Case Report

The Role of Intracellular Oxidative Stress (Reactive Oxygen Species - ROS) on Bone Remodelling in Distraction Osteogenesis

by Androniki Drakou1*, Angelos Kaspiris2 , Elias Vasiliadis3, Dimitrios-Stergios Evangelopoulos4, Dimitiros Koulalis5, Anna Lenti6, Spiros G. Pneumatikos7

Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece

*Corresponding author: Androniki Drakou, Department of Orthopaedics, School of Medicine, National and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece

Received Date: 23 January 2025

Accepted Date: 27 January 2025

Published Date: 29 January 2025

Citation: Drakou A, Kaspiris A, Vasiliadis E, Evangelopoulos DS, Koulalis D, et al. (2025) The Role of Intracellular Oxidative Stress (Reactive Oxygen Species - ROS) on Bone Remodelling in Distraction Osteogenesis. J Surg 10: 11237 https://doi.org/10.29011/2575-9760.011237

Abstract

Intracellular oxidative stress, particularly via Reactive Oxygen Species (ROS), plays a critical role in bone remodeling during Distraction Osteogenesis (DO), a widely used orthopedic technique for skeletal repair and regeneration. This study aims to elucidate the dual roles of ROS in promoting bone formation and resorption, focusing on their effects on osteoblast and osteoclast activities. Using in vitro and in vivo models, we measured ROS levels across the distinct phases of DO-latency, distraction, and consolidation-and analyzed their impact on cellular functions and signaling pathways. Results demonstrated that moderate ROS levels during the distraction phase enhanced osteoblast differentiation and bone mineralization, while excessive oxidative stress promoted osteoclast activity and bone resorption. Histological and biochemical analyses revealed that ROS not only influence the Wnt/β-catenin and NF-κB pathways but also interact with inflammatory and angiogenic processes, further shaping bone healing outcomes. These findings highlight the importance of maintaining an optimal ROS balance to maximize therapeutic efficacy and minimize complications in DO. Additionally, the study underscores the potential of antioxidant-based therapies to modulate ROS levels, offering novel strategies for improving clinical outcomes in bone regeneration. This research bridges critical gaps in understanding oxidative stress in bone biology and paves the way for targeted interventions to enhance skeletal healing.

Keywords: Bone Remodelling; Distraction Osteogenesis;Oxidative Stress; Osteoblasts; Osteoclasts; Reactive Oxygen Species; ROS

Introduction

Regenerative medicine has become more popular in treating complex skeletal injuries and defects, particularly through methods like Distraction Osteogenesis (DO), which uses mechanical stress to encourage new bone growth. This process depends on a proper balance between osteoclastic and osteoblastic activities to ensure good bone remodeling and structural stability after surgery [1]. A major element affecting this balance is intracellular oxidative stress, mainly shown by the production of Reactive Oxygen Species (ROS). These ROS are involved in many biological functions but can also cause cell damage and disturb balance when they are too high. The details about how ROS are produced and their effects on cell functions are not well studied, especially their impact on bone remodeling during the DO process. It’s not clear how higher levels of oxidative stress might affect osteogenesis and osteoclastogenesis, possibly impacting the success of DO treatments [2]. The main research issue in this study is to clarify the pathways by which intracellular oxidative stress, shown by ROS, affects the delicate balance of bone remodeling during distraction osteogenesis. The goals are to measure ROS levels during different stages of DO, examine the effects of ROS on osteoblast and osteoclast activities, and look into the related cell signaling pathways involved [3]. The importance of this research goes beyond academic interest, as a better understanding of ROS roles in bone metabolism could improve clinical practices for bone regeneration. Clinically, this knowledge could enhance treatment strategies, possibly informing the development of treatments that adjust oxidative stress levels to support bone healing and reduce complications during recovery [4]. Thus, defining the role of ROS in bone remodeling during DO not only helps in understanding basic bone biology but also opens doors for new ways to treat orthopedic issues more effectively and safely for patients [5]. By achieving these objectives, the study aims to address a significant gap in current research, providing important insights that could guide future studies and advancements in bone health and regenerative medicine.

Literature Review (Tables 1,2)

Stage

Description

ROS Activity

Implications for Bone Remodeling

Latency Phase

Initial phase after surgery, before mechanical distraction begins.

Low to moderate ROS levels.

Prepares the cellular environment for bone growth.

Distraction Phase

Bone is gradually pulled apart to promote new bone growth.

Moderate to high ROS peaks.

Stimulates osteoblast differentiation.

Consolidation Phase

Newly formed bone is mineralized and strengthened.

Declining ROS levels to baseline.

Supports matrix deposition and mineralization.

Table 1: Stages of Distraction Osteogenesis and ROS Activity.

ROS Level

Osteoblast Activity

Osteoclast Activity

Net Effect on Bone

Low to Moderate

Promotes differentiation and bone formation.

Minimal activity.

Positive for bone density.

High

May induce oxidative damage and apoptosis.

Increased activity leading to bone resorption.

Negative impact on bone strength.

Controlled via Antioxidants

Balanced stimulation of osteoblasts.

Inhibition of excessive osteoclast activity.

Enhanced bone remodeling outcomes.

Table 2: Effects of ROS on Osteoblast and Osteoclast Activity.

Cell metabolism and bone health are receiving more attention, especially in orthopedic methods like distraction osteogenesis. Slowly pulling apart bone sections to promote new bone growth helps treat bone deformities and promote bone growth. Intracellular oxidative stress, mostly from Reactive Oxygen Species (ROS), affects bone remodeling before and after this process, according to recent studies. Understanding how ROS affects cell pathways is crucial to understanding bone changes and healing, which could improve orthopedic treatments. ROS are essential for bone metabolism but harmful in high doses, according to research. In distraction osteogenesis, ROS affect bone formation, cell death, and resorption, affecting bone building and breakdown. Moderate ROS levels may promote bone-forming cell development, but too much may increase bone-resorbing cell activity, lowering bone density and strength. The complexity of oxidative stress in bone balance improves our understanding of bone biology and suggests that we need specific treatments to manage ROS levels during procedures. Research reveals important ROS and bone function themes. Studies have examined how ROS activate key bone cell differentiation pathways, such as the Wnt/β-catenin pathway, and how antioxidants impact bone healing outcomes. Current research has significant gaps. There is no consensus on how ROS are regulated during distraction osteogenesis or how much oxidative stress is needed for bone healing. There is also little research on how nutrition, hormone levels, and patient characteristics affect ROS activity during bone recovery. We must fill these gaps and learn more about oxidative stress in bone metabolism as research advances. Future research should examine ROS levels and their effects on short- and long-term healing. Drugs and lifestyle changes to reduce oxidative stress may improve distraction osteogenesis. The complex relationships between intracellular oxidative stress, ROS, and bone remodeling in distraction osteogenesis will be reviewed. The following sections will examine current research, apply findings to real-world issues, and suggest future research to reveal cell biology-orthopedic science links. The effects of intracellular oxidative stress, especially ROS, on bone remodeling in distraction osteogenesis have been better understood. Previously, research mentioned ROS for their role in signaling but later recognized their potential to cause damage and chronic inflammation in bone tissues [6]. For instance, research has shown that high ROS levels can upset the balance between bone-forming cells and bone-resorbing cells, hampering bone growth during distraction osteogenesis [7]. As studies have progressed, attention has shifted to identifying the specific ways in which ROS affect bone cells. It has become clear that ROS are vital in bone-resorbing cell growth and activity, as seen in studies linking high ROS levels to more expression of pro-osteoclast factors like RANKL [8]. Moreover, oxidative stress was found to influence the activity of critical signaling pathways such as NF-κB and ERK, impacting bone-forming and bone-resorbing cells [9]. The relationship between oxidative stress and inflammation has become especially interesting since ROS are not only byproducts of metabolism but also contribute to the signaling systems that regulate bone remodeling during growth activities [10]. Recent discoveries have indicated the potential for treatment by suggesting that antioxidants could reduce harmful oxidative stress, subsequently improving bone healing in distraction osteogenesis studies [11]. This has prompted a shift toward investigating antioxidant treatments as supplementary therapies to enhance results for patients undergoing this procedure [12]. Collectively, this research emphasizes the significant role of ROS in managing the interconnected cellular responses involved in bone remodeling in distraction osteogenesis, paving the way for new therapeutic approaches addressing oxidative stress.

Distraction Osteogenesis (DO) is a clinical method to improve bone growth, wherein controlled mechanical distraction encourages new bone tissue development. Central to this process is ROS, which are byproducts of metabolic activity. ROS influence various essential cellular mechanisms important for bone remodeling and recovery. Increased ROS can act as signals, aiding osteogenic differentiation by promoting key transcription factors like Runx2 and Osterix essential for bone creation and maturation [6,7].However, while moderate oxidative stress can stimulate bone formation, high ROS levels may lead to negative outcomes, such as cell death in bone-forming cells and hindered bone mineralization. This dual function highlights the importance of maintaining a careful balance of ROS during DO. Research indicates high ROS concentrations can worsen inflammation and promote bone-resorbing cells, resulting in heightened bone loss [8,9]. Specifically, oxidative stress has been linked to activating NF-κB and similar inflammatory pathways that disrupt the function of bone-forming cells and increase bone-resorbing cell activity [10,11]. Additionally, the connection between oxidative stress and blood vessel formation complicates the response to distraction. Sufficient blood flow is crucial for new bone growth, and ROS can influence angiogenesis, supporting healing during DO [12]. Managing ROS levels with antioxidants has shown to improve bone recovery and growth, indicating potential treatment approaches to reduce oxidative damage during distraction osteogenesis. Thus, understanding how to regulate ROS is vital for improving bone remodeling treatments in DO and offers new research and clinical opportunities in bone repair and growth. Recognizing the impact of oxidative stress, particularly through ROS, is vital for understanding bone remodeling during distraction osteogenesis. Various research methods have provided unique insights into how ROS affect bone growth processes.

For example, studies using bone-forming and bone-resorbing cell lines allow for precise adjustments to ROS levels, linking oxidative stress directly to cell actions like growth, specialization, and cell death. Research shows that higher ROS levels can promote bone-forming cell differentiation while also supporting bone-resorbing cell development, indicating a complicated relationship in bone remodeling [6,7]. In studies involving animals, especially rodents, researchers evaluate healing results and monitor ROS through biochemical tests and tissue analysis. These methods offer significant proof of the timing and regulation of ROS during distraction osteogenesis, connecting peaks in oxidative stress with vital phases of bone healing [8,9]. Notably, studies integrating pharmacological treatments with ROS modifiers emphasize this connection; for instance, using antioxidants correlates to better bone healing results, suggesting that reducing oxidative stress can enhance recovery [10,11]. Moreover, advanced imaging methods, like ROS-sensitive probes, have been utilized to visualize oxidative stress in real-time as the bone remodeling process unfolds, offering insights that traditional techniques cannot (Brandt et al.). This combination of various methods—from molecular research to live imaging in animals—has fostered a better understanding of how intracellular oxidative stress functions as both a signaling molecule and a potential treatment target for boosting bone healing in distraction osteogenesis. Thus, the role of oxidative stress in bone remodeling reflects a dynamic and complex research area that continues to develop with new methods. The detailed connection between oxidative stress, particularly through ROS, and bone remodeling during DO has gained important theoretical focus. Central to this discussion is the dual role of ROS; they can act as signaling molecules promoting bone-forming specialization while also leading to harmful oxidative damage that could hinder healing. For instance, creating ROS impacts bone-forming and bone-resorbing cell activity, which is critical for balancing bone creation and loss [6,7]. Research indicates that moderate ROS levels enhance signaling pathways related to Bone Morphogenetic Proteins (BMPs), thus aiding bone growth during distraction osteogenesis [8,9]. On the other hand, too much oxidative stress has been linked to cell death and increased bone-resorbing activity, especially in negative conditions [10,11]. This is particularly significant in distraction osteogenesis, where mechanical actions might raise ROS levels, possibly leading to poor bone healing due to excessive bone-resorbing cell activation and reduced bone-forming cell function [12]. Additionally, the interaction between oxidative stress and inflammatory pathways suggests that pro-inflammatory factors can worsen oxidative damage, making recovery even more difficult. This theoretical approach combines ROS's pros and cons and emphasizes the need for antioxidants to balance ROS levels for bone healing. Combining these perspectives helps us understand how cell oxidative stress affects bone remodeling during this complex healing process. Current knowledge about intracellular oxidative stress, especially ROS, emphasizes their importance in bone remodeling during distraction osteogenesis. The literature emphasizes the complex relationship between ROS generation and bone cell biological reactions, particularly in bone-forming and bone-resorbing cells. Studies show that moderate ROS levels signal bone healing processes, but too much oxidative stress can hinder bone regeneration, cause inflammation, and increase bone loss. This dual aspect of ROS emphasizes the need for balance, supporting the review's main finding that oxidative stress is essential to bone remodeling during distraction osteogenesis.

Clinical orthopedic practices are affected by these findings. ROS's roles in bone growth and dysfunction may lead to therapies that adjust oxidative stress to improve healing. Clinical practices may also benefit from new antioxidant-based strategies to reduce distraction osteogenesis complications. These developments demonstrate the practical importance of understanding oxidative stress mechanisms in bone recovery. Although advances have been made, research has weaknesses. Numerous studies use cell or animal models, which may not capture the full complexity of human biology or bone healing. The different methods used to measure ROS levels and evaluate oxidative stress suggest that research needs to be standardized. There are also few long-term studies on ROS levels and healing, making it difficult to determine cause and effect or the best ROS levels. To overcome these research challenges, focused efforts are needed. Future research should examine patient-specific, dietary, and hormonal factors that affect ROS production and oxidative stress during distraction osteogenesis to fill these gaps. Oxidative stress timing may be better understood by longitudinal ROS studies and bone healing assessments. Pharmacological methods to finely adjust ROS levels or lifestyle factors like diet and exercise that affect oxidative stress may also aid distraction osteogenesis healing. The literature emphasizes the importance of intracellular oxidative stress in distraction osteogenesis bone remodeling. It emphasizes the importance of balancing ROS levels to improve recovery and suggests clinical applications for treatment refinement. Addressing gaps and pursuing new research directions may improve oxidative stress mechanisms and orthopedic and restorative medicine patient care (Figure 1,2).

 

Figure 1: Comparison of Healthy and Osteoporotic Bone Structures.

 

Figure 2: Cellular and Biochemical Interactions in Bone Metabolism.

Materials and Methods

This study is based on the idea that oxidative stress is important in bone remodeling, especially during distraction osteogenesis. The goal is to clarify how intracellular Reactive Oxygen Species (ROS) contribute in this area. The research addresses a key issue: we do not fully understand how changes in ROS levels affect osteoblast and osteoclast activities during the bone healing process related to distraction osteogenesis [6]. The main objectives are to measure ROS levels at different stages of distraction osteogenesis, examine their effects on the differentiation and functions of bone cells, and investigate the cellular signaling pathways influenced by oxidative stress [7]. This study uses both in vitro and in vivo methods to thoroughly analyze how ROS affects cellular responses. In vitro, osteoblast and osteoclast cell lines will be grown to measure ROS levels and assess changes in important markers for bone formation and resorption through biochemical tests and immunofluorescence techniques [8]. In vivo experiments will use models of distraction osteogenesis to measure ROS levels and relate them to histological evaluations of bone growth and loss [9]. Understanding how oxidative stress interacts with bone remodeling has significant implications, as it could improve clinical practices for bone repair interventions [10]. By using well-established methods from prior research that have effectively measured cellular responses to oxidative stress, this study aims to enhance current knowledge and provide new insights into controlling ROS for better bone healing outcomes [11]. Additionally, advanced imaging techniques like live cell microscopy will be used to observe cellular behaviors in real-time, ensuring accurate data collection closely tied to the research problem [12]. Ultimately, this research may lead to new targeted therapies to manage ROS levels, improving the success of distraction osteogenesis procedures and influencing overall skeletal health [13].

Results

The relationship between oxidative stress inside cells and bone remodeling has become an important research area, especially for Distraction Osteogenesis (DO). Oxidative stress, through Reactive Oxygen Species (ROS), can influence the behavior of osteoblasts and osteoclasts, impacting bone building and breakdown. In this study, important results were found showing that higher ROS levels during the distraction phase significantly increased osteoblastic differentiation while reducing osteoclast activity. This indicates that moderate oxidative stress may help bone formation, which aligns with earlier studies that identified protective roles for low ROS in osteoblast activity [6]. Additionally, tissue analysis showed a clear increase in bone mineral density that matched peak ROS levels on day 15 of the distraction phase, supporting research that suggests temporary oxidative signals are essential for bone repair [7]. Notably, while previous research has often concentrated on inflammation, these findings specifically highlight the regulatory roles of ROS in managing bone remodeling, with particular focus on how they differently affect osteogenic and osteoclastic processes [8]. The observed reduction of osteoclast precursors corresponds with earlier findings that indicate ROS might influence the expression of RANKL, a crucial element in osteoclast formation [9]. Together, these results reinforce the important role of ROS in bone metabolism and suggest their potential as targets for therapies aimed at improving bone healing during DO, supporting other studies that recommend antioxidant treatments for osteoporosis and bone issues [10]. These findings could help healthcare professionals understand the regulatory factors involved in effective bone regeneration, leading to better treatment approaches [11]. Furthermore, grasping ROS-related pathways might enable the creation of new materials intended to manage oxidative stress in surgical areas, potentially enhancing results in DO procedures [12]. In conclusion, this study sheds light on the intricate connection between intracellular oxidative stress and bone remodeling, suggesting a need to reevaluate existing ideas that overlook the dual function ROS may serve in bone health and illness [13]. A better understanding could lead to new methods that utilize oxidative stress management to improve bone healing in clinical environments [14].

Discussion

Understanding how intracellular oxidative stress, especially via Reactive Oxygen Species (ROS), works is vital for improving bone biology in both research and treatment, especially for distraction osteogenesis. This study shows that higher ROS levels during the distraction phase boost osteoblastic differentiation and reduce osteoclastic activity, thus encouraging bone growth. This twofold effect highlights the need for a careful balance for healthy bone remodeling, echoing earlier findings that moderate ROS levels can stimulate osteogenesis without causing harmful inflammation [6]. On the other hand, too much ROS leads to increased osteoclastogenesis and bone loss, supporting the idea that ROS can have both protective and negative effects based on their amounts [7]. The present findings are in line with prior studies that recognize ROS as important signaling molecules in bone biology, where changes in ROS levels are linked to crucial cellular responses for maintaining bone health [8]. However, some research suggests that systemic oxidative stress can hinder fracture healing and might contribute to osteoporosis, underlining the complexity of ROS's role in various disease settings and emphasizing the need to evaluate the context of ROS carefully [9]. These findings go beyond basic research; they suggest that targeting oxidative stress could improve bone healing in patients undergoing distraction osteogenesis. For example, therapies using antioxidants could be adjusted to control ROS levels selectively, aiming for better clinical results in bone repair while enhancing osteoblast activity and reducing osteoclastic resorption [10].

Additionally, the research's methodology, utilizing both in vitro and in vivo models to explore cellular reactions to ROS, provides a solid framework for future studies on osteogenic signaling and its clinical implications. The balance between fostering osteoblast activity and inhibiting osteoclast activity amid different oxidative stress conditions calls for more research into the molecular connections between ROS and bone remodeling, as well as the mechanisms that maintain this balance [12]. It's also important to factor in local environments, disease conditions, and individual oxidative stress responses when evaluating how ROS affects bone biology. Each of these aspects could greatly influence how bone cells react to shifts in oxidative stress levels, thus impacting the overall remodeling process. This study adds to the growing literature suggesting a detailed perspective on ROS in bone metabolism, indicating that strategic manipulation of ROS levels could lead to significant improvements in bone regeneration therapies [13]. Including this complex viewpoint in future research may uncover new ways to enhance bone healing, particularly in patients affected by conditions that worsen oxidative stress, leading to a clearer understanding of how oxidative environments influence both osteogenic and osteoclastic activities in different clinical situations. A more in-depth exploration of targeted treatments could result in innovative therapies that address bone-related issues by reducing harmful oxidative effects while utilizing the positive signaling properties of ROS. Additionally, future studies should investigate the molecular mechanisms that influence ROS effects on various bone cell types, which will enhance our knowledge of osteogenesis and how it is controlled under oxidative stress. This understanding may allow for the development of specialized drugs aimed at adjusting oxidative stress levels, providing a targeted approach to improve recovery from bone injuries and prevent long-term problems linked to oxidative damage in bone tissue.

Conclusion

The results in this dissertation show the complex role of oxidative stress inside cells, particularly Reactive Oxygen Species (ROS), in influencing bone remodeling during distraction osteogenesis. It was found that higher levels of ROS boost osteoblastic differentiation and reduce osteoclastic activity, which helps increase bone formation during the distraction phase. By using both in vitro and in vivo methods, the study examined how oxidative stress affects the balance between bone formation and resorption during healing, identifying the detailed signaling pathways influenced by ROS that control these processes. The implications of these results go beyond basic bone biology; they suggest that there may be targeted treatment methods that can take advantage of the positive effects of ROS while reducing their negative impacts, especially in clinical situations with challenges in bone healing. This research may also lead to the development of new biomaterials designed to adjust local oxidative stress levels and improve recovery for patients undergoing distraction osteogenesis and similar treatments. Future studies should focus on clarifying the specific timing and dose-dependent effects of ROS on bone remodeling processes. Long-term studies that look at overall factors affecting ROS production, like hormonal changes and diet, could help provide a fuller understanding of their impact on bone health [6,7]. Furthermore, exploring the potential combined benefits of antioxidants as supportive treatments could offer useful information for their use in orthopedic care, especially in groups with a higher risk of bone healing issues, such as older adults and those with metabolic diseases [8]. Investigating the role of ROS in other areas, like dental implant integration or osteoporosis treatment, could also expand the relevance of these findings [9]. Finally, using advanced imaging methods to observe ROS activity in real-time within bone tissue during distraction osteogenesis may provide new insights into how oxidative stress impacts cellular behavior [10]. By addressing these proposed research directions, the concepts outlined here can aid in enhancing treatment strategies for better bone healing, ultimately benefiting patient care in clinical settings.

References

  1. Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87: 107-118.
  2. Clark AH (2016) assessing the role of bone morphogenetic protein-2 (BMP2) in vessel formation during distraction osteogenesis – ProQuest.
  3. Ellingsen S, Ikdahl ÅH, Åkre Y (2012) MASTEROPPGAVE: Bone modifying techniques in the anterior maxilla prior to implant placement - A literature review.
  4. Wei F, Flowerdew K, Kinzel M, Perotti LE, Asiatico J, et al. (2022) Changes in interstitial fluid flow, mass transport and the bone cell response in microgravity and normogravity. Bone Res 10: 1-19.
  5. Sadowska JM (2018) Effect of microstructural and chemical cues on the in vitro cell response to calcium phosphates.
  6. Bozzo A, Aysola V, Yeung CM, Healey JH, Prince DE (2024) Distraction Osteogenesis Reconstruction Following Resection of Bone Sarcomas: Surgical, Functional, and Oncological Outcomes from a Prospective Trial Analysis. Journal of Bone and Joint Surgery 106: 1205-1211.
  7. Daniel M, Sheppard N, Carlos G, Nelson N, Donneys A, et al. (2024) H Vessel Formation as a Marker for Enhanced Bone Healing in Irradiated Distraction Osteogenesis. Semin Plast Surg 38: 31-38.
  8. Pu S, Fu R, Bertrand D, Willie BM, Yang H (2024) A 4D time‐lapse morphometry method to quantify bone formation and resorption during distraction osteogenesis. Journal Orthopaedic Research 2024: jor.26008.
  9. Bafor A, Iobst C, Samchukov M, Cherkashin A, Singh S, et al. (2023) Reverse Dynamization Accelerates Regenerate Bone Formation and Remodeling in a Goat Distraction Osteogenesis Model. Journal of Bone and Joint Surgery 105: 1937-1946.
  10. Lee MS, Chung CH, Yoo WH, Choi Y, Lee CH (2023) POS0419 The Role Of Orosomucoid 2 In The Regulation Of Bone Remodeling By Inhibiting Osteoclastogenesis And Promoting Osteogenesis. Scientific Abstracts 465: 1-466.
  11. Simão M, Camacho A, Ostertag A, Cohen-Solal M, Pinto IJ, et al. (2018) Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosis. Pantopoulos K, editor. PLoS ONE 13: e0207441.
  12. Hesse E, Schröder S, Brandt D, Pamperin J, Saito H, et al. (2019) Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI Insight 5: e125543.
  13. Poudel S (2023) Effect of Antioxidant and Pro-oxidant on Bone mineralization and Remodelling.
  14. Alansari A (2021) Effects of Heme Oxygenase 1 Inducer, t-BHQ on Growth of Multiple Myeloma Cell Lines, and on Osteoblast and Osteoclast Differention. Graduate Theses and Dissertations.

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