Sage Journals: Discover world-class research

Abstract

Postmenopausal osteoporosis (PMOP) poses substantial health risks, motivating interest in natural therapies. Here we systematically evaluated Eucommia ulmoides cortex (EUC), a traditional Chinese medicinal plant, in PMOP animal models. Meta-analysis of 14 studies comprising 343 ovariectomized rats showed that EUC markedly increased bone mineral density (standardized mean difference (SMD) = 2.16, 95% confidence interval (CI) = 1.63-2.69) and improved trabecular microarchitecture, including bone volume fraction (SMD = 1.39, 95% CI = 0.85-1.94), trabecular number (SMD = 4.33, 95% CI = 3.22-5.44) and trabecular thickness (SMD = 2.25, 95% CI = 0.87-3.62), while reducing trabecular separation (SMD = −4.87, 95% CI = −6.08 to −3.67). EUC also enhanced biomechanical strength (SMD = 1.14, 95% CI = 0.68-1.60) and lowered serum alkaline phosphatase (SMD = −1.66, 95% CI = −3.26 to −0.06), whereas serum osteocalcin was not significantly altered (SMD = −0.42, 95% CI = −1.94 to 1.10). Several outcomes exhibited moderate-to-high heterogeneity. Collectively, these findings suggest that EUC mitigates estrogen-deficiency–associated bone loss in preclinical PMOP models by preserving bone mass, structure and strength, plausibly through coordinated effects on bone resorption and formation. As a botanical derivative, EUC may hold promise as a dietary supplement or adjunctive approach for PMOP management; however, mechanistic studies and more standardized preclinical protocols are needed to strengthen translational relevance.

Systematic Review Registration

https://inplasy.com/inplasy-2022-11-0093/, identifier [INPLASY2022110093].

Keywords

Animal model postmenopausal osteoporosis Eucommia ulmoides cortex Antiosteoporosis

Introduction

Postmenopausal osteoporosis (PMOP) is a prevalent skeletal disorder in older women, driven by the decline in ovarian function and estrogen production. This hormonal deficiency results in diminished bone strength and an increased fracture risk.¹ Around 200 million women globally have osteoporosis, and 30% of all postmenopausal cases occur in the United States (US) and Europe.^2,3 Vertebral fractures are the most prevalent clinical symptom of osteoporosis, with an incidence of 15% in Chinese women over 50 and 36.6% in women over 80.⁴ Although there may be significant differences between individuals based on factors such as age, region, and ethnicity; morbidity and risk of osteoporosis-related fractures of female patients with PMOP are significantly higher than in men.⁵ Consequently, treating patients with PMOP is a great priority. However, as a chronic disease, it is difficult to manage. Long-term treatment for PMOP may compromise treatment adherence and satisfaction, thereby affecting emotional health, quality of life, work capacity, and social relationships.

Currently, calcium and vitamin D supplements, dietary therapies, and exercise therapy are the fundamental options for patients with OP.^6,7 Hormone replacement therapy (HRT) is more suitable for women with PMOP and menopausal symptoms.⁸ Strengthening regular gynecologic assessment for patients with HRT is considered necessary to prevent the consequent risks, including breast and endometrial cancer.^9,10 Possible substitutes to conventional HRT include selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene. However, SERMs elevate the risk of venous thrombosis.^11,12 Given the risks of hormone-based therapies, non-hormonal strategies have been explored for osteoporosis management. Among these, natural plant-based therapies, long used for bone health, may offer an alternative for patients unsuitable or unwilling to receive hormones.

Eucommia ulmoides cortex (EUC) is one of the earliest tonics used in traditional Chinese medicine.¹³ China, Japan, and Korea have commonly utilized the leaf, stem, cortex, and staminate flower of EU to treat various disorders. Among these, the cortex is the most widely used.¹⁴ In China, Eucommia ulmoides cortex (EUC) has been commonly utilized in famous botanical tonics and antirheumatic supplements for over 2000 years. According to traditional Chinese medicine, it can be used alone or combined with other substances to medicate several diseases, such as osteoporosis, menopause syndrome, hypertension, and lower back pain.¹⁵ Pharmacological studies have suggested that crude extracts and total glycosides derived from Eucommia ulmoides may exert protective effects against osteoporosis in preclinical settings.¹⁶ Aucubin, geniposide, and niposidic acid are representative components of EUC, which have frequently been used to investigate potential anti-osteoporotic mechanisms. The lignans in EUC can inhibit osteoclast formation by increasing osteoprotegerin (OPG) and lowering the expression of receptor activator of nuclear factor-κB ligand (RANKL).¹⁷ Eucommia extract can change the composition of intestinal microflora in mice, increasing short-chain fatty acids synthesis and inhibiting the formation of osteoclasts.¹⁸ EUC extract can inhibit the expression of TRAP, CTSK, and H + ATPase, inhibiting the osteoclast differentiation of RAW264.7 cells and reducing bone resorption activity.¹⁹ However, these beneficial effects observed in those studies have not yet been fully translated into clinical benefits. However, the mechanisms underlying EU's effects and its potential adverse reactions remain incompletely understood. To consolidate existing preclinical evidence, we conducted a systematic review and meta-analysis of EUC in PMOP animal models, aiming to evaluate its efficacy on bone density, microarchitecture, strength, and biochemical markers, and to inform future research and potential clinical application.

Methods

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and followed recommendations from the SYRCLE risk-of-bias tool for animal studies.

Literature Retrieval

EMBASE, PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chinese VIP Database (VIP), Chinese Biomedical Literature Database (SinMed), and Wanfang Database were searched electronically.There were no restrictions on language, and the literature search was conducted from database inception to August 2025. The search strategy combined terms related to Eucommia ulmoides and osteoporosis using Boolean operators. The following search string was adapted for each database: (“Eucommia ulmoides” OR “Du-zhong” OR “Du zhong”) AND (osteoporosis OR “bone loss” OR “postmenopausal osteoporosis” OR “osteoporotic”) AND (rat OR mouse OR animal OR ovariectomized OR OVX). Furthermore, Google Scholar and references included in the literature were searched to retrieve potentially relevant studies.

Inclusion Criteria

Studies were included if they met all of the following:

Used an animal model of postmenopausal osteoporosis (typically ovariectomized rodents); (2) Administered EUC as a monotherapy in the experimental group, with a control group receiving placebo, vehicle, or no treatment; (3) Reported at least one outcome of interest (see Section 2.4); (4) Were original experimental studies (any design).

Exclusion Criteria

Studies were excluded if they:

Lacked usable quantitative data (eg, mean ± standard deviation); (2) Were duplicates or overlapping publications; (3) Were reviews, meta-analyses, conference abstracts, case reports, editorials, or letters.

Outcome Measurements

Herein, the primary finding was bone mineral density (BMD), and the secondary outcomes were bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), maximum bone load, serum osteocalcin (S-OCN), and serum alkaline phosphatase (S-ALP).

Data Recovery

Two authors independently recovered data, which a third author then examined. The authors of these papers were contacted as necessary to acquire pertinent data. All results were recovered for every research author, publication date, animal species, age, gender, body weight, sample size, OP modeling techniques, anesthetics procedure, and therapeutic regimen for control and experimental groups. The mean and standard deviation (SD) for continuous variables were extracted. The correct term crude drug equivalent would be adjusted if EUC extract was utilized in the trial. If multiple doses of EUC were utilized, only the highest dose data would be recorded. If image-based data were not provided by the authors, values were extracted using GetData Graph Digitizer (v2.25.0.32).

Data Analysis

Data were analyzed utilizing the Stata program (Stata SE, version 16). A sensitivity analysis was conducted to determine the potential reason when significant heterogeneity (I² ≥ 50%) was found. When I² > 50%, a random-effects model was applied. While a fixed-effects model was utilized when heterogeneity was undiscovered (I² < 50%) or when the effects of significant clinical heterogeneity were eliminated. P < 0.05 was judged statistically significant. Furthermore, Egger's test was applied to evaluate publication bias impacts. We estimated the pooled estimate for continuous outcomes as a standard mean difference (SMD) with a 95% confidence interval (CI).

Results

Literature Selection

After scanning 8 databases, 1921 articles were selected, of which 832 were discarded due to duplication. After analyzing the titles and abstracts, an additional 362 publications were discarded. The remaining 263 articles were read in entirety, and 249 were rejected for the next reasons: lack of corresponding blank control group, lack of appropriate data, case report, review article, and abstract. Eventually, 14 articles were chosen, including 1 published in English²⁰ and 13 published in Chinese^21–33 (Figure 1).

Figure 1.

Literature selection.

Basic Information of Involved Studies

Table 1 depicts the characteristics of 14 included articles. All articles were published between 1999 and 2025, and 343 animals were involved, 165 in the experimental group and 178 in the control group. Sample sizes of the involved articles ranged from 12 to 40 (median = 27.5). Herein, all rat models were used, and three studies^23,32,33 used Wistar rats, while eleven studies^20–22^,24–31 used Sprague-Dawley (SD) rats. Methods of PMOP animal models were established by bilateral ovariectomy (OVX) for all studies. In twelve studies^20–23^,25–31,33 rats were given oral EUC at doses ranging from 0.5007/kg B.W·d to 24 g/kg.d, based on their body weights, and the remaining two^24,32 were dosed individually, the dosage of EUC was 10 g/kg.d for each rat. Regarding the main finding, BMD was detected in eleven articles,^20–23^,25–31 while six articles^{20,21,24,26,31,32} quantified maximum bone load. Additionally, we detected the BV/TV value in five articles,^{20,21,23,28,33} trabecular number (Tb.N) in two studies,^20,28 trabecular thickness (Tb.Th) in three studies,^20,21,28 Tb.Sp in three studies^20,21,28 S-OCN in four studies,^20,21,26,32 and S-ALP in eight studies.^{20,21,24,25,28,30,32,33}

Table 1.

Basic Information of the Included Studies.

Frist Author(year）	Animal			Sample Size		Intervantion		Duration	Outcome Indicators
Frist Author(year）	species	weight	age	experimental	control	experimental	control	Duration	Outcome Indicators
Ma ZS et al (1999)	Female Wistar rats	200 ± 30g	3 months	6	10	EUC (2.5 g/kgB.W·d) + OVX	Equivalent water + OVX	2 months	(1)(3)
Xiao LP (2001)	Female Wistar rats	250g	3.5 months	6	6	EUC (10 g/kgB.W·d) + OVX	Equivalent deionized water + OVX	12 weeks	(3)(5)
Ge WJ (2008)	Female Wistar rats	270 ± 30g	10 months	20	20	EUC (10 g for each rat) + OVX	Equivalent distilled water + OVX	3 months	(2)(4)(5)
Zhang X et al (2009)	Female SD rats	270 ± 20g	10 months	20	20	EUC (3.3 g/kgB.W·d) + OVX	Equivalent distilled water + OVX	3 months	(1)(2)(7)
Tong Y et al (2009)	Female SD rats	220 ± 10g	NG	15	15	EUC 24 g/kgB.W·d + OVX	Equivalent normal saline + OVX	12 weeks	(1)
Cai JP et al (2009)	Female SD rats	250∼290g	4 months	20	20	EUC (10 g for each rat) + OVX	Equivalent water + OVX	3 months	(2)(5)
Zhang R et al (2009)	Female SD rats	220 ± 12g	3 months	10	20	EUC (5 g/kgB.W·d) + OVX	Equivalent distilled water + OVX	16 weeks	(1)(2)(3)(4)(5)(6)(7)
Tong Y et al (2013)	Female SD rats	220 ± 10g	NG	15	15	EUC (6 g/kgB.W·d) + OVX	Equivalent distilled water + OVX	12 weeks	(1)
Weng ZB et al (2014)	Female SD rats	235 ± 15g	NG	10	10	EUC (4 g/kgB.W·d) + OVX	Equivalent normal saline + OVX	12 weeks	(1)(7)(5)
Luo Y et al (2016)	Female SD rats	276 ± 14g	3 months	13	12	EUC (6 g/kgB.W·d) + OVX	Equivalent 0.5% CMC-Na + OVX	16 weeks	(1) (4)(5)(6) (7)(5)
Zhao L et al (2019)	Female SD rats	200 ± 10g	3 months	10	10	EUC (6 g/kgB.W·d) + OVX	Equivalent normal saline + OVX	12 weeks	(1)(7)(5)
Wang FJ et al (2020)	Female SD rats	300 ± 20g	3 months	10	10	EUC (0.5007 g/kgB.W·d) + OVX	Equivalent distilled water + OVX	3 months	(1)(7)(5)
Luo LL et al (2024)	Female SD rats	180-220g	NG	6	6	EUC (2.16 g/kgB.W·d) + OVX	10 ml/kgB.W·d normal saline + OVX	200 days	(1)
He ZJ et al (2025)	Female SD rats	180-220g	6 weeks	10	10	EUC (2.76 g/kgB.W·d) + OVX	Equivalent normal saline + OVX	12 weeks	(1)(3)(5)(6)(7)(8)

(1) BMD, (2) bone maximum load, (3) BV/TV, (4) Tb.N, (5) Tb.Th, (6) Tb.Sp, (7) S-OCN, (8) S-ALP.

NG: not given, OVX: ovariectomy, SD: Sprague-Dawley, CMC-Na: carboxymethylcellulose sodium salt.

Bias Risk

Study quality was assessed using the CAMARADES 10-item checklist, with minor adaptations for osteoporosis studies^34,35 (Table 2): Items covered peer-reviewed publication, temperature control, randomization, blinding, appropriate anesthesia, animal model relevance, sample size calculation, welfare compliance, and conflict of interest declaration. Scores ranged from 0 to 10. The range of study quality scores was from 2 to 5 (mean ± SD: 3.93 ± 1.10).

Table 2.

Risk of Bias of the Included Studies.

Study (year)	(1)	(2)	(3)	(6)	(9)	Total
Ma ZS et al (1999)	√	√	√	√	√	5
Xiao LP (2001)		√	√	√	√	4
Ge WJ (2008)			√	√		2
Zhang X et al (2009)	√		√	√		3
Tong Y et al (2009)	√	√	√	√	√	5
Cai JP et al (2009)	√			√		2
Zhang R et al (2009)	√	√	√	√	√	5
Tong Y et al (2013)	√	√	√	√	√	5
Weng ZB et al (2014)	√	√	√		√	4
Luo Y et al (2016)	√		√	√	√	4
Zhao L et al (2019)	√	√	√	√	√	5
Wang FJ et al (2020)	√		√	√		3
Luo LL et al (2024)	√	√	√			3
He ZJ et al (2025)	√	√	√	√	√	5

(1) publication in a peer-reviewed journal; (2) statement of control of temperature; (3) randomization of treatment or control; (4) blinded induction of model; (5) blinding of outcome assessment; (6) use of anesthetic without proven protective measures that may have toxic effects on bones; (7) appropriate animal model (aged, diabetic, or hypertensive); (8) sample size estimation; (9) compliance with animal welfare regulations; (10) declared any potential conflict of interest.

BMD

In 11 studies,^20–23^,25–31 14 comparisons demonstrated significant impacts of EUC for improved BMD values contrasted with control groups (SMD = 2.16; 95% CI = 1.63 to 2.69; heterogeneity Chi² = 46.96, df = 13, P < 0.001, I² = 72.3%, Figure 2). Due to the significant heterogeneity of the incorporated research, the random-effects model was utilized.

Figure 2.

Bone mineral density.

Bone Histomorphometric and Biomechanical Parameters

BV/TV

Five studies^{20,21,23,28,33} demonstrated significant impacts of EUC for improved BV/TV compared with control groups (SMD = 1.84; 95% CI = 1.00 to 2.68; heterogeneity Chi² = 10.52, df = 4, P = 0.033, I² = 62%). Sensitivity analyses identified that the source of the heterogeneity was mainly from one study,²¹ and the I² value was reduced to 6.1% when this study was eliminated. The fixed-effects model revealed that EUC treatment increased BV/TV significantly more than control intervention (SMD = 1.39; 95% CI = 0.85 to 1.94; p = 0.362, heterogeneity Chi² = 3.2, df = 3, Figure 3).

Figure 3.

Bone volume over total volume.

Tb.N

Tb.N^20,28 was reported in two studies^, and the finding revealed that EUC therapy significantly improved Tb.N measures when contrasted with the control group (SMD = 4.33; 95% CI = 3.22 to 5.44; heterogeneity Chi² = 0.83, df = 1, P < 0.001, I² = 0%, Figure 4).

Figure 4.

Trabecular number.

Tb.Th

Tb.Th^20,21,28 was reported in three studies^, and the finding revealed that EUC therapy significantly improved Tb.Th measures when contrasted with the control group (SMD = 2.25; 95% CI = 0.87 to 3.62; heterogeneity Chi² = 9.00, df = 2, P = 0.011, I² = 77.8%, Figure 5).

Figure 5.

Trabecular thickness.

Tb.Sp

Tb.Sp^20,21,28 was reported in three studies^, and the findings revealed that EUC therapy was linked to a significant decline contrasted with the control group (SMD = −3.635; 95% CI = −6.214 to −1.056; heterogeneity Chi² = 18.99, df = 2, P < 0.001, I² = 89.5%). Sensitivity analyses identified that the source of the heterogeneity was mainly from one study,²¹ and the I² value was reduced to 0% when this study was eliminated. The fixed-effects model revealed that EUC treatment decreased Tb.Sp significantly more than control intervention (SMD = −4.87; 95% CI = −6.08 to −3.67; heterogeneity Chi² = 0.05, df = 1, P < 0.001, I² = 0%, Figure 6).

Figure 6.

Trabecular separation.

Maximum Bone Load

Six studies^{20,21,24,26,31,32} examined maximum bone load, and the finding revealed that EUC therapy significantly improved it contrasted with the control group (SMD = 1.14; 95%CI = 0.68 to 1.60; heterogeneity Chi² = 10.41, df = 5, P < 0.001, I² = 52%, Figure 7).

Figure 7.

Bone Maximum load.

Bone Biochemical Markers

Serum Osteocalcin(S-OCN)

Four studies^20,21,26,32 declared S-OCN findings indicated that EUC therapy did not result in a significant difference relative to the control group (SMD = −0.42; 95% CI = −1.93 to 1.10; heterogeneity Chi² = 41.17, df = 3, P = 0.588, I² = 92.7%, Figure 8).

Figure 8.

Serum osteocalcin.

Serum Alkaline Phosphatase(S-ALP)

Eight studies^{20,21,24,25,28,30,32,33} on S-ALP showed a significant decrease in the EUC treatment group relative to the control group (SMD = −1.66; 95% CI = −3.26 to −0.06; heterogeneity χ² = 134.62, df = 7, P < 0.001, I² = 94.8%, Figure 9).

Figure 9.

Serum alkaline phosphatase.

Publication Bias and Sensitivity Analysis

Herein, Egger's test was employed to evaluate the publication bias possibility, revealing a publishing bias (P = 0.019, Figure 10). Additionally, sensitivity analyses were conducted by deleting each trial, and no noticeable effect was discovered (Figure 11).

Figure 10.

Egger's test.

Figure 11.

Sensitivity analysis. (A–H) represent the sensitivity of BMD, BV/TV, Tb.N, Tb.Th, Tb.Sp, Maximum bone load, S-OCN, and S-ALP, respectively. The sensitivity analysis was conducted by omitting single studies one by one, and no study with critical influence was found.

Discussion

This research is the first preclinical systematic review and meta-analysis of the anti-osteoporosis effectiveness of EUC. Across 14 studies involving 343 ovariectomized rats, EUC significantly increased BMD, BV/TV, Tb.N, and Tb.Th, while reducing Tb.Sp and S-ALP. EUC was also associated with improved maximum bone load. Serum osteocalcin (S-OCN) did not differ significantly between groups.

A systematic review of preclinical data facilitates a thorough understanding of disease pathways and the pharmacological actions of medications. The following summarizes the potential EUC pathways that mediated anti-OP actions in the reviewed investigations: (1) by up-regulating the level of serum E2 and increasing the content of IGF-1, EUC administration was associated with improved bone remodeling–related outcomes in ovariectomized rat models. Meanwhile, the results of HE staining showed that long-term administration of EUC had no obvious stimulating effect on the uterus weight of rats.²⁷ (2) EUC treatment was associated with changes in bone turnover–related markers, including serum ALP and osteocalcin, suggesting a potential modulatory effect on bone metabolism.²⁵ (3) The observed anti-osteoporotic effects of EUC may be mediated by multiple bioactive compounds, although definitive causal pathways remain to be validated. The anti-osteoporosis effects of EUC may be mediated by multiple bioactive compounds, but mechanistic pathways require further experimental confirmation. Glycine, lysine, tryptophan, docosahexaenoic acid, and glucose may serve as potential metabolic biomarkers, which were analyzed by GC-MS metabolomics technology used in osteoporosis rat serum by oral EUC administration.³¹ Glycine is a constituent amino acid of endogenous antioxidant reduced glutathione (GSH) of the body. GSH significantly increases BMD in osteoporotic rats.³⁶ Lysine is an essential component of bone collagen synthesis, which prevent osteoporosis by enhancing NO generation and type I collagen synthesis by osteoblasts in both normal and osteopenic bone.³⁷ Moreover, lysine changes the physical properties of bone collagen fibers, helping the intestinal tract absorb calcium, reducing renal excretion of calcium, and preventing bone loss.³⁸ As a product of hydroxylation and synthesis of tryptophan, 5-HT stimulates the proliferation of osteoid cells by inhibiting the release of prostaglandin E2 or binding to osteoblasts.³⁹ Docosahexenoic acid (DHA) can improve the biomechanical properties of ovariectomized rat bone and reduce the incidence of osteoporosis-related fracture by regulating osteoblast, blood alkaline phosphatase activity, and prostaglandin synthesis to maintain a high bone mass.^40,41 The inhibitory effect of osteoporosis rats on lipase in adipose tissue decreased, with the decrease in estrogen levels, prompting the increase of fat synthesis, which is one of the reasons for postmenopausal obesity in women.⁴²

Osteoporosis is a systemic bone disorder characterized by a loss in bone mass, damage of bone microarchitecture, and an elevated risk of fracture, posing a serious threat to the health of the elderly, especially postmenopausal women. In menopausal women, estrogen insufficiency may result in raised bone remodeling and excessive bone loss.⁴³ Osteoporosis-induced fractures impose a large financial, disability, and death impact on older men. Moreover, only half of them could return to normal life functions before the onset of symptoms among those aged ≥65 years.⁴⁴ The animal experiment is essential, which means that the ongoing disease process contributes to the overall clinical condition and leads to clinical disease. Animal models of OP include several animals and experimental techniques. OP animal models can be classified into two categories based on their pathogenesis: models with diminished bone formation (senile osteoporosis, senescence accelerated mouse strain P6, and glucocorticoid) and models with increased bone resorption (ovariectomized osteoporosis, disuse osteoporosis, and nutritional osteoporosis). Ovariectomized rat models had the advantages of simple manipulation, good technique repeatability, short cycles, and fewer ethical restrictions, which were considered the gold standard animal models for postmenopausal osteoporosis.⁴⁵

Osteocalcin (OCN) is formed by non-proliferative osteoblasts and is the main component of non-collagen in bone tissue.⁴⁶ Mature OCN is mainly deposited in the interstitial cells of bone tissue and dentin, and a small part is released into the blood circulation.⁴⁷ Some in vitro and in vivo experiments have revealed that OCN is involved in osteoblast differentiation, matrix mineralization, and bone resorption regulation.^48–51 In our study, ovariectomized rats exhibited elevated serum OCN levels, which showed a non-significant decrease following EUC treatment. Although we performed the subgroup analysis according to the different factors of rat: age, drug dose, and time of drug intervention, no obvious difference was seen.

ALP is a widely distributed enzyme found in several tissues, and its low density is evaluated in normal human serum.⁵² Moreover, ALP activity is commonly used as a marker of early osteoblast differentiation, and this enzyme is a product of osteoblast activity.⁵³ Previous studies have suggested that increased bone ALP activity after ovariectomy may indicate a high bone turnover state, with increases in both osteoblastic and osteoclastic activity; however, relatively greater osteoclastic activity can lead to net bone loss. In our meta-analysis, EUC supplementation was associated with lower S-ALP levels compared with control, suggesting a potential effect on bone turnover. However, this pooled effect was marginal, with the upper confidence interval approaching zero, which limits the certainty of this finding.

Limitations

This study has multiple shortcomings. First, we missed a few results, although we searched eight databases with no language constrain. Second, since research with unfavorable outcomes may be less likely to be published, selection bias may exist. Third, the heterogeneity of EUC by crude preparation or extraction methods or even by origin should be regarded, as this may jeopardize the validity of our findings. We call for standardization of expert consensus on the crude or extraction methods of different varieties of TCM in the experiments of osteoporosis management. Such a benefit can save drug resources and ultimately increase the preclinical research evidence credibility for TCM treatment of osteoporosis.

Conclusion

EUC therapy promoted BMD, bone microarchitecture, bone biomechanics, as well as biochemical bone markers in PMOP animal models. These findings suggest that Eucommia ulmoides cortex may exert protective effects against estrogen deficiency–induced bone loss in preclinical models However, because of the limited available animal research and the low quality of their studies, future studies should focus on standardized extract preparation, dose-response relationships, and mechanistic validation using molecular and genetic approaches before clinical translation can be considered.

Footnotes

Acknowledgements

None.

ORCID iD

Shen Wang

Ethics Considerations

Not applicable.

Consent to Participate

Not applicable.

Consent to Publication

Not applicable.

Author Contributions

Conceptualization: Daming Wang.

Data curation: Shen Wang, Yang Liu.

Formal analysis: Shen Wang, Yang Liu.

Funding acquisition: Li Wang.

Investigation: Yifeng Yuan.

Methodology: Shen Wang, Yang Liu, Daming Wang

Software: Simiao Chen.

Supervision: Liliang Zou.

Validation: Shen Wang, Yang Liu.

Writing – original draft: Shen Wang.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Zhejiang Provincial Natural Science Foundation of China, Zhejiang Key Laboratory of Intelligent Rehabilitation and Translational Neuroelectronics, Clinical Research Program of Zhejiang Provincial Administration of Traditional Chinese Medicine, Traditional Chinese Medicine Inheritance and Innovation Talent Support Program of Zhejiang, (grant number No: ZCLQ24H2701, No: 2024E10108, No: 2026ZL0459, No: 2023ZR104).

Clinical Research Program of Zhejiang Provincial Administration of Traditional Chinese Medicine (2026ZL0459). Traditional Chinese Medicine Inheritance and Innovation Talent Support Program of Zhejiang (2023ZR104). Zhejiang Key Laboratory of Intelligent Rehabilitation and Translational Neuroelectronics (2024E10108). Zhejiang Provincial Natural Science Foundation of China (ZCLQ24H2701)

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability

All data generated or analysed during this study are included in this published article

References

Black

Rosen

. Postmenopausal osteoporosis. N Engl J Med 2016;374(3):254-262. doi:10.1056/NEJMcp1513724

Hawarden

Bullock

Cox

, et al. Osteoporosis care in primary care settings: a national UK e-survey. Arch Osteoporos. 2025;20(1):109. doi:10.1007/s11657-025-01591-8

Ayers

Kansagara

Lazur

Kwon

Harrod

. 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. 2023;176(2):182-195. doi:10.7326/M22-0684

Liang

Chen

Shi

, et al. Global epidemiology and burden of osteoporosis among postmenopausal women: insights from the Global Burden of Disease Study 2021. NPJ Aging. 2025;11(1):78. doi:10.1038/s41514-025-00269-2

Drake

Khosla

. Male osteoporosis. Endocrinol Metab Clin North Am. 2012;41(3):629-641. doi:10.1016/j.ecl.2012.05.001

Bouillon

Carmeliet

Verlinden

, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29(6):726-776. doi:10.1210/er.2008-0004

Holick

. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–281. doi:10.1056/NEJMra070553

Grodstein

Stampfer

Colditz

, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336(25):1769-1775. doi:10.1056/NEJM199706193362501

Song

Wang

, et al. Simvastatin induces estrogen receptor-alpha expression in bone, restores bone loss, and decreases ERα expression and uterine wet weight in ovariectomized rats. J Bone Miner Metab. 2011;29(4):396-403. doi:10.1007/s00774-010-0231-y

10.

Mohd Effendy

Mohamed

Muhammad

Mohamad

Shuid

. The effects of tualang honey on bone metabolism of postmenopausal women. Evid Based Complement Alternat Med. 2012;2012(1):938574. doi:10.1155/2012/938574

11.

Adomaityte

Farooq

Qayyum

. Effect of raloxifene therapy on venous thromboembolism in postmenopausal women: a meta-analysis. Thromb Haemost. 2008;99(2):338-342. doi:10.1160/TH07-07-0468

12.

Hernandez

Sørensen

Pedersen

Jacobsen

Lash

. Tamoxifen treatment and risk of deep venous thrombosis and pulmonary embolism. Cancer. 2009;115(19):4442-4449. doi:10.1002/cncr.24508

13.

Wang

, et al. Eucommia ulmoides Oliv.: ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine. J Ethnopharmacol 2014;151(1):78-92. doi:10.1016/j.jep.2013.11.023

14.

Xing

Wang

, et al. Chemical constituents, biological functions and pharmacological effects for comprehensive utilization of Eucommia ulmoides Oliver. Food Science and Human Wellness. 2019;8(2):177-188. doi:10.1016/j.fshw.2019.03.013

15.

Hussain

Tan

Liu

, et al. Health-promoting properties of Eucommia ulmoides: a review. Evidence-Based Complementary Altern Med. 2016;2016(1):e5202908. doi:10.1155/2016/5202908

16.

Wang

Yuan

Chen

, et al. Extract from Eucommia ulmoides Oliv. Ameliorates arthritis via regulation of inflammation, synoviocyte proliferation and osteoclastogenesis in vitro and in vivo. J Ethnopharmacol. 2016;194:609-616. doi:10.1016/j.jep.2016.10.038

17.

Zhang

Pan

Kong

Juan

Mei

. Effects of total lignans from Eucommia ulmoides barks prevent bone loss in vivo and in vitro. J Ethnopharmacol. 2014;155(1):104-112. doi:10.1016/j.jep.2014.04.031

18.

Zhao

Wang

Nie

, et al. Eucommia ulmoides leaf extract alters gut microbiota composition, enhances short-chain fatty acids production, and ameliorates osteoporosis in the senescence-accelerated mouse P6 (SAMP6) model. Food Sci Nutr 2020;8(9):4897-4906. doi:10.1002/fsn3.1779

19.

Cheng

Chien-Fu Lin

Tsai

, et al. 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 2019;244:112074. doi:10.1016/j.jep.2019.112074

20.

Zhang

Liu

, et al. Du-Zhong (Eucommia ulmoides Oliv.) cortex extract prevent OVX-induced osteoporosis in rats. Bone. 2009;45(3):553-559. doi:10.1016/j.bone.2008.08.127

21.

Liu

Liang

. Effect and mechanism of Eucommia ulmoides in regulating the JAK2/STAT3 signaling pathway in ovariectomized osteoporotic rats. Chin J Surg Integr Trad Western Med. 2025;31(2):223-228. doi:10.3969/j.issn.1007-6948.2025.02.012

22.

Luo

Zhang

Ren

, et al. Study on the effect and mechanism of Eucommiae cortex decoction on osteoporosis in ovariectomized rats. Trad Chin Drug Res Clin Pharmacol. 2024;35(4):461-468. doi:10.19378/j.issn.1003-9783.2024.04.002

23.

Wang

Qiu

Zheng

Zhang

. Bone morphometric study on prevention and treatment of osteoporosis in ovariectomized rats by single kidney-tonifying Chinese herb. Tianjin Med J. 1999;27(3):131-134.

24.

Cal

Zhang

Xia

Xie

. Effect of Eucommia bark on weight of femur, mineral content, anti-bend strength of tibiae and Serum ALP in ovariectomized rats. Lishizhen Med Mater. 2009;20(8):1967-1969. doi:10.3969/j.issn.1008-0805.2009.08.065

25.

Zhao

Chen

. Effect of salt -processed Eucommia on biochemical indexes of bone metabolism in ovariectomized osteoporosis rat. Lishizhen Med Mater Medica Res. 2019;30(3):587-588. doi:10.3969/ j.issn.1008-0805.2019.03.025

26.

Zhang

Cai

Ding

, et al. Effect of salt Eucommiaon biochemical markers of bone metabolism, bone density and biomechanics of ovariectomized rats. J Sichuan Trad Chin Med. 2009;27(3):12-14.

27.

Tong

. Effects of EmeiDuZhong on BMD and Serum IGF-1 in rats after ovariectomy. J Anhui Agric Sci. 2009;37(16):7458-7459. doi:10.3969/j.issn.0517-6611.2009.16.063

28.

Luo

Chen

Guan

, et al. Effects of Eucommia extract on bone metabolism, bone mineral density and bone microstructure in ovariectomized rats. J Chin Med Mater. 2016;39(11):2624-2628. doi:10.13863/j.issn1001-4454.2016.11.047

29.

Tong

. Effects of salt-processing Eucommiae Cortex on BMD and Serum IGF-I in Ｒats after ovariectomy. Chin Jo Exp Trad Med Formulae. 2013;19(17):255-257. doi:10.11653/syfj2013170255

30.

Weng

Yan

Cai

Chen

. Study of the effect of salt—roast processing product of Eucommia ulmoides Oliv．on osteoporosis in ovariectomized rats. Chin J Osteoporosis. 2014;20(12):1457-1463.

31.

Wang

Luo

Zhang

Liu

. Study on anti-osteoporosis effect of Eucommiae Cortex based on GC-MS metabonomics. China J Chin Materia Medica. 2020;45(22):5555-5560. doi:10.19540/j.cnki.cjcmm.20200624.202

32.

. The experimental research about Eucommia’s effect on OVX rats [Master’s thesis]. Nanjing Univ Trad Chin Med; 2008. doi:10.7666/d.y1645873

33.

Xiao

. The Study of Antiosteoporotie Elements from Epimedium, Drynaria and Eucommia and Their Mechanism [Doctoral dissertation]. Tianjin Medical University; 2001.

34.

Macleod

Collins

Howells

Donnan

. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. 2004;35(5):1203-1208. doi:10.1161/01.STR.0000125719.25853.20

35.

Bao

Zheng

Tong

, et al. Danshensu for myocardial ischemic injury: preclinical evidence and novel methodology of quality assessment tool. Front Pharmacol. 2018;9:1445. doi:10.3389/fphar.2018.01445

36.

Muthusami

Ramachandran

Muthusamy

, et al. Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats. Clin Chim Acta 2005;360(1):81-86. doi:10.1016/j.cccn.2005.04.014

37.

Fini

Torricelli

Giavaresi

Carpi

Nicolini

Giardino

. Effect of L-lysine and L-arginine on primary osteoblast cultures from normal and osteopenic rats. Biomed Pharmacother 2001;55(4):213-220. doi:10.1016/S0753-3322(01)00054-3

38.

Liu

Zhang

, et al. Metabolomic profiles delineate signature metabolic shifts during estrogen deficiency-induced bone loss in rat by GC-TOF/MS. PLoS One. 2013;8(2):e54965. doi:10.1371/journal.pone.0054965

39.

Bliziotes

Eshleman

Burt-Pichat

, et al. Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone. 2006;39(6):1313-1321. doi:10.1016/j.bone.2006.06.009

40.

Fallon

Nazarian

Nehra

, et al. The effect of docosahexaenoic acid on bone microstructure in young mice and bone fracture in neonates. J Surg Res 2014;191(1):148-155. doi:10.1016/j.jss.2014.04.005

41.

Högström

Nordström

. N⁻3 fatty acids are positively associated with peak bone mineral density and bone accrual in healthy men: the NO2 study. Am J Clin Nutr 2007;85(3):803-807. doi:10.1093/ajcn/85.3.803

42.

Saarinen

Saukkonen

Kivelä

, et al. Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin Endocrinol (Oxf) 2010;72(4):481-488. doi:10.1111/j.1365-2265.2009.03680.x

43.

Cohen

Dempster

Recker

, et al. Abdominal fat is associated with lower bone formation and Inferior bone quality in healthy premenopausal women: a transiliac bone biopsy study. J Clin Endocrinol Metab. 2013;98(6):2562-2572. doi:10.1210/jc.2013-1047

44.

Boonen

Laan

Barton

Watts

. Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies. Osteoporos Int. 2005;16(10):1291-1298. doi:10.1007/s00198-005-1945-x

45.

Kalu

Liu

Hardin

Hollis

. The aged rat model of ovarian hormone deficiency bone loss. Endocrinology. 1989;124(1):7-16. doi:10.1210/endo-124-1-7

46.

Atalay

Elci

Kayadibi

Onder

Aka

. Diagnostic utility of osteocalcin, undercarboxylated osteocalcin, and alkaline phosphatase for osteoporosis in premenopausal and postmenopausal women. Ann Lab Med. 2011;32(1):23-30. doi:10.3343/alm.2012.32.1.23

47.

Hauschka

Lian

Cole

Gundberg

. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev. 1989;69(3):990-1047. doi:10.1152/physrev.1989.69.3.990

48.

Christopoulou

Stavropoulou

Anastassopoulos

, et al. Evaluation of modal damping factor as a diagnostic tool for osteoporosis and its relation with serum osteocalcin and collagen I N-telopeptide for monitoring the efficacy of alendronate in ovariectomized rats. J Pharm Biomed Anal 2006;41(3):891-897. doi:10.1016/j.jpba.2005.12.038

49.

Deepak

Kayastha

McNamara

. Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes. FASEB J 2017;31(7):3027-3039. doi:10.1096/fj.201601280R

50.

Luvizuto

Dias

SMD

Queiroz

, et al. Osteocalcin immunolabeling during the alveolar healing process in ovariectomized rats treated with estrogen or raloxifene. Bone. 2010;46(4):1021-1029. doi:10.1016/j.bone.2009.12.016

51.

Wang

Shu

Chen

. Equol promotes rat osteoblast proliferation and differentiation through activating estrogen receptor. Genet Mol Res. 2014;13(3):5055-5063. doi:10.4238/2014.July.4.21

52.

Vimalraj

. Alkaline phosphatase: structure, expression and its function in bone mineralization. Gene. 2020;754:144855. doi:10.1016/j.gene.2020.144855

53.

Holtorf

Jansen

Mikos

. Ectopic bone formation in rat marrow stromal cell/titanium fiber mesh scaffold constructs: effect of initial cell phenotype. Biomaterials. 2005;26(31):6208-6216. doi:10.1016/j.biomaterials.2005.04.006

Antiosteoporosis Effect of Eucommia Ulmoides Cortex in Postmenopausal Osteoporosis Animal Models: A Systematic Review and Meta-Analysis

Abstract

Systematic Review Registration

Keywords

Introduction

Methods

Literature Retrieval

Inclusion Criteria

Exclusion Criteria

Outcome Measurements

Data Recovery

Data Analysis

Results

Literature Selection

Basic Information of Involved Studies

Bias Risk

BMD

Bone Histomorphometric and Biomechanical Parameters

BV/TV

Tb.N

Tb.Th

Tb.Sp

Maximum Bone Load

Bone Biochemical Markers

Serum Osteocalcin(S-OCN)

Serum Alkaline Phosphatase(S-ALP)

Publication Bias and Sensitivity Analysis

Discussion

Limitations

Conclusion

Footnotes

Acknowledgements

ORCID iD

Ethics Considerations

Consent to Participate

Consent to Publication

Author Contributions

Funding

Declaration of Conflicting Interests

Data Availability

References