Bone health: Quality versus quantity

Abstract

Healthy bone has the ability to resist deformation and fracture while adapting to applied mechanical loads. These properties of bone depend on characteristics of its extracellular matrix. This review focuses on the contribution of bone quality and quantity to bone health and highlights current and promising future clinical approaches to measure bone health in the pediatric population. Bone's unique material properties are derived from its highly organized, hierarchical composite structure, together with its modeling and remodeling dynamics and microdamage mechanisms. Pediatric bone diseases and disorders affect the biological processes that regulate its quality, negatively impacting the extracellular matrix and causing bone fragility. Laboratory bone analysis from human biopsies or animal models of human bone diseases allows high detail examination of the mechanisms contributing to bone fragility. Conversely, clinical measurements of bone fragility are difficult and limited due to the inaccessibility of the material. Because bone quality directly affects fracture resistance, both structure and composition should be used in fracture risk calculation rather than bone mineral density or bone quantity alone. Thus, to advance clinical evaluation of bone fragility, future studies are needed to determine which characteristics of bone quality can be applied to clinical practice to predict bone fragility. New and effective clinical tools are needed to predict fracture risk taking bone quality into consideration.

Key concepts: (1)Bone quality and bone quantity are both fundamental for resistance to deformity and fracture.(2)Pediatric bone diseases and disorders alter bone's composition and structure, compromising bone quality and increasing vulnerability to fracture.(3)Current clinical approaches to assess bone fragility and fracture risk rely mainly on bone quantity measurements from DEXA scans.(4)DEXA bone mineral density poorly correlates with bone's resistance to fracture, both in adults and children.(5)Future clinical approaches to measure bone health should account for bone quality in order to predict fracture risk.

Keywords: Bone; Fragility; Health; Quality; Quantity.

Figure 1

The hierarchical structure of bone from macro- to nanoscale. For specific operating length scales, there are reported the techniques that provide structural, compositional and mechanical properties of bone, either currently used in laboratories, clinically or that are promising for future clinical use. MRI femur image with permission from Carriero et al., 2009 . Fibril picture with permission from Klosowski et al., 2016 . AFM, atomic force microscopy; BSF-SEM, backscattered electron scanning electron microscopy; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; EDX, energy-dispersive x-ray analysis; FIB-SEM, focused ion beam SEM; FTIR, fourier transform infrared; HR-MRI, high-resolution magnetic resonance imaging; HR-pQCT, high-resolution peripheral quantitative CT; NMR, nuclear magnetic resonance imaging; pQCT, peripheral quantitative CT; qBEI, quantitative backscattered electron imaging; QCT, quantitative CT; SAXS, small-angle x-ray scattering; SHG, second harmonic generation microscopy; SORS, spatially offset Raman spectroscopy; UET MRI, ultrashort echo time MRI; WAXD, wide-angle x-ray diffraction; XRD, x-ray diffraction analysis.

Figure 2

(A) Stacks of mineral lamellae (thin polycrystalline plates, otherwise referred to as platelets) wrap around circular dark “holes” of collagen fibrils as seen in transmission electron microscopy (TEM) images of transverse cortical femur cross-section of a healthy 19-year-old male. Single mineral lamellae passing through collagen fibrils are marked with white arrows. (B) Schematic of mineral lamellae platelets (orange) surrounding fibrils (gray) as marked by the white arrow. Red arrow shows mineral lamellae sheets that are stacked between adjacent collagen fibrils. Adapted with permission from Grandfield et al., 2018 .

Figure 3

Crack profiles, schematic diagrams and environmental SEM fractography images of human cortical bone in the transverse and longitudinal orientations show that bone is more difficult to break than to split. In the transverse (‘breaking’) direction (A-C), the crack path is (A) tortuous with (B) many deflections at the cement lines and (C) through-thickness twists which lead to a very rough fracture surface. In the longitudinal (‘splitting’) direction (D-F), the crack trajectory is (D) straight and much smoother with (E) no visible deflections at the cement sheaths but instead following them leading to (F) a relatively flat fracture surface. Adapted with permission from Koester et al., 2008 . SEM, scanning electron microscopy.

Figure 4

CT reconstruction of a mouse tibia with a posterior midshaft insert scanned with synchrotron CT to show high details of the canal porosity modeled using finite element analysis. The bone blocks were loaded in compression (the volume of interest highlighted in yellow). The two finite element models of healthy and cortical bone blocks shows in green the locations of high risk of fracture initiation when samples are under loading , . These locations appear to be around the vascular canals discontinuities and at their intersections. Figure is adapted with permission from Muñoz et al., 2021 . CT, computed tomography.

Figure 5

(A) Histology sections of cortical and cancellous with normal osteoid formation and no mineralization defects. Scale bars, 600 µm. (B) Bone sections from vitamin D−deficient subjects reveal an altered bone structure with a thicker layer of unmineralized osteoid coating the surface of mineralized bone as marked by the yellow arrows. Black is mineralized bone tissue; red is bone marrow (von Kossa–stained). Scale bars, 600 µm. (C) 3D reconstruction of the crack path in healthy bone via high-resolution synchrotron radiation micro–computed tomography (SRμCT) exposes crack deflections by splitting along the cement lines surrounding the osteons as well as pronounced crack bridging. Scale bar, 200 µm. (D) In vitamin D–deficient bone, the crack path is much more flat and no crack bridging is visible. Scale bar, 200 µm. (E-F) Environmental SEM images of the crack propagation during fracture toughness for (E) healthy and (F) vitamin D–deficient bone. Uncracked ligament bridges, a major toughening mechanism in bone, are formed in (E) healthy bone but absent in (F) vitamin D–deficient bone. Adapted with permission from Busse et al., 2013 . SEM, scanning electron microscopy.

Figure 6

A compilation of current techniques used clinically for the assessment of bone quantity or bone quality parameters in children. (A) Pediatric whole body DEXA scan excluding the head. (B) DEXA image of pediatric lateral spine (C) MRI image of the lateral spine. Yellow arrow indicate vertebral fractures. (D) MRI scan of a whole pediatric femur. (E) MRI scan of the knees. Yellow arrows indicate bone fracture locations and white arrow indicates a growth plate region. (F) Distal femur MRI scan. (G) Proximal tibia MRI scan. (H) A 3D reconstruction of trabecular bone from a proximal tibia 3T MRI scan. (I) CT scout view of tibia. (J-K) pQCT performed in midshaft (J) and distal tibia (K) showing cortical bone and trabecular bone respectively. With pQCT, BMD and microstructural properties of cortical and trabecular bone separately can be determined. (L) 3D reconstruction of distal tibia using HR-pQCT whose structural parameters of both trabecular and cortical bones can be measured. (M) HR-pQCT can distinguish between cortical bone (light grey), intracortical porosity (red), and trabecular bone (dark gray) at each slice of the scan region in the distal tibia so that 3D visualization of the segmented cortical bone (white, transparent) and intracortical porosity (red) shown on the far right can be used for further analysis. Figures are adapted with permission from (A) Bachrach et al., 2007 , (B) Binkovitz et al., 2007 , (C) Mehany et al., 2021 , (D) Carriero et al., 2009 , (E) Li et al., 2020 , (F) Lerisson et al., 2019 , (G) Liu et al., 2018 , (H) Abdalrahaman et al., 2015 , (I-L) Adams et al., 2014 , (M) Burghardt et al., 2010 . BMD, bone mineral density; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; MRI, magnetic resonance imaging.

Figure 7

Future directions (A) Acoustic impedance image obtained from quantitative ultrasound (QUS) of an excised radius sample from an adult human. QUS can be used to quantitatively assess bone material properties as it can extract structural parameters of bone with high accuracy. M = medial, P = posterior, L = lateral, A = anterior. (B) Ultrashort echo time (UET) MRI-derived concentration maps for bound water and pore water from 2D scans of the tibia mid-diaphysis (top) and 3D scans of the distal radius (bottom). QUS and UET MRI images adapted with permission from Raum et al., 2005 , and Nyman et al., 2023 , respectively.