Adding Marrow Adiposity and Cortical Porosity to Femoral Neck Areal Bone Mineral Density Improves the Discrimination of Women With Nonvertebral Fractures From Controls.

Advancing age is accompanied by a reduction in bone formation and remodeling imbalance, which produces microstructural deterioration. This may be partly caused by a diversion of mesenchymal cells towards adipocytes rather than osteoblast lineage cells. We hypothesized that microstructural deterioration would be associated with an increased marrow adiposity, and each of these traits would be independently associated with nonvertebral fractures and improve discrimination of women with fractures from controls over that achieved by femoral neck (FN) areal bone mineral density (aBMD) alone. The marrow adiposity and bone microstructure were quantified from HR-pQCT images of the distal tibia and distal radius in 77 women aged 40 to 70 years with a recent nonvertebral fracture and 226 controls in Melbourne, Australia. Marrow fat measurement from HR-pQCT images was validated using direct histologic measurement as the gold standard, at the distal radius of 15 sheep, with an agreement (R2 = 0.86, p < 0.0001). Each SD higher distal tibia marrow adiposity was associated with 0.33 SD higher cortical porosity, and 0.60 SD fewer, 0.24 SD thinner, and 0.72 SD more-separated trabeculae (all p < 0.05). Adjusted for age and FN aBMD, odds ratios (ORs) (95% CI) for fracture per SD higher marrow adiposity and cortical porosity were OR, 3.39 (95% CI, 2.14 to 5.38) and OR, 1.79 (95% CI, 1.14 to 2.80), respectively. Discrimination of women with fracture from controls improved when cortical porosity was added to FN aBMD and age (area under the receiver-operating characteristic curve [AUC] 0.778 versus 0.751, p = 0.006) or marrow adiposity was added to FN aBMD and age (AUC 0.825 versus 0.751, p = 0.002). The model including FN aBMD, age, cortical porosity, trabecular thickness, and marrow adiposity had an AUC = 0.888. Results were similar for the distal radius. Whether marrow adiposity and cortical porosity indices improve the identification of women at risk for fractures requires validation in prospective studies. © 2019 American Society for Bone and Mineral Research.

Women with fracture, unidentified by FRAX, but identified by cortical porosity, have a set of characteristics that contribute to their increased fracture risk beyond high FRAX score and high cortical porosity.

The Fracture Risk Assessment Tool (FRAX) is widely used to identify individuals at increased risk for fracture. However, cortical porosity is associated with risk for fracture independent of FRAX and is reported to improve the net reclassification of fracture cases. We wanted to test the hypothesis that women with fracture who are unidentified by high FRAX score, but identified by high cortical porosity, have a set of characteristics that contribute to their fracture risk beyond high FRAX score and high cortical porosity. We quantified FRAX score with femoral neck areal bone mineral density (FN aBMD), and femoral subtrochanteric architecture, in 211 postmenopausal women aged 54-94 years with non-vertebral fractures, and 232 fracture-free controls in Tromsø, Norway, using StrAx software. Of 211 fracture cases, FRAX score > 20% identified 53 women (sensitivity 25.1% and specificity 93.5%), while cortical porosity cut-off > 80th percentile identified 61 women (sensitivity 28.9% and specificity 87.9%). The 43 (20.4%) additional fracture cases identified by high cortical porosity alone, had lower FRAX score (12.3 vs. 26.2%) than those identified by FRAX alone, they were younger, had higher FN aBMD (806 vs. 738 mg/cm2), and fewer had a prior fracture (23.3 vs. 62.9%), all p < 0.05. They had higher cortical porosity (48.7 vs. 42.1%), thinner cortices (3.75 vs. 4.12 mm), lower cortical and total volumetric BMD (942 vs. 1053 and 586 vs. 699 mg HA/cm3), larger medullary and total cross-sectional areas (245 vs. 190 and 669 vs. 593 mm2), and higher cross-sectional moment of inertia (2619 vs. 2388 cm4) all p < 0.001. When the fracture cases and controls with high cortical porosity were compared, cases had higher cortical porosity, lower cortical vBMD, lower total vBMD, smaller cortical CSA/Total CSA, larger medullary CSA and larger total CSA than controls (all p ≤ 0.05). Thus, fracture cases, unidentified by FRAX, but identified by cortical porosity, had an architecture where the positive impact of larger bone size did not offset the negative effect of thinner cortices with increased porosity. A measurement of cortical porosity may be a marker of other characteristics that capture additional fracture risk components, not captured by FRAX.

Increased cortical porosity and reduced cortical thickness of the proximal femur are associated with nonvertebral fracture independent of Fracture Risk Assessment Tool and Garvan estimates in postmenopausal women.

The Fracture Risk Assessment Tool (FRAX) and Garvan Calculator have improved the individual prediction of fracture risk. However, additional bone measurements that might enhance the predictive ability of these tools are the subject of research. There is increasing interest in cortical parameters, especially cortical porosity. Neither FRAX nor Garvan include measurements of cortical architecture, important for bone strength, and providing independent information beyond the conventional approaches. We tested the hypothesis that cortical parameters are associated with fracture risk, independent of FRAX and Garvan estimates. This nested case-control study included 211 postmenopausal women aged 54-94 years with nonvertebral fractures, and 232 controls from the Tromsø Study in Norway. We assessed FRAX and Garvan 10-year risk estimates for fragility fracture, and quantified femoral subtrochanteric cortical porosity, thickness, and area from computed tomography images using StrAx1.0 software. Per standard deviation higher cortical porosity, thinner cortices, and smaller cortical area, the odds ratio (95% confidence interval) for fracture was 1.71 (1.38-2.11), 1.79 (1.44-2.23), and 1.52 (1.19-1.95), respectively. Cortical porosity and thickness, but not area, remained associated with fracture when adjusted for FRAX and Garvan estimates. Adding cortical porosity and thickness to FRAX or Garvan resulted in greater area under the receiver operating characteristic curves. When using cortical porosity (>80th percentile) or cortical thickness (<20th percentile) combined with FRAX (threshold >20%), 45.5% and 42.7% of fracture cases were identified, respectively. Using the same cutoffs for cortical porosity or thickness combined with Garvan (threshold >25%), 51.2% and 48.3% were identified, respectively. Specificity for all combinations ranged from 81.0-83.6%. Measurement of cortical porosity or thickness identified 20.4% and 17.5% additional fracture cases that, were unidentified using FRAX alone, and 16.6% and 13.7% fracture cases unidentified using Garvan alone. In conclusion, cortical parameters may help to improve identification of women at risk for fracture.

Women with type 2 diabetes mellitus have lower cortical porosity of the proximal femoral shaft using low-resolution CT than nondiabetic women, and increasing glucose is associated with reduced cortical porosity.

Increased cortical porosity has been suggested as a possible factor increasing fracture propensity in patients with type 2 diabetes mellitus (T2DM). This is a paradox because cortical porosity is generally associated with high bone turnover, while bone turnover is reduced in patients with T2DM. We therefore wanted to test the hypothesis that women with T2DM have lower bone turnover markers (BTM) and lower cortical porosity than those without diabetes, and that higher serum glucose and body mass index (BMI) are associated with lower BTM, and with lower cortical porosity. This cross-sectional study is based on a prior nested case-control study including 443 postmenopausal women aged 54-94years from the Tromsø Study, 211 with non-vertebral fracture and 232 fracture-free controls. Of those 443 participants, 22 women exhibited T2DM and 421 women did not have diabetes. All had fasting blood samples assayed for procollagen type I N-terminal propeptide (PINP), C-terminal cross-linking telopeptide of type I collagen (CTX) and glucose, and femoral subtrochanteric architecture was quantified using low-resolution clinical CT and StrAx1.0 software. Women with T2DM had higher serum glucose (7.2 vs. 5.3mmol/L), BMI (29.0 vs. 26.4kg/m2), and higher femoral subtrochanteric total volumetric bone mineral density (vBMD) (783 vs. 715mgHA/cm3), but lower cortical porosity (40.9 vs. 42.8%) than nondiabetic women (all p<0.05). Each standard deviation (SD) increment in glucose was associated with 0.10-0.12 SD lower PINP and CTX, and 0.13 SD lower cortical porosity (all p<0.05). Each SD increment in BMI was associated with 0.10-0.18 SD lower serum PINP and CTX, and 0.19 SD thicker cortices (all p<0.05). Increasing glucose and BMI were associated with lower bone turnover suggesting that reduced intracortical and endocortical remodeling leads to reduced porosity and thicker cortices. Using low-resolution clinical CT, cortical porosity was lower in women with T2DM compared to women without diabetes. This indicates that other changes in bone qualities, not increased cortical porosity, are likely to explain the increased fracture propensity in patients with T2DM.

Determinants of Transitional Zone Area and Porosity of the Proximal Femur Quantified In Vivo in Postmenopausal Women.

Bone architecture as well as size and shape is important for bone strength and risk of fracture. Most bone loss is cortical and occurs by trabecularization of the inner part of the cortex. We therefore wanted to identify determinants of the bone architecture, especially the area and porosity of the transitional zone, an inner cortical region with a large surface/matrix volume available for intracortical remodeling. In 211 postmenopausal women aged 54 to 94 years with nonvertebral fractures and 232 controls from the Tromsø Study, Norway, we quantified femoral subtrochanteric architecture in CT images using StrAx1.0 software, and serum levels of bone turnover markers (BTM, procollagen type I N-terminal propeptide and C-terminal cross-linking telopeptide of type I collagen). Multivariable linear and logistic regression analyses were used to quantify associations of age, weight, height, and bone size with bone architecture and BTM, and odds ratio (OR) for fracture. Increasing age, height, and larger total cross-sectional area (TCSA) were associated with larger transitional zone CSA and transitional zone CSA/TCSA (standardized coefficients [STB] = 0.11 to 0.80, p ≤ 0.05). Increasing weight was associated with larger TCSA, but smaller transitional zone CSA/TCSA and thicker cortices (STB = 0.15 to 0.22, p < 0.01). Increasing height and TCSA were associated with higher porosity of the transitional zone (STB = 0.12 to 0.46, p < 0.05). Increasing BTM were associated with larger TCSA, larger transitional zone CSA/TCSA, and higher porosity of each of the cortical compartments (p < 0.01). Fracture cases exhibited larger transitional zone CSA and higher porosity than controls (p < 0.001). Per SD increasing CSA and porosity of the transitional zone, OR for fracture was 1.71 (95% CI, 1.37 to 2.14) and 1.51 (95% CI, 1.23 to 1.85), respectively. Cortical bone architecture is determined mainly by bone size as built during growth and is modified by lifestyle factors throughout life through bone turnover. Fracture cases exhibited larger transitional zone area and porosity, highlighting the importance of cortical bone architecture for fracture propensity.

Bone turnover markers are associated with higher cortical porosity, thinner cortices, and larger size of the proximal femur and non-vertebral fractures.

Bone turnover markers (BTM) predict bone loss and fragility fracture. Although cortical porosity and cortical thinning are important determinants of bone strength, the relationship between BTM and cortical porosity has, however, remained elusive. We therefore wanted to examine the relationship of BTM with cortical porosity and risk of non-vertebral fracture. In 211 postmenopausal women aged 54-94 years with non-vertebral fractures and 232 age-matched fracture-free controls from the Tromsø Study, Norway, we quantified femoral neck areal bone mineral density (FN aBMD), femoral subtrochanteric bone architecture, and assessed serum levels of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX). Fracture cases exhibited higher PINP and CTX levels, lower FN aBMD, larger total and medullary cross-sectional area (CSA), thinner cortices, and higher cortical porosity of the femoral subtrochanter than controls (p≤0.01). Each SD increment in PINP and CTX was associated with 0.21-0.26 SD lower total volumetric BMD, 0.10-0.14 SD larger total CSA, 0.14-0.18 SD larger medullary CSA, 0.13-0.18 SD thinner cortices, and 0.27-0.33 SD higher porosity of the total cortex, compact cortex, and transitional zone (all p≤0.01). Moreover, each SD of higher PINP and CTX was associated with increased odds for fracture after adjustment for age, height, and weight (ORs 1.49; 95% CI, 1.20-1.85 and OR 1.22; 95% CI, 1.00-1.49, both p<0.05). PINP, but not CTX, remained associated with fracture after accounting for FN aBMD, cortical porosity or cortical thickness (OR ranging from 1.31 to 1.39, p ranging from 0.005 to 0.028). In summary, increased BTM levels are associated with higher cortical porosity, thinner cortices, larger bone size and higher odds for fracture. We infer that this is produced by increased periosteal apposition, intracortical and endocortical remodeling; and that these changes in bone architecture are predisposing to fracture.