10 research outputs found

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

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    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

    Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases.

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    High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance.This study was supported by The Wellcome Trust and NIHR CRN (portfolio number 5163). CLG was funded by a Wellcome Trust Clinical Research Training Fellowship (080280/Z/06/Z), the EU 7th Framework Programme under grant agreement number 247642 (GEoCoDE), a British Geriatric Society travel grant, and is now funded by Arthritis Research UK (grant ref 20000). SH acknowledges Arthritis Research UK support (grant ref 19580). KESP acknowledges the support of Cambridge NIHR Biomedical Research Centre. KAW is supported by the core programme of the MRC Nutrition and Bone Health group at MRC Human Nutrition Research, funded by the UK Medical Research Council (Grant code U10590371). EM acknowledges support of the Sheffield Teaching Hospitals Foundation Trust Clinical Research Facility. The SGC is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer, Boehringer Ingelheim, Genome Canada (Ontario Genomics Institute OGI- 055), GlaxoSmithKline, Janssen, Lilly Canada, Novartis Research Foundation, Ontario Ministry of Economic Development & Innovation, Pfizer, Takeda, and Wellcome Trust (092809/Z/10/Z).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/jbmr.270

    Bone Density, Microstructure and Strength in Obese and Normal Weight Men and Women in Younger and Older Adulthood

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    Obesity is associated with greater areal BMD (aBMD) and is considered protective against hip and vertebral fracture. Despite this, there is a higher prevalence of lower leg and proximal humerus fracture in obesity. We aimed to determine if there are site‐specific differences in BMD, bone structure, or bone strength between obese and normal‐weight adults. We studied 100 individually‐matched pairs of normal (body mass index [BMI] 18.5 to 24.9 kg/m2) and obese (BMI >30 kg/m2) men and women, aged 25 to 40 years or 55 to 75 years. We assessed aBMD at the whole body (WB), hip (TH), and lumbar spine (LS) with dual‐energy X‐ray absorptiometry (DXA), LS trabecular volumetric BMD (Tb.vBMD) by quantitative computed tomography (QCT), and vBMD and microarchitecture and strength at the distal radius and tibia with high‐resolution peripheral QCT (HR‐pQCT) and micro–finite element analysis. Serum type 1 procollagen N‐terminal peptide (P1NP) and collagen type 1 C‐telopeptide (CTX) were measured by automated electrochemiluminescent immunoassay (ECLIA). Obese adults had greater WB, LS, and TH aBMD than normal adults. The effect of obesity on LS and WB aBMD was greater in older than younger adults (p < 0.01). Obese adults had greater vBMD than normal adults at the tibia (p < 0.001 both ages) and radius (p < 0.001 older group), thicker cortices, higher cortical BMD and tissue mineral density, lower cortical porosity, higher trabecular BMD, and higher trabecular number than normal adults. There was no difference in bone size between obese and normal adults. Obese adults had greater estimated failure load at the radius (p < 0.05) and tibia (p < 0.01). Differences in HR‐pQCT measurements between obese and normal adults were seen more consistently in the older than the younger group. Bone turnover markers were lower in obese than in normal adults. Greater BMD in obesity is not an artifact of DXA measurement. Obese adults have higher BMD, thicker and denser cortices, and higher trabecular number than normal adults. Greater differences between obese and normal adults in the older group suggest that obesity may protect against age‐related bone loss and may increase peak bone mass

    Validation of calcaneus trabecular microstructure measurements by HR-pQCT

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    OBJECTIVE: Assessment of calcaneus microstructure using high-resolution peripheral quantitative computed tomography (HR-pQCT) might be used to improve fracture risk predictions or to assess responses to pharmacological and physical interventions. To develop a standard clinical protocol for the calcaneus, we validated calcaneus trabecular microstructure measured by HR-pQCT against 'gold-standard' micro-CT measurements. METHODS: Ten human cadaveric feet were scanned in situ using HR-pQCT (isotropic 82μm voxel size) at 100, 150 and 200ms integration times, and at 100ms integration time following removal of the calcaneus from the foot (ex vivo). Dissected portions of these bones were scanned using micro-computed tomography (micro-CT) at an isotropic 17.4μm voxel size. HR-pQCT images were rigidly registered to those obtained with micro-CT and divided into multiple 5mm sided cubes to evaluate and compare morphometric parameters between the modalities. Standard HR-pQCT measurements (derived bone volume fraction (BV/TV(d)); trabecular number, Tb.N; derived trabecular thickness, Tb.Th(d); derived trabecular spacing, Tb.Sp(d)) and corresponding micro-CT voxel-based measurements (BV/TV, Tb.N, Tb.Th, Tb.Sp) were compared. RESULTS: A total of 108 regions of interest were analysed across the 10 specimens. At all integration times HR-pQCT BV/TV(d) was strongly correlated with micro-CT BV/TV (r(2)=0.95-0.98, RMSE=1%), but BV/TV(d) was systematically lower than that measured by micro-CT (mean bias=5%). In contrast, HR-pQCT systematically overestimated Tb.N at all integration times; of the in situ scans, 200ms yielded the lowest mean bias and the strongest correlation with micro-CT (r(2)=0.61, RMSE=0.15mm(-1)). Regional analysis revealed greater accuracy for Tb.N in the superior regions of the calcaneus at all integration times in situ (mean bias=0.44-0.85mm(-1); r(2)=0.70-0.88, p<0.001 versus mean bias=0.63-1.46mm(-1); r(2)<0.10, p≥0.21 for inferior regions). Tb.Sp(d) was underestimated by HR-pQCT compared to micro-CT, but showed similar trends with integration time and the region evaluated as Tb.N. HR-pQCT Tb.Th(d) was also underestimated (mean bias=0.081-0.102mm) and moderately correlated (r(2)=0.55-0.59) with micro-CT Tb.Th, independently from the integration time. Stronger correlations, smaller biases and error were found in the scans of the calcaneus ex vivo compared to in situ. CONCLUSION: Calcaneus trabecular BV/TV(d) and trabecular microstructure, particularly in the superior region of the calcaneus, can be assessed by HR-pQCT. The highest integration time examined, 200ms, compared best with micro-CT. Weaker correlations for microstructure at inferior regions, and also with lower integration times, might limit the use of the proposed protocol, which warrants further investigation in vivo

    The effect of teriparatide treatment on circulating periostin and its relationship to regulators of bone formation and BMD in postmenopausal women with osteoporosis

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    Context: Treatment of postmenopausal osteoporosis with teriparatide (PTH 1-34) increases bone formation and improves bone microarchitecture. A possible modulator of this mechanism of action is periostin. In vitro experiments have shown that periostin may regulate osteoblast differentiation and bone formation through Wnt signaling. Periostin secretion is increased by PTH in preclinical models, but the effect of teriparatide treatment of postmenopausal osteoporosis on periostin is not currently known. Objectives, to: i) determine the effect of teriparatide treatment on circulating levels of periostin and other regulators of bone formation and ii) investigate how changes in periostin relate to changes in bone turnover markers, regulators of bone formation and bone mineral density. Participants and design: 20 women with postmenopausal osteoporosis, a two-year open-label single-arm study. Intervention: Teriparatide 20 mcg was administered by subcutaneous injection daily over 104 weeks. Periostin, sclerostin and DKK-1, PINP and CTX were measured in fasting serum collected at baseline (two visits) then at weeks 1,2,4,12,26,52,78 and 104. BMD was measured at the lumbar spine, total hip and femoral neck by DXA. Results: Periostin levels increased by 6.6% (95% CI -0.4, 13.5) after 26 weeks teriparatide treatment and significantly by 12.5% (95% CI 3.3,21.0, P<0.01) after 52 weeks. Change in periostin was positively correlated with change in lumbar spine BMD at week 52 (r=0.567(95% CI 0.137,0.817), P<0.05) and femoral neck BMD at week 104(r=0.682(95% CI 0.261,0.885), P<0.01). Conclusion: Teriparatide therapy increases periostin secretion; it is unclear whether this increase mediates the effect of the drug on bone

    Bone remodeling and responsiveness to mechanical stimuli in individuals with type 1 diabetes mellitus.

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    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

    Personalised 3D assessment of trochanteric soft tissues improves hip fracture classification accuracy

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    CT-based 3D characterisation of trochanteric soft-tissue thickness for more accurate hip fracture risk predictio

    High-impact exercise stimulated localised adaptation of microarchitecture across distal tibia in postmenopausal women

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    SummaryWe provided evidence that a 6-month regular hopping exercise intervention can increase trabecular number and possibly trabecular volume fraction of the distal tibia. Our novel localised analysis demonstrated region-specific changes, predominantly in the anterior region, in postmenopausal women.IntroductionThe localisation of bone remodelling and microarchitectural adaptation to exercise loading has not been demonstrated previously in vivo in humans. The aim of this study is to assess the feasibility of using 3D image registration and high-resolution peripheral quantitative computed tomography (HR-pQCT) to investigate the effect of high-impact exercise on human trabecular bone variables and remodelling rate across the distal tibia.MethodsTen postmenopausal women were recruited for 6-month unilateral hopping exercises, with HR-pQCT scans taken of both exercise leg (EL) and control leg (CL) for each participant before and after the intervention. A 3D image registration was used to ensure measurements were taken at the same region. Short-term reproducibility tests were conducted prior to the assessment using identical setup. The results were assessed comparing CL and EL, and interaction (time × leg) using a two-way repeated measures analysis of variance (RM-ANOVA).ResultsAcross the whole tibia, we observed significant increases in trabecular number (Tb.N) (+ 4.4%) and trabecular bone formation rate (tBFR) (3.3%), and a non-significant increase in trabecular bone volume fraction (BV/TV) (+ 1%) in the EL. Regional resorption was higher in the CL than the EL, with this difference being statistically significant at the lateral tibia. In the EL, tBFR was significantly higher in the anterior region than the medial but a trabecular bone resorption rate (tBRR) showed no significant regional variation. Conversely in the CL, both tBFR and tBRR were significantly higher in the anterior and lateral than the medial region.ConclusionWe demonstrated that it was possible to detect exercise-related bone adaptation with 3D registration of HR-pQCT scan data. Regular hopping exercise increased Tb.N and possibly BV/TV across the whole distal tibia. A novel finding of the study was that tBFR and tBRR responses to loading were localised: changes were achieved by formation rate exceeding resorption rate in the exercise leg, both globally and at the anterior region where turnover was greatest.Trial registrationclinicaltrials.gov: NCT03225703</div
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