Hyperlipidemia affects multiscale structure and strength of murine femur

Abstract

To improve bone strength prediction beyond limitations of assessment founded solely on the bone mineral component, we investigated the effect of hyperlipidemia, present in more than 40% of osteoporotic patients, on multiscale structure of murine bone. Our overarching purpose is to estimate bone strength accurately, to facilitate mitigating fracture morbidity and mortality in patients. Because i) orientation of collagen type I affects, independently of degree of mineralization, cortical bone’s micro-structural strength; and, ii) hyperlipidemia affects collagen orientation and µCT volumetric tissue mineral density (vTMD) in murine cortical bone, we have constructed the first multiscale finite element (mFE), mouse-specific femoral model to study the effect of collagen orientation and vTMD on strength in Ldlr−/−, a mouse model of hyperlipidemia, and its control wild type, on either high fat diet or normal diet. Each µCT scan-based mFE model included either element-specific elastic orthotropic properties calculated from collagen orientation and vTMD (collagen-density model) by experimentally validated formulation, or usual element-specific elastic isotropic material properties dependent on vTMD-only (density-only model). We found that collagen orientation, assessed by circularly polarized light and confocal microscopies, and vTMD, differed among groups; and that microindentation results strongly correlate with elastic modulus of collagen-density models (r2=0.85, p=10−5). Collagen-density models yielded 1) larger strains, and therefore lower strength, in simulations of 3-point bending and physiological loading; and 2) higher correlation between mFE-predicted strength and 3-point bending experimental strength, than density-only models. This novel method supports ongoing translational research to achieve the as yet elusive goal of accurate bone strength prediction.

PTH(1‐34) effects on repairing experimentally drilled holes in rat femur: novel aspects – qualitative vs. quantitative improvement of osteogenesis

“…Our results also are in accordance with the observations of Ascenzi et al (2012) showing that the treatment of osteoporotic women with PTH(1-34) was found to alter the heterogeneity of the orientation of collagen type I in secondary osteons in a beneficial rejuvenating way. Further, genetic and environmental changes may also impair PTH(1-34) effects on collagen type I orientation in murine models (Sage et al 2011;Pirih et al 2012;Ascenzi et al 2014), thus affecting bone strength.…”

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

“…In this approach a small reference probe penetrates the skin and rests on the surface of the bone, typically at the tibia mid‐diaphysis, while an indentation probe initiates a microcrack and subsequently propagates the crack through repeated indentations . This methodology has been shown to correlate with crack growth toughness, a known component of whole‐bone fragility that may reflect collagen apatite orientation . The first indentation was made at the midpoint between the patella and ankle joint, and seven indentations each 5 mm apart were obtained in a linear fashion both proximally and distally from the first indentation to yield a total of 15 sites/limb.…”

“…Because BMD only captures the loss of bone mass, methods using BMD alone to discriminate fracture risk do not fully account for the hierarchical factors that contribute to bone strength. Bone's ability to resist fracture is a culmination of multiple factors at varying length scales such as BMD, porosity, mineral properties, bone tissue material behavior, collagen‐mineral orientation and organization, and crosslinking profile . Thus, accurate assessment of bone fracture resistance requires the quantitative measurements of the contributions and interactions of these factors.…”

Site-Dependent Reference Point Microindentation Complements Clinical Measures for Improved Fracture Risk Assessment at the Human Femoral Neck

“…Finally, greater indentation depth may not universally indicate increased fracture risk and, despite relationships to microcracking and material properties, (5,(9)(10)(11)(12) the mechanisms involved are not fully elucidated. Consequently, a handful of murine models have implied that some conditions relating to elevated fracture risk (eg, hyperlipidemia, (30) osteogenesis imperfecta, (31) and chronic kidney disease (32) ) may show increased indentation distance, whereas others (eg, diabetes (33) ) may reduce indentation depth. The applicability of these diseases and other conditions linked to fracture risk (eg, rheumatoid arthritis, hyperparathyroidism, or hyperthyroidism) or being protective of osteoporosis (eg, osteoarthritis) and their translation to human bone is currently unclear and requires investigation for interpretation of RPI.…”