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Activation of osteoblast ferroptosis by risperidone accelerates bone loss in mice models of schizophrenia

Journal of Orthopaedic Surgery and Research volume 20, Article number: 83 (2025) Cite this article

Abstract

Background

Ferroptosis is an iron-dependent regulatory cell death, which plays an essential role in bone loss. This study investigated whether the mechanism of risperidone (RIS)-induced bone loss is related to ferroptosis.

Methods

The schizophrenia mice were induced by administering MK-801. Subsequently, RIS were injected, or ferroptosis inhibitor Ferrostatin-1 (Fer-1) co-injected for 8 weeks. Bone loss of schizophrenia mice were assessed using microCT, H&E staining, ALP staining, ARS staining and WB, respectively. Ferroptosis of schizophrenia mice were detected by Iron Colorimetric Assay Kit and WB, respectively. In addition, ALP staining, ARS staining, and WB were performed to reveal the role of RIS in osteogenic differentiation of MC3T3-E1 and BMSCs cells.

Results

RIS treatment facilitates bone loss in schizophrenia mice and inhibit osteogenic differentiation of MC3T3-E1 and BMSCs cells. Moreover, up-regulated ferroptosis was found in vivo and in vitro after RIS treatment. Interesting, the bone loss and inhibition of osteogenic differentiation induced by RIS in schizophrenia mice were reversed by ferroptosis inhibitor Fer-1.

Conclusion

Ferroptosis induced by RIS aggravates the bone loss of schizophrenia mice via inhibiting osteogenic differentiation.

Introduction

The increasing prevalence of schizophrenia worldwide has become a significant concern, as the disease burden associated with it ranks among the highest for chronic illnesses [1, 2]. Currently, antipsychotic drugs remain the primary treatment option for managing symptoms; however, their use is not without potential adverse reactions. One such side effect that has been observed in patients using antipsychotic medications is bone loss [3,4,5]. Bone loss is frequently associated with osteoporosis, a metabolic bone disease characterized by the excessive depletion of bone protein and minerals [6,7,8]. This leads to diminished bone density and strength. The etiology of this condition is intricately linked to bone metabolism, which results in the deterioration of bone microstructure, rendering bones more fragile and brittle, and consequently increasing the risk of fractures [9,10,11]. Risperidone (RIS), a commonly prescribed anti-schizophrenia medication in clinical practice, has been extensively studied regarding its impact on bone health [12]. Previous research has indicated that RIS may contribute to bone loss in individuals receiving this drug. Amini et al. found that RIS accelerates bone loss in rats with autistic-like deficits [13]. Motyl et al. ‘s study also found that RIS can cause bone loss in mice [14]. Besides, The incidence of osteoporosis was significantly increased in patients with schizophrenia treated with RIS [15]. However, the specific molecular mechanism of the effect of RIS on bone loss in mice remains unclear, and it is crucial to elucidate the mode of operation of RIS in order to ensure the drug’s safety and enhance patients’ quality of life.

Ferroptosis is a non-apoptotic cell death pathway, mainly characterized by mitochondrial shrinkage, ridge reduction, membrane density increase, and outer membrane rupture [16]. At chemical level, the main manifestations were glutathione depletion, glutathione peroxidase 4 decline, intracellular accumulation of iron ionites, ROS overproduction and lipid peroxidation [17,18,19]. Previous studies have shown that Ferroptosis is involved in the occurrence and development of bone loss. Yang et al. found that ferroptosis contributes to the inflammatory bone loss associated with apical periodontitis [20]. Zhu et al. found that high-fat diet increases bone loss by inducing ferroptosis in osteoblasts [21]. In addition, berberine mitigates bone loss caused by nonalcoholic fatty liver disease through the inhibition of ferroptosis in the past research [22]. The function of ferroptosis is regulated by various mechanisms and has different effects in diverse cells and diseases. However, the relationship between RIS and ferroptosis has not been investigated in any studies. This study aims to investigate whether RIS causes bone loss in mice with schizophrenia by affecting ferroptosis in osteoblasts and mesenchymal stem cells.

Materials and methods

Materials

Mouse bone marrow mesenchymal stem cells (BMSCs) and were MC3T3-E1 cells purchased from Wuhan Pricella Biotechnology Co., Ltd (Shanghai, China). Hematoxylin staining solution, Eosin staining solution, Alkaline phosphatase staining solution and Alizarin red staining solution were purchased from Solaibao Technology Co., LTD (Beijing, China). Antibodies against ACSL4, COX2, SCL7A11, GPX4, β-Actin, ALP, OCN and OPN were from Abcam (Cambridge, United Kingdom). Risperidone were purchased from Shanghai Yuanye Bio-Technology Co., Ltd (Shanghai, China). MK-801 and Ferrostatin-1 (Fer-1) were purchased from MedChemExpress LLC (New Jersey, USA).

Animal model establishment and intervention

After 7 days of adaptive feeding, mice were intraperitoneally injected with MK-801 (0.5 mg/kg) for 2 weeks to establish a mouse model of schizophrenia, designated as the MK-801 group [23]. All experimental animal procedures were approved by the Animal Care Welfare Committee of Guizhou Medical University (permission No. 2000731). Control group mice were injected with the same amount of normal saline. The MK-801 + RIS group was treated with intraperitoneal injection of RIS (1 mg/kg/d) for 8 weeks in the schizophrenia mouse model. The MK-801 + RIS + Fer-1 group was intraperitoneally injected with ferrostatin-1 (5 mg/kg/3d) after RIS injection in the schizophrenia mouse model [24]. After 8 weeks of intervention, mice were killed by intraperitoneal injection of 0.75% pentobarbital sodium, and femurs were collected for further examination (A workflow of animal experiments was shown in Fig. 1A).

Fig. 1
figure 1

Effect of RIS on bone loss in mice with schizophrenia. (A) A workflow of animal part experiments, (B) representative images of microCT, (C) quantitative analysis of new bone formation area for bone mineral density (BMD), (D) directly measured bone volume fraction (BV/TV), (E) trabecular thickness (Tb.Th), (F) trabecular number (Tb.N), (G) H&E staining. Data are presented as the mean ± SD. *P < 0.05 vs. Control; #P < 0.05 vs. MK-801

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Microcomputed tomography (micro-CT)

Mice were euthanized under general anesthesia, and their femurs were then explanted and fixed in 4% paraformaldehyde. The subsequent steps taken were in accordance with those described previously [25]. The three-dimensional (3D) superior aspect images and transverse views were generated using Avizo software. Micro-CT images were analyzed using PMOD 3.4 software (Pmod Technologies, Zurich, Switzerland) to calculate indexes including tissue volume (TV), bone volume (BV), directly measured bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N).

Hematoxylin and eosin (H&E) staining

Slices were put into xylene for 15 min, washed with 100% anhydrous ethanol for 3 min, 90% ethanol for 3 min and 75% ethanol for 3 min, followed by gradient ethanol dewaxing to water. Hematoxylin staining was performed for 5 min, followed by washing and soaking in PBS for 5 min, eosin staining for 2 min, washing with water, gradient alcohol dehydration, xylene treatment twice for 5 min each and neutral resin blocked cover slips. Subsequently, the femur damage were observed under an optical microscope (magnification, x400).

Western blotting

The total protein was extracted and the content was tested using a BCA protein assay kit. Then the protein (30 mg) was separated by 10% SDS-PAGE and transferred onto a PVDF membrane. Membranes for target protein (and β-actin) were blocked with 5% skimmed milk at 25 °C for 1 h. Relative membranes were incubated with primary antibody of ACSL4 (1:1000), COX2 (1:1000), SCL7A11 (1:1000), GPX4 (1:1000), ALP (1:1000), OCN (1:1000), and OPN (1:1000), followed by incubation with secondary antibody for 1 h. Finally, the protein bands were tested by an ECL-detecting kit and β-actin was served as loading control.

Measurement of iron concentration

The mouse femur tissue samples or different cells were collected following the kit’s operating instructions, and the standard product was diluted to create a solution with an A-H concentration gradient. 200uL of working liquid was added to each well of a 96-well plate, followed by the addition of the test sample and standard solution. After mixing, incubation at 37 °C for 30 min took place. The absorbance at 562 nm was measured using a fully automatic enzyme marker, and the sample content was determined using a standard curve.

Cell culture and treatment

MC3T3-E1 cells and BMSCs were cultured in the RPMI-1640 medium containing 10% fetal bovine serum, penicillin (100U/ml), streptomycin (100 μg/ml). Both of the different cells were subsequently treated with RIS (100 μm) and Fer-1 (5 μm) for 48 h.

Alkaline phosphatase (ALP) staining

ALP staining was performed using the alkaline phosphatase detection kit according to the manufacturer’s instructions.

Alizarin red S (ARS) staining

According to the instructions of the kit, alizarin red staining solution was added and incubated at room temperature in the dark for 30 min, washed with distilled water, and observed by microscope.

Statistical analyses

SPSS 26.0 was applied for statistical analysis, and experimental data were expressed as mean ± standard deviation (x ± s). The statistical analysis was performed using one-way analysis of variance (ANOVA) with Tukey post test for multiple comparisons or unpaired Student’s t-test, and P < 0.05 was considered a statistically significant difference.

Results

Effect of RIS on bone loss in mice with schizophrenia

As shown in Fig. 1B, relevant bone loss in mice with schizophrenia was assessed following RIS treatment using micro-CT analysis. And the quantification results were shown in Fig. 1C-F, the MK-801 + RIS group exhibited lower BMD (Fig. 1C), BV/TV (Fig. 1D), TB.TH (Fig. 1E), and TB.N (Fig. 1F) compared to the Control group, while no significant differences in these parameters were observed between the Control group and the MK-801 group. In addition, as depicted in Fig. 1G, the joint surface exhibited a smooth texture, the tissue structure was well-defined, and there was a high density of trabecular bone area in femur tissues of both the Control group and MK-801 group. However, following RIS intervention, femur tissues of mice displayed signs of bone trabecular fracture and loss. These findings suggest that schizophrenic mice may experience bone loss as a result of RIS treatment.

Effect of RIS on ferroptosis in mice with schizophrenia

To assess the effect of RIS on ferroptosis in mice with schizophrenia, the iron concentration (Fig. 2A) and the expression of ferroptosis-related proteins (Fig. 2B) in femur tissues of mice were measured. Compared with the MK-801 group, the iron concentration in MK-801 + RIS group were significantly increased (P < 0.05). Besides, the ACSL4 and COX2 protein expression in MK-801 + RIS group were significantly increased compared with the MK-801 group (P < 0.05). Moreover, the SLC7A11 and GPX4 protein expression in MK-801 + RIS group were significantly decreased compared with the MK-801 group (P < 0.05). These results indicated that RIS activated ferroptosis in mice with schizophrenia.

Fig. 2
figure 2

Effect of RIS on ferroptosis in mice with schizophrenia. (A) Iron concentration detection, (B) ferroptosis-related protein expression were detected by WB, (C-F) quantitative analysis of autophagy-related protein expression, (C) ACSL4, (D) COX2, (E) GPX4, (F) SLC7A11. Data are presented as the mean ± SD. *P < 0.05 vs. MK-801

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Effect of Fer-1 on RIS-induced bone loss in schizophrenia mice

As shown in Fig. 3A-B, ALP staining and ARS staining was used to detect the level of bone loss in each group. Compared with the MK-801 group, Dyeing strength, and calcium deposition in MK-801 + RIS group was significantly decreased. Fer-1 functions as a classic ferroptosis inhibitor, the dyeing strength and calcium deposition were increased after Fer-1 treatment compared with MK-801 + RIS group. Moreover, the expression of osteogenic related proteins in femur tissues of mice was detected by WB (Fig. 3C). As shown in Fig. 3D, the ALP, OCN, and OPN protein expression in the MK-801 + RIS group were significantly decreased compared with the MK-801 group (P < 0.05), while it was significantly increased in the MK-801 + RIS + Fer-1 group compared with the MK-801 + RIS group (P < 0.05). These results suggest that RIS can induce bone loss in schizophrenia mice by activating ferroptosis.

Fig. 3
figure 3

Effect of Fer-1 on RIS-induced bone loss in schizophrenia mice. (A) ALP staining, (B) ARS staining, (C) osteogenic-related protein expression were detected by WB, (D) quantitative analysis of osteogenic-related protein expression. Data are presented as the mean ± SD. *P < 0.05 vs. MK-801; #P < 0.05 vs. MK-801 + RIS

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Effect of RIS on ferroptosis in MC3T3-E1 cells

To investigate the impact of RIS on ferroptosis in MC3T3-E1 cells, a 48-hour treatment with 100μM RIS was administered to assess its effect. The results of iron concentration revealed that compared with the Control group, the iron concentration in the RIS group was significantly increased (P < 0.05) (Fig. 4A). In addition, WB was used to detect the expression of ferroptosis-related proteins in MC3T3-E1 cells (Fig. 4B). The results showed that the protein expression level of ACSL4 and COX2 were significantly increased in the RIS group compared to the Control group (P < 0.05) (Fig. 4C-D). And compared with the Control group, the SLC7A11 and GPX4 protein expression in the RIS group were significantly decreased (P < 0.05) (Fig. 4E-F). These results indicated that RIS treatment promotes ferroptosis in MC3T3-E1 cells.

Fig. 4
figure 4

Effect of RIS on ferroptosis in MC3T3-E1 cells. (A) Iron concentration detection, (B) ferroptosis-related protein expression were detected by WB, (C-F) quantitative analysis of ferroptosis-related protein expression, (C) ACSL4, (D) COX2, (E) GPX4, (F) SLC7A11. Data are presented as the mean ± SD. *P < 0.05 vs. Control

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Fer-1 treatment reverses the inhibitory effect of RIS on osteogenesis in MC3T3-E1 cells

To investigate whether Fer-1 affects the osteogenesis of MC3T3-E1 cells, the cells were treated with 5μM Fer-1 for 48 h to explore the effect of Fer-1 on osteogenesis in MC3T3-E1 cells. First, ALP staining and ARS staining were used to detect the osteogenic effect of each group on MC3T3-E1 cells (Fig. 5A-B). Compared with the control group, Dyeing strength, and calcium deposition in RIS group was significantly decreased, whereas it was increased in the RIS + Fer-1 group. Then, the expression of osteogenic related proteins in MC3T3-E1 cells was detected by WB (Fig. 5C). The results are shown in Fig. 5D-F, the ALP, OCN, and OPN protein expression in the RIS group were significantly decreased compared with the control group (P < 0.05), while it was significantly increased in the RIS + Fer-1 group compared with the RIS group (P < 0.05). These results suggest that RIS can inhibit osteogenesis in MC3T3-E1 cells by promoting ferroptosis.

Fig. 5
figure 5

Fer-1 treatment reverses the inhibitory effect of RIS on osteogenesis in MC3T3-E1 cells. (A) ALP staining, (B) ARS staining, (C) osteogenic-related protein expression were detected by WB, (D-F) quantitative analysis of autophagy-related protein expression, (D) ALP, (E) OCN, (F) OPN. Data are presented as the mean ± SD. *P < 0.05 vs. RIS

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Effect of RIS on ferroptosis in BMSCs

As shown in Fig. 6A, compared with the Control group, the iron concentration of BMSCs in the RIS group was significantly increased (P < 0.05). Besides, the expression of ferroptosis-related proteins in BMSCs were examined using WB (Fig. 6B). The results showed that the protein expression level of ACSL4 and COX2 of BMSCs were significantly increased in the RIS group compared to the Control group (P < 0.05) (Fig. 6C-D). And compared with the Control group, the SLC7A11 and GPX4 protein expression of BMSCs in the RIS group were significantly decreased (P < 0.05) (Fig. 6E-F). These results indicated that RIS treatment can also enhance ferroptosis in BMSCs.

Fig. 6
figure 6

Effect of RIS on ferroptosis in BMSCs. (A) Iron concentration detection, (B) ferroptosis-related protein expression were detected by WB, (C-F) quantitative analysis of ferroptosis-related protein expression, (C) ACSL4, (D) COX2, (E) GPX4, (F) SLC7A11. Data are presented as the mean ± SD. *P < 0.05 vs. Control

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Fer-1 treatment reverses the inhibitory effect of RIS on osteogenesis in BMSCs

The effect of RIS on the osteogenic differentiation of mouse BMSCS via ferroptosis was further investigated, and the results are presented below. As shown in Fig. 7A-B, ALP staining and ARS staining were further used to detect the osteogenic effect of RIS and Fer-1 on BMSCs. Compared with the control group, Dyeing strength, and calcium deposition in RIS group was significantly decreased, whereas it was increased in the RIS + Fer-1 group. Furthermore, the expression of osteogenic related proteins in BMSCs was detected by WB (Fig. 7C).

Fig. 7
figure 7

Fer-1 treatment reverses the inhibitory effect of RIS on osteogenesis in BMSCs. (A) ALP staining, (B) ARS staining, (C) osteogenic-related protein expression were detected by WB, (D-F) quantitative analysis of autophagy-related protein expression, (D) ALP, (E) OCN, (F) OPN. Data are presented as the mean ± SD. *P < 0.05 vs. RIS

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Compared with the RIS group, Fer-1 treatment significantly increased the ALP, OCN, and OPN protein expression in BMSCs (P < 0.05) (Fig. 7D-F). These results indicated that RIS inhibited the osteogenic differentiation of BMSC cells by activating ferroptosis.

Discussion

Risperidone (RIS) is a widely utilized antipsychotic medication in clinical practice [26, 27]. An increasing body of evidence has demonstrated the association between risperidone and the occurrence of bone loss in patients. Becker et al. found that risperidone treatment in female premenopausal schizophrenia patients leads to hyperprolactinemia and a clinically significant reduction in bone mineral density [28]. Moreover, prolonged administration of risperidone may impose significant physical, emotional, and financial burdens on individuals [29, 30]. In this research, we employed MK-801 to establish a mouse model of schizophrenia. Following 8 weeks of treatment with RIS, the mice exhibited indications of osteoporosis, including a significant presence of fractured and missing trabecular bone. Interesting, Motyl et al. ‘s [14, 31] study also found RIS treatment can induce bone loss in schizophrenic mice. However, elucidating the precise molecular mechanism underlying risperidone-induced bone loss holds paramount importance for promoting rational drug utilization and facilitating the development of novel therapeutic interventions for schizophrenia patients.

Bone loss is usually caused by the imbalance of bone homeostasis in the host, and one of the key reasons is the weakened bone formation ability of osteoblasts [32,33,34]. In addition, altered differentiation potential of BMSCs is responsible to bone loss in vivo [35]. A multitude of factors, including environmental conditions, genetic makeup, and pharmacological agents, influence the differentiation potential of BMSCs [36, 37]. Barnaba et al. ‘s found that exogenous electromagnetic fields stimulation on human osteoblasts accelerates cellular proliferation [38]. Therefore, We investigated the effect of RIS on bone formation ability of MC3T3-E1 cells and BMSCs. The results showed that RIS inhibited the expression of ALP, OCN, OPN, and calcium deposition in MC3T3-E1 cells and BMSCs. Meanwhile, the mechanism of RIS affecting bone formation ability of MC3T3-E1 cells and BMSCs also need to be further explored.

Ferroptosis is a non-apoptotic cell death pathway, characterized by cellular damage resulting from iron accumulation and lipid peroxidation [39, 40]. Modulating iron-mediated cell death can effectively regulate the extent of damage and the progression of osteoblasts demise, thereby promoting bone homeostasis equilibrium, attenuating bone loss progression, and ultimately ameliorating clinical manifestations such as osteoporosis in patients [41]. Lin et al. found that high glucose and high fat induced ferroptosis in osteoblasts may be the main cause of osteoporosis in Diabetes mellitus [42]. Besides, osteocyte ferroptosis contributes to cortical bone loss during ageing mice [43]. There is a close relationship between ROS and ferroptosis, and excessive ROS can promote the occurrence of ferroptosis [44]. In addition, a large number of studies have shown that excessive ROS production also promotes bone loss in the body [20, 45]. However, to date, no studies have reported the potential association between RIS and ferroptosis. In this study, we found that RIS can activate ferroptosis in schizophrenic mice, MC3T3-E1 cells, and BMSCs. Furthermore, Fer-1, a classic ferroptosis inhibitor, can reverse the inhibitory effect of RIS on osteogenesis in MC3T3-E1 cells and BMSCs. And Fer-1 can alleviate RIS-induced bone loss in schizophrenia mice.

Collectively, our findings indicate that the induction of ferroptosis by RIS hampers the osteogenic differentiation of both MC3T3-E1 cells and BMSCs, thereby disrupting the delicate equilibrium of bone metabolism and ultimately leading to the development of osteoporosis. Our study aims to identify a therapeutic target to address the RIS-induced bone loss in patients with schizophrenia. Furthermore, patients experiencing age-related bone loss or those undergoing fracture healing should consider discontinuing risperidone under medical supervision. However, this study also has some limitations. As it is widely acknowledged, ferroptosis is modulated by diverse signaling pathways. Despite our findings indicating that RIS can induce ferroptosis in osteoblasts, the specific signaling pathway targeted by risperidone to activate ferroptosis in osteoblasts remains elusive. In forthcoming investigations, we will delve into elucidating the precise signaling pathway involved in risperidone’s regulation of osteoblast ferroptosis.

Conclusions

According to the findings of our study, it can be inferred that RIS has the potential to impede osteogenic differentiation in both MC3T3-E1 cells and BMSCs by triggering ferroptosis. This may lead to a reduction in bone density among mice with schizophrenia.

Data availability

No datasets were generated or analysed during the current study.

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Funding

This research was supported by grants from the National Natural Science Foundation of China [grant numbers:82060651] and the Doctoral Research Fund of Affiliated Hospital of Guizhou Medical University [grant numbers: GYFYBSKY-2021-67].

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Author notes

  1. Hongyan Fan and Zaihong Yang contributed equally to this work.

Authors and Affiliations

  1. Guizhou Medical University, Guiyang, China

    Hongyan Fan, Zaihong Yang, Lan Pang & Lei Zheng

  2. Department of Psychiatry, Affiliated Hospital of Guizhou Medical University, Guiyang, China

    Peifan Li, Changrong Duan, Guangyuan Xia & Lei Zheng

Authors
  1. Hongyan Fan
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  2. Zaihong Yang
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  3. Lan Pang
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  4. Peifan Li
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  6. Guangyuan Xia
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  7. Lei Zheng
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Contributions

HF and ZY contribute to conception and design, data acquisition, drafting the article. LP, PL, CD, GX data acquisition, drafting the article. LZ data acquisition; reviewing the article. All the authors took part in the experiment. All the authors read and approvaled the manuscript.

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Correspondence to Lei Zheng.

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Fan, H., Yang, Z., Pang, L. et al. Activation of osteoblast ferroptosis by risperidone accelerates bone loss in mice models of schizophrenia. J Orthop Surg Res 20, 83 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13018-025-05520-w

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13018-025-05520-w

Keywords

Journal of Orthopaedic Surgery and Research

ISSN: 1749-799X