Application of High‐Resolution Skeletal Imaging to Measurements of Volumetric BMD and Skeletal Microarchitecture in Chinese‐American and White Women: Explanation of a Paradox

Asian women have lower rates of hip and forearm fractures despite lower areal BMD (aBMD) by DXA compared with white women and other racial groups. We hypothesized that the lower fracture rates may be explained by more favorable measurements of volumetric BMD (vBMD) and microarchitectural properties, despite lower areal BMD. To address this hypothesis, we used high‐resolution pQCT (HRpQCT), a new method that can provide this information noninvasively. We studied 63 premenopausal Chinese‐American (n = 31) and white (n = 32) women with DXA and HRpQCT. aBMD by DXA did not differ between groups for the lumbar spine (1.017 ± 0.108 versus 1.028 ± 0.152 g/cm²; p = 0.7), total hip (0.910 ± 0.093 versus 0.932 ± 0.134 g/cm²; p = 0.5), femoral neck (0.788 ± 0.083 versus 0.809 ± 0.129 g/cm²; p = 0.4), or one‐third radius (0.691 ± 0.052 versus 0.708 ± 0.047 g/cm²; p = 0.2). HRpQCT at the radius indicated greater trabecular (168 ± 41 versus 137 ± 33 mg HA/cm³; p = <0.01) and cortical (963 ± 46 versus 915 ± 42 mg HA/cm³; p < 0.0001) density; trabecular bone to tissue volume (0.140 ± 0.034 versus 0.114 ± 0.028; p = <0.01); trabecular (0.075 ± 0.013 versus 0.062 ± 0.009 mm; p < 0.0001) and cortical thickness (0.98 ± 0.16 versus 0.80 ± 0.14 mm; p < 0.0001); and lower total bone area (197 ± 34 versus 232 ± 33 mm²; p = <0.001) in the Chinese versus white women and no difference in trabecular number, spacing, or inhomogeneity before adjustment for covariates. Similar results were observed at the weight‐bearing tibia. At the radius, adjustment for covariates did not change the direction or significance of differences except for bone, which became similar between the groups. However, at the tibia, adjustment for covariates attenuated differences in cortical BMD and bone area and accentuated differences in trabecular microarchitecture such that Chinese women additionally had higher trabecular number and lower trabecular spacing, as well as inhomogeneity after adjustment. Using the high‐resolution technology, the results provide a mechanistic explanation for why Chinese women have fewer hip and forearm fractures than white women.     

Tracking of Environmental Determinants of Bone Structure and Strength Development in Healthy Boys: An Eight‐Year Follow Up Study on the Positive Interaction Between Physical Activity and Protein Intake From Prepuberty to Mid‐Late Adolescence

High protein (> median:Hprot) vs. moderate (< median:MProt) intake was shown to enhance the positive impact of high physical activity (HPA) on proximal femur BMC/aBMD/Area in healthy prepubertal boys. We tested the hypothesis that this synergistic effect would track and influence bone structure and strength until mid‐adolescence. BMC/aBMD/Area was measured at femoral neck (FN) and total hip (TotHip) by DXA in 176 boys at 7.4 ± 0.4 and 15.2 ± 0.5 years (± SD). Distal tibia (DistTib) microstructure and strength were also assessed at 15.2 years by high‐resolution peripheral computerized tomography (HR‐pQCT) and micro‐finite element analysis (µFEA). The positive impact of HProt vs. MProt on FN and TotHip BMC/aBMD/Area, recorded at 7.4 years remained unabated at 15.2 years. At this age, at DistTib, HProt‐HPA vs. MProt‐HPA was associated (p < 0.001) with larger cross‐sectional area (CSA, mm²), trabecular number (Tb.N, mm^?1) and lower trabecular separation (Tb.Sp, µm). The interaction between physical activity and protein intake was significant for CSA (p = 0.012) and Tb.N (p = 0.043). Under MProt (38.0 ± 6.9 g.d^?1), a difference in PA from 168 ± 40 to 303 ± 54 kcal.d^?1 was associated with greater stiffness (kN/mm) and failure load (N) of +0.16 and +0.14 Z‐score, respectively. In contrast, under HProt (56.2 ± 9.5 g.d^?1), a difference in PA of similar magnitude, from 167 ± 33 to 324 ± 80 kcal.d^?1, was associated with a larger difference in stiffness and failure load of +0.50 and +0.57 Z‐score, respectively. In conclusion, the positive influence of relatively HProt on the impact of HPA on proximal femur macrostructure tracks from prepuberty to mid‐late puberty. At this stage, the impact of HProt on HPA is also associated with microstructural changes that should confer greater mechanical resistance to weight‐bearing bones. These results underscore the importance of protein intake and exercise synergistic interaction in the early prevention of adult osteoporosis. © 2014 American Society for Bone and Mineral Research.     

Early impairment of trabecular microarchitecture assessed with HR‐pQCT in patients with stage II‐IV chronic kidney disease

Bone fragility is a complication of chronic kidney disease (CKD). The aim of this study was to assess whether volumetric bone mineral density (vBMD) and microarchitecture could be impaired early in the course of CKD. Bone microarchitecture was examined with a noninvasive 3D imaging technique [high‐resolution peripheral quantitative computed tomography (HR‐pQCT)] at the tibia and radius in 70 stage II‐IV CKD patients older than 50 years of age; controls belonged to two cohorts of healthy subjects comparable for age and gender (OFELY cohort in women and STRAMBO cohort in men). We examined 46 men and 24 women; 19 patients were diabetic. Mean age was 70.8 ± 8.5 years, mean glomerular filtration rate (GFR) was 34 ± 12 mL/min per 1.73 m², and mean serum parathyroid hormone (PTH) level was 87 ± 59 pg/mL. Both CKD men and women experienced a moderate but significant trabecular (Tb) impairment, positioning CKD patient values between those of normal and osteopenic controls (e.g., CKD men versus healthy controls: Tb vBMD 172 ± 35 versus 188 ± 34 mg HA/cm³; Tb number 1.75 ± 0.27 versus 1.86 ± 0.26 mm^?1, and Tb separation 503 ± 94 versus 465 ± 78 µm; p < .05). Cortical thickness (Ct.Th) in men also was significantly decreased compared with healthy controls (e.g., CKD men versus healthy controls: tibial Ct.Th 1171 ± 331 versus 1288 ± 283 µm; p < .05). In conclusion, this study, using a noninvasive bone‐imaging device, shows for the first time an early impairment of trabecular microarchitecture in stage II‐IV CKD patients. Further longitudinal studies should be performed to validate HR‐pQCT as a tool for predicting the fracture risk in CKD. © 2010 American Society for Bone and Mineral Research.     

Deleterious Effect of Late Menarche on Distal Tibia Microstructure in Healthy 20‐Year‐Old and Premenopausal Middle‐Aged Women

Late menarche is a risk factor for fragility fractures. We hypothesized that pubertal timing–dependent alterations in bone structural components would persist from peak bone mass to menopause, independent of premenopausal bone loss. We studied the influence of menarcheal age (MENA) on femoral neck BMD (FN aBMD) by DXA and microstructure of distal tibia by HR‐pQCT in healthy young adult (YAD; 20.4 ± 0.6 [SD] yr, n = 124) and premenopausal middle‐aged (PREMENO; 45.8 ± 3.4 yr, n = 120) women. Median of MENA was 13.0 ± 1.2 and 13.1 ± 1.7 yr in YAD and PREMENO, respectively. In YAD and PREMENO (n = 244), FN aBMD (R = ?0.29, p = 0.013), as well as total volumetric BMD (Dtot; R = ?0.23, p = 0.006) and cortical thickness (Ct.Th; R = ?0.18, p = 0.011) of distal tibia were inversely correlated to MENA. After segregation by the median of MENA in EARLY and LATE subgroups, the significant influences of both MENA (p = 0.004) and chronological age (p < 0.0001) were observed for FN aBMD and trabecular bone volume fraction of the distal tibia with similar differences in T‐scores between LATE and EARLY subgroups in YAD (?0.36 and ?0.31 T‐scores) and PREMENO (?0.35 and ?0.42 T‐scores) women. Ct.Th was negatively influenced by MENA, whereas trabecular thickness (Tb.Th) was negatively influenced by chronological age. There was a striking inverse relationship between cross‐sectional area and Ct.Th (R = ?0.57, p < 0.001). In conclusion, the negative influence of late menarcheal age at weight‐bearing sites as observed by the end of skeletal growth remains unattenuated a few years before menopause and is independent of premenopausal bone loss. Alterations in both bone mineral mass and microstructural components may explain the increased risk of fragility fractures associated with later menarcheal age.     

Trabecular volumetric bone mineral density is associated with previous fracture during childhood and adolescence in males: The GOOD study

Areal bone mineral density (aBMD) measured with dual‐energy X‐ray absorptiometry (DXA) has been associated with fracture risk in children and adolescents, but it remains unclear whether this association is due to volumetric BMD (vBMD) of the cortical and/or trabecular bone compartments or bone size. The aim of this study was to determine whether vBMD or bone size was associated with X‐ray‐verified fractures in men during growth. In total, 1068 men (aged 18.9 ± 0.6 years) were included in the population‐based Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study. Areal BMD was measured by DXA, whereas cortical and trabecular vBMD and bone size were measured by peripheral quantitative computerized tomography (pQCT). X‐ray records were searched for fractures. Self‐reported fractures in 77 men could not be confirmed in these records. These men were excluded, resulting in 991 included men, of which 304 men had an X‐ray‐verified fracture and 687 were nonfracture subjects. Growth charts were used to establish the age of peak height velocity (PHV, n = 600). Men with prevalent fractures had lower aBMD (lumbar spine 2.3%, p = .005; total femur 2.6%, p = .004, radius 2.1%, p < .001) at all measured sites than men without fracture. Using pQCT measurements, we found that men with a prevalent fracture had markedly lower trabecular vBMD (radius 6.6%, p = 7.5 × 10^?8; tibia 4.5%, p = 1.7 × 10^?7) as well as a slightly lower cortical vBMD (radius 0.4%, p = .0012; tibia 0.3%, p = .015) but not reduced cortical cross‐sectional area than men without fracture. Every SD decrease in trabecular vBMD of the radius and tibia was associated with 1.46 [radius 95% confidence interval (CI) 1.26–1.69; tibia 95% CI 1.26–1.68] times increased fracture prevalence. The peak fracture incidence coincided with the timing of PHV (±1 year). In conclusion, trabecular vBMD but not aBMD was independently associated with prevalent X‐ray‐verified fractures in young men. Further studies are needed to determine if assessment of trabecular vBMD could enhance prediction of fractures during growth in males. © 2010 American Society for Bone and Mineral Research     

Trabecular and Cortical Microarchitecture in Postmenopausal HIV-Infected Women

Our objective was to assess the effects of HIV infection and antiretroviral therapy on trabecular and cortical microarchitecture in postmenopausal minority women. A subgroup of 106 (46 HIV-infected, 60 uninfected) postmenopausal Hispanic and African American women from an established cohort had areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry and trabecular and cortical volumetric BMD (vBMD) and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) at the radius and tibia. HIV-infected women were slightly younger (58 ± 1 vs. 61 ± 1 years, p = 0.08), and had lower body mass index (BMI; 28 ± 1 vs. 32 ± 1 kg/m², p < 0.01). BMI-adjusted aBMD Z scores were lower in HIV-infected women at the lumbar spine, total hip, and ultradistal radius. Serum N-telopeptide and C-telopeptide levels were also higher in HIV-infected women. Trabecular and cortical vBMD were similar at the radius, but cortical area (105.5 ± 2.4 vs. 120.6 ± 2.0 mm², p < 0.01) and thickness (956 ± 33 vs. 1,075 ± 28 μm, p < 0.01) at the tibia were approximately 11–12 % lower in HIV-infected women. Differences remained significant after adjusting for age, BMI, and race/ethnicity. In contrast, cortical porosity was similar in the two groups. Although HIV-infected postmenopausal women had lower aBMD at the spine, total hip, and ultradistal radius and higher levels of bone resorption markers, the only differences detected by HRpQCT were lower cortical thickness and area at the tibia.     

Skeletal phenotype of the leptin receptor–deficient db/db mouse

Leptin, a major hormonal product of the adipocyte, regulates appetite and reproductive function through its hypothalamic receptors. The leptin receptor is present in osteoblasts and chondrocytes, and previously we have shown leptin to be an anabolic bone factor in vitro, stimulating osteoblast proliferation and inhibiting osteoclastogenesis. Leptin increases bone mass and reduces bone fragility when administered peripherally but also can indirectly reduce bone mass when administered into the central nervous system. However, data from animal models deficient in either leptin (ob/ob) or its receptor (db/db) remain contradictory. We compared the bone phenotype of leptin receptor–deficient (db/db) and wild‐type mice using micro–computed tomographic (µCT) analysis of the proximal tibias and vertebrae. In the tibia, db/db mice had reduced percent trabecular bone volume (13.0 ± 1.62% in wild‐type versus 6.01 ± 0.601% in db/db mice, p = .002) and cortical bone volume (411 ± 21.5 µm³ versus 316 ± 3.53 µm³, p = .0014), trabecular thickness (48.4 ± 001.07 µm versus 45.1 ± 0.929 µm, p = .041) and trabecular number (2.68 ± 0.319 mm^?1 versus 1.34 ± 0.148 mm^?1, p = .0034). In the fifth lumbar vertebral body, the trabecular thickness and cortical thickness were decreased in the db/db versus wild‐type mice (0.053 ± 0.0011 mm versus 0.047 ± 0.0013 mm, p = .0002 and 0.062 ± 0.00054 mm versus 0.056 ± 0.0009 mm, p = .0001), respectively, whereas the trabecular and cortical percent bone volume and trabecular number did not reach significance. The total (endosteal and periosteal) cortical perimeter (12.2 ± 0.19 mm versus 13.2 ± 0.30 mm, p = .01) was increased. The serum osteocalcin levels were reduced in the db/db mice, suggesting that bone formation rates are decreased. The material properties of db/db femurs were determined by three‐point bending and nanoindentation, showing decreased bone strength (13.3 ± 0.280 N versus 7.99 ± 0.984 N, p = .0074) and material stiffness (28.5 ± 0.280 GPa versus 25.8 ± 0.281 GPa, p < .0001). These results demonstrate that bone mass and strength are reduced in the absence of leptin signaling, indicating that leptin acts in vivo as an anabolic bone factor. This concurs with results of in vitro studies and of peripheral leptin administration in vivo and suggests that leptin's direct effects on bone cells are likely to override its actions via the central nervous system. © 2011 American Society for Bone and Mineral Research     

Current Physical Activity Is Independently Associated With Cortical Bone Size and Bone Strength in Elderly Swedish Women

Physical activity is believed to have the greatest effect on the skeleton if exerted early in life, but whether or not possible benefits of physical activity on bone microstructure or geometry remain at old age has not been investigated in women. The aim of this study was to investigate if physical activity during skeletal growth and young adulthood or at old age was associated with cortical geometry and trabecular microarchitecture in weight‐bearing and non–weight‐bearing bone, and areal bone mineral density (aBMD) in elderly women. In this population‐based cross‐sectional study 1013 women, 78.2 ± 1.6 (mean ± SD) years old, were included. Using high‐resolution 3D pQCT (XtremeCT), cortical cross‐sectional area (Ct.CSA), cortical thickness (Ct.Th), cortical periosteal perimeter (Ct.Pm), volumetric cortical bone density (D.Ct), trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) were measured at the distal (14% level) and ultra‐distal tibia and radius, respectively. aBMD was assessed using DXA (Hologic Discovery A) of the spine and hip. A standardized questionnaire was used to collect information about previous exercise and the Physical Activity Scale for the Elderly (PASE) was used for current physical activity. A linear regression model (including levels of exercise during skeletal growth and young adulthood [10 to 30 years of age], PASE score, and covariates) revealed that level of current physical activity was independently associated with Ct.CSA (β = 0.18, p < 0.001) and Ct.Th (β = 0.15, p < 0.001) at the distal tibia, Tb.Th (β = 0.11, p < 0.001) and BV/TV (β = 0.10, p = 0.001) at the ultra‐distal tibia, and total hip aBMD (β = 0.10, p < 0.001). Current physical activity was independently associated with cortical bone size, in terms of thicker cortex but not larger periosteal circumference, and higher bone strength at the distal tibia on elderly women, indicating that physical activity at old age may decrease cortical bone loss in weight‐bearing bone in elderly women. © 2016 American Society for Bone and Mineral Research.     

Effects of Parathyroid Hormone Administration on Bone Strength in Hypoparathyroidism

The microstructural skeletal phenotype of hypoparathyroidism (HypoPT), a disorder of inadequate parathyroid hormone secretion, is altered trabecular microarchitecture with increased trabecular bone volume and thickness. Using 2‐D histomorphometric analysis, we previously found that 2 years of PTH(1‐84) in HypoPT is associated with reduced trabecular thickness (Tb.Th) and an increase in trabecular number (Tb.N). We have now utilized direct 3‐D microstructural analysis to determine the extent to which these changes may be related to bone strength. Iliac crest bone biopsies from HypoPT subjects (n = 58) were analyzed by microcomputed tomography (μCT) and by microfinite element (μFE) analysis. Biopsies were performed at baseline and at 1 or 2 years of recombinant human PTH(1‐84) [rhPTH(1‐84)]. In a subset of subjects (n = 13) at 3 months, we demonstrated a reduction in trabecular separation (Tb.Sp, 0.64 ± 0.1 to 0.56 ± 0.1 mm; p = 0.005) and in the variance of trabecular separation (Tb.SD, 0.19 ± 0.1 to 0.17 ± 0.1 mm; p = 0.01), along with an increase in bone volume/total volume (BV/TV, 26.76 ± 10.1 to 32.83 ± 13.5%; p = 0.02), bone surface/total volume (BS/TV, 3.85 ± 0.7 to 4.49 ± 1.0 mm²/mm³; p = 0.005), Tb.N (1.84 ± 0.5 versus 2.36 ± 1.3 mm^?1; p = 0.02) and Young's modulus (649.38 ± 460.7 to 1044.81 ± 1090.5 N/mm²; p = 0.049). After 1 year of rhPTH(1‐84), Force increased (144.08 ± 102.4 to 241.13 ± 189.1 N; p = 0.04) and Young's modulus tended to increase (662.15 ± 478.2 to 1050.80 ± 824.1 N/m²; p = 0.06). The 1‐year change in cancellous mineralizing surface (MS/BS) predicted 1‐year changes in μCT variables. The biopsies obtained after 2 years of rhPTH(1‐84) showed no change from baseline. These data suggest that administration of rhPTH(1‐84) in HypoPT is associated with transient changes in key parameters associated with bone strength. The results indicate that rhPTH(1‐84) improves skeletal quality in HypoPT early in treatment. © 2016 American Society for Bone and Mineral Research.     

Bone geometry, density, and microarchitecture in the distal radius and tibia in adults with osteogenesis imperfecta type I assessed by high-resolution pQCT

Osteogenesis imperfecta (OI) is a hereditary disorder characterized by decreased biosynthesis or impaired morphology of type I collagen that leads to decreased bone mass and increased bone fragility. We hypothesized that patients with OI have altered bone microstructure and bone geometry. In this cross‐sectional study we compared patients with type I OI to age‐ and gender‐matched healthy controls. A total of 39 (13 men and 26 women) patients with OI, aged 53 (range, 21–77) years, and 39 controls, aged 53 (range, 21–77) years, were included in the study. Twenty‐seven of the patients had been treated with bisphosphonates. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and dual‐energy X‐ray absorptiometry of total hip, femoral neck, trochanteric region, and the lumbar spine (L1–L4) were performed. The patients were shorter than the controls (159 ± 10 cm versus 170 ± 9 cm, p < 0.001), but had similar body weight. In OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with controls. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in OI compared with controls. At radius, total bone area was 5% lower in OI than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the controls (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI in both tibia and radius (p < 0.001 at both sites) when compared with controls. We conclude that patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age‐ and gender‐matched controls. © 2012 American Society for Bone and Mineral Research.     

Vertebral Size,Bone Density,and Strength in Men and Women Matched for Age and Areal Spine BMD

To explore the possible mechanisms underlying sex‐specific differences in skeletal fragility that may be obscured by two‐dimensional areal bone mineral density (aBMD) measures, we compared quantitative computed tomography (QCT)‐based vertebral bone measures among pairs of men and women from the Framingham Heart Study Multidetector Computed Tomography Study who were matched for age and spine aBMD. Measurements included vertebral body cross‐sectional area (CSA, cm²), trabecular volumetric BMD (Tb.vBMD, g/cm³), integral volumetric BMD (Int.vBMD, g/cm³), estimated vertebral compressive loading and strength (Newtons) at L₃, the factor‐of‐risk (load‐to‐strength ratio), and vertebral fracture prevalence. We identified 981 male‐female pairs (1:1 matching) matched on age (± 1 year) and QCT‐derived aBMD of L₃ (± 1%), with an average age of 51 years (range 34 to 81 years). Matched for aBMD and age, men had 20% larger vertebral CSA, lower Int.vBMD (–8%) and Tb.vBMD (–9%), 10% greater vertebral compressive strength, 24% greater vertebral compressive loading, and 12% greater factor‐of‐risk than women (p < 0.0001 for all), as well as higher prevalence of vertebral fracture. After adjusting for height and weight, the differences in CSA and volumetric bone mineral density (vBMD) between men and women were attenuated but remained significant, whereas compressive strength was no longer different. In conclusion, vertebral size, morphology, and density differ significantly between men and women matched for age and spine aBMD, suggesting that men and women attain the same aBMD by different mechanisms. These results provide novel information regarding sex‐specific differences in mechanisms that underlie vertebral fragility. © 2014 American Society for Bone and Mineral Research.     

X‐ray–verified fractures are associated with finite element analysis–derived bone strength and trabecular microstructure in young adult men

It has been suggested that fracture during childhood could be a predictor of low peak bone mass and thereby a potential risk factor for osteoporosis and fragility fractures later in life. The aim of this cross‐sectional, population‐based study was to investigate whether prevalent fractures, occurring from birth to young adulthood, were related to high‐resolution peripheral quantitative computed tomography (HR‐pQCT)–derived trabecular and cortical microstructure, as well as bone strength estimated by finite element (FEA) analysis of the radius and tibia in 833 young adult men around the time of peak bone mass (ages 23 to 25 years). In total, 292 subjects with prevalent X‐ray–verified fractures were found. Men with prevalent fractures had lower trabecular bone volume fraction (BV/TV) at the radius (5.5%, p < 0.001) and tibia (3.7%, p < 0.001), as well as lower cortical thickness (5.1%, p < 0.01) and cortical cross‐sectional area (4.1%, p < 0.01) at the tibia. No significant differences were seen for the cortical porosity or mean pore diameter. Using a logistic regression model (including age, smoking, physical activity, calcium intake, height, and weight as covariates), every SD decrease of FEA‐estimated failure load was associated with an increased prevalence of fractures at both the radius (odds ratio [OR] 1.22 [1.03–1.45]) and tibia (OR 1.32 [1.11–1.56]). Including dual‐energy X‐ray absorptiometry (DXA)–derived radius areal bone mineral density (aBMD), cortical thickness, and trabecular BV/TV simultaneously in a logistic regression model (with age, smoking, physical activity, calcium intake, height, and weight as covariates), BV/TV was inversely and independently associated with prevalent fractures (OR 1.28 [1.04–1.59]), whereas aBMD and cortical thickness were not (OR 1.19 [0.92–1.55] and OR 0.91 [0.73–1.12], respectively). In conclusion, prevalent fractures in young adult men were associated with impaired trabecular BV/TV at the radius, independently of aBMD and cortical thickness, indicating that primarily trabecular bone deficits are of greatest importance for prevalent fracture in this population. © 2013 American Society for Bone and Mineral Research.     

Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation

Children requiring allogeneic hematopoietic stem cell transplantation (alloHSCT) have multiple risk factors for impaired bone accrual. The impact of alloHSCT on volumetric bone mineral density (vBMD) and cortical structure has not been addressed. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained in 55 alloHSCT recipients, ages 5 to 26 years, a median of 7 (range, 3–16) years after alloHSCT. pQCT outcomes were converted to sex‐ and race‐ specific Z‐scores relative to age based on reference data in >700 concurrent healthy participants. Cortical section modulus (Zp; a summary measure of cortical bone structure and strength), and muscle and fat area Z‐scores were further adjusted for tibia length for age Z‐scores. AlloHSCT survivors had lower height Z‐scores (?1.21 ± 1.25 versus 0.23 ± 0.92; p < 0.001), versus reference participants; BMI Z‐scores did not differ. AlloHSCT survivors had lower trabecular vBMD (?1.05; 95% confidence interval [CI], ?1.33 to ?0.78; p < 0.001), cortical Zp (?0.63; 95% CI, ?0.91 to ?0.35; p < 0.001), and muscle (?1.01; 95% CI, ?1.30 to ?0.72; p < 0.001) Z‐scores and greater fat (0.82; 95% CI, 0.54–1.11; p < 0.001) Z‐scores, versus reference participants. Adjustment for muscle deficits eliminated Zp deficits in alloHSCT. Total body irradiation (TBI) was associated with lower trabecular vBMD (?1.30 ± 1.40 versus ?0.49 ± 0.88; p = 0.01) and muscle (?1.34 ± 1.42 versus ?0.34 ± 0.87; p < 0.01) Z‐scores. Growth hormone deficiency (GHD) was associated with lower Zp Z‐scores (?1.64 ± 2.47 versus ?0.28 ± 1.24; p = 0.05); however, muscle differences were not significant (?1.69 ± 1.84 versus ?0.78 ± 1.01; p = 0.09). History of graft versus host disease was not associated with pQCT outcomes. In summary, alloHSCT was associated with significant deficits in trabecular vBMD, cortical geometry, and muscle area years after transplantation. TBI and GHD were significant risk factors for musculoskeletal deficits. Future studies are needed to determine the metabolic and fracture implications of these deficits, and to identify therapies to improve bone accrual following alloHSCT during childhood. © 2012 American Society for Bone and Mineral Research.     

Heritability and Genetic Correlations for Bone Microarchitecture: The Framingham Study Families

High‐resolution peripheral quantitative computed tomography (HR‐pQCT) measures bone microarchitecture and volumetric bone mineral density (vBMD), important risk factors for osteoporotic fractures. We estimated the heritability (h²) of bone microstructure indices and vBMD, measured by HR‐pQCT, and genetic correlations (ρ_G) among them and between them and regional aBMD measured by dual‐energy X‐ray absorptiometry (DXA), in adult relatives from the Framingham Heart Study. Cortical (Ct) and trabecular (Tb) traits were measured at the distal radius and tibia in up to 1047 participants, and ultradistal radius (UD) aBMD was obtained by DXA. Heritability estimates, adjusted for age, sex, and estrogenic status (in women), ranged from 19.3% (trabecular number) to 82.8% (p < 0.01, Ct.vBMD) in the radius and from 51.9% (trabecular thickness) to 98.3% (cortical cross‐sectional area fraction) in the tibia. Additional adjustments for height, weight, and radial aBMD had no major effect on h² estimates. In bivariate analyses, moderate to high genetic correlations were found between radial total vBMD and microarchitecture traits (ρ_G from 0.227 to 0.913), except for cortical porosity. At the tibia, a similar pattern of genetic correlations was observed (ρ_G from 0.274 to 0.948), except for cortical porosity. Environmental correlations between the microarchitecture traits were also substantial. There were high genetic correlations between UD aBMD and multivariable‐adjusted total and trabecular vBMD at the radius (ρ_G = 0.811 and 0.917, respectively). In summary, in related men and women from a population‐based cohort, cortical and trabecular microarchitecture and vBMD at the radius and tibia were heritable and shared some h² with regional aBMD measured by DXA. These findings of high heritability of HR‐pQCT traits, with a slight attenuation when adjusting for aBMD, supports further work to identify the specific variants underlying volumetric bone density and fine structure of long bones. Knowledge that some of these traits are genetically correlated can serve to reduce the number of traits for genetic association studies. © 2016 American Society for Bone and Mineral Research.     

Microarchitectural deterioration of cortical and trabecular bone: Differing effects of denosumab and alendronate

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double‐blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C‐telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (?2.1% to ?0.8%) at the distal radius after 12 months. Alendronate prevented the decline (?0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab. © 2010 American Society for Bone and Mineral Research     

Type 2 Diabetes Mellitus Is Associated With Better Bone Microarchitecture But Lower Bone Material Strength and Poorer Physical Function in Elderly Women: A Population‐Based Study

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures according to several studies. The underlying mechanisms remain unclear, although small case‐control studies indicate poor quality of the cortical bone. We have studied a population‐based sample of women aged 75 to 80 years in Gothenburg, randomly invited from the population register. Areal bone mineral density (aBMD) was measured by dual‐energy X‐ray absorptiometry (Hologic Discovery A), bone microarchitecture by high‐resolution peripheral quantitative computed tomography (HR‐pQCT; ExtremeCT from Scanco Medical AG), and reference point indentation was performed with Osteoprobe (Active Life Scientific). Women with T2DM (n = 99) had higher aBMD compared to controls (n = 954). Ultradistal tibial and radial trabecular bone volume fraction (+11% and +15%, respectively), distal cortical volumetric BMD (+1.6% and +1.7%), cortical area (+11.5% and +9.3%), and failure load (+7.7% and +12.9%) were higher in diabetics than in controls. Cortical porosity was lower (mean ± SD: 1.5% ± 1.1% versus 2.0% ± 1.7%, p = 0.001) in T2DM in the distal radius but not in the ultradistal radius or the tibia. Adjustment for covariates (age, body mass index, glucocorticoid treatment, smoking, physical activity, calcium intake, bone‐active drugs) eliminated the differences in aBMD but not in HR‐pQCT bone variables. However, bone material strength index (BMSi) by reference point indentation was lower in T2DM (74.6 ± 7.6 versus 78.2 ± 7.5, p < 0.01), also after adjustment, and women with T2DM performed clearly worse in measures of physical function (one leg standing: –26%, 30‐s chair‐stand test: –7%, timed up and go: +12%, walking speed: +8%; p < 0.05‐0.001) compared to controls. In conclusion, we observed a more favorable bone microarchitecture but no difference in adjusted aBMD in elderly women with T2DM in the population compared to nondiabetics. Reduced BMSi and impaired physical function may explain the increased fracture risk in T2DM. © 2016 American Society for Bone and Mineral Research.     

Effects of Odanacatib on the Radius and Tibia of Postmenopausal Women: Improvements in Bone Geometry,Microarchitecture, and Estimated Bone Strength

The cathepsin K inhibitor odanacatib (ODN), currently in phase 3 development for postmenopausal osteoporosis, has a novel mechanism of action that reduces bone resorption while maintaining bone formation. In phase 2 studies, odanacatib increased areal bone mineral density (aBMD) at the lumbar spine and total hip progressively over 5 years. To determine the effects of ODN on cortical and trabecular bone and estimate changes in bone strength, we conducted a randomized, double‐blind, placebo‐controlled trial, using both quantitative computed tomography (QCT) and high‐resolution peripheral (HR‐p)QCT. In previously published results, odanacatib was superior to placebo with respect to increases in trabecular volumetric BMD (vBMD) and estimated compressive strength at the spine, and integral and trabecular vBMD and estimated strength at the hip. Here, we report the results of HR‐pQCT assessment. A total of 214 postmenopausal women (mean age 64.0 ± 6.8 years and baseline lumbar spine T‐score –1.81 ± 0.83) were randomized to oral ODN 50 mg or placebo, weekly for 2 years. With ODN, significant increases from baseline in total vBMD occurred at the distal radius and tibia. Treatment differences from placebo were also significant (3.84% and 2.63% for radius and tibia, respectively). At both sites, significant differences from placebo were also found in trabecular vBMD, cortical vBMD, cortical thickness, cortical area, and strength (failure load) estimated using finite element analysis of HR‐pQCT scans (treatment differences at radius and tibia = 2.64% and 2.66%). At the distal radius, odanacatib significantly improved trabecular thickness and bone volume/total volume (BV/TV) versus placebo. At a more proximal radial site, odanacatib attenuated the increase in cortical porosity found with placebo (treatment difference = –7.7%, p = 0.066). At the distal tibia, odanacatib significantly improved trabecular number, separation, and BV/TV versus placebo. Safety and tolerability were similar between treatment groups. In conclusion, odanacatib increased cortical and trabecular density, cortical thickness, aspects of trabecular microarchitecture, and estimated strength at the distal radius and distal tibia compared with placebo. © 2014 American Society for Bone and Mineral Research     

Genetic and hormonal control of bone volume,architecture, and remodeling in XXY mice

Klinefelter syndrome is the most common chromosomal aneuploidy in men (XXY karyotype, 1 in 600 live births) and results in testicular (infertility and androgen deficiency) and nontesticular (cognitive impairment and osteoporosis) deficits. The extent to which skeletal changes are due to testosterone deficiency or arise directly from gene overdosage cannot be determined easily in humans. To answer this, we generated XXY mice through a four‐generation breeding scheme. Eight intact XXY and 9 XY littermate controls and 8 castrated XXY mice and 8 castrated XY littermate controls were euthanized at 1 year of age. Castration occurred 6 months prior to killing. A third group of 9 XXY and 11 XY littermates were castrated and simultaneously implanted with a 1‐cm Silastic testosterone capsule 8 weeks prior to sacrifice. Tibias were harvested from all three groups and examined by micro–computed tomography and histomorphometry. Blood testosterone concentration was assayed by radioimmunoassay. Compared with intact XY controls, intact androgen‐deficient XXY mice had lower bone volume (6.8% ± 1.2% versus8.8% ± 1.7%, mean ± SD, p = .01) and thinner trabeculae (50 ± 4 µm versus 57 ± 5 µm, p = .007). Trabecular separation (270 ± 20 µm versus 270 ± 20 µm) or osteoclast number relative to bone surface (2.4 ± 1.0/mm² versus 2.7 ± 1.5/mm²) did not differ significantly. Testosterone‐replaced XXY mice continued to show lower bone volume (5.5% ± 2.4% versus 8.1% ± 3.5%, p = .026). They also exhibited greater trabecular separation (380 ± 69 µm versus 324 ± 62 µm, p = .040) but equivalent blood testosterone concentrations (6.3 ± 1.8 ng/mL versus 8.2 ± 4.2 ng/mL, p = .28) compared with testosterone‐replaced XY littermates. In contrast, castration alone drastically decreased bone volume (p < .001), trabecular thickness (p = .05), and trabecular separation (p < .01) to such a great extent that differences between XXY and XY mice were undetectable. In conclusion, XXY mice replicate many features of human Klinefelter syndrome and therefore are a useful model for studying bone. Testosterone deficiency does not explain the bone phenotype because testosterone‐replaced XXY mice show reduced bone volume despite similar blood testosterone levels. © 2010 American Society for Bone and Mineral Research.     

Early smoking is associated with peak bone mass and prevalent fractures in young,healthy men

Smoking is associated with lower areal bone mineral density (aBMD) and higher fracture risk, although most evidence has been derived from studies in elderly subjects. This study investigates smoking habits in relation to areal and volumetric bone parameters and fracture prevalence in young, healthy males at peak bone mass. Healthy male siblings (n = 677) at the age of peak bone mass (25 to 45 years) were recruited in a cross‐sectional population‐based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mass was determined using dual energy X‐ray absorptiometry (DXA). Sex steroids and bone markers were determined using immunoassays. Prevalent fractures and smoking habits were assessed using questionnaires. Self‐reported fractures were more prevalent in the current and early smokers than in the never smokers (p < .05), with a fracture prevalence odds ratio for early smokers of 1.96 (95% confidence interval 1.18–3.24) after adjustment for age, weight, educational level, and alcohol use and exclusion of childhood fractures. Current smoking was associated with a larger endosteal circumference (β = 0.027 ± 0.009, p = .016) and a decreased cortical thickness (β = ?0.034 ± 0.01, p = .020) at the tibia. In particular, early smokers (≤16 years) had a high fracture risk and lower areal BMD, together with a lower cortical bone area at the tibia and lower trabecular and cortical bone density at the radius. An interaction between free estradiol and current smoking was observed in statistical models predicting cortical area and thickness (β = 0.29 ± 0.11, p = .01). In conclusion, smoking at a young age is associated with unfavorable bone geometry and density and is associated with increased fracture prevalence, providing arguments for a disturbed acquisition of peak bone mass during puberty by smoking, possibly owing to an interaction with sex steroid action. © 2010 American Society for Bone and Mineral Research     

Skeletal microstructural abnormalities in postmenopausal women with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with osteoporosis and fragility fractures. The objectives of this study were to assess static and dynamic indices of cancellous and cortical bone structure in postmenopausal women with COPD. Twenty women with COPD who had not received chronic oral glucocorticoids underwent bone biopsies after double tetracycline labeling. Biopsies were analyzed by histomorphometry and µCT and compared with age‐matched controls. Distribution of the patients according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was: Type I (15%), Type II (40%), Type III (30%), and Type IV (15%). Mean (±SD) cancellous bone volume (15.20 ± 5.91 versus 21.34 ± 5.53%, p = .01), trabecular number (1.31 ± 0.26 versus 1.77 ± 0.51/mm, p = .003), and trabecular thickness (141 ± 23 versus 174 ± 36 µm, p = .006) were lower in patients than in controls. Connectivity density was lower in COPD (5.56 ± 2.78 versus 7.94 ± 3.08/mm, p = .04), and correlated negatively with smoking (r = ?0.67; p = .0005). Trabecular separation (785 ± 183 versus 614 ± 136 µm, p = .01) and cortical porosity (4.11 ± 1.02 versus 2.32 ± 0.94 voids/mm²; p < .0001) were higher in COPD while cortical width (458 ± 214 versus 762 ± 240 µm; p < .0001) was lower. Dynamic parameters showed significantly lower mineral apposition rate in COPD (0.56 ± 0.16 versus 0.66 ± 0.12 µm/day; p = .01). Patients with more severe disease, GOLD III and IV, presented lower bone formation rate than GOLD I and II (0.028 ± 0.009 versus 0.016 + 0.011 µm³/µm²/day; p = 04). This is the first evaluation of bone microstructure and remodeling in COPD. The skeletal abnormalities seen in cancellous and cortical bone provide an explanation for the high prevalence of vertebral fractures in this disease. © 2010 American Society for Bone and Mineral Research