Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

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 "onesize-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 < 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.

Genetic Deletion of Menin in Mouse Mesenchymal Stem Cells: An Experimental and Computational Analysis

“…Increasingly, it has been recognized that measurement of BMD alone may not accurately demonstrate bone fragility and predisposition to fracture, and additional approaches to complement BMD measurements in osteoporosis have been reported. ( 34 ) We, therefore, provided a detailed analysis of the biomechanical properties of bone caused by deletion of menin early in the osteoblast lineage. Thus, the mechanical behavior of bone is strongly dependent on its complex organization and hierarchical structure.…”

Hip Fractures in Older Adults Are Associated With the Low Density Bone Phenotype and Heterogeneous Deterioration of Bone Microarchitecture

“…The bone phenotypes are based on information captured by standard HR-pQCT measures, which provides extensive information on bone characteristics but is not exhaustive in capturing all attributes that determine bone health, such as the manifestation of void spaces (a new HR-pQCT measure), or tissue-level organization of the extracellular matrix. Although phenotyping may not capture exhaustive information about bone health, the OR analysis reinforced the insight gained with bone phenotyping, revealing that BMD parameters (primarily Tt.BMD and Ct.BMD at the tibia), which were previously identified as imaging biomarkers of fracture for the low density phenotype, (22) were of highest importance in differentiating hip fractures from controls. These findings suggest that the combination of bone characteristics associated with the low density phenotype predispose an individual to higher risk of hip fracture, and thus stratifying the population based on bone phenotypes alongside using phenotype-specific imaging biomarkers could be incorporated into future fracture prediction models to improve patient-specific assessment of fracture risk.…”

“…The bone microarchitecture phenotypes of all participants were estimated using a clustering model we recently established with the Bone Microarchitecture International Consortium (BoMIC). (22) Fig. 1.…”

Bone fragility: conceptual framework, therapeutic implications, and COVID-19-related issues

“…Large case–control and cross-sectional observational studies documented that the micro-architecture of the bone significantly influenced the fracture risk. 85,86 In these studies, it was shown that among osteopenic women those with fragility fractures had a lower trabecular density and a more heterogeneous trabecular distribution compared with non-fractured women with the same BMD. Similarly, HR-pQCT measurements of the cortical parameters of the distal tibia, and in particular its porosity, can distinguish osteopenic women with fractured wrists from non-fractured women.…”

“…Large case-control and cross-sectional observational studies documented that the micro-architecture of the bone significantly influenced the fracture risk. 85,86 In these studies, it was shown that among osteopenic women those with fragility fractures had a lower trabecular density and a more heterogeneous trabecular distribution compared with non-fractured women with the same BMD.…”