Traditional Chinese medicine in osteoporosis: from pathogenesis to potential activity

Abstract

Osteoporosis characterized by decreased bone density and mass, is a systemic bone disease with the destruction of microstructure and increase in fragility. Osteoporosis is attributed to multiple causes, including aging, inflammation, diabetes mellitus, and other factors induced by the adverse effects of medications. Without treatment, osteoporosis will further progress and bring great trouble to human life. Due to the various causes, the treatment of osteoporosis is mainly aimed at improving bone metabolism, inhibiting bone resorption, and promoting bone formation. Although the currently approved drugs can reduce the risk of fragility fractures in individuals, a single drug has limitations in terms of safety and effectiveness. By contrast, traditional Chinese medicine (TCM), a characteristic discipline in China, including syndrome differentiation, Chinese medicine prescription, and active ingredients, shows unique advantages in the treatment of osteoporosis and has received attention all over the world. Therefore, this review summarized the pathogenic factors, pathogenesis, therapy limitations, and advantages of TCM, aiming at providing new ideas for the prevention and treatment of OP.

1 Introduction

Osteoporosis (OP), characterized by the decrease in bone mineral density (BMD) and disorders of the bone microstructure, is a chronic metabolic bone disease (Noh et al., 2020). OP is a result of the imbalance of bone homeostasis that is maintained by coordinated cycles of bone resorption and formation and can contribute to the increase in bone fragility as well as the risk of fractures (El-Gazzar and Högler, 2021; Zhang et al., 2023). These fragility fractures lead to a disproportionately high mortality rate and drastically reduce the quality of life, all of which make osteoporosis a growing and enormous threat to public health that affects 200 million people worldwide (Muñoz et al., 2020). From the perspective of etiology, osteoporosis can be divided into two types: primary and secondary (Eastell et al., 2016; Compston et al., 2019). Among them, primary osteoporosis is a result of aging, and its most common form is postmenopausal osteoporosis (PMOP), which is caused by the decrease in estrogen secretion after menopause (Compston et al., 2019), while secondary osteoporosis occurs when BMD is reduced by other factors such as drugs (Compston et al., 2019; S., 2011). Based on various induction factors of osteoporosis, a series of therapeutic drugs for osteoporosis have been developed for clinical practice, including estrogen, calcitonin, bisphosphonates, and teriparatide (Khosla and Hofbauer, 2017). Among these, estrogens, used in the prevention and therapy of osteoporosis, have certain side effects, including increased risk of cardiovascular events and breast cancer (Rossouw et al., 2002). Calcitonin was developed based on animal and human studies and is now rarely used for the treatment of osteoporosis due to its limited efficacy on osteoporosis and concerns that its long-term use may increase the risk of cancer (Chesnut et al., 2000). In addition, bisphosphonates are the most widely used drugs, but poor adherence is a major limiting factor for their treatment of osteoporosis, which is largely associated with gastrointestinal adverse events (Cramer et al., 2007). Moreover, treatment with high doses of teriparatide may increase the risk of developing osteosarcoma in growing rodents (Vahle et al., 2016). Therefore, it is urgent to seek some effective drugs with few side effects for the treatment of osteoporosis. Despite some progress in the treatment of osteoporosis, the side effects of these drugs are of concern (Khosla and Hofbauer, 2017). Therefore, exploring the pathogenesis of OP and finding its therapeutic drugs are crucial.

OP is closely associated with aging, endocrine diseases, chronic kidney diseases, gastrointestinal diseases, and so on (Lane, 2006). It is worth mentioning that osteoporosis is often accompanied by pain, spinal deformity, and fracture, even limitation of movement and disability, all of which seriously affect the quality of daily life (Tsai et al., 2019). Under the inducement of these factors, the formation of OP is associated with osteoblasts that maintain functional cells of bone formation and osteoclasts that participate in bone resorption. Osteoblasts are the main functional cells in bone for bone resorption. Osteoblasts play an important role in the synthesis, secretion, and mineralization of the bone matrix, while osteoclasts, known as bone-resorbing cells, are a component of bone tissue and mainly regulate the function of bone resorption (Chotiyarnwong and McCloskey, 2020). In OP, osteoclasts accomplish the transformation from bone resorption to bone formation by transmitting coupling signals to osteoblasts (Ikebuchi et al., 2018). During this process, the receptor activator of NF-κB (RANK)/receptor activator of the NF-κB ligand (RANKL)/osteoprotegerin (OPG) axis plays a key role (Zhao et al., 2020). Studies showed that the inhibition of RANKL can be a therapeutic strategy for excessive bone resorption, such as recombinant, which is still in the research stage due to its uncertain side effects. Therefore, it is urgent to seek some effective drugs with few side effects for the treatment of OP (He et al., 2019).

Traditional Chinese medicine (TCM), with few side effects, has unique advantages in the treatment of chronic disease. Studies showed that TCM has a long history in the prevention and treatment of OP (Zhang et al., 2016), such as Eucommiae Folium, Cornus officinalis, and Radix Angelicae sinensis. Moreover, TCM treatment based on syndrome differentiation is the accumulation of clinical practice gathered over centuries (Fu et al., 2021) and has specific advantages in the treatment of OP. In this review, we summarized the pathogenic factors, pathogenesis, therapy limitations, and advantages of TCM, aiming at providing new ideas for the prevention and treatment of OP.

2 Pathogenic factors of osteoporosis

2.1 Aging is a major cause of osteoporosis

The skeletal system grows rapidly, mainly from the postnatal period to puberty after birth and adolescence, reaches its peak at about 35 years of age (Wayne Sampson, 2002), and then, gradually decreases with age in both men and women (Yamakawa et al., 2020). Therefore, aging is a baseline risk factor in the development of OP and bone fracture, as well as a predictor of poor outcomes after fracture (VanderWalde and Hurria, 2011). In women, primary OP, also called postmenopausal OP, is mainly induced by menopause plus the cessation of ovarian function, specifically, a decline in postmenopausal ovarian endocrine function, resulting in the decrease in Es level and leading to greater bone resorption than bone formation (Wu et al., 2021). Of note, up to one-third of fragility fractures occur in older men and are usually accompanied by severe osteoporotic fractures, especially hip fractures. Due to these problems, OP in the elderly is an important threat to the life quality of individual patients and a huge burden to society (Kaufman, 2021). Therefore, exploring the pathogenesis of aging-related OP is crucial for the treatment of OP. Qadir et al. stated that due to aging, bone marrow stromal cells were more likely to differentiate into adipocytes rather than osteoblasts, which contributes to the decrease in bone formation, leading to the development of senile OP (Qadir et al., 2020). Moreover, with aging, the excessive accumulation of reactive oxygen species (ROS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and other cytokines in cells will affect the differentiation of osteoclasts and the formation of osteoblasts, leading to osteoporotic bone loss (Yu and Wang, 2016). Therefore, inflammation is another cause of osteoporosis.

2.2 Inflammation is involved in the development of osteoporosis

Innate immune cells are the major source of proinflammatory factors, such as IL-6 and TNF-α, and can immediately respond to various challenges in the body, which has been considered one of the main inducements of skeletal diseases (Hato and Dagher, 2015). In OP, osteoblasts undergo programmed necrosis and release NOD-like receptor protein 3 (NLRP3), thereby resulting in inflammatory responses. During these processes, IL-1β and IL-18 were cleaved by caspase-1 and turned into mature forms that could be released into the extracellular environment, which promoted excessive bone resorption (Vijayaraj et al., 2021). Moreover, other immune cells, such as DCs, macrophages, and monocytes, can also take part in osteoclast formation because they share a common developmental niche (Ponzetti and Rucci, 2019). Analogous eosinophils, mast cells, and neutrophils could also contribute to the development of OP (Yu et al., 2015; Ragipoglu et al., 2020). It can be seen that inflammation plays a critical role in OP due to its role in bone loss and osteoblast function (Amarasekara et al., 2015), which is characterized by BMD reduction and the production of cytokines in diseases such as periodontitis (Yu and Wang, 2022) and rheumatoid arthritis (RA) (Forsblad D'Elia et al., 2003).

2.3 OP is often a complication of diabetes mellitus

OP is also closely associated with diabetes mellitus (DM), which is characterized by polyphagia, polyuria, and hyperglycemia (Fang et al., 2021). DM is usually divided into two types: type 1 diabetes mellitus (T1DM) and type 2 diabetes. Among them, T1DM is known as insulin-dependent diabetes and can induce bone loss due to calcium and phosphorus imbalance (Lecka-Czernik, 2017), while type 2 diabetes is non-insulin-dependent diabetes mellitus that is considered a risk factor for OP (Barrett-Connor E, 1992), mainly due to that increased obesity in diabetic patients will affect the function of osteoblasts and osteoclasts (Rathinavelu et al., 2018). In addition, a variety of chronic complications related to diabetes mellitus, such as diabetic liver disease (fatty liver), diabetic nephropathy (Paschou et al., 2017), microvascular disease (Samakkarnthai et al., 2020), and diabetic neuropathy (Paschou et al., 2017), can also contribute to the development of OP.

2.4 Other factors contribute to osteoporosis

In addition, other factors, such as cerebral apoplexy, breast cancer (Sozel and Yilmaz, 2021), decompensated cirrhosis (Yang and Kim, 2021), gastrointestinal disease (Klaus et al., 2002), bowel disease, celiac disease, and hyperuricemia (Lee et al., 2021) and its induction divisors (smoking, alcohol, virus, etc.) (Lo et al., 2020), can also contribute to various degrees of osteoporosis. It is worth mentioning that the current treatment drugs for the above diseases include rosiglitazone, bisphosphonate (Sheu et al., 2022), unfractionated heparin, and low-molecular-weight heparin (Zhang B. et al., 2021). Proton pump inhibitors also play critical roles in the development of OP. In addition, a study showed that weight was also closely associated with the incidence of OP (Andreoli et al., 2011), which is due to that a high body mass index is related to high BMD and reduction of fracture risk in postmenopausal females (Tariq et al., 2017). Furthermore, other factors that affect body weight are also involved in the development of OP, such as nutrition and exercise. To be specific, malnutrition caused by low-protein diets can reduce the expression of insulin-like growth factor 1 (IGF-1), suppress the absorption of intestinal calcium and phosphorus, and inhibit bone calcification (Muñoz and Argente, 2002); exercise can regulate the biological activity of osteoblasts, increase mass accumulation of bone, and prolong bone turnover rate; furthermore, long-term plus regular weight-bearing exercise can increase BMD and reduce bone loss (Stein and Shane, 2003) (Figure 1).

FIGURE 1

3 Treatment of OP

Due to the variety of pathogenic factors of OPG, the application of TCM and Western medicine in the treatment of OP is also very different. For Western medicine, the treatment strategy for OP is mainly to prevent fractures, and reducing bone resorption or stimulating bone formation in this process are common means (Gennari et al., 2020). Based on this, the main therapeutic drugs for OP are anti-absorption drugs and anabolic agents (Li et al., 2021). Among them, bisphosphonates are the most widely used anti-bone resorption drugs, which can reduce bone turnover markers to a lower concentration before menopause and have achieved considerable results in reducing the fracture rate and the treatment of OP (Eastell and Szulc, 2017). However, the study revealed that the patients who were treated with bisphosphonates for 3 years or more were at an increased risk for osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFFs), but the absolute risks were low (Ayers et al., 2023). Moreover, poor adherence to bisphosphonate therapy is a major limiting factor in OP treatment, which is largely associated with gastrointestinal adverse events (Pagnotti et al., 2019). In addition, treatment using bisphosphonates can also cause other side effects, such as fever and myalgia, especially after the treatment is started (Ayers et al., 2023). It is worth noting that these side reactions caused by bisphosphonates can be alleviated by TCM, which is due to the characteristics of TCM with multiple approaches, multiple targets, and the four diagnostic methods of TCM, namely, observation, listening, asking, and cutting (Zhang et al., 2016).

Compared with the single treatment using bisphosphonates, TCM can develop personalized treatment plans according to the different physiques of patients. Specifically, for patients with poor spleen and stomach function, accompanied by general weakness, drugs with properties of strengthening the spleen and replenishing qi can be used; for patients with spleen and stomach disorders, accompanied by diarrhea and abdominal pain, drugs with an effect of strengthening the spleen and stopping diarrhea can be used; TCM can also improve blood circulation, promote the delivery of bone nutrients, and alleviate pain in patients with OP through methods such as acupuncture and moxibustion (Zhuo et al., 2022). Therefore, TCM has unique advantages in the treatment of OP, including alleviating symptoms, improving prognosis, and reducing fracture incidence.

However, the mechanism and pharmacodynamic components of TCM on OP treatment are still unclear, and the main limiting factors of its development are also problems that need to be solved urgently.

4 TCM in the treatment of OP based on syndrome differentiation

TCM has a long history of being used to prevent and treat osteoporosis. According to the pathology and clinical manifestations of OP in modern medicine, OP in TCM can be classified into the scope of “ostealgia (Gu bi)” and “atrophic debility of bones (Gu wei)” according to “Nei jing.” Among them, kidney deficiency, blood stasis, and qi and yin deficiency are the main pathogenesis, and the disease location is bone. The nature is “deficiency of kidney essence, spleen deficiency, and nourishment loss,” whose features are blood stasis block (Mohammad et al., 2018). For the treatment of this disease, some TCM preparations, acupoint application, acupuncture, massage, and other TCM therapies are also applied to improve BMD. According to the TCM theory, bone diseases are closely related to the health status of the kidney. Therefore, people with kidney qi deficiency and kidney yin deficiency are more prone to suffer from OP. Traditional treatments mainly use the method of tonifying the kidney and strengthening the bone based on syndrome differentiation. In addition to drug treatment, acupuncture and acupoint application can effectively prevent and treat the disease. The research of single Chinese medicine and effective components mainly involves Epimedii Folium, Eucommiae Cortex, and Salviae Miltiorrhizae Radix et Rhizoma (Figure 2).

FIGURE 2

4.1 Herbal extracts

Chinese herbal medicine formulations with the advantages of multiple components and targets have been widely considered by researchers in the treatment of chronic disease (Cui et al., 2010). Bellavia et al. revealed the potential effects of flavonoids in bone resorption and promoting bone formation via a review of literature records in the last 5 years (Bellavia et al., 2021). In addition, saponins, iridoid glycosides, and lignans in Chinese herbal medicine also showed certain therapeutic effects on OP, whose mechanism was associated with Wnt/β-catenin, BMP/Smad, and mitogen-activated protein kinase (MAPK) pathways, RANKL/OPG signaling, and others (Zhang et al., 2016). For example, the dry leaf of Epimedium brevicornu Maxim. has a long history in the treatment of bone diseases in China due to its effect of tonifying kidney yang and strengthening muscles and bones. According to modern research, total flavonoids of Epimedium brevicornu Maxim. can treat osteoporotic distal radius fractures (Xue et al., 2016). Icariin (ICA), as the main active flavonoid glycoside in Epimedium brevicornu Maxim., has the effect of enhancing osteogenic activity through the regulation of the JNK/c-Jun signaling pathway, Wnt/β-catenin pathway, and Notch signaling pathway (Huang et al., 2020; Xu et al., 2019; Yu et al., 2020). In addition, Eucommiae Folium extract can promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by regulating the Wnt/β-catenin signaling pathway and decreasing RANKL-induced bone resorption-related genes, such as TRAP (Cheng et al., 2019). The aqueous extract of Eucommiae Folium after salt roasting can promote the proliferation and differentiation of MC3T3-E1 cells, elevate the OPG level, and inhibit the secretion and expression of RANKL protein by regulating ERK, NF-κB, AKT pathways (Guan et al., 2021). Furthermore, Salviae Miltiorrhizae Radix et Rhizoma, also known as Danshen in Chinese, has a long history of being used to treat bone disorders (Guo et al., 2014). With the development of modern analytical techniques, many compounds have been isolated and identified from Danshen. Tanshinol is one of these compounds, and importantly, it can also play a role in reducing bone formation disorders through KLF15/PPARγ2 signaling (Yang Y.-j. et al., 2018). In addition, tanshinones are thought to inhibit osteoclast differentiation and may be a candidate for the treatment of OP (Lee et al., 2005). Moreover, Danshen has been reported to combine with Puerariae Lobatae Radix to alleviate OP through autophagy and oxidative stress-mediated osteoclast differentiation (Qin et al., 2021). Drynariae Rhizoma is introduced to improve glucocorticoid-induced OP by regulating the activity of osteoblasts and osteoclasts. Naringin has been identified as an effective anti-OP component of Drynariae Rhizoma (Peng C.-H. et al., 2022). Like naringin, the other five flavonoids, namely, aglycones, kurarinone, kushennol F, xanthogalenol, and sophoraflavanone G, have a potential protective effect against ovariectomized-induced osteoporosis, which may be related to the activation of endoplasmic reticulum signaling pathways (Wang et al., 2011). Achyranthis Bidentatae Radix is a TCM used to treat OP (Zhang M. et al., 2018). Polysaccharides have been the most studied in all components of Achyranthis Bidentatae Radix, and it has been reported that these polysaccharides can promote bone formation and, thus, play a potential role in anti-OP therapy (Zhang S. et al., 2018). In addition, Dipsaci Radix is a typical Chinese medicine used to treat OP by regulating immune-related pathways. In this study, ursolic acid and beta-sitosterol were shown to be the effective compounds (Zhang W. et al., 2019). Sweroside is the major active iridoid glycoside isolated from Dipsaci Radix. It has been reported that sweroside can exert beneficial effects on anti-OP by interacting with the membrane estrogen receptor-α and GPR30 to activate the p38 signaling pathway (Wu et al., 2020). As a triterpenoid saponin, asperosaponin VI exhibits anti-osteoclastogenic activity by inhibiting RANKL-induced osteoclast differentiation and function (Liu et al., 2019). Some compounds in Psoraleae Fructus display anti-OP activity by activating the ER-Wnt-β-catenin signaling pathway, among which isoflavones have the strongest activity (Cai et al., 2021). As a representative flavonoid, corylifol A can reduce ROS production through the activation of Nrf2, leading to the inhibition of osteoclast production and activation (Li et al., 2024). Similarly, corylin is also a flavonoid in Psoraleae Fructus, which increases the expression of osteogenic markers such as Runt-related transcription factor 2 (Runx2), osterix, type I collagen (Col1), and alkaline phosphatase (ALP), thus targeting the treatment of osteoblast-mediated OP (Yu TX. Y. et al., 2020). Cistanches Herba is an edible Chinese medicine that inhibits the RANKL/Rank-induced activation of downstream NF-κB and PI3K/AKT pathways and blocks the activity of the key osteoclastogenic proteins NFAT2 and c-Fos (Zhang B. et al., 2019). Cistanches Herba polysaccharide reduces RANKL-mediated ROS production in osteoclasts, which impairs osteoclastogenesis and bone resorption (Song et al., 2018). Cistanoside A is a phenylethanol glycoside compound isolated from Cistanches Herba, which has the potential to treat OP by downregulating TRAF6 (Xu et al., 2017). In summary, numerous TCM formulations and compounds derived from them have showed potential therapeutic effects in the prevention and treatment of OP (Table 1).

4.2 Traditional Chinese medicine formula

“Shen nong ben cao jing” recorded that medicine should be in harmony with the king and minister (Jun–chen–zuo–shi). Due to this theory, TCM preparations consisting of multiple herbs have attracted increasing international attention because of their characteristics and curative effects. Among these, OP Liuwei Dihuang pill (LWD), which mainly consists of Rehmannia glutinosa Libosch, Paeonia suffruticosa Andr, Dioscorea opposita Thunb., Poria cocos (Schw.) Wolf, Alisma orientale (Sam.) Juz., and Cornus officinalis Sieb. et Zucc., was used in the treatment of OP, showing that miR-574 plays critical roles in osteoporosis, and kaempferol and quercetin actives may be the ingredients of LWD targeting MAPK1 to mediate MiR-574, thereby regulating the bone microenvironment and improving OP (Liu et al., 2022). Additionally, Shuai Bo et al. found that Qing’e Pill (QEP), consisting of Eucommia ulmoides Oliv., Psoralea corylifolia L., Juglans regia L., and Allium sativum L, could improve the microstructure of cancellous bone in ovariectomized mice by increasing the expression of β-catenin. Further study revealed that QEP could prevent osteoblast ferroptosis and increase osteogenesis (Shuai et al., 2019; Hao et al., 2022). Yangyang et al. confirmed that Yishen Bugu Ye (YSBGY) showed potential anti-osteoporotic effects through the modulation of the osteoblast/osteoclast balance and serum concentrations of inflammatory factors (Li et al., 2020). As a famous Chinese medicine preparation, Erzhi Wan (EZW) has a favorable anti-OP potential, mainly through inhibiting osteoclast bone absorption (Zhang et al., 2008). Zuogui Pill (ZGP) is a classic kidney-tonifying drug that can promote the osteogenic differentiation of bone marrow mesenchymal stem cells, which provides a scientific basis for its effective treatment of OP (Yang et al., 2018a). In addition, details of other traditional Chinese medicine formulas used in OP therapy are shown in Table 2.

5 Therapeutic mechanism of TCM on anti-osteoporosis

Although TCM has certain advantages in the treatment of osteoporosis, its therapeutic mechanism has not been fully elucidated, which is undoubtedly a huge challenge for researchers. In this study, we summarize and generalize the signaling pathways involved in OP, which may provide a certain theoretical basis for further elucidation of OP treatment with TCM. According to previous studies, Wnt/β-catenin, BMP-SMAD, MAPK, and RANK/NF-κB/OPG play a key role in OP (Wang et al., 2022; Wei et al., 2022) (Table3).

5.1 Wnt/β-catenin signaling pathway

Wnt signaling is a critical signal transduction pathway and mainly regulates embryonic development and tissue regeneration (Nusse and Clevers, 2017). As a kind of secretory glycoprotein, Wnt-regulating signaling was associated with multiple genes and various receptors, all of which could regulate canonical β-catenin-dependent and non-canonical β-catenin-independent pathways (Wang et al., 2019). Among them, the canonical Wnt signaling pathway could be regulated at many levels, including negative regulation. During this process, DKK1, a negative regulator, can bind to the LRP receptor, thereby suppressing the Wnt signaling pathway. When cells were not exposed to Wnt signaling, major signaling components, such as β-catenin and receptors, were in a closed state (Nusse, 2012). When it was at an active state, Wnt signaling could activate the intracellular protein DVL and inhibit the degradation activity of the β-catenin degradation complex formed by GSK-3β. In non-canonical β-catenin-independent signaling pathways, Wnt could induce cytoskeletal re-arrangement through the activation of GTPase, including Rho and Rac (van Amerongen et al., 2008).

Wnt/β-catenin could regulate bone metabolism by controlling the differentiation and function of mesenchymal stem cells (Zhu et al., 2019), adipose-derived stem cells (Shao et al., 2017), osteoblasts, and osteoclasts. The specific mechanism of action was as follows: Runx2, a specific transcription factor, plays a vital role in osteoblast differentiation and chondrocyte maturation (Komori, 2018). Cai et al. found that Wnt/β-catenin could directly regulate the expression of Runx2, thereby promoting vascular smooth muscle cells to transdifferentiation (Cai et al., 2016). In addition, Runx2 could cooperate with the forkhead box protein O3 transcription factor (FoxO3) that belongs to a subclass of forkhead transcription factors (Yuan et al., 2022). Moreover, Runx2 could cross-conduce with the Wnt signal, all of which were involved in the elimination of superoxide, thereby remodeling normal bone. In addition, miR-29a, a downstream factor of Wnt/β-catenin, could ameliorate age-induced osteoblast loss and OP by targeting Dnmt3b-mediated FoxO3 methylation, upregulating the expressions of antioxidant proteins and DNA methylation (Lian et al., 2021). Similarly, FoxO1 was also involved in the degradation of spontaneous cartilage and the formation of osteoarthritis. Matsuzaki et al. found that the ectopic expression of FoxO1 could synergize with the stimulation of transforming growth factor-β (TGF-β), leading to the differentiation of macrophages along with the release of IL-1β (Matsuzaki et al., 2018). In addition, TGF-βin osteoclast can induce the secretion of Wnt1, thereby combining bone resorption with bone formation (Weivoda et al., 2016). Moreover, the paracrine secretion of DKK1 (a Wnt inhibitor) induced by TGF-β is essential for osteoclastogenesis. Subsequently, Esposito found that TGF-β could induce the biomolecular aggregation of DACT1, which suppresses the Wnt signaling pathway and promotes bone metastasis (Esposito et al., 2021). Furthermore, Zhang et al. found that insulin inhibited autophagy and promoted premature aging through the TGF-β pathway, thus inhibiting BMSC osteogenesis. (Zhang et al., 2020). IGF could directly affect the differentiation of osteoblasts and enhance the function of mature osteoblasts, thereby promoting the formation of bone collagen and bone matrix (Xian et al., 2012). During this process, IGF-1 antagonized the Wnt/β-catenin signaling pathway by catalyzing the transcription of Axin2 and stabilizing the Axin1 protein. Meanwhile, the IGF-1 receptor can phosphorylate and degrade β-catenin, activate GSK-3β, and degrade insulin receptor substrate 1, all of which contribute to glucose and bone metabolism (E., 2018; Lindsey and Mohan, 2016; Zhang B. et al., 2019) (Figure 3). Additionally, the physiological dose of glucocorticoid can stimulate the differentiation of osteoblasts, thereby inhibiting bone formation through BMPs and other classical pathways (Compston, 2018).

FIGURE 3

5.2 TGF-β/BMP signaling pathway

Similar to the role of the Wnt/β-catenin signaling pathway, the TGF-β/BMP signaling pathway also plays a crucial regulatory role in the body, especially in the homeostasis of postnatal bone and differentiation of mesenchymal cells into osteoblasts (Chen G. et al., 2012; Wu et al., 2016), which may be due to DNA synthesis and cell replication. Specifically, there are three main forms of TGF-β in mammals: TGF-β1, TGF-β2, and TGF-β3 (Derynck and Erine, 2019), all of which could be activated and bind to TGF-β I receptors (TβRI) and two type II receptors (TβRII). Subsequently, TGF-β could transmit its signals to the Smad signaling pathway both in canonical-dependent and non-canonical-independent forms (Wu et al., 2016). For example, Smad2/3 could be activated by TGF-β, regulating the TGF-β-induced differentiation of chondrocyte and osteoblast through the Smad pathway. Moreover, Smad2/3 also recruited HDACs 4/5 and inhibited Runx2 function, all of which could participate in osteoblast differentiation (Kang et al., 2005), while in the Smad-independent pathway, TGF-β accelerates the proliferation and differentiation of osteoblast by regulating MAPK and Smad2/3 signaling pathways (Matsunobu et al., 2009). In addition, MAPK could positively regulate the function of Runx2, contributing to the differentiation of MSCs (Li et al., 2009).

In bone, BMP signals were also mediated by their receptors and formed complex bodies with them, further regulating the transcription of related genes involved in the differentiation of osteoblast and formation of bone (Wu et al., 2016). Among BMPs, BMP-2 could promote osteogenesis by regulating the expression of Runx2, ALP, and integrin-binding sialoprotein and activate osteoclast through the upregulation of TNF-α and NF-κB ligands (Ingwersen et al., 2022). Moreover, BMP/Smad1 could regulate the activity of atonal homolog 8 and inhibit the expression ratio of RANKL/OPG, thereby regulating the osteoclast number negatively and promoting bone resorption and loss (Yahiro et al., 2020) (Figure 4).

FIGURE 4

5.3 MAPK signaling pathway

MAPK is a class of conserved serine/threonine protein kinases and plays a role in cell proliferation, differentiation, and apoptosis (Zhang W, 2003). In mammals, three families of MAPK have been identified: JNK kinase, extracellular signal-regulated protein kinase (ERK), and p38 MAPK. Among these, the MAPK-mediated pathway is within an enzymatic cascade, which comprises at least three continuously activated enzymes (Widmann et al., 1999).

In OP, the MAPK pathway was related to the osteoclastogenesis as well as bone resorption, which was due to its role in the phosphorylation of ERK1/2 that could, in sequence, regulate the transcription and expression of the main osteoclast transcription factor, such as a recombinant nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) (Long et al., 2022). In addition, Ren et al. found that the expression of MAPK/p38MAPK could be increased by RUNX2, along with the increases of ALP, OCN, and OSX, all of which were associated with the osteoblast differentiation and downregulation of autophagy genes, including Beclin-1, ATG1, and p62 (Ren et al., 2022). In addition, the MAPK signaling pathway also takes part in high-glucose-caused osteoclast differentiation, which was associated with Dickkopf-1 and tartrate-resistant acid phosphatase 5B (TRAP5b), c-terminal telopeptides of type 1 (CTX1), cathepsin K, and Nqo1 (Ren et al., 2022). Moreover, downstream of MAPK, pathways such as P38, ERK, and JNK can be activated by AGEs and contribute to the release of TNF-α, IL-1β, and IL-6 (Wang et al., 2020) (Figure 5).

FIGURE 5

5.4 RANKL/NF-κB/OPG signaling pathway

The RANKL/NF-kB/OPG pathway, mainly involved in osteoclast formation (Whyte, 2006), is a process initiated by the binding of RANKL to RANK (Yang W. et al., 2021). RNAKL, known as TNF superfamily member 11 (TNFSF11), mainly regulates the differentiation of osteoclasts and the formation of OP (Luo et al., 2016). During osteoclast differentiation, leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) (a receptor of RANKL) could competitively bind RANKL to RANK and block classical RANK way, along with activations of the glycogen synthase kinase-3 (GSK3)-β, α subunit of inhibitory G protein (Gαq), and NFATC1 (Luo et al., 2016). In addition, TNF could regulate the activation of the NF-κB pathway through the expressions of FoxO1, Sod2, and catalase and accumulation of ROS (Liao et al., 2016); under normal conditions, NF-κB can form a dimer with IκBα in the cytoplasm; upon stimulation, the dimer was dissociated, along with NF-κB entering the nucleus and IκBα phosphorylation, resulting in the synthesis and release of inflammatory factors, all of which promoted osteoclast formation, osteoclast differentiation, and osteolysis (Zou et al., 2020). Additionally, long-term use or overdose of glucocorticoids contribute to the formation of osteoclast and expressions of RANKL and macrophage colony-stimulating factor (MCSF), inhibiting the level of serum OPG and activating osteoclasts (Chotiyarnwong and McCloskey, 2020). Moreover, estrogen could promote the accumulation of superoxide involved in bone remodeling and promote osteogenic differentiation. In postmenopausal osteoporosis, deficiency of estrogen led to unbalanced bone homeostasis, a decrease in OPG expression, and increases in RANKL and M-CSF (Karim et al., 2021) (Figure 6).

FIGURE 6

5.5 Other pathways related to the pathogenesis of osteoporosis

In addition to the above signal paths, relevant research showed that PI3K/AKT/mTOR, ERα-AMPK, GH/IGF (Lindsey and Mohan, 2016), and calcium signaling pathways also participate in OP pathogenesis. The osteoblast-related gene expressions, including Alp, cbfa1, Col1a1, and osteocalcin (OCN), can be upregulated by the phosphorylation of PI3K and Akt (Xie et al., 2022). Low levels of glucocorticoids can promote the apoptosis and autophagy of OB through inhibiting the mammalian target of rapamycin (mTOR) pathway (Chotiyarnwong and McCloskey, 2020). ER, including ER-α and ER-β, can directly increase the activity of LKBl, which is the most important upstream protein kinase of AMPK. In addition, the mutual promotion of AMPK and Sirt1 can also modulate the autophagy or apoptosis of osteoblasts, suggesting that the ERα-AMPK-Sirt1 signaling pathway may play an important role in OP (Xiao et al., 2022). Furthermore, growth hormone facilitated longitudinal bone growth primarily via the production of hepatic IGF-I, and the growth hormone receptor was activated and then induced the phosphorylation of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway (Lindsey and Mohan, 2016). Of note, the JAK-STAT pathway can disrupt normal bone remodeling by targeting osteoclasts and osteoblasts in the joint and in the joint exoskeleton (Damerau et al., 2020).

6 Clinical or preclinical studies of TCM in OP treatment

TCM has unique advantages in the treatment of osteoporosis, which mainly lies in the overall regulation of the balance of yin and yang of the human body (Hu et al., 2019), fundamentally improving bone metabolism and repair, and preventing and treating the occurrence and development of OP from various aspects (Qian et al., 2021). As we mentioned, TCM has made certain progress in the treatment of OP, which is not only reflected in preclinical research but has also achieved good results in clinical research. At present, the National Medical Products Administration has approved many Chinese patent drugs for the treatment of OP in China. Among them, the Xianling Gubao capsule (tablet) (Xiao et al., 2022), Gushukang capsule (granule) (Li et al., 2022), Jintiange capsule (Liang et al., 2022), and Qianggu capsule (Huang et al., 2022) are more widely used. In addition, the characteristic therapy of OP in Chinese medicine includes acupuncture, moxibustion, treatment by way of pasting on acupuncture points, massage, and so on (Peng Z. et al., 2022). To sum up, there are various methods for the treatment of OP by TCM, but it is worth noting that appropriate therapies should be selected according to different syndrome types under the guidance of the TCM theory.

7 Conclusion and future prospects

The pathogenic factors and related pathways in OP reported in this review provide a basis for better elucidating the pathogenesis of osteoporosis. TCM, including syndrome differentiation, single herbs, and prescription, shows a unique advantage in the treatment of osteoporosis, which undoubtedly points out the direction for researchers. However, besides the abovementioned diseases related to osteoporosis, whether there are other diseases that can affect OP or not needs to be studied.

Although TCM has certain advantages in the treatment of osteoporosis, the material basis is unclear, which brings challenges to clinical application. Compared with the single target of chemical drugs, the multi-pathway and multi-target characteristics of TCM are not only advantages but also disadvantages, which is also a major challenge for the internationalization of TCM. This review summarizes the potential of TCM in the treatment of osteoporosis, but its specific mechanism is worth further research. The solution to this problem will be beneficial to the long-term development of TCM in the treatment of osteoporosis.

References

• 1

  AmarasekaraD. S.YuJ.RhoJ. (2015). Bone loss triggered by the cytokine network in inflammatory autoimmune diseases. J. Immunol. Res.2015, 832127. 10.1155/2015/832127

  • CrossRef
  • Google Scholar

• 2

  AnJ.YangH.ZhangQ.LiuC.ZhaoJ.ZhangL.et al (2016). Natural products for treatment of osteoporosis: the effects and mechanisms on promoting osteoblast-mediated bone formation. Life Sci.147, 46–58. 10.1016/j.lfs.2016.01.024

  • CrossRef
  • Google Scholar

• 3

  AndreoliA.BazzocchiA.CeliM.LauroD.SorgeR.TarantinoU.et al (2011). Relationship between body composition, body mass index and bone mineral density in a large population of normal, osteopenic and osteoporotic women. Radiol. Med.116, 1115–1123. 10.1007/s11547-011-0689-2

  • CrossRef
  • Google Scholar

• 4

  AyersC.KansagaraD.LazurB.FuR.KwonA.HarrodC. (2023). Effectiveness and safety of treatments to prevent fractures in people with low bone mass or primary osteoporosis: a living systematic review and network meta-analysis for the American college of physicians. Ann. Intern Med.176, 182–195. 10.7326/M22-0684

  • CrossRef
  • Google Scholar

• 5

  Barrett-ConnorE. H. T.HolbrookT. L. (1992). Sex differences in osteoporosis in older adults with non-insulin-dependent diabetes mellitus. JAMA268, 3333–3337. 10.1001/jama.1992.03490230063029

  • CrossRef
  • Google Scholar

• 6

  BellaviaD.DimarcoE.CostaV.CarinaV.De LucaA.RaimondiL.et al (2021). Flavonoids in bone erosive diseases: perspectives in osteoporosis treatment. Trends Endocrinol. Metab.32, 76–94. 10.1016/j.tem.2020.11.007

  • CrossRef
  • Google Scholar

• 7

  CaiT.SunD.DuanY.WenP.DaiC.YangJ.et al (2016). WNT/β-catenin signaling promotes VSMCs to osteogenic transdifferentiation and calcification through directly modulating Runx2 gene expression. Exp. Cell Res.345, 206–217. 10.1016/j.yexcr.2016.06.007

  • CrossRef
  • Google Scholar

• 8

  CaiX.-y.ZhangZ.-j.XiongJ.-l.YangM.WangZ.-t. (2021). Experimental and molecular docking studies of estrogen-like and anti-osteoporosis activity of compounds in Fructus Psoraleae. J. Ethnopharmacol.276, 114044. 10.1016/j.jep.2021.114044

  • CrossRef
  • Google Scholar

• 9

  CaoH. J.LiC. R.WangL. Y.ZiadlouR.GradS.ZhangY.et al (2019). Effect and mechanism of psoralidin on promoting osteogenesis and inhibiting adipogenesis. Phytomedicine61, 152860. 10.1016/j.phymed.2019.152860

  • CrossRef
  • Google Scholar

• 10

  ChenG.DengC.LiY. P. (2012a). TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int. J. Biol. Sci.8, 272–288. 10.7150/ijbs.2929

  • CrossRef
  • Google Scholar

• 11

  ChenG.WangC.WangJ.YinS.GaoH.XiangL. U.et al (2016). Antiosteoporotic effect of icariin in ovariectomized rats is mediated via the Wnt/β-catenin pathway. Exp. Ther. Med.12, 279–287. 10.3892/etm.2016.3333

  • CrossRef
  • Google Scholar

• 12

  ChenH.WuM.KuboK. (2012b). Combined treatment with a traditional Chinese medicine, Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) and alendronate improves bone microstructure in ovariectomized rats. J. Ethnopharmacol.142, 80–85. 10.1016/j.jep.2012.04.017

  • CrossRef
  • Google Scholar

• 13

  ChengC. F.Chien-Fu LinJ.TsaiF. J.ChenC. J.ChiouJ. S.ChouC. H.et al (2019). Protective effects and network analysis of natural compounds obtained from Radix dipsaci, Eucommiae cortex, and Rhizoma drynariae against RANKL-induced osteoclastogenesis in vitro. J. Ethnopharmacol.244, 112074. 10.1016/j.jep.2019.112074

  • CrossRef
  • Google Scholar

• 14

  ChesnutC. H.3rdSilvermanS.AndrianoK.GenantH.GimonaA.HarrisS.et al (2000). A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am. J. Med.109, 267–276. 10.1016/s0002-9343(00)00490-3

  • CrossRef
  • Google Scholar

• 15

  ChotiyarnwongP.McCloskeyE. V. (2020). Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat. Rev. Endocrinol.16, 437–447. 10.1038/s41574-020-0341-0

  • CrossRef
  • Google Scholar

• 16

  CompstonJ. (2018). Glucocorticoid-induced osteoporosis: an update. Endocrine61, 7–16. 10.1007/s12020-018-1588-2

  • CrossRef
  • Google Scholar

• 17

  CompstonJ. E.McClungM. R.LeslieW. D. (2019). Osteoporosis. Lancet393, 364–376. 10.1016/S0140-6736(18)32112-3

  • CrossRef
  • Google Scholar

• 18

  CramerJ. A.GoldD. T.SilvermanS. L.LewieckiE. M. (2007). A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos. Int.18, 1023–1031. 10.1007/s00198-006-0322-8

  • CrossRef
  • Google Scholar

• 19

  CuiX.TrinhK.WangY. J. (2010). Chinese herbal medicine for chronic neck pain due to cervical degenerative disc disease. Spine (Phila Pa 1976)35, 2121–2127. 10.1097/BRS.0b013e3181edfd17

  • CrossRef
  • Google Scholar

• 20

  DamerauA.GaberT.OhrndorfS.HoffP. (2020). JAK/STAT activation: a general mechanism for bone development, homeostasis, and regeneration. Int. J. Mol. Sci.21, 9004. 10.3390/ijms21239004

  • CrossRef
  • Google Scholar

• 21

  DerynckR.ErineH. B. (2019). Specificity, versatility, and control of TGF-β family signaling. Sci. Signal12, eaav5183. 10.1126/scisignal.aav5183

  • CrossRef
  • Google Scholar

• 22

  EastellR.O'NeillT. W.HofbauerL. C.LangdahlB.ReidI. R.GoldD. T.et al (2016). Postmenopausal osteoporosis. Nat. Rev. Dis. Prim.2, 16069. 10.1038/nrdp.2016.69

  • CrossRef
  • Google Scholar

• 23

  EastellR.SzulcP. (2017). Use of bone turnover markers in postmenopausal osteoporosis. Lancet Diabetes Endocrinol.5, 908–923. 10.1016/S2213-8587(17)30184-5

  • CrossRef
  • Google Scholar

• 24

  El-GazzarA.HöglerW. (2021). Mechanisms of bone fragility: from osteogenesis imperfecta to secondary osteoporosis. Int. J. Mol. Sci.22, 625. 10.3390/ijms22020625

  • CrossRef
  • Google Scholar

• 25

  ErnestoC. (2018). Management of endocrine disease: novel anabolic treatments for osteoporosis. Eur. J. Endocrinol.178, R33–R44. 10.1530/eje-17-0920

  • CrossRef
  • Google Scholar

• 26

  EspositoM.FangC.CookK. C.ParkN.WeiY.SpadazziC.et al (2021). TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis. Nat. Cell Biol.23, 257–267. 10.1038/s41556-021-00641-w

  • CrossRef
  • Google Scholar

• 27

  FangP.SheY.HanL.WanS.ShangW.ZhangZ.et al (2021). A promising biomarker of elevated galanin level in hypothalamus for osteoporosis risk in type 2 diabetes mellitus. Mech. Ageing Dev.194, 111427. 10.1016/j.mad.2020.111427

  • CrossRef
  • Google Scholar

• 28

  Forsblad D'EliaH. L. A.WaltbrandE.KvistG.MellströmD.SaxneT.OhlssonC.et al (2003). Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis. Ann. Rheum. Dis.62, 617–623. 10.1136/ard.62.7.617

  • CrossRef
  • Google Scholar

• 29

  FuQ.HuS.YangJ.HaoX.ZhuB.WangQ.et al (2010). Comparison of effects of Wujia Bugu decoction and alendronate sodium on protection the bone loss of hindlimb unloaded rats. Zhongguo gu shang = China J. Orthop. traumatology23, 524–528.

  • Google Scholar

• 30

  FuR.LiJ.YuH.ZhangY.XuZ.MartinC. (2021). The Yin and Yang of traditional Chinese and western medicine. Med. Res. Rev.41, 3182–3200. 10.1002/med.21793

  • CrossRef
  • Google Scholar

• 31

  GanD.XuX.ChenD.FengP.XuZ. (2019). Network pharmacology-based pharmacological mechanism of the Chinese medicine rhizoma drynariae against osteoporosis. Med. Sci. Monit.25, 5700–5716. 10.12659/MSM.915170

  • CrossRef
  • Google Scholar

• 32

  GeX.ZhouG. (2021). Protective effects of naringin on glucocorticoid-induced osteoporosis through regulating the PI3K/Akt/mTOR signaling pathway. Am. J. Transl. Res.13, 6330–6341.

  • Google Scholar

• 33

  GennariL.MerlottiD.FalchettiA.Eller VainicherC.CossoR.ChiodiniI. (2020). Emerging therapeutic targets for osteoporosis. Expert Opin. Ther. Targets24, 115–130. 10.1080/14728222.2020.1726889

  • CrossRef
  • Google Scholar

• 34

  GongW.ZhangN.ChengG.ZhangQ.HeY.ShenY.et al (2019). Rehmannia glutinosa Libosch extracts prevent bone loss and architectural deterioration and enhance osteoblastic bone formation by regulating the IGF-1/PI3K/mTOR pathway in streptozotocin-induced diabetic rats. Int. J. Mol. Sci.20, 3964. 10.3390/ijms20163964

  • CrossRef
  • Google Scholar

• 35

  GuanM.PanD.ZhangM.LengX.YaoB.Elvy SuhanaM. R. (2021). The aqueous extract of Eucommia leaves promotes proliferation, differentiation, and mineralization of osteoblast-like mc3t3-E1 cells. Evidence-Based Complementary Altern. Med.2021, 3641317. 10.1155/2021/3641317

  • CrossRef
  • Google Scholar

• 36

  GuoY.LiY.XueL.SeverinoR. P.GaoS.NiuJ.et al (2014). Salvia miltiorrhiza: an ancient Chinese herbal medicine as a source for anti-osteoporotic drugs. J. Ethnopharmacol.155, 1401–1416. 10.1016/j.jep.2014.07.058

  • CrossRef
  • Google Scholar

• 37

  HaoJ.BeiJ.LiZ.HanM.MaB.MaP.et al (2022). Qing`e Pill Inhibits Osteoblast Ferroptosis via ATM Serine/Threonine Kinase (ATM) and the PI3K/AKT Pathway in Primary Osteoporosis. Front. Pharmacol.13, 902102. 10.3389/fphar.2022.902102

  • CrossRef
  • Google Scholar

• 38

  HatoT.DagherP. C. (2015). How the innate immune system senses trouble and causes trouble. Clin. J. Am. Soc. Nephrol.10, 1459–1469. 10.2215/CJN.04680514

  • CrossRef
  • Google Scholar

• 39

  HeJ.LiX.WangZ.BennettS.ChenK.XiaoZ.et al (2019). Therapeutic anabolic and anticatabolic benefits of natural Chinese medicines for the treatment of osteoporosis. Front. Pharmacol.10, 1344. 10.3389/fphar.2019.01344

  • CrossRef
  • Google Scholar

• 40

  HuQ.YuT.LiJ.YuQ.ZhuL.GuY. (2019). End-to-End syndrome differentiation of Yin deficiency and Yang deficiency in traditional Chinese medicine. Comput. Methods Programs Biomed.174, 9–15. 10.1016/j.cmpb.2018.10.011

  • CrossRef
  • Google Scholar

• 41

  HuaS.ZhangX. (2019). Effects of Achyranthes bidentata alcohol on proliferation capacity of osteoblasts and miRNA in Runx2. Exp. Ther. Med.18, 1545–1550. 10.3892/etm.2019.7723

  • CrossRef
  • Google Scholar

• 42

  HuangA. Y.XiongZ.LiuK.ChangY.ShuL.GaoG.et al (2022). Identification of kaempferol as an OSX upregulator by network pharmacology-based analysis of qianggu Capsule for osteoporosis. Front. Pharmacol.13, 1011561. 10.3389/fphar.2022.1011561

  • CrossRef
  • Google Scholar

• 43

  HuangM.WangY.PengR. (2020). Icariin alleviates glucocorticoid-induced osteoporosis through EphB4/ephrin-B2 Axis. Evid. Based Complement. Altern. Med.2020, 2982480. 10.1155/2020/2982480

  • CrossRef
  • Google Scholar

• 44

  IkebuchiY.AokiS.HonmaM.HayashiM.SugamoriY.KhanM.et al (2018). Coupling of bone resorption and formation by RANKL reverse signalling. Nature561, 195–200. 10.1038/s41586-018-0482-7

  • CrossRef
  • Google Scholar

• 45

  IngwersenL. C.FrankM.NaujokatH.LogerK.BaderR.Jonitz-HeinckeA. (2022). BMP-2 long-term stimulation of human pre-osteoblasts induces osteogenic differentiation and promotes transdifferentiation and bone remodeling processes. Int. J. Mol. Sci.23, 3077. 10.3390/ijms23063077

  • CrossRef
  • Google Scholar

• 46

  KangJ. S.AllistonT.DelstonR.DerynckR. (2005). Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3. EMBO J.24, 2543–2555. 10.1038/sj.emboj.7600729

  • CrossRef
  • Google Scholar

• 47

  KarimK.GiribabuN.SallehN. (2021). Marantodes pumilum Var Alata (Kacip Fatimah) ameliorates derangement in RANK/RANKL/OPG pathway and reduces inflammation and oxidative stress in the bone of estrogen-deficient female rats with type-2 diabetes. Phytomedicine91, 153677. 10.1016/j.phymed.2021.153677

  • CrossRef
  • Google Scholar

• 48

  KaufmanJ. M. (2021). Management of osteoporosis in older men. Aging Clin. Exp. Res.33, 1439–1452. 10.1007/s40520-021-01845-8

  • CrossRef
  • Google Scholar

• 49

  KhoslaS.HofbauerL. C. (2017). Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes and Endocrinol.5, 898–907. 10.1016/S2213-8587(17)30188-2

  • CrossRef
  • Google Scholar

• 50

  KlausJ. A. G.SteinkampM.BrückelJ.RieberA.AdlerG.ReinshagenM.et al (2002). High prevalence of osteoporotic vertebral fractures in patients with Crohn's disease. Gut51, 654–658. 10.1136/gut.51.5.654

  • CrossRef
  • Google Scholar

• 51

  KomoriT. (2018). Runx2, an inducer of osteoblast and chondrocyte differentiation. Histochem Cell Biol.149, 313–323. 10.1007/s00418-018-1640-6

  • CrossRef
  • Google Scholar

• 52

  LaneN. E. (2006). Epidemiology, etiology, and diagnosis of osteoporosis. Am. J. Obstet. Gynecol.194, S3–S11. 10.1016/j.ajog.2005.08.047

  • CrossRef
  • Google Scholar

• 53

  Lecka-CzernikB. (2017). Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia60, 1163–1169. 10.1007/s00125-017-4269-4

  • CrossRef
  • Google Scholar

• 54

  LeeH. W.SuhJ. H.KimH.-N.KimA. Y.ParkS. Y.ShinC. S.et al (2008). Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J. Bone Mineral Res.23, 1227–1237. 10.1359/jbmr.080325

  • CrossRef
  • Google Scholar

• 55

  LeeJ. W.KwonB. C.ChoiH. G. (2021). Analyses of the relationship between hyperuricemia and osteoporosis. Sci. Rep.11, 12080. 10.1038/s41598-021-91570-z

  • CrossRef
  • Google Scholar

• 56

  LeeS. R.JeonH.KwonJ. E.SuhH.KimB. H.YunM. K.et al (2020). Anti-osteoporotic effects of Salvia miltiorrhiza Bunge EtOH extract both in ovariectomized and naturally menopausal mouse models. J. Ethnopharmacol.258, 112874. 10.1016/j.jep.2020.112874

  • CrossRef
  • Google Scholar

• 57

  LeeS. Y.ChoiD. Y.WooE. R. (2005). Inhibition of osteoclast differentiation by tanshinones from the root of Salvia miltiorrhiza bunge. Archives pharmacal Res.28, 909–913. 10.1007/BF02973876

  • CrossRef
  • Google Scholar

• 58

  LiH.DengW.YangJ.LinY.ZhangS.LiangZ.et al (2024). Corylifol A suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss via attenuating ROS production and impairing mitochondrial function. Biomed. Pharmacother.171, 116166. 10.1016/j.biopha.2024.116166

  • CrossRef
  • Google Scholar

• 59

  LiJ.ZhaoZ.YangJ.LiuJ.WangJ.LiX.et al (2009). p38 MAPK mediated in compressive stress-induced chondrogenesis of rat bone marrow MSCs in 3D alginate scaffolds. J. Cell Physiol.221, 609–617. 10.1002/jcp.21890

  • CrossRef
  • Google Scholar

• 60

  LiS.-S.HeS.-H.XieP.-Y.LiW.ZhangX.-X.LiT.-F.et al (2021). Targeting the wnt/β-catenin signaling pathway as a potential therapeutic strategy in renal tubulointerstitial fibrosis. Front. Pharmacol.12, 719880. 10.3389/fphar.2021.719880

  • CrossRef
  • Google Scholar

• 61

  LiX.-L.WangL.HeM.-C.LiW.-X.ZhangJ.-L.FuY.-F.et al (2022). A clinical herbal prescription Gu-Shu-Kang capsule exerted beneficial effects on the musculoskeletal system of dexamethasone-treated mice by acting on tissue IGF-1 signalling pathway. Pharm. Biol.60, 2098–2109. 10.1080/13880209.2022.2132029

  • CrossRef
  • Google Scholar

• 62

  LiY.ZhangY.MengW.LiY.HuangT.WangD.et al (2020). The antiosteoporosis effects of yishen Bugu Ye based on its regulation on the differentiation of osteoblast and osteoclast. Biomed. Res. Int.2020, 9467683. 10.1155/2020/9467683

  • CrossRef
  • Google Scholar

• 63

  LianW. S.WuR. W.ChenY. S.KoJ. Y.WangS. Y.JahrH.et al (2021). MicroRNA-29a mitigates osteoblast senescence and counteracts bone loss through oxidation resistance-1 control of FoxO3 methylation. Antioxidants (Basel)10, 1248. 10.3390/antiox10081248

  • CrossRef
  • Google Scholar

• 64

  LiangH.WangO.ChengZ.XiaP.WangL.ShenJ.et al (2022). Jintiange combined with alfacalcidol improves muscle strength and balance in primary osteoporosis: a randomized, double-blind, double-dummy, positive-controlled, multicenter clinical trial. J. Orthop. Transl.35, 53–61. 10.1016/j.jot.2022.05.002

  • CrossRef
  • Google Scholar

• 65

  LiaoL.SuX.YangX.HuC.LiB.LvY.et al (2016). TNF-Α inhibits FoxO1 by upregulating miR-705 to aggravate oxidative damage in bone marrow-derived mesenchymal stem cells during osteoporosis. Stem Cells34, 1054–1067. 10.1002/stem.2274

  • CrossRef
  • Google Scholar

• 66

  LinZ.XiongY.HuY.ChenL.PanayiA. C.XueH.et al (2021). Polydatin ameliorates osteoporosis via suppression of the mitogen-activated protein kinase signaling pathway. Front. Cell Dev. Biol.9, 730362. 10.3389/fcell.2021.730362

  • CrossRef
  • Google Scholar

• 67

  LindseyR. C.MohanS. (2016). Skeletal effects of growth hormone and insulin-like growth factor-I therapy. Mol. Cell. Endocrinol.432, 44–55. 10.1016/j.mce.2015.09.017

  • CrossRef
  • Google Scholar

• 68

  LiuK.LiuY.XuY.NandakumarK. S.TanH.HeC.et al (2019). Asperosaponin VI protects against bone destructions in collagen induced arthritis by inhibiting osteoclastogenesis. Phytomedicine63, 153006. 10.1016/j.phymed.2019.153006

  • CrossRef
  • Google Scholar

• 69

  LiuM. M.LvN. N.GengR.HuaZ.MaY.HuangG. C.et al (2022). Uncovering the key miRNAs and targets of the liuwei Dihuang pill in diabetic nephropathy-related osteoporosis based on weighted gene Co-expression network and network pharmacology analysis. Endocr. Metab. Immune Disord. Drug Targets22, 274–289. 10.2174/1871530321666210215161921

  • CrossRef
  • Google Scholar

• 70

  LoB.HolmJ. P.Vester-AndersenM. K.BendtsenF.VindI.BurischJ. (2020). Incidence, risk factors and evaluation of osteoporosis in patients with inflammatory bowel disease: a Danish population-based inception cohort with 10 Years of follow-up. J. Crohns Colitis14, 904–914. 10.1093/ecco-jcc/jjaa019

  • CrossRef
  • Google Scholar

• 71

  LongF.ChenR.SuY.LiangJ.XianY.YangF.et al (2022). Epoxymicheliolide inhibits osteoclastogenesis and resists OVX-induced osteoporosis by suppressing ERK1/2 and NFATc1 signaling. Int. Immunopharmacol.107, 108632. 10.1016/j.intimp.2022.108632

  • CrossRef
  • Google Scholar

• 72

  LuoJ.YangZ.MaY.YueZ.LinH.QuG.et al (2016). LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat. Med.22, 539–546. 10.1038/nm.4076

  • CrossRef
  • Google Scholar

• 73

  MatsunobuT.TorigoeK.IshikawaM.de VegaS.KulkarniA. B.IwamotoY.et al (2009). Critical roles of the TGF-beta type I receptor ALK5 in perichondrial formation and function, cartilage integrity, and osteoblast differentiation during growth plate development. Dev. Biol.332, 325–338. 10.1016/j.ydbio.2009.06.002

  • CrossRef
  • Google Scholar

• 74

  MatsuzakiA.-G. O.MokudaS.NagiraK.OlmerM.GaminiR.MiyataK.et al (2018). FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis. Sci. Transl. Med.10, eaan0746. 10.1126/scitranslmed.aan0746

  • CrossRef
  • Google Scholar

• 75

  MoH.ZhangN.LiH.LiF.PuR. (2019). Beneficial effects of Cuscuta chinensis extract on glucocorticoid-induced osteoporosis through modulation of RANKL/OPG signals. Braz. J. Med. Biol. Res.52, e8754. 10.1590/1414-431X20198754

  • CrossRef
  • Google Scholar

• 76

  MohammadN. A.RazalyN. I.Mohd RaniM. D.Mohd ArisM. S.Mohd EffendyN. (2018). An evidence-based review: the effects of Malaysian traditional herbs on osteoporotic rat models. Malays. J. Med. Sci.25, 6–30. 10.21315/mjms2018.25.4.2

  • CrossRef
  • Google Scholar

• 77

  MuñozJ.AkhavanN. S.MullinsA. P.ArjmandiB. H. (2020). Macrophage polarization and osteoporosis: a review. Nutrients12, 2999. 10.3390/nu12102999

  • CrossRef
  • Google Scholar

• 78

  MuñozM. T.ArgenteJ. (2002). Anorexia nervosa in female adolescents: endocrine and bone mineral density disturbances. Eur. J. Endocrinol.147, 275–286. 10.1530/eje.0.1470275

  • CrossRef
  • Google Scholar

• 79

  NohJ. Y.YangY.JungH. (2020). Molecular mechanisms and emerging therapeutics for osteoporosis. Int. J. Mol. Sci.21, 7623. 10.3390/ijms21207623

  • CrossRef
  • Google Scholar

• 80

  NusseR. (2012). Wnt signaling. Cold Spring Harb. Perspect. Biol.4, a011163. 10.1101/cshperspect.a011163

  • CrossRef
  • Google Scholar

• 81

  NusseR.CleversH. (2017). Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities. Cell169, 985–999. 10.1016/j.cell.2017.05.016

  • CrossRef
  • Google Scholar

• 82

  PagnottiG. M.StynerM.UzerG.PatelV. S.WrightL. E.NessK. K.et al (2019). Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity. Nat. Rev. Endocrinol.15, 339–355. 10.1038/s41574-019-0170-1

  • CrossRef
  • Google Scholar

• 83

  ParkB.SongH. S.KwonJ. E.ChoS. M.JangS. A.KimM. Y.et al (2017). Effects of Salvia miltiorrhiza extract with supplemental liquefied calcium on osteoporosis in calcium-deficient ovariectomized mice. BMC Complement. Altern. Med.17, 545. 10.1186/s12906-017-2047-y

  • CrossRef
  • Google Scholar

• 84

  PaschouS. A.DedeA. D.AnagnostisP. G.VryonidouA.MorgansteinD.GoulisD. G. (2017). Type 2 diabetes and osteoporosis: a guide to optimal management. J. Clin. Endocrinol. Metab.102, 3621–3634. 10.1210/jc.2017-00042

  • CrossRef
  • Google Scholar

• 85

  PengC.-H.LinW.-Y.LiC.-Y.DhariniK. K.ChangC.-Y.HongJ.-T.et al (2022a). Gu Sui Bu (Drynaria fortunei J. Sm.) antagonizes glucocorticoid-induced mineralization reduction in zebrafish larvae by modulating the activity of osteoblasts and osteoclasts. J. Ethnopharmacol.297, 115565. 10.1016/j.jep.2022.115565

  • CrossRef
  • Google Scholar

• 86

  PengZ.XuR.YouQ. (2022b). Role of traditional Chinese medicine in bone regeneration and osteoporosis. Front. Bioeng. Biotechnol.10, 911326. 10.3389/fbioe.2022.911326

  • CrossRef
  • Google Scholar

• 87

  PonzettiM.RucciN. (2019). Updates on osteoimmunology: what's new on the cross-talk between bone and immune system. Front. Endocrinol. (Lausanne)10, 236. 10.3389/fendo.2019.00236

  • CrossRef
  • Google Scholar

• 88

  QadirA.LiangS.WuZ.ChenZ.HuL.QianA. (2020). Senile osteoporosis: the involvement of differentiation and senescence of bone marrow stromal cells. Int. J. Mol. Sci.21, 349. 10.3390/ijms21010349

  • CrossRef
  • Google Scholar

• 89

  QianD.ZhouH.FanP.YuT.PatelA.O'BrienM.et al (2021). A traditional Chinese medicine plant extract prevents alcohol-induced osteopenia. Front. Pharmacol.12, 754088. 10.3389/fphar.2021.754088

  • CrossRef
  • Google Scholar

• 90

  QinH.ZhaoW.JiaoY.ZhengH.ZhangH.JinJ.et al (2021). Aqueous extract of salvia miltiorrhiza bunge-radix Puerariae herb pair attenuates osteoporosis in ovariectomized rats through suppressing osteoclast differentiation. Front. Pharmacol.11, 581049. 10.3389/fphar.2020.581049

  • CrossRef
  • Google Scholar

• 91

  QinT.WuL.HuaQ.SongZ.PanY.LiuT. (2020). Prediction of the mechanisms of action of Shenkang in chronic kidney disease: a network pharmacology study and experimental validation. J. Ethnopharmacol.246, 112128. 10.1016/j.jep.2019.112128

  • CrossRef
  • Google Scholar

• 92

  QuN.KuramasuM.NagahoriK.OgawaY.HayashiS.HirayanagiY.et al (2020). Co-administration of the traditional medicines hachimi-jio-Gan and hochu-ekki-to can reverse busulfan-induced aspermatogenesis. Int. J. Mol. Sci.21, 1716. 10.3390/ijms21051716

  • CrossRef
  • Google Scholar

• 93

  RagipogluD.DudeckA.Haffner-LuntzerM.VossM.KronerJ.IgnatiusA.et al (2020). The role of mast cells in bone metabolism and bone disorders. Front. Immunol.11, 163. 10.3389/fimmu.2020.00163

  • CrossRef
  • Google Scholar

• 94

  RathinaveluS.Guidry-ElizondoC.BanuJ. (2018). Molecular modulation of osteoblasts and osteoclasts in type 2 diabetes. J. Diabetes Res.2018, 6354787. 10.1155/2018/6354787

  • CrossRef
  • Google Scholar

• 95

  RenC.XuY.LiuH.WangZ.MaT.LiZ.et al (2022). Effects of runt-related transcription factor 2 (RUNX2) on the autophagy of rapamycin-treated osteoblasts. Bioengineered13, 5262–5276. 10.1080/21655979.2022.2037881

  • CrossRef
  • Google Scholar

• 96

  RobertS. W. (2011). Clinical practice. Glucocorticoid-induced bone disease. N. Engl. J. Med.365, 62–70. 10.1056/NEJMcp1012926

  • CrossRef
  • Google Scholar

• 97

  RossouwJ. E.AndersonG. L.PrenticeR. L.LaCroixA. Z.KooperbergC.StefanickM. L.et al (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA288, 321–333. 10.1001/jama.288.3.321

  • CrossRef
  • Google Scholar

• 98

  SakamotoS.SassaS.KudoH.SuzukiS.MitamuraT.ShinodaH. (2000). Preventive effects of a herbal medicine on bone loss in rats treated with a GnRH agonist. Eur. J. Endocrinol.143, 139–142. 10.1530/eje.0.1430139

  • CrossRef
  • Google Scholar

• 99

  SamakkarnthaiP.SfeirJ. G.AtkinsonE. J.AchenbachS. J.WennbergP. W.DyckP. J.et al (2020). Determinants of bone material strength and cortical porosity in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab.105, e3718–e3729. 10.1210/clinem/dgaa388

  • CrossRef
  • Google Scholar

• 100

  ShaoX. R.LinS. Y.PengQ.ShiS. R.LiX. L.ZhangT.et al (2017). Effect of tetrahedral DNA nanostructures on osteogenic differentiation of mesenchymal stem cells via activation of the Wnt/β-catenin signaling pathway. Nanomedicine13, 1809–1819. 10.1016/j.nano.2017.02.011

  • CrossRef
  • Google Scholar

• 101

  SheuA.BliucD.TranT.WhiteC. P.CenterJ. R. (2022). Fractures in type 2 diabetes confer excess mortality: the Dubbo osteoporosis epidemiology study. Bone159, 116373. 10.1016/j.bone.2022.116373

  • CrossRef
  • Google Scholar

• 102

  ShuaiB.ZhuR.YangY. P.ShenL.XuX. J.MaC.et al (2019). Positive Effects of Qing'e Pill on Trabecular Microarchitecture and its Mechanical Properties in Osteopenic Ovariectomised Mice. Chin. J. Integr. Med.25, 270–277. 10.1007/s11655-016-2604-0

  • CrossRef
  • Google Scholar

• 103

  SongD.CaoZ.LiuZ.TicknerJ.QiuH.WangC.et al (2018). Cistanche deserticola polysaccharide attenuates osteoclastogenesis and bone resorption via inhibiting RANKL signaling and reactive oxygen species production. J. Cell Physiol.233, 9674–9684. 10.1002/jcp.26882

  • CrossRef
  • Google Scholar

• 104

  SongN.ZhaoZ.MaX.SunX.MaJ.LiF.et al (2017). Naringin promotes fracture healing through stimulation of angiogenesis by regulating the VEGF/VEGFR-2 signaling pathway in osteoporotic rats. Chem. Biol. Interact.261, 11–17. 10.1016/j.cbi.2016.10.020

  • CrossRef
  • Google Scholar

• 105

  SozelH.YilmazF. (2021). Symptomatic hypocalcemia following a single dose of zoledronic acid in a patient with bone metastases secondary to breast cancer. J. Oncol. Pharm. Pract.27, 494–497. 10.1177/1078155220940411

  • CrossRef
  • Google Scholar

• 106

  SteinE.ShaneE. (2003). Secondary osteoporosis. Endocrinol. Metabolism Clin. N. Am.32, 115–134. 10.1016/s0889-8529(02)00062-2

  • CrossRef
  • Google Scholar

• 107

  SunC.ChenX.YangS.JinC.DingK.ChenC. (2023). LBP1C-2 from Lycium barbarum alleviated age-related bone loss by targeting BMPRIA/BMPRII/Noggin. Carbohydrate Polymers 310.

  • Google Scholar

• 108

  SunX.WeiB.PengZ.FuQ.WangC.ZhenJ.et al (2019). Protective effects of Dipsacus asper polysaccharide on osteoporosis in vivo by regulating RANKL/RANK/OPG/VEGF and PI3K/Akt/eNOS pathway. Int. J. Biol. Macromol.129, 579–587. 10.1016/j.ijbiomac.2019.02.022

  • CrossRef
  • Google Scholar

• 109

  TangX.HuangY.FangX.TongX.YuQ.ZhengW.et al (2023). Cornus officinalis: a potential herb for treatment of osteoporosis. Front. Med.10, 1289144. 10.3389/fmed.2023.1289144

  • CrossRef
  • Google Scholar

• 110

  TariqS.TariqS.LoneK. P. (2017). Relationship of anthropometric measures with bone mineral density in postmenopausal non-osteoporotic, osteopenic and osteoporotic women. J. Pak Med. Assoc.67, 590–594.

  • Google Scholar

• 111

  TsaiJ. N.LeeH.DavidN. L.EastellR.LederB. Z. (2019). Combination denosumab and high dose teriparatide for postmenopausal osteoporosis (DATA-HD): a randomised, controlled phase 4 trial. Lancet Diabetes and Endocrinol.7, 767–775. 10.1016/S2213-8587(19)30255-4

  • CrossRef
  • Google Scholar

• 112

  VahleJ. L.LongG. G.SanduskyG.WestmoreM.MaY. L.SatoM. (2016). Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicol. Pathol.32, 426–438. 10.1080/01926230490462138

  • CrossRef
  • Google Scholar

• 113

  van AmerongenR.MikelsA.NusseR. (2008). Alternative wnt signaling is initiated by distinct receptors. Sci. Signal1, re9. 10.1126/scisignal.135re9

  • CrossRef
  • Google Scholar

• 114

  VanderWaldeA.HurriaA. (2011). Aging and osteoporosis in breast and prostate cancer. CA Cancer J. Clin.61, 139–156. 10.3322/caac.20103

  • CrossRef
  • Google Scholar

• 115

  VijayarajS. L.FelthamR.RashidiM.FrankD.LiuZ.SimpsonD. S.et al (2021). The ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation. Nat. Commun.12, 2713. 10.1038/s41467-021-22979-3

  • CrossRef
  • Google Scholar

• 116

  WangJ.YangJ.TangZ.YuY.ChenH.YuQ.et al (2023). Curculigo orchioides polysaccharide COP70-1 stimulates osteogenic differentiation of MC3T3-E1 cells by activating the BMP and Wnt signaling pathways. Int. J. Biol. Macromol.248, 125879. 10.1016/j.ijbiomac.2023.125879

  • CrossRef
  • Google Scholar

• 117

  WangM. Y.AnM. F.FanM. S.ZhangS. S.SunZ. R.ZhaoY. L.et al (2022). FAEE exerts a protective effect against osteoporosis by regulating the MAPK signalling pathway. Pharm. Biol.60, 467–478. 10.1080/13880209.2022.2039216

  • CrossRef
  • Google Scholar

• 118

  WangN.XuP.WangX.YaoW.WangB.WuY.et al (2020). Timosaponin AIII attenuates inflammatory injury in AGEs-induced osteoblast and alloxan-induced diabetic osteoporosis zebrafish by modulating the RAGE/MAPK signaling pathways. Phytomedicine75, 153247. 10.1016/j.phymed.2020.153247

  • CrossRef
  • Google Scholar

• 119

  WangW.MaoJ.ChenY.ZuoJ.ChenL.LiY.et al (2021). Naringin promotes osteogenesis and ameliorates osteoporosis development by targeting JAK2/STAT3 signalling. Clin. Exp. Pharmacol. Physiology49, 113–121. 10.1111/1440-1681.13591

  • CrossRef
  • Google Scholar

• 120

  WangX.ZhenL.ZhangG.WongM.-S.QinL.YaoX. (2011). Osteogenic effects of flavonoid aglycones from an osteoprotective fraction of Drynaria fortunei—an in vitro efficacy study. Phytomedicine18, 868–872. 10.1016/j.phymed.2011.01.022

  • CrossRef
  • Google Scholar

• 121

  WangY.CuiK.ZhaoH.LiD.WangW.ZhuY. (2009). Bushen Ningxin Decoction pharmacological serum promotes the proliferation and suppresses the apoptosis of murine osteoblasts through MAPK pathway. J. Ethnopharmacol.122, 221–226. 10.1016/j.jep.2009.01.026

  • CrossRef
  • Google Scholar

• 122

  WangY.FanX.XingL.TianF. (2019). Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun. Signal17, 97. 10.1186/s12964-019-0411-x

  • CrossRef
  • Google Scholar

• 123

  Wayne SampsonH. (2002). Alcohol and other factors affecting osteoporosis risk in women. Alcohol Res. Health26, 292–298.

  • Google Scholar

• 124

  WeiW.PengC.GuR.YanX.YeJ.XuZ.et al (2022). Urolithin A attenuates RANKL-induced osteoclastogenesis by co-regulating the p38 MAPK and Nrf2 signaling pathway. Eur. J. Pharmacol.921, 174865. 10.1016/j.ejphar.2022.174865

  • CrossRef
  • Google Scholar

• 125

  WeivodaM. M.RuanM.PedersonL.HachfeldC.DaveyR. A.ZajacJ. D.et al (2016). Osteoclast TGF-β receptor signaling induces Wnt1 secretion and couples bone resorption to bone formation. J. Bone Min. Res.31, 76–85. 10.1002/jbmr.2586

  • CrossRef
  • Google Scholar

• 126

  WhyteM. P. (2006). Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling. Ann. N. Y. Acad. Sci.1068, 143–164. 10.1196/annals.1346.016

  • CrossRef
  • Google Scholar

• 127

  WidmannG. S.JarpeM. B.JohnsonG. L. (1999). Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev.79, 143–180. 10.1152/physrev.1999.79.1.143

  • CrossRef
  • Google Scholar

• 128

  WuD.Cline-SmithA.ShashkovaE.PerlaA.KatyalA.AuroraR. (2021). T-cell mediated inflammation in postmenopausal osteoporosis. Front. Immunol.12, 687551. 10.3389/fimmu.2021.687551

  • CrossRef
  • Google Scholar

• 129

  WuM.ChenG.LiY. P. (2016). TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res.4, 16009. 10.1038/boneres.2016.9

  • CrossRef
  • Google Scholar

• 130

  WuQ.-c.TangX.-y.DaiZ.-q.DaiY.XiaoH.-h.YaoX.-s. (2020). Sweroside promotes osteoblastic differentiation and mineralization via interaction of membrane estrogen receptor-α and GPR30 mediated p38 signalling pathway on MC3T3-E1 cells. Phytomedicine68, 153146. 10.1016/j.phymed.2019.153146

  • CrossRef
  • Google Scholar

• 131

  XianL.WuX.PangL.LouM.RosenC. J.QiuT.et al (2012). Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat. Med.18, 1095–1101. 10.1038/nm.2793

  • CrossRef
  • Google Scholar

• 132

  XiaoJ.LiW.LiG.TanJ.DongN. (2022). STK11 overexpression prevents glucocorticoid-induced osteoporosis via activating the AMPK/SIRT1/PGC1α axis. Human Cell.

  • Google Scholar

• 133

  XiaoJ.ZhangG.MaiJ.HeQ.ChenW.LiJ.et al (2022). Bioinformatics analysis combined with experimental validation to explore the mechanism of XianLing GuBao capsule against osteoarthritis. J. Ethnopharmacol.294, 115292. 10.1016/j.jep.2022.115292

  • CrossRef
  • Google Scholar

• 134

  XieQ.XieJ.DongT.SuJ.CaiD.ChenJ.et al (2012). Effect of a derived herbal recipe from an ancient Chinese formula, Danggui Buxue Tang, on ovariectomized rats. J. Ethnopharmacol.144, 567–575. 10.1016/j.jep.2012.09.041

  • CrossRef
  • Google Scholar

• 135

  XieX.HuL.MiB.PanayiA. C.XueH.HuY.et al (2022). SHIP1 activator AQX-1125 regulates osteogenesis and osteoclastogenesis through PI3K/Akt and NF-κb signaling. Front. Cell Dev. Biol.10, 826023. 10.3389/fcell.2022.826023

  • CrossRef
  • Google Scholar

• 136

  XuX.ZhangZ.WangW.YaoH.MaX. (2017). Therapeutic effect of cistanoside A on bone metabolism of ovariectomized mice. Molecules22, 197. 10.3390/molecules22020197

  • CrossRef
  • Google Scholar

• 137

  XuY.LiL.TangY.YangJ.JinY.MaC. (2019). Icariin promotes osteogenic differentiation by suppressing Notch signaling. Eur. J. Pharmacol.865, 172794. 10.1016/j.ejphar.2019.172794

  • CrossRef
  • Google Scholar

• 138

  XueL.JiangY.HanT.ZhangN.QinL.XinH.et al (2016). Comparative proteomic and metabolomic analysis reveal the antiosteoporotic molecular mechanism of icariin from Epimedium brevicornu maxim. J. Ethnopharmacol.192, 370–381. 10.1016/j.jep.2016.07.037

  • CrossRef
  • Google Scholar

• 139

  YahiroY.MaedaS.MorikawaM.KoinumaD.JokojiG.IjuinT.et al (2020). BMP-induced Atoh8 attenuates osteoclastogenesis by suppressing Runx2 transcriptional activity and reducing the Rankl/Opg expression ratio in osteoblasts. Bone Res.8, 32. 10.1038/s41413-020-00106-0

  • CrossRef
  • Google Scholar

• 140

  YamakawaH.KusumotoD.HashimotoH.YuasaS. (2020). Stem cell aging in skeletal muscle regeneration and disease. Int. J. Mol. Sci.21, 1830. 10.3390/ijms21051830

  • CrossRef
  • Google Scholar

• 141

  YangA.YuC.YouF.HeC.LiZ. (2018a). Mechanisms of zuogui pill in treating osteoporosis: perspective from bone marrow mesenchymal stem cells. Evidence-Based Complementary Altern. Med.2018, 3717391–3717398. 10.1155/2018/3717391

  • CrossRef
  • Google Scholar

• 142

  YangA.YuC.YouF.HeC.LiZ. (2018b). Mechanisms of zuogui pill in treating osteoporosis: perspective from bone marrow mesenchymal stem cells. Evid. Based Complement. Altern. Med.2018, 3717391. 10.1155/2018/3717391

  • CrossRef
  • Google Scholar

• 143

  YangF.LinZ. W.HuangT. Y.ChenT. T.CuiJ.LiM. Y.et al (2019). Ligustilide, a major bioactive component of Angelica sinensis, promotes bone formation via the GPR30/EGFR pathway. Sci. Rep.9, 6991. 10.1038/s41598-019-43518-7

  • CrossRef
  • Google Scholar

• 144

  YangL.FanL.WangK.ChenY.LiangL.QinX.et al (2021a). Analysis of molecular mechanism of erxian decoction in treating osteoporosis based on formula optimization model. Oxid. Med. Cell Longev.2021, 6641838. 10.1155/2021/6641838

  • CrossRef
  • Google Scholar

• 145

  YangW.LuX.ZhangT.HanW.LiJ.HeW.et al (2021b). TAZ inhibits osteoclastogenesis by attenuating TAK1/NF-κB signaling. Bone Res.9, 33. 10.1038/s41413-021-00151-3

  • CrossRef
  • Google Scholar

• 146

  YangY. J.KimD. J. (2021). An overview of the molecular mechanisms contributing to musculoskeletal disorders in chronic liver disease: osteoporosis, sarcopenia, and osteoporotic sarcopenia. Int. J. Mol. Sci.22, 2604. 10.3390/ijms22052604

  • CrossRef
  • Google Scholar

• 147

  YangY.-j.ZhuZ.WangD.-t.ZhangX.-l.LiuY.-y.LaiW.-x.et al (2018c). Tanshinol alleviates impaired bone formation by inhibiting adipogenesis via KLF15/PPARγ2 signaling in GIO rats. Acta Pharmacol. Sin.39, 633–641. 10.1038/aps.2017.134

  • CrossRef
  • Google Scholar

• 148

  YuA. X.XuM. L.YaoP.KwanK. K.LiuY. X.DuanR.et al (2020a). Corylin, a flavonoid derived from Psoralea Fructus, induces osteoblastic differentiation via estrogen and Wnt/β-catenin signaling pathways. FASEB J.34, 4311–4328. 10.1096/fj.201902319RRR

  • CrossRef
  • Google Scholar

• 149

  YuB.WangC. Y. (2016). Osteoporosis: the result of an 'aged' bone microenvironment. Trends Mol. Med.22, 641–644. 10.1016/j.molmed.2016.06.002

  • CrossRef
  • Google Scholar

• 150

  YuB.WangC. Y. (2022). Osteoporosis and periodontal diseases - an update on their association and mechanistic links. Periodontol89, 99–113. 10.1111/prd.12422

  • CrossRef
  • Google Scholar

• 151

  YuT. X. Y.LuuS.YouX.LiB.XiaJ.ZhuH.et al (2020b). The shared KEGG pathways between icariin-targeted genes and osteoporosis. Aging (Albany NY)12, 8191–8201. 10.18632/aging.103133

  • CrossRef
  • Google Scholar

• 152

  YuX. Y.LiX. S.LiY.LiuT.WangR. T. (2015). Neutrophil-lymphocyte ratio is associated with arterial stiffness in postmenopausal women with osteoporosis. Arch. Gerontol. Geriatr.61, 76–80. 10.1016/j.archger.2015.03.011

  • CrossRef
  • Google Scholar

• 153

  YuanS.ZhangL.JiL.ZhongS.JiangL.WanY.et al (2022). FoxO3a cooperates with RUNX1 to promote chondrogenesis and terminal hypertrophic of the chondrogenic progenitor cells. Biochem. Biophys. Res. Commun.589, 41–47. 10.1016/j.bbrc.2021.12.008

  • CrossRef
  • Google Scholar

• 154

  ZhangB.YangL. L.DingS. Q.LiuJ. J.DongY. H.LiY. T.et al (2019a). Anti-osteoporotic activity of an edible traditional Chinese medicine cistanche deserticola on bone metabolism of ovariectomized rats through RANKL/RANK/TRAF6-Mediated signaling pathways. Front. Pharmacol.10, 1412. 10.3389/fphar.2019.01412

  • CrossRef
  • Google Scholar

• 155

  ZhangZ. D.RenH.WangW. X.ShenG. Y.HuangJ. J.ZhanM. Q.et al (2019b). IGF-1R/β-catenin signaling axis is involved in type 2 diabetic osteoporosis. J. Zhejiang Univ. Sci. B20, 838–848. 10.1631/jzus.B1800648

  • CrossRef
  • Google Scholar

• 156

  ZhangW.XueK.GaoY.HuaiY.WangW.MiaoZ.et al (2019c). Systems pharmacology dissection of action mechanisms of Dipsaci Radix for osteoporosis. Life Sci.235, 116820. 10.1016/j.lfs.2019.116820

  • CrossRef
  • Google Scholar

• 157

  ZhangB.YuanP.XuG.ChenZ.LiZ.YeH.et al (2021a). DUSP6 expression is associated with osteoporosis through the regulation of osteoclast differentiation via ERK2/Smad2 signaling. Cell Death Dis.12, 825. 10.1038/s41419-021-04110-y

  • CrossRef
  • Google Scholar

• 158

  ZhangH.XingW.-W.LiY.-S.ZhuZ.WuJ.-Z.ZhangQ.-Y.et al (2008). Effects of a traditional Chinese herbal preparation on osteoblasts and osteoclasts. Maturitas61, 334–339. 10.1016/j.maturitas.2008.09.023

  • CrossRef
  • Google Scholar

• 159

  ZhangM.WangY.ZhangQ.WangC.ZhangD.WanJ.-B.et al (2018a). UPLC/Q-TOF-MS-based metabolomics study of the anti-osteoporosis effects of Achyranthes bidentata polysaccharides in ovariectomized rats. Int. J. Biol. Macromol.112, 433–441. 10.1016/j.ijbiomac.2018.01.204

  • CrossRef
  • Google Scholar

• 160

  ZhangN.-D.HanT.HuangB.-K.RahmanK.JiangY.-P.XuH.-T.et al (2016). Traditional Chinese medicine formulas for the treatment of osteoporosis: implication for antiosteoporotic drug discovery. J. Ethnopharmacol.189, 61–80. 10.1016/j.jep.2016.05.025

  • CrossRef
  • Google Scholar

• 161

  ZhangP.LinJ.XiaoT.XuR.FuY.ZhangY.et al (2020). Insulin impedes osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence via the TGF-β1 pathway. Aging (Albany NY)12, 2084–2100. 10.18632/aging.102723

  • CrossRef
  • Google Scholar

• 162

  ZhangS.ZhangQ.ZhangD.WangC.YanC. (2018b). Anti-osteoporosis activity of a novel Achyranthes bidentata polysaccharide via stimulating bone formation. Carbohydr. Polym.184, 288–298. 10.1016/j.carbpol.2017.12.070

  • CrossRef
  • Google Scholar

• 163

  ZhangW.ZhouX.HouW.ChenE.YeC.ChenM.et al (2023). Reversing the imbalance in bone homeostasis via sustained release of SIRT-1 agonist to promote bone healing under osteoporotic condition. Bioact. Mater.19, 429–443. 10.1016/j.bioactmat.2022.04.017

  • CrossRef
  • Google Scholar

• 164

  ZhangW. L. H.LiuH. T. (2003). MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res.12, 9–18. 10.1038/sj.cr.7290105

  • CrossRef
  • Google Scholar

• 165

  ZhangY.MaJ.ZhangW. (2021b). Berberine for bone regeneration: therapeutic potential and molecular mechanisms. J. Ethnopharmacol.277, 114249. 10.1016/j.jep.2021.114249

  • CrossRef
  • Google Scholar

• 166

  ZhaoY.LiJ.LiuY.YuK.ZhangJ.ChenX. (2007). Gu Ling Pian, a traditional Chinese medicine, regulates function and OPG/RANKL synthesis of osteoblasts via the p38 MAPK pathway. J. Pharm. Pharmacol.59, 1167–1173. 10.1211/jpp.59.8.0016

  • CrossRef
  • Google Scholar

• 167

  ZhaoY.WangH. L.LiT. T.YangF.TzengC. M. (2020). Baicalin ameliorates dexamethasone-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway. Drug Des. Devel Ther.14, 195–206. 10.2147/DDDT.S225516

  • CrossRef
  • Google Scholar

• 168

  ZhuN.HouJ. (2020). Exploring the mechanism of action Xianlingubao Prescription in the treatment of osteoporosis by network pharmacology. Comput. Biol. Chem.85, 107240. 10.1016/j.compbiolchem.2020.107240

  • CrossRef
  • Google Scholar

• 169

  ZhuY.WangY.JiaY.XuJ.ChaiY. (2019). Catalpol promotes the osteogenic differentiation of bone marrow mesenchymal stem cells via the Wnt/β-catenin pathway. Stem Cell Res. Ther.10, 37. 10.1186/s13287-019-1143-y

  • CrossRef
  • Google Scholar

• 170

  ZhuoY.LiM.JiangQ.KeH.LiangQ.ZengL.-F.et al (2022). Evolving roles of natural terpenoids from traditional Chinese medicine in the treatment of osteoporosis. Front. Endocrinol. (Lausanne)13, 901545. 10.3389/fendo.2022.901545

  • CrossRef
  • Google Scholar

• 171

  ZouB.ZhangY.LiT.LiuJ.DengW.TanY.et al (2020). A mutation of cysteine 46 in IKK-β promotes mPGES-1 and caveolin-1 expression to exacerbate osteoclast differentiation and osteolysis. Biochem. Pharmacol.172, 113762. 10.1016/j.bcp.2019.113762

  • CrossRef
  • Google Scholar