Osteoblasts are specialised bone-forming cells that play many roles in bone remodelling. Osteoblasts develop from multipotent mesenchymal cells under the influence of regulatory transcription factors runt-related transcription factor 2 (RUNX2) and osterix, which also can grow into other cell lineages such as adipocytes, myocytes and chondrocytes [1]. Osteoblasts produce organic bone matrix (osteoid) and subsequently mineralise it during skeletal modelling and bone remodelling [2]. The differentiation and function of osteoblasts are regulated by several signalling pathways, one of which is the canonical Wingless and Int-1 (Wnt) signalling pathway. It is activated by the binding of Wnt1 and Wnt3a protein with Fizzled and low-density lipoprotein receptor-related protein 5/6. This leads to the inhibition of glycogen synthase kinase-3 beta, which phosphorylates cytoplasmic beta-catenin, causing its degradation. The accumulation of beta-catenin leads to its nuclear translocation, forming a complex with T-cell factor/lymphocyte enhancer factor 1 and cAMP response element-binding-binding protein and translation of genes responsible for osteoblast differentiation and bone formation. Sclerostin (SOST) and dickkopf-1 (DKK1) are inhibitors of the Wnt signalling pathway secreted by osteocytes [3,4]. Osteoblasts also secrete receptor activator of nuclear factor kappa-Β (RANK) ligand (RANKL), which binds with RANK on osteoclasts precursors and stimulates their differentiation. At the same time, osteoblasts also secrete osteoprotegerin (OPG), which is a decoy receptor for RANKL, to prevent the binding of RANKL with RANK and suppress osteoclast formation. These signalling pathways are influenced by various endogenous and exogenous factors, including inflammatory cytokines, oxidative stress and glucocorticoids (GCs) [5].

GCs are widely used as the treatment for inflammatory diseases and as chemotherapeutic agents. They are crucial for the induction of osteoblast differentiation and the formation of a mineralised extracellular matrix, as they influence the signals coordinating the differentiation of multipotent mesenchymal precursors cells into osteoblasts [6,7,8]. GCs have been reported to stimulate the expression of differentiation markers of both osteoblasts and adipocytes in in vitro studies [9]. However, the prolonged use of GCs leads to osteoporosis. High GC levels have been reported to suppress osteoblastic differentiation and function [10] and induce osteoblast apoptosis, leading to the suppression of bone formation [11]. The effects of high GC on osteoblast are mainly mediated by suppression of the Wnt signalling pathway [12].

The current prevention for GC-induced osteoporosis (GIO) is ensuring an adequate intake of vitamin D and calcium among patients on GCs. The assessment of fall risk in patients taking high doses of GCs should be performed. Lifestyle modifications similar to those adopted by patients with postmenopausal osteoporosis, which include weight-bearing exercise and the elimination of other risk factors, such as smoking or alcohol, should also be implemented by chronic GC users [13]. Patients using GCs at moderate or high osteoporosis risk are recommended to start with pharmacologic agents. The first-line agent is bisphosphonate therapy due to its efficacy, safety and low cost. Bisphosphonates, such as once-weekly oral alendronate or once-monthly oral ibandronate, have been the most studied agents for the prevention and treatment of GIO. Treatment with bisphosphonates has been proven to improve bone mineral density (BMD) or vertebral fracture risk and reduced the hip fracture risk [14]. If bisphosphonates are contraindicated, teriparatide is suggested as the second-line agent, which is followed by denosumab. Teriparatide, an anabolic agent, has also been shown to reduce fracture risk [15]. Denosumab, a receptor activator of nuclear factor kappa-Β (RANK) ligand (RANKL) inhibitor, has been reported to increase lumbar spine and hip BMD. However, the data regarding its efficacy and safety are still very limited [16]. The search for other alternative agents to preserve skeletal health in GC users is still ongoing.

Vitamin E encompasses both tocotrienol and tocopherol, both of which are potent antioxidants. They could be divided into alpha (α), beta (β), gamma (γ) and delta (δ) isomers. Tocotrienol and tocopherol share a similar structure, which consists of a chromanol ring and a long carbon tail. Tocotrienols have three double bonds, whereas tocopherols have only single bonds on the carbon tail (Figure 1) [17]. The main sources of tocotrienol include rice bran, palm, and annatto. Palm-derived tocotrienol (PTT) contains approximately 75% tocotrienol and 25% tocopherol, whereas annatto-derived tocotrienol (ATT) contains solely tocotrienol (99.9%) [18]. Previous studies have established the role of tocotrienol as an anti-oxidative, anti-inflammatory, anti-hyperlipidaemic and anti-hyperglycaemic agent [18,19,20,21].