Osteoporosis (OP) is the most known and common bone disease. OP occurs worldwide in all populations, with a higher prevalence among postmenopausal women and aged people. A low bone mineral density, which increases fracture risk, is the hallmark of OP. OP is usually characterized by metabolic disorders of bone tissue, and usage of metabolomics to study pathophysiology has gained popularity
[36]. Animal models are commonly used to study the molecular mechanisms of OP in vivo. Ovariectomized (OVX) mice is an animal model of OP that mimics postmenopausal women with low BMD. Using this model, ovarian extraction results in a decrease in estrogen and progesterone, with consequences elevating the rate of bone loss
[36]. Lipid metabolisms, especially arachidonic acid metabolism, linoleic acid metabolism, and glycerophospholipid metabolism, are impacted by the decrease in estrogen
[37][38]. Polyunsaturated fatty acids (PUFAs) are well known for their influence on BMD
[39]. Two different families of PUFAs, n-3 PUFA, derived from α- linolenic acid, and n-6 PUFA, derived from linoleic acid, are frequently occurring in metabolomics studies with their opponent functions
[22]. In fact, elevated levels of arachidonic acid (AA), an n-6 PUFA, have been observed in oophorectomized rats and postmenopausal women with OP
[37][38][40]. Arachidonic acid can stimulate the expression of receptor activator of NF-kB ligand (RANKL), leading to a high plasma RANKL level
[22]. As the cytokine essential for osteoclast differentiation, a high concentration of RANKL can remarkably promote osteoclastogenesis, resulting in the loss of bone tissue
[41]. On the contrary, docosahexaenoic acid (DHA), an n-3 PUFA, suppresses osteoclast formation from human CD14-positive monocytes by the reduction of key signaling transduction pathways of kinases (JNK, ERK, and p38 MAPKs)
[22][42]. Thus, DHA inhibits osteoclastogenesis by blocking RANKL-induced activation from primary macrophages. At the same time, prostaglandin and leukotrienes, the downstream metabolic products of arachidonic acid, were also proved to impact Wnt signaling (osteoblastogenesis) and osteoclastic resorption, respectively
[43][44]. A high-level accumulation of other lipid metabolites has been found in postmenopausal women and oophorectomized rats as well
[45][46][47]. Lipid metabolisms not only impact osteoclastogenesis but also influence osteoblastogenesis. The increased lipid oxidation, followed by high oxidative stress, can activate peroxisome proliferator-activated receptor γ, consequently inhibiting osteoblastogenesis and promoting adipogenesis
[48]. PUFAs also play various roles in osteoblastogenesis. Fatty acids can activate peroxisome proliferator-activated receptor γ (PPARγ)
[49]. PPARγ plays a pivotal part in cell-fate determination, guiding the MSCs to differentiate into adipocytes
[50]. This could explain the bone loss of the patients with a high-fat diet. AA decreases the expression of osteogenic markers and the osteoprotegerin/RANKL ratio, causing the appearance of adipocytes in MSC differentiating during osteoblastogenesis
[51]. However, n-3 PUFA such as DHA and eicosapentaenoic acid do not have such an impact on MSCs
[51][52]. In an attempt to characterize the pathological mechanism of the postmenopausal OP, metabolomics was employed to analyze the OVX mice-related femur tissue. The obtained data indicated altered levels of 93 lipid metabolites such as fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and sterols, among which levels of many fatty acids were increased in the OVX model
[53]. To sum up, PUFAs play a critical role in osteoporosis by (1) promoting osteoclastogenesis through the expression of RANKL and (2) altering the differentiation of MSCs by inducing adipogenesis.
Ageing is another leading cause of low BMD. The fractures due to senile OP are highly life-threatening for the aged population, especially those over the age of 70
[1]. It is known that the functionality of osteoblasts, adipocytes, and osteoclasts changes with ageing. A higher adipogenesis level was estimated with the accumulation of bone marrow fat, not found in postmenopausal OP, which may be a critical cause for lower osteoclastogenic activity
[54][55]. An in vitro study verified that adipocytes, with their metabolites, inhibit osteoblast differentiation by downregulating histone acetylation
[56]. Again, lipid metabolism appears to have an essential role in the age-associated reduction of BMD, as demonstrated by a metabolomics study on senescent osteoblasts
[57]. The authors identified the downregulation of n-3 PUFAs in the fatty acid metabolism due to the severe oxidative stress damage. The decrease in n-3 PUFAs, as explained before, could result in an elevation of bone loss through osteoclasts.
At the clinical level, a plasma metabolites profiling conducted on 1552 individuals to identify BMD-associated metabolomic markers detected a higher level of creatine, dimethylglycine, and glycine
[58]. The authors suggested that these metabolites were causally negatively associated with BMD by altering bioenergetic processes as well as glycine and threonine metabolism pathways. As a major component of the protein collagen, hydroxyproline is also considered an OP-specific marker
[59]. Serum metabolite components of postmenopausal women with low BMD were investigated using CE-MS and showed that the level of hydroxyproline could be a marker of OP
[60]. Increased concentration of hydroxyproline indicates the degradation of collagen type I from the bone matrix and it was reduced after treatments
[61]. Similarly, other catabolites developed in bone from collagen, such as deoxypyridinoline (collagen stabilizer) and pyridinoline (cross-linking compound of collagen fibers), can also serve as the markers of OP
[59]. However, changes in their levels are the results rather than the causes of OP; therefore, they are more suitable for the development of diagnosis but not treatment.