Cortical measurements of the tibia from high resolution peripheral quantitative computed tomography images: A comparison with synchrotron radiation micro-computed tomography

High resolution-peripheral quantitative computed tomography (HR-pQCT) measurements are carried out in clinical research protocols to analyze cortical bone. Micro-computed tomography (micro-CT) is a standard tool for ex vivo examination of bone in 3D. The aim of this work was to evaluate cortical measurements derived from HR-pQCT images compared to those from synchrotron radiation (SR) micro-CT in a distal position (4.2 cm from the distal pilon).Twenty-nine tibia specimens were scanned with HR-pQCT using protocols provided by the manufacturer. The standard measured outcomes included volumetric bone density (g HA/cm³) of the cortical region (Dcomp), and the cortical thickness (Ct.Th, mm). New features, such as cortical porosity (Ct.Po) and mean pore diameter (Ct.Po.Dm), were measured by an auto-contouring process. All tibias were harvested from the posterior region and imaged with SR micro-CT (voxel size = 7.5μm). The cortical thickness, (Ct.Th_micro-CT), porosity (PoV/TV), pore diameter, pore spacing, pore number, and degree of mineralization of bone (DMB) were obtained for SR micro-CT images. For standard measurements on HR-pQCT images, site matched analyses with micro-CT were completed to obtain Dcomp_local and Ct.Th_local.Dcomp was highly correlated to PoV/TV (r = − 0.84,p < 10^− 4) but not to DMB. Dcomp_local was correlated to PoV/TV (r = − 0.72, p < 10^− 4) and to DMB (r = 0.40, p > 0.05). Ct.Th_local and Ct.Th_micro-CT were moderately correlated (r = 0.53,p < 0.01). Ct.Th and Ct.Po results from the autocontouring process are influenced by the level of trabecularization of the cortical bone and need manual correction of the endosteal contour.Distal tibia is a reliable region to study cortical bone with Dcomp as the best parameter because it reflects both the micro-porosity (Havers canals) and macro-porosity (resorption lacunae) of the cortical bone.     

Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT

Quantitative cortical microarchitectural end points are important for understanding structure–function relations in the context of fracture risk and therapeutic efficacy. This technique study details new image-processing methods to automatically segment and directly quantify cortical density, geometry, and microarchitecture from HR-pQCT images of the distal radius and tibia.An automated segmentation technique was developed to identify the periosteal and endosteal margins of the distal radius and tibia and detect intracortical pore space morphologically consistent with Haversian canals. The reproducibility of direct quantitative cortical bone indices based on this method was assessed in a pooled data set of 56 subjects with two repeat acquisitions for each site. The in vivo precision error was characterized using root mean square coefficient of variation (RMSCV%) from which the least significant change (LSC) was calculated. Bland–Altman plots were used to characterize bias in the precision estimates.The reproducibility of cortical density and cross-sectional area measures was high (RMSCV < 1% and < 1.5%, respectively) with good agreement between young and elder medians. The LSC for cortical porosity (Ct.Po) was somewhat smaller in the radius (0.58%) compared with the distal tibia (0.84%) and significantly different between young and elder medians in the distal tibia (LSC: 0.75% vs. 0.92%, p < 0.001). The LSC for pore diameter and distribution (Po.Dm and Po.Dm.SD) ranged between 15 and 23 µm. Bland–Altman analysis revealed moderate bias for integral measures of area and volume but not for density or microarchitecture.This study indicates that HR-pQCT measures of cortical bone density and architecture can be measured in vivo with high reproducibility and limited bias across a biologically relevant range of values. The results of this study provide informative data for the design of future clinical studies of bone quality.     

Relationships between bone geometry,volumetric bone mineral density and bone microarchitecture of the distal radius and tibia with alcohol consumption

PurposeChronic heavy alcohol consumption is associated with bone density loss and increased fracture risk, while low levels of alcohol consumption have been reported as beneficial in some studies. However, studies relating alcohol consumption to bone geometry, volumetric bone mineral density (vBMD) and bone microarchitecture, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), are lacking.MethodsHere we report an analysis from the Hertfordshire Cohort Study, in which we studied associations between HR-pQCT measures at the distal radius and tibia and alcohol consumption in 376 participants (198 men and 178 women) aged 72.1–81.4 years.ResultsA total of 30 (15.2%), 90 (45.5%) and 78 (39.4%) men drank minimal/none (< 1 unit/week), low (≥ 1 unit/week and < 11 units/week) and moderate/high (≥ 11 units/week) amounts of alcohol respectively. These figures were 74 (41.8%), 80 (45.2%) and 23 (13.0%) respectively in women for minimal/none (< 1 unit/week), low (≥ 1 unit/week and < 8 units/week) and moderate/high (≥ 8 units/week). At the distal radius, after adjustment for confounding factors (age, BMI, smoking status, dietary calcium intake, physical activity and socioeconomic status and years since menopause and HRT use for women), men that drank low alcohol had lower cortical thickness (p = 0.038), cortical vBMD (p = 0.033), and trabecular vBMD (p = 0.028) and higher trabecular separation (p = 0.043) than those that drank none/minimal alcohol. Similar differences were shown between minimal/none and moderate/high alcohol although these only reached statistical significance for the cortical parameters. Interestingly, after similar adjustment, women showed similar differences in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia. However, women that drank moderate/high alcohol had significantly higher trabecular vBMD (p = 0.007), trabecular thickness (p = 0.026), and trabecular number (p = 0.042) and higher trabecular separation (p = 0.026) at the distal radius than those that drank low alcohol.ConclusionsOur results suggest that alcohol consumption (low and moderate/high) may have a detrimental impact on bone health in men in both the cortical and trabecular compartments at the distal radius with similar results in women in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia suggesting that avoidance of alcohol may be beneficial for bone health.     

Spatial distribution of intracortical porosity varies across age and sex

Cortical bone porosity is a major determinant of strength, stiffness, and fracture toughness of cortical tissue. The goal of this work was to investigate changes in spatial distribution and microstructure of cortical porosity associated with aging in men and women. The specific aims were to: 1) develop an automated technique for spatial analysis of cortical microstructure based on HR-pQCT data, and; 2) apply this technique to explore sex- and age-specific spatial distribution and microstructure of porosity within the cortex. We evaluated HR-pQCT images of the distal tibia from a cross-sectional cohort of 145 individuals, characterizing detectable pores as being in the endosteal, midcortical, or periosteal layers of the cortex. Metrics describing porosity, pore number, and pore size were quantified within each layer and compared across sexes, age groups, and cortical layers. The elderly cohort (65–78 years, n = 22) displayed higher values than the young cohort (20–29 years, n = 29) for all parameters both globally and within each layer. While all three layers displayed significant age-related porosity increases, the greatest difference in porosity between the young and elderly cohort was in the midcortical layer (+ 344%, p < 0.001). Similarly, the midcortical layer reflected the greatest differences between young and elderly cohorts in both pore number (+ 243%, p < 0.001) and size (+ 28%, p < 0.001). Females displayed greater age-related changes in porosity and pore number than males. Females and males displayed comparable small to non-significant changes with age in pore size. In summary, considerable variability exists in the spatial distribution of detectable cortical porosity at the distal tibia, and this variability is dependent on age and sex. Intracortical pore distribution analysis may ultimately provide insight into both mechanisms of pore network expansion and biomechanical consequences of pore distribution.     

The pitfall of treating low bone turnover: Effects on cortical porosity

Although it is recognized that cortical bone contributes significantly to the mechanical strength of the skeleton, little is known about this compartment from bone biopsy studies, particularly in CKD patients. In addition, there is no prospective data on the effects of CKD-MBD therapy on cortical porosity (Ct.Po). This is a post hoc analysis on data from a randomized controlled trial on the effects of different phosphate binders on bone remodelling. Therapy was adjusted according to the first biopsy, and included sevelamer or calcium acetate, calcitriol and changes in calcium dialysate concentration. We measured Ct.Po at baseline and one year after. Fifty-two patients (46 ± 13 years old, 67% women and 60% white) were enrolled. Ct.Po was already high at baseline in 85% of patients [30% (17, 46)] and correlated with PTH (p = 0.001). Low bone turnover was seen in 28 patients (54.9%). After one-year treatment, PTH increased in patients with low turnover, as intended. However, increased Ct.Po was seen in 49 patients (94%). This increase correlated with the delta of phosphate (p = 0.015) and the delta of PTH (p = 0.03); it was also higher among non-white patients than in white patients (p = 0.039). The risk of increase in Ct.Po was 4.5 higher among non-white patients. Adjusted multiple regression analysis showed that the delta of Ct.Po was dependent on delta PTH and race (r² = 0.193). We concluded that in an attempt to increase bone turnover, the increase in PTH levels might be associated with higher cortical porosity, particularly in non-white patients. Whether this finding leads to a high risk of fracture deserves further investigation.     

Changes in cortical microarchitecture are independent of areal bone mineral density in patients with fragility fractures

Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) are commonly used to assess the areal bone mineral density (aBMD) and peripheral microstructure, respectively. While DXA is the standard to diagnose osteoporosis, HR-pQCT provides information about the cortical and trabecular architecture. Many fragility fractures occur in patients who do not meet the osteoporosis criterion (i.e., T-score ≤ −2.5). We hypothesize that patients with T-score above −2.5 and fragility fracture may have abnormal bone microarchitecture. Therefore, in this retrospective clinical study, HR-pQCT data obtained from patients with fragility fractures and T-scores ≥ −2.5 (n = 71) were compared to corresponding data from patients with fragility fractures and T-scores ≤ −3.5 (n = 56). Types of secondary osteoporosis were excluded from the study. To verify the dependency of alterations in bone microarchitecture and T-score, the association between HR-pQCT values and aBMD as reflected by the T-score at both proximal femora, was assessed. At the distal tibia, cortical thickness was lower (p < 0.001), cortical porosity was similar (p = 0.61), trabecular number was higher (p < 0.001), and bone volume fraction (BV/TV) was higher (p < 0.001) in patients with T-scores ≥ −2.5 than in patients with T-scores ≤ −3.5. Trabecular number and BV/TV correlated with T-score (r = 0.68, p < 0.001; r = 0.61, p < 0.001), whereas the cortical values did not. Our results thus demonstrate the importance of bone structure, as assessed by HR-pQCT, in addition to the standard DXA T-score in the diagnosis of osteoporosis.     

Significant bone microarchitecture impairment in premenopausal women with active celiac disease

Patients with active celiac disease (CD) are more likely to have osteoporosis and increased risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) permits three-dimensional exploration of bone microarchitectural characteristics measuring separately cortical and trabecular compartments, and giving a more profound insight into bone disease pathophysiology and fracture. We aimed to determine the volumetric and microarchitectural characteristics of peripheral bones—distal radius and tibia—in an adult premenopausal cohort with active CD assessed at diagnosis. We prospectively enrolled 31 consecutive premenopausal women with newly diagnosed CD (median age 29 years, range: 18–49) and 22 healthy women of similar age (median age 30 years, range 21–41) and body mass index. Compared with controls, peripheral bones of CD patients were significantly lower in terms of total volumetric density mg/cm³ (mean ± SD: 274.7 ± 51.7 vs. 324.7 ± 45.8, p 0.0006 at the radius; 264.4 ± 48.7 vs. 307 ± 40.7, p 0.002 at the tibia), trabecular density mg/cm³ (118.6 ± 31.5 vs. 161.9 ± 33.6, p < 0.0001 at the radius; 127.9 ± 28.7 vs. 157.6 ± 15.6, p < 0.0001 at the tibia); bone volume/trabecular volume ratio % (9.9 ± 2.6 vs. 13.5 ± 2.8, p < 0.0001 at the radius; 10.6 ± 2.4 vs. 13.1 ± 1.3, p < 0.0001 at the tibia); number of trabeculae 1/mm (1.69 ± 0.27 vs. 1.89 ± 0.26, p 0.009 at the radius; 1.53 ± 0.32 vs. 1.80 ± 0.26, p 0.002 at the tibia); and trabecular thickness mm (0.058 ± 0.010 vs. 0.071 ± 0.008, p < 0.0001 at the radius with no significant difference at the tibia). Cortical density was significantly lower in both regions (D comp mg/cm³ 860 ± 57.2 vs. 893.9 ± 43, p 0.02; 902.7 ± 48.7 vs. 932.6 ± 32.6, p 0.01 in radius and tibia respectively). Although cortical thickness was lower in CD patients, it failed to show any significant inter-group difference (a—8% decay with p 0.11 in both bones). Patients with symptomatic CD (n = 22) had a greater bone microarchitectural deficit than those with subclinical CD. HR-pQCT was used to successfully identify significant deterioration in the microarchitecture of trabecular and cortical compartments of peripheral bones. Impairment was characterized by lower trabecular number and thickness—which increased trabecular network heterogeneity—and lower cortical density and thickness. In the prospective follow-up of this group of patients we expect to be able to assess whether bone microarchitecture recovers and to what extend after gluten-free diet.     

The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: Findings from a pQCT case–control study

High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans.pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls.HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm³), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p < 0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β ? 0.01 [? 0.02, 0.01], p = 0.41), but declined in family controls (? 0.05 [? 0.03, ? 0.07], p < 0.001) interaction p = 0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD.HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.     

Lean mass and fat mass have differing associations with bone microarchitecture assessed by high resolution peripheral quantitative computed tomography in men and women from the Hertfordshire Cohort Study

Understanding the effects of muscle and fat on bone is increasingly important in the optimisation of bone health. We explored relationships between bone microarchitecture and body composition in older men and women from the Hertfordshire Cohort Study. 175 men and 167 women aged 72–81 years were studied. High resolution peripheral quantitative computed tomography (HRpQCT) images (voxel size 82 μm) were acquired from the non-dominant distal radius and tibia with a Scanco XtremeCT scanner. Standard morphological analysis was performed for assessment of macrostructure, densitometry, cortical porosity and trabecular microarchitecture. Body composition was assessed using dual energy X-ray absorptiometry (DXA) (Lunar Prodigy Advanced). Lean mass index (LMI) was calculated as lean mass divided by height squared and fat mass index (FMI) as fat mass divided by height squared. The mean (standard deviation) age in men and women was 76 (3) years. In univariate analyses, tibial cortical area (p < 0.01), cortical thickness (p < 0.05) and trabecular number (p < 0.01) were positively associated with LMI and FMI in both men and women. After mutual adjustment, relationships between cortical area and thickness were only maintained with LMI [tibial cortical area, β (95% confidence interval (CI)): men 6.99 (3.97,10.01), women 3.59 (1.81,5.38)] whereas trabecular number and density were associated with FMI. Interactions by sex were found, including for the relationships of LMI with cortical area and FMI with trabecular area in both the radius and tibia (p < 0.05). In conclusion, LMI and FMI appeared to show independent relationships with bone microarchitecture. Further studies are required to confirm the direction of causality and explore the mechanisms underlying these tissue-specific associations.     

Effects of insulin therapy on porosity,non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitus

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats.Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0 IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence.Diabetes led to increased NEG (+ 50.1%, p = 0.001) and Ct.Po (+ 22.9%, p = 0.004), as well as to reduced mechanical competence (max. stress: − 14.2%, p = 0.041, toughness: − 29.7%, p = 0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R² = 0.41, p < 0.001, Ct.Po: R² = 0.34, p = 0.003) and HbA1c (NEG: R² = 0.42, p < 0.001, Ct.Po: R² = 0.28, p = 0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R² = 0.21, p = 0.023, yield stress: R² = 0.17, p = 0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue.A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone.     

A case–control study of fractures in men with idiopathic osteoporosis: Fractures are associated with older age and low cortical bone density

ObjectivesTo determine biochemical, radiological and micro-architectural bone factors related to fragility fractures in idiopathic male osteoporosis (IMO) patients. IMO is a rare disorder characterized by low areal bone mineral density (aBMD) (Z-score < ? 2) occurring in men after excluding secondary causes of low BMD.MethodsWe conducted a case–control study in 31 patients with fragility fracture (IMO F +) that had occurred after the age of 40 years and 37 without fracture (IMO F–). We first compared IMO group to 40 age-matched disease-free men. We measured aBMD and bone micro-architectural indices at distal radius and tibia sites with a HR-pQCT scan (XtremeCT) using standard and extended cortical analysis. Urine and blood samples were collected in order to determine the levels of bone-turnover markers and the potential determinant of bone fragility. Models of analysis of covariance, including age, height and weight as adjustment factors, were used to compare the groups.ResultsCompared to their controls, IMO patients showed marked disturbance of their micro‐architectural parameters at tibia and radius affecting both trabecular and cortical parameters. IMO F + subjects were significantly older than IMO F ? subjects (58 ± 8 vs. 53 ± 9 yrs, p = 0.01). BMD Z-score at the total-hip was significantly lower in IMO F + (? 1.3 ± 0.5 vs. ? 0.9 ± 0.8 g/cm², p = 0.01). After adjustment, trabecular micro‐architectural parameters, biochemical markers and hormonal parameters were not different in the 2 groups. At distal tibia, cortical v-BMD was significantly lower in IMO F + patients (799 ± 73 vs. 858 ± 60 mg/cm³, p = 0.03), while cortical thickness was not different.ConclusionOur results show that patients with IMO display a marked disturbance of trabecular and cortical bone micro-architecture, and that age and low cortical density are determinants of the fracture occurrence.     

Lower Cortical Porosity and Higher Tissue Mineral Density in Chinese American Versus White Women

Asian women have lower rates of hip and forearm fractures compared to other racial groups despite lower areal bone mineral density (aBMD). We have demonstrated microarchitectural differences, including greater cortical thickness (Ct.Th) and cortical volumetric BMD (Ct.BMD), in Chinese American versus white women. Yet it is not known whether greater Ct.BMD in Chinese American women is a result of greater tissue mineral density (TMD) or reduced cortical porosity (Ct.Po). Using an advanced segmentation algorithm based on high‐resolution peripheral quantitative computed tomography (HR‐pQCT) images, we tested the hypothesis that Chinese American women have better cortical skeletal integrity owing to lower Ct.Po and higher Ct.TMD compared with white women. A total of 78 Chinese American women (49 premenopausal and 29 postmenopausal) and 114 white women (46 premenopausal and 68 postmenopausal) were studied. Premenopausal Chinese American versus white women had greater Ct.Th, Ct.BMD, and Ct.TMD at both the radius and tibia, and decreased Ct.Po (p < 0.05). A similar pattern was observed between postmenopausal Chinese American and white women. As expected, postmenopausal versus premenopausal women had lower Ct.BMD at the radius and tibia in both races (p < 0.001). Ct.Po largely increased between premenopausal and postmenopausal women, whereas Ct.TMD decreased by 3% to 8% (p < 0.001) in both races. Age‐related differences in Ct.Po and Ct.TMD did not differ by race. In summary, both reduced Ct.Po and greater Ct.TMD explain higher Ct.BMD in Chinese American versus white women. Thicker and preserved cortical bone structure in Chinese American women may contribute to greater resistance to fracture compared to white women. © 2014 American Society for Bone and Mineral Research.     

Tibia and radius bone geometry and volumetric density in obese compared to non-obese adolescents

Childhood obesity is associated with biologic and behavioral characteristics that may impact bone mineral density (BMD) and structure. The objective was to determine the association between obesity and bone outcomes, independent of sexual and skeletal maturity, muscle area and strength, physical activity, calcium intake, biomarkers of inflammation, and vitamin D status. Tibia and radius peripheral quantitative CT scans were obtained in 91 obese (BMI > 97th percentile) and 51 non-obese adolescents (BMI > 5th and < 85th percentiles). Results were converted to sex- and race-specific Z-scores relative to age. Cortical structure, muscle area and muscle strength (by dynamometry) Z-scores were further adjusted for bone length. Obese participants had greater height Z-scores (p < 0.001), and advanced skeletal maturity (p < 0.0001), compared with non-obese participants. Tibia cortical section modulus and calf muscle area Z-scores were greater in obese participants (1.07 and 1.63, respectively, both p < 0.0001). Tibia and radius trabecular and cortical volumetric BMD did not differ significantly between groups. Calf muscle area and strength Z-scores, advanced skeletal maturity, and physical activity (by accelerometry) were positively associated with tibia cortical section modulus Z-scores (all p < 0.01). Adjustment for muscle area Z-score attenuated differences in tibia section modulus Z-scores between obese and non-obese participants from 1.07 to 0.28. After multivariate adjustment for greater calf muscle area and strength Z-scores, advanced maturity, and less moderate to vigorous physical activity, tibia section modulus Z-scores were 0.32 (95% CI − 0.18, 0.43, p = 0.06) greater in obese, vs. non-obese participants. Radius cortical section modulus Z-scores were 0.45 greater (p = 0.08) in obese vs. non-obese participants; this difference was attenuated to 0.14 with adjustment for advanced maturity. These findings suggest that greater tibia cortical section modulus in obese adolescents is attributable to advanced skeletal maturation and greater muscle area and strength, while less moderate to vigorous physical activities offset the positive effects of these covariates. The impact of obesity on cortical structure was greater at weight bearing sites.     

Increased cortical area and thickness in the distal radius in subjects with SHOX-gene mutation

IntroductionShort-stature homeobox (SHOX) gene haploinsufficiency may cause skeletal dysplasia including Léri–Weill Dyschondrosteosis (LWD), a clinical entity characterised by the triad of low height, mesomelic disproportion and Madelung's deformity of the wrist. Bone microarchitecture and estimated strength in adult SHOX mutation carriers have not been examined.MethodsTwenty-two subjects with a SHOX mutation including 7 males and 15 females with a median age of 38.8 [21.1–52.2] years were recruited from five unrelated families. The control group consisted of 22 healthy subjects matched on age and sex. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Bone geometry, volumetric density, microarchitecture and finite element estimated (FEA) bone strength were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). A full region of interest (ROI) image analysis and height-matched ROI analyses adjusting for differences in body height between the two groups were performed.ResultsAreal BMD and T-scores showed no significant differences between cases and controls. Total radius area was smaller in cases than controls (207 [176–263] vs. 273 [226–298] mm, p < 0.01). Radius cortical bone area (74 ± 20 vs. 58 ± 17 mm², p = 0.01) and thickness (1.16 ± 0.30 vs. 0.84 ± 0.26 mm, p < 0.01) as well as total density (428 ± 99 vs. 328 ± 72 mg/cm³, p < 0.01) were higher in SHOX mutation carriers compared to controls. Radius trabecular bone area (119 [103–192] vs. 202 [168–247] mm², p < 0.01) and trabecular number (1.61 [1.46–2.07] vs. 1.89 [1.73–2.08] mm^− 1, p = 0.01) were smaller in SHOX mutation carriers. Tibia trabecular thickness was lower in cases (0.067 ± 0.012 vs. 0.076 ± 0.012 mm, p = 0.01). These results remained significant after adjustment for differences in body height and when restricting analyses to females. There were no differences in BMD, radius and tibia cortical porosity or FEA failure load between groups. A segment of cortical bone defect was identified in the distal radius adjacent to ulna in five unrelated SHOX mutation carriers.ConclusionSubjects with a SHOX mutation presented with a different bone geometry in radius and tibia while there were no differences in BMD or failure load compared to controls, suggesting that mutations in SHOX gene may have an impact on bone microarchitecture albeit not bone strength.     

Regional fat depots and their relationship to bone density and microarchitecture in young oligo-amenorrheic athletes

ContextVarious fat depots have differential effects on bone. Visceral adipose tissue (VAT) is deleterious to bone, whereas subcutaneous adipose tissue (SAT) has positive effects. Also, marrow adipose tissue (MAT), a relatively newly recognized fat depot is inversely associated with bone mineral density (BMD). Bone mass in athletes depends on many factors including gonadal steroids and muscle mass. Exercise increases muscle mass and BMD, whereas, estrogen deficiency decreases BMD. Thus, the beneficial effects of weight-bearing exercise on areal and volumetric BMD (aBMD and vBMD) in regularly menstruating (eumenorrheic) athletes (EA) are attenuated in oligo-amenorrheic athletes (OA). Of note, data regarding VAT, SAT, MAT and regional muscle mass in OA compared with EA and non-athletes (C), and their impact on bone are lacking.MethodsWe used (i) MRI to assess VAT and SAT at the L4 vertebra level, and cross-sectional muscle area (CSA) of the mid-thigh, (ii) 1H-MRS to assess MAT at L4, the proximal femoral metaphysis and mid-diaphysis, (iii) DXA to assess spine and hip aBMD, and (iv) HRpQCT to assess vBMD at the distal radius (non-weight-bearing bone) and tibia (weight-bearing bone) in 41 young women (20 OA, 10 EA and 11 C 18–25 years). All athletes engaged in weight-bearing sports for ≥ 4 h/week or ran ≥ 20 miles/week.Main outcome measuresVAT, SAT and MAT at L4; CSA of the mid-thigh; MAT at the proximal femoral metaphysis and mid-diaphysis; aBMD, vBMD and bone microarchitecture.ResultsGroups had comparable age, menarchal age, BMI, VAT, VAT/SAT and spine BMD Z-scores. EA had higher femoral neck BMD Z-scores than OA and C. Fat mass was lowest in OA. SAT was lowest in OA (p = 0.048); L4 MAT was higher in OA than EA (p = 0.03). We found inverse associations of (i) VAT/SAT with spine BMD Z-scores (r = − 0.42, p = 0.01), (ii) L4 MAT with spine and hip BMD Z-scores (r = − 0.44, p = 0.01; r = − 0.36, p = 0.02), and vBMD of the radius and tibia (r = − 0.49, p = 0.002; r = − 0.41, p = 0.01), and (iii) diaphyseal and metaphyseal MAT with vBMD of the radius (r ≤ − 0.42, p ≤ 0.01) and tibia (r ≤ − 0.34, p ≤ 0.04). In a multivariate model including VAT/SAT, L4 MAT and thigh CSA, spine and hip BMD Z-scores were predicted inversely by L4 MAT and positively by thigh CSA, and total and cortical radius and total tibial vBMD were predicted inversely by L4 MAT. VAT/SAT did not predict radius or tibia total vBMD in this model, but inversely predicted spine BMD Z-scores. When L4 MAT was replaced with diaphyseal or metaphyseal MAT in the model, diaphyseal and metaphyseal MAT did not predict aBMD Z-scores, but diaphyseal MAT inversely predicted total vBMD of the radius and tibia. These results did not change after adding percent body fat to the model.ConclusionsVAT/SAT is an inverse predictor of lumbar spine aBMD Z-scores, while L4 MAT is an independent inverse predictor of aBMD Z-scores at the spine and hip and vBMD measures at the distal tibia and radius in athletes and non-athletes. Diaphyseal MAT independently predicts vBMD measures of the distal tibia and radius.     

Bone micro-architecture,estimated bone strength,and the muscle-bone interaction in elite athletes: An HR-pQCT study

Athletes participating in sports characterized by specific loading modalities have exhibited different levels of augmentation of bone properties; however, the extent to which these loading environments affect bone micro-architecture and estimated bone strength (i.e. bone quality) remains unclear. Furthermore, the relative role of impact loading versus loading due to muscle forces in determining bone properties is confounded. The objectives of this study were 1) to examine the role of impact loading on bone quality of the distal radius and distal tibia in elite athletes, as determined by high resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA), and 2) to investigate the relationship between bone quality and muscle strength in elite athletes. Ninety-five females (n = 59) and males (n = 36) between the ages of 16–30 years participated in the study. Participants included alpine skiers (high-impact), soccer players (moderate impact), swimmers (low-impact), and non-athletic controls.All group comparisons were made after accounting for age, height, and body mass. As expected, minimal differences in HR-pQCT parameters across groups were observed at the non weight-bearing distal radius. At the weight-bearing distal tibia, female alpine skiers and soccer players had significantly higher bone density, cortical thickness, and failure load (i.e. bone strength (N) in compression estimated by FEA) than swimmers (p < 0.05). Female alpine skiers also had lower trabecular separation than swimmers and controls. Male alpine skiers had 20% higher trabecular bone mineral density than swimmers, and male soccer players exhibited 22% higher trabecular number than swimmers at the distal tibia (p < 0.05). Male alpine skiers and soccer players had 28–38% higher failure load at the distal tibia than swimmers. No differences in bone parameters were observed between swimmers and controls for either sex at either site. Both muscle strength and sporting activity were predictors of failure load at the distal tibia in the female cohort. Sporting activity, but not muscle strength, was a significant predictor of failure load in the male cohort at both the radius and tibia. This data suggests that impact loading in sporting activity is highly associated with bone quality. Longitudinal and interventional studies are required to further clarify the muscle–bone interaction.     

Objectively measured physical activity is associated with parameters of bone in 70-year-old men and women

As the world's population ages, the occurrence of osteoporosis-related fractures is projected to increase. Low areal bone mineral density (aBMD), a well-known risk factor for fractures, may be influenced by physical activity (PA). In this cross-sectional study, we aimed to investigate potential associations between objective measures of PA and bone properties, in a population-based cohort of 1228 70-year-old men and women. We measured volumetric BMD (vBMD, mg/cm³) together with cross-sectional area (CSA, mm²) by peripheral quantitative computed tomography at sites located 4% and 66% in the distal–proximal trajectory at the tibia and radius. We also measured aBMD (g/cm²) by dual energy X-ray absorptiometry at the femoral neck, lumbar spine (L1–L4) and radius. Participants wore triaxial accelerometers for 7 consecutive days to obtain objective estimates of PA. The intensity of the objective PA was divided into light (100–1951 counts/min [CPM]), moderate (1952–5724 cpm) and vigorous (≥ 5725 cpm). Maximal accelerations for the anterior–posterior (z), medio-lateral (x), and vertical (y) axes were also separately assessed. Associations were investigated using bivariate correlations and multiple linear regression, adjusted for height, weight and sex. Vigorous PA showed the strongest association with femoral neck aBMD (β = 0.09, p < 0.001), while both moderate and vigorous PAs were associated with cortical area and trabecular vBMD in the weight-bearing tibia (all p < 0.05). Peak vertical accelerations were associated significantly with cortical area (β = 0.09, p < 0.001) and trabecular vBMD (β = 0.09, p = 0.001) of the tibia, whereas peak anterior–posterior accelerations showed no correlation with these properties. No positive association was found between objectively measured PA and bone parameters of the radius. In conclusion, vertical accelerations and moderate to vigorous PA independently predict bone properties, especially in the weight-bearing tibia, in 70-year-old men and women.     

Effects of parathyroid hormone on cortical porosity,non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitus

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and the efficacy of bone-forming agents are unclear. We studied diabetes and parathyroid hormone (PTH) treatment effects on cortical porosity (Ct.Po), non-enzymatic glycation (NEG) and bone mechanics in Zucker diabetic fatty (ZDF) rats.Eleven-week old ZDF diabetic (DB) and non-diabetic (ND) rats were given 75 μg/kg PTH (1–84) or vehicle 5 days per week over 12 weeks. The right femora and L4 vertebrae were excised, micro-CT scanned, and tested in 3-point bending and uniaxial compression, respectively. NEG of the samples was determined using fluorescence.Diabetes increased Ct.Po (vertebra (vert): + 40.6%, femur (fem): + 15.5% vs. ND group, p < 0.05) but had no effect on NEG. PTH therapy reduced vertebral NEG in the ND animals only (− 73% vs untreated group, p < 0.05), and increased femoral NEG in the DB vs. ND groups (+ 63%, p < 0.05). PTH therapy had no effect on Ct.Po. Diabetes negatively affected bone tissue mechanics where reductions in vertebral maximum strain (− 22%) and toughness (− 42%) were observed in the DB vs. ND group (p < 0.05). PTH improved maximum strain in the vertebra of the ND animals (+ 21%, p < 0.05) but did not have an effect in the DB group. PTH increased femoral maximum strain (+ 21%) and toughness (+ 28%) in ND and decreased femoral maximum stress (− 13%) and toughness (− 27%) in the DB animals (treated vs. untreated, p < 0.05). Ct.Po correlated negatively with maximum stress (fem: R = − 0.35, p < 0.05, vert: R = − 0.57, p < 0.01), maximum strain (fem: R = − 0.35, p < 0.05, vert: R = − 0.43, p < 0.05) and toughness (fem: R = − 0.34, p < 0.05, vert: R = − 0.55, p < 0.01), and NEG correlated negatively with toughness at the femur (R = − 0.34, p < 0.05) and maximum strain at the vertebra (R = − 0.49, p < 0.05).Diabetes increased cortical porosity and reduced bone mechanics, which were not improved with PTH treatment. PTH therapy alone may worsen diabetic bone mechanics through formation of new bone with high AGEs cross-linking. Optimal treatment regimens must address both improvements of bone mass and glycemic control in order to successfully reduce diabetic bone fragility.This article is part of a Special Issue entitled “Bone and diabetes”.     

Effect of odanacatib on bone turnover markers,bone density and geometry of the spine and hip of ovariectomized monkeys: A head-to-head comparison with alendronate

Odanacatib (ODN) is a selective and reversible Cathepsin K (CatK) inhibitor currently being developed as a once weekly treatment for osteoporosis. Here, effects of ODN compared to alendronate (ALN) on bone turnover, DXA-based areal bone mineral density (aBMD), QCT-based volumetric BMD (vBMD) and geometric parameters were studied in ovariectomized (OVX) rhesus monkeys. Treatment was initiated 10 days after ovariectomy and continued for 20 months. The study consisted of four groups: L-ODN (2 mg/kg, daily p.o.), H-ODN (8/4 mg/kg daily p.o.), ALN (15 μg/kg, twice weekly, s.c.), and VEH (vehicle, daily, p.o.). L-ODN and ALN doses were selected to approximate the clinical exposures of the ODN 50-mg and ALN 70-mg once-weekly, respectively. L-ODN and ALN effectively reduced bone resorption markers uNTx and sCTx compared to VEH. There was no additional efficacy with these markers achieved with H-ODN. Conversely, ODN displayed inversely dose-dependent reduction of bone formation markers, sP1NP and sBSAP, and L-ODN reduced formation to a lesser degree than ALN. At month 18 post-OVX, L-ODN showed robust increases in lumbar spine aBMD (11.4%, p < 0.001), spine trabecular vBMD (13.7%, p < 0.001), femoral neck (FN) integral (int) vBMD (9.0%, p < 0.001) and sub-trochanteric proximal femur (SubTrPF) int vBMD, (6.4%, p < 0.001) compared to baseline. L-ODN significantly increased FN cortical thickness (Ct.Th) and cortical bone mineral content (Ct.BMC) by 22.5% (p < 0.001) and 21.8% (p < 0.001), respectively, and SubTrPF Ct.Th and Ct.BMC by 10.9% (p < 0.001) and 11.3% (p < 0.001) respectively. Compared to ALN, L-ODN significantly increased FN Ct. BMC by 8.7% (p < 0.05), and SubTrPF Ct.Th by 7.6% (p < 0.05) and Ct.BMC by 6.2% (p < 0.05). H-ODN showed no additional efficacy compared to L-ODN in OVX-monkeys in prevention mode. Taken together, the results from this study have demonstrated that administration of ODN at levels which approximate clinical exposure in OVX-monkeys had comparable efficacy to ALN in DXA-based aBMD and QCT-based vBMD. However, FN cortical mineral content clearly demonstrated superior efficacy of ODN versus ALN in this model of estrogen-deficient non-human primates.     

Challenges in longitudinal measurements with HR-pQCT: Evaluation of a 3D registration method to improve bone microarchitecture and strength measurement reproducibility

Definition of identical regions between repeated computed tomography (CT) scans is a key factor to monitor changes in bone microarchitecture. In longitudinal studies, accurate determination of the volume of interest (VOI), using three dimensional (3D) registration may improve precision. Therefore, the aim of our study was to investigate the short-term reproducibility of bone geometry, density, microstructure and biomechanical parameters assessed by HR-pQCT and micro-finite element (μFE) derived analyses, using the cross-sectional area (CSA) registration method in comparison with the use of 3D registration, to find overlapping regions between scans.Fifteen healthy individuals (aged 21–47 years) underwent 3 separate scans at the distal radius and tibia, within a one-month interval. Reproducibility was assessed after double contouring the cortical compartment and after applying three different methods to determine the common region between repeated scans: (i) the VOI was determined with no registration, i.e., on 110 slices, (ii) the VOI was determined after CSA-based registration, and (iii) the VOI was determined after 3D registration.Both pre- and post-registration short-term reproducibility for each subject was determined. With no registration, CV_rms of geometry parameters ranged from 0.5 to 3.7%, showing a slight variation in the CSA between scans. When the CSA registration method was employed, the variability of geometry (CV_rms < 1.8%) and density parameters (CV_rms < 1.8%), was better than that obtained without registration. By removing the effect of repositioning, the 3D registration further improved the reproducibility of cortical bone measurements compared to other methods. Indeed, significant improvements were found for cortical geometry and microstructure measurements (CV_rms ranged from 0.4% to 10.7% at both sites; p < 0.05), whereas the impact on trabecular bone measurements was restricted to its geometry parameter. The repositioning error was significantly reduced, most markedly at the radius compared to the tibia.For μFE measures, the impact of 3D registration on whole bone stiffness was negligible, indicating adequate assessment of longitudinal changes in estimated biomechanical properties, even without registration.In conclusion, we have shown that the 3D registration improved the identification of the common region retained for longitudinal analysis, contributing to improve the reproducibility of cortical bone parameter measurements. We also quantified the minimally detectable bone changes to help designing future studies with HR-pQCT.