Comprehensive Assessment of Osteoporosis and Bone Fragility with CT Colonography.

PURPOSE: To evaluate the ability of additional analysis of computed tomographic (CT) colonography images to provide a comprehensive osteoporosis assessment. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act-compliant study was approved by our institutional review board with a waiver of informed consent. Diagnosis of osteoporosis and assessment of fracture risk were compared between biomechanical CT analysis and dual-energy x-ray absorptiometry (DXA) in 136 women (age range, 43-92 years), each of whom underwent CT colonography and DXA within a 6-month period (between January 2008 and April 2010). Blinded to the DXA data, biomechanical CT analysis was retrospectively applied to CT images by using phantomless calibration and finite element analysis to measure bone mineral density and bone strength at the hip and spine. Regression, Bland-Altman, and reclassification analyses and paired t tests were used to compare results. RESULTS: For bone mineral density T scores at the femoral neck, biomechanical CT analysis was highly correlated (R(2) = 0.84) with DXA, did not differ from DXA (P = .15, paired t test), and was able to identify osteoporosis (as defined by DXA), with 100% sensitivity in eight of eight patients (95% confidence interval [CI]: 67.6%, 100%) and 98.4% specificity in 126 of 128 patients (95% CI: 94.5%, 99.6%). Considering both the hip and spine, the classification of patients at high risk for fracture by biomechanical CT analysis--those with osteoporosis or "fragile bone strength"--agreed well against classifications for clinical osteoporosis by DXA (T score ≤-2.5 at the hip or spine), with 82.8% sensitivity in 24 of 29 patients (95% CI: 65.4%, 92.4%) and 85.7% specificity in 66 of 77 patients (95% CI: 76.2%, 91.8%). CONCLUSION: Retrospective biomechanical CT analysis of CT colonography for colorectal cancer screening provides a comprehensive osteoporosis assessment without requiring changes in imaging protocols.

The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men.

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

Osteoporosis treatment prevents hip fracture similarly in both sexes: the FOCUS observational study.

Randomized trials have not been performed, and may never be, to determine if osteoporosis treatment prevents hip fracture in men. Addressing that evidence gap, we analyzed data from an observational study of new hip fractures in a large integrated healthcare system to compare the reduction in hip fractures associated with standard-of-care osteoporosis treatment in men versus women. Sampling from 271 389 patients age ≥ 65 who had a hip-containing computed tomography scan during care between 2005-2018, we selected all who subsequently had a first hip fracture (cases) after the CT scan (start of observation) and a sex-matched equal number of randomly selected patients. From those, we analyzed all who tested positive for osteoporosis (DXA-equivalent hip bone mineral density T-score ≤ -2.5, measured from the CT scan using VirtuOst). We defined "treated" as at least six months of any osteoporosis medication by prescription fill data during follow up; "not-treated" was no prescription fill. Sex-specific odds ratios of hip fracture for treated versus not-treated patients were calculated by logistic regression; adjustments included age, BMD T-score, a BMD-treatment interaction, body mass index, race/ethnicity, and seven baseline clinical risk factors. At two-year follow-up, 33.9% of the women (750/2211 patients) and 24.0% of the men (175/728 patients) were treated, primarily with alendronate; 51.3% and 66.3%, respectively, were not-treated; and 721 and 269, respectively, had a first hip fracture since the CT scan. Odds ratio of hip fracture for treated versus not-treated was 0.26 (95% confidence interval: 0.21-0.33) for women and 0.21 (0.13-0.34) for men; the ratio of these odds ratios (men:women) was 0.81 (0.47-1.37), indicating no significant sex effect. Various sensitivity and stratified analyses confirmed these trends, including results at five-year follow-up. Given these results and considering the relevant literature, we conclude that osteoporosis treatment prevents hip fracture similarly in both sexes.

Much evidence suggests that osteoporosis treatment should prevent hip fracture similarly in both sexes. However, because of their expense, randomized clinical trials to demonstrate that definitively have not been performed and may never be. As a result, osteoporosis testing and treatment is not as widely adopted for men as it is for women. Addressing that evidence gap, we analyzed data from over 250 000 patients in the Kaiser Permanente healthcare system in Southern California. Sampling a subset of all patients over a 13-year period who had had a computed tomography (CT or CAT) scan as part of their medical care for any reason, we measured bone mineral density from the CT scans to identify all patients who had osteoporosis at the hip and then used data from the electronic health records to determine statistically the risk of a future hip fracture for those who were treated for osteoporosis versus those who were not treated. We found that the reduction in risk of hip fracture associated with treatment did not differ between the sexes. These results demonstrate that treating osteoporosis in patients at high risk of hip fracture should reduce the risk of hip fracture similarly in both sexes.

Increased risks of vertebral fracture and reoperation in primary spinal fusion patients who test positive for osteoporosis by Biomechanical Computed Tomography analysis.

BACKGROUND CONTEXT: While osteoporosis is a risk factor for adverse outcomes in spinal fusion patients, diagnosing osteoporosis reliably in this population has been challenging due to degenerative changes and spinal deformities. Addressing that challenge, biomechanical computed tomography analysis (BCT) is a CT-based diagnostic test for osteoporosis that measures both bone mineral density and bone strength (using finite element analysis) at the spine; CT scans taken for spinal evaluation or previous care can be repurposed for the analysis. PURPOSE: Assess the effectiveness of BCT for preoperatively identifying spinal fusion patients with osteoporosis who are at high risk of reoperation or vertebral fracture. STUDY DESIGN: Observational cohort study in a multi-center integrated managed care system using existing data from patient medical records and imaging archives. PATIENT SAMPLE: We studied a randomly sampled subset of all adult patients who had any type of primary thoracic (T4 or below) or lumbar fusion between 2005 and 2018. For inclusion, patients with accessible study data needed a preop CT scan without intravenous contrast that contained images (before any instrumentation) of the upper instrumented vertebral level. OUTCOME MEASURES: Reoperation for any reason (primary outcome) or a newly documented vertebral fracture (secondary outcome) occurring up to 5 years after the primary surgery. METHODS: All study data were extracted using available coded information and CT scans from the medical records. BCT was performed at a centralized lab blinded to the clinical outcomes; patients could test positive for osteoporosis based on either low values of bone strength (vertebral strength ≤ 4,500 N women or 6,500 N men) and/or bone mineral density (vertebral trabecular bone mineral density ≤ 80 mg/cm3 both sexes). Cox proportional hazard ratios were adjusted by age, presence of obesity, and whether the fusion was long (four or more levels fused) or short (3 or fewer levels fused); Kaplan-Meier survival was compared by the log rank test. This project was funded by NIH (R44AR064613) and all physician co-authors and author 1 received salary support from their respective departments. Author 6 is employed by, and author 1 has equity in and consults for, the company that provides the BCT test; the other authors declare no conflicts of interest. RESULTS: For the 469 patients analyzed (298 women, 171 men), median follow-up time was 44.4 months, 11.1% had a reoperation (median time 14.5 months), and 7.7% had a vertebral fracture (median time 2.0 months). Overall, 25.8% of patients tested positive for osteoporosis and no patients under age 50 tested positive. Compared to patients without osteoporosis, those testing positive were at almost five-fold higher risk for vertebral fracture (adjusted hazard ratio 4.7, 95% confidence interval = 2.2-9.7; p<.0001 Kaplan-Meier survival). Of those positive-testing patients, those who tested positive concurrently for low values of both bone strength and bone mineral density (12.6% of patients overall) were at almost four-fold higher risk for reoperation (3.7, 1.9-7.2; Kaplan-Meier survival p<.0001); the remaining positive-testing patients (those who tested positive for low values of either bone strength or bone mineral density but not both) were not at significantly higher risk for reoperation (1.6, 0.7-3.7) but were for vertebral fracture (4.3, 1.9-10.2). For both clinical outcomes, risk remained high for patients who underwent short or long fusion. CONCLUSION: In a real-world clinical setting, BCT was effective in identifying primary spinal fusion patients aged 50 or older with osteoporosis who were at elevated risks of reoperation and vertebral fracture.

Once-monthly oral ibandronate improves biomechanical determinants of bone strength in women with postmenopausal osteoporosis.

CONTEXT: Bone strength and fracture resistance are determined by bone mineral density (BMD) and structural, mechanical, and geometric properties of bone. DESIGN, SETTING, AND OBJECTIVES: This randomized, double-blind, placebo-controlled outpatient study evaluated effects of once-monthly oral ibandronate on hip and lumbar spine BMD and calculated strength using quantitative computed tomography (QCT) with finite element analysis (FEA) and dual-energy x-ray absorptiometry (DXA) with hip structural analysis (HSA). PARTICIPANTS: Participants were women aged 55-80 yr with BMD T-scores -2.0 or less to -5.0 or greater (n = 93). INTERVENTION: Oral ibandronate 150 mg/month (n = 47) or placebo (n = 46) was administered for 12 months. OUTCOME MEASURES: The primary end point was total hip QCT BMD change from baseline; secondary end points included other QCT BMD sites, FEA, DXA, areal BMD, and HSA. All analyses were exploratory, with post hoc P values. RESULTS: Ibandronate increased integral total hip QCT BMD and DXA areal BMD more than placebo at 12 months (treatment differences: 2.2%, P = 0.005; 2.0%, P = 0.003). FEA-derived hip strength to density ratio and femoral, peripheral, and trabecular strength increased with ibandronate vs. placebo (treatment differences: 4.1%, P < 0.001; 5.9%, P < 0.001; 2.5%, P = 0.011; 3.5%, P = 0.003, respectively). Ibandronate improved vertebral, peripheral, and trabecular strength and anteroposterior bending stiffness vs. placebo [7.1% (P < 0.001), 7.8% (P < 0.001), 5.6% (P = 0.023), and 6.3% (P < 0.001), respectively]. HSA-estimated femoral narrow neck cross-sectional area and moment of inertia and outer diameter increased with ibandronate vs. placebo (respectively 3.6%, P = 0.003; 4.0%, P = 0.052; 2.2%, P = 0.049). CONCLUSIONS: Once-monthly oral Ibandronate for 12 months improved hip and spine BMD measured by QCT and DXA and strength estimated by FEA of QCT scans.

Cost-Effectiveness of Osteoporosis Screening Using Biomechanical Computed Tomography for Patients With a Previous Abdominal CT.

Osteoporosis screening rates by DXA are low (9.5% women, 1.7% men) in the US Medicare population aged 65 years and older. Addressing this care gap, we estimated the benefits of a validated osteoporosis diagnostic test suitable for patients age 65 years and older with an abdominal computed tomography (CT) scan taken for any indication but without a recent DXA. Our analysis assessed a hypothetical cohort of 1000 such patients in a given year, and followed them for 5 years. Separately for each sex, we used Markov modeling to compare two mutually exclusive scenarios: (i) utilizing the CT scans, perform one-time "biomechanical computed tomography" (BCT) analysis to identify high-risk patients on the basis of both femoral strength and hip BMD T-scores; (ii) ignore the CT scan, and rely instead on usual care, consisting of future annual DXA screening at typical Medicare rates. For patients with findings indicative of osteoporosis, 50% underwent 2 years of treatment with alendronate. We found that BCT provided greater clinical benefit at lower cost for both sexes than usual care. In our base case, compared to usual care, BCT prevented hip fractures over a 5-year window (3.1 per 1000 women; 1.9 per 1000 men) and increased quality-adjusted life years (2.95 per 1000 women; 1.48 per 1000 men). Efficacy and savings increased further for higher-risk patient pools, greater treatment adherence, and longer treatment duration. When the sensitivity and specificity of BCT were set to those for DXA, the prevented hip fractures versus usual care remained high (2.7 per 1000 women; 1.5 per 1000 men), indicating the importance of high screening rates on clinical efficacy. Therefore, for patients with a previously taken abdominal CT and without a recent DXA, osteoporosis screening using biomechanical computed tomography may be a cost-effective alternative to current usual care. © 2019 American Society for Bone and Mineral Research.

Osteoporosis and Hip Fracture Risk From Routine Computed Tomography Scans: The Fracture, Osteoporosis, and CT Utilization Study (FOCUS).

Methods now exist for analyzing previously taken clinical computed tomography (CT) scans to measure a dual-energy X-ray absorptiometry (DXA)-equivalent bone mineral density (BMD) at the hip and a finite element analysis-derived femoral strength. We assessed the efficacy of this "biomechanical CT" (BCT) approach for identifying patients at high risk of incident hip fracture in a large clinical setting. Using a case-cohort design sampled from 111,694 women and men aged 65 or older who had a prior hip CT scan, a DXA within 3 years of the CT, and no prior hip fracture, we compared those with subsequent hip fracture (n = 1959) with randomly selected sex-stratified controls (n = 1979) and analyzed their CT scans blinded to all other data. We found that the age-, race-, and body mass index (BMI)-adjusted hazard ratio (HR; per standard deviation) for femoral strength was significant before (women: HR = 2.8, 95% confidence interval [CI] 2.2-3.5; men: 2.8, 2.1-3.7) and after adjusting also for the (lowest) hip BMD T-score by BCT (women: 2.1, 1.4-3.2; men: 2.7, 1.6-4.6). The hazard ratio for the hip BMD T-score was similar between BCT and DXA for both sexes (women: 2.1, 1.8-2.5 BCT versus 2.1, 1.7-2.5 DXA; men: 2.8, 2.1-3.8 BCT versus 2.5, 2.0-3.2 DXA) and was higher than for the (lowest) spine/hip BMD T-score by DXA (women: 1.6, 1.4-1.9; men: 2.1, 1.6-2.7). Compared with the latter as a clinical-practice reference and using both femoral strength and the hip BMD T-score from BCT, sensitivity for predicting hip fracture was higher for BCT (women: 0.66 versus 0.59; men: 0.56 versus 0.48), with comparable respective specificity (women: 0.66 versus 0.67; men: 0.76 versus 0.78). We conclude that BCT analysis of previously acquired routine abdominal or pelvic CT scans is at least as effective as DXA testing for identifying patients at high risk of hip fracture. © 2018 American Society for Bone and Mineral Research.

Phantomless calibration of CT scans for measurement of BMD and bone strength-Inter-operator reanalysis precision.

Patient-specific phantomless calibration of computed tomography (CT) scans has the potential to simplify and expand the use of pre-existing clinical CT for quantitative bone densitometry and bone strength analysis for diagnostic and monitoring purposes. In this study, we quantified the inter-operator reanalysis precision errors for a novel implementation of patient-specific phantomless calibration, using air and either aortic blood or hip adipose tissue as internal calibrating reference materials, and sought to confirm the equivalence between phantomless and (traditional) phantom-based measurements. CT scans of the spine and hip for 25 women and 15 men (mean±SD age of 67±9years, range 41-86years), one scan per anatomic site per patient, were analyzed independently by two analysts using the VirtuOst software (O.N. Diagnostics, Berkeley, CA). The scans were acquired at 120kVp, with a slice thickness/increment of 3mm or less, on nine different CT scanner models across 24 different scanners. The main parameters assessed were areal bone mineral density (BMD) at the hip (total hip and femoral neck), trabecular volumetric BMD at the spine, and vertebral and femoral strength by finite element analysis; other volumetric BMD measures were also assessed. We found that the reanalysis precision errors for all phantomless measurements were ≤0.5%, which was as good as for phantom calibration. Regression analysis indicated equivalence of the phantom- versus phantomless-calibrated measurements (slope not different than unity, R2≥0.98). Of the main parameters assessed, non-significant paired mean differences (n=40) between the two measurements ranged from 0.6% for hip areal BMD to 1.1% for mid-vertebral trabecular BMD. These results indicate that phantom-equivalent measurements of both BMD and finite element-derived bone strength can be reliably obtained from CT scans using patient-specific phantomless calibration.

Comparison of non-invasive assessments of strength of the proximal femur.

It is not clear which non-invasive method is most effective for predicting strength of the proximal femur in those at highest risk of fracture. The primary aim of this study was to compare the abilities of dual energy X-ray absorptiometry (DXA)-derived aBMD, quantitative computed tomography (QCT)-derived density and volume measures, and finite element analysis (FEA)-estimated strength to predict femoral failure load. We also evaluated the contribution of cortical and trabecular bone measurements to proximal femur strength. We obtained 76 human cadaveric proximal femurs (50 women and 26 men; age 74±8.8years), performed imaging with DXA and QCT, and mechanically tested the femurs to failure in a sideways fall configuration at a high loading rate. Linear regression analysis was used to construct the predictive model between imaging outcomes and experimentally-measured femoral strength for each method. To compare the performance of each method we used 3-fold cross validation repeated 10 times. The bone strength estimated by QCT-based FEA predicted femoral failure load (R2adj=0.78, 95%CI 0.76-0.80; RMSE=896N, 95%CI 830-961) significantly better than femoral neck aBMD by DXA (R2adj=0.69, 95%CI 0.66-0.72; RMSE=1011N, 95%CI 952-1069) and the QCT-based model (R2adj=0.73, 95%CI 0.71-0.75; RMSE=932N, 95%CI 879-985). Both cortical and trabecular bone contribute to femoral strength, the contribution of cortical bone being higher in femurs with lower trabecular bone density. These findings have implications for optimizing clinical approaches to assess hip fracture risk. In addition, our findings provide new insights that will assist in interpretation of the effects of osteoporosis treatments that preferentially impact cortical versus trabecular bone.

Virtual stress testing of fracture stability in soldiers with severely comminuted tibial fractures.

Virtual stress testing (VST) provides a non-invasive estimate of the strength of a healing bone through a biomechanical analysis of a patient's computed tomography (CT) scan. We asked whether VST could improve management of patients who had a tibia fracture treated with external fixation. In a retrospective case-control study of 65 soldier-patients who had tibia fractures treated with an external fixator, we performed VST utilizing CT scans acquired prior to fixator removal. The strength of the healing bone and the amount of tissue damage after application of an overload were computed for various virtual loading cases. Logistic regression identified computed outcomes with the strongest association to clinical events related to nonunion within 2 months after fixator removal. Clinical events (n = 9) were associated with a low tibial strength for compression loading (p < 0.05, AUC = 0.74) or a low proportion of failed cortical bone tissue for torsional loading (p < 0.005, AUC = 0.84). Using post-hoc thresholds of a compressive strength of four times body-weight and a proportional of failed cortical bone tissue of 5%, the test identified all nine patients who failed clinically (100% sensitivity; 40.9% positive predictive value) and over three fourths of those (43 of 56) who progressed to successful healing (76.8% specificity; 100% negative predictive value). In this study, VST identified all patients who progressed to full, uneventful union after fixator removal; thus, we conclude that this new test has the potential to provide a quantitative, objective means of identifying tibia-fracture patients who can safely resume weight bearing. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:805-811, 2017.

Vertebral and femoral bone mineral density and bone strength in prostate cancer patients assessed in phantomless PET/CT examinations.

PURPOSE: Bone fracture risk assessed ancillary to positron emission tomography with computed tomography co-registration (PET/CT) could provide substantial clinical value to oncology patients with elevated fracture risk without introducing additional radiation dose. The purpose of our study was to investigate the feasibility of obtaining valid measurements of bone mineral density (BMD) and finite element analysis-derived bone strength of the hip and spine using PET/CT examinations of prostate cancer patients by comparing against values obtained using routine multidetector-row computed tomography (MDCT) scans-as validated in previous studies-as a reference standard. MATERIALS AND METHODS: Men with prostate cancer (n=82, 71.6±8.3 years) underwent Fluorine-18 NaF PET/CT and routine MDCT within three months. Femoral neck and total hip areal BMD, vertebral trabecular BMD and femur and vertebral strength based on finite element analysis were assessed in 63 paired PET/CT and MDCT examinations using phantomless calibration and Biomechanical-CT analysis. Men with osteoporosis or fragile bone strength identified at either the hip or spine (vertebral trabecular BMD ≤80mg/cm3, femoral neck or total hip T-score ≤-2.5, vertebral strength ≤6500N and femoral strength ≤3500N, respectively) were considered to be at high risk of fracture. PET/CT- versus MDCT-based BMD and strength measurements were compared using paired t-tests, linear regression and by generating Bland-Altman plots. Agreement in fracture-risk classification was assessed in a contingency table. RESULTS: All measurements from PET/CT versus MDCT were strongly correlated (R2=0.93-0.97; P<0.0001 for all). Mean differences for total hip areal BMD (0.001g/cm2, 1.1%), femoral strength (-60N, 1.3%), vertebral trabecular BMD (2mg/cm3, 2.6%) and vertebral strength (150N; 1.7%) measurements were not statistically significant (P>0.05 for all), whereas the mean difference in femoral neck areal BMD measurements was small but significant (-0.018g/cm2; -2.5%; P=0.007). The agreement between PET/CT and MDCT for fracture-risk classification was 97% (0.89 kappa for repeatability). CONCLUSION: Ancillary analyses of BMD, bone strength, and fracture risk agreed well between PET/CT and MDCT, suggesting that PET/CT can be used opportunistically to comprehensively assess bone integrity. In subjects with high fracture risk such as cancer patients this may serve as an additional clinical tool to guide therapy planning and prevention of fractures.

Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial.

Importance: As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture. Objective: To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength. Design, Setting, and Participants: Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization. Interventions: Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year. Main Outcomes and Measures: Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months. Results: There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, -1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, -1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD. Conclusions and Relevance: Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

Quantitative computed tomography estimates of the mechanical properties of human vertebral trabecular bone.

The objective of this study was to report our quantitative computed tomography (QCT) density-mechanical property regressions for trabecular bone for use in biomechanical modelling of the human spine. Cylindrical specimens of human vertebral trabecular bone (from T10 to L4) were cored from 32 cadavers (mean +/- SD age = 70.1 +/- 16.8; 13 females, 19 males) and scanned using QCT. Mechanical tests were conducted using a protocol that minimized end-artifacts over the apparent density range tested (0.09-0.38 g/cm3). To account for the presence of multiple specimens per donor in this data set, donor was treated as a random effect in the regression model. Mean modulus (319 +/- 189 MPa) was higher and mean yield strain (0.78 +/- 0.06%) was lower than typical values reported previously due to minimization of the end-artifact errors. QCT density showed a strong positive correlation with modulus (n = 76) and yield stress (r2 = 0.90-0.95, n = 53, p < 0.001). There was a weak positive linear correlation with yield strain (r2 = 0.58, n = 53, p = 0.07). Prediction errors, incurred when estimating modulus or strength for specimens from a new donor, were 30-36% of the mean values of these properties. Direct QCT density-mechanical property regressions gave more precise predictions of mechanical properties than if physically measured wet apparent density was used as an intermediate variable to predict mechanical properties from QCT density. Use of these QCT density-mechanical property regressions should improve the fidelity of QCT-based biomechanical models of the human spine for whole bone and bone-implant analyses.

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.

Assessing the Effects of Teriparatide Treatment on Bone Mineral Density, Bone Microarchitecture, and Bone Strength.

BACKGROUND: To gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans. METHODS: In this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 µg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm2) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety. RESULTS: Thirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed. CONCLUSIONS: High-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

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.

Femoral strength in osteoporotic women treated with teriparatide or alendronate.

To gain insight into the clinical effect of teriparatide and alendronate on the hip, we performed non-linear finite element analysis of quantitative computed tomography (QCT) scans from 48 women who had participated in a randomized, double-blind clinical trial comparing the effects of 18-month treatment of teriparatide 20 µg/d or alendronate 10mg/d. The QCT scans, obtained at baseline, 6, and 18 months, were analyzed for volumetric bone mineral density (BMD) of trabecular bone, the peripheral bone (defined as all the cortical bone plus any endosteal trabecular bone within 3 mm of the periosteal surface), and the integral bone (both trabecular and peripheral), and for overall femoral strength in response to a simulated sideways fall. At 18 months, we found in the women treated with teriparatide that trabecular volumetric BMD increased versus baseline (+4.6%, p<0.001), peripheral volumetric BMD decreased (-1.1%, p<0.05), integral volumetric BMD (+1.0%, p=0.38) and femoral strength (+5.4%, p=0.06) did not change significantly, but the ratio of strength to integral volumetric BMD ratio increased (+4.0%, p=0.04). An increase in the ratio of strength to integral volumetric BMD indicates that overall femoral strength, compared to baseline, increased more than did integral density. For the women treated with alendronate, there were small (<1.0%) but non-significant changes compared to baseline in all these parameters. The only significant between-treatment difference was in the change in trabecular volumetric BMD (p<0.005); related, we also found that, for a given change in peripheral volumetric BMD, femoral strength increased more for teriparatide than for alendronate (p=0.02). We conclude that, despite different compartmental volumetric BMD responses for these two treatments, we could not detect any overall difference in change in femoral strength between the two treatments, although femoral strength increased more than integral volumetric BMD after treatment with teriparatide.

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.

Age-dependence of femoral strength in white women and men.

Although age-related variations in areal bone mineral density (aBMD) and the prevalence of osteoporosis have been well characterized, there is a paucity of data on femoral strength in the population. Addressing this issue, we used finite-element analysis of quantitative computed tomographic scans to assess femoral strength in an age-stratified cohort of 362 women and 317 men, aged 21 to 89 years, randomly sampled from the population of Rochester, MN, and compared femoral strength with femoral neck aBMD. Percent reductions over adulthood were much greater for femoral strength (55% in women, 39% in men) than for femoral neck aBMD (26% in women, 21% in men), an effect that was accentuated in women. Notable declines in strength started in the mid-40s for women and one decade later for men. At advanced age, most of the strength deficit for women compared with men was a result of this decade-earlier onset of strength loss for women, this factor being more important than sex-related differences in peak bone strength and annual rates of bone loss. For both sexes, the prevalence of "low femoral strength" (<3000 N) was much higher than the prevalence of osteoporosis (femoral neck aBMD T-score of -2.5 or less). We conclude that age-related declines in femoral strength are much greater than suggested by age-related declines in femoral neck aBMD. Further, far more of the elderly may be at high risk of hip fracture because of low femoral strength than previously assumed based on the traditional classification of osteoporosis.

Finite element analysis of the proximal femur and hip fracture risk in older men.

Low areal BMD (aBMD) is associated with increased risk of hip fracture, but many hip fractures occur in persons without low aBMD. Finite element (FE) analysis of QCT scans provides a measure of hip strength. We studied the association of FE measures with risk of hip fracture in older men. A prospective case-cohort study of all first hip fractures (n = 40) and a random sample (n = 210) of nonfracture cases from 3549 community-dwelling men > or =65 yr of age used baseline QCT scans of the hip (mean follow-up, 5.6 yr). Analyses included FE measures of strength and load-to-strength ratio and BMD by DXA. Hazard ratios (HRs) for hip fracture were estimated with proportional hazards regression. Both femoral strength (HR per SD change = 13.1; 95% CI: 3.9-43.5) and the load-to-strength ratio (HR = 4.0; 95% CI: 2.7-6.0) were strongly associated with hip fracture risk, as was aBMD as measured by DXA (HR = 5.1; 95% CI: 2.8-9.2). After adjusting for age, BMI, and study site, the associations remained significant (femoral strength HR = 6.5, 95% CI: 2.3-18.3; load-to-strength ratio HR = 4.3, 95% CI: 2.5-7.4; aBMD HR = 4.4, 95% CI: 2.1-9.1). When adjusted additionally for aBMD, the load-to-strength ratio remained significantly associated with fracture (HR = 3.1, 95% CI: 1.6-6.1). These results provide insight into hip fracture etiology and demonstrate the ability of FE-based biomechanical analysis of QCT scans to prospectively predict hip fractures in men.