Angiotensin II receptor blockers and their applications in orthopaedic surgery and musculoskeletal medicine

Introduction

Fibrosis is one of the primary factors contributing to tissue healing and functional recovery in the field of orthopaedic surgery (1). It comprises a biologically complex process with a multitude of factors, pervasive throughout the human body and extending well beyond musculoskeletal injury (1). Despite numerous pro-fibrotic molecular pathways delineated in the literature, effective treatments of these pathways in orthopaedic patients remain scarce (1). Consequently, post-operative stiffness remains a significant concern, exerting negative effects on patient outcomes and healthcare expenditures. Pathologic fibrosis has been described following many orthopaedic interventions such as total knee arthroplasty (TKA), hip arthroscopy, and rotator cuff repair (2-6).

Angiotensin II receptor blockers (ARBs), such as losartan, valsartan, and olmesartan, conventionally prescribed for hypertension and heart failure, demonstrate well-described antifibrotic properties (7,8). However, they have only recently emerged as a potential therapy to combat fibrosis-mediated stiffness in orthopaedic patients. Given their novelty in the field, the mechanism and indications for the use of ARBs for reducing fibrosis are not yet widely understood. The purpose of this review is to highlight:

• The pharmacology of ARBs with particular emphasis on their implications for orthopaedic surgery and musculoskeletal medicine.
• The basic science research related to the use of these agents in orthopaedic surgery.
• The distinct subspecialties within orthopaedic practice which may be affected by the administration of ARBs.

Pharmacology and basic science review

Etiology and pathogenesis of fibrosis

Fibrosis involves the deposition of extracellular matrix (ECM) proteins, notably collagen, by fibroblasts (1). While fibrosis is a complex and multifactorial process, the current review will focus on pertinent biological aspects concerning the effects of ARBs. Transforming growth factor-β (TGF-β) is a key mediator of fibrosis, activating fibroblasts and upregulating Smad signaling to trigger overexpression of pro-fibrotic genes (7,8). Dysregulation of this pathway constitutes a major mechanism in the process of pathologic tissue fibrosis, particularly in the expression of type-1 collagen (7,8). Therefore, TGF-β is an appealing target for pharmacologic intervention.

There are other important molecular mediators which have been shown to be affected by ARBs. For example, in a rat model, metabolites of losartan have been shown to prevent excessive myocardial collagen deposition and crosslinking, as well as decrease the levels of connective tissue growth factor (CTGF), which is an important fibrosis mediator (9). In a rat model of priapism, the administration of losartan was shown to result in a significantly lower type-1 collagen concentration (an important marker of fibrosis) compared to a control group, demonstrating potential benefit in suppressing the pathologic fibrosis seen in priapism (10). In a lung model, treatment of rats with an agonist of angiotensin-receptor blocker’s target receptor (AT2) led to significantly decreased levels of various fibrotic markers including collagen 1 and 3, CTGF, and interleukin-13 (11).

There are various reasons why fibrosis can be pathogenic in the realm of orthopaedic surgery. For example, in spine surgery, excessive post-operative epidural fibrosis can provide a compressive or tensile force on neural elements or the microvasculature, thus leading to pain and ischemic sensation (12). In sports medicine, arthrofibrosis can lead to post-operative stiffness, which may require return to the operating room for manipulation under anesthesia (MUA), or lysis of adhesions (LOA), and result in a suboptimal outcome (5). In hand surgery, excessive scar formation following flexor tendon repair can lead to poor tendon gliding and diminished range of motion (13). While the fibrotic response is an essential part of soft-tissue healing following orthopaedic surgery, the above examples prove that excessive and pathologic fibrosis may be a target for anti-fibrotic agents such as ARBs.

Pharmacology of ARBs as antifibrotic drugs

ARBs are primarily used in cardiovascular conditions and function by inhibiting the binding of angiotensin II (AII) to AT1 or AT2 receptors (14,15). Under normal circumstances, this binding of AII to AT1 or AT2 triggers the up-regulation of Alk1 receptors, which in turn stimulates TGF-β synthesis (14,15). In the presence of ARBs, this pathway is impeded, leading to attenuated TGF-β activity and limited fibrotic deposition, which has been demonstrated in both animal and human studies (14,15). This indirect inhibition of TGF-β is significant, as direct inhibition may yield undesirable consequences due to the molecule’s involvement in the immune response (16). The half-life of ARBs vary, but generally ranges between 2 and 24 hours (17). They have moderate to good oral bioavailability, ranging from 26–80%, and are variably excreted by the kidneys or biliary/fecal routes (17).

Preclinical evidence of ARBs as antifibrotic agents

Extensive literature has been published on the antifibrotic efficacy of ARBs across various tissue types and organs, including the liver, kidney, and lungs (15,18,19). More recently, there has been growing evidence and interest in the use of ARBs as antifibrotic agents in musculoskeletal tissues.

In skeletal muscle, ARBs exhibit diverse effects on muscle regeneration, fibrosis, and pain following injury (20-23). Bedair et al. found that ARBs significantly reduced muscle fibrosis and provided an improvement in the number of regenerating muscle fibers in mice, suggesting the potential for ARBs to be used to enhance muscle recovery after injury (20). Garg et al. demonstrated that losartan administration led to decreased fibrosis in injured rat muscle while also inhibiting tissue regeneration and functional recovery after muscle injury (21). In a murine model, Tawfik et al. showed that ARBs have similar effects as exercise on reduction of pain after muscle and bone damage, and may be useful in patients who are unable to exercise or after injuries where restricted mobility is necessary (22). Additionally, Burks et al. reported on a mouse model that demonstrated improved muscle remodeling and reduced disuse atrophy with losartan use (23).

Several studies have also used ARBs in combination with other regenerative muscle therapies. A combination therapy of platelet-rich plasma (PRP) and losartan, introduced by Terada et al. showed significant improvements in mouse muscle regeneration and function after contusion injury (24). When used concurrently with muscle derived stem cells in a murine model, the administration of losartan resulted in significantly reduced scar tissue formation, increased number of regenerating myofibrils and overall improved functional muscle recovery (25).

While fewer studies explore the benefits of ARBs in tendon repair, initial findings are promising. Lacheta et al. published losartan in combination with bone marrow stimulation increased tensile strength and improved tendon morphology in rabbits, noting increased formation of type I collagen and decreased type III collagen (26). In Achilles tendon repair in rats, Nazari et al. reported that telmisartan (another ARB) and enalapril (an angiotensin-converting enzyme inhibitor) reduced inflammation and adhesive tissue formation while increasing tensile strength of the tendon (27). This data also suggests that ARBs may not have an adverse effect on pro-fibrotic tissue healing necessary for tendon healing (i.e., rotator cuff repair).

ARBs have also been demonstrated to have benefits in cartilage pathologies. Several studies have shown to reduce cartilage degeneration, inflammation, and fibrosis, especially in osteoarthritic cartilage (28). In infrapatellar fat pad and synovial fibrosis, rats that received losartan had improved weight-bearing tolerance and pain behavior scores (29). Additionally, when biologically regulated bone marrow stimulation was performed in conjunction with losartan intake in rabbits, increased hyaline cartilage formation and reduced fibrocartilage formation were observed when compared to the control group (30,31). Yamaura et al. notably developed a sustained-release nanofiber formulation of losartan, showing that, in vitro, it had added benefits in preventing degeneration and inflammation of chondrocytes (32).

The collective body of basic science literature has highlighted the beneficial effects of ARBs on musculoskeletal tissues encompassing in vitro and in vivo settings. ARBs demonstrate efficacy in reducing fibrosis, inflammation, and may improve tissue regeneration in skeletal muscle, tendon, and cartilage. Extrapolating from these studies, it is reasonable to speculate that ARBs may reduce the risk of arthrofibrosis in patients undergoing orthopaedic surgery. Subsequent sections will review the early clinical data and future directions regarding the utilization of ARBs in orthopaedics (Table 1).

Knee arthroplasty

Arthrofibrosis represents an unfortunate yet frequent complication following TKA with nearly 20% of patients reporting knee stiffness 6 weeks post-operatively (40). The consequences of arthrofibrosis are not limited to its resultant stiffness but also encompass substantial financial burdens. The average costs per patient are 1.5 to 7.5 times higher when stiffness is reported after TKA as a result of subsequent interventions such as MUA, arthroscopic LOA, and revision TKA (6,41). Unsurprisingly, the principal driver of the fibrotic response resulting in stiffness is TGF-β, an important target of ARBs, as previously discussed (42).

While ARBs are not a standard course of treatment in patients undergoing TKA, recent studies have investigated their effects with mixed results. In a single-center study of 79 patients, Arraut et al. reported no differences in postoperative range of motion, rates of 90-day MUA, or reoperation among patients administered losartan for 3 months prior to surgery (33). Similarly, Langston et al. found that ARB use resulted in no difference in postoperative range of motion after TKA; this study however involved only 19 patients taking ARBs preoperatively and significantly higher number of diabetic patients than in the control cohort which may affect the applicability of its findings (34). In contrast, a study analyzing 101,366 TKA patients, perioperative losartan usage incurred significantly lower risk of undergoing MUA relative to a control group (37). Similarly, Albright et al. reported reduced 2-year MUA, LOA, and revision surgery rates in 82,065 patients receiving postoperative ARBS for at least three months following primary TKA (35). Losartan was determined to have greatest protective effect when compared with other ARBs in the study (35). The result of the large database studies suggest that the smaller studies may in fact be underpowered to detect certain important differences in outcomes amongst those taking ARBs compared to those who are not; however, further well-designed, large clinical studies are imperative to elucidate the true effect of ARBs and arthrofibrosis following TKA.

In addition to their post-TKA utility, ARBs have also been trialed as a means of preserving knee strength and function in older adults. In a randomized trial, Lee et al. studied the effects of losartan on knee strength and fragility scores in 25 prefrail older adults aged 70–90 years (36). Patients administered losartan for 6 months had higher knee strength and frailty scores than the control/placebo group (36). Given that knee strength and frailty scores generally correlate with postoperative complications and mortality rates following TKA (43,44), further investigation regarding the role of ARBs in this setting is warranted.

Hip arthroscopy

Hip arthroscopy is performed frequently in younger patients as the preferred surgical intervention for femoroacetabular impingement (FAI) (45). Following hip arthroscopy, patient satisfaction ranges from 80–95%, with roughly 6% of patients undergoing reoperation (46,47). A common cause of reoperation is postoperative adhesion formation, particularly capsulolabral adhesions (48). Willimon et al. found adhesion formation to be more common in patients under 30 years of age and in those who do not receive hip circumduction physical therapy (49).

While the pathophysiology of postoperative hip adhesion formation is not well understood, it is hypothesized that adhesions arise in part through a fibrosis mechanism catalyzed by a highly vascularized capsule and labrum, as well as residual suture material in the area (46). Capsulolabral fibrosis has been linked to the TGF-β signaling pathway as previously discussed (3). Therefore, ARBs, as a noninvasive method of reducing adhesions, present a promising opportunity to reduce reoperation rates following hip arthroscopy (46). To our knowledge, there are no clinical studies that have examined the effects of ARBs on adhesion formation in hip arthroscopy.

Shoulder surgery

Shoulder stiffness is a common clinical finding arising from various etiologies, including idiopathic conditions like adhesive capsulitis, or acquired in the post-traumatic or post-operative setting (4,5). Postoperative stiffness following rotator cuff repair is reported in 4–15% of cases (50). Treatment options include intra-articular corticosteroids, physical therapy, and surgery, including MUA and arthroscopic capsular release (50).

While the etiology of post-operative shoulder stiffness is believed to be multifactorial, upregulation of TGF-β signaling has been observed in patients with shoulder stiffness following rotator cuff repair (51). Thus, ARBs may reduce this fibrotic response via their anti-TGF-β mechanism. It is important to note however that some degree of fibrotic remodeling is beneficial to rotator cuff tendon healing, necessitating a balance between the healing and scarring responses (52).

Recent investigations have explored the effects of ARBs on post-operative shoulder stiffness. In a retrospective review, Bi et al. found no significant decrease in MUA or arthroscopic capsular release rates following shoulder arthroscopy in patients who were taking an angiotensin converting enzyme (ACE) inhibitor or ARB (38). However, this study addressed only preoperative use the ARBs and those taking ARBs had significantly higher rates of diabetes mellitus, which may limit the applicability of the results even in the context of appropriate statistical controlling. Moreover, the authors suggested that larger cohort studies may reach a statistically significant difference. More recently, Testa et al. reported significantly lower rates of newly diagnosed adhesive capsulitis and adhesive capsulitis necessitating surgical intervention at both 1- and 2-year timepoints in patients taking ARBs compared to controls (39). This retrospective study evaluated 1 million patients taking ARBs, with a total of 4 million patients studied, and controlled for various known co-pathologies of adhesive capsulitis such as diabetes mellitus and thyroid disease. These findings suggest a potential protective effect of ARBs against adhesive capsulitis development, providing further evidence of the potential benefits of the antifibrotic properties of ARBs in relation to the musculoskeletal system.

While evidence regarding the effectiveness of ARBs in reducing shoulder stiffness is mixed, further investigation is warranted to elucidate the underlying mechanisms and establish causal relationships, especially considering the existing evidence of their benefits in the knee.

Adverse effects and risks

While ARBs have shown promise in mitigating fibrosis, their use may entail certain risks, particularly in the context of orthopaedic surgery. One potential concern is the possibility of hypotension, especially in patients who are already predisposed to hemodynamic instability, such as those undergoing major orthopaedic procedures (53). This hypotension has the potential to lead to syncopal or pre-syncopal episodes, and thus poses a potential fall-risk for the patient. Additionally, there is a need to consider potential adverse effects such as renal dysfunction or electrolyte imbalances (53). The long-term effects of ARBs on musculoskeletal tissues and their overall impact on patient outcomes following orthopaedic interventions have yet to be reported, and requires further study. Importantly, the proposed dosing of losartan to prevent postoperative adhesions is 12.5 mg twice daily for 6 weeks following surgery, which is a substantially lower dose than the typical starting dose of adults with hypertension at 50 mg once daily (46,54). However, the optimal dose of losartan to mitigate postoperative fibrosis must be further studied, particularly in the context of adverse reactions and minimally clinically effective dosing. As always, clinicians must weigh the potential benefits against the risks and consider individual patient factors when making treatment decisions.

Conclusions

Fibrosis represents a significant challenge for orthopaedic patients as it leads to joint stiffness, adhesions, limited range of motion, and has been implicated in muscle atrophy and osteoarthritis. Through an anti-TGF-β signaling mechanism, ARBs have demonstrated preclinical success in preventing fibrosis and improving healing. In clinical settings, ARBs have been shown to decrease postoperative intervention following TKA, but their evidence in the shoulder and hip is limited due to a paucity of data. Further investigation is warranted to elucidate the potential perioperative risks and benefits of ARBs and their applications in the field of orthopaedic surgery.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://aoj.amegroups.com/article/view/10.21037/aoj-24-12/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoj.amegroups.com/article/view/10.21037/aoj-24-12/coif). The authors have no conflicts of interest to declare.

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