## 2 OP-Derived Alterations of Bone Quality
### OP-Related Modifications of Bone Structure and Composition
#### 2.2.6 Alterations in Bone Composition  
Bone can be considered a composite material consisting in an organic matrix, mainly type I collagen, enriched by an inorganic phase, i.e., hydroxyapatite (HA). The organisation of these two materials in an ordered and hierarchical structure confers superior mechanical properties to bone compared to both components considered separately. In fact, thanks to the combination of the toughness of collagen with the stiffness of the mineral phase, bone shows, simultaneously, fracture resistance and load bearing ability [32]. Besides the previously described changes in the structural features, the modification of the properties of bone components (organic and inorganic phases) can lead to an alteration of the mechanical behaviour. In particular, OP and ageing are known to cause a decrease in the amount of collagen enzymatic crosslinking in favour of non-enzymatic crosslinking. The enzymatic crosslinks, mostly present in the healthy bone tissue in a head-to-tail fashion between the collagen fibrils, are responsible for improved mechanical properties (Figure 5). On the contrary, the non-enzymatic crosslinks are found in any positions along the collagen fibrils and the formed bonds involve the aldehyde group of a sugar molecule (usually glucose). The latter reaction leads to the formation of advanced glycation end-products (AGEs), which accumulate in the bone tissue, causing the stiffening of the organic matrix and the alteration of Ob cellular functions through the activation of the advanced glycation end-products receptor (RAGE) present on their membrane [2]. The RAGE activation is associated with the inhibition of Ob proliferation and differentiation and the increase in their apoptosis rate [33]. The main consequence of the AGE accumulation is thus the decrease in collagen matrix production and, consequently, bone formation. Furthermore, several studies have demonstrated an alteration of the collagen secondary structure in the presence of OP, leading to an increase in the random coil conformation combined with a  
Figure 5: Schematic representation of collagen enzymatic and non-enzymatic crosslinking. Legend: advanced glycation end-product (AGE). decrease in the \(\alpha\)-helix arrangement. The modification of collagen structure toward a less organised conformation can be considered one of the most important causes of the decrease in the mechanical properties of osteopororotic bone. In fact, while the \(\alpha\)-helix can support larger plastic deformations thanks to its mechanism of molecular unfolding based on the reversible breaking of its hydrogen bonds, the random coil conformation has inferior mechanical resistance [34]. In addition, as reported in the literature, the features of HA crystals are also strongly affected by the properties of the organic matrix. Therefore, alterations in the collagen conformation are expected to influence the main characteristics of the inorganic phase [35]. This assumption has been confirmed in a recent work by the authors, who observed greater HA crystal dimensions in samples of trabecular bone derived from osteopororotic humeral heads when compared to samples of healthy tissue [26]. Similarly, [PERSON] and collaborators [36] reported that OP iliac crest biopsies extracted from low-trauma fractured patients possessed HA with larger dimensions and higher crystallinity. However, these authors ascribed this superior HA size to the increased resorption rate typical of OP, leading to the preferential resorption of smaller HA crystals due to their higher solubility. In general, the increase in the mineral size proved to have significant consequences at the mechanical level, as larger HA crystals cannot properly align with the fibres of the collagen matrix, causing the decrease in the mechanical performances of the composite structure and, consequently, an increase in the fracture risk. Furthermore, in relation to the surface-dependent nature of the resorption mechanisms, osteopororotic bone matrix shows an increased apparent mineralisation degree.