Osteoporosis is a systemic skeletal disease that is particularly prevalent among postmenopausal women and elderly people [1], [2]. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to increased bone fragility and a higher risk of fractures [3], [4]. Bone is a dynamic tissue that is constantly remodeled by bone cells to maintain a healthy skeleton [5]. Bone remodeling is essential for adult bone homeostasis. It is governed by two processes: osteoblast-mediated bone formation and osteoclast-mediated bone resorption [5].When osteoclastic resorption exceeds bone formation, the bone remodeling balance is disrupted, leading to bone loss and osteoporosis.

Currently, most drugs for treating osteoporosis are aimed at reducing bone loss by inhibiting bone resorption, but the use of anti-resorptive drugs alone does not restore lost bone structure. For example, the main effect of anti-resorptive drugs such as bisphosphonates is to inhibit the recruitment and activity of osteoclasts, thereby reversing the transient deficit caused by resorptive cavities, resulting in a slight increase in bone mineral density (BMD). The side effects of bisphosphonates, including severe gastrointestinal reactions and renal damage, severely limit their use [6], [7]. Anabolic drugs such as subcutaneous teriparatide reduce the risk of vertebral and non-vertebral fractures and stimulate bone formation. However, given its increased risk of osteosarcoma, teriparatide should not be used for more than 24 months [6], [7]. Estrogen, used for treating postmenopausal osteoporosis, can lead to endometrial hyperplasia and can increase the incidence of endometrial cancer and possibly breast cancer [8]. Denosumab is a fully human monoclonal antibody of the receptor activator of nuclear factor-κB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, reducing bone resorption and increasing BMD. However, denosumab can have some adverse effects on the body's immune system and the skin system such as dermatitis, rash, and eczema [9]. Therefore, novel drugs are being developed to regulate bone homeostasis to treat osteoporosis by simultaneously promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption [10], [11].

Many factors are involved in the regulation process of the bone remodeling cycle. The RANKL/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) signaling pathway plays a pivotal role in regulating bone homeostasis [12], [13], [14], [15]. RANKL functions as a key regulator in the differentiation of osteoclasts and boosts bone resorption by mature osteoclasts [16]. RANKL interacts with its receptor, RANK, resulting in the activation of intracellular signaling cascades in osteoclast precursor cells, which subsequently prompt the development of osteoclasts. OPG, a competitive bait receptor of RANKL, inhibits the formation and activity of osteoclasts by hindering the binding of RANKL to RANK [17]. It has been reported that activation of peroxisome proliferator-activated receptor delta (PPARδ) could increase the expression of osteogenic marker genes, including OPG expression [18] and runt-related transcription factor 2 (RUNX2), in osteoblasts [19], [20], thus promoting bone formation and preventing osteoporosis. Researchers have made efforts to develop novel PPARδ agonists such as GW501516 (Cardarine) [18], GW0742 [21], L165041 [22], [23], and 31a [24] to treat osteoporosis by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption. Although the clinical phase II trials of cardarine were halted in 2007 because of carcinogenicity during 2 years toxicity studies in rodents, lanifbranor, elafibranor, and seladelpar in clinical phase Ⅲ trials to treat metabolic diseases have more recently been found to not be problematic. Therefore, the previous studies have highlighted the potential of activating PPARδ and RANKL/RANK/OPG signaling pathway as therapeutic targets for treating osteoporosis.

The small molecule E09241 was previously identified as a novel OPG upregulator using a cell-based OPG upregulator high-throughput screening model [25]. E09241 exhibited good anti-osteoporotic effects both in vitro and in ovariectomized (OVX) rats. However, the oral bioavailability (F%) of E09241 in rats is only 0.89. According to the structure–activity relationship (SAR) analysis, E0924G (N-(4-methoxy-pyridine-2-yl)-5-methylfuran-2-formamide; Fig. 1A), a new derivative of E09241 (Fig. S3A), was synthesized [26] with better OPG upregulating activity and oral bioavailability in rats than E09241. In the present study, we demonstrated that E0924G could effectively promote osteogenesis and inhibit osteoclastogenesis through activating the PPARδ signaling pathway. Importantly, E0924G could significantly inhibit osteoporosis in both OVX-induced and aging-related osteoporotic mice. Therefore, this study provides a novel promising PPARδ agonist E0924G for the treatment of osteoporosis.