## 2 OP-Derived Alterations of Bone Quality
### OP-Related Variations of Bone Remodelling Mechanism  
In physiological conditions, the remodelling mechanism (Figure 1) starts with the bone resorption phase, regulated by osteoclasts (Oc). In particular, Oc precursors are activated by an increased production of receptor activator of nuclear factor-kB (RANK) ligand (RANKL) by osteocytes and osteoblasts in response to tissue microdamage or an endocrine stimulus, such as an increased parathyroid hormone concentration associated with hypocalcaemia. The newly formed RANKL binds to its receptors on Oc precursor cells, stimulating their fusion in a syncytium and, consequently, the formation of a multinucleated mature Oc [14]. To promote the adhesion of these cells on the bone surface and the consequent implementation of their resorption action, the lining cells present at the bone surface form a raised canopy over the site to be resorbed [1]. After the adhesion, Oc reorganise their cytoskeleton in order to create a sealed zone where the bone matrix resorption can occur. In detail, in the region facing the bone surface to be resorbed, the osteoclastic membrane forms several folds, creating the so-called ruffled border which provides an enhanced secretory region for the dissolution of the underlying bone matrix [15]. In fact, Oc can dissolve the bone mineral phase by creating an acidic environment in the sealed zone, characterised by the coupled introduction of H\({}^{+}\) ions, by means of the H\({}^{+}\)-ATPase pump and Cl\({}^{-}\) ions, through their chloride channels, with the consequent formation of hydrochloric acid. Subsequently, the collagen-based matrix is degraded by metalloproteinases and proteases, such as cathepsin K, creating a lacuna on the bone surface. At the end of the resorption phase, Oc undergo a programmed death and the tissue present at the surface of the newly created lacuna is prepared to allow osteoblast (Ob) adhesion and the following bone formation phase [1]. In particular, Ob synthesise and deposit the osteoid, a matrix rich in type I collagen that will be successively mineralised through a series of phosphate and calcium ion exchanges with the extracellular environment. Sometimes, during the mineralisation process, some Ob can differentiate in osteocytes and can be entrapped in the osteoid. Once the mineralisation is complete, the Ob not embedded in the osteoid can have several fates: undergo apoptosis or become bone-lining cells [16; 17]. During the physiological remodelling process, the bone resorption rate equals the formation one, but, in the presence of OP, these two processes become unbalanced toward bone resorption, causing bone loss. The imbalance between Ob and Oc activities is the result of altered cell signalling mechanisms that derive from several factors, such as a reduced production of oestrogens in post-menopausal osteoporosis, by increased secretion of parathyroid hormone (PTH) and reactive oxygen species concentrations in age-related osteoporosis, along with excessive thinness, alcohol and corticosteroid use [1]. In physiological conditions, oestrogens limit the production of RANKL and induce the secretion of osteoprotegerin (OPG) from Ob, a soluble decoy receptor that binds to RANKL in an antagonistic way to the RANK receptor, therefore modulating the Oc signalling downstream of RANK. On the other hand, an oestrogen deficiency is associated with an increased osteoclast differentiation and resorption activity due to the higher secretion of RANKL from Ob and with impaired mechanosensing by osteocytes [18]. Oestrogen deficiency is the main condition leading to the onset and fast progression of osteoporosis in the trabecular compartment of women in their first 3-5 years of menopause. For this reason, the oestrogen-dependent bone loss is defined as postmenopausal osteoporosis and it can lead to a high number of fractures, especially in bones characterised by a higher trabecular fraction (e.g., vertebral bodies) [18].