Prediction of new clinical vertebral fractures in elderly men using finite element analysis of CT scans

Vertebral strength, as estimated by finite element analysis of computed tomography (CT) scans, has not yet been compared against areal bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA) for prospectively assessing the risk of new clinical vertebral fractures. To do so, we conducted a case‐cohort analysis of 306 men aged 65 years and older, which included 63 men who developed new clinically‐identified vertebral fractures and 243 men who did not, all observed over an average of 6.5 years. Nonlinear finite element analysis was performed on the baseline CT scans, blinded to fracture status, to estimate L1 vertebral compressive strength and a load‐to‐strength ratio. Volumetric BMD by quantitative CT and areal BMD by DXA were also evaluated. We found that, for the risk of new clinical vertebral fracture, the age‐adjusted hazard ratio per standard deviation change for areal BMD (3.2; 95% confidence interval [CI], 2.0–5.2) was significantly lower (p < 0.005) than for strength (7.2; 95% CI, 3.6–14.1), numerically lower than for volumetric BMD (5.7; 95% CI, 3.1–10.3), and similar for the load‐to‐strength ratio (3.0; 95% CI, 2.1–4.3). After also adjusting for race, body mass index (BMI), clinical center, and areal BMD, all these hazard ratios remained highly statistically significant, particularly those for strength (8.5; 95% CI, 3.6–20.1) and volumetric BMD (9.4; 95% CI, 4.1–21.6). The area‐under‐the‐curve for areal BMD (AUC = 0.76) was significantly lower than for strength (AUC = 0.83, p = 0.02), volumetric BMD (AUC = 0.82, p = 0.05), and the load‐to‐strength ratio (AUC = 0.82, p = 0.05). We conclude that, compared to areal BMD by DXA, vertebral compressive strength and volumetric BMD consistently improved vertebral fracture risk assessment in this cohort of elderly men. © 2012 American Society for Bone and Mineral Research.     

Mechanical contributions of the cortical and trabecular compartments contribute to differences in age‐related changes in vertebral body strength in men and women assessed by QCT‐based finite element analysis

The biomechanical mechanisms underlying sex‐specific differences in age‐related vertebral fracture rates are ill defined. To gain insight into this issue, we used finite element analysis of clinical computed tomography (CT) scans of the vertebral bodies of L3 and T10 of young and old men and women to assess age‐ and sex‐related differences in the strength of the whole vertebra, the trabecular compartment, and the peripheral compartment (the outer 2 mm of vertebral bone, including the thin cortical shell). We sought to determine whether structural and geometric changes with age differ in men and women, making women more susceptible to vertebral fractures. As expected, we found that vertebral strength decreased with age 2‐fold more in women than in men. The strength of the trabecular compartment declined significantly with age for both sexes, whereas the strength of the peripheral compartment decreased with age in women but was largely maintained in men. The proportion of mechanical strength attributable to the peripheral compartment increased with age in both sexes and at both vertebral levels. Taken together, these results indicate that men and women lose vertebral bone differently with age, particularly in the peripheral (cortical) compartment. This differential bone loss explains, in part, a greater decline in bone strength in women and may contribute to the higher incidence of vertebral fractures among women than men. © 2011 American Society for Bone and Mineral Research.     

Prediction of Incident Hip Fracture with the Estimated Femoral Strength by Finite Element Analysis of DXA Scans in the Study of Osteoporotic Fractures

A bone fractures only when loaded beyond its strength. The purpose of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of dual‐energy X‐ray absorptiometry (DXA) scans, with incident hip fracture in comparison to hip bone mineral density (BMD), Fracture Risk Assessment Tool (FRAX), and hip structure analysis (HSA) variables. This prospective case‐cohort study included a random sample of 1941 women and 668 incident hip fracture cases (295 in the random sample) during a mean ± SD follow‐up of 12.8 ± 5.7 years from the Study of Osteoporotic Fractures (n = 7860 community‐dwelling women ≥67 years of age). We analyzed the baseline DXA scans (Hologic 1000) of the hip using a validated plane‐stress, linear‐elastic finite element (FE) model of the proximal femur and estimated the femoral strength during a simulated sideways fall. Cox regression accounting for the case‐cohort design assessed the association of estimated femoral strength with hip fracture. The age–body mass index (BMI)‐adjusted hazard ratio (HR) per SD decrease for estimated strength (2.21; 95% CI, 1.95–2.50) was greater than that for total hip (TH) BMD (1.86; 95% CI, 1.67–2.08; p < 0.05), FN BMD (2.04; 95% CI, 1.79–2.32; p > 0.05), FRAX scores (range, 1.32–1.68; p < 0.0005), and many HSA variables (range, 1.13–2.43; p < 0.005), and the association was still significant (p < 0.05) after further adjustment for hip BMD or FRAX scores. The association of estimated strength with incident hip fracture was strong (Harrell's C index 0.770), significantly better than TH BMD (0.759; p < 0.05) and FRAX scores (0.711–0.743; p < 0.0001), but not FN BMD (0.762; p > 0.05). Similar findings were obtained for intracapsular and extracapsular fractures. In conclusion, the estimated femoral strength from FE analysis of DXA scans is an independent predictor and performs at least as well as FN BMD in predicting incident hip fracture in postmenopausal women. © 2014 American Society for Bone and Mineral Research.     

Reduction in Torsional Stiffness and Strength at the Proximal Tibia as a Function of Time Since Spinal Cord Injury

Spinal cord injury (SCI) is characterized by marked bone loss and a high rate of low‐energy fracture around regions of the knee. Changes in the mechanical integrity of bone after SCI are poorly defined, and a better understanding may inform approaches to prevent fractures. The purpose of this study was to quantify reductions in torsional stiffness and strength at the proximal tibia as a function of time since SCI. Sixty adults with SCI ranging from 0 to 50 years of duration and a reference group of 10 able‐bodied controls received a CT scan of the proximal tibia. Measures of integral bone mineral were calculated for the total proximal tibia, and localized measures of cortical and trabecular bone mineral were calculated for the epiphysis, metaphysis, and diaphysis. Torsional stiffness (K) and strength (T_ult) for the total proximal tibia were quantified using validated subject‐specific finite element models. Total proximal tibia measures of integral bone mineral, K, and T_ult decreased exponentially (r² = 0.52 to 0.70) and reached a new steady state within 2.1 to 2.7 years after SCI. Whereas new steady‐state values for integral bone mineral and K were 52% to 56% (p < 0.001) lower than the reference group, the new steady state for T_ult was 69% (p < 0.001) lower than the reference group. Reductions in total proximal tibia measures occurred through a combination of trabecular and endocortical resorption, leaving a bone comprised primarily of marrow fat rather than hydroxyapatite. These findings illustrate that a short therapeutic window exists early (ie, 2 years) after SCI, during which bone‐specific intervention may attenuate reductions in mechanical integrity and ultimately prevent SCI‐related fragility fracture. © 2015 American Society for Bone and Mineral Research.     

Femoral and Vertebral Strength Improvements in Postmenopausal Women With Osteoporosis Treated With Denosumab

In the randomized, placebo‐controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n = 48 placebo; n = 51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p < 0.0001) and through 36 months (8.6%; p < 0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (–5.6%; p < 0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p < 0.0001) and decreased by –4.2% for the placebo group (p = 0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p < 0.0001) and 22.4% (p < 0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.     

Distribution of bone density in the proximal femur and its association with hip fracture risk in older men: The osteoporotic fractures in men (MrOS) study

This prospective case‐cohort study aimed to map the distribution of bone density in the proximal femur and examine its association with hip fracture. We analyzed baseline quantitative computed tomography (QCT) scans in 250 men aged 65 years or older, which comprised a randomly‐selected subcohort of 210 men and 40 cases of first hip fracture during a mean follow‐up period of 5.5 years. We quantified cortical, trabecular, and integral volumetric bone mineral density (vBMD), and cortical thickness (CtTh) in four quadrants of cross‐sections along the length of the femoral neck (FN), intertrochanter (IT), and trochanter (TR). In most quadrants, vBMDs and CtTh were significantly (p < 0.05) lower in cases compared to the subcohort and these deficits were present across the entire proximal femur. To examine the association of QCT measurements with hip fracture, we merged the two quadrants in the medial and lateral aspects of the FN, IT, and TR. At most sites, QCT measurements were associated significantly (p < 0.001) with hip fracture, the hazard ratio (HR) adjusted for age, body mass index (BMI), and clinical site for a 1‐SD decrease ranged between 2.28 (95% confidence interval [CI], 1.44–3.63) to 6.91 (95% CI, 3.11–15.53). After additional adjustment for total hip (TH) areal BMD (aBMD), trabecular vBMDs at the FN, TR, and TH were still associated with hip fracture significantly (p < 0.001), the HRs ranged from 3.21 (95% CI, 1.65–6.24) for the superolateral FN to 6.20 (95% CI, 2.71–14.18) for medial TR. QCT measurements alone or in combination did not predict fracture significantly (p > 0.05) better than TH aBMD. With an area under the receiver operating characteristic curve (AUC) of 0.901 (95% CI, 0.852–0.950), the regression model combining TH aBMD, age, and trabecular vBMD predicted hip fracture significantly (p < 0.05) better than TH aBMD alone or TH aBMD plus age. These findings confirm that both cortical and trabecular bone contribute to hip fracture risk and highlight trabecular vBMD at the FN and TR as an independent risk factor. © 2012 American Society for Bone and Mineral Research.     

Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: a cross-sectional study using high-resolution-pQCT

Although bone mass appear ample for bone size in Turner syndrome (TS), epidemiological studies have reported an increased risk of fracture in TS. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to measure standard morphological parameters of bone geometry and microarchitecture, as well as estimated bone strength by finite element analysis (FEA) to assess bone characteristics beyond bone mineral density (BMD) that possibly contribute to the increased risk of fracture. Thirty‐two TS patients (median age 35, range 20–61 years) and 32 healthy control subjects (median age 36, range 19–58 years) matched with the TS participants with respect to age and body‐mass index were studied. A full region of interest (ROI) image analysis and a height‐matched ROI analysis adjusting for differences in body height between groups were performed. Mean bone cross‐sectional area was lower in TS patients in radius (?15%) and tibia (?13%) (both p < 0.01) whereas cortical thickness was higher in TS patients in radius (18%, p < 0.01) but not in tibia compared to controls. Cortical porosity was lower in TS patients at both sites (?32% in radius, ?36% in tibia, both p < 0.0001). Trabecular integrity was compromised in TS patients with lower bone volume per tissue volume (BV/TV) (?27% in radius, ?22% in tibia, both p < 0.0001), trabecular number (?27% in radius, ?12% in tibia, both p < 0.05), and higher trabecular spacing (54% in radius, 23% in tibia, both p < 0.01). In the height‐matched ROI analysis, differences remained significant apart from total area at both sites, cortical thickness in radius, and trabecular number in tibia. FEA estimated failure load was lower in TS patients in both radius (?11%) and tibia (?16%) (both p < 0.01) and remained significantly lower in the height‐matched ROI analysis. Conclusively, TS patients had compromised trabecular microarchitecture and lower bone strength at both skeletal sites, which may partly account for the increased risk of fracture observed in these patients. © 2012 American Society for Bone and Mineral Research.     

Influence of vertical trabeculae on the compressive strength of the human vertebra

Vertebral strength, a key etiologic factor of osteoporotic fracture, may be affected by the relative amount of vertically oriented trabeculae. To better understand this issue, we performed experimental compression testing, high‐resolution micro–computed tomography (µCT), and micro–finite‐element analysis on 16 elderly human thoracic ninth (T₉) whole vertebral bodies (ages 77.5 ± 10.1 years). Individual trabeculae segmentation of the µCT images was used to classify the trabeculae by their orientation. We found that the bone volume fraction (BV/TV) of just the vertical trabeculae accounted for substantially more of the observed variation in measured vertebral strength than did the bone volume fraction of all trabeculae (r² = 0.83 versus 0.59, p < .005). The bone volume fraction of the oblique or horizontal trabeculae was not associated with vertebral strength. Finite‐element analysis indicated that removal of the cortical shell did not appreciably alter these trends; it also revealed that the major load paths occur through parallel columns of vertically oriented bone. Taken together, these findings suggest that variation in vertebral strength across individuals is due primarily to variations in the bone volume fraction of vertical trabeculae. The vertical tissue fraction, a new bone quality parameter that we introduced to reflect these findings, was both a significant predictor of vertebral strength alone (r² = 0.81) and after accounting for variations in total bone volume fraction in multiple regression (total R² = 0.93). We conclude that the vertical tissue fraction is a potentially powerful microarchitectural determinant of vertebral strength. © 2011 American Society for Bone and Mineral Research.     

Active shape modeling of the hip in the prediction of incident hip fracture

The objective of this study was to evaluate right proximal femur shape as a risk factor for incident hip fracture using active shape modeling (ASM). A nested case‐control study of white women 65 years of age and older enrolled in the Study of Osteoporotic Fractures (SOF) was performed. Subjects (n = 168) were randomly selected from study participants who experienced hip fracture during the follow‐up period (mean 8.3 years). Controls (n = 231) had no fracture during follow‐up. Subjects with baseline radiographic hip osteoarthritis were excluded. ASM of digitized right hip radiographs generated 10 independent modes of variation in proximal femur shape that together accounted for 95% of the variance in proximal femur shape. The association of ASM modes with incident hip fracture was analyzed by logistic regression. Together, the 10 ASM modes demonstrated good discrimination of incident hip fracture. In models controlling for age and body mass index (BMI), the area under receiver operating characteristic (AUROC) curve for hip shape was 0.813, 95% confidence interval (CI) 0.771–0.854 compared with models containing femoral neck bone mineral density (AUROC = 0.675, 95% CI 0.620–0.730), intertrochanteric bone mineral density (AUROC = 0.645, 95% CI 0.589–0.701), femoral neck length (AUROC = 0.631, 95% CI 0.573–0.690), or femoral neck width (AUROC = 0.633, 95% CI 0.574–0.691). The accuracy of fracture discrimination was improved by combining ASM modes with femoral neck bone mineral density (AUROC = 0.835, 95% CI 0.795–0.875) or with intertrochanteric bone mineral density (AUROC = 0.834, 95% CI 0.794–0.875). Hips with positive standard deviations of ASM mode 4 had the highest risk of incident hip fracture (odds ratio = 2.48, 95% CI 1.68–3.31, p < .001). We conclude that variations in the relative size of the femoral head and neck are important determinants of incident hip fracture. The addition of hip shape to fracture‐prediction tools may improve the risk assessment for osteoporotic hip fractures. © 2011 American Society for Bone and Mineral Research.     

A comparison of bone quality at the distal radius between Asian and white adolescents and young adults: An HR‐pQCT study

Paradoxically, Asians have lower areal bone mineral density (aBMD), but their rates of hip and wrist fractures are lower than whites. Therefore, we used high‐resolution pQCT (HR‐pQCT) to determine whether differences in bone macrostructure and microstructure, BMD, and bone strength at the distal radius were apparent in Asian (n = 91, 53 males, 38 females, [mean ± SD] 17.3 ± 1.5 years) and white (n = 89, 46 males, 43 females, 18.1 ± 1.8 years) adolescents and young adults. HR‐pQCT outcomes included total BMD (Tt.BMD), trabecular bone volume fraction (BV/TV), and trabecular number (Tb.N), thickness (Tb.Th), and separation (Tb.Sp). We used an automated segmentation algorithm to determine total bone area (Tt.Ar), and cortical BMD (Ct.BMD), porosity (Ct.Po), and thickness (Ct.Th), and we applied finite element (FE) analysis to HR‐pQCT scans to estimate bone strength. We fit sex‐specific multivariable regression models to compare bone outcomes between Asians and whites, adjusting for age, age at menarche (girls), lean mass, ulnar length, dietary calcium intake, and physical activity. In males, after adjusting for covariates, Asians had 11% greater Tt.BMD, 8% greater Ct.BMD, and 25% lower Ct.Po than whites (p < 0.05). Also, Asians had 9% smaller Tt.Ar and 27% greater Ct.Th (p < 0.01). In females, Asians had smaller Tt.Ar than whites (16%, p < 0.001), but this difference was not significant after adjusting for covariates. Asian females had 5% greater Ct.BMD, 12% greater Ct.Th, and 11% lower Tb.Sp than whites after adjusting for covariates (p < 0.05). Estimated bone strength did not differ between Asian and white males or females. Our study supports the notion of compensatory elements of bone structure that sustain bone strength; smaller bones as observed between those of Asian origin compared with white origin have, on average, more dense, less porous, and thicker cortices. Longitudinal studies are needed to determine whether ethnic differences in bone structure exist in childhood, persist into old age, and whether they influence fracture risk.     

Comparative effects of teriparatide and risedronate in glucocorticoid‐induced osteoporosis in men: 18‐month results of the EuroGIOPs trial

Data on treatment of glucocorticoid‐induced osteoporosis (GIO) in men are scarce. We performed a randomized, open‐label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T‐score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L₁–L₃) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high‐resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X‐ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18‐month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE‐derived strength than risedronate.     

Romosozumab improves lumbar spine bone mass and bone strength parameters relative to alendronate in postmenopausal women: results from the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial

The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://clinicaltrials.gov/ct2/show/NCT01631214 ) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for ≥12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p < 0.001 at all time points). Most newly formed bone was accrued in the cortical compartment, with romosozumab showing larger absolute BMC gains than alendronate (p < 0.001 at all time points). In conclusion, romosozumab significantly improved bone mass and bone strength parameters at the lumbar spine compared with alendronate. These results are consistent with greater vertebral fracture risk reduction observed with romosozumab versus alendronate in ARCH and provide insights into structural determinants of this differential treatment effect. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Finite element analysis performed on radius and tibia HR‐pQCT images and fragility fractures at all sites in men

Few studies have investigated bone microarchitecture and biomechanical properties in men. This study assessed in vivo both aspects in a population of 185 men (aged 71 ± 10 years) with prevalent fragility fractures, compared to 185 controls matched for age, height, and weight, from the Structure of the Aging Men's Bones (STRAMBO) cohort. In this case‐control study, areal BMD (aBMD) was measured by DXA, bone microarchitecture was assessed by high resolution (HR)‐pQCT, and finite element (µFE) analysis was based on HR‐pQCT images of distal radius and tibia. A principal component (PC) analysis (PCA) was used to study the association of synthetic PCs with fracture by computing their odds ratio (OR [95%CI]) per SD change. Specific associations with vertebral fracture (n = 100), and nonvertebral fracture (n = 85) were also computed. At both sites, areal and volumetric BMD, cortical thickness and trabecular number, separation, and distribution were significantly worse in cases than in controls, with differences ranging from ?6% to 15%. µFE‐derived stiffness and failure load were 8% to 9% lower in fractures (p < .01). No difference in load distribution was found between the two groups. After adjustment for aBMD, only differences of µFE‐derived stresses, stiffness, and failure load at the tibia remained significant (p < .05). PCA resulted in defining 4 independent PCs, explaining 83% of the total variability of bone characteristics. Nonvertebral fractures were associated with PC1, reflecting bone quantity and strength at the radius (tibia) with OR = 1.64 [1.27–2.12] (2.21 [1.60–3.04]), and with PC2, defined by trabecular microarchitecture, with OR = 1.27 [1.00–1.61]. Severe vertebral fractures were associated with PC1, with OR = 1.56 [1.16–2.09] (2.21 [1.59–3.07]), and with PC2, with OR = 1.55 [1.17–2.06] (1.45 [1.06–1.98]). In conclusion, microarchitecture and biomechanical properties derived from µFE were associated with all types of fractures in men, showing that radius and tibia mechanical properties were relatively representative of distant bone site properties. © 2011 American Society for Bone and Mineral Research.     

Biomechanical effects of simulated resorption cavities in cancellous bone across a wide range of bone volume fractions

Resorption cavities formed during bone remodeling may act as “stress risers” and impair cancellous bone strength, but biomechanical analyses of the effects of stress risers have been limited. To provide further insight, we assessed the theoretical biomechanical effects of virtually-added resorption cavities in cancellous bone specimens spanning a wide range of bone volume fraction (BV/TV = 0.05–0.36) and across different anatomic sites (hip and spine) and species (human and canine). Micro-CT scans of 40 cubes of cancellous bone were converted into nonlinear finite element models (voxel element size ∼ 20 µm) for strength assessment. In each model, uniform trench-like resorption cavities with nominal dimensions 500 µm (length) × 200 µm (width) × 40 µm (depth), were virtually added either at random locations throughout the specimen, or, preferentially at locations of high tissue-level strain. We found that cancellous bone strength (p < 0.0001) and its relation with BV/TV (p < 0.001) were both altered by the virtual addition of the resorption cavities. When the resorption cavities were added at random locations throughout the specimen, the reduction in strength did not depend on BV/TV or anatomic site or species. When the resorption cavities were instead added preferentially at locations of high tissue-level strain, the effect was accentuated and was greatest in low-BV/TV bone. We conclude that, in theory, uniform-sized resorption cavities can reduce cancellous bone strength over the full range of BV/TV and across species, and the effect is larger if the cavities occur at highly strained locations in low-BV/TV bone. © 2012 American Society for Bone and Mineral Research.     

Cortical porosity is higher in boys compared with girls at the distal radius and distal tibia during pubertal growth: an HR-pQCT study

The aim of this study was to determine the sex- and maturity-related differences in bone microstructure and estimated bone strength at the distal radius and distal tibia in children and adolescents. We used high-resolution pQCT to measure standard morphological parameters in addition to cortical porosity (Ct.Po) and estimated bone strength by finite element analysis. Participants ranged in age from 9 to 22 years (n = 212 girls and n = 186 boys) who were scanned annually for either one (11%) or two (89%) years at the radius and for one (15%), two (39%), or three (46%) years at the tibia. Participants were grouped by the method of Tanner into prepubertal, early pubertal, peripubertal, and postpubertal groups. At the radius, peri- and postpubertal girls had higher cortical density (Ct.BMD; 9.4% and 7.4%, respectively) and lower Ct.Po (-118% and -56%, respectively) compared with peri- and postpubertal boys (all p < 0.001). Peri- and postpubertal boys had higher trabecular bone volume ratios (p < 0.001) and larger cortical cross-sectional areas (p < 0.05, p < 0.001) when compared with girls. Based upon the load-to-strength ratio (failure load/estimated fall force), boys had lower risk of fracture than girls at every stage except during early puberty. Trends at the tibia were similar to the radius with differences between boys and girls in Ct.Po (p < 0.01) and failure load (p < 0.01) at early puberty. Across pubertal groups, within sex, the most mature girls and boys had higher Ct.BMD and lower Ct.Po than their less mature peers (prepuberty) at both the radius and tibia. Girls in early, peri-, and postpubertal groups and boys in peri- and postpubertal groups had higher estimates of bone strength compared with their same-sex prepubertal peers (p < 0.001). These results provide insight into the sex- and maturity-related differences in bone microstructure and estimated bone strength.     

Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans

Finite element analysis of computed tomography (CT) scans provides noninvasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a 5‐year case‐control study of 1110 women and men over age 65 years from the AGES‐Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that for incident radiographically confirmed spine fractures (n = 167), the age‐adjusted odds ratio for vertebral strength was significant for women (2.8, 95% confidence interval [CI] 1.8 to 4.3) and men (2.2, 95% CI 1.5 to 3.2) and for men remained significant (p = 0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n = 171), the age‐adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI 2.6 to 6.9) and men (3.5, 95% CI 2.3 to 5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p = 0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD‐based interventional thresholds for osteoporosis and at corresponding preestablished thresholds for “fragile bone strength” (spine: women ≤ 4500 N, men ≤ 6500 N; hip: women ≤ 3000 N, men ≤ 3500 N). Because it is well established that individuals over age 65 years who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have fragile bone strength at the hip or spine should also be considered at high risk of fracture. © 2014 American Society for Bone and Mineral Research.     

Trends in hip fracture rates in Canada: An age‐period‐cohort analysis

Age‐standardized rates of hip fracture in Canada declined during the period 1985 to 2005. We investigated whether this incidence pattern is explained by period effects, cohort effects, or both. All hospitalizations during the study period with primary diagnosis of hip fracture were identified. Age‐ and sex‐specific hip fracture rates were calculated for nineteen 5‐year age groups and four 5‐year calendar periods, resulting in 20 birth cohorts. The effect of age, calendar period, and birth cohort on hip fracture rates was assessed using age‐period‐cohort models as proposed by Clayton and Schiffers. From 1985 to 2005, a total of 570,872 hospitalizations for hip fracture were identified. Age‐standardized rates for hip fracture have progressively declined for females and males. The annual linear decrease in rates per 5‐year period were 12% for females and 7% for males (both p < 0.0001). Significant birth cohort effects were also observed for both sexes (p < 0.0001). Cohorts born before 1950 had a higher risk of hip fracture, whereas those born after 1954 had a lower risk. After adjusting for age and constant annual linear change (drift term common to both period and cohort effects), we observed a significant nonlinear birth cohort effect for males (p = 0.0126) but not for females (p = 0.9960). In contrast, the nonlinear period effect, after adjustment for age and drift term, was significant for females (p = 0.0373) but not for males (p = 0.2515). For males, we observed no additional nonlinear period effect after adjusting for age and birth cohort, whereas for females, we observed no additional nonlinear birth cohort effect after adjusting for age and period. Although hip fracture rates decreased in both sexes, different factors may explain these changes. In addition to the constant annual linear decrease, nonlinear birth cohort effects were identified for males, and calendar period effects were identified for females as possible explanations.     

Low‐trauma fractures indicate increased risk of hip fracture in frail older people

This study aims to investigate the risk of subsequent fractures after low‐trauma fracture in frail older people. A total of 1412 elderly residents (mean age 86.2 years, SD 7.0 years, female 77%) were recruited from aged care facilities in Australia. Residents were assessed and then followed for any fracture for 2 years and hip fractures for at least 5 years. Residents with and without a newly acquired fracture in the first 2 years were compared for risk of subsequent hip fracture. Residents with a nonhip fracture in the first 2 years had an increased risk of subsequent hip fracture for about 2.5 years, whereas those with a hip fracture had a similar risk over the whole period compared with those with no fracture. During these 2.5 years, 60, 28, and 6 subsequent hip fractures occurred in the nonfracture group (n = 953), the nonhip fracture group (n = 194), and the hip fracture group (n = 101), respectively, resulting in the probability of subsequent hip fracture of 8.0%, 19.9%, and 10.4%, respectively. Compared with the nonfracture group, the hazard ratio (HR) was 2.82 [95% confidence interval (CI) 1.73–4.59; p < .001] for the nonhip fracture group and 1.48 (95% CI 0.63–3.49, p = .37) for the hip fracture group after adjusting for age, sex, residence type, calcaneal broadband ultrasound attenuation, fracture history, weight, lower leg length, immobility, cognitive function, and medications. Frail institutionalized older people with newly acquired fractures are at increased risk of subsequent hip fracture for the next few years. Accordingly, despite their advanced age, they are a high‐priority target group to investigate interventions that might reduce the risk of hip fracture. © 2011 American Society for Bone and Mineral Research.     

Multiscale Predictors of Femoral Neck In Situ Strength in Aging Women: Contributions of BMD,Cortical Porosity,Reference Point Indentation,and Nonenzymatic Glycation

The diagnosis of fracture risk relies almost solely on quantifying bone mass, yet bone strength is governed by factors at multiple scales including composition and structure that contribute to fracture resistance. Furthermore, aging and conditions such as diabetes mellitus alter fracture incidence independently of bone mass. Therefore, it is critical to incorporate other factors that contribute to bone strength in order to improve diagnostic specificity of fracture risk. We examined the correlation between femoral neck fracture strength in aging female cadavers and areal bone mineral density, along with other clinically accessible measures of bone quality including whole‐bone cortical porosity (Ct.Po), bone material mechanical behavior measured by reference point indentation (RPI), and accumulation of advanced glycation end‐products (AGEs). All measurements were found to be significant predictors of femoral neck fracture strength, with areal bone mineral density (aBMD) being the single strongest correlate (aBMD: r = 0.755, p < 0.001; Ct.Po: r = –0.500, p < 0.001; RPI: r = –0.478, p < 0.001; AGEs: r = –0.336, p = 0.016). RPI‐derived measurements were not correlated with tissue mineral density or local cortical porosity as confirmed by micro–computed tomography (μCT). Multiple reverse stepwise regression revealed that the inclusion of aBMD and any other factor significantly improve the prediction of bone strength over univariate predictions. Combining bone assays at multiple scales such as aBMD with tibial Ct.Po (r = 0.835; p < 0.001), tibial difference in indentation depth between the first and 20th cycle (IDI) (r = 0.883; p < 0.001), or tibial AGEs (r = 0.822; p < 0.001) significantly improves the prediction of femoral neck strength over any factor alone, suggesting that this personalized approach could greatly enhance bone strength and fracture risk assessment with the potential to guide clinical management strategies for at‐risk populations. © 2015 American Society for Bone and Mineral Research.     

Milk intake and risk of hip fracture in men and women: A meta‐analysis of prospective cohort studies

Milk contains calcium, phosphorus, and protein and is fortified with vitamin D in the United States. All these ingredients may improve bone health. However, the potential benefit of milk on hip fracture prevention is not well established. The objective of this study was to assess the association of milk intake with risk of hip fracture based on a meta‐analysis of cohort studies in middle‐aged or older men and women. Data sources for this study were English and non‐English publications via Medline (Ovid, PubMed) and EMBASE search up to June 2010, experts in the field, and reference lists. The idea was to compare prospective cohort studies on the same scale so that we could calculate the relative risk (RR) of hip fracture per glass of milk intake daily (approximately 300 mg calcium per glass of milk). Pooled analyses were based on random effects models. The data were extracted by two independent observers. The results show that in women (6 studies, 195,102 women, 3574 hip fractures), there was no overall association between total milk intake and hip fracture risk (pooled RR per glass of milk per day = 0.99; 95% confidence interval [CI] 0.96–1.02; Q‐test p = .37). In men (3 studies, 75,149 men, 195 hip fractures), the pooled RR per daily glass of milk was 0.91 (95% CI 0.81–1.01). Our conclusion is that in our meta‐analysis of cohort studies, there was no overall association between milk intake and hip fracture risk in women but that more data are needed in men. © 2011 American Society for Bone and Mineral Research.