Sclerostin antibody and interval treadmill training effects in a rodent model of glucocorticoid-induced osteopenia

Glucocorticoids have a beneficial anti-inflammatory and immunosuppressive effect, but their use is associated with decreased bone formation, bone mass and bone quality, resulting in an elevated fracture risk. Exercise and sclerostin antibody (Scl-Ab) administration have both been shown to increase bone formation and bone mass, therefore the ability of these treatments to inhibit glucocorticoid-induced osteopenia alone or in combination were assessed in a rodent model. Adult (4 months-old) male Wistar rats were allocated to a control group (C) or one of 4 groups injected subcutaneously with methylprednisolone (5 mg/kg/day, 5 days/week). Methylprednisolone treated rats were injected subcutaneously 2 days/week with vehicle (M) or Scl-Ab-VI (M + S: 25 mg/kg/day) and were submitted or not to treadmill interval training exercise (1 h/day, 5 days/week) for 9 weeks (M + E, M + E + S). Methylprednisolone treatment increased % fat mass and % apoptotic osteocytes, reduced whole body and femoral bone mineral content (BMC), reduced femoral bone mineral density (BMD) and osteocyte lacunae occupancy. This effect was associated with lower trabecular bone volume (BV/TV) at the distal femur. Exercise increased BV/TV, osteocyte lacunae occupancy, while reducing fat mass, the bone resorption marker NTx, and osteocyte apoptosis. Exercise did not affect BMC or cortical microarchitectural parameters. Scl-Ab increased the bone formation marker osteocalcin and prevented the deleterious effects of M on bone mass, further increasing BMC, BMD and BV/TV to levels above the C group. Scl-Ab increased femoral cortical bone parameters at distal part and midshaft. Scl-Ab prevented the decrease in osteocyte lacunae occupancy and the increase in osteocyte apoptosis induced by M. The addition of exercise to Scl-Ab treatment did not result in additional improvements in bone mass or bone strength parameters. These data suggest that although our exercise regimen did prevent some of the bone deleterious effects of glucocorticoid treatment, particularly in trabecular bone volume and osteocyte apoptosis, Scl-Ab treatment resulted in marked improvements in bone mass across the skeleton and in osteocyte viability, resulting in decreased bone fragility.     

Heavy ion irradiation and unloading effects on mouse lumbar vertebral microarchitecture,mechanical properties and tissue stresses

Astronauts are exposed to both musculoskeletal disuse and heavy ion radiation in space. Disuse alters the magnitude and direction of forces placed upon the skeleton causing bone remodeling, while energy deposited by ionizing radiation causes free radical formation and can lead to DNA strand breaks and oxidative damage to tissues. Radiation and disuse each result in a net loss of mineralized tissue in the adult, although the combined effects, subsequent consequences for mechanical properties and potential for recovery may differ. First, we examined how a high dose (2 Gy) of heavy ion radiation (⁵⁶Fe) causes loss of mineralized tissue in the lumbar vertebrae of skeletally mature (4 months old), male, C57BL/6 mice using microcomputed tomography and determined the influence of structural changes on mechanical properties using whole bone compression tests and finite element analyses. Next, we tested if a low dose (0.5 Gy) of heavy particle radiation prevents skeletal recovery from a 14-day period of hindlimb unloading. Irradiation with a high dose of ⁵⁶Fe (2 Gy) caused bone loss (?14%) in the cancellous-rich centrum of the fourth lumbar vertebra (L4) 1 month later, increased trabecular stresses (+ 27%), increased the propensity for trabecular buckling and shifted stresses to the cortex. As expected, hindlimb unloading (14 days) alone adversely affected microarchitectural and mechanical stiffness of lumbar vertebrae, although the reduction in yield force was not statistically significant (?17%). Irradiation with a low dose of ⁵⁶Fe (0.5 Gy) did not affect vertebrae in normally loaded mice, but significantly reduced compressive yield force in vertebrae of unloaded mice relative to sham-irradiated controls (?24%). Irradiation did not impair the recovery of trabecular bone volume fraction that occurs after hindlimb unloaded mice are released to ambulate normally, although microarchitectural differences persisted 28 days later (96% increase in ratio of rod- to plate-like trabeculae). In summary, ⁵⁶Fe irradiation (0.5 Gy) of unloaded mice contributed to a reduction in compressive strength and partially prevented recovery of cancellous microarchitecture from adaptive responses of lumbar vertebrae to skeletal unloading. Thus, irradiation with heavy ions may accelerate or worsen the loss of skeletal integrity triggered by musculoskeletal disuse.     

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.     

Effect of resistance exercise on bone mineral density in premenopausal women

ObjectiveTo assess the effect of 9 months of strength training on total body and regional bone mineral density (BMD, g/cm²) in 58 premenopausal women aged 30–50 years.MethodsParticipants were randomized to either twice weekly supervised strength training for 15 weeks followed by 24 weeks of unsupervised training (treatment group) or control group. Height, weight, maximal muscular strength, nutrient intake and physical activity were assessed. Total body dual energy X-ray absorptiometry (DXA, Lunar Prodigy) scans were taken and analyzed for body composition (lean and fat mass), and BMD for total body and its sub-regions (spine, hip, arms and legs). All measurements were performed at baseline, 15 and 39 weeks. Analysis of covariance was used to assess group differences in BMD change adjusted for baseline BMD, weight, energy and calcium intake.ResultsAt baseline, the two groups had similar BMD and body size characteristics ( P < 0.05 for all), except that the treatment group had lower body weight (?7.1 kg), and higher energy (+259 kJ/d) and calcium (+232 mg/d) intake at baseline. Adjusted % change in BMD over 15 weeks (0.5% vs. 0.4%) or 39 weeks (0.9% vs. 1.2%) did not differ significantly between the exercise and control groups, respectively. The exercise group increased BMD at the spine and legs (1–2.2%), while there was no change in the controls, but differences between groups were not significant.ConclusionStrength training over 9 months did not lead to significantly greater change in total body or regional BMD in premenopausal women.     

Age- and gender-related differences in cortical geometry and microstructure: Improved sensitivity by regional analysis

ObjectiveWhile the importance of cortical structure quantification is increasingly underscored by recent literature, conventional analysis techniques obscure potentially important regional variations in cortical structure. The objective of this study was to characterize the spatial variability in cortical geometry and microstructure at the distal radius and tibia using high resolution peripheral quantitative computed tomography (HR-pQCT). We show that spatially-resolved analysis is able to identify cortical sub-regions with increased sensitivity to the effects of gender and aging.MethodsHR-pQCT scans of 146 volunteers (92 female/54 male) spanning a wide range of ages (20–78 years) were analyzed. For each subject, radius and tibia scans were obtained using a clinical HR-pQCT system. Measures describing geometry (cortical bone thickness (Ct.Th)), microstructure (porosity (Ct.Po), pore diameter (Ct.Po.Dm), and pore size heterogeneity (Ct.Po.Dm SD)), and cortical bone density were calculated from the image data. Biomechanical parameters describing load and stress distribution were calculated using linear finite element analysis. Cortical quadrants were defined based on anatomic axes to quantify regional parameter variation. Subjects were categorized by gender, and age, and menopausal status for analysis.ResultsSignificant regional variation was found in all geometric and microstructural parameters in both the radius and tibia. In general, the radius showed more pronounced and significant variations in all parameters as compared with the tibia. At both sites, Ct.Po displayed the greatest regional variations. Correlation coefficients for Ct.Po and Ct.Th with respect to load and stress distribution provided evidence of an association between regional cortical structure and biomechanics in the tibia. Comparing women to men, differences in Ct.Po were most pronounced in the anterior quadrant of the radius (36% lower in women (p < 0.01)) and the posterior quadrant of the tibia (27% lower in women (p < 0.01)). Comparing elderly to young women, differences in Ct.Po were most pronounced in the lateral quadrant of the radius (328% higher in elderly women (p < 0.001)) and the anterior quadrant of the tibia (433% higher in elderly women (p < 0.001)). Comparing elderly to young men, the most pronounced age differences were found in the anterior radius (205% higher in elderly men, (p < 0.001)) and the anterior tibia (190% higher in elderly men (p < 0.01)). All subregional Ct.Po differences provided greater sensitivity to gender and age effects than those based on the global means.ConclusionThese results show significant regional variation in all geometric and microarchitectural parameters studied in both the radius and tibia. Quantification of region-specific parameters provided increased sensitivity in the analysis of age- and gender-related differences, in many cases providing statistically significant differentiation of groups where conventional global analysis failed to detect differences. These results suggest that regional analysis may be important in studies of disease and therapeutic effects, particularly where microstructural parameters based on global analyses have thus far failed to identify a response in bone quality.     

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.     

Cortical bone is more sensitive to alcohol dose effects than trabecular bone in the rat

ObjectiveWhile chronic alcohol consumption is known to decrease bone mineral content (BMC), bone mineral density (BMD), and negatively modify trabecular bone microarchitecture, the impact of alcohol on cortical microarchitecture is still unclear. The aim of this study was to investigate the effects of various doses of alcohol on bone density, trabecular and cortical parameters and bone strength in rats.MethodsForty-eight male Wistar rats were divided into four groups: control (C), alcohol 25% v/v (A25), alcohol 30% v/v (A30) and alcohol 35% v/v (A35). Rats in the alcohol groups were fed a solution composed of ethanol and water for 17 weeks while the control group drank only water. Bone quality and quantity were evaluated through the analysis of density, trabecular and cortical bone microarchitectural parameters, osteocalcin and N-Telopeptide concentrations and a 3-point bending test.ResultsBone density along with trabecular and cortical thickness were lower in alcohol groups compared to C. BMD was lower in A35 vs. A30 and cortical thickness was lower in A35 vs. A25 and A30. Pore number was increased by alcohol and the porosity was greater in A35 compared to C. N-Telopeptide concentration was decreased in alcohol groups compared to control whereas no differences were observed in osteocalcin concentrations. Maximal energy to failure was lower in A25 and A35 compared to C.ConclusionChronic ethanol consumption increases cortical bone damage in rats and may have detrimental effects on bone strength. These effects were dose-dependent, with greater negative effects proportionate to greater alcohol doses.     

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.     

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.     

Effect of immobilization,off-loading and zoledronic acid on bone mineral density in patients with acute Charcot neuroarthropathy: A prospective randomized trial

BackroundBisphosphonates are commonly used as an adjuvant in the management of acute Charcot neuroarthropathy (CNA), although the clinical efficacy of the treatment is controversial. The aim of the present study is to investigate the effect of immobilization and zoledronic acid on bone mineral density (BMD) changes during the treatment of acute CNA.MethodsThirty-five patients with acute midfoot CNA were randomly assigned to treatment with either zolendronic acid or placebo. BMD of the lumbar spine and both hips was measured at baseline and after six months of treatment.ResultsComparison between BMD at presentation and at 6 months demonstrated a significant fall in BMD in the placebo group at the CNA-affected femoral neck (?3.2%, p = 0.016) and in the CNA-free hip (?1.2%, p = 0.026). Conversely, a significant rise in BMD was observed in the zolendronic acid group at all measured areas of the CNA-free hip.Discussion and conclusionsImmobilization and off-loading does not lead to marked disuse osteoporosis in patients with acute CNA after 6 months of treatment. Treatment with zoledronic acid led to a statistically significant increase in hip BMD compared to placebo.     

Changes in bone mineral density after allogenic stem cell transplantation

ObjectiveOsteoporosis is a complication after allogenic stem cell transplantation (alloSCT). The purpose of this study was to assess changes in bone mineral density (BMD) 6 months and 3 years after alloSCT, as well as predictors of bone loss.MethodsA longitudinal, prospective, single-center study was conducted at Lille University Hospital between 2005 and 2016. Clinical, biological, radiologic (thoracic and lumbar spine) and densitometric (DXA) assessments were carried out at baseline (pre-transplant), 6 months and 3 years. Patients with myeloma were not included.ResultsTwo hundred and fifty-eight patients were included (144 men). Among them, 60.1% had leukemia and 65.8% of them, acute myeloid leukemia. At baseline, 6 months and 3 years, DXA-confirmed that osteoporosis was observed in 17%, 22.8% and 17.5% of the patients, respectively, mainly at the femoral neck. At baseline, 6 months and 3 years, 9 (8.5%), 53 (21.5%) and 38 (16.7%) patients, respectively, were receiving anti-osteoporotic treatment. From baseline to 6-month follow-up, BMD decreased significantly (p < 0.001) at the lumbar spine (?36 [95%CI; ?51 to ?20] mg/cm² of hydroxyapatite), femoral neck (?43 [95%CI; ?57 to ?29] mg/cm² of hydroxyapatite) and total hip (?53 [95%CI; ?68 to ?39] mg/cm² of hydroxyapatite). From 6-month to 3-year follow-up, a significant increase in BMD was observed at the lumbar spine only (+31 [95%CI; 20 to 42] mg/cm² of hydroxyapatite, p < 0.001). At all 3 sites, changes in BMD did not differ between patients treated or untreated by anti-osteoporotic treatment from 6-month to 3 year follow-up. Incident fractures were found in 4.1% and 5.7% of the patients at 6 months and 3 years, respectively. Between baseline and 6 months, bone loss at all 3 sites was associated with corticosteroid intake. At the total hip, 23.3% of the decrease in BMD from baseline to 6 months was due to an active hematological disease (p < 0.05), a bone marrow stem cells (p < 0.01) and a corticosteroid intake (p < 0.01).ConclusionOur study found evidence of bone fragility in alloSCT patients. Low BMD persisted at the hip 3 years after transplantation due to slower improvement at this site.     

High resolution quantitative computed tomography-based assessment of trabecular microstructure and strength estimates by finite-element analysis of the spine,but not DXA,reflects vertebral fracture status in men with glucocorticoid-induced osteoporosis

High-resolution quantitative computed tomography (HRQCT)-based analysis of spinal bone density and microstructure, finite element analysis (FEA), and DXA were used to investigate the vertebral bone status of men with glucocorticoid-induced osteoporosis (GIO). DXA of L1–L3 and total hip, QCT of L1–L3, and HRQCT of T12 were available for 73 men (54.6 ± 14.0 years) with GIO. Prevalent vertebral fracture status was evaluated on radiographs using a semi-quantitative (SQ) score (normal = 0 to severe fracture = 3), and the spinal deformity index (SDI) score (sum of SQ scores of T4 to L4 vertebrae). Thirty-one (42.4%) subjects had prevalent vertebral fractures. Cortical BMD (Ct.BMD) and thickness (Ct.Th), trabecular BMD (Tb.BMD), apparent trabecular bone volume fraction (app.BV/TV), and apparent trabecular separation (app.Tb.Sp) were analyzed by HRQCT. Stiffness and strength of T12 were computed by HRQCT-based nonlinear FEA for axial compression, anterior bending and axial torsion. In logistic regressions adjusted for age, glucocorticoid dose and osteoporosis treatment, Tb.BMD was most closely associated with vertebral fracture status (standardized odds ratio [sOR]: Tb.BMD T12: 4.05 [95% CI: 1.8–9.0], Tb.BMD L1–L3: 3.95 [1.8–8.9]). Strength divided by cross-sectional area for axial compression showed the most significant association with spine fracture status among FEA variables (2.56 [1.29–5.07]). SDI was best predicted by a microstructural model using Ct.Th and app.Tb.Sp (r² = 0.57, p < 0.001). Spinal or hip DXA measurements did not show significant associations with fracture status or severity.In this cross-sectional study of males with GIO, QCT, HRQCT-based measurements and FEA variables were superior to DXA in discriminating between patients of differing prevalent vertebral fracture status. A microstructural model combining aspects of cortical and trabecular bone reflected fracture severity most accurately.     

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.     

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.     

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.     

Evidence for Enhanced Characterization of Cortical Bone Using Novel pQCT Shape Software

Bone shape, mass, structural geometry, and material properties determine bone strength. This study describes novel software that uses peripheral quantitative computed tomography (pQCT) images to quantify cortical bone shape and investigates whether the combination of shape-sensitive and manufacturer's software enhances the characterization of tibiae from contrasting populations. Existing tibial pQCT scans (4% and 50% sites) from Gambian (n = 38) and British (n = 38) women were used. Bone mass, cross-sectional area (CSA), and geometry were determined using manufacturer's software; cross-sectional shape was quantified using shape-sensitive software. At 4% site, Gambian women had lower total bone mineral content (BMC: ?15.4%), CSA (?13.4%), and trabecular bone mineral density (BMD: ?19%), but higher cortical subcortical BMD (6.1%). At 50% site, Gambian women had lower cortical BMC (?7.6%), cortical CSA (?12.6%), and mean cortical thickness (?15.0%), but higher cortical BMD (4.9%) and endosteal circumference (8.0%). Shape-sensitive software supported the finding that Gambian women had larger tibial endosteal circumference (9.8%), thinner mean cortical thickness (?26.5%) but smaller periosteal circumference (?5.6%). Shape-sensitive software revealed that Gambian women had tibiae with shorter maximum width (?7.6%) and thinner cortices (?22% to ?41.2%) and more closely resembled a circle or ellipse. Significant differences remained after adjusting for age, height, and weight. In conclusion, shape-sensitive software enhanced the characterization of tibiae in 2 contrasting groups of women.     

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.     

Eating disorders,menstrual dysfunction,weight change and DMPA use predict bone density change in college-aged women

IntroductionThere are limited longitudinal studies that have evaluated bone mineral density (BMD) changes in college-aged women. Our objective was to simultaneously evaluate factors influencing 4-year BMD change.MethodsThis was a longitudinal cohort study of healthy, physically active women in the US Military Academy (n = 91; average age = 18.4 years). Assessments over four years included: height, weight, calcium intake, physical fitness, menstrual function (annual number cycles), oral contraceptives (OCs) or depot-medroxyprogesterone acetate (DMPA) use, and eating disorder behavior (Eating Disorder Inventory; (EDI)). BMD was measured annually at the lumbar spine and total hip by dual X-ray absorptiometry and calcaneal BMD by PIXI. Slope of 4 year BMD change at each skeletal site (spine total hip and calcaneus) was calculated for each woman.ResultsBMD gains occurred at the spine in 50% and the hip in 36% of women. In unadjusted analyses, spine bone gain was positively related to menstrual cycle frequency (p = 0.04). Spine and hip BMD loss occurred in those using DMPA (p < 0.01) and those with the highest EDI quartile scores (p < 0.05). BMD change was unrelated to OC use. Hip and calcaneus BMD decreased with weight loss (average 4.8 + 2.2 lb/year) as compared to those with stable weight/weight gain (p < 0.05). In multivariable analysis, spine BMD increase was significantly related to African American (AA) race, normal EDI score and normal menses. Hip BMD increase was related to AA race, weight increase and normal menses. DMPA use was associated with spine, hip, and calcaneus bone loss.ConclusionOn average, BMD may modestly increase in college-aged women, in the absence of risk factors. However, risk factors including subclinical eating disorders, weight loss, menstrual dysfunction and DMPA use can have significant detrimental effects on BMD in young healthy physically active women.     

Associations among endocrine,inflammatory, and bone markers,body composition and weight loss induced bone loss

IntroductionWeight loss reduces co-morbidities of obesity, but decreases bone mass.PurposeOur aims were to 1) determine if adequate dairy intake attenuates weight loss-induced bone loss; 2) evaluate the associations of endocrine, inflammatory and bone markers, anthropometric and other parameters to bone mineral density and content (BMD, BMC) pre- and post-weight loss; and 3) model the contribution of these variables to post weight-loss BMD and BMC.MethodsOverweight/obese women (BMI: 28–37 kg/m²) were enrolled in an energy reduced (− 500 kcal/d; − 2092 kJ/d) diet with adequate dairy (AD: 3–4 servings/d; n = 25, 32.2 ± 8.8 years) or low dairy (LD: ≤ 1 serving/d; n = 26, 31.7 ± 8.4 years). BMD, BMC and body composition were measured by DXA. Bone markers (CTX, PYD, BAP, OC), endocrine (PTH, vitamin D, leptin, adiponectin, ghrelin, amylin, insulin, GLP-1, PAI-1, HOMA) and inflammatory markers (CRP, IL1-β, IL-6, IL-8, TNF-α, cortisol) were measured in serum or plasma. PA was assessed by accelerometry.ResultsFollowing weight loss, AD intake resulted in significantly greater (p = 0.004) lumbar spine BMD and serum osteocalcin (p = 0.004) concentration compared to LD. Pre- and post-body fat was negatively associated with hip and lumbar spine BMC (r = − 0.28, p = 0.04 to − 0.45, p = 0.001). Of note were the significant negative associations among bone markers and IL-1β, TNFα and CRP ranging from r = − 0.29 (p = 0.04) to r = − 0.34 (p = 0.01); magnitude of associations did not change with weight loss. Adiponectin was negatively related to change in osteocalcin. Factor analysis resulted in 8 pre- and post-weight loss factors. Pre-weight loss factors accounted for 13.7% of the total variance in pre-weight loss hip BMD; post-weight loss factors explained 19.6% of the total variance in post-weight loss hip BMD. None of the factors contributed to the variance in lumbar spine BMD.ConclusionAD during weight loss resulted in higher lumbar spine BMD and osteocalcin compared to LD. Significant negative associations were observed between bone and inflammatory markers suggesting that inflammation suppresses bone metabolism. Using factor analysis, 19.6% of total variance in post-weight loss hip BMD could be explained by endocrine, immune, and anthropometric variables, but not lumbar spine BMD.     

Effects of ovariectomy on the changes in microarchitecture and material level properties in response to hind leg disuse in female rats

BackgroundOvariectomy (OVX) and immobilization are known to decrease bone mineral density and alter its microarchitecture. Their effects on the material level properties of bone, a determinant of bone strength, are still largely unknown. We investigated the effect of OVX and/or disuse achieved by sciatic neurectomy (NX) in 6-month-old Sprague Dawley female rats.MethodsAt baseline, animals underwent OVX or sham operation. At week 16, NX was performed on the left hindlimb while the right hindlimb was sham-operated. All animals were sacrificed at week 40. Proximal tibiae and vertebral bodies (L4) were evaluated by micro-computed tomographic morphometry (μCT). Material level properties (elastic modulus, hardness, and dissipated energy) were evaluated by a nanoindentation test.ResultsAt the proximal tibia, OVX and NX decreased relative bone volume, the former mainly through a reduction in trabecular number, and the latter through a decrease in trabecular thickness. NX decreased modulus (? 10%; p < 0.001) and dissipated energy (? 13.3%, p < 0.001) in cortical bone, and modulus (? 16.8%, p = 0.004), hardness (? 29.3%, p = 0.004), and dissipated energy (? 17.7%, p = 0.01) in trabecular bone, while OVX decreased cortical bone dissipated energy (? 14.6%, p < 0.001) and trabecular bone hardness (? 19.4%, p = 0.05). In the vertebral body, OVX altered mainly the trabecular microarchitecture and nanoindentation variables.ConclusionThese results show that NX with and without OVX markedly alter material level properties in addition to an alteration of bone microarchitecture, although not in the same manner.