Bone Geometry,Volumetric Density,Microarchitecture, and Estimated Bone Strength Assessed by HR‐pQCT in Adult Patients With Hypophosphatemic Rickets

Hypophosphatemic rickets (HR) is characterized by a generalized mineralization defect. Although densitometric studies have found the patients to have an elevated bone mineral density (BMD), data on bone geometry and microstructure are scarce. The aim of this cross‐sectional in vivo study was to assess bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated bone strength in adult patients with HR using high‐resolution peripheral quantitative computed tomography (HR‐pQCT). Twenty‐nine patients (aged 19 to 79 years; 21 female, 8 male patients), 26 of whom had genetically proven X‐linked HR, were matched with respect to age and sex with 29 healthy subjects. Eleven patients were currently receiving therapy with calcitriol and phosphate for a median duration of 29.1 years (12.0 to 43.0 years). Because of the disproportionate short stature in HR, the region of interest in HR‐pQCT images at the distal radius and tibia were placed in a constant proportion to the entire length of the bone in both patients and healthy volunteers. In age‐ and weight‐adjusted models, HR patients had significantly higher total bone cross‐sectional areas (radius 36%, tibia 20%; both p < 0.001) with significantly higher trabecular bone areas (radius 49%, tibia 14%; both p < 0.001) compared with controls. In addition, HR patients had lower total vBMD (radius ?20%, tibia ?14%; both p < 0.01), cortical vBMD (radius ?5%, p < 0.001), trabecular number (radius ?13%, tibia ?14%; both p < 0.01), and cortical thickness (radius ?19%; p < 0.01) compared with controls, whereas trabecular spacing (radius 18%, tibia 23%; p < 0.01) and trabecular network inhomogeneity (radius 29%, tibia 40%; both p < 0.01) were higher. Estimated bone strength was similar between the groups. In conclusion, in patients with HR, the negative impact of lower vBMD and trabecular number on bone strength seems to be compensated by an increase in bone diameter, resulting in HR patients having normal estimates of bone strength. © 2014 American Society for Bone and Mineral Research.     

Bone Geometry,Volumetric Density,Microarchitecture, and Estimated Bone Strength Assessed by HR‐pQCT in Klinefelter Syndrome

Although the expected skeletal manifestations of testosterone deficiency in Klinefelter's syndrome (KS) are osteopenia and osteoporosis, the structural basis for this is unclear. The aim of this study was to assess bone geometry, volumetric bone mineral density (vBMD), microarchitecture, and estimated bone strength using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) in patients with KS. Thirty‐one patients with KS confirmed by lymphocyte chromosome karyotyping aged 35.8 ± 8.2 years were recruited consecutively from a KS outpatient clinic and matched with respect to age and height with 31 healthy subjects aged 35.9 ± 8.2 years. Dual‐energy X‐ray absorptiometry (DXA) and HR‐pQCT were performed in all participants, and blood samples were analyzed for hormonal status and bone biomarkers in KS patients. Twenty‐one KS patients were on long‐term testosterone‐replacement therapy. In weight‐adjusted models, HR‐pQCT revealed a significantly lower cortical area (p < 0.01), total and trabecular vBMD (p = 0.02 and p = 0.04), trabecular bone volume fraction (p = 0.04), trabecular number (p = 0.05), and estimates of bone strength, whereas trabecular spacing was higher (p = 0.03) at the tibia in KS patients. In addition, cortical thickness was significantly reduced, both at the radius and tibia (both p < 0.01). There were no significant differences in indices of bone structure, estimated bone strength, or bone biomarkers in KS patients with and without testosterone therapy. This study showed that KS patients had lower total vBMD and a compromised trabecular compartment with a reduced trabecular density and bone volume fraction at the tibia. The compromised trabecular network integrity attributable to a lower trabecular number with relative preservation of trabecular thickness is similar to the picture found in women with aging. KS patients also displayed a reduced cortical area and thickness at the tibia, which in combination with the trabecular deficits, compromised estimated bone strength at this site. © 2014 American Society for Bone and Mineral Research.     

Abnormal microarchitecture and reduced stiffness at the radius and tibia in postmenopausal women with fractures

Measurement of areal bone mineral density (aBMD) by dual‐energy x‐ray absorptiometry (DXA) has been shown to predict fracture risk. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) yields additional information about volumetric BMD (vBMD), microarchitecture, and strength that may increase understanding of fracture susceptibility. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA and trabecular and cortical vBMD and trabecular microarchitecture of the radius and tibia measured by HR‐pQCT. Finite‐element analysis (FEA) of HR‐pQCT scans was performed to estimate bone stiffness. DXA T‐scores were similar in women with and without fracture at the spine, hip, and one‐third radius but lower in patients with fracture at the ultradistal radius (p < .01). At the radius fracture, patients had lower total density, cortical thickness, trabecular density, number, thickness, higher trabecular separation and network heterogeneity (p < .0001 to .04). At the tibia, total, cortical, and trabecular density and cortical and trabecular thickness were lower in fracture patients (p < .0001 to .03). The differences between groups were greater at the radius than at the tibia for inner trabecular density, number, trabecular separation, and network heterogeneity (p < .01 to .05). Stiffness was reduced in fracture patients, more markedly at the radius (41% to 44%) than at the tibia (15% to 20%). Women with fractures had reduced vBMD, microarchitectural deterioration, and decreased strength. These differences were more prominent at the radius than at the tibia. HR‐pQCT and FEA measurements of peripheral sites are associated with fracture prevalence and may increase understanding of the role of microarchitectural deterioration in fracture susceptibility. © 2010 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.     

A longitudinal HR‐pQCT study of alendronate treatment in postmenopausal women with low bone density: Relations among density,cortical and trabecular microarchitecture,biomechanics, and bone turnover

The goal of this study was to characterize longitudinal changes in bone microarchitecture and function in women treated with an established antifracture therapeutic. In this double‐blind, placebo‐controlled pilot study, 53 early postmenopausal women with low bone density (age = 56 ± 4 years; femoral neck T‐score = ?1.5 ± 0.6) were monitored by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) for 24 months following randomization to alendronate (ALN) or placebo (PBO) treatment groups. Subjects underwent annual HR‐pQCT imaging of the distal radius and tibia, dual‐energy X‐ray absorptiometry (DXA), and determination of biochemical markers of bone turnover (BSAP and uNTx). In addition to bone density and microarchitecture assessment, regional analysis, cortical porosity quantification, and micro‐finite‐element analysis were performed. After 24 months of treatment, at the distal tibia but not the radius, HR‐pQCT measures showed significant improvements over baseline in the ALN group, particularly densitometric measures in the cortical and trabecular compartments and endocortical geometry (cortical thickness and area, medullary area) (p < .05). Cortical volumetric bone mineral density (vBMD) in the tibia alone showed a significant difference between treatment groups after 24 months (p < .05); however, regionally, significant differences in Tb.vBMD, Tb.N, and Ct.Th were found for the lateral quadrant of the radius (p < .05). Spearman correlation analysis revealed that the biomechanical response to ALN in the radius and tibia was specifically associated with changes in trabecular microarchitecture (|ρ| = 0.51 to 0.80, p < .05), whereas PBO progression of bone loss was associated with a broad range of changes in density, geometry, and microarchitecture (|ρ| = 0.56 to 0.89, p < .05). Baseline cortical geometry and porosity measures best predicted ALN‐induced change in biomechanics at both sites (ρ > 0.48, p < .05). These findings suggest a more pronounced response to ALN in the tibia than in the radius, driven by trabecular and endocortical changes. © 2010 American Society for Bone and Mineral Research.     

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

Obesity is associated with greater areal BMD (aBMD) and is considered protective against hip and vertebral fracture. Despite this, there is a higher prevalence of lower leg and proximal humerus fracture in obesity. We aimed to determine if there are site‐specific differences in BMD, bone structure, or bone strength between obese and normal‐weight adults. We studied 100 individually‐matched pairs of normal (body mass index [BMI] 18.5 to 24.9 kg/m²) and obese (BMI >30 kg/m²) men and women, aged 25 to 40 years or 55 to 75 years. We assessed aBMD at the whole body (WB), hip (TH), and lumbar spine (LS) with dual‐energy X‐ray absorptiometry (DXA), LS trabecular volumetric BMD (Tb.vBMD) by quantitative computed tomography (QCT), and vBMD and microarchitecture and strength at the distal radius and tibia with high‐resolution peripheral QCT (HR‐pQCT) and micro–finite element analysis. Serum type 1 procollagen N‐terminal peptide (P1NP) and collagen type 1 C‐telopeptide (CTX) were measured by automated electrochemiluminescent immunoassay (ECLIA). Obese adults had greater WB, LS, and TH aBMD than normal adults. The effect of obesity on LS and WB aBMD was greater in older than younger adults (p < 0.01). Obese adults had greater vBMD than normal adults at the tibia (p < 0.001 both ages) and radius (p < 0.001 older group), thicker cortices, higher cortical BMD and tissue mineral density, lower cortical porosity, higher trabecular BMD, and higher trabecular number than normal adults. There was no difference in bone size between obese and normal adults. Obese adults had greater estimated failure load at the radius (p < 0.05) and tibia (p < 0.01). Differences in HR‐pQCT measurements between obese and normal adults were seen more consistently in the older than the younger group. Bone turnover markers were lower in obese than in normal adults. Greater BMD in obesity is not an artifact of DXA measurement. Obese adults have higher BMD, thicker and denser cortices, and higher trabecular number than normal adults. Greater differences between obese and normal adults in the older group suggest that obesity may protect against age‐related bone loss and may increase peak bone mass. © 2014 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     

Bone density,geometry, microstructure,and stiffness: Relationships between peripheral and central skeletal sites assessed by DXA,HR‐pQCT,and cQCT in premenopausal women

High‐resolution peripheral quantitative computed tomography (HR‐pQCT) is a new in vivo imaging technique for assessing 3D microstructure of cortical and trabecular bone at the distal radius and tibia. No studies have investigated the extent to which measurements of the peripheral skeleton by HR‐pQCT reflect those of the spine and hip, where the most serious fractures occur. To address this research question, we performed dual‐energy X‐ray absorptiometry (DXA), central QCT (cQCT), HR‐pQCT, and image‐based finite‐element analyses on 69 premenopausal women to evaluate relationships among cortical and trabecular bone density, geometry, microstructure, and stiffness of the lumbar spine, proximal femur, distal radius, and distal tibia. Significant correlations were found between the stiffness of the two peripheral sites (r = 0.86), two central sites (r = 0.49), and between the peripheral and central skeletal sites (r = 0.56–0.70). These associations were explained in part by significant correlations in areal bone mineral density (aBMD), volumetric bone mineral density (vBMD), and cross‐sectional area (CSA) between the multiple skeletal sites. For the prediction of proximal femoral stiffness, vBMD (r = 0.75) and stiffness (r = 0.69) of the distal tibia by HR‐pQCT were comparable with direct measurements of the proximal femur: aBMD of the hip by DXA (r = 0.70) and vBMD of the hip by cQCT (r = 0.64). For the prediction of vertebral stiffness, trabecular vBMD (r = 0.58) and stiffness (r = 0.70) of distal radius by HR‐pQCT were comparable with direct measurements of lumbar spine: aBMD by DXA (r = 0.78) and vBMD by cQCT (r = 0.67). Our results suggest that bone density and microstructural and mechanical properties measured by HR‐pQCT of the distal radius and tibia reflect the mechanical competence of the central skeleton. © 2010 American Society for Bone and Mineral Research.     

Differences in Macro‐ and Microarchitecture of the Appendicular Skeleton in Young Chinese and White Women

To identify the racial differences in macro‐ and microstructure of the distal radius and tibia that may account for the lower fracture rates in Asians than whites, we studied 61 healthy premenopausal Chinese and 111 white women 18–45 yr of age using high‐resolution pQCT (HR‐pQCT). The Chinese were shorter and leaner. Distal radius total cross‐sectional area (CSA) was 14.3% smaller in Chinese because of an 18.0% smaller trabecular area (p < 0.001). Cortical thickness was 8.8% greater in the Chinese, but cortical area was no different. Total volumetric BMD (vBMD) was 10.3% higher in the Chinese because of the 8.8% higher cortical thickness and 2.8% greater cortical density (all p < 0.01). Trabecular vBMD and bone volume/tissue volume (BV/TV) did not differ by race because trabeculae were 7.0% fewer but 10.8% thicker in Chinese than whites (both p < 0.01). Similar results were found at the distal tibia. Lower fracture risk in Chinese women may be partly caused by thicker cortices and trabeculae in a smaller bone‐more bone within the bone than in whites.     

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     

Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: a one-year prospective controlled study using high-resolution peripheral quantitative computed tomography

Following parathyroidectomy (PTX), bone mineral density (BMD) increases in patients with primary hyperparathyroidism (PHPT), yet information is scarce concerning changes in bone structure and strength following normalization of parathyroid hormone levels postsurgery. In this 1‐year prospective controlled study, high‐resolution peripheral quantitative computed tomography (HR‐pQCT) was used to evaluate changes in bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated strength in female patients with PHPT before and 1 year after PTX, compared to healthy controls. Twenty‐seven women successfully treated with PTX (median age 62 years; range, 44–75 years) and 31 controls (median age 63 years; range, 40–76 years) recruited by random sampling from the general population were studied using HR‐pQCT of the distal radius and tibia as well as with dual‐energy X‐ray absorptiometry (DXA) of the forearm, spine, and hip. The two groups were comparable with respect to age, height, weight, and menopausal status. In both radius and tibia, cortical (Ct.) vBMD and Ct. thickness increased or were maintained in patients and decreased in controls (p < 0.01). Radius cancellous bone architecture was improved in patients through increased trabecular number and decreased trabecular spacing compared with changes in controls (p < 0.05). No significant cancellous bone changes were observed in tibia. Estimated bone failure load by finite element modeling increased in patients in radius but declined in controls (p < 0.001). Similar, albeit borderline significant changes in estimated failure load were found in tibia (p = 0.06). This study showed that females with PHPT had improvements in cortical bone geometry and increases in cortical and trabecular vBMD in both radius and tibia along with improvements in cancellous bone architecture and estimated strength in radius 1 year after PTX, reversing or attenuating age‐related changes observed in controls. © 2012 American Society for Bone and Mineral Research.     

Divergent Effects of Glucocorticoids on Cortical and Trabecular Compartment BMD in Childhood Nephrotic Syndrome

Glucocorticoid (GC) effects on skeletal development have not been established. The objective of this pQCT study was to assess volumetric BMD (vBMD) and cortical dimensions in childhood steroid‐sensitive nephrotic syndrome (SSNS), a disorder with minimal independent deleterious skeletal effects. Tibia pQCT was used to assess trabecular and cortical vBMD, cortical dimensions, and muscle area in 55 SSNS (age, 5–19 yr) and >650 control participants. Race‐, sex‐, and age‐, or tibia length‐specific Z‐scores were generated for pQCT outcomes. Bone biomarkers included bone‐specific alkaline phosphatase and urinary deoxypyridinoline. SSNS participants had lower height Z‐scores (p < 0.0001) compared with controls. In SSNS, Z‐scores for cortical area were greater (+0.37; 95% CI = 0.09, 0.66; p = 0.01), for cortical vBMD were greater (+1.17; 95% CI = 0.89, 1.45; p < 0.0001), and for trabecular vBMD were lower (?0.60; 95% CI, = ?0.89, ?0.31; p < 0.0001) compared with controls. Muscle area (+0.34; 95% CI = 0.08, 0.61; p = 0.01) and fat area (+0.56; 95% CI = 0.27, 0.84; p < 0.001) Z‐scores were greater in SSNS, and adjustment for muscle area eliminated the greater cortical area in SSNS. Bone formation and resorption biomarkers were significantly and inversely associated with cortical vBMD in SSNS and controls and were significantly lower in the 34 SSNS participants taking GCs at the time of the study compared with controls. In conclusion, GCs in SSNS were associated with significantly greater cortical vBMD and cortical area and lower trabecular vBMD, with evidence of low bone turnover. Lower bone biomarkers were associated with greater cortical vBMD. Studies are needed to determine the fracture implications of these varied effects.     

Bone mass and strength in older men with type 2 diabetes: The Osteoporotic Fractures in Men Study

The effects of type 2 diabetes mellitus (T2DM) on bone volumetric density, bone geometry, and estimates of bone strength are not well established. We used peripheral quantitative computed tomography (pQCT) 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 and bending strength in a subset (n = 1171) of men (≥65 years of age) who participated in the multisite Osteoporotic Fractures in Men (MrOS) study. Analysis of covariance–adjusted bone data for clinic site, age, and limb length (model 1) and further adjusted for body weight (model 2) were used to compare data between participants with (n = 190) and without (n = 981) T2DM. At both the distal tibia and radius, patients with T2DM had greater bone vBMD (+2% to +4%, model 1, p < .05) and a smaller bone area (ToA ?1% to ?4%, model 2, p < .05). The higher vBMD compensated for lower bone area, resulting in no differences in estimated compressive bone strength at the distal trabecular bone regions. At the mostly cortical bone midshaft sites of the radius and tibia, men with T2DM had lower ToA (?1% to ?3%, p < .05), resulting in lower bone bending strength at both sites after adjusting for body weight (?2% to ?5%, p < .05) despite the lack of difference in cortical vBMD at these sites. These data demonstrate that older men with T2DM have bone strength that is low relative to body weight at the cortical‐rich midshaft of the radius despite no difference in cortical vBMD. © 2010 American Society for Bone and Mineral Research     

Bone Microarchitecture Assessed by HR‐pQCT as Predictor of Fracture Risk in Postmenopausal Women: The OFELY Study

Several cross‐sectional studies have shown that impairment of bone microarchitecture contributes to skeletal fragility. The aim of this study was to prospectively investigate the prediction of fracture (Fx) by bone microarchitecture assessed by high‐resolution peripheral computed tomography (HR‐ pQCT) in postmenopausal women. We measured microarchitecture at the distal radius and tibia with HR‐pQCT in the OFELY study, in addition to areal BMD with dual‐energy X‐ray absorptiometry (DXA) in 589 women, mean ± SD age 68 ± 9 years. During a median [IQ] 9.4 [1.0] years of follow‐up, 135 women sustained an incident fragility Fx, including 81 women with a major osteoporotic Fx (MOP Fx). After adjustment for age, women who sustained Fx had significantly lower total and trabecular volumetric densities (vBMD) at both sites, cortical parameters (area and thickness at the radius, vBMD at the tibia), trabecular number (Tb.N), connectivity density (Conn.D), stiffness, and estimated failure load at both sites, compared with control women. After adjustment for age, current smoking, falls, prior Fx, use of osteoporosis‐related drugs, and total hip BMD, each quartile decrease of several baseline values of bone microarchitecture at the radius was associated with significant change of the risk of Fx (HR of 1.39 for Tb.BMD [p = 0.001], 1.32 for Tb.N [p = 0.01], 0.76 for Tb.Sp.SD [p = 0.01], 1.49 [p = 0.01] for Conn.D, and 1.27 for stiffness [p = 0.02]). At the tibia, the association remained significant for stiffness and failure load in the multivariate model for all fragility Fx and for Tt.BMD, stiffness, and failure load for MOP Fx. We conclude that impairment of bone microarchitecture—essentially in the trabecular compartment of the radius—predict the occurrence of incident fracture in postmenopausal women. This assessment may play an important role in identifying women at high risk of fracture who could not be adequately detected by BMD measurement alone, to benefit from a therapeutic intervention. © 2017 American Society for Bone and Mineral Research.     

Diabetes and Deficits in Cortical Bone Density,Microarchitecture, and Bone Size: Framingham HR‐pQCT Study

Older adults with type 2 diabetes (T2D) tend to have normal or greater areal bone mineral density (aBMD), as measured by DXA, than those who do not have diabetes (non‐T2D). Yet risk of fracture is higher in T2D, including 40% to 50% increased hip fracture risk. We used HR‐pQCT to investigate structural mechanisms underlying skeletal fragility in T2D. We compared cortical and trabecular bone microarchitecture, density, bone area, and strength in T2D and non‐T2D. In secondary analyses we evaluated whether associations between T2D and bone measures differed according to prior fracture, sex, and obesity. Participants included 1069 members of the Framingham Study, who attended examinations in 2005 to 2008 and underwent HR‐pQCT scanning in 2012 to 2015. Mean age was 64 ± 8 years (range, 40 to 87 years), and 12% (n = 129) had T2D. After adjustment for age, sex, weight, and height, T2D had lower cortical volumetric BMD (vBMD) (p < 0.01), higher cortical porosity (p = 0.02), and smaller cross‐sectional area (p = 0.04) at the tibia, but not radius. Trabecular indices were similar or more favorable in T2D than non‐T2D. Associations between T2D and bone measures did not differ according to sex or obesity status (all interaction p > 0.05); however, associations did differ in those with a prior fracture and those with no history of fracture. Specifically, cortical vBMD at the tibia and cortical thickness at the radius were lower in T2D than non‐T2D, but only among those individuals with a prior fracture. Cortical porosity at the radius was higher in T2D than non‐T2D, but only among those who did not have a prior fracture. Findings from this large, community‐based study of older adults suggest that modest deterioration in cortical bone and reductions in bone area may characterize diabetic bone disease in older adults. Evaluation of these deficits as predictors of fracture in T2D is needed to develop prevention strategies in this rapidly increasing population of older adults. © 2017 American Society for Bone and Mineral Research.     

Abdominal Aortic Calcification,BMD, and Bone Microstructure: A Population‐Based Study

To better define the relationship between vascular calcification and bone mass/structure, we assessed abdominal aortic calcification (AAC), BMD, and bone microstructure in an age‐stratified, random sample of 693 Rochester, MN, residents. Participants underwent QCT of the spine and hip and high‐resolution pQCT (HRpQCT) of the radius to define volumetric BMD (vBMD) and microstructural parameters. AAC was quantified with the Agatston scoring method. In men, AAC correlated with lower vertebral trabecular and femoral neck vBMD (p < 0.001), but not after age or multivariable (age, body mass index, smoking status) adjustment. Separation into <50 and ≥50 yr showed this pattern only in the older men. BV/TV and Tb.Th inversely correlated with AAC in all men (p < 0.001), and Tb.Th remained significantly correlated after age adjustment (p < 0.05). Tb.N positively correlated with AAC in younger men (p < 0.001) but negatively correlated in older men (p < 0.001). The opposite was true with Tb.Sp (p = 0.01 and p < 0.001, respectively). Lower Tb.N and higher Tb.Sp correlated with AAC in older men even after multivariable adjustment. Among all women and postmenopausal women, AAC correlated with lower vertebral and femoral neck vBMD (p < 0.001) but not after adjustment. Lower BV/TV and Tb.Th correlated with AAC (p = 0.03 and p = 0.04, respectively) in women, but not after adjustment. Our findings support an age‐dependent association between AAC and vBMD. We also found that AAC correlates with specific bone microstructural parameters in older men, suggesting a possible common pathogenesis for vascular calcification and deterioration in bone structure. However, sex‐specific differences exist.     

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.     

Differences in skeletal microarchitecture and strength in African‐American and white women

African‐American women have a lower risk of fracture than white women, and this difference is only partially explained by differences in dual‐energy X‐ray absorptiometry (DXA) areal bone mineral density (aBMD). Little is known about racial differences in skeletal microarchitecture and the consequences for bone strength. To evaluate potential factors underlying this racial difference in fracture rates, we used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to assess cortical and trabecular bone microarchitecture and estimate bone strength using micro–finite element analysis (µFEA) in African‐American (n = 100) and white (n = 173) women participating in the Study of Women's Health Across the Nation (SWAN). African‐American women had larger and denser bones than whites, with greater total area, aBMD, and total volumetric BMD (vBMD) at the radius and tibia metaphysis (p < 0.05 for all). African‐Americans had greater trabecular vBMD at the radius, but higher cortical vBMD at the tibia. Cortical microarchitecture tended to show the most pronounced racial differences, with higher cortical area, thickness, and volumes in African‐Americans at both skeletal sites (p < 0.05 for all), and lower cortical porosity in African‐Americans at the tibia (p < 0.05). African‐American women also had greater estimated bone stiffness and failure load at both the radius and tibia. Differences in skeletal microarchitecture and estimated stiffness and failure load persisted even after adjustment for DXA aBMD. The densitometric and microarchitectural predictors of failure load at the radius and tibia were the same in African‐American and white women. In conclusion, differences in bone microarchitecture and density contribute to greater estimated bone strength in African‐Americans and probably explain, at least in part, the lower fracture risk of African‐American women. © 2013 American Society for Bone and Mineral Research.     

Comparative Effects of Teriparatide,Denosumab, and Combination Therapy on Peripheral Compartmental Bone Density,Microarchitecture, and Estimated Strength: the DATA‐HRpQCT Study

Combined teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high‐resolution peripheral quantitative computed tomography (HR‐pQCT) assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive teriparatide 20 µg daily (n = 31), denosumab 60 mg every 6 months (n = 33), or both (n = 30) for 12 months. In the teriparatide group, total volumetric bone mineral density (vBMD) did not change at either anatomic site but increased in both other groups at both sites. The increase in vBMD at the tibia was greater in the combination group (3.1 ± 2.2%) than both the denosumab (2.2 ± 1.9%) and teriparatide groups (–0.3 ± 1.9%) (p < 0.02 for both comparisons). Cortical vBMD decreased by 1.6 ± 1.9% at the tibia and by 0.9 ± 2.8% at the radius in the teriparatide group, whereas it increased in both other groups at both sites. Tibia cortical vBMD increased more in the combination group (1.5 ± 1.5%) than both monotherapy groups (p < 0.04 for both comparisons). Cortical thickness did not change in the teriparatide group but increased in both other groups. The increase in cortical thickness at the tibia was greater in the combination group (5.4 ± 3.9%) than both monotherapy groups (p < 0.01 for both comparisons). In the teriparatide group, radial cortical porosity increased by 20.9 ± 37.6% and by 5.6 ± 9.9% at the tibia but did not change in the other two groups. Bone stiffness and failure load, as estimated by finite element analysis, did not change in the teriparatide group but increased in the other two groups at both sites. Together, these findings suggest that the use of denosumab and teriparatide in combination improves HR‐pQCT measures of bone quality more than either drug alone and may be of significant clinical benefit in the treatment of postmenopausal osteoporosis. © 2014 American Society for Bone and Mineral Research.     

Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR‐pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age‐ and sex‐related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, –11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients. © 2015 American Society for Bone and Mineral Research.