Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction

ContextYoung amenorrheic athletes (AA) have lower bone mineral density (BMD) and an increased prevalence of fracture compared with eumenorrheic athletes (EA) and non-athletes. Trabecular morphology is a determinant of skeletal strength and may contribute to fracture risk.ObjectivesTo determine the variation in trabecular morphology among AA, EA, and non-athletes and to determine the association of trabecular morphology with fracture among AA.Design and settingA cross-sectional study performed at an academic clinical research center.Participants161 girls and young women aged 14–26 years (97 AA, 32 EA, and 32 non-athletes).Main outcome measureWe measured volumetric BMD (vBMD) and skeletal microarchitecture using high-resolution peripheral quantitative computed tomography. We evaluated trabecular morphology (plate-like vs. rod-like), orientation, and connectivity by individual trabecula segmentation.ResultsAt the non-weight-bearing distal radius, the groups did not differ for trabecular vBMD. However, plate-like trabecular bone volume fraction (pBV/TV) was lower in AA vs. EA (p = 0.03), as were plate number (p = 0.03) and connectivity (p = 0.03). At the weight-bearing distal tibia, trabecular vBMD was higher in athletes vs. non-athletes (p = 0.05 for AA and p = 0.009 for EA vs. non-athletes, respectively). pBV/TV was higher in athletes vs. non-athletes (p = 0.04 AA and p = 0.005 EA vs. non-athletes), as were axially-aligned trabeculae, plate number, and connectivity. Among AA, those with a history of recurrent stress fracture had lower pBV/TV, axially-aligned trabeculae, plate number, plate thickness, and connectivity at the distal radius.ConclusionsTrabecular morphology and alignment differ among AA, EA, and non-athletes. These differences may be associated with increased fracture risk.     

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.     

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.     

Muscle volume is related to trabecular and cortical bone architecture in typically developing children

IntroductionMuscle is strongly related to cortical bone architecture in children; however, the relationship between muscle volume and trabecular bone architecture is poorly studied. The aim of this study was to determine if muscle volume is related to trabecular bone architecture in children and if the relationship is different than the relationship between muscle volume and cortical bone architecture.Materials and methodsForty typically developing children (20 boys and 20 girls; 6 to 12 y) were included in the study. Measures of trabecular bone architecture [i.e., apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp)] in the distal femur, cortical bone architecture [cortical volume, total volume, section modulus (Z) and polar moment of inertia (J)] in the midfemur, muscle volume in the midthigh and femur length were assessed using magnetic resonance imaging. Total physical activity and moderate-to-vigorous physical activity were assessed using an accelerometer-based activity monitor worn around the waist for four days. Calcium intake was assessed using diet records. Relationships among the measures were tested using multiple linear regression analysis.ResultsMuscle volume was moderately-to-strongly related to measures of trabecular bone architecture [appBV/TV (r = 0.81), appTb.N (r = 0.53), appTb.Th (r = 0.67), appTb.Sp (r = − 0.71); all p < 0.001] but more strongly related to measures of cortical bone architecture [cortical volume (r = 0.96), total volume (r = 0.94), Z (r = 0.94) and J (r = 0.92; all p < 0.001)]. Similar relationships were observed between femur length and measures of trabecular (p < 0.01) and cortical (p < 0.001) bone architecture. Sex, physical activity and calcium intake were not related to any measure of bone architecture (p > 0.05). Because muscle volume and femur length were strongly related (r = 0.91, p < 0.001), muscle volume was scaled for femur length (muscle volume/femur length^2.77). When muscle volume/femur length^2.77 was included in a regression model with femur length, sex, physical activity and calcium intake, muscle volume/femur length^2.77 was a significant predictor of appBV/TV, appTb.Th and appTb.Sp (partial r = 0.44 to 0.49, p < 0.05) and all measures of cortical bone architecture (partial r = 0.47 to 0.54; p < 0.01).ConclusionsThe findings suggest that muscle volume in the midthigh is related to trabecular bone architecture in the distal femur of typically developing children. The relationship is weaker than the relationship between muscle volume in the midthigh and cortical bone architecture in the midfemur, but the discrepancy is driven, in large part, by the greater dependence of cortical bone architecture measures on femur length.     

Longitudinal changes in lean mass predict pQCT measures of tibial geometry and mineralisation at 6–7 years

BackgroundStudies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However, little is known of the relationships between longitudinal changes in fat (FM) and lean mass (LM) and bone development in pre-pubertal children. We therefore investigated these associations in a population-based mother-offspring cohort, the Southampton Women's Survey.MethodsTotal FM and LM were assessed at birth and 6–7 years of age by dual-energy x-ray absorptiometry (DXA). At 6–7 years, total cross-sectional area (CSA) and trabecular volumetric BMD (vBMD) at the 4% site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength–strain index (SSI) were measured at the 38% site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (ΔLM) or FM (ΔFM) was represented by change in z-score from birth to 7 years old and conditioned on the birth measurement. Linear regression was used to explore the associations between ΔLM or ΔFM and standardised pQCT outcomes, before and after mutual adjustment and for linear growth. The β-coefficient represents SD change in outcome per unit SD change in predictor.ResultsDXA at birth, in addition to both DXA and pQCT scans at 6–7 years, were available for 200 children (48.5% male). ΔLM adjusted for ΔFM was positively associated with tibial total CSA at both the 4% (β = 0.57SD/SD, p < 0.001) and 38% sites (β = 0.53SD/SD, p < 0.001), cortical CSA (β = 0.48SD/SD, p < 0.001) and trabecular vBMD (β = 0.30SD/SD, p < 0.001), but not with cortical vBMD. These relationships persisted after adjustment for linear growth. In contrast, ΔFM adjusted for ΔLM was only associated with 38% total and cortical CSA, which became non-significant after adjustment for linear growth.ConclusionIn this study, gain in childhood LM was positively associated with bone size and trabecular vBMD at 6–7 years of age. In contrast, no relationships between change in FM and bone were observed, suggesting that muscle growth, rather than accrual of fat mass, may be a more important determinant of childhood bone development.     

Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa

BackgroundAnorexia nervosa (AN) is a psychiatric disorder characterized by self-induced starvation and low body weight. Women with AN have impaired bone formation, low bone mass and an increased risk of fracture. FGF-21 is a hormone secreted by the liver in starvation and FGF-21 transgenic mice have significant bone loss due to an uncoupling of bone resorption and bone formation. We hypothesized that FGF-21 may contribute to the low bone mass state of AN.Subjects and methodsWe studied 46 women: 20 with AN (median age [interquartile range]: 27.5 [25, 30.75] years) and 26 normal-weight controls (NWC) of similar age (25 [24, 28.5] years). We investigated associations between serum FGF-21 and 1) aBMD measured by dual energy X-ray absorptiometry, 2) parameters of bone microarchitecture in the distal radius and tibia measured by high-resolution peripheral quantitative CT and 3) bone strength, estimated by microfinite element analysis.ResultsFGF-21 levels were similar in AN and NWC (AN: 33.1 [18.1, 117.0] pg/ml vs. NWC: 57.4 [23.8, 107.1] pg/ml; p = 0.54). There was a significant inverse association between log FGF-21 and trabecular number in the radius in both AN (R = − 0.57, p < 0.01) and NWC (R = − 0.53, p < 0.01) and a significant positive association between log FGF-21 and trabecular separation in the radius in AN (R = 0.50, p < 0.03) and NWC (R = 0.52, p < 0.01). Estimates of radial bone strength were inversely associated with log FGF-21 in AN (R = − 0.50, p < 0.03 for both stiffness and failure load). There were no associations between FGF-21 and aBMD, cortical parameters or tibial parameters in the AN or NWC groups.ConclusionsFGF-21 may be an important determinant of trabecular skeletal homeostasis in AN.     

Low volumetric BMD is linked to upper-limb fracture in pubertal girls and persists into adulthood: A seven-year cohort study

The aetiology of increased incidence of fracture during puberty is unclear. This study aimed to determine whether low volumetric bone mineral density (vBMD) in the distal radius is associated with upper-limb fractures in growing girls, and whether any such vBMD deficit persists into adulthood. Fracture history from birth to 20 years was obtained and verified by medical records in 1034 Finnish girls aged 10–13 years. Bone density and geometry at distal radius, biomarkers and lifestyle/behavioural factors were assessed in a subset of 396 girls with a 7.5-year follow-up. We found that fracture incidence peaked during puberty (relative risk 3.1 at age of 8–14 years compared to outside this age window), and 38% of fractures were in the upper-limb. Compared to the non-fracture cohort, girls who sustained upper-limb fracture at ages 8–14 years had lower distal radial vBMD at baseline (258.9 ± 37.5 vs. 287.5 ± 34.1 mg/cm³, p  = 0.001), 1-year (252.0 ± 29.3 vs. 282.6 ± 33.5 mg/cm³, p  = 0.001), 2-year (258.9 ± 32.2 vs. 289.9 ± 40.1 mg/cm³, p  = 0.003), and 7-year follow-ups (early adulthood, 307.6 ± 35.9 vs. 343.6 ± 40.9 mg/cm³, p  = 0.002). There was a consistent trend towards larger bone cross-sectional area in the fracture cohort compared to non-fracture. In a logistic regression model, lower vBMD (p  = 0.001) was the only significant predictor of upper-limb fracture during the period of 8–14 years. Our results indicate that low BMD is an important factor underlying elevated upper-limb fracture risk during puberty, and that low BMD in pubertal girls with fracture persists into adulthood. Hence low vBMD during childhood is not a transient deficit. Methods to monitor vBMD and to maximise bone mineral accrual and reduce risks of falling in childhood should be developed.     

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

IntroductionOsteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization.We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.MethodsIn this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined.Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis.Results64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p < 0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~ 0; p = 0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p = 0.029). ucOC levels were higher in the fracture group although not significantly (p = 0.058). No differences were found regarding total OC (p = 0.602), apoE (p = 0.467) and Vitamin K (p = 0.371).In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β = 0.607; p = 0.013) and stiffness (β = 0.693; p = 0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β = ? 0.411; p = 0.030) and stiffness (β = ? 0.487; p = 0.009).ConclusionWe demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.     

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

IntroductionOsteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization.We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.MethodsIn this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined.Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis.Results64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p < 0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~ 0; p = 0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p = 0.029). ucOC levels were higher in the fracture group although not significantly (p = 0.058). No differences were found regarding total OC (p = 0.602), apoE (p = 0.467) and Vitamin K (p = 0.371).In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β = 0.607; p = 0.013) and stiffness (β = 0.693; p = 0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β = − 0.411; p = 0.030) and stiffness (β = − 0.487; p = 0.009).ConclusionWe demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.     

Deficits in bone density and structure in children and young adults following Fontan palliation

BackgroundSurvival of patients with congenital heart disease has improved such that there are now more adults than children living with these conditions. Complex single ventricle congenital heart disease requiring Fontan palliation is associated with multiple risk factors for impaired bone accrual. Bone density and structure have not been characterized in these patients.MethodsTibia peripheral quantitative computed tomography (pQCT) was used to assess trabecular and cortical volumetric bone mineral density (vBMD), cortical dimensions, and calf muscle area in 43 Fontan participants (5–33 years old), a median of 10 years following Fontan palliation. pQCT outcomes were converted to sex- and race-specific Z-scores relative to age based on > 700 healthy reference participants. Cortical dimensions and muscle area were further adjusted for tibia length.ResultsHeight Z-scores were lower in Fontan compared to reference participants (mean ± SD: − 0.29 ± 1.00 vs. 0.25 ± 0.93, p < 0.001); BMI Z-scores were similar (0.16 ± 0.88 vs. 0.35 ± 1.02, p = 0.1). Fontan participants had lower trabecular vBMD Z-scores (− 0.85 ± 0.96 vs. 0.01 ± 1.02, p < 0.001); cortical vBMD Z-scores were similar (− 0.17 ± 0.98 vs. 0.00 ± 1.00, p = 0.27). Cortical dimensions were reduced with lower cortical area (− 0.59 ± 0.84 vs. 0.00 ± 0.88, p < 0.001) and periosteal circumference (− 0.50 ± 0.82 vs. 0.00 ± 0.84, p < 0.001) Z-scores, compared to reference participants. Calf muscle area Z-scores were lower in the Fontan participants (− 0.45 ± 0.98 vs. 0.00 ± 0.96, p = 0.003) and lower calf muscle area Z-scores were associated with smaller periosteal circumference Z-scores (R = 0.62, p < 0.001). Musculoskeletal deficits were not associated with age, Fontan characteristics, parathyroid hormone or vitamin D levels.ConclusionsChildren and young adults demonstrate low trabecular vBMD, cortical structure and muscle area following Fontan. Muscle deficits were associated with smaller periosteal dimensions. Future studies should determine the fracture implications of these deficits and identify interventions to promote musculoskeletal development.     

Comparison of the Relationship Between Bone Marrow Adipose Tissue and Volumetric Bone Mineral Density in Children and Adults

Several large-scale studies have reported the presence of an inverse relationship between bone mineral density (BMD) and bone marrow adipose tissue (BMAT) in adults. We aim to determine if there is an inverse relationship between pelvic volumetric BMD (vBMD) and pelvic BMAT in children and to compare this relationship in children and adults. Pelvic BMAT and bone volume (BV) was evaluated in 181 healthy children (5–17 yr) and 495 healthy adults (≥18 yr) with whole-body magnetic resonance imaging (MRI). Pelvic vBMD was calculated using whole-body dual-energy X-ray absorptiometry to measure pelvic bone mineral content and MRI-measured BV. An inverse correlation was found between pelvic BMAT and pelvic vBMD in both children (r = −0.374, p < 0.001) and adults (r = −0.650, p < 0.001). In regression analysis with pelvic vBMD as the dependent variable and BMAT as the independent variable, being a child or adult neither significantly contribute to the pelvic BMD (p = 0.995) nor did its interaction with pelvic BMAT (p = 0.415). The inverse relationship observed between pelvic vBMD and pelvic BMAT in children extends previous findings that found the inverse relationship to exist in adults and provides further support for a reciprocal relationship between adipocytes and osteoblasts.     

Effect of alcohol consumption on bone mineral density and hormonal parameters in physically active male soldiers

BackgroundPrevious studies on the influence of alcohol intake and smoking on bone mineral density (BMD) in men are inconsistent and the effect of these variables on BMD in physically active men is yet to be explored.ObjectiveTo investigate the influence of alcohol intake and smoking on BMD in a cohort of males with well-defined lifestyle conditions.DesignMen from the armed forces (n = 400) having uniform and defined routines were enrolled. BMD was measured by DXA and participants were grouped according to lifestyle variables. Hormonal parameters were measured by immunoassays.ResultsParticipants with intake of > 24 g/wk of alcohol had significantly higher BMD at femur compared to non-alcohol consumers (p = 0.0001) and a linear increase in mean femoral BMD over increasing categories of alcohol intake (p_trend < 0.0001) was observed. Smoking was negatively associated with femoral BMD. In multiple regression analysis, age, BMI, alcohol consumption and smoking were independent predictors of femoral BMD, explaining 10.6% variance. At lumbar spine, age, height and BMI were independent predictors, explaining 9.4% variance in BMD. The concentrations of total testosterone, free testosterone, bioavailable testosterone and PTH were low (p < 0.0001) whereas estradiol (p = 0.02), free and bioavailable estradiol (p < 0.001) were high in alcohol consumers compared to non-consumers. In multiple regression analysis alcohol intake and height explained 5.5% variance in estradiol_.ConclusionsIn physically active men with well-defined lifestyle conditions, alcohol consumption was associated with higher femoral BMD, the effect of alcohol is complex and is probably partly mediated by influencing the sex steroid levels.     

Race and sex differences in bone mineral density and geometry at the femur

IntroductionDifferences in osteoporotic hip fracture incidence between American whites and blacks and between women and men are considered to result, in part, from differences in bone mineral density and geometry at the femur. The aim of this study was to quantify differences in femoral bone density and geometry between a large sample of healthy American white and black women and men.Subjects and methodsHealthy American white (n = 612) and black (n = 164) premenopausal women, aged 23 to 57 years, and healthy American white (n = 492) and black (n = 169) men, aged 20 to 63 years, had volumetric bone mineral density (vBMD) and geometry variables measured at the femur by computerized tomography (CT), and areal bone mineral density (aBMD) at femoral neck measured by dual X-ray absorptiometry (DXA).ResultsAmerican blacks had higher vBMD at the femoral neck and femoral shaft cortex than American whites whereas femoral axis length and femoral neck area were not different. Men had lower vBMD at the femoral neck and femoral cortex than women but had greater femoral axis length and femoral neck area than women. The higher aBMD in American blacks than whites persisted after correction for measured area whereas the higher aBMD in men than women disappeared.ConclusionsAt the femoral neck, American whites have lower bone density than American blacks but similar geometry. Women have higher bone density than men in both races but have smaller geometry variables. The differences in bone density may account in part for the differences in hip fracture incidence between American blacks and whites, whereas the differences in femur size may account for the differences in hip fracture rates between men and women.     

Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure

Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of childhood osteoporosis and blindness due to inactivating mutations in LDL receptor-like protein 5 (LRP5). We and others have reported improvement in areal bone mineral density (aBMD) by DXA in OPPG on short term bisphosphonates. Long-term data on bisphosphonate use in OPPG and measures of volumetric BMD (vBMD) and cortical structure are not available. In addition, no long-term DXA data on untreated OPPG is available. The aims of this study were to: (1) record low trauma fractures and longitudinal aBMD by DXA in 5 OPPG patients on chronic bisphosphonate treatment, and in 4 OPPG patients never treated (2) to perform tibia peripheral quantitative CT (pQCT) to evaluate volumetric bone mineral density (vBMD), cortical structure and calf muscle area in 6 OPPG patients and 14 unaffected first degree family members. pQCT results were converted to sex-specific Z-scores for age and adjusted for tibia length based on data in > 700 reference participants. We observed 4 fractures (3 femoral shafts) in 3 OPPG patients while on bisphosphonates, after each achieved significant improvement in aBMD. OPPG participants had significantly lower mean trabecular vBMD (− 1.51 vs. 0.17, p = 0.002), cortical area (− 2.36 vs. 0.37; p < 0.001) and periosteal circumference (− 1.86 vs. − 0.31, p = 0.001) Z-scores, compared with unaffected participants and had a trend toward lower muscle area Z-score (− 0.69 vs. 0.47, p = 0.12). These data demonstrate substantial bone fragility despite improvements in aBMD. The pQCT data provide insight into the fragility with substantial deficits in trabecular vBMD and cortical dimensions, consistent with OPPG effects of bone formation. Treatment that improves bone quality is needed to reduce fractures in OPPG.     

Muscle power and physical activity are associated with bone strength in older men: The osteoporotic fractures in men study

The purpose of these analyses was to explore whether physical activity score, leg power or grip strength were associated with tibia and radius estimates of bone strength, cortical density, or total bone area. Peripheral quantitative computed tomography (pQCT) was used to compare tibial and radial bone volumetric density (vBMD, mg/cm³), total (ToA, mm²) and cortical (CoA, mm²) bone area, and estimates of bone compressive strength (bone strength index, BSI) and bending strength (polar strength strain index, SSIp) in a subset (n = 1171) of men (≥ 65 years) who participated in the multi-site Osteoporotic Fractures in Men (MrOS) study. Physical activity was assessed by questionnaire (PASE), leg power by Nottingham Power Rig, and grip strength by a hand-held Dynamometer. Participants were categorized into quartiles of PASE, grip strength or leg power. The model was adjusted for age, race, clinic, weight, and limb length. In the tibia, BSI (+ 7%) and SSIp (+ 4%) were highest in the most active physically quartile compared to the least active (p < 0.05). At the 4% site of the tibia, men with the greatest leg power had both greater ToA (+ 5%, p < 0.001) and BSI (+ 5.3%, p = 0.086) compared to men with the least leg power. At the 66% site of the tibia, the men with the highest leg power, compared to the men with the lowest leg power, had greater ToA (+ 3%, p = 0.045) SSIp (+ 5%, p = 0.008). Similar results were found at both the distal and midshaft of the radius. The findings of this study suggest the importance of maintaining levels of physical activity and muscle strength in older men to prevent bone fragility.     

Improvements in hip trabecular,subcortical, and cortical density and mass in postmenopausal women with osteoporosis treated with denosumab

In the FREEDOM study, denosumab treatment (60 mg every 6 months) decreased bone resorption, increased bone mineral density (BMD), and reduced new vertebral, nonvertebral, and hip fractures over 36 months in postmenopausal women with osteoporosis. In a subset of these women, hip quantitative computed tomography (QCT) was performed at baseline and months 12, 24, and 36. These scans were analyzed using Medical Image Analysis Framework (MIAF) software, which allowed assessment of total hip integral, trabecular, subcortical, and cortical compartments; the cortical compartment was further divided into 2 areas of interest (outer and inner cortex). This substudy reports changes in BMD and bone mineral content (BMC) from baseline and compared placebo with denosumab over 36 months of treatment (placebo N = 26; denosumab N = 36). Denosumab treatment resulted in significant improvements in total hip integral volumetric BMD (vBMD) and BMC from baseline at each time point. At month 36, the mean percentage increase from baseline in total hip integral vBMD and BMC was 6.4% and 4.8%, respectively (both p < 0.0001). These gains were accounted for by significant increases in vBMD and BMC in the trabecular, subcortical, and cortical compartments. In the placebo group, total hip integral vBMD and BMC decreased at month 36 from baseline by − 1.5% and − 2.6%, respectively (both p < 0.05). The differences between denosumab and placebo were also significant at months 12, 24, and 36 for integral, trabecular, subcortical, and cortical vBMD and BMC (all p < 0.05 to < 0.0001). While the largest percentage differences occurred in trabecular vBMD and BMC, the largest absolute differences occurred in cortical vBMD and BMC. In summary, denosumab significantly improved both vBMD and BMC from baseline and placebo, assessed by QCT MIAF, in the integral, trabecular, subcortical, and cortical hip compartments, all of which are relevant to bone strength.     

Dextran sodium sulfate-induced colitis causes rapid bone loss in mice

IntroductionOsteopenia is a common complication of human inflammatory bowel disease (IBD). We evaluated the contribution of colonic inflammation to osteopenia and its mechanism in a murine colitis model.MethodsColitis was induced by adding dextran sodium sulfate (DSS) to the drinking water for 2 weeks to nine-week-old Balb/C male mice. 5% DSS was added on the first week and was reduced to 2.5% on the second week. Age- and sex-matched Balb/C mice served as the control group. Indices of femoral bone mass and architecture were determined by micro computed tomography (μCT). Bone formation parameters and osteoclast number were determined by dynamic histomorphometry. The degree of colonic inflammation was assessed by a clinical disease activity index, and colonic mucosal myeloperoxidase activity.ResultsDSS-treated mice exhibited a significantly lower bone mass compared to controls as indicated by decreased trabecular bone volume (BV/TV) of 32%. This reduction was accompanied by decreased trabecular number (23%) and connectivity density (37%) compared to the controls. No changes were observed in cortical bone indices. Osteopenia resulted from suppressed bone formation, as indicated by decreased trabecular double-labeled surface (dL%) of 90%, mineralizing surface (MS) of 62%, and bone formation rate (BFR) of 67%, and increased bone resorption as indicated by a 34% increase in osteoclast number in DSS-treated mice compared to the controls. Myeloperoxidase activity inversely correlated with trabecular BV/TV (r = − 0.67, p = 0.02), trabecular number (r = − 0.86, p = 0.0008) and connectivity density (r = − 0.63, p = 0.03). Myeloperoxidase activity inversely correlated with the bone formation indices: dL%, MS, and BFR (r = − 0.79, p = 0.007, r = − 0.84, p = 0.002, r = − 0.83, p = 0.003, respectively).ConclusionsDSS-induced colitis is associated with reduced femoral bone mass and altered micro architecture, which results from suppressed bone formation and increased bone resorption. The decrease in indices of bone mass, structure and formation are directly linked to the degree of colonic mucosal inflammation. DSS-induced colitis can be used to study pharmacological interventions for bone loss in colitis.     

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.     

Adiponectin and bone mass density: The InCHIANTI study

IntroductionAdiponectin serum concentration has been reported to be inversely correlated with bone mineral density (BMD) in humans. The data on this issue, however, are biased by small study sample size and lack of controlling for body composition.MethodsWe used data from the third follow-up of the InCHIANTI study, which included measurements of BMD using quantitative CT of the tibia and of body composition using bioimpedenziometry. Serum adiponectin was measured using radioimmunoassay. We excluded participants with diabetes, hyperthyroidism, using hormone replacement or corticosteroid therapy. We evaluated the correlation of adiponectin with total, trabecular, and cortical BMD using Pearson's coefficient, and linear regression models to estimate the association between adiponectin and BMD controlling for potential confounders (age, body mass index, alcohol intake, fat mass, smoking).ResultsOur sample was made up of 320 men (mean age: 67 years, SD: 15.8, range: 29–97 years) and 271 postmenopausal women (mean age: 76 years, SD: 8.2, range: 42–97 years). In men, serum adiponectin was not independently associated with BMD. In women, after correction for potential confounders, adiponectin was associated with total (β = ?0.626, P < 0.001), trabecular (β = ?0.696, P < 0.001), and cortical (β = ?1.076, P = 0.001) BMD.ConclusionOur results show that adiponectin is inversely associated with bone mass in women. Further studies are needed to confirm these findings prospectively and then to clarify the explanatory mechanisms.     

Children with nephrotic syndrome have greater bone area but similar volumetric bone mineral density to healthy controls

BackgroundGlucocorticoid use has been associated with an increased fracture risk and reduced bone mineral density (BMD), particularly in the trabecular compartment. However the contribution of the underlying inflammatory disease process to these outcomes is poorly understood. Childhood nephrotic syndrome (NS) typically follows a relapsing–remitting course often requiring recurrent courses of glucocorticoids, but with low systemic inflammation during remission. NS therefore represents a useful clinical model to investigate the effects of glucocorticoids on BMD and bone geometry in childhood.MethodsChildren with NS were compared to age and sex matched healthy controls. Body composition and areal BMD (whole body, lumbar spine and hip) were assessed by DXA. Peripheral quantitative computed tomography (pQCT) scans were obtained at metaphyseal (4%) and diaphyseal (66%) sites of the tibia to determine volumetric BMD and bone cross-sectional geometry. Lifetime cumulative glucocorticoid exposure was calculated from medical records.Results29 children with NS (55% male, age 10.7 ± 3.1 years) were compared to 29 healthy controls (55% male, age 11.0 ± 3.0 years). The children with NS were of similar height SDS to controls (p = 0.28), but were heavier (0.65 ± 1.28SDS vs − 0.04 ± 0.89SDS, p = 0.022) and had greater body fat percentage SDS (0.31 ± 1.01 vs − 0.52 ± 1.10, p = 0.008). Tibial trabecular and cortical vBMD were similar between the two groups but bone cross-sectional area (CSA) was significantly greater in children with NS at both the metaphysis (954 ± 234 mm² vs 817 ± 197 mm², p = 0.002) and diaphysis (534.9 ± 162.7 mm² vs 463.2 ± 155.5 mm², p = 0.014). Endosteal and periosteal circumferences were greater in children with NS than controls (both p < 0.01), resulting in reduced cortical thickness (2.4 ± 0.7 mm vs 2.8 ± 0.7 mm, p = 0.018), but similar cortical CSA (p = 0.22). The differences in cortical geometry were not statistically significant when weight was included as a confounding factor. There were no associations between cumulative steroid exposure, duration of NS or number of relapses and any bone parameter.ConclusionsTibial bone CSA is increased in children with NS. We speculate that this is a compensatory response to increased body weight. Defects in trabecular BMD were not identified in this cohort of children with NS.