Intra-articular treatments for hindfoot osteoarthritis

Abstract

Hindfoot osteoarthritis (HFOA) leads to pain, impaired function, and reduced quality of life. Conservative management aims to alleviate symptoms and delay surgical interventions such as arthrodesis, particularly in young patients with post-traumatic HFOA. Intra-articular injections of corticosteroids and hyaluronic acid are widely used as alternatives for treating foot and ankle osteoarthritis to provide temporary pain relief and functional improvement. Recently, orthobiologic treatments have gained interest for their potential regenerative effects. This review aims to summarize the current evidence on intra-articular injections for HFOA, highlighting the potential benefits, perspectives, and mechanisms of action of conventional and orthobiologic treatments such as platelet-rich plasma, bone marrow aspirate concentrate, and adipose-derived stem cells.

Key Words: Hindfoot; Foot; Ankle; Osteoarthritis; Intra-articular injection; Corticosteroids; Hyaluronic acid; Platelet-rich plasma; Bone marrow aspirate concentrate; Mesenchymal stem cells

Core Tip: Hindfoot osteoarthritis (HFOA), whose prevalence has been increasing over the years, leads to pain, impaired function, and reduced quality of life. Moreover, it becomes symptomatic approximately 15 years earlier than hip and knee osteoarthritis, leading to the need for procedures for long-lasting relief of foot and ankle pain. Intra-articular treatments such as corticosteroids, hyaluronic acid, platelet-rich plasma, bone marrow aspirate concentrate, and adipose-derived stem cells may improve HFOA symptoms.

TO THE EDITOR

Osteoarthritis (OA) is a chronic condition, and as it progresses, patients experience pain, functional impairment, and reduced quality of life[1]. In August 2024, Soufan et al[2] reviewed the intra-articular treatments for OA. As the knee joint is mostly affected by OA, it has been the focus of most studies. However, interest in treating other joints, such as the foot and ankle, has increased in the recent years. The prevalence of foot radiographic OA is 22%, whereas foot symptomatic radiographic OA is 5%[3]. The prevalence of ankle radiographic OA is 2%[4] and symptomatic radiographic OA is 3.4%[5]. Hindfoot OA (HFOA) prevalence has also increased over the years[6] and may be associated with OA in other articulations. Hand and knee radiographic OA are more common in patients with foot OA[7]. Moreover, HFOA becomes symptomatic approximately 15 years before hip and knee OA, leading to the need for joint-preserving surgeries or procedures for long-lasting relief of foot and ankle pain[8].

HFOA management involves a set of measures, including patient education, weight loss, physical therapy, exercise, and pharmacological treatment[9]. Intra-articular injections are widely used as alternatives for the treatment of HFOA because arthrodesis aims to abolish articulation mobility[10,11]. Considering that most patients with HFOA are young adults and that the condition often have a posttraumatic cause, strategies to delay arthrodesis should be considered, especially because it increases the risk of requiring arthrodesis in adjacent joints. Corticosteroid and hyaluronic acid intra-articular injection are established treatments for knee OA, decreasing pain and partially restoring function, at least temporarily[12]. However, the indication for their use in treating HFOA remains uncertain[11,13]. Orthobiologics, defined as the use of biologic materials in the treatment of musculoskeletal diseases, including platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and adipose tissue-derived treatments, have been increasingly used in orthopedics for the treatment of OA[14].

Patients with symptomatic OA, including those with HFOA secondary to trauma, may benefit from intra-articular injections[15]. Therefore, the goal of the present manuscript is to comment on HFOA conservative treatment with intra-articular injections, including orthobiologics such as PRP, BMAC, and adipose-derived stem cells.

CORTICOSTEROIDS INJECTIONS

Corticosteroid analogs are similar to the endogenous hormone, hence presenting an anti-inflammatory action, which results in a reduced release of cytokines and immune system cell activity[16,17] (Figure 1). Corticosteroids bind to glucocorticoid receptors, promoting receptor dimerization and nuclear translocation, where they regulate gene expression through glucocorticoid response elements[16]. This leads to decreased cytokine secretion and suppression of immune cell activity, thereby providing short-term symptomatic relief. However, repeated intraarticular corticosteroid injections have been associated with cartilage degeneration and potential OA progression, particularly in weight-bearing joints such as the hindfoot[16,17]. They are highly effective for pain relief and immediate gain of function, although some reports have indicated long-term adverse effects[18]. A prospective long-term follow-up study by Ward et al[19] showed a significant improvement in foot-related quality of life scores after treatment with intra-articular corticosteroid injection. Additionally, a retrospective study concluded that corticosteroids were effective and safe for the treatment of several ankle conditions[20]. Some studies have described limited evidence regarding corticosteroids use in HFOA, including patients that presented good short-term results with triamcinolone hexacetonide and betamethasone[13,21]. Other reports showed pain reduction and functional improvement one month after corticosteroid injection in the subtalar and ankle joints; however, by the three-month follow-up, symptoms had returned to their previous pattern[22]. On the other hand, a recent retrospective study demonstrated considerable analgesic effects with high patient satisfaction, although pain relief was greater after the first injection than after the second[23].

Figure 1 Mechanisms of action of corticosteroids and hyaluronic acid in joints. In the left panel, corticosteroids bind to glucocorticoid receptors, leading to receptor dimerization and translocation to the nucleus, where they regulate gene expression via glucocorticoid response elements. This results in reduced cytokine secretion, via IKKβ-inhibition of NF-kB, and decreased immune cell activity, potentially providing short-term symptomatic relief. In the right panel, high molecular weight hyaluronic acid interacts with CD44 receptors, contributing to anti-inflammatory effects by reducing IL-8, TNF-α, and iNOS expression. Hyaluronic acid also plays a biomechanical role in shock absorption, lubrication, and regulation of interstitial fluid dynamics within the joint. Conversely, degraded low molecular weight hyaluronic acid activates Toll-like receptors TLR2 and TLR4, promoting NF-κB-mediated pro-inflammatory signaling.

Adverse events after corticosteroid injection in the ankle are uncommon, occurring in approximately 5.8%, according to Anderson et al[24], with postinjection flare being the most common, while infection was not reported.

No specific protocol exists for corticosteroid use in the foot and ankle joints because the available guidelines are divergent. Therefore, some authors recommend limiting its use to three or four applications per year for patients with higher grades of ankle OA presenting with persistent pain[19]. The American College of Rheumatology strongly recommends corticosteroid injections[25], whereas the OA Research Society International (OARSI) conditionally recommends their short-term use for symptomatic relief[26], and the American Academy of Orthopedic Surgeons has an uncertain recommendation for symptomatic knee OA[27]. Taken together, we consider that intra- articular use of corticosteroids should be limited to specific cases, prioritizing short-term symptom relief.

VISCOSUPPLEMENTATION WITH HYALURONIC ACID

Viscosupplementation is the intra-articular injection of exogenous hyaluronic acid, a molecule produced by chondrocytes, synoviocytes, and fibroblasts[28,29]. Hyaluronic acid is composed of a chain of thousands of interspersed repeats of β-D-glucuronic acid linked to N-acetyl-β-D-glucosamine, with an average weight of approximately 108 Da[26]. This molecule is an essential regulator of synovial viscoelasticity and articular cartilage homeostasis and has been used pharmacologically as a treatment option with broader activity compared to corticosteroids, although it is more expensive[29,30]. Viscosupplementation restores the rheological properties of synovial fluid, inhibits the degradation of endogenous hyaluronic acid, and stimulates its synthesis by synoviocytes[26]. Moreover, hyaluronic acid presents physicochemical properties such as shock absorption, lubrication, water flow regulation, and stabilization of the joint structure[28]. Depending on the size of hyaluronic acid molecule, different effects on inflammatory processes may occur based on its interaction with surface molecules such as CD44[26,31]. As a result, inflammatory signaling cascades, such as Toll-like receptors pathways, are minimally activated, thus inhibiting the activation of NF-κB and p38MAPK kinases[32] (Figure 1). High molecular weight hyaluronic acid interacts with CD44 receptors, exerting anti-inflammatory effects by downregulating IL-8, TNF-α, and iNOS expression[26,32]. It also contributes to joint biomechanics through shock absorption, lubrication, and the regulation of interstitial fluid dynamics. Conversely, low molecular weight and degraded hyaluronic acid can activate the Toll-like receptors TLR2 and TLR4, triggering pro-inflammatory signaling via the NF-κB pathway[32].

A systematic review found that intra-articular ankle injection of hyaluronic acid is a safe treatment, promoting substantial improvement in patients’ functional scores but with no superiority compared to other treatment modalities[11]. A meta-analysis suggested ankle pain reduction after intra-articular hyaluronic acid injection in patients with ankle OA, recommending the use of multiple injections[33]. A randomized, double-blind, saline-controlled trial suggested that a five weekly sodium hyaluronate injections were a safe and effective option for ankle OA treatment[34], a finding also supported by another prospective clinical trial[35]. Moreover, a prospective clinical trial of patients receiving three weekly injections of hyaluronic injection concluded that this treatment reduces pain and improves function in patients with early to moderate HFOA[36]. Recently, a study by Mansur et al[37] concluded that treatment with hyaluronic acid reduces pain and improves function in patients with subtalar OA following intra-articular calcaneal fracture. Based on these findings, we believe that multiple-dose hyaluronic acid treatment may be appropriate for patients with HFOA.

Currently, no consensus exists on the conservative treatment of HFOA, but hyaluronic acid can be conditionally recommended in cases of inadequate response to simple analgesics[38]. Nonetheless, the European Consensus Group on viscosupplementation recommends its use when treatment with nonsteroidal anti-inflammatory drugs fails[39]. Furthermore, the OARSI postulates that hyaluronic acid may have a safer long-term profile than intra-articular corticosteroids[26].

A strategy used to improve HFOA treatment is the combination of intra-articular hyaluronic acid and corticosteroids. Gomes et al[22] found that this combination provided greater and longer-lasting analgesic and functional improvements compared to intra-articular corticosteroids only (Figure 1).

PRP

PRP is an autologous product characterized by a platelet concentration three to five times higher than physiologic levels and rich in growth factors such as PDGF, TGF-β, IGF, and FGF2, which enhance chondrocyte differentiation, reduce chondrocyte apoptosis, and promote cartilage protection. Additionally, PRP stimulates osteoblast proliferation and collagen deposition while reducing osteoclast formation, thereby contributing to bone remodeling. Its immunomodulatory profile includes increased levels of anti-inflammatory cytokines (IL-4, IL-10, IL-13) and reduced expression of pro-inflammatory mediators (IL-1β, TNF-α)[40]. The efficacy of PRP has been widely discussed due to the heterogeneity of protocols available in the literature, leading to criticism of its use[41]. Despite that, PRP is offered worldwide as a therapeutic option for knee OA[42].

Regarding the ankle joint, few publications are available on PRP-based treatments[43]. A randomized clinical trial by Paget et al[44] found that PRP ankle injections did not improve symptoms and function compared to placebo over 52 weeks. In contrast, a prospective study concluded that a single PRP injection is safe and effective for ankle OA for up to six months[10]. Recently, a systematic review and meta-analysis by Ding et al[45] supported the safety of PRP injections for ankle OA based on improvements in pain and AOFAS score at ≥ six months follow-up. Moreover, Repetto et al[46] suggested that PRP is a safe alternative for postponing surgery, resulting in pain and functional improvements. PRP has been reported as the most well-studied treatment with positive levels I and II evidence applicable to the treatment of foot and ankle injuries[47]. Nonetheless, late-stage OA cases have been associated with greater pain and worse functional scores compared to early stage OA[48].

A systematic review demonstrated that clinical studies evaluating outcomes following the use of PRP in osteochondral lesions of the talus poorly adhered to MIBO guidelines. None of the included studies achieved adherence rates ≥ 50% and only one of the 12 MIBO categories had adherence rates ≥ 80%. No difference was observed in the mean adherence rates between studies conducted before and after the publication of the MIBO guidelines in May 2017[49].

BMAC

Interest in BMAC is based on the presence of mesenchymal stem cells (MSC) within its constituents, although their percentage is relatively low, ranging from 0.001% to 0.01%[50]. BMAC not only contains similar platelet factors but also includes angiogenic and osteoinductive molecules, such as VEGF and BMP2/7, along with MSCs capable of differentiating into chondroblasts and osteoblasts. Its anti-inflammatory effect is further enhanced by the presence of IL-1 receptor antagonists (IL1Ra) and promotion of M2 macrophage polarization, fostering a regenerative microenvironment[51].

The positive effects of BMAC in the treatment of OA of joints such as the knee[50,52], hip[53], and shoulder[54] have been reported in some systematic reviews. However, publications regarding BMAC use in HFOA are scarce[55] and mainly focused on other ankle and foot pathologies, especially as an adjuvant treatment of osteochondral lesions of the talus, osteonecrosis, and arthrodesis[56,57]. Buda et al[58] reported encouraging short-term clinical and radiological outcomes in the treatment of osteochondral lesions of the talus concomitant with ankle OA using BMAC (Figure 2).

Figure 2 Mechanisms of action of platelet-rich plasma and bone marrow aspirate concentrate in joints. The left panel illustrates the mechanism of action of platelet-rich plasma (PRP), highlighting its rich content of platelet-derived growth factors (PDGF, TGF-β, IGF, FGF2) and its role in inflammatory modulation, characterized by increased IL-4, IL-10, and IL-13, and decreased IL-1β and TNF-α. PRP promotes chondrocyte differentiation, reduces chondrocyte apoptosis, and contributes to cartilage protection. Additionally, it enhances osteoblast proliferation and formation, collagen deposition, and inhibits osteoclast formation. The right panel depicts bone marrow aspirate concentrate (BMAC) action, which contains a broader range of bioactive molecules compared with PRP, including PDGF, TGF-β, IGF, FGF, VEGF, and BMP2/7. BMAC exerts anti-inflammatory effects through upregulation of IL-4, IL-8, IL-10, and downregulation of IL-1β, supported by IL-1 receptor antagonism. Mesenchymal stem cells, present in BMAC, differentiate into chondroblasts and osteoblasts, aiding cartilage protection and bone regeneration. Furthermore, BMAC promotes M2 macrophage polarization, contributing to a regenerative microenvironment. PRP: Platelet-rich plasma; BMAC: Bone marrow aspirate concentrate.

ADIPOSE-DERIVED STEM CELLS

Adipose-derived stem cells have also been identified as a source of MSC, which are more abundant than BMAC[59] and are mainly obtained as microfragmented adipose tissue (MFAT) or stromal vascular fraction[60,61].

A retrospective study involving patients who underwent arthroscopic debridement and MFAT injection for ankle OA concluded that the procedure is safe with potential benefits when combined with ankle arthroscopy for pain reduction, although more than one-third of the patients reported dissatisfaction with the procedure[62]. The authors suggested restricting the procedure to patients with grade 3 ankle OA rather than grade 4[62]. In contrast, a prospective non-randomized clinical trial concluded that intra-articular MFAT is a safe, effective, and minimally invasive treatment option for ankle OA[63]. Recently, a systematic review on the use of adipose-derived stem cells for the treatment of ankle pathologies reported no serious complications, suggesting that it may be a simple and promising treatment for ankle OA[64].

CLINICAL APPLICATION GUIDANCE

Considering the heterogeneity of available treatments and limited high-quality evidence for HFOA, a pragmatic and stepwise treatment paradigm may assist clinicians in decision-making. For early stage HFOA, conservative management should prioritize non-pharmacological measures such as weight reduction, physical therapy, and activity modification.

Intra-articular injections can be considered when symptoms persist despite intervention. In such cases, viscosupplementation with hyaluronic acid, either alone or in combination with corticosteroids, may be a suitable initial option owing to its favorable safety profile and potential for short- to medium-term symptom relief. Corticosteroid injections alone may offer rapid but temporary relief and can be reserved for acute exacerbations, with attention paid to limiting repeat use owing to potential adverse effects. In intermediate stages or when symptoms persist after standard injections, orthobiologic therapies such as PRP or adipose-derived stem cells may be considered, particularly for patients seeking to delay or avoid surgery. Although promising, these options require careful patient selection and counseling, owing to the variability in protocols and outcomes. Surgical interventions including arthrodesis may be indicated for advanced-stage HFOA with substantial joint degeneration and functional limitations. This decision should consider the benefits of pain relief and joint stabilization against the risks of adjacent joint overload and long-term biomechanical alterations. Future studies with standardized protocols and long-term outcomes are essential to refine the treatment algorithm and improve individualized patient care. Table 1 presents the main characteristics of the treatments described in this study and Table 2 summarizes the stepwise approach to HOA treatment.

Table 1 Main characteristics of orthobiologics used in hindfoot osteoarthritis treatment.

Treatment	Presence of growth factors	Presence of stem cells	Source
Corticosteroids	None	None	Exogenous
Viscosupplementation	None	None	Exogenous
Platelet-rich plasma	High	None	Peripheral blood
Bone marrow aspirate	High	Minimum	Bone marrow
Adipose derived stem cells	High	High	Adipose tissue

Table 2 Stepwise treatment paradigm for hindfoot osteoarthritis.

HFOA stage	Recommended clinical approach	Remarks
Early stage	Weight reduction	Prioritize conservative measures
	Physical therapy and activity modification	Injections may provide short- to midterm symptomatic relief
	Intra-articular hyaluronic acid injection (alone or with corticosteroids)
Intermediate stage	Limited repetition of corticosteroid injections during flare-ups	Careful patient selecion is key
	Orthobiologic therapies (e.g., PRP, adipose derived stem cells)	Protocols and supporting evidence are still evolving
Advanced stage	Surgical intervention (e.g., subtalar or triple arthrodesis)	Consider biomechanical implications and risk of adjacente joint overload

HFOA: Hindfoot osteoarthritis; PRP: Platelet-rich plasma.

HFOA is a chronic degenerative disease that causes pain, impaired function, and reduced quality of life. Although intra-articular treatments such as corticosteroids, hyaluronic acid, and orthobiologic agents have demonstrated efficacy in larger joints like the knee, their outcomes in HFOA may differ due to several anatomical, biomechanical, and synovial factors. The hindfoot joints, including the subtalar and talonavicular articulations, are small, irregularly shaped, and often present more complex joint congruencies and motion patterns than the knees or hips. These joints also experience distinct load distribution and mechanical stress due to their role in gait and weight transfer, particularly following trauma, which is a common etiology of HFOA. Moreover, the synovial environment and vascularization in the hindfoot differ, potentially affecting the diffusion and persistence of the injected agents. These unique characteristics may influence both the pharmacokinetics of injectable therapies and the biological response of the joint, possibly accounting for the variability in treatment outcomes observed in HFOA compared with other forms of OA.

Conservative HFOA treatment with intra-articular injections such as corticosteroids and hyaluronic acid has long been used for pain relief and functional improvement. The use of orthobiologics such as PRP, BMAC, and adipose-derived stem cells, has recently gained attention due to their promising regenerative roles. However, although these treatments are widely used for knee OA treatment, concerns remain regarding the heterogeneity of data. Regarding the ankle joint, the available literature is even more limited. Few articles report that the use of PRP, BMAC, and adipose-derived stem cells yields good results without major complications. Important limitations must be acknowledged regarding the use of BMAC and ADSCs in HFOA, particularly in advanced cases, where outcomes tend to be less favorable. The low concentration of stem cells in BMAC and the lack of standardized preparation and application protocols contribute to variability in clinical outcomes. These limitations hinder reproducibility and highlight the need for high-quality controlled studies.

A literature search revealed no articles concerning subtalar intra-articular injection of PRP, BMAC, or adipose-derived stem cells, highlighting those alternative therapies for foot joints, especially smaller ones, are rarely considered and represent an untapped niche for exploration.

To strengthen future evidence-based guidelines for the use of orthobiologics in HFOA, higher evidence studies with improved standardization of their concentration, treatment protocols, and outcome measures are required.