Osteoporosis is a major global health problem. The increase in the incidence of osteoporosis in the elderly poses a challenge to treat and also results in an economic burden for the nation. Osteoporosis has been given more importance in females, and there is an urgent need to address this disease in males. Various drugs, such as nitrogen-containing bisphosphonates, RANK ligand inhibitors, parathormones, and alendronate, have been used for effective treatment of osteoporosis. Alendronate (alendronic acid), a nitrogen-containing bisphosphonate that inhibits bone resorption by osteoclasts, was synthesized during the 1970s. In the present review, we discuss the pharmacokinetics, mechanism of action, adverse effects, contraindications, and toxicity monitoring of alendronate. The drug may be effectively used for the treatment of male osteoporosis in order to increase bone mineral density and prevent fractures.

The effects of daily teriparatide (D-PTH, 20 μg/day), weekly high-dose teriparatide (W-PTH, 56.5 μg/week), or bisphosphonate (BP) on the vertebra and proximal femur were investigated using quantitative computed tomography (QCT).

A total of 131 postmenopausal women with a history of fragility fractures were randomized to receive D-PTH, W-PTH, or bisphosphonate (oral alendronate or risedronate). QCT were evaluated at baseline and after 18 months of treatment.

A total of 86 participants were evaluated by QCT (Spine: D-PTH: 25, W-PTH: 21, BP: 29. Hip: PTH: 22, W-PTH: 21, BP: 32. Dropout rate: 30.5 %). QCT of the vertebra showed that D-PTH, W-PTH, and BP increased total vBMD (+34.8 %, +18.2 %, +11.1 %), trabecular vBMD (+50.8 %, +20.8 %, +12.2 %), and marginal vBMD (+20.0 %, +14.0 %, +11.5 %). The increase in trabecular vBMD was greater in the D-PTH group than in the W-PTH and BP groups. QCT of the proximal femur showed that D-PTH, W-PTH, and BP increased total vBMD (+2.8 %, +3.6 %, +3.2 %) and trabecular vBMD (+7.7 %, +5.1 %, +3.4 %), while only W-PTH and BP significantly increased cortical vBMD (-0.1 %, +1.5 %, +1.6 %). Although there was no significant increase in cortical vBMD in the D-PTH group, cortical bone volume (BV) increased in all three treatment groups (+2.1 %, +3.6 %, +3.1 %).

D-PTH had a strong effect on trabecular bone of vertebra. Although D-PTH did not increase cortical BMD of proximal femur, it increased cortical BV. W-PTH had a moderate effect on trabecular bone of vertebra, while it increased both cortical BMD and BV of proximal femur. Although BP had a limited effect on trabecular bone of vertebra compared to teriparatide, it increased both cortical BMD and BV of proximal femur.

Osteoporosis (OP) is a disorder of bone remodeling caused by an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, inhibiting excessive osteoclast activity is one of the promising strategies for treating OP. A major transient receptor potential cation channel, known as transient receptor potential ankyrin 1 (TRPA1), was found to alleviate joint pain and cartilage degeneration in osteoarthritis. However, little research has focused on TRPA1 function in OP. As a result, this study aimed to explore the TRPA1 characteristics and its potential therapeutic function during osteoclastogenesis. The TRPA1 expression gradually increased in the osteoclast differentiation process; however, its suppression with small interfering RNA and an inhibitor (HC030031) significantly controlled the osteoclast count and the expression of osteoclast characteristic genes. Its suppression also inhibited endoplasmic reticulum (ER) stress-related pancreatic ER kinase (PERK) pathways. An ER stress inhibitor (thapsigargin) reversed the down-regulated levels of ER stress and osteoclast differentiation by suppressing TRPA1. Transcriptome sequencing results demonstrated that TRPA1 negatively regulated reactive oxygen species (ROS) and significantly increased the expression of an antioxidant gene, SRXN1. The osteoclast differentiation and the levels of ER stress were enhanced with SRXN1 inhibition. Finally, TRPA1 knockdown targeting macrophages by adeno-associated virus-9 could relieve osteoclast differentiation and osteopenia in ovariectomized mice. In summary, silencing TRPA1 restrained osteoclast differentiation through ROS-mediated down-regulation of ER stress via inhibiting PERK pathways. The study also indicated that TRPA1 might become a prospective treatment target for OP.

Osteoporosis is a systemic bone disease which can increase the risk of osteoporotic fractures. Dual-energy X-ray absorptiometry (DXA) is considered as the clinical standard for diagnosing osteoporosis by detecting the bone mineral density (BMD) in patients, but it has flaws in distinguishing between calcification and other degenerative diseases, thus leading to inaccurate BMD levels in subjects. Mindways quantitative computed tomography (Mindways QCT) is a classical QCT system. Similar to DXA, Mindways QCT can directly present the density of trabecular bone, vascular or tissue calcification; therefore, it is more accurate and sensitive than DXA and has been widely applied in clinic to evaluate osteoporosis. iCare QCT osteodensitometry was a new phantom-based QCT system, recently developed by iCare Inc. (China). It has been gradually applied in clinic by its superiority of taking 3-dimensional BMD of bone and converting BMD values to T value automatically. This study aimed at evaluating the osteoporosis detection rate of iCare QCT, compared with synchronous Mindways QCT (USA).

In this study, 131 patients who underwent hip phantom-based CT scan were included. Bone mineral density (BMD) of the unified region of interests (ROI) defined at the European spine phantom (ESP, German QRM) including L1 (low), L2 (medium), and L3 (high) vertebral bodies was detected for QCT quality control and horizontal calibration. Every ESP scan were taken for 10 times, and the mean BMD values measured by iCare QCT and Mindways QCT were compared. Hip CT scan was conducted with ESP as calibration individually. T-scores gained from iCare QCT and Mindways QCT were analyzed with Pearson correlation test. The detection rates of osteoporosis were compared between iCare QCT and Mindways QCT. The unified region of interests (ROI) was delineated in the QCT software.

The results showed that there was no significant difference between iCare QCT and Mindways QCT in the evaluation of L1, L2, and L3 vertebrae bodies in ESP. A strong correlation between iCare QCT and Mindways QCT in the assessment of hip T-score was found. It was illustrated that iCare QCT had a higher detection rate of osteoporosis with the assessment of hip T-score than Mindways QCT did. In patients < 50 years subgroup, the detection rate of osteoporosis with iCare QCT and Mindways QCT was equal. In patients ≥ 50 years subgroup, the detection rate of osteoporosis with iCare QCT (35/92, 38.0%) was higher than that with Mindways QCT. In female subgroup, the detection rate of osteoporosis with iCare QCT was significantly higher than Mindways QCT. In male subgroup, the detection rate of osteoporosis with iCare QCT was also markedly higher than Mindways QCT. The detection rate of osteoporosis by iCare QCT was higher than Mindways QCT with hip bone assessment. Of course, the results of the present study remain to be further verified by multicenter studies in the future.

Vertebral fracture is one of the most serious consequences of osteoporosis. Estimation of vertebral strength from magnetic resonance imaging (MRI) scans may provide a new approach for the prediction of vertebral fractures. To that end, we sought to establish a biomechanical MRI (BMRI) method to compute vertebral strength and test its ability to distinguish fracture from non-fracture subjects. This case-control study included 30 subjects without vertebral fractures and 15 subjects with vertebral fractures. All subjects underwent MRI with a mDIXON-Quant sequence and quantitative computed tomography (QCT), from which proton fat fraction-based bone marrow adipose tissue (BMAT) content and volumetric bone mineral density (vBMD) were measured, respectively. Nonlinear finite element analysis was applied to MRI and QCT scans of L2 vertebrae to compute vertebral strength (BMRI- and BCT-strength). The differences in BMAT content, vBMD, BMRI-strength and BCT-strength between the two groups were examined by t-tests. Receiver operating characteristic (ROC) analysis was performed to assess the ability of each measured parameter to distinguish fracture from non-fracture subjects. Results showed that the fracture group had 23 % lower BMRI-strength (P < .001) and 19 % higher BMAT content (P < .001) than the non-fracture group, whereas no significant difference in vBMD was detected between the two groups. A poor correlation was found between vBMD and BMRI-strength (R² = 0.33). Compared to vBMD and BMAT content, BMRI- and BCT-strength had the larger area under the curve (0.82 and 0.84, respectively) and provided better sensitivity and specificity in separating fracture from non-fracture subjects. In conclusion, BMRI is capable of detecting reduced bone strength in patients with vertebral fracture, and may serve as a new approach for risk assessment of vertebral fracture.

Prolonged use of antiresorptives such as the bisphosphonate alendronate (ALN) and the RANKL inhibitor denosumab (DMAb) are associated with rare cases of atypical femoral fracture (AFF). The etiology of AFF is unclear, but it has been hypothesized that potent osteoclast inhibitors may reduce bone fatigue resistance. The purpose of this study was to quantify the relationship between antiresorptive treatment and fatigue life (cycles to failure) in bone from ovariectomized cynomolgus monkeys. We analyzed humeral bone from 30 animals across five treatment groups. Animals were treated for 12 months with subcutaneous (sc) vehicle (VEH), sc DMAb (25 mg/kg/month), or intravenous (iv) ALN (50 μg/kg/month). Another group received 6 months VEH followed by 6 months DMAb (VEH-DMAb), and the final group received 6 months ALN followed by 6 months DMAb (ALN-DMAb). A total of 240 cortical beam samples were cyclically tested in four-point bending at 80, 100, 120, or 140 MPa peak stress. High-resolution imaging and density measurements were performed to evaluate bone microstructure and composition. Samples from the ALN (p = 0.014), ALN-DMAb (p = 0.008), and DMAb (p < 0.001) groups illustrated higher fatigue-life measurements than VEH. For example, at 140 MPa the VEH group demonstrated a median ± interquartile range (IQR) fatigue life of 1987 ± 10593 cycles, while animals in the ALN, ALN-DMAb, and DMAb groups survived 9850 ± 13648 (+395% versus VEH), 10493 ± 16796 (+428%), and 14495 ± 49299 (+629%) cycles, respectively. All antiresorptive treatment groups demonstrated lower porosity, smaller pore size, greater pore spacing, and lower number of canals versus VEH (p < 0.001). Antiresorptive treatment was also associated with greater apparent density, dry density, and ash density (p ≤ 0.03). We did not detect detrimental changes following antiresorptive treatments that would explain their association with AFF. In contrast, 12 months of treatment may have a protective effect against fatigue fractures. © 2022 American Society for Bone and Mineral Research (ASBMR).

Following primary fractures and percutaneous kyphoplasty (PKP), patients have a high risk of incurring a subsequent vertebral fracture (SVF). Given that SVF is a consequence of mechanical deterioration of the vertebra, we sought to examine whether vertebral strength derived from QCT-based finite element analysis (i.e., BCT) can predict the risk of SVF. Sixty-six patients who underwent PKP were categorized into two groups: control or non-SVF group (age: 70 ± 7 years; n = 40) and SVF group (age: 69 ± 8 years; n = 26). BCT was performed on L4 or L3 vertebrae to noninvasively measure vertebral strength. Vertebral strength was also estimated based upon the geometry and material properties of the vertebra. Additionally, trabecular volumetric bone mineral density (vBMD) and L1 Hounsfield unit (HU) were measured. t-Test, χ² test or Mann Whitney U test were used to compare differences in these parameters between the two groups. The predictive abilities of BCT strength and other measured parameters were evaluated using the receiver operating characteristic (ROC) analysis. Results showed no significant difference in either vBMD or L1 HU between the control and SVF groups (p > 0.05), whereas BCT-computed and estimated vertebral strength values were significantly reduced by 33 % and 24 % for the SVF group relative to the non-SVF group, respectively. ROC curve indicated that BCT strength had the largest area under the curve, compared to other parameters. These results suggest that BCT-computed vertebral strength may serve as a surrogate for assessing risk of SVF.

To evaluate the effects of physiological dose 17 beta-estradiol (E₂) replacement on low bone mineral density (BMD) and compare the results of oral and transdermal (TD) E₂ administration in adolescents and young women with hypogonadism DESIGN, SETTING, AND PARTICIPANTS: We retrospectively reviewed the medical records of patients aged 15 to 24 years who were diagnosed with hypogonadism, who had begun receiving oral or TD E₂ replacement, and whose initial dual-energy X-ray absorptiometry scan detected a lumbar spine BMD Z-score of -1 or lower between 2014 and 2018. The patients were divided into 2 groups according to the E₂ route of administration as those who received 2 mg orally (Group 1) and 0.1 mg TD (Group 2).

None MAIN OUTCOME MEASURE: BMD scans of the patients at baseline and repeated within 2 years after E₂ replacement RESULTS: In total, 43 patients who met the inclusion criteria were included in the study. Two groups did not differ for BMD scores at baseline. A significant improvement in BMD was observed with physiological dose E₂ replacement in both groups. Mean BMD Z-score increased by +0.7 (95% CI, 0.47-0.93) in response to TD E₂ administration, compared with +0.41 (95% CI, 0.25-0.58) during oral E₂ replacement (P = .037).

We conclude that physiological dose E₂ replacement, even within a short period of 2 years, has a significant beneficial effect on bone mass acquisition on the lumbar spine. Our study also demonstrates the possible superiority of TD E2 replacement over the oral route in increasing lumbar spine BMD.

Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (μCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n = 10), s.c. denosumab (DMAb; 25 mg/kg, n = 9), or i.v. alendronate (ALN; 50 μg/kg, n = 10). Two more groups received 6 months of VEH followed by 6 months of DMAb (VEH-DMAb; n = 7) or 6 months of ALN followed by 6 months of DMAb (ALN-DMAb; n = 9). After treatment, humeri were harvested and μCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, μCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via μCT; no effects on trabecular morphology were observed. FE estimated strength based on μCT was higher after 12-months DMAb (p = 0.020) and ALN-DMAb (p = 0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.

Patients with ossification of the posterior longitudinal ligament (OPLL) are often reported to have increased bone mineral density (BMD). The bone strength of the proximal femur measured by quantitative computed tomography-based finite element analysis (QCT/FEA) is reportedly comparable between healthy subjects with and without OPLL. However, the bone strength in symptomatic OPLL patients remains unknown.

To investigate bone strength measured by QCT/FEA in symptomatic patients with OPLL.

A single-center prospective observational study.

A total of 157 patients with cervical or thoracic compressive myelopathy were included in the study.

We analyzed patients' characteristics, Japanese Orthopedic Association (JOA) score, serum laboratory tests including calcium (Ca), inorganic phosphate (Pi), and bone turnover markers, BMD of the proximal femur and lumbar spine measured using dual-energy X-ray absorptiometry, and predicted bone strength (PBS) of the proximal femur and lumbar spine measured using QCT/FEA.

Eligible patients were divided into the non-OPLL and OPLL groups. We compared the patients' characteristics, JOA scores, laboratory data, BMD, and PBS of the proximal femur and lumbar spine between the non-OPLL and OPLL groups among total, male, and female patients by performing Fisher's exact test for categorical variables and the unpaired t test for continuous variables. Then, we used the inverse probability weighted logistic regression model after calculating propensity scores to compare the bone metabolism-associated markers, BMD, and PBS measurements between the groups.

Among the eligible 157 patients, 68 were in the non-OPLL group and 89 were in the OPLL group. Compared with the non-OPLL group, the OPLL group had a significantly younger age and higher BMI in the total, male, and female patients. The JOA scores in the total and female patients were significantly higher in the OPLL group than in the non-OPLL group. The OPLL group showed significantly lower Ca levels in the female patients and significantly lower Pi levels in the total or male patients compared with the non-OPLL group in the inverse probability weighting method. The BMD of the proximal femur and lumbar spine and the PBS of the proximal femur were significantly higher in the OPLL group than in the non-OPLL group. There were no significant differences in the PBS and BMD between the male subgroups. However, the BMD and PBS of the proximal femur and lumbar spine were significantly higher in the OPLL females than in the non-OPLL females.

Hyperostosis of the posterior longitudinal ligament in OPLL was associated with higher bone strength by QCT/FEA, especially in female OPLL patients.

Osteoporosis is prevalent and entails alterations of vertebral bone and marrow. Yet, the spine is also a common site of metastatic spread. Parameters that can be non-invasively measured and could capture these alterations are the volumetric bone mineral density (vBMD), proton density fat fraction (PDFF) as an estimate of relative fat content, and failure displacement and load from finite element analysis (FEA) for assessment of bone strength. This study's purpose was to investigate if osteoporotic and osteoblastic metastatic changes in lumbar vertebrae can be differentiated based on the abovementioned parameters (vBMD, PDFF, and measures from FEA), and how these parameters correlate with each other.

Seven patients (3 females, median age: 77.5 years) who received 3-Tesla magnetic resonance imaging (MRI) and multi-detector computed tomography (CT) of the lumbar spine and were diagnosed with either osteoporosis (4 patients) or diffuse osteoblastic metastases (3 patients) were included. Chemical shift encoding-based water-fat MRI (CSE-MRI) was used to extract the PDFF, while vBMD was extracted after automated vertebral body segmentation using CT. Segmentation masks were used for FEA-based failure displacement and failure load calculations. Failure displacement, failure load, and PDFF were compared between patients with osteoporotic vertebrae versus patients with osteoblastic metastases, considering non-fractured vertebrae (L1-L4). Associations between those parameters were assessed using Spearman correlation.

Median vBMD was 59.3 mg/cm³ in osteoporotic patients. Median PDFF was lower in the metastatic compared to the osteoporotic patients (11.9% vs. 43.8%, p=0.032). Median failure displacement and failure load were significantly higher in metastatic compared to osteoporotic patients (0.874 mm vs. 0.348 mm, 29,589 N vs. 3,095 N, p=0.034 each). A strong correlation was noted between PDFF and failure displacement (rho -0.679, p=0.094). A very strong correlation was noted between PDFF and failure load (rho -0.893, p=0.007).

PDFF as well as failure displacement and load allowed to distinguish osteoporotic from diffuse osteoblastic vertebrae. Our findings further show strong associations between PDFF and failure displacement and load, thus may indicate complimentary pathophysiological associations derived from two non-invasive techniques (CSE-MRI and CT) that inherently measure different properties of vertebral bone and marrow.

We re-evaluated clinical applications of image-to-FE models to understand if clinical advantages are already evident, which proposals are promising, and which questions are still open.

CT-to-FE is useful in longitudinal treatment evaluation and groups discrimination. In metastatic lesions, CT-to-FE strength alone accurately predicts impending femoral fractures. In osteoporosis, strength from CT-to-FE or DXA-to-FE predicts incident fractures similarly to DXA-aBMD. Coupling loads and strength (possibly in dynamic models) may improve prediction. One promising MRI-to-FE workflow may now be tested on clinical data. Evidence of artificial intelligence usefulness is appearing. CT-to-FE is already clinical in opportunistic CT screening for osteoporosis, and risk of metastasis-related impending fractures. Short-term keys to improve image-to-FE in osteoporosis may be coupling FE with fall risk estimates, pool FE results with other parameters through robust artificial intelligence approaches, and increase reproducibility and cross-validation of models. Modeling bone modifications over time and bone fracture mechanics are still open issues.

Being able to predict the mechanical properties of vertebrae in patients with osteoporosis and other relevant pathologies is essential to prevent fractures and to develop the most favorable fracture treatments. Furthermore, a reliable prediction is important for developing more patient- and pathology-specific biomaterials. A plethora of studies correlating bone density to mechanical properties has been reported; however, the results are variable, due to a variety of factors, including anatomical site and methodological differences. The aim of this study was to provide a comprehensive literature review on density and mechanical properties of human vertebral trabecular bone as well as relationships found between these properties. A literature search was performed to include studies, which investigated mechanical properties and bone density of trabecular bone. Only studies on vertebral trabecular bone tissue, reporting bone density or mechanical properties, were kept. A large variation in reported vertebral trabecular bone densities, mechanical properties, and relationships between the two was found, as exemplified by values varying between 0.09 and 0.35 g/cm3 for the wet apparent density and from 0.1 to 976 MPa for the elastic modulus. The differences were found to reflect variations in experimental and analytical processes that had been used, including testing protocol and specimen geometry. The variability in the data decreased in studies where bone tissue testing occurred in a standardized manner (eg, the reported differences in average elastic modulus decreased from 400% to 10%). It is important to take this variability into account when analyzing the predictions found in the literature, for example, to calculate fracture risk, and it is recommended to use the models suggested in the present review to reduce data variability.

In this case-control study, we evaluated different quantitative parameters derived from routine multi-detector computed tomography (MDCT) scans with respect to their ability to predict incident osteoporotic vertebral fractures of the thoracolumbar spine.

16 patients who received baseline and follow-up contrast-enhanced MDCT and were diagnosed with an incident osteoporotic vertebral fracture at follow-up, and 16 age-, sex-, and follow-up-time-matched controls were included in the study. Vertebrae were labelled and segmented using a fully automated pipeline. Volumetric bone mineral density (vBMD), finite element analysis (FEA)-based failure load (FL) and failure displacement (FD), as well as 24 texture features were extracted from L1 - L3 and averaged. Odds ratios (OR) with 95% confidence intervals (CI), expressed per standard deviation decrease, receiver operating characteristic (ROC) area under the curve (AUC), as well as logistic regression models, including all analyzed parameters as independent variables, were used to assess the prediction of incident vertebral fractures.

The texture feature Correlation (AUC = 0.754, p = 0.014; OR = 2.76, CI = 1.16-6.58) and vBMD (AUC = 0.750, p = 0.016; OR = 2.67, CI = 1.12-6.37) classified incident vertebral fractures best, while the best FEA-based parameter FL showed an AUC = 0.719 (p = 0.035). Correlation was the only significant predictor of incident fractures in the logistic regression analysis of all parameters (p = 0.022).

MDCT-derived FEA parameters and texture features, averaged from L1 - L3, showed only a moderate, but no statistically significant improvement of incident vertebral fracture prediction beyond BMD, supporting the hypothesis that vertebral-specific parameters may be superior for fracture risk assessment.

Osteoporosis is characterized by reduced bone strength predisposing to an increased risk of fracture. Biomechanical computed tomography (BCT), predicting bone strength via CT-based finite element analysis (FEA), is now clinically available in the USA for diagnosing osteoporosis or assessing fracture risk. However, it has not been previously validated using a cohort of only Chinese subjects. Additionally, the effect of various modeling approaches on BCT outcomes remains elusive. To address these issues, we performed DXA and QCT scanning, compression testing, and BCT analyses on thirteen vertebrae derived from Chinese donors. Three BCT models were created (voxBCT and tetBCT: voxel-based and tetrahedral element-based FE models generated by a commercial software; matBCT: tetrahedral element-based FE model generated by a custom MATLAB program). BCT-computed outcomes were compared with experimental measures or between different BCT models. Results showed that, DXA-measured areal bone mineral density (aBMD) showed weak correlations with experimentally-measured vertebral stiffness (R² = 0.28) and strength (R² = 0.34). Compared to DXA-aBMD, BCT-computed stiffness provided improved correlations with experimentally-measured stiffness (voxBCT: R² = 0.82; tetBCT: R² = 0.77; matBCT: R² = 0.76) and strength (voxBCT: R² = 0.55; tetBCT: R² = 0.57; matBCT: R² = 0.53); BCT-computed mechanical parameters (stiffness, stress and strain) of the three different models were highly correlated with each other, with coefficient of determination (R²) values of 0.89-0.98. These results, based on a cohort of Chinese vertebral cadavers, suggest that BCT is superior over aBMD to consistently predict vertebral mechanical characteristics, regardless of the modeling approaches of choice.

A main purpose of osteoporosis diagnosis is to evaluate the bone fracture risk. Some bone mass indices evaluated using bone mineral density has been utilized clinically to assess the degree of osteoporosis. On the other hand, Computed tomography image based finite element analysis has been developed to evaluate bone strength of vertebral bodies. The strength of a vertebra is defined as the load at the onset of compressive fracture. The objective of this study was therefore to propose a new feasible method to combine the advantages of the two osteoporotic indices such as the bone mass index and the bone strength.

Three-dimensional finite element models of 246 vertebral bodies from 88 patients were constructed using the computed tomography images. Finite element analysis was then conducted to evaluate their strength values. The Pearson's correlation analysis was also conducted between the vertebral strength and bone mass indices.

It was found that relatively weak positive correlations existed between the strength and the bone mass indices. A new assessment method was then proposed by combining the strength and the bone mass index. "high risk zone" corresponding to low strength with normal bone mass was found from the assessment method.

Singe bone mass index cannot predict the fracture risk with high standard. The results of fracture risk assessment conducted by the new method clearly indicated the necessity and effectiveness to take both the strength and the bone mass index into account.

The objective of this study was to quantitatively evaluate the effects of daily teriparatide on rheumatoid arthritis patients using predicted bone strength (PBS) assessed by quantitative computed tomography-based finite-element analysis (QCT/FEA) and using bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA), and to prospectively investigate clinical determinants associated with PBS and BMD increases.

Participants comprised 39 patients (mean age, 69 years; disease activity score assessing 28 joints with CRP, 3.0; previous vertebral fractures, 82%) enrolled in this study. BMD by DXA and PBS by QCT/FEA of lumbar spine (LS) and proximal femur were measured at baseline, and after 6 and 12 months. In the groups showing increases in these values, variables that may have affected these increases were evaluated using univariate logistic regression analysis.

Daily teriparatide treatment significantly increased not only LS BMD, but also LS PBS in RA patients with osteoporosis after both 6 and 12 months of treatment. Increases in N-terminal type I procollagen propeptide (PINP) at 1 and 3 months were significantly associated with increased LS PBS at 12 months according to univariate logistic regression analysis. The threshold value for increased PINP at 1 month for increased PBS at 12 months was 75 µg/L.

Increased LS PBS at 12 months was predicted by increased PINP at 1 month from baseline.

Opportunistic screening for osteoporosis can be performed using low-dose computed tomography (LDCT) imaging obtained for other clinical indications. In this study we explored the CT-derived bone mineral density (BMD) and prevalence of osteoporosis from thoracic LDCT in a large population cohort of Chinese men and women. A total of 69,095 adults (40,733 men and 28,362 women) received a thoracic LDCT scan for the purpose of lung cancer screening between 2018 and 2019, and data were obtained for analysis from the China Biobank Project, a prospective nationwide multicenter population study. Lumbar spine (L₁ -L₂ ) trabecular volumetric bone mineral density (vBMD) was derived from these scans using quantitative computed tomography (QCT) software and the American College of Radiology QCT diagnostic criteria for osteoporosis were applied. Geographic regional differences in the prevalence of osteoporosis were assessed and the age-standardized, population prevalence of osteoporosis in Chinese men and women was estimated from the 2010 China census. The prevalence of osteoporosis by QCT for the Chinese population aged >50 years was 29.0% for women and 13.5% for men, equating to 49.0 million and 22.8 million, respectively. In women, this rate is comparable to estimates from dual-energy X-ray absorptiometry (DXA), but in men, the prevalence is double. Prevalence varied geographically across China, with higher rates in the southwest and lower rates in the northeast. Trabecular vBMD decreased with age in both men and women. Women had higher peak trabecular vBMD (185.4 mg/cm³ ) than men (176.6 mg/cm³ ) at age 30 to 34 years, but older women had lower trabecular vBMD (62.4 mg/cm³ ) than men (92.1 mg/cm³ ) at age 80 years. We show that LDCT-based opportunistic screening could identify large numbers of patients with low lumbar vBMD, and that future cohort studies are now required to evaluate the clinical utility of such screening in terms of fracture prevention and supporting national health economic analyses. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

To investigate whether finite element (FE) analysis of the spine in routine thoracic/abdominal multi-detector computed tomography (MDCT) can predict incidental osteoporotic fractures at vertebral-specific level; Baseline routine thoracic/abdominal MDCT scans of 16 subjects (8(m), mean age: 66.1 ± 8.2 years and 8(f), mean age: 64.3 ± 9.5 years) who sustained incidental osteoporotic vertebral fractures as confirmed in follow-up MDCTs were included in the current study. Thoracic and lumbar vertebrae (T5-L5) were automatically segmented, and bone mineral density (BMD), finite element (FE)-based failure-load, and failure-displacement were determined. These values of individual vertebrae were normalized globally (g), by dividing the absolute value with the average of L1-3 and locally by dividing the absolute value with the average of T5-12 and L1-5 for thoracic and lumbar vertebrae, respectively. Mean-BMD of L1-3 was determined as reference. Receiver operating characteristics (ROC) and area under the curve (AUC) were calculated for different normalized FE (Kload, Kdisplacement,K(load)g, and K(displacement)g) and BMD (KBMD, and K(BMD)g) ratio parameter combinations for identifying incidental fractures. Kload, K(load)g, KBMD, and K(BMD)g showed significantly higher discriminative power compared to standard mean BMD of L1-3 (BMDStandard) (AUC = 0.67 for Kload; 0.64 for K(load)g; 0.64 for KBMD; 0.61 for K(BMD)g vs. 0.54 for BMDStandard). The combination of Kload, Kdisplacement, and KBMD increased the AUC further up to 0.77 (p < 0.001). The combination of FE with BMD measurements derived from routine thoracic/abdominal MDCT allowed an improved prediction of incidental fractures at vertebral-specific level.

Given non-optimal testing rates for dual-energy X-ray absorptiometry (DXA) and the high use of computed tomography (CT) in some Asian countries, biomechanical computed tomography analysis (BCT)-based bone strength testing, which utilizes previously taken clinical CT scans, may improve osteoporosis testing rates. However, an understanding of ethnic differences in such bone strength measurements between Whites and Asians is lacking, which is an obstacle to clinical interpretation. Using previously taken CT and DXA scans, we analyzed bone strength and bone mineral density (BMD) at the hip and spine in two sex- and age-matched community-based cohorts, aged 40 to 80 years: Whites (Rochester, MN, USA) and Koreans (Seoul, South Korea). For both the spine and femur, the age dependence of bone strength was similar for both groups, White (n = 371; women n = 202, 54.5%) and Korean (n = 396; women n = 199, 50.3%). For both sexes, mean spine strength did not differ between groups, but femur strength was 9% to 14% higher in Whites (p ≤ 0.001), an effect that became non-significant after weight adjustment (p = 0.375). For Koreans of both sexes, the fragile bone strength thresholds for classifying osteoporosis, when derived from regional DXA BMD T-score references, equaled the clinically validated thresholds for Whites (in women and men, femoral strength, 3000 N and 3500 N; vertebral strength 4500 N and 6500 N, respectively). Using these thresholds, classifications for osteoporosis for Koreans based on bone strength versus based on DXA BMD T-scores were consistent (89.1% to 94.4% agreement) at both the hip and spine and for both sexes. The BCT-based, clinically validated bone strength thresholds for Whites also applied to Koreans, which may facilitate clinical interpretation of CT-based bone strength measurements for Koreans. © 2020 American Society for Bone and Mineral Research (ASBMR).

Narrative review.

This article seeks to provide a narrative review regarding the ability of opportunistic information available from computed tomography (CT) scans to guide decisions in spine surgery related to patient bone quality.

A review of the literature (limited to human and English language) was performed via PubMed and Google Scholar using the search terms; "osteoporosis" AND "opportunistic" AND "computed tomography" AND "spine surgery." The titles and then abstracts of all identified citations were reviewed for inclusion by 2 of the authors (MS, BAF). Relevant articles were then studied in full text.

A review of the literature found 25 articles that were selected for inclusion in this narrative review. These articles were broadly divided into 4 subcategories: (1) opportunistic CT (oCT) and osteoporosis detection, (2) oCT data and the quality of screw fixation, (3) utilization of Hounsfield units to assess clinical and/or radiographic outcomes following spine fusion, and (4) virtual stress testing in spine surgery.

The literature on oCT, as well as associated virtual stress-testing techniques, demonstrate the potential to enhance spine surgery outcomes by preoperatively identifying at-risk patients in need of bone health optimization and informing best techniques for performing spinal fusion surgery on patients with diminished bone quality. While our narrative summary of the limited literature to date suggests a promising future for oCT data, significant additional research and/or radiographic workflow standardization is needed to validate these methods for clinical use.

Spinal cord injury (SCI) is associated with bone fragility and fractures around the knee. The purpose of this investigation was to validate a computed tomography (CT) based finite element (FE) model of the proximal tibia and distal femur under biaxial loading, and to retrospectively quantify the relationship between model predictions and fracture incidence. Twenty-six cadaveric tibiae and femora (n = 13 each) were loaded to 300 N of compression, then internally rotated until failure. FE predictions of torsional stiffness (K) and strength (T_ult) explained 74% (n = 26) and 93% (n = 7) of the variation in experimental measurements, respectively. Univariate analysis and logistic regression were subsequently used to determine if FE predictions and radiographic measurements from CT and dual energy X-ray absorptiometry (DXA) were associated with prevalent lower-limb fracture in 50 individuals with SCI (n = 14 fractures). FE and CT measures, but not DXA, were lower in individuals with fracture. FE predictions of T_ult at the tibia demonstrated the highest odds ratio (4.98; p = 0.006) and receiver operating characteristic (0.84; p = 0.008) but did not significantly outperform other metrics. In conclusion, CT-based FE model predictions were associated with prevalent fracture risk after SCI; this technique could be a powerful tool in future clinical research.

After fifty years of experience with several generations of bisphosphonates (BPs), and 25 years after these drugs were approved for use in humans, their mechanical effects on bone are still not fully understood. Certainly, these drugs have transformed the treatment of osteoporosis in both men and women. There is no question that they do prevent fractures related to low bone mass, and there is widespread agreement that they increase strength and stiffness of the vertebrae. There is less consensus, however, about their effects on cortical bone, or on bone tissue properties in either trabecular or cortical bone, or their effects with longer periods of treatment. The consensus of most studies, both those based on ovariectomized and intact animal models and on testing of human bone, is that long-term treatment and/or high doses with certain BPs make the bone tissue more brittle and less tough. This translates into reduced energy to fracture and potentially a shorter bone fatigue life. Many studies have been done, but Interpretation of the results of these studies is complicated by variations in which BP is used, the animal model used, dose, duration, and methods of testing. Duration effects and effects on impact properties of bone are gaps that should be filled with additional testing.

The spatial heterogeneity in trabecular bone density within the vertebral centrum is associated with vertebral strength and could explain why volumetric bone mineral density (vBMD) exhibits low sensitivity in identifying fracture risk. This study evaluated whether the heterogeneity and spatial distribution of trabecular vBMD are associated with prevalent vertebral fracture. We examined the volumetric quantitative computed tomography (QCT) scans of the L3 vertebra in 148 participants in the Framingham Heart Study Multidetector CT study. Of these individuals, 37 were identified as cases of prevalent fracture, and 111 were controls, matched on sex and age with three controls per case. vBMD was calculated within 5-mm contiguous cubic regions of the centrum. Two measures of heterogeneity were calculated: (i) interquartile range (IQR); and (ii) quartile coefficient of variation (QCV). Ratios in the spatial distributions of the trabecular vBMD were also calculated: anterior/posterior, central/outer, superior/mid-transverse, and inferior/mid-transverse. Heterogeneity and spatial distributions were compared between cases and controls using Wilcoxon rank sum tests and t tests and tested for association with prevalent fractures with conditional logistic regressions independent of integral vBMD. Prevalent fracture cases had lower mean ± SD integral vBMD (134 ± 38 versus165 ± 42 mg/cm3 , p < .001), higher QCV (0.22 ± 0.13 versus 0.17 ± 0.09, p = .003), and lower anterior/posterior rBMD (0.65 ± 0.13 versus 0.78 ± 0.16, p < .001) than controls. QCV was positively associated with increased odds of prevalent fracture (OR 1.61; 95% CI, 1.04 to 2.49; p = .034), but this association was not independent of integral vBMD (p = .598). Increased anterior/posterior trabecular vBMD ratio was associated with decreased odds of prevalent fracture independent of integral vBMD (OR 0.38; 95% CI, 0.20 to 0.71; p = .003). In conclusion, increased trabecular vBMD in the anterior versus posterior centrum, but not trabecular vBMD heterogeneity, was associated with decreased risk of prevalent fracture independent of integral vBMD. Regional measurements of trabecular vBMD could aid in determining the risk and underlying mechanisms of vertebral fracture. © 2019 American Society for Bone and Mineral Research.

Bone is organized in a hierarchical 3D architecture. Traditionally, analysis of the skeletal system was based on bone mass assessment by radiographic methods or on the examination of bone structure by 2D histological sections. Advanced imaging technologies and big data analysis now enable the unprecedented examination of bone and provide new insights into its 3D macrostructure and microstructure. These technologies comprise ex vivo and in vivo methods including high-resolution computed tomography (CT), synchrotron-based imaging, X-ray microscopy, ultra-high-field magnetic resonance imaging (MRI), light-sheet fluorescence microscopy, confocal and intravital two-photon imaging. In concert, these techniques have been used to detect and quantify a novel vascular system of trans-cortical vessels in bone. Furthermore, structures such as the lacunar network, which harbours and connects osteocytes, become accessible for 3D imaging and quantification using these methods. Next-generation imaging of the skeletal system and its blood supply are anticipated to contribute to an entirely new understanding of bone tissue composition and function, from macroscale to nanoscale, in health and disease. These insights could provide the basis for early detection and precision-type intervention of bone disorders in the future.

Success after lateral transpsoas interbody fusion (LLIF) partially depends on avoidance of subsidence to maintain spinal alignment, disc space height, and indirect neural decompression. Techniques for preventing subsidence have focused largely on surgical and biomechanical properties of spinal reconstruction; however, medical management may also affect subsidence rates as well. The purpose of this study is to examine the effect of alendronate on minimally invasive LLIF patients with regard to radiographic and catastrophic subsidence.

We followed 26 patients who had LLIF at the L4-5 level (13 on alendronate, 13 control) and 22 patients at the L3-4 level (10 on alendronate, 12 control). Radiographs were reviewed to obtain measurements of subsidence at the 4 corners of the cage at 3 follow-up time points (2-3, 5-8, and 10-12 months). A Tobit mixed model was used to confirm the results.

We found no relationship between alendronate and subsidence for L3-4 fusion. At L4-5 we observed increased subsidence in the control group compared to the alendronate group (difference = 0.07 cm, 95% confidence interval [CI]: -0.01, 0.16, P = .08). There was a decrease in subsidence noted for the alendronate group for each time period (differences: 2-3: -0.06 cm, 95% CI: -0.28, 0.15], P = .27; 5-8: -0.14 cm, 95% CI: -0.36, .08, P = .10; 10-12: -0.21 cm, 95% CI: -0.48, .04, P = .05).

A clear reduction in subsidence was found with the use of postoperative alendronate in patients undergoing L4-5 LLIF. Alendronate had a significant decrease in subsidence at L4-5 after 10-12 months as compared to the control group. Additionally, no patients treated with alendronate had catastrophic subsidence. These data suggest the need for further study of alendronate in the prevention of subsidence after LLIF.

3.

A retrospective case-control study assessing the association of DXA-derived 3D measurements with osteoporosis-related vertebral fractures was performed. Trabecular volumetric bone mineral density was the measurement that best discriminates between fracture and control groups.

The aim of the present study was to evaluate the association of DXA-derived 3D measurements at the lumbar spine with osteoporosis-related vertebral fractures.

We retrospectively analyzed a database of 74 postmenopausal women: 37 subjects with incident vertebral fractures and 37 age-matched controls without any type of fracture. DXA scans at the lumbar spine were acquired at baseline (i.e., before the fracture event for subjects in the fracture group), and areal bone mineral density (aBMD) was measured. DXA-derived 3D measurements, such as volumetric BMD (vBMD), were assessed using a DXA-based 3D modeling software (3D-SHAPER). vBMD was computed at the trabecular, cortical, and integral bone. Cortical thickness and cortical surface BMD were also measured. Differences in DXA-derived measurements between fracture and control groups were evaluated using unpaired t test. Odds ratio (OR) and area under the receiver operating curve (AUC) were also computed. Subgroup analyses according to fractured vertebra were performed.

aBMD of fracture group was 9.3% lower compared with control group (p < 0.01); a higher difference was found for trabecular vBMD in the vertebral body (- 16.1%, p < 0.001). Trabecular vBMD was the measurement that best discriminates between fracture and control groups, with an AUC of 0.733, against 0.682 for aBMD. Overall, similar findings were observed within the subgroup analyses. The L1 vertebral fractures subgroup had the highest AUC at trabecular vBMD (0.827), against aBMD (0.758).

This study showed the ability of cortical and trabecular measurements from DXA-derived 3D models to discriminate between fracture and control groups. Large cohorts need to be analyzed to determine if these measurements could improve fracture risk prediction in clinical practice.

Prior studies show vertebral strength from computed tomography-based finite element analysis may be associated with vertebral fracture risk. We found vertebral strength had a strong association with new vertebral fractures, suggesting that vertebral strength measures identify those at risk for vertebral fracture and may be a useful clinical tool.

We aimed to determine the association between vertebral strength by quantitative computed tomography (CT)-based finite element analysis (FEA) and incident vertebral fracture (VF). In addition, we examined sensitivity and specificity of previously proposed diagnostic thresholds for fragile bone strength and low BMD in predicting VF.

In a case-control study, 26 incident VF cases (13 men, 13 women) and 62 age- and sex-matched controls aged 50 to 85 years were selected from the Framingham multi-detector computed tomography cohort. Vertebral compressive strength, integral vBMD, trabecular vBMD, CT-based BMC, and CT-based aBMD were measured from CT scans of the lumbar spine.

Lower vertebral strength at baseline was associated with an increased risk of new or worsening VF after adjusting for age, BMI, and prevalent VF status (odds ratio (OR) = 5.2 per 1 SD decrease, 95% CI 1.3-19.8). Area under receiver operating characteristic (ROC) curve comparisons revealed that vertebral strength better predicted incident VF than CT-based aBMD (AUC = 0.804 vs. 0.715, p = 0.05) but was not better than integral vBMD (AUC = 0.815) or CT-based BMC (AUC = 0.794). Additionally, proposed fragile bone strength thresholds trended toward better sensitivity for identifying VF than that of aBMD-classified osteoporosis (0.46 vs. 0.23, p = 0.09).

This study shows an association between vertebral strength measures and incident vertebral fracture in men and women. Though limited by a small sample size, our findings also suggest that bone strength estimates by CT-based FEA provide equivalent or better ability to predict incident vertebral fracture compared to CT-based aBMD. Our study confirms that CT-based estimates of vertebral strength from FEA are useful for identifying patients who are at high risk for vertebral fracture.

Vertebral fractures are the most common osteoporotic fracture and result in functional decline and excess mortality. Dual-energy x-ray absorptiometry (DXA) is the gold standard for the diagnosis of osteoporosis to identify patients at risk for fragility fractures; however, advances in imaging have expanded the role of computed tomography (CT) and magnetic resonance imaging (MRI) in evaluating bone health.

The utility of CT and MRI in the assessment of bone density is starting to gain traction, particularly when used opportunistically. DXA, conventional radiography, CT, and MRI can all be used to assess for vertebral fractures, and MRI can determine the acuity of fractures. Finally, advances in imaging allow for non-invasive assessment of measures of bone quality, including microarchitecture, bone strength, and bone turnover, to help identify and treat at-risk patients prior to sustaining a vertebral fracture. CT and MRI techniques remain primarily research tools to assess metabolic bone dysfunction, while use of DXA can be clinically expanded beyond measurement of bone density to assess for vertebral fractures and bone architecture to improve fracture risk assessment and guide treatment.

Local variations in bone loss may be of great importance to individually predict osteoporotic fractures but are neglected by current densitometry techniques. The purpose of this study was to evaluate regional variations of normal bone loss at the spine among different age groups using voxel-based morphometry. Non-contrast MDCT scans of 16 patients under the age of 40 (mean age 26years) without spinal pathology were identified as a reference cohort, where each thoracolumbar vertebra was assessed individually. For comparison, 38 patients >40years were grouped by decades in 4 cohorts of 10 patients each, except the youngest, including 8 patients only. All spines were automatically detected, segmented and non-rigidly registered for spatially normalized vertebral bodies. Afterwards, statistical and T-score mapping was performed to highlight local density differences in comparison to the reference cohort. The calculated statistical maps of significantly affected density regions (ADR) started to highlight small local changes of volumetric bone mineral density (vBMD) distribution within the vertebra of L5 (ADR: 7.9%) in the fifties cohort. Regions near the endplates were most affected. The effect dramatically increased in the sixties cohort, where bone loss was most prominent from T12 to L2. In the seventies cohort, around 50% of voxels in T10 to L5 showed significantly decreased vBMD. In conclusion, ADR and local T-score maps of the spine showed age-related local variations in a healthy population, corresponding to known areas of fracture origination and increased fracture incidence. It thus might provide a powerful tool in diagnosis of osteoporosis.

Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naïve postmenopausal women with low bone mass, romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 μg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L₁ vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p < 0.0001); changes in femoral strength for romosozumab showed similar but smaller changes, increasing more with romosozumab versus teriparatide (3.6% versus -0.7%; p = 0.027), and trending higher versus placebo (3.6% versus -0.1%; p = 0.059). Compartmental analysis revealed that the bone-strengthening effects for romosozumab were associated with positive contributions from both the cortical and trabecular bone compartments at both the lumbar spine and hip. Taken together, these findings suggest that romosozumab may offer patients with osteoporosis a new bone-forming therapeutic option that increases both vertebral and femoral strength within 12 months. © 2017 American Society for Bone and Mineral Research.

The aim of this study was to evaluate the longitudinal changes of trabecular bone score (TBS) during and after bisphosphonate (BP) treatment in postmenopausal Korean women with osteoporosis.

We analyzed 191 patients who took BP and underwent bone mineral density (BMD) test for the period from January 2010 to December 2015. The mean follow up period during treatment and after treatment was 22.8 months and 18 months, respectively. The TBS and BMD values were evaluated by the percent changes relative to the baseline.

In 191 patients, who treated with BPs, L-spine BMD increased 3.65±0.5% and TBS increased 0.26±0.4% from baseline during first 1 year. At 2 to 4 years, the changes of BMD and TBS from baseline gradually increased up to 9.3±3.25% and 2.69±0.98% and both results showed statistically significant correlation. In 86 patients who stopped BPs, L-spine BMD decreased -0.54±1.07% and TBS increased 0.33±1.96% from baseline during 3 years follow up period.

Lumbar spine TBS increase over time with BPs treatment although the changes were less than that of BMD. Also, it preserve for years after stopping treatment, as the changes of lumbar spine BMD. The results of BMD and TBS showed significant correlation during treatment but not during drug withdrawal.

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.

The purpose of this study was to develop and validate a finite element (FE) model to predict vertebral bone strength in vitro using multidetector computed tomography (MDCT) images in multiple myeloma (MM) patients, to serve as a complementing tool to assess fracture risk. In addition, it also aims to differentiate MM patients with and without vertebral compression fractures (VCFs) by performing FE analysis on vertebra segments (T1-L5) obtained from in vivo routine MDCT imaging scans. MDCT-based FE models were developed from the in vitro vertebrae samples and were then applied to the in vivo vertebrae segments of MM patients (n = 4) after validation. Predicted fracture load using FE models correlated significantly with experimentally measured failure load (r = 0.85, P < 0.001). Interestingly, an erratic behavior was observed in patients with fractures (n = 2) and a more gradual change in FE-predicted strength values in patients without fractures (n = 2). Severe geometric deformations were also observed in models that have already attained fractures. Since BMD is not a reliable parameter for fracture risk prediction in MM subjects, it is necessary to use advanced tools such as FE analysis to predict individual fracture risk. If peaks are observed between adjacent segments in an MM patient, it can be safe to conclude that the spine is experiencing regions of structural instability. Such an FE visualization may have therapeutic consequences to prevent MM associated vertebral fractures.

Beyond bone mineral density (BMD), bone quality designates the mechanical integrity of bone tissue. In vivo images based on X-ray attenuation, such as CT reconstructions, provide size, shape, and local BMD distribution and may be exploited as input for finite element analysis (FEA) to assess bone fragility. Further key input parameters of FEA are the material properties of bone tissue. This review discusses the main determinants of bone mechanical properties and emphasizes the added value, as well as the important assumptions underlying finite element analysis. Bone tissue is a sophisticated, multiscale composite material that undergoes remodeling but exhibits a rather narrow band of tissue mineralization. Mechanically, bone tissue behaves elastically under physiologic loads and yields by cracking beyond critical strain levels. Through adequate cell-orchestrated modeling, trabecular bone tunes its mechanical properties by volume fraction and fabric. With proper calibration, these mechanical properties may be incorporated in quantitative CT-based finite element analysis that has been validated extensively with ex vivo experiments and has been applied increasingly in clinical trials to assess treatment efficacy against osteoporosis.

Apparent modulus and failure stress of trabecular bone structure from 45 women with osteoporosis treated with bisphosphonates for varying durations were studied using finite element analyses and statistical modeling. Following adjustments for patient age and bone volume, increasing bisphosphonate treatment duration for up to 7.3 years was associated with treatment-time-dependent increases in bone apparent modulus and failure stress. Treatment durations exceeding 7.3 years were associated with time-dependent decreases in apparent modulus and failure stress from the peak values observed.

The purpose of this study was to clarify the relationship between bisphosphonate (BP) treatment duration and human bone quality. This study quantified changes in the apparent modulus and failure stress of trabecular bone biopsied from patients with osteoporosis who were treated with BPs for widely varying durations.

Forty-five iliac crest bone samples were obtained from women with osteoporosis who were continuously treated with oral BPs for varying periods of up to 16 years. Micro-CT imaging was used to develop three-dimensional virtual models of the trabecular bone from these samples. Apparent modulus and failure stress of these virtual models were determined using finite element analyses (FEA). Polynomial regression and cubic splines, adjusted for relevant (age and BV/TV) covariates, were used to statistically model the data and quantify the relationships between BP treatment duration and apparent modulus or failure stress.

Second-order polynomial models were needed to relate apparent modulus or failure stress to BP treatment duration. These models showed that these bone quality parameters (a) increased with increasing BP treatment duration up to approximately 7.3 years, (b) reached a maximum at this (~7.3 years) time, and then (c) declined with BP treatment durations exceeding ~7.3 years. A similar result was obtained by modeling with cubic splines.

Changes in FEA-derived apparent stiffness and failure stress are attributable to changes in trabecular bone structure, which in turn are related to the duration of BP treatment. These relationships are evident even after adjustments are made in the statistical models for changes in age and BV/TV. According to these models, increases in trabecular bone apparent stiffness and failure stress linked to BPs cease and appear to reverse after approximately 7.3 years of treatment. Conclusions regarding optimal BP therapy duration await study of additional bone quality parameters.

Tissue-level mechanical properties characterize mechanical behavior independently of microscopic porosity. Specifically, quasi-static nanoindentation provides measurements of modulus (stiffness) and hardness (resistance to yielding) of tissue at the length scale of the lamella, while dynamic nanoindentation assesses time-dependent behavior in the form of storage modulus (stiffness), loss modulus (dampening), and loss factor (ratio of the two). While these properties are useful in establishing how a gene, signaling pathway, or disease of interest affects bone tissue, they generally do not vary with aging after skeletal maturation or with osteoporosis. Heterogeneity in tissue-level mechanical properties or in compositional properties may contribute to fracture risk, but a consensus on whether the contribution is negative or positive has not emerged. In vivo indentation of bone tissue is now possible, and the mechanical resistance to microindentation has the potential for improving fracture risk assessment, though determinants are currently unknown.

Finite element analysis has not yet been validated for measuring changes in whole-bone strength at the hip or spine in people after treatment with an osteoporosis agent. Toward that end, we assessed the ability of a clinically approved implementation of finite element analysis to correctly quantify treatment effects on vertebral strength, comparing against direct mechanical testing, in cynomolgus monkeys randomly assigned to one of three 16-month-long treatments: sham surgery with vehicle (Sham-Vehicle), ovariectomy with vehicle (OVX-Vehicle), or ovariectomy with denosumab (OVX-DMAb). After treatment, T12 vertebrae were retrieved, scanned with micro-CT, and mechanically tested to measure compressive strength. Blinded to the strength data and treatment codes, the micro-CT images were coarsened and homogenized to create continuum-type finite element models, without explicit porosity. With clinical translation in mind, these models were then analyzed for strength using the U.S. Food and Drug Administration (FDA)-cleared VirtuOst software application (O.N. Diagnostics, Berkeley, CA, USA), developed for analysis of human bones. We found that vertebral strength by finite element analysis was highly correlated (R(2)  = 0.97; n = 52) with mechanical testing, independent of treatment (p = 0.12). Further, the size of the treatment effect on strength (ratio of mean OVX-DMAb to mean OVX-Vehicle, as a percentage) was large and did not differ (p = 0.79) between mechanical testing (+57%; 95% CI [26%, 95%]) and finite element analysis (+51% [20%, 88%]). The micro-CT analysis revealed increases in cortical thickness (+45% [19%, 73%]) and trabecular bone volume fraction (+24% [8%, 42%]). These results show that a preestablished clinical finite element analysis implementation-developed for human bone and clinically validated in fracture-outcome studies-correctly quantified the observed treatment effects of denosumab on vertebral strength in cynomolgus monkeys. One implication is that the treatment effects in this study are well explained by the features contained within these finite element models, namely, the bone geometry and mass and the spatial distribution of bone mass. © 2016 American Society for Bone and Mineral Research.