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The protective effect and experimental research progress of pleotropic statins in intervertebral disc degeneration

Journal of Orthopaedic Surgery and Research volume 20, Article number: 122 (2025) Cite this article

Abstract

Intervertebral disc degeneration (IVDD) is one of the primary causes of low back pain, significantly affecting the quality of life in the elderly population and imposing a substantial economic burden. Currently, clinical treatments for IVDD mainly focus on symptom management, with no available therapies capable of reversing or curing the disease. In recent years, statins, a class of drugs traditionally used in the treatment of cardiovascular diseases, have been shown to exert beneficial effects on IVDD through multiple mechanisms. With the advancement of research into the pleiotropic effects of statins, an increasing body of evidence suggests their potential as effective therapeutic agents for IVDD. This review summarizes the pleiotropic effects of statins and explores their potential mechanisms and actions in IVDD, with particular emphasis on changes in the expression of relevant molecular markers. Furthermore, recent advancements in the application of statins for IVDD treatment are discussed, along with the potential of combining statins with other drugs as part of multi-target therapeutic strategies. This review aims to provide a scientific reference for further investigations into the use of statins in the treatment of IVDD.

Highlights

  • Outlines the structural function and pathomechanisms of intervertebral disc degeneration.

  • Summarizes the pleiotropic properties of statins and their effects and mechanisms on disc degeneration.

  • Describes experimental advances in the treatment of disc degeneration with statins.

  • A reference for further research on statins in the treatment of intervertebral disc degeneration.

Introduction

In recent years, the incidence of degenerative musculoskeletal disorders has been steadily increasing, with chronic low back pain emerging as a leading cause of reduced quality of life in the elderly population [1]. Intervertebral disc degeneration (IVDD) is recognized as a primary cause of low back pain and represents a critical target for its diagnosis and treatment [2]. Epidemiological studies indicate that the progression and prevalence rates of IVDD are 52.0% and 31.6% in men, and 60.4% and 44.7% in women, respectively [3]. Research has identified genetics and aging as the primary risk factors for IVDD, while environmental factors also play a significant role in its onset and progression [4]. Aging is a gradual and irreversible physiological process characterized by the accumulation of molecular and cellular damage over time. This process disrupts tissue homeostasis, increases oxidative stress, induces cellular senescence, triggers chronic inflammation, and impairs autophagic function, collectively increasing the risk of various systemic diseases [5, 6]. The musculoskeletal system, in particular, undergoes progressive structural and functional degeneration, ultimately leading to conditions such as IVDD and other degenerative musculoskeletal diseases [7,8,9]. These disorders impose a substantial economic burden on families and society. Therefore, slowing the progression and improving the treatment of IVDD is critical for enhancing the quality of life in the elderly and alleviating socioeconomic burdens.

Currently, clinical management of IVDD primarily relies on surgical interventions. However, surgical treatment is associated with risks such as infection, recurrence, and adjacent segment degeneration [10, 11]. In recent years, studies have reported the potential role of statins in delaying the progression of IVDD. Statins function by competitively inhibiting hydroxymethylglutaryl-CoA (HMG-CoA) reductase, thereby reducing intracellular cholesterol levels. They are widely used in the treatment of hypercholesterolemia and have demonstrated significant efficacy in the management of cardiovascular diseases [12]. Extensive research has shown that statins possess diverse biological effects, including improving endothelial function, slowing the progression of atherosclerosis, stabilizing atherosclerotic plaques, and reducing levels of inflammatory biomarkers [13,14,15]. These effects suppress chronic inflammation in the development of atherosclerosis, contributing to improved cardiovascular outcomes. Notably, statins have been shown to inhibit macrophage-mediated secretion of matrix metalloproteinases (MMPs) and prevent extracellular matrix degradation, exerting antioxidative, immunomodulatory, and anti-inflammatory effects [16,17,18]. These mechanisms suggest a potential role for statins in improving IVDD.

Despite substantial research on the effects of statins on IVDD and their underlying mechanisms, a comprehensive and systematic review of the available evidence is still lacking. This review summarizes recent advances in understanding the relationship between statins and IVDD. Furthermore, it analyzes the potential molecular mechanisms through which statins exert their effects on IVDD and explores the prospects of combining statins with other drugs in multi-target therapeutic strategies. This review aims to provide a scientific basis for the potential applications of statins in the management and prevention of IVDD.

Overview of IVDD

Structure and function of the IVD

The intervertebral disc (IVD) is composed of three distinct components: the nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP), forming a critical structure that connects the vertebral bodies of the spine [19, 20]. The NP, located at the center of the IVD, is a highly hydrated and elastic gel-like substance. Its primary components include collagen, proteoglycans, NP cells, and water, accounting for 50–60% of the IVD’s cross-sectional area and serving as its core structure. The NP is encapsulated by the outer AF and the superior and inferior CEP, creating a sealed, hypoxic environment that supports the growth of NP cells. Although the NP contains a high water content, this gradually decreases with aging, leading to a reduction in elasticity and load-bearing capacity [21]. The AF has a concentric lamellar structure, consisting of inner, middle, and outer rings. Its primary constituents are type I and type II collagen, which make it a tough and resilient structure surrounding the NP. The AF functions to distribute the mechanical pressure exerted on the NP and provides protective support [21]. The CEP is a hyaline cartilage-like tissue composed mainly of collagen, proteoglycans, and cells similar to those found in articular cartilage. It covers the superior and inferior surfaces of the NP and AF and facilitates material exchange between the NP and the external environment through surface micropores [22]. The IVD is the largest avascular tissue in the human body, primarily relying on the micropores of the CEP and the outer AF for nutrient diffusion and the removal of metabolic waste. Consequently, its self-repair capacity is limited, making it susceptible to degeneration [22,23,24].

Pathophysiological mechanisms of IVDD

The exact etiology and pathogenesis of IVDD remain incompletely understood and are still under active investigation. It is widely accepted that IVDD results from the interplay of multiple factors, including genetic predisposition, aging, inflammation, oxidative stress, mechanical stress-induced injury, and the precipitation of calcium salts, with genetic factors considered the most critical [10, 25, 26]. Reports suggest that more than 70% of IVDD cases are attributed to genetic factors, and programmed cell death is believed to directly accelerate the onset and progression of IVDD [27].

As IVDD progresses, significant structural and functional changes occur within the IVD (Fig. 1). An imbalance between the anabolic and catabolic processes of the extracellular matrix (ECM) is observed, characterized by reduced expression of anabolic factors, such as aggrecan, IGF-1, TGF-β, and BMP, and increased expression of catabolic factors, such as MMPs and ADAMTS [28, 29]. This metabolic imbalance leads to ECM degradation, and the resulting degradation products further activate inflammatory responses, resulting in significantly elevated levels of inflammatory cytokines, including IL-1, IL-6, IL-8, and TNF-α [30]. These inflammatory cytokines accelerate the degradation of type II collagen and aggrecan in the ECM, exacerbating ECM breakdown, ultimately disrupting the IVD’s internal microenvironment. This disruption impairs the proliferative capacity of NP cells and may even lead to cell death, further driving the progression of IVDD [31]. Moreover, inflammatory cytokines activate signaling pathways associated with apoptosis, pyroptosis, and autophagy, further reducing the number and functionality of cells within the IVD, thereby exacerbating the pathological progression of IVDD [28, 32].

Fig. 1
figure 1

Pathologic mechanisms and molecular changes in intervertebral disc degeneration. IVD: intervertebral disc; IVDD: intervertebral disc degeneration; ECM:extracellular matrix;IGF-1:insulin-like growth factors-1; TGF-β:transforming growth factor-β；BMP:bone morphogenetic protein； IL-1:interleukin—1;IL-6:interleukin—6;IL-8:interleukin—8; TNF-α:tumor necrosis factor-α;MMPs:Matrix metalloproteinases; ADAMTs:a disintegrin and metallo-proteinase with thrombospondin motifs

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Introduction of statins

Development history

Statins were first developed in 1971 when Akira Endo and his team at Sankyo Pharmaceutical Company isolated mevastatin from Penicillium citrinum [33, 34]. The introduction of lovastatin, the first FDA-approved statin in 1987, marked their clinical application [33, 35]. Subsequent advancements led to the development of second- and third-generation statins, such as atorvastatin and rosuvastatin, which improved drug safety and efficacy [36,37,38,39]. These developments have established statins as a cornerstone in cardiovascular disease treatment.

Pleiotropic effects

With the widespread clinical application of statins, studies have demonstrated that, in addition to lowering cholesterol levels by blocking the mevalonate pathway as HMG-CoA reductase inhibitors, statins also exhibit significant biological effects, including anti-inflammatory, antioxidant, and anti-apoptotic activities [40,41,42,43] (Fig. 2). These effects have increasingly garnered attention in research related to IVDD.

Fig. 2
figure 2

The pleiotropic effects of statins. HMG-CoA: 3-hydroxy-3-methyl glutaryl coenzyme A reductase; CRP: C-reactive protein; ILs: interleukins; TNF-α: tumor necrosis factor-α

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Anti-inflammatory effects and IVDD

In the pathological process of IVDD, inflammatory cytokines such as IL-1β and IL-6 are considered critical regulators of NP cell apoptosis and ECM degradation [44, 45]. Numerous studies have demonstrated that statins significantly reduce the expression of IL-1β and IL-6 by inhibiting the activation of the NF-κB signaling pathway [46,47,48,49]. This inhibition alleviates inflammatory responses in intervertebral disc tissues and reduces CRP and TNF-α levels, thereby improving the disc microenvironment and slowing the pathological progression of IVDD [50]. Furthermore, statins can modulate the activity of activator protein-1 (AP-1) and hypoxia-inducible factor-1α (HIF-1α), increase endothelial nitric oxide synthase (eNOS) levels, and activate the PI3K-Akt signaling pathway, further reducing the expression of inflammatory markers [43, 51]. Clinical studies have further validated the anti-inflammatory effects of statins. One study, which included 1,702 participants without a history of cardiovascular disease (primary prevention cohort) and 1,182 patients with confirmed cardiovascular disease (secondary prevention cohort), reported that after 24 weeks of pravastatin treatment, the median CRP levels decreased by 16.9% in the primary prevention cohort (P < 0.001). In the secondary prevention cohort, CRP levels were reduced by 14.3% and 13.1% after 12 and 24 weeks of treatment, respectively (P < 0.005) [52]. Other similar studies further support the efficacy of statins in reducing CRP levels [53, 54]. In summary, statins suppress inflammatory responses through multiple mechanisms and play an essential role in mitigating the pathological progression of IVDD.

Antioxidant effects and IVDD

Excessive production of reactive oxygen species (ROS) is considered one of the key factors in the pathological progression of IVDD. ROS accelerates the degradation of the ECM and induces apoptosis in intervertebral disc cells, further driving disease progression [55,56,57]. Statins mitigate oxidative stress by inhibiting the activity of NADPH oxidase, thereby reducing ROS production, and by upregulating the expression levels of superoxide dismutase (SOD) and catalase (CAT), enhancing ROS scavenging capacity [58,59,60,61]. These effects significantly alleviate oxidative stress-induced damage to intervertebral disc cells. Additionally, statins suppress oxidative stress-related signaling pathways, such as NF-κ B, thereby reducing the release of inflammatory cytokines and further mitigating damage to intervertebral disc tissues [62].

Other effects

In addition to their significant anti-inflammatory and antioxidant effects, statins indirectly support the treatment of IVDD by improving endothelial function and inhibiting thrombogenesis [63,64,65]. However, their potential adverse effects, including muscle-related side effects, metabolic abnormalities, and complex impacts on the musculoskeletal system, require further systematic investigation [40, 66, 67].

In summary, the role of statins in degenerative and systemic inflammatory diseases has gained increasing prominence, particularly in their potential applications for conditions such as Alzheimer’s disease, rheumatoid arthritis, and skeletal degenerative disorders like IVDD [68,69,70]. Studies on the musculoskeletal system suggest that statins can promote osteogenesis and improve bone metabolism, thereby playing a crucial role in the treatment of osteoporosis [71, 72]. In addition, statins have a role in other conditions [73]. In recent years, accumulating evidence has highlighted the potential of statins in improving IVDD through mechanisms such as inhibiting disc cell apoptosis, slowing ECM degradation, and enhancing the local microenvironment. However, their efficacy in conditions like sarcopenia remains controversial and warrants further exploration [74,75,76,77].

The effects and mechanisms of statins on IVDD

Statins exert protective effects in IVDD through multiple mechanisms (Fig. 3), including regulating the expression of bone morphogenetic protein-2 (BMP-2) and matrix metalloproteinases (MMPs), improving blood supply to the peripheral vasculature of the intervertebral disc, and reducing inflammation levels. These mechanisms not only promote the repair of the ECM but also play a positive role in slowing the pathological progression of IVDD.

Fig. 3
figure 3

Partial mechanism of action of statins on disc degeneration. IVD: intervertebral disc; IVDD: intervertebral disc degeneration; ACAN:aggrecan;COL II:Collagentype II; MMP-3:Matrix metalloproteinase 3;MMP-13:Matrix metalloproteinase 13; IL-1:interleukin—1;IL-6:interleukin—6;IL-8:interleukin—8; TNF-α:tumor necrosis factor-α;BMP-2:bone morphogenetic protein-2; mSREBP1:mature form of sterol regulatory element-binding protein 1

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Statins improve IVDD by modulating BMP-2 and MMPs

Bone morphogenetic protein-2 (BMP-2), a critical member of the bone morphogenetic protein family, plays a pivotal role in bone formation and cartilage repair and is essential for ECM repair in IVDD [78]. Studies have shown that the biological function of BMP-2 primarily depends on the activation of its downstream Smad signaling pathway. Upon binding to specific membrane receptors, BMP-2 induces the phosphorylation of Smad1/5/8, leading to the formation of Smad complexes that translocate to the nucleus. This process activates the expression of genes such as aggrecan, type II collagen (COL2), and proteoglycans (PG), thereby promoting cartilage matrix synthesis and repair [79,80,81,82,83]. Statins improve IVDD by promoting BMP-2 expression and activating its downstream signaling pathways through multiple mechanisms.Hatano et al. [84] demonstrated that statins significantly enhance the mRNA expression levels of BMP-2, aggrecan, and COL2 while increasing proteoglycan (PG) synthesis. Furthermore, Zhang et al. [85] revealed that simvastatin upregulates BMP-2 mRNA expression in a dose-dependent manner and significantly promotes extracellular matrix synthesis in intervertebral disc cells. Collectively, these studies highlight the potential of statins to enhance chondrogenesis and ECM repair by activating BMP-2 and its associated signaling pathways.

Matrix metalloproteinases (MMPs), the primary mediators of ECM degradation, play a destructive role in intervertebral disc structure and accelerate degeneration when overexpressed [86]. Studies have indicated that statins protect the ECM by inhibiting the NF-κB signaling pathway, thereby reducing the expression of MMPs, such as MMP-3 and MMP-9, as well as inflammatory cytokines like IL-1, IL-6, and TNF-α [87]. Additionally, statins upregulate the expression of transforming growth factor-β (TGF-β), which further suppresses MMP activity and enhances ECM stability [88,89,90].

In conclusion, statins play a critical role in regulating the balance between BMP-2 and MMPs, providing a robust theoretical foundation for their potential to improve IVDD.

Statins improve IVDD by lowering cholesterol

The nutrient supply to intervertebral disc cells is associated with the blood supply from the peripheral blood vessels of the disc, and reduced blood supply has been identified as a critical pathological mechanism in IVDD [24, 91]. Insufficient vascular perfusion accelerates apoptosis of disc cells and degradation of the ECM, thereby triggering the onset and progression of IVDD [92]. Studies have shown that elevated cholesterol levels can accelerate IVDD progression through multiple mechanisms. On one hand, increased cholesterol induces atherosclerosis, which reduces blood flow perfusion to the peripheral vasculature of the IVD, thereby restricting nutrient delivery and impeding the clearance of metabolic waste [93,94,95]. On the other hand, elevated cholesterol levels activate the mSREBP1 signaling pathway, inducing endoplasmic reticulum stress, which subsequently leads to pyroptosis of NP cells and ECM degradation [96]. Additionally, cholesterol metabolism dysregulation upregulates the expression of inflammatory cytokines such as IL-1 and TNF-α, exacerbating inflammation within the disc tissue [41, 97].

Statins reduce serum cholesterol levels significantly, thereby decreasing the occurrence of atherosclerosis and improving blood supply to the intervertebral disc [74, 98]. This mechanism not only alleviates the early pathological changes in IVDD caused by insufficient blood supply but also reduces endoplasmic reticulum stress, mitigating pyroptosis in NP cells [96, 99]. Moreover, enhanced vascular perfusion provides IVD cells with increased oxygen and nutrients, further promoting ECM synthesis and repair [92]. In summary, existing studies suggest that statins, by improving cholesterol levels, not only regulate the blood supply to the IVD but also play a crucial role in the metabolism and regeneration of disc tissues.

The role of statins in chronic pain

Chronic pain is one of the primary clinical symptoms of IVDD, significantly affecting patients’ quality of life. The underlying mechanisms of chronic pain are complex and include nerve root compression caused by IVDD, inflammatory responses induced by NP protrusion, and abnormal processing of pain signals by the nervous system [100,101,102]. During the progression of IVDD, large amounts of inflammatory cytokines, such as IL-1β and TNF-α, are released. These cytokines not only exacerbate damage to NP cells and disc tissues but also activate nociceptors on peripheral nerve endings, such as TRPV1 and TRPM8, thereby inducing the persistent transmission of pain signals [103, 104]. Additionally, sensory nerve endings surrounding the NP and annulus fibrosus (AF) release neuropeptides such as substance P and calcitonin gene-related peptide (CGRP), further amplifying the pain response and creating a vicious cycle [105, 106].

Statins play an important role in alleviating IVDD-associated chronic pain by modulating neuroinflammation. Specifically, statins inhibit the NF-κB signaling pathway, thereby significantly reducing the release of pro-inflammatory cytokines such as IL-1β and TNF-α [50, 62, 107, 108]. These cytokines are known to activate nerve endings and regulate the transmission of pain signals; thus, their suppression effectively alleviates neuroinflammation-induced pain responses.

Furthermore, oxidative stress is considered one of the major drivers of neuroinflammation. Statins alleviate oxidative stress-induced damage to the nervous system by inhibiting NADPH oxidase activity and reducing reactive oxygen species (ROS) levels [58, 65]. Research has shown that rosuvastatin mitigates oxidative stress caused by mechanical stress through the regulation of the Nrf2/HO-1 signaling pathway and reduces the sensitivity of nerve endings [109].

In summary, the potential application of statins in the treatment of IVDD demonstrates promising prospects. On one hand, statins promote chondrogenesis and ECM repair by regulating bone morphogenetic protein-2 (BMP-2) and its downstream signaling pathways. On the other hand, they improve intervertebral disc blood supply by lowering cholesterol levels, thereby mitigating the pathological progression of IVDD. However, the long-term safety of statins and their potential adverse effects, such as muscle-related side effects and metabolic abnormalities, require further in-depth investigation. Moreover, the combined use of statins with existing IVDD treatment strategies warrants further exploration in future clinical studies.

Experimental studies on the effects of statins on IVDD

In recent years, the potential role of statins in IVDD has garnered widespread attention. Table 1 summarizes the experimental data from existing studies on key statins, including the types of studies conducted, dosage ranges, and their effects on IVDD-related parameters. In the following sections, these findings will be discussed in detail in conjunction with the data presented in Table 1.

Table 1 Effect of statins on IVDD from cellular and animal experiments
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Simvastatin

In studies investigating the effects of statins on IVDD, simvastatin, the most extensively studied statin, has demonstrated significant protective effects in both in vivo and in vitro experiments, as shown in Table 1. Research by Zhang et al. [98] revealed that intradiscal injection of 2 µL of 5 mg/mL simvastatin in a rat model significantly increased the content of aggrecan and sulfated glycosaminoglycans (sGAG) in the NP, while also enhancing the expression of cartilag e matrix-related proteins such as BMP-2 and COLII. Furthermore, magnetic resonance imaging (MRI) assessments indicated a marked increase in T2 signal intensity in the degenerated discs, suggesting significant cartilage matrix repair. These findings highlight that simvastatin can significantly delay the pathological progression of IVDD by promoting chondrogenesis and ECM repair.Further dose-response studies demonstrated that intradiscal injections of 10 mg/mL and 15 mg/mL simvastatin in the rat model significantly upregulated the expression levels of BMP-2, aggrecan, and COLII, while reducing histological scores [110]. This suggests a potential dose-dependent therapeutic effect of simvastatin in the treatment of IVDD.In vitro studies have also shown that simvastatin exerts significant biological effects on NP cells derived from both human and animal sources. Tu et al. [87] reported that simvastatin, within a concentration range of 5–50 µM, significantly inhibited IL-1β-induced apoptosis of NP cells and downregulated the expression of inflammatory mediators such as MMP-3 and ADAMTS-4. Moreover, simvastatin suppressed inflammation by inhibiting the activation of the NF-κB and MAPK signaling pathways, thereby mitigating IVDD progression. These in vitro findings further support the potential role of simvastatin in improving the disc microenvironment and delaying the pathological progression of IVDD.

Other statins

In recent years, the roles of other statins in IVDD have gradually attracted increasing attention. As shown in Table 1, the effects of lovastatin are primarily associated with promoting ECM synthesis in the intervertebral disc. Hu et al. [113] demonstrated in a Wistar rat coccygeal disc model that lovastatin, at concentrations ranging from 1 to 5 µM, significantly upregulated the expression of SOX9 and BMP-2. This suggests that lovastatin may delay the pathological progression of IVDD by promoting cartilage matrix synthesis.

In addition, the roles of synthetic statins, such as atorvastatin and rosuvastatin, in IVDD have also been increasingly recognized. Table 1 indicates that atorvastatin not only improves ECM metabolism but also protects NP cells by modulating inflammasome activity. In an in vitro study, Chen et al. [116] reported that atorvastatin significantly inhibited TNF-α-induced activation of the NLRP3 inflammasome and reduced the activity of MMP-3 and MMP-13 by enhancing autophagy. Furthermore, atorvastatin suppressed the NF-κB signaling pathway, thereby ameliorating IVDD. These findings suggest that atorvastatin could serve as a potential therapeutic agent for IVDD.Rosuvastatin has also demonstrated unique therapeutic potential in mitigating disc cell pyroptosis and inflammation. Chen et al. [99] found that rosuvastatin significantly reduced pyroptosis levels in NP cells and downregulated the expression of MMP-3 and ADAMTS-5 by inhibiting the HMGB1 and NF-κB signaling pathways. These effects provide a theoretical foundation for the potential application of rosuvastatin in IVDD treatment.

Comparison and analysis of statin efficacy

Although existing studies have demonstrated the potential therapeutic value of various statins in the treatment of IVDD, an analysis of the data presented in Table 1 reveals significant differences among statins in terms of mechanisms of action, efficacy, and applicability. Simvastatin, the most extensively studied statin, has shown remarkable effects in anti-inflammatory activity, chondrogenesis promotion, and ECM repair. However, its therapeutic effects exhibit a dose-dependent relationship, with high doses (> 15 mg/mL) potentially increasing the risk of adverse effects.Compared to simvastatin, lovastatin demonstrates relatively weaker anti-inflammatory and antioxidant properties but exhibits unique advantages in promoting ECM synthesis and maintaining ECM stability. Studies suggest that atorvastatin provides more comprehensive effects in anti-inflammatory and antioxidant activities as well as autophagy regulation. However, further optimization of dosage and delivery methods is required to enhance its therapeutic efficacy.Additionally, rosuvastatin has demonstrated unique potential in protecting NP cells from pyroptosis and promoting ECM synthesis. Nevertheless, its efficacy may be weaker compared to that of simvastatin.

Limitations of experimental studies

Despite extensive research confirming the potential effects of statins in IVDD, these studies still have notable limitations that may affect their applicability to human diseases and the reliability of their conclusions.

Currently, in vitro studies predominantly use NP cells or intervertebral disc-derived mesenchymal stem cells (MSCs) from human or animal sources [87, 99, 114, 116]. However, significant differences exist between the experimental conditions of in vitro studies and the microenvironment of the human intervertebral disc. Under in vitro culture conditions, it is challenging to replicate the hypoxic and ischemic microenvironment present in the human intervertebral disc, which plays a crucial role in the pathological progression of IVDD. Furthermore, in vitro experiments fail to recapitulate the complex multisystem interactions present in vivo, including mechanical stress, inflammatory responses, and immune system involvement, which may result in findings that deviate from actual physiological and pathological conditions.

Additionally, existing animal studies primarily use rat or mouse IVDD models, but these models exhibit significant biological differences compared to humans [98, 110, 112, 115]. Compared to human intervertebral discs, the nucleus pulposus of rats and mice contains a higher water content, degenerates more rapidly, and is subjected to lower mechanical stress. In contrast, human IVDD typically progresses as a chronic condition influenced by complex mechanical, environmental, and genetic factors. These differences may lead to overestimation of the therapeutic effects of statins or underestimation of their potential adverse effects in animal models.Moreover, the use of animal models raises ethical concerns, including the selection of appropriate animal species and the methods used to construct degeneration models to balance research feasibility with clinical translatability. In some experiments, researchers induce degeneration by mechanical injury, such as needle puncture of the caudal disc. While this method effectively creates acute degeneration models, it does not adequately reflect the chronic progression of human IVDD.In summary, these limitations highlight the need for more sophisticated in vitro and in vivo models that better mimic human IVDD pathology, as well as further research to validate the therapeutic potential of statins in human clinical settings.

Synergistic effects of statins with other drugs

Although existing studies have demonstrated the promising potential of statins in anti-inflammatory, antioxidant, and ECM repair functions, their efficacy as a monotherapy remains limited. In recent years, synergistic drug interactions and multi-target combination therapies have become research hotspots in the field of degenerative disease treatment. Exploring the combined application of statins with other therapeutic approaches may provide a novel direction for the treatment of IVDD.

Anti-inflammatory drugs (e.g., IL-1 antagonists, COX-2 inhibitors) can significantly reduce inflammation levels, thereby slowing the progression of IVDD [117,118,119,120]. Statins, in addition to their anti-inflammatory properties, regulate oxidative stress and enhance nutrient supply, which may synergize with anti-inflammatory drugs to provide enhanced therapeutic efficacy. Therefore, it is hypothesized that the combined use of statins and anti-inflammatory drugs could more effectively improve the intervertebral disc microenvironment while potentially reducing adverse effects associated with the use of single drugs.

Growth factors (e.g., BMP-2, TGF-β), as potential therapeutic agents for IVDD, play a critical role in promoting ECM repair and chondrogenesis, thereby facilitating disc tissue regeneration [29, 121,122,123]. However, during the pathological progression of IVDD, the therapeutic effectiveness of growth factors is often constrained by the inflammatory state of the disc microenvironment. Existing studies have shown that statins significantly improve inflammation in the intervertebral disc microenvironment by inhibiting signaling pathways such as NF-κB. Thus, it is hypothesized that the combination of statins and growth factors could simultaneously improve the inflammatory microenvironment and promote disc tissue repair and regeneration, providing a synergistic effect for the comprehensive treatment of IVDD.

Challenges and strategies for clinical translation

Although numerous experimental studies have provided important theoretical evidence for the potential role of statins in the treatment of IVDD, significant challenges remain in translating these findings into clinical applications. Therefore, exploring effective strategies for clinical translation is of great significance.

Dosage

The doses of statins used in experimental studies are significantly higher than those commonly administered in clinical practice. For example, in rat models, the injected dose of simvastatin can range from 5 to 15 mg/mL, while the typical oral dose in humans is 10–40 mg/day. Direct application of such high doses to clinical settings may result in toxic side effects rather than the desired therapeutic effects. Therefore, dose-response studies are essential during the clinical translation process to determine appropriate therapeutic doses for humans that balance safety and efficacy.

Delivery methods

The delivery methods commonly used in experimental studies include oral administration and local intradiscal injection. Oral administration enables systemic anti-inflammatory and cholesterol-lowering effects via gastrointestinal absorption, but the concentration of the drug reaching the degenerated disc may be insufficient to achieve the desired therapeutic outcomes. In contrast, local intradiscal injection significantly increases the drug concentration at the target site, enhancing its therapeutic efficacy. However, intradiscal injection is technically complex and carries potential risks, such as mechanical injury at the injection site and infection. Therefore, the clinical translation process should explore optimized drug delivery strategies, incorporating sustained-release technologies and nanotechnology-based targeted delivery systems to enhance drug bioavailability while minimizing side effects.

Individual variability

Experimental studies often fail to account for the individual variability seen in human populations. Most studies use animal models or cell lines with homogeneous genetic backgrounds, which do not adequately reflect the genetic diversity of human patients. Factors such as age, sex, ethnicity, and metabolic status can significantly influence the therapeutic efficacy of statins. Consequently, during clinical translation, scientifically designed clinical trials are needed to systematically evaluate these variables and provide evidence for the development of personalized treatment strategies.

Patient selection criteria

Due to individual variability, different patient groups exhibit significant differences in sensitivity to statin therapy, leading to variable therapeutic outcomes. For example, IVDD patients with hypercholesterolemia or metabolic syndrome may be more responsive to statin treatment, making them a priority population for research. Thus, in the clinical translation process, it is necessary to establish scientifically sound stratification criteria based on imaging findings and biomarker levels to identify patient populations most likely to benefit from statin therapy.

Clinical studies

Currently, research on the use of statins for IVDD treatment is predominantly focused on basic science, with a lack of high-quality clinical studies, such as randomized controlled trials, to evaluate their safety and efficacy in clinical practice. Therefore, during clinical translation, well-designed, high-quality clinical studies are imperative to comprehensively assess the safety and efficacy of statins in clinical applications.

Future research directions

Although numerous studies have provided theoretical support for the application of statins in the treatment of intervertebral disc degeneration (IVDD), many unresolved issues remain. The following research directions warrant further exploration in the future.

Conducting clinical studies

Future studies should prioritize high-quality randomized controlled trials (RCTs) to evaluate the clinical efficacy and safety of statins in IVDD treatment. For example, multicenter RCTs can be designed to investigate the applicability of statins across different age groups, genders, and metabolic statuses. These trials should also compare the therapeutic effects of oral administration and local injection of statins in IVDD patients.

Development of biomarkers

Future research should focus on the development of biomarkers that can monitor the therapeutic efficacy of statins in IVDD treatment. Such biomarkers would enable clinicians to make more precise and reliable decisions. For instance, imaging parameters or changes in the levels of inflammatory cytokines in the blood could serve as indicators of the therapeutic effects of statins.

Exploring dosage and delivery methods

In clinical applications, safer and more efficient delivery methods should be explored. Combining sustained-release formulations with nanotechnology-based targeted delivery systems could allow drugs to act precisely on degenerated intervertebral discs, reducing potential side effects. Additionally, studies should determine the optimal dosage of statins for IVDD treatment to balance safety and efficacy.

Optimization of experimental models

Future studies should adopt experimental models that better replicate the pathological features of human IVDD. This could involve establishing animal models with chronic and long-term IVDD progression similar to human conditions or using in vitro cell cultures that simulate the human microenvironment more closely. These approaches would provide a more realistic understanding of the mechanisms of action of statins.

Exploring multi-target combination therapy

Future efforts should focus on designing experiments to investigate the combined application of statins with other therapeutic interventions, such as growth factors and anti-inflammatory drugs, at both the basic research and clinical levels. Strategies for multi-target combination therapy can be developed by designing experimental models to evaluate the synergistic effects of statins and other drugs. Furthermore, RCTs can be conducted to validate the safety and efficacy of combining statins with other treatments.

In-depth study of mechanisms of action

Future research should aim to elucidate the specific mechanisms underlying the therapeutic effects of statins in IVDD treatment. While current studies suggest that statins improve IVDD through anti-inflammatory and antioxidant mechanisms, the complete molecular pathways remain unclear and require further investigation.

Conclusion and outlook

IVDD is a major contributor to the onset and progression of various degenerative spinal diseases. Early intervention and treatment of IVDD are therefore critical for safeguarding patients’ physical and mental health. Numerous studies have demonstrated that statins exert beneficial effects on IVDD by mechanisms such as upregulating BMP-2, promoting cartilage repair, and reducing cholesterol levels, thereby improving skeletal health and enhancing disc nutrition.Both in vivo and in vitro studies suggest that various statins possess potential therapeutic effects on IVDD. However, current research is predominantly focused on cellular and animal models, with a lack of clinical studies to validate these findings. Consequently, future research should emphasize the design and implementation of high-quality clinical studies. These studies should adopt scientifically robust methodologies, select representative samples, and include larger sample sizes to comprehensively evaluate the therapeutic value of statins.Moreover, the potential mechanisms of statins in IVDD treatment beyond their known effects require further experimental exploration. The optimal administration routes, dosages, and potential side effects of statins in IVDD treatment must also be thoroughly investigated and refined to enable clinicians to use these drugs more safely and effectively.Despite the challenges that remain, statins show significant potential in alleviating and improving the pathological progression of IVDD. With continued research, statins could become a promising therapeutic option in the management of IVDD.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors thank the financial support of the CuiYing Science and Technology Innovation plan project of Lanzhou University Second Hospital (Grant No. CY2021-MS-A03). The authors appreciates Figdraw for providing the drawing materials.

Funding

This work was supported by the CuiYing Science and Technology Innovation plan project of Lanzhou University Second Hospital (Grant No. CY2021-MS-A03).

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Authors and Affiliations

  1. Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, Gansu, 730000, P.R. China

    Xianxu Zhang, Shicheng Li, Xin Liu, Zhong Ma, Qiang Zhang, Yuji Zhang, Jiangdong An & Zhiqiang Luo

  2. Orthopaedics Key Laboratory of Gansu Province, Lanzhou, Gansu, 730000, China

    Xianxu Zhang, Shicheng Li, Xin Liu, Zhong Ma, Qiang Zhang, Yuji Zhang, Jiangdong An & Zhiqiang Luo

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  1. Xianxu Zhang
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  2. Shicheng Li
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  3. Xin Liu
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  4. Zhong Ma
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  5. Qiang Zhang
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  6. Yuji Zhang
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  7. Jiangdong An
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  8. Zhiqiang Luo
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Contributions

Xianxu Zhang collected the literature and wrote the article. Zhiqiang Luo and Jiangdong An revised the article. Zhong Ma and Zhiqiang Luo designed the study. Shicheng Li, Xin Liu, Zhong Ma, Qiang Zhang, and Yuji Zhang prepared figures. All authors contributed to data analysis, drafted and critically revised the paper and agreed to be accountable for all aspects of the work.

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Correspondence to Zhiqiang Luo.

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Zhang, X., Li, S., Liu, X. et al. The protective effect and experimental research progress of pleotropic statins in intervertebral disc degeneration. J Orthop Surg Res 20, 122 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13018-025-05487-8

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13018-025-05487-8

Keywords

Journal of Orthopaedic Surgery and Research

ISSN: 1749-799X