href="#ulink_e61ed381-5667-56e7-aa32-f752f7835f78">Figure 2.8 Diagrammatic representation of an isolated secondary osteon complex in longitudinal (left) and transverse sections, illustrating its branching course and different stages of development. The branch to the right illustrates a group of mobilized osteoclasts that are resorbing bone in a coordinated manner to form a tunnel. Osteoblasts follow secrete successive layers of osteoid on the walls of the tunnel, progressively filling it in to form a secondary osteon.
Source: Riggs and Evans [10]. Reproduced with permission of John Wiley & Sons.
Remodelled bone, containing a high proportion of secondary osteons, is typically weaker and less stiff than the primary tissue that it replaced. This begs the question of the functional (evolutionary) value of remodelling. For many years, the primary physiological role of remodelling was thought to relate to mineral homeostasis: resorption of bone provides a rapid supply of calcium ions from the skeleton to meet systemic metabolic requirements. More recently, focus has shifted to the role of remodelling in maintaining the structural integrity of bone as a load‐bearing tissue: it is a mechanism whereby damaged matrix can be removed and replaced with fresh, healthy tissue [12, 13]. A large proportion of researchers interested in the effects of loading on bone support the concept of microdamage as a common phenomenon. Minute cracks (micrometres in length) in bone matrix, regularly illustrated in publications and frequently associated with previous loading, are purported to represent localized damage as a consequence of loading [14, 15]. In addition, there is growing support for the hypothesis that damage to the matrix induces apoptosis of surrounding osteocytes, which in turn acts as a stimulus for localized recruitment and activation of osteoclasts [16]. This provides an elegant physiological mechanism whereby remodelling is specifically targeted to repair damage at varying scales of magnitude: bone that contains cracks is removed and replaced with healthy tissue. However, this hypothesis is not universally accepted and some argue that, in most cases, ‘microdamage’ is no more than an artefact created by the techniques used to study it and that there is no evidence that remodelling is directly coupled to damage [17]. Boyde has provided evidence from clinical material from a number of species, including the horse, to illustrate that when they do occur, microcracks can be effectively managed physiologically and mechanically through alternative means that include bonding cracks by filling them with mineral‐rich matrix and ‘bandaging’ trabeculae with surface new bone [17]. It is not inconceivable that both mechanisms of repair occur, the balance being determined by the loading environment.
Remodelling also provides a mechanism through which bone can be ‘fine‐tuned’ so that its microstructure, as well as macrostructure, is modified to best match prevailing mechanical demands: a form of ‘microadaptation’. For instance, primary bone in the caudal cortex of the equine radius, which contains predominantly longitudinally orientated collagen fibres, is largely remodelled within the first two to three years of life and replaced with secondary osteons containing predominantly transversely orientated fibres, which are more suited to resist the compressive strains that predominate at this location [18].
Ultrastructure
Bone matrix is a composite of organic and inorganic components. The primary structural protein, type I collagen, is common to many other connective tissues. Collagen makes a significant contribution to the toughness and strength of bone. The process of mineralization and complex interaction of mineral crystals and collagen within its matrix give bone its unique composite strength and stiffness.
Organic Component
Type I collagen is present in bone in the form of relatively long fibres. The manner in which these fibres are deposited, their orientation relative to each other and their pattern of mineralization determine the bone's microstructure and material properties. The relatively small amounts of type III and V collagens that are also present in the organic matrix modulate the structure of the fibrils formed by type I collagen.
Approximately 10% of osteoid consists of non‐collagenous proteins, including osteocalcin, osteonectin, osteopontin, fibronectin and bone sialoprotein II, BMPs, growth factors and an array of proteoglycans and glycosaminoglycans [19]. These molecules serve important functions in cell communication, which influence formation and resorption, in determining bonds within and between collagen fibres, which influence the spatial organization of the extracellular matrix, and in the mineralization process.
Type I collagen is formed through a combination of intra‐ and extracellular processes. Three polypeptide chains, each composed of around 1000 amino acids, are transcribed and bind intracellularly to form a triple helix with N‐(amino)‐ and C‐(carboxy)‐terminal non‐helical propeptides on the end of each procollagen chain. Procollagen is secreted via secretory granules into the extracellular space, where it undergoes further modification that includes cleavage of the N‐ and C‐terminal propeptides by procollagen peptidase to form tropocollagen. The resultant molecule is approximately 300 nm in length and is relatively rigid. Excision of the terminal propeptides allows the molecules to polymerize into fibrils, which are stabilized by covalent cross‐links between hydroxylysine and lysine residues. Chains of tropocollagen molecules pack together side by side to form fibrils. Adjacent molecules are precisely staggered by roughly quarter of their length (67 nm) relative to each other, and collinear molecules are separated by a gap of approximately 40 nm. Consequently, there is a periodic pattern with zones in the fibrils where there are gaps within the cross‐section and areas where there are not (Figure 2.9). This produces a striated effect that can be seen in electron micrographs of stained collagen fibrils. Each gap in the fibril is surrounded by around six tropocollagen molecules and forms a cavity approximately 1.4 nm wide and 40 nm long. Although it is easier to visualize the structure as linear arrays of tropocollagen, there is evidence that the molecules inside the fibril are actually twisted into a complex 3D structure [21].
Figure 2.9 Model of hierarchical structure of collagen fibrils. Three helical (two α1 and one α2) collagen molecules form a triple helix 300 nm long; these are assembled into a fibril containing a staggered array of helices with 40 nm gap between C and N termini of collinear helices. Gaps are aligned across the width of fibrils. Alongside each 40 nm wide ‘gap zone’ (white) is a zone 27 nm wide in which no gaps exist.
Source: Schwarcz et al. [20].
Licensed under CC BY 4.0.
There is evidence that difference in the quality of the collagenous matrix accounts for some of the variation in bone strength that is widely noted. Collagen molecules undergo a large number of complex post‐translational modifications, both within and outside the cell, which require action of several different enzymatic and non‐enzymatic processes. These are carefully orchestrated and when disrupted can have profound effects on the structural properties of bone. Furthermore, racemization and isomerization reactions are age‐related changes that occur spontaneously and result in conformational modifications within the molecules that alter their physical properties.
Inorganic Component
The principal inorganic components of bone are phosphate and calcium ions, which nucleate to form apatite crystals (nanocrystals), most commonly hydroxyapatite represented by the chemical formula Ca10(PO4)6(OH)2. Significant amounts of bicarbonate, sodium, potassium, citrate, magnesium, carbonate, fluorite, zinc, barium, and strontium are also present. Infrared spectrometry shows the presence of different apatite molecules and carbonate substituting for both PO4 and OH in many cases [22].
The precise form that the