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- Materials and Methods
- Supporting Information
The finite element analysis technique, which uses computational biomechanical principles coupled with patient-specific information in clinical CT scans to mechanistically simulate bone failure, has been validated in cadaver studies by numerous groups for both the spine[4-6, 39] and hip[7-12] and clinically has been shown to be significantly associated with incident and prevalent fracture in multiple cohorts.[13-18, 20, 40] Our new data provide further clinical validation. For the spine, vertebral strength was associated with fracture in both women and men; consistently had the (numerically) highest odds ratios compared with the other predictors; was associated with fracture independently of vBMD in men; and for men with more severe fracture (SQ2/3) remained significant, whereas vBMD lost significance. For the hip, femoral strength was associated with fracture independently of femoral neck areal BMD in women and total hip areal BMD in both sexes. With clinical translation in mind, we introduced and prospectively evaluated interventional thresholds for bone strength and confirmed that these thresholds for fragile bone strength were associated with fracture probability levels equivalent to those for well-established thresholds for osteoporosis, both at the hip and spine and in women and men. The probability of fracture in this study depends on the nature of the case-control design and does not represent actual clinical fracture risk. However, 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 clinical risk of fracture, and because strength was associated with fracture at least as well as was BMD at both the hip and spine in the present study, these results indicate that individuals who have fragile bone strength at the hip or spine should also be considered at high clinical risk of fracture.
One novel aspect of this study is the use of FEA-based vertebral strength assessment and vertebral trabecular BMD for prediction of incident vertebral fractures in women, the first study of its kind. Our findings are consistent with those from the Osteoporotic Fractures in Men (MrOS) study of men over age 65 years, which showed that vertebral compressive strength (and the load-to-strength ratio) were highly significant predictors of incident clinical vertebral fracture in men. Similar to our reported odds ratios, hazard ratios for strength in that study were numerically higher for strength compared with vBMD, although that study evaluated integral vBMD (trabecular and cortical) and not trabecular vBMD as in this study. We are aware of no studies for women reporting on incident spine fracture and CT-based BMD or strength. In the current study, the association between vertebral strength and vertebral fracture was uniformly stronger in women than men, both before and after adjusting for age and prevalent fracture, and in particular when restricted to more severe fractures (SQ2/3). Spine DXA was not used in this study. However, in the MrOS study of elderly men, the age-adjusted hazard ratio was twofold higher (p < 0.01) for strength than for DXA-measured lumbar spine areal BMD, and strength was associated with fracture independent of DXA areal BMD.
Although no prior study has investigated FEA predictors of incident vertebral fracture in women, several cross-sectional studies in the USA and Japan have shown statistically significant associations between FEA and prevalent vertebral fracture, supporting the generality of our spine results. In 1991, Faulkner found that an FEA-estimated vertebral yield stress better distinguished women aged 20 to 79 years with a prevalent vertebral fracture than did a QCT-based measure of bone mineral content. More recently, two studies of women over age 50 years in the Rochester MN, area found that vertebral strength, load-to-strength ratio, and vBMD were all highly associated with prevalent vertebral fractures.[17, 18] Imai and colleagues also found a trend for the association of prevalent vertebral fracture in Japanese women to be greater for strength than for CT-measured vBMD or DXA-measured spine areal BMD. In all these more recent studies, vertebral strength consistently performed statistically better than lumbar spine areal BMD as measured by DXA. DXA at the spine is limited by its two-dimensional nature and its inclusion of the posterior elements and any aortic calcification in the BMD measure. Given these limitations, and because our findings show consistent agreement with these prior FEA studies, the collective literature suggests that vertebral strength can reasonably be expected to perform better than DXA for assessing risk of incident spine fractures in both women and men.
Another novel aspect of this study was our prospective validation of previously established interventional thresholds for bone strength, which enables FEA to be used clinically to identify women and men at high risk of fracture. We found that the women and men in this study who had fragile bone strength were at an equivalently high probability of fracture as were the women and men who had BMD-defined osteoporosis, the latter criterion placing them clinically in a high-risk category for fracture. Because the thresholds for bone strength were derived from a previously measured strength-BMD relationship for whites, these thresholds should remain valid for any population with a similar strength-BMD relationship. The AGES-Reykjavik cohort shows such a correspondence (Fig. 6), the value of strength at the threshold for fragile bone strength being—as per design—just slightly higher than the value of strength directly corresponding to the osteoporosis threshold. In general, the relation between whole-bone strength and BMD by FEA analysis depends on such morphological characteristics as the size and shape of the bone and the spatial distribution of bone density, including the trabecular-cortical characteristics. As such, the strength thresholds reported here might not be directly applicable to bones in nonwhite populations having different morphological characteristics that would alter the relation between BMD and whole-bone strength.
Figure 6. Femoral strength versus femoral neck areal BMD for women (top) and men (bottom), showing the interventional thresholds for fragile bone strength, low bone strength, osteoporosis, and low bone mass. The shaded regions identify the subset of individuals with low bone mass (aka osteopenia) who also have fragile bone strength.
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For the hip, our findings for women that femoral strength was associated with fracture independently of areal BMD and that reclassification improved when using a combination of femoral strength and areal BMD, together suggest that more individuals at high risk of fracture can be identified by using measures of both femoral strength and hip BMD than by using measures of hip BMD alone. Part of this effect is that some individuals with low bone mass (aka osteopenia) who fractured also had fragile bone strength, as shown in a plot of femoral strength and femoral neck areal BMD from this study (Fig. 6, see shaded region) and as observed also in the MrOS study of elderly men. The underlying biophysical mechanisms for this effect are not yet clear, perhaps related to geometry, or relatively low trabecular to cortical mass, or locally weak regions within the bone, any of which might go undetected by an areal BMD measure because of its projectional nature. Regardless, these findings illustrate that women and men who have low bone mass can be at as high a risk of fracture as the risk associated with having osteoporosis if they also have fragile bone strength. Whether such osteopenic high-risk individuals would correspond with those identified using an absolute-risk approach that incorporates various clinical risk factors[42, 43] is unclear and remains a topic for future research.
The generality of our hip strength results is supported by reports of similar findings from the only other two incident hip-fracture studies that analyzed both areal BMD and FEA-estimated hip strength. Femoral neck areal BMD was not reported in either of these two studies but total hip areal BMD was. In the first prior study, an analysis of incident hip fractures in men over age 65 years in the MrOS cohort that used the same software as in the current analysis, age-adjusted hazard ratios were numerically higher for femoral strength (6.5, 95% CI 2.3 to 18.3) than for DXA-measured total hip areal BMD (4.4, 95% CI 2.1 to 9.1). That finding is consistent with ours of a higher odds ratio for femoral strength compared with total hip areal BMD. In the second prior study, an age- and sex-matched nested case-control analysis of a subset of the AGES-Reykjavik participants performed using different image-processing and FEA software by Keyak and colleagues, femoral strength in a stance loading configuration remained a significant predictor of hip fracture after accounting for total hip areal BMD in men (p = 0.01) and just missed statistical significance for women (p = 0.06). Similar trends (p = 0.06) were seen in the fall loading condition for both women and men, and it is likely these trends would have reached statistical significance had the number of fractures in that analysis (71 women and 45 men) been greater. These results are, therefore, also consistent with our findings.
Despite this consistency between these past studies and the current study, Keyak and colleagues concluded that femoral strength may be a more important fracture risk predictor for men than for women, in apparent contradiction to our findings that the odds ratio for femoral strength was higher for women than for men. The Keyak and colleagues conclusion was based on their finding that the ratio of the mean difference in femoral strength between their age-matched cases and controls, divided by the sex-specific standard deviation, was larger for men (ratio = 0.72 for men versus 0.32 for women). We used a sex-pooled standard deviation in our odds ratio calculations. However, to compare against Keyak and colleagues, we also normalized our strength differences by sex-specific standard deviations and then adjusted our strength results to age 80 years (the mean age in the Keyak and colleagues study) and found a similar trend of a higher ratio for men than for women (ratio = 0.83 for men versus 0.59 for women), indicating congruence in the two studies. Further, when we also normalized our logistic regression parameters by sex-specific standard deviations, we found that the age-adjusted odds ratio (95% CI) for strength was numerically higher for men 3.2 (2.1 to 4.7) than for women 2.8 (2.0 to 3.9), again consistent with the Keyak and colleagues findings. This apparent reversal in our odds ratios was because of the women having a lower standard deviation relative to the sex-pooled standard deviation than men, which in turn was because of the lower mean value of femoral strength for women. For our primary analysis, we normalized by the sex-pooled standard deviation to provide insight into risk differences between women and men. Our finding of a higher odds ratio for women than for men, when using a sex-pooled standard deviation, indicates that a fixed decrement of bone strength elevates risk more for women than for men. It is well established that women lose femoral strength at a greater absolute rate with aging than do men.[44, 45] Thus, our results help explain the known higher rate of hip fracture in women than in men. Further, evaluated in this way, our results suggest that the association between femoral strength and hip fracture is at least as important for women as for men.
There are a number of limitations for this study. Most important, the analysis sample lacked racial variation and, as noted above, potential differences in the general relation between areal BMD and whole-bone strength may affect the generality of the strength thresholds in certain nonwhite populations. However, because hip strength and hip areal BMD are quite well correlated (Fig. 6, for example) and because hip areal BMD is a robust predictor of fracture across races, strength should also be associated with fracture risk across races. This is consistent with results from prevalent and incident fracture-outcome studies from multiple different cohorts from the USA,[13, 14, 17, 18] Japan, and Iceland. A second limitation is that we did not use DXA. However, as shown by others[15, 22] and by our own data (Supplemental Data), the hip areal BMD T-score as measured from CT is highly correlated and numerically equivalent to that as measured by DXA, and thus our results should remain substantially unchanged had real DXA been used. Even so, future studies are required to confirm the expected advantage of vertebral strength over DXA for predicting incident spine fractures in women and more generally to confirm our various results in other cohorts.
An additional limitation is that we used a case-control approach rather than a case-cohort approach that would have allowed direct estimation of prevalence and absolute risk. This choice was a trade-off in the spine arm to increase statistical power by including morphologic vertebral fractures as (incident) cases, which required follow-up CT scans for adjudication. Excluding those without a follow-up exam meant that the random sample, although useful for selecting controls, underrepresented cases because of an association between incident fracture and dropout. Even so, the case-control design still allowed us to evaluate odds ratios for strength and to show that the probability of fracture associated with fragile bone strength and osteoporosis were similarly high. We note also that despite the general trend for larger odds ratios for strength compared with BMD, there were only small differences in the AUC values between the various predictors. This is not surprising because typically large differences in an odds ratio need to occur before the AUC changes appreciably. However, because the AUC represents the performance of a predictor across the entire range of sensitivities and specificities, a finding of only a small difference in AUC values between predictors may not represent potential benefits in clinical practice and decision-making, which depends more on where an individual patient falls with respect to any relevant interventional threshold. For example, we found improved reclassification when both strength and BMD were used instead of just BMD, presumably because a statistically significant subset of individuals had lower than expected bone strength for their BMD and were therefore at higher than expected risk of fracture. Clinically, that should translate to a subset of individuals with low bone mass, but fragile bone strength, who are indeed at higher risk of fracture.
There are also inherent limitations with the finite element technique. Although our technique has shown good agreement in strength values compared with cadaver testing,[4, 8] our current implementation did not include some potentially important features, such as microscale effects, fine resolution of the thin cortex, and multiple loading conditions. There is also potential to improve the load-to-strength ratio formulation, which in this study did not include patient-specific modeling of the intervertebral discs, spinal curvature, or muscle morphology. In the hip, a CT-based measure of patient-specific soft-tissue thickness over the greater trochanter was not included, although our preliminary analyses indicated that including such detail did not improve the age-adjusted odds ratio after adjustment for BMI. Development of methods to better utilize such patient-specific model inputs remains a topic for future research.
When viewed in the context of the available literature that has now accumulated on FEA of CT scans, these new results suggest that FEA (which clinically would also include a CT-based BMD analysis) can provide an alternative clinical tool to DXA for meeting the increasing need for additional osteoporosis and fracture risk assessment. Although the use of a dedicated CT scan would introduce additional radiation compared with the use of DXA, the use of an ancillary approach, in which a previously acquired CT is utilized,[48-50] would circumvent this limitation, and tens of millions of such CT scans are taken annually in women and men over age 50 years. As noted above, such an approach may not only identify individuals with osteoporosis and fragile bone strength but also a subset of individuals with low bone mass who have fragile bone strength and are thus at high risk of fracture.