Boyd, Steven K.

Abstract Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ −2.5, whereas 53% had T-scores between −1.0 and −2.5 and 37% had T-scores ≥−1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

Abstract Fracture risk increases with lower areal bone mineral density (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) dual energy X-ray absorptiometry (DXA) which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40–96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures.

ABSTRACT Most fracture risk assessment tools use clinical risk factors combined with bone mineral density (BMD) to improve assessment of osteoporosis; however, stratifying fracture risk remains challenging. This study developed a fracture risk assessment tool that uses information about volumetric bone density and three‐dimensional structure, obtained using high‐resolution peripheral quantitative compute tomography (HR‐pQCT), to provide an alternative approach for patient‐specific assessment of fracture risk. Using an international prospective cohort of older adults ( n = 6802) we developed a tool to predict osteoporotic fracture risk, called μFRAC. The model was constructed using random survival forests, and input predictors included HR‐pQCT parameters summarizing BMD and microarchitecture alongside clinical risk factors (sex, age, height, weight, and prior adulthood fracture) and femoral neck areal BMD (FN aBMD). The performance of μFRAC was compared to the Fracture Risk Assessment Tool (FRAX) and a reference model built using FN aBMD and clinical covariates. μFRAC was predictive of osteoporotic fracture (c‐index = 0.673, p < 0.001), modestly outperforming FRAX and FN aBMD models (c‐index = 0.617 and 0.636, respectively). Removal of FN aBMD and all clinical risk factors, except age, from μFRAC did not significantly impact its performance when estimating 5‐year and 10‐year fracture risk. The performance of μFRAC improved when only major osteoporotic fractures were considered (c‐index = 0.733, p < 0.001). We developed a personalized fracture risk assessment tool based on HR‐pQCT that may provide an alternative approach to current clinical methods by leveraging direct measures of bone density and structure. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

ABSTRACT Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p &lt; 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).

Abstract High-resolution peripheral quantitative computed tomography (HR-pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technology to address important skeletal health questions requires translation to standardized multicenter data pools. Our goal was to evaluate the feasibility of pooling data in multicenter HR-pQCT imaging trials. Reproducibility imaging experiments were performed using structure and composition-realistic phantoms constructed from cadaveric radii. Single-center precision was determined by repeat scanning over short-term (&lt;72 hours), intermediate-term (3–5 months), and long-term intervals (28 months). Multicenter precision was determined by imaging the phantoms at nine different HR-pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters. Single-center short-term RMSCVs were &lt;1% for all parameters except cortical thickness (Ct.Th) (1.1%), spatial variability in cortical thickness (Ct.Th.SD) (2.6%), standard deviation of trabecular separation (Tb.Sp.SD) (1.8%), and porosity measures (6% to 8%). Intermediate-term RMSCVs were generally not statistically different from short-term values. Long-term variability was significantly greater for all density measures (0.7% to 2.0%; p &lt; 0.05 versus short-term) and several structure measures: cortical thickness (Ct.Th) (3.4%; p &lt; 0.01 versus short-term), cortical porosity (Ct.Po) (15.4%; p &lt; 0.01 versus short-term), and trabecular thickness (Tb.Th) (2.2%; p &lt; 0.01 versus short-term). Multicenter RMSCVs were also significantly higher than short-term values: 2% to 4% for density and micro–finite element analysis (µFE) measures (p &lt; 0.0001), 2.6% to 5.3% for morphometric measures (p &lt; 0.001), whereas Ct.Po was 16.2% (p &lt; 0.001). In the absence of subject motion, multicenter precision errors for HR-pQCT parameters were generally less than 5%. Phantom-based multicenter precision was comparable to previously reported in in vivo single-center precision errors, although this was approximately two to five times worse than ex vivo short-term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multicenter study designs. © 2013 American Society for Bone and Mineral Research.

Abstract The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (−2.1% to −0.8%) at the distal radius after 12 months. Alendronate prevented the decline (−0.6% to 2.4%, p = .051 to &lt;.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p &lt; .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p &lt; .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab. © 2010 American Society for Bone and Mineral Research