Osteoporosis, characterized by diminished bone mass and microstructural deterioration, poses a significant challenge to public health globally, acknowledged as the second most prevalent concern after cardiovascular disease by the World Health Organization (Consensus development conference, 1993, Kadam et al., 2018). A 2022 survey reveals a worldwide osteoporosis incidence of 19.7% and osteopenia at 40.4%, with developing nations exhibiting a higher prevalence (22.1%) compared to developed ones (14.5%) (Xiao et al., 2022). In 2005, the direct medical costs of osteoporosis in the United States were estimated to be between $13.7 billion and $20.3 billion. By 2025, it is projected that over three million osteoporotic fractures will occur annually, with an estimated cost of $25.3 billion (Rashki Kemmak et al., 2020). Due to increasing life expectancy and an aging population, the prevalence of osteoporosis is rising. Projections indicate that by 2050, the number of individuals with osteoporotic fractures will double, surpassing 120 million from the current 60 million (Watts et al., 2021).

The pathogenesis of osteoporosis involves an imbalance favoring bone resorption over formation, disrupting bone homeostasis and turnover (Langdahl, 2020). Bone homeostasis relies on the interplay between osteoclasts (OCs) responsible for bone resorption and osteoblasts (OBs) involved in bone formation. OCs derived from hematopoietic stem cells and OBs from mesenchymal stem cells are pivotal in bone homeostasis (Kenkre and Bassett, 2018). The coupling of bone resorption and formation is typically temporal and spatial, though the extent of coupling may vary (Hattner et al., 1965). When bone resorption and bone formation occur to an equal degree, bone density remains stable, establishing bone homeostasis.

Preclinical pharmacotherapies for osteoporosis include antiresorptive and anabolic drugs (Reid and Billington, 2022). Antiresorptive drugs impede osteoclast recruitment and activity, attenuating bone remodeling and modestly increasing bone mineral density (Compston et al., 2019). Despite progress in antiresorptive pharmacotherapies, concerns about adverse effects and insufficient evidence of long-term efficacy discourage many from adhering to these treatments. Additionally, in patients with very low initial bone mass, anti-resorption therapy may not effectively increase bone density to prevent fractures. (McConnell and Shieh, 2022).

Anabolic drugs stimulate bone formation, enhancing strength, density, and fracture resistance. (Bandeira and Lewiecki, 2022). Despite evidence indicating that anabolic drugs can yield a more substantial augmentation in bone mineral density compared to their anti-resorptive counterparts, it is noteworthy that the effects of these drugs are transient (Cheng et al., 2020). Current anabolic drugs act as parathyroid hormone type I (PTHI) receptor agonists (teriparatide, abaloparatide) or sclerostin-targeting antibodies (romosozumab) (Reid and Billington, 2022). Teriparatide and abaloparatide stimulate the PTHI receptor, while romosozumab, an anti-sclerostin monoclonal antibody, activates the WNT signaling pathway (Kendler et al., 2019). Table 1 illustrates commonly prescribed medications for osteoporosis treatment, their registered indications, associated adverse effects, and subsequent therapeutic recommendations.

The objective of this paper is to systematically review the emerging targets identified within key signaling pathways facilitating bone formation over the preceding five years, as well as to explore emerging cross-talk targets. This comprehensive study aims to enhance the strategic delineation of drug targets for bone-related conditions, thereby augmenting the potential for the development of pharmaceutical interventions.