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

Abstract

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

Keywords: BONE MINERAL DENSITY; BONE QUALITY; BONE STRENGTH; DXA; HIP FRACTURE; POSTMENOPAUSAL OSTEOPOROSIS.

Fig. 1

DXA scans and mechanical testing were done at the proximal femur, whereas cortical porosity, reference point indentation, and advanced glycation end-product content were measured from the mid-diaphysis of the tibia from the same side (A). The age (B), T-score (C), and aBMD (D) distributions of the cohort in this study.

Fig. 2

Although advanced glycation end-products did not trend with age in this population (A), there were significant age-related declines in indentation distance increase (B), cortical porosity (C), and failure load of the femoral neck (D). However, increasing aBMD correlated with a decline in advanced glycation end-products (E), reduction of indentation distance increase (F), decrease of cortical porosity (G), and increasing bone strength (H).

Fig. 3

Individual regressions revealed significant associations between bone strength with advanced glycation end-products (A), indentation distance increase (B), cortical porosity (C), and T-score (D). Of these, T-score and indentation distance increase are the strongest individual predictors of bone strength.

Fig. 4

Backward stepwise multiple regression of the multiscale factors with bone strength was performed to identify the predictors sets that uniquely improve the ability to predict femoral neck failure load. Although each of the univariate factors significantly predicted bone strength (A), combining aBMD with IDI (B, C), cortical porosity (D), or AGEs (E) significantly improves the correlation coefficient. Moreover, the addition of these variables beyond aBMD appears to be particularly effective in predicting bone strength over a wide range in osteopenic and osteoporotic bones.