Cortical Bone Mechanics and Composition: Effects of Age and Gender - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 55

than a few micrometers. The collagen crosslinks not only determine fibril
arrangement, but also affect the later mineralization process. The enzymatic
control of crosslinks occurs through the lysyl and hydroxylysyl residues at both C-
and N-terminal ends of collagen molecule [ 19 ]. In addition, pyrrole (another non-
reducible, enzymatic crosslink) is formed when hydroxylysyl aldehyde reacts with
non-hydroxylated lysine [ 20 ]. There are more divalent than trivalent crosslinks at
the beginning of collagen fibril formation but the discrepancy decreases as the
skeleton matures [ 21 ]. Collagen crosslinks may also form through age-related non-
enzymatic pathways, namely glycation. Briefly, glucoses react with certain amino
groups (e.g., lysine and arginine) of long-lived proteins, resulting in a rearrange-
ment of aldimine linkages into more stable keto-imine linkages and producing so
called Amadori products [ 22 ]. Further oxidative breakdown occurs over time
(tissue aging), thus causing reactions with other amino acid residues to form
advanced glycation end-products (AGEs) [ 23 ]. The collagen crosslinks induced by
AGEs have shown a significant correlation with changes in the toughness of bone
[ 24 , 25 ].
Numerous non-collagenous proteins found in bone may influence the recruit-
ment, attachment and differentiation of bone cells, and also the structural integrity
of the tissue [ 26 ]. The most abundant non-collagenous protein is osteocalcin,
which is produced by osteoblasts and believed to be related to bone calcification
[ 27 - 29 ]. As structural proteins, non-collagenous proteins may also contribute to
bone mechanical integrity including strength, hardness and flexibility [ 30 , 31 ].
2.1.3 Water
Water is distributed throughout bone in three forms: freely mobile in vascular-
lacunar-canalicular space, bound to the surface of the collagen and mineral phase,
and solid-like within the collagen and mineral molecules [ 32 - 34 ]. Water (H 2 O)
molecules are polar in nature, having a more negative charge on the oxygen side
and a more positive charge on the hydrogen side. Thus, H 2 O naturally associates
itself with mineral (PO 4 - or Ca 2+ ) and collagen (glycine, hydroxyproline, car-
boxyl, and hydroxylysine). Water associates with collagen at two levels: the
hydrogen bonds within the triple helix of collagen molecules (due to the hydroxyl
group of hydroxyproline) and the hydrogen bonds with the polar side chains of
collagen fibrils [ 35 , 36 ].
2.2 Microstructure of Cortical Bone
Osteons and interstitial tissues in human cortical bone are formed by lamellae [ 1 ].
A lamella is a sheet-like structure of *3-5 lm thick and resembles a fiber rein-
forced composite material, in which collagen fibrils act as the reinforcement phase
and mineral crystals as the matrix (Fig. 2 ). In general, collagen fibrils in lamellae