br Conclusion The following are the supplementary data relat

Conclusion The following are the supplementary data related to this article.
Authors Contributions
Declaration of Competing Interests
Funding This work was conducted on behalf of the Early Cancer Detection Consortium, within the programme of work for work packages 1 & 2. The Early Cancer Detection Consortium is funded by Cancer Research UK under grant number: C50028/A18554.
Introduction Maintenance of bone mass and quality across a lifetime is a direct function of bone remodeling. Three types of d-xylose are essential for this process and their role is coordinated in a highly sequenced manner. Osteoclasts remove old bone, osteoblasts form new bone, and osteocytes orchestrate this process through production of cytokines including receptor activator of nuclear factor kappa-B ligand (RANKL), sclerostin and dickkopf-related protein 1 (DKK1), which balance bone resorption and formation directly at the remodeling site. Animal studies have shed light on a close relationship between bone and energy metabolism, demonstrating that bone remodeling is closely linked to the osteoblastic response to insulin. Insulin induces osteoblastogenesis and RANKL production leading to high bone mass that is associated with increased bone turnover (Fulzele et al., 2010, Ferron et al., 2010). In contrast, in models of insulin resistance, induced by either high-fat diet feeding or genetic manipulation, bone turnover is decreased (Wei et al., 2014, Lecka-Czernik et al., 2015). Numerous epidemiologic studies have shown that skeletal fragility in individuals with Type 2 diabetes (T2D) is increased at least 2-fold despite normal or high bone mineral density (BMD) and greater body mass index (BMI), the factors which are considered protective for most fractures in non-diabetic adults. The lack of the association between higher BMD and lower incidence of fractures indicates that in T2D bone biomechanical properties are compromised. Indeed, diabetic bone, particularly in the appendicular skeleton, has a number of structural characteristics which predispose to fractures, including greater cortical porosity, smaller cortical area, decreased bone material strength, and high bone marrow adiposity (Lecka-Czernik and Rosen, 2015). Histomorphometric studies in humans indicate that bone turnover in older T2D patients is compromised, which may result in higher BMD but decreased bone quality (Krakauer et al., 1995). Furthermore, patients with T2D have decreased circulating levels of bone turnover markers, higher levels of sclerostin, a negative regulator of bone formation, and lower numbers of circulating osteoprogenitors. Moreover, highly reactive glucose metabolites (AGEs) are increased in T2D. These may impact bone ‘quality’ by slowing bone turnover and increasing bone stiffness and fragility through aberrant cross-links between collagen fibers (Lecka-Czernik and Rosen, 2015). Skeletal homeostasis is linked to insulin sensitivity through the nuclear receptor PPARγ. PPARγ regulates lineage commitment of mesenchymal cells toward osteoblasts and adipocytes, and recruitment of osteoclasts from a pool of hematopoietic cells. Activation of PPARγ with the full agonist rosiglitazone suppresses osteoblastogenesis and induces adipocyte differentiation. This results in decreased bone formation and accumulation of adipocytes in the marrow cavity (Lazarenko et al., 2007). PPARγ activation also supports osteoclast differentiation through direct and indirect mechanisms. In monocytes, rosiglitazone stimulates osteoclast differentiation through a PPARγ coactivator 1-beta (PGC-1β)-dependent mechanism, while in mesenchymal cells it increases support for osteoclastogenesis by stimulating RANKL production (Wei et al., 2010, Lazarenko et al., 2007). Thiazolidinediones (TZDs), full agonists of PPARγ, have consistently afforded robust efficacy for treatment of T2D. However, safety concerns including bone loss and increased fracture rates, particularly in postmenopausal women (Kahn et al., 2008), have restricted their use in T2D. Previously we demonstrated that the insulin sensitization provided by full and partial PPARγ agonists correlates with the ability of these drugs to block phosphorylation of PPARγ at serine 273 (pS273) (Choi et al., 2010), and that PPARγ anti-osteoblastic and insulin-sensitizing activity can be separated using selective modulators which block pS273 but have no activity toward phosphorylated serine 112 (pS112) (Kolli et al., 2014). Recently, we reported that the PPARγ inverse agonist SR2595 promoted osteoblastogenesis when tested in cultured human mesenchymal stem cells (MSCs) (Marciano et al., 2015). Synthetic optimization led to the identification of 2-phenoxy propanoic acids that exhibited superior pharmacokinetic properties over compounds in the biphenyl-2-carboxylic acid series (e.g., SR1664 and SR2595).