs 842 pmol/l, p < 0.001), but not different between age 30–32 and over age 70. Periostin was inversely correlated with tibia cortical thickness and density (R − 0.229, − 0.233, both p = 0.003). It was positively correlated with PINP (R 0.529, p < 0.001), CTX (R 0.427, p < 0.001) and IGF-1 (R 0.440, p < 0.001). When assessed within each age group these correlations were only significant at age 16–18, except for PINP which was also significant over age 70. We conclude that periostin may have a role in IGF-1 driven cortical modeling and consolidation in young adults, but it may not be an important mediator in older adults

Diagnostic accuracy of biomarkers and imaging for bone turnover in renal osteodystrophy

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.MethodsWe 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.ResultsLevels 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.ConclusionsThe 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

Oxygen uptake in the frequency domain as a test for cardiorespiratory fitness.

Oxygen uptake kinetics describe the characteristics of the rate of change of VO[2] in response to the onset of exercise or a change in work rate. There is a lack of knowledge concerning the use of VO[2] kinetics in the frequency domain as a test for cardiorespiratory fitness. The PRBS exercise test has been developed to study the dynamic responses of the cardiorespiratory system to random changes in submaximal work rate. This exercise test technique provides a multi-frequent assessment of VO[2] kinetics that can be expressed in terms of amplitude (ml-min[-1]W[-1]) or phase shift (degrees) over a frequency range of 0.0022 to 0.0089 Hz. The VO[2] kinetics of young women were investigated using this submaximal test during which the work rate was alternated between two levels. The upper work rate level was chosen to be below the ventilatory threshold. In the first experiment, the variability of replicate tests was investigated in a cohort of eight moderately active women (age = 22.6 +/- 0.8 years). Although there were wide limits of agreement between the two tests there was no significant difference between test 1 and test 2.In a second experiment to test the discriminant ability, oxygen uptake kinetics were compared to VO[2peak] in twenty-eight sedentary or moderately active young women (age = 22.9 +/-3.1 years). The PRBS exercise test technique was able to discriminate between a group of subjects with lower VO[2peak] (VO[2peak] = 32.3 +/- 3.3 ml-kg-1min-1) and a group of subjects with higher VO[2peak] (VO[2peak] = 41.1 +/- 3.2 ml-kg-1min-1). Differences in VO[2] kinetics occurred at frequencies of 0.0022 Hz for amplitude, and at frequencies of 0.0022 Hz to 0.0067 Hz for phase shift. Significant relationships were found to exist between VO[2peak] and VO[2] kinetics at frequencies of 0.0022Hz, 0.0044 Hz and 0.0067 Hz. The following model explained the highest proportion of the variation between VO[2peak] and VO[2] kinetics (r = - 0.72, P0.001): VO[2peak] (in ml-kg[-1]min[-1]) = 0.503(phase shift at 0.0067 Hz) (in degrees) + 72.24In a third experiment to test the sensitivity to detect change, both VO[2] kinetics and VO[2peak] were measured before, during and after an eight week endurance-type training programme completed by fifteen young women (age = 21.6 +/- 1.9 years). Thirteen young women (age = 24.3 +/-3.5 years) acted as a non-training control group. Faster VO[2] kinetics were measured at a frequency of 0.0044 Hz for amplitude and at frequencies of 0.0022Hz to 0.0067 Hz for phase shift following the training programme. Increases in VO[2peak] also occurred as a result of the exercise regimen. No changes in either VO[2] kinetics or VO[2peak] were observed in the non-training group. This study showed that the PRBS exercise test technique was sensitive to short-term endurance-type training adaptations. In conclusion, the parameters measured during the PRBS exercise test provide valuable information that can not be gained from a standard assessment of VO[2] kinetics in the time domain. It is proposed that this exercise test technique has potential as a means of assessing cardiorespiratory fitness within the area of sports science and within the clinical environment

Characterising variability and regional correlations of microstructure and mechanical competence of human tibial trabecular bone: An in-vivo HR-pQCT study.

OBJECTIVE: Quantifying spatial distribution of trabecular bone mechanical competence and microstructure is important for early diagnosis of skeletal disorders and potential risk of fracture. The objective of this study was to determine a spatial distribution of trabecular mechanical and morphological properties in human distal tibia and examine the contribution of regional variability of trabecular microarchitecture to mechanical competence. METHODS: A total of 340 representative volume elements at five anatomic regions of trabecular bone - anterior, posterior, lateral, medial and centre - from ten white European-origin postmenopausal women were studied. Region-specific trabecular parameters such as trabecular volume fraction, trabecular thickness, trabecular number, trabecular surface area, trabecular separation, plate-like structure fraction and finite element analysis of trabecular stiffness were determined based on in-vivo high resolution peripheral quantitative computed tomographic (HR-pQCT) images of distal tibiae from ten postmenopausal women. Mean values were compared using analysis of variance. The correlations between morphological parameters and stiffness were calculated. RESULTS: Significant regional variation in trabecular microarchitecture of the human distal tibia was observed (0.001 ≤ p ≤ 0.05), with up to 106% differences between lowest (central and anterior) and highest (medial and posterior) regions. Higher proportion of plate-like trabecular morphology (63% and 53%) was found in medial and posterior regions in the distal tibia. Stiffness estimated from finite element models also differed significantly (0.001 ≤ p ≤ 0.05), with stiffness being 4.5 times higher in the highest (medial) than lowest (central) regions. The bone volume fraction was the strongest correlate of stiffness in all regions. CONCLUSION: A novel finding of this study is the fact that significant regional variation of stiffness derived from two-phased FEA model with individual trabecula representation correlated highly to regional morphology obtained from in-vivo HR-pQCT images at the distal tibia. The correlations between regional morphological parameters and mechanical competence of trabecular bone were consistent at all regions studied, with regional BV/TV showing the highest correlation. The method developed for regional analysis of trabecular mechanical competence may offer a better insight into the relationship between mechanical behaviour and microstructure of bone. The findings provide evidence needed to further justify a larger-cohort feasibility study for early detection of bone degenerative diseases: examining regional variations in mechanical competence and trabecular specifications may allow better understanding of fracture risks in addition to others contributing factors

Personalised 3D Assessment of Trochanteric Soft Tissues Improves HIP Fracture Classification Accuracy

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

Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis

Summary 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