Early diagnosis and targeted intervention based on the pathogenesis of rapidly progressive osteoarthritis of the hip

Abstract

Early diagnosis of rapidly progressive osteoarthritis of the hip (RPOH) remains clinically challenging due to the lack of unified guidelines and standardized diagnostic criteria. Current diagnostic criteria (chondrolysis > 2 mm/year) require follow-up for at least 12 months. This review characterizes two types of early-stage RPOH progression: Chondrolysis with or without subsequent femoral head destruction within 12 months of onset. Based on their association with early disease progression in RPOH, elevated serum matrix metalloproteinase-3 levels and spinopelvic malalignment may serve as predictive factors for subsequent bone destruction when only joint space narrowing is observed. This review also proposes potential mechanisms of pathogenesis and intervention strategies for RPOH at its initial stage. Cartilage matrix fragments generated by stress concentrations on the hip joint, resulting from spinopelvic malalignment, may trigger inflammatory pathways involving proinflammatory cytokines and inflammasome activation, ultimately leading to joint destruction in the initial phase of RPOH. Suppression of these early pathological events may prevent joint destruction caused by RPOH. However, further elucidation of the cellular and molecular pathways involved in rapid joint destruction is necessary to identify specific biomarkers for early diagnosis and to facilitate the development of targeted therapies in the initial phase of RPOH.

Key Words: Rapidly progressive osteoarthritis; Hip joint; Classification; Early diagnosis; Early intervention; Imaging; Matrix metalloproteinase-3; Spinopelvic alignment; Pathophysiology

Core Tip: Disease progression of rapidly progressive hip osteoarthritis in the early stages may be classified into two distinct types: Chondrolysis with or without subsequent femoral head destruction. Serum matrix metalloproteinase-3 levels and spinopelvic malalignment may be predictive factors for subsequent bone destruction when only joint space narrowing is observed. Cartilage matrix fragments generated by stress concentrations on the hip joint due to spinopelvic malalignment may trigger inflammatory pathways involving cytokine and inflammasome activation, resulting in joint destruction during the initial phase of rapidly progressive hip osteoarthritis. A clear understanding of its pathogenesis is essential for early diagnosis and effective intervention.

INTRODUCTION

Rapidly progressive osteoarthritis of the hip (RPOH), also known as rapidly destructive arthritis/osteoarthritis (OA) or coxopathy, is a rare entity of unknown etiology. Patients with RPOH develop rapid chondrolysis in the affected hip joint. Swift joint space narrowing is observed in the early stages of RPOH. Thereafter, the femoral head and acetabulum are destroyed within the subsequent 6-24 months in some patients with RPOH. Massive deformation of the femoral head and acetabulum due to RPOH may result in complete resorption of the femoral head[1,2]. However, some patients with RPOH exhibit joint space narrowing without bone destruction[3]. Given that the rapid progression of this disease limits the acquisition of sequential radiographs in its early stages[1], the details of early-stage RPOH progression remain unclear. Significant bone defects in the acetabulum observed in the advanced stage of RPOH may lead to poor outcomes and decreased survival after total hip arthroplasty[4]. Therefore, early diagnosis and intervention are needed to prevent extensive bone destruction in RPOH. Currently, no unified guidelines exist for the early diagnosis of RPOH, and information on the pathophysiology of its initial stage remains limited. This article aimed to characterize the clinical features, disease progression, risk factors, and early pathogenesis of RPOH, and to explore possibilities of early diagnosis and intervention.

DIAGNOSTIC CRITERIA

RPOH was first defined by Lequesne et al[5] as a rate of joint space narrowing exceeding 2 mm per year or a loss of more than 50% of the joint space within 1 year, in the absence of other rapidly progressive arthropathies such as antecedent OA, osteonecrosis, neuropathy, infection, or inflammatory disease. The diagnostic criteria have been widely adopted. Another definition of RPOH involves bone loss, or a combined loss of bone and articular cartilage, occurring at a rate exceeding 5 mm per year[6]. These definitions require patient follow-up for at least 12 months. Although RPOH typically demonstrates radiographic changes within 12 months from the onset of symptoms[7-9], there remains a practical need for early diagnosis without requiring a 12-month follow-up. Currently, no definitive diagnostic criteria exist for the early phases of RPOH. Therefore, further efforts are needed to establish unified guidelines and standardized criteria to improve early diagnosis and treatment strategies for RPOH.

CLASSIFICATION SYSTEM

Although there is no universally recognized classification system for RPOH, several have been proposed (Table 1).

Table 1 Summary of classification system for rapidly progressive osteoarthritis of the hip.

Ref.	Classification	Description	Follow-up period
Irwin and Roberts[6], 1998	Rapid	Chondrolysis for about 18 months followed by bone loss of 10-15 mm/year	> 18 months
	Moderate	Chondrolysis for 18-30 months followed by bone loss at 5-10 mm/year	> 18-30 months
	Delayed	Normal progression for 3-5 years after initial symptoms, then sudden change to rapid or moderate patterns	> 3-5 years
Pivec et al[3], 2013	Type 1	Rapid joint space narrowing, no rapid femoral head dissolution or acetabular bone loss	> 12 months
	Type 2	Severe joint degeneration, rapid progression with femoral head and acetabular destructive changes within 6-18 months	6-18 months
Zazgyva et al[2], 2017	Grade 1	Partial joint space narrowing; no deformation/ascension of the femoral head	> 3.5 years
	Grade 2	Complete disappearance of the joint space; deformed femoral head and acetabulum; femoral head ascension ≤ 0.5 cm above radiological teardrop	> 3.5 years
	Grade 3	Complete disappearance of the joint space; partial osteolysis of the femoral head; femoral head ascension > 0.5 cm above radiological teardrop	> 3.5 years
Yasuda et al[9], 2020	Type 1	Joint space narrowing with no femoral head destruction within 12 months after onset of hip pain	< 12 months
	Type 2	Rapid joint space narrowing and femoral head destruction within 12 months after onset of hip pain	< 12 months

Irwin and Roberts[6] identified three types of RPOH progression based on the duration of chondrolysis and subsequent bone loss: Rapid, defined as 18 months of chondrolysis followed by bone loss of 10-15 mm per year; moderate, 18-30 months of chondrolysis followed by bone loss of 5-10 mm per year; and delayed, characterized by normal progression for 3-5 years followed by a sudden shift to one of the other two patterns.

Pivec et al[3] diagnosed RPOH based on Lequesne’s criteria - joint space narrowing of 2 mm or more per year[5] - and classified RPOH progression into two types. Type 1 is characterized by joint space narrowing without femoral head dissolution or acetabular bone loss. Type 2 involves severe joint degeneration, including extensive destructive changes to the femoral head and acetabulum within 6-18 months of initial presentation. However, there is concern that the authors may have misidentified subchondral insufficiency fractures (SIF) of the femoral head as RPOH.

Zazgyva et al[2] proposed a radiological grading system that clarifies RPOH into three grades by correlating patient history and clinical data with radiographic findings of the hip joint at a single time point, based on joint space narrowing and the extent of femoral head deformation and ascension. Grade 1 is defined by partial joint space narrowing without deformation or ascension of the femoral head. Grade 2 is characterized by complete joint space loss, deformation of the femoral head and acetabulum, and femoral head ascension of ≤ 0.5 cm above the radiological teardrop. In addition to the radiological features of grade 2, grade 3 includes osteolysis of the femoral head and femoral head ascension > 0.5 cm above the radiological teardrop. The authors emphasized the presence of subchondral cysts (geodes) in the acetabulum and femoral head, along with a relative absence of osteophytes, as hallmark features of RPOH. The clinical presentation includes a three-year history of hip pain that worsens over the last 6 months, with relatively preserved hip mobility.

The RPOH classification systems describe different patterns and progression rates. However, none of the classification systems has detailed the progression during the early stages of RPOH. A recent retrospective study[9] evaluated serial radiographs and computed tomography (CT) scans obtained every 2-3 months for over 12 months following the onset of hip pain. As a result, RPOH progression during the first 12 months after onset was classified into two types based on the absence (Figure 1) or presence (Figure 2) of femoral head destruction. Currently, this remains the only system that classifies early-stage RPOH progression within the first 12 months of disease onset. This newly proposed classification system holds potential clinical value and should therefore be prospectively validated to facilitate timely diagnosis without requiring a 12-month follow-up.

Figure 1 Right hip joint with rapidly progressive osteoarthritis of the hip showing chondrolysis greater than 2 mm/year on a series of radiographs without femoral head destruction on computed tomography at 12 months after the onset. Magnetic resonance imaging at 6 months after the onset demonstrates inhomogeneous high intensity on the short τ inversion recovery sequence image, including the superolateral portion of the femoral head. CT: Computed tomography; MRI: Magnetic resonance imaging.

Figure 2 Right hip joint with rapidly progressive osteoarthritis of the hip demonstrating partial destruction of the anterior portion of the femoral head on computed tomography at 6 months after the onset subsequent to rapid chondrolysis. Magnetic resonance imaging at 4 months after the onset shows high intensity on the short τ inversion recovery sequence image in the proximal femur, including the femoral neck and head. CT: Computed tomography; MRI: Magnetic resonance imaging.

CLINICAL FEATURES

Pain

The pain caused by RPOH is remarkable because of its acute severity and rapid onset. Patients typically report a sudden and intense onset of pain in a hip that appears radiologically normal[10]. This abrupt and severe presentation of pain is a distinguishing feature of RPOH, setting it apart from the gradually progressive forms of OA. The pain is particularly exacerbated during nighttime, leading to significant impairment in patient comfort and sleep quality[7].

Range of motion

Patients in the early stages of RPOH typically show a normal passive range of motion (ROM) of the affected hip joint. A significant feature of RPOH is that excruciating pain is elicited during active ROM movements, particularly those involving weight-bearing. The combination of normal passive ROM and painful active weight-bearing ROM is a characteristic of RPOH, distinguishing it from other forms of OA, and indicating the likelihood of rapid joint destruction[11].

Imaging

Radiographs: In the early stages of RPOH, the affected hip joint demonstrates minimal joint space narrowing, absence of osteophytes, and mild subchondral sclerosis[12], which may appear as either normal anatomical features or subtle degenerative changes on plain radiographs. In addition, there is concern about the potential misinterpretation of other pathologies, such as septic arthritis, inflammatory arthropathies, or avascular necrosis. Thus, plain radiographs may have limited diagnostic utility in the early stages of RPOH[13]. However, follow-up radiographs are important in patients with persistent hip pain of unknown cause, as sequential radiographs obtained a few months later may reveal the rapid progression of RPOH[9], as shown in Figures 1 and 2.

CT: Although CT is not essential for the diagnosis of RPOH, it is helpful in assessing the degree of joint destruction. CT scans can reveal partial destruction of the anterior portion of the femoral head in the early stages of RPOH[9] before such changes become apparent on plain radiographs, as demonstrated in Figure 2.

Magnetic resonance imaging: In the initial stage of rapidly destructive coxopathy, which may show slight joint space narrowing on plain radiographs, magnetic resonance imaging (MRI) reveals a subchondral area with low signal intensity on T1-weighted spin-echo images and inhomogeneous high intensity on short τ inversion recovery (STIR) sequence images and/or T2-weighted images in the superolateral portion of the femoral head[1,9], as shown in Figure 1. Following chondrolysis, when partial destruction of the femoral head is observed, a more extensive area of low signal intensity on T1-weighted images and high signal intensity on STIR and/or T2-weighted images is seen in the proximal femur, including the femoral neck and head[1,9], as demonstrated in Figure 2. Similar to early-stage RPOH, OA within the first 12 months of hip pain may demonstrate low signal intensity lesions on T1-weighted images and high signal intensity on STIR and/or T2-weighted images in the superior, weight-bearing portion of the femoral head[9]. These MRI findings may reflect bone marrow edema caused by inflammation due to RPOH and OA. In contrast, MRI is useful in differentiating RPOH from osteonecrosis of the femoral head, which specifically shows a band-like pattern of low intensity on T1-weighted images and high intensity on STIR sequences and/or T2-weighted images[3].

DIFFERENTIAL DIAGNOSIS

RPOH should be differentiated from antecedent OA, osteonecrosis, neuropathy, infection, and inflammatory disease[5]. Among the other forms of rapidly progressive arthropathy, SIF is most commonly confused with RPOH[3,14,15]. SIF is associated with osteoporosis[14], whereas there is no difference in bone mineral density between patients with RPOH and OA[16,17]. A key radiographic finding in RPOH is that the affected hip joint initially shows joint space narrowing, followed by femoral head destruction[1,9]. In contrast, with SIF, a fracture in the subchondral area of the femoral head occurs first (Figure 3), followed by joint space narrowing. MRI is also helpful in differentiating between the two distinct diseases. Hip joints with RPOH demonstrate joint effusion and bone marrow edema in the femoral head and neck, acetabulum, or both[1,9]. Crucial MRI findings of SIF include a band-like hypointense lesion on T1-weighted images, surrounded by a diffuse bone marrow edema pattern near the articular surface of the femoral head, and a linear high signal intensity pattern on T2-weighted images[3,18]. Key findings for differential diagnosis of RPOH are summarized in Table 2.

Figure 3  Right hip joint with subchondral insufficiency fracture of the femoral head showing fracture on the subchondral area in the superolateral portion of the femoral head without joint space narrowing. CT: Computed tomography.

Table 2 Key findings for differential diagnosis of rapidly progressive osteoarthritis of the hip in the early stage.

Findings	RPOH	OA	ON	SIF
Pain	Acute and severe, nocturnal	Slow onset, at exertion	At rest and constant	Acute, at rest and exertion
ROM	Normal passive ROM and painful active, weight-bearing ROM	Restricted ROM, Joint stiffness	Joint stiffness less common	Joint stiffness less common
X-ray	Rapid joint space narrowing, lack of osteophytes, and scant/minimal subchondral sclerosis	Gradual joint space narrowing, osteophyte formation, and subchondral sclerosis	Femoral head lucency or sclerosis, and a crescent sign within the femoral head	Fracture on the subchondral area in the femoral head, followed by joint space narrowing
	Femoral head destruction after joint space narrowing
MRI	T1 a subchondral area of low signal intensity	T1: Diffuse low-intensity lesions	T1: Serpentine low-intensity lesions	T1 a band-like hypointense lesion surrounded by a diffuse bone marrow edema pattern
	T2 inhomogeneous high intensity	T2: Diffuse high-intensity lesions	T2: Serpentine high-intensity lesions	T2 a linear pattern of high signal intensity
	Location: The superolateral portion of the femoral head	Location: Weight-bearing portion of femoral head	Location: Any portion and orientation random	Location: Adjacent to the articular surface of the femoral head

RPOH: Rapidly progressive osteoarthritis of the hip; OA: Osteoarthritis of the hip; ON: Osteonecrosis of the femoral head; SIF: Subchondral insufficiency fracture of the femoral head; ROM: Range of hip joint motion; MRI: Magnetic resonance imaging.

RISK FACTORS

Age and sex

RPOH predominantly affects elderly individuals aged 60-70 years[19]. In a retrospective analysis, the mean age of patients with RPOH was reported to be 72 years[20]. Women have a significantly higher risk of developing RPOH than men[9,20,21].

Sagittal spinopelvic alignment

In patients with spinal disorders, an interaction exists between sagittal spinopelvic alignment (SSPA) and compensatory mechanisms[22]. Among the SSPA parameters (Figure 4)[23], pelvic incidence (PI) is a fundamental and fixed anatomical parameter of the pelvis, as the sacroiliac joint has limited mobility. Pelvic tilt (PT) and sacral slope (SS) determine the sagittal orientation of the pelvis in relation to the femoral head. This relationship is defined by the equation PI = PT + SS. PT quantifies the pelvic rotation around the femoral head. Sagittal vertical axis (SVA) quantifies the progressive anterior translation of the head relative to the pelvis, assessing overall spinal alignment. Thoracic kyphosis and lumbar lordosis (LL) are also included among the SSPA parameters. In addition, Scoliosis Research Society-Schwab classification modifiers were used to investigate the degree of sagittal malalignment[24]. Accordingly, the degree of PI-LL mismatch was categorized as < 10°, 10°-20°, and > 20°. PT was stratified as < 20°, 20°-30°, and > 30°. SVA was classified as < 40 mm, 40-95 mm, or > 95 mm.

Figure 4 Illustration of the radiological parameters of the sagittal spinopelvic alignment. Pelvic tilt is the angle between the vertical and the line from the center of the femoral heads to the midpoint of the sacral endplate. Sacral slope is the angle between the horizontal and the first sacral endplate. Pelvic incidence is calculated using the following equation: Pelvic incidence = pelvic tilt + sacral slope. Sagittal vertical axis is defined as the sagittal offset of the seventh cervical vertebra plumb line from the posterosuperior corner of the first sacral endplate. Thoracic kyphosis angle is the angle between the upper endplate of the fourth thoracic vertebra and the lower endplate of the twelfth thoracic vertebra. Lumbar lordosis angle is the angle between the upper endplate of the first lumbar vertebra and the first sacral endplate. PT: Pelvic tilt; SS: Sacral slope; PI: Pelvic incidence; SVA: Sagittal vertical axis; C7: Seventh cervical vertebra; TK: Thoracic kyphosis angle; T4: Fourth thoracic vertebra; T12: Twelfth thoracic vertebra; LL: Lordosis angle.

Increasing evidence suggests that SSPA parameters contribute to the development of hip disorders[25]. Lumbar degenerative kyphosis may increase posterior PT, reducing anterior acetabular coverage of the femoral head[26,27], which may lead to hip OA even with normal acetabular anatomy. Previous studies have shown that patients with end-stage RPOH exhibit increased posterior PT and reduced LL and SS compared to those with hip OA[28,29]. In a retrospective study of early-stage RPOH using images taken within 12 months of symptom onset[30], PT and PI-LL were similarly higher in patients with RPOH than in those with hip OA. The SS and LL were lower in the RPOH group than in the hip OA group. The extent of femoral head collapse was associated with the PT, SS, SVA, LL, and PI-LL. PI-LL > 20° and PT > 30° correlated with a greater extent of femoral head destruction by RPOH. According to regression analysis, SS and SVA were significantly correlated with the extent of femoral head destruction within the first 12 months of disease onset. Based on finite element analysis[31], a posterior PT of 20º increased stress on the anterosuperior portion of the femoral head by approximately 1.5 times compared to the neutral pelvic position. Thus, the loss of LL and increased PT, closely associated with decreased SS may function as mechanical factors that accelerate stress concentration in the anterior portion of the femoral head during weightbearing, leading to bone destruction in the early stage of RPOH, as shown in Figure 2. Furthermore, a positive correlation was found between hip contact forces and SVA[32]. Global spinopelvic malalignment, as indicated by SVA, may cause an additional increase in the forces applied to the femoral head, resulting in rapid femoral head destruction. Overall, it is likely that femoral head destruction in the early stage of RPOH is partly attributable to the combined mechanical factors of decreased acetabular coverage over the femoral head due to posterior PT and increased contact force on the femoral head due to global spinal malalignment.

PATHOGENESIS

Currently, it remains unclear which pathological factor(s) lead to RPOH at disease onset. Synovial tissues from the hip joint with early-stage RPOH show increased cellularity and hyperplasia[33], which are observed in synovial tissues affected by rheumatoid arthritis (RA)[34]. Synovial lining hyperplasia is associated with increased infiltration of macrophages and T lymphocytes in RPOH synovial tissues[33], similar to the histological features of RA synovial tissues[34]. These histological findings have also been observed in synovial tissues from hip joints in advanced RPOH[2]. Thus, synovial hyperplasia may be the cause of the disease and trigger joint destruction.

As described in the classification system section, hip joints with RPOH demonstrate rapid chondrolysis within the first year after onset. Some patients with RPOH subsequently develop femoral head destruction within the first 12 months after onset[9]. Increased levels of matrix metalloproteinase (MMP)-3, which is involved in cartilage degradation[35], have been found in the synovial fluid of hip joints with RPOH[36]. Synovial fibroblasts from the hip joint with RPOH secrete MMP-3[37,38]. These findings suggest that MMP-3 could contribute to rapid chondrolysis during the first 12 months after disease onset[9]. Previous histological studies have revealed the presence of mature and activated osteoclasts in the synovial tissues[39] and femoral head[40] of advanced-stage RPOH. Massive osteoclast activation may play a central role in femoral head destruction following rapid chondrolysis of the hip joints in RPOH. Proinflammatory cytokines such as interleukin (IL)-1β are increased in the synovial fluid from the hip joints with RPOH[36]. T cells from the femoral head and synovial membrane of patients with RPOH produce IL-6. T cells from peripheral blood mononuclear cells in patients with RPOH produce tumor necrosis factor α (TNFα)[41]. These cytokines potentially induce MMP-3 expression in synovial fibroblasts because MMP-3 expression is regulated by proinflammatory cytokines[42]. Synovial cells isolated from patients with femoral head destruction by RPOH demonstrate high mRNA expression of receptor activator of nuclear factor κB ligand (RANKL)[39,43], the major mediator of osteoclastogenesis[44]. While one study reported no difference in RANKL expression in synovial fibroblasts between RPOH and hip OA[39], another found elevated expression in synovial fibroblasts from RPOH-affected hip joints compared to those from joints with OA or osteonecrosis[43]. Thus, the role of RANKL in massive osteoclastogenesis in hip joints with RPOH remains controversial. An alternative mechanism underlying osteoclast differentiation in hip joints with RPOH is proinflammatory cytokine-induced osteoclastogenesis. A combination of TNFα and IL-1 can lead to osteoclast differentiation[45]. Another combination of IL-6 and TNFα can induce osteoclast-like cells with bone-resorptive activity[46]. These combinations of proinflammatory cytokines are elevated in hip joints with RPOH and may promote osteoclastogenesis.

Among the proinflammatory cytokines, IL-6 may contribute to joint destruction caused by RPOH in the early stages. In synovial fibroblasts from RA patients, a combination of IL-6 and soluble IL-6 receptor α induces MMP-3 gene expression[47]. IL-6 signaling induces phosphorylation of signal transducer and activator of transcription 3 (STAT3), leading to its dimerization, nuclear translocation, and subsequent binding to the MMP-3 promoter in RA synovial fibroblasts[47]. The IL-6/gp130-associated Janus kinase (JAK)/STAT3 axis plays a major role in mediating inflammatory signaling[48]. Recently, constitutive activation of STAT3 was demonstrated in synovial tissues obtained from RPOH-affected hip joints within 5-7 months after onset[33], as shown in Figure 5. In contrast, no apparent STAT3 activation was observed in the synovial tissues of OA joints[49]. The IL-6/JAK/STAT axis has also been recognized as a trigger of bone resorption because of its essential role in inducing RANKL expression[50,51]. Furthermore, IL-6 directly promote osteoclastogenesis[52]. STAT3 plays a significant role in osteoclast differentiation and bone metabolism by regulating the transcription of nuclear factor of activated T cells, cytoplasm 1, in osteoclasts[53].

Figure 5 Immunohistochemistry of the synovial tissues from the hip joint with rapidly progressive osteoarthritis of the hip at 6 months from the disease onset. Tissue sections of the synovial tissues were subjected to immunohistochemical staining using anti-phospho-signal transducer and activator of transcription 3 with or without treatment with tofacitinib. Original magnification × 200.

The aforementioned mechanisms of MMP-3 induction and osteoclastogenesis indicate the involvement of common pathways that stimulate proinflammatory cytokine production during the early stages of RPOH. Mechanical stress concentration increases in the cartilage of the anterosuperior portion of the femoral head due to spinopelvic malalignment, as described in the section on SSPA. Consequently, cartilage matrix degradation products may be generated in the hip joints at the onset of RPOH. In fact, tissue-derived particulate debris from bone or cartilage is observed exclusively in the synovial tissues of patients with RPOH, but not in those with hip OA or osteonecrosis[43]. There is evidence that cartilage degradation products act as amplifiers or catalysts in diseased joints, including RA and OA[54]. Cartilage matrix degradation products such as fibronectin fragments[55,56], hyaluronan fragments[57,58], and collagen hydrolysates[59], can function as danger-associated molecular patterns (DAMPs)[60] and may create a vicious cycle of cartilage damage. Fibronectin fragments stimulate the release of proinflammatory cytokines, including TNFα, IL-1β, and IL-6 from articular cartilage[61]. Fibronectin fragments can induce MMP-3 and collagenase (MMP-1 and MMP-13) expression in chondrocytes[62,63] and synovial fibroblasts[64]. Fibronectin fragments can induce aggrecanases in synovial fibroblasts[65]. In addition, mononuclear cells in RA synovial fluid can produce proinflammatory cytokines, including TNFα, IL-1, and IL-6, in response to exposure to type II collagen[66].

DAMPs derived from the extracellular matrix act through toll-like receptors (TLRs), typically TLR-2 or TLR-4, to stimulate proinflammatory gene expression[67]. TLR-2, TLR-3, TLR-4, and TLR-5 expression is elevated in OA cartilage compared to that in normal cartilage[68]. TLRs have also been detected in synovial fibroblasts[69]. In addition to increased TLR-2 expression, fibronectin fragments can enhance the production of MMP-3, MMP-1, and MMP-13 via the TLR-2 signaling pathway in chondrocytes[68]. Similar effects of fibronectin fragments have been observed in synovial fibroblasts[70]. Hyaluronan fragments stimulate pro-inflammatory cytokines via TLR-4 activation in chondrocytes[58]. Once cells recognize danger signals via TLRs, these receptors initiate innate pattern recognition and activate cytosolic receptors, including nucleotide-binding and oligomerization domain-like receptors (NLRs), through a cascade of signaling pathways. Subsequently, NLRs assemble into a specialized multiprotein intracellular complex called the inflammasome[71].

The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic protein complex that plays a key role in the innate immune and inflammatory responses. NLRP3 activation is regulated by DAMPs[72]. The activation phase of NLRP3 begins when DAMPs bind to TLRs, leading to activation of the nuclear factor-κB (NF-κB) pathway[73]. NF-κB signaling promotes the transcription of NLRP3, caspase family proteins, and the precursors of IL-1β and IL-18[74]. DAMPs also activate NLRP3 via TLR-and BRCA1/BRCA2-containing complex subunit 3-mediated deubiquitination, preparing it for NLRP3 inflammasome assembly[75]. The assembly of the NLRP3 inflammasome recruits and activates caspase-1, which releases proinflammatory cytokines, including IL-1β and IL-18[74]. NLRP3 inflammasome activation also cleaves gasdermin D (GSDMD) at its N-terminus[76]. The N-terminal pore-forming GSDMD fragment oligomerizes to form membrane pores by binding to acidic phospholipids on the inner leaflet of the plasma membrane, disrupting the membrane and releasing inflammatory cytokines, including IL-1β, IL-18, and cellular DAMPs[77-80]. In addition, DAMPs stimulate the release of MMPs via activation of the NLRP3 inflammasome[81].

There is evidence that the NLRP3 inflammasome is involved in autoinflammatory syndromes, as well as metabolic and inflammatory disorders[82]. The transcription of NLRP3 inflammasome components is substantially increased in patients[83]. Cartilage fragments, along with the release of inflammatory mediators acting as DAMPs, can trigger synovial macrophage pyroptosis, exacerbating the inflammatory microenvironment[84]. Recently, synovitis activated by inflammasome signaling has received attention in OA[85] and RA[86]. A recent study demonstrated increased activation of NLRP3 inflammasomes and GSDMD in synovial fibroblasts and macrophages located in the synovium of hip joints with RPOH, resulting in higher levels of proinflammatory cytokines and increased osteoclastogenesis[43]. Prolonged activation of NLRP3 may accelerate pyroptosis in the synovium, which could promote the rapid proliferation and stimulation of synovial fibroblasts. Stimulated synovial fibroblasts are likely to enhance inflammation and promote the development of chronic synovitis, which mediates osteoclastogenesis and leads to joint destruction. Thus, the roles of the NLRP3 inflammasome and downstream effectors, such as GSDMD, in the excessive activation of inflammatory pathways and subsequent joint destruction should be further investigated to understand the pathogenesis at the onset of RPOH.

The hypothetical pathophysiology of the initial stage of RPOH is shown in Figure 6. Future studies are needed to determine whether mechanical stress concentrated on the femoral head due to spinopelvic malalignment produces cartilage degradation products, such as DAMPs, which in turn lead to synovitis and inflammasome activation.

Figure 6 Putative pathophysiology at the initial stage of rapidly progressive osteoarthritis of the hip. DAMP: Danger-associated molecular pattern; TLR: Toll-like receptor; NF-κB: Nuclear factor κB; NLRP3: Nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3; GSDMD: Gasdermin D; GSDMD-NT: N-terminal pore-forming gasdermin D fragment; IL: Interleukin; TNF-α: Tumor necrosis factor α; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; MAPK: Mitogen-activated protein kinase; MMPs: Matrix metalloproteinases; RANKL: Receptor activator of nuclear factor-κB ligand; RPOH: Rapidly progressive osteoarthritis of the hip.

EARLY DIAGNOSIS

Delayed treatment of patients with RPOH who present with severe bone destruction may cause considerable difficulties during total hip arthroplasty due to bone stock deficiency and intraoperative blood loss[2]. This finding highlights the importance of early identification of patients with RPOH at risk before significant bone destruction begins. MMP-3 may serve as a candidate biomarker for predicting femoral head destruction before it becomes radiographically apparent in RPOH. Based on serum MMP-3 Levels prior to CT-detected femoral head destruction, logistic regression and receiver operating characteristic curve analyses suggested that elevated MMP-3 concentrations may predict femoral head destruction in the early stages of RPOH[9]. Evidence also indicates an association between femoral head destruction due to RPOH and elevated serum levels of tartrate-resistant acid phosphatase-5b and bone alkaline phosphatase within the first 12 months after disease onset[87]. Among the SSPA parameters, SS and SVA correlate with the extent of femoral head destruction due to RPOH within the first 12 months after disease onset, with severe spinopelvic mismatch (PI-LL > 20° and PT > 30°)[32]. Thus, a combination of biomarker measurements and SSPA evaluation before the initiation of femoral head destruction may help predict subsequent bone destruction due to RPOH. Notably, the reference intervals for MMP-3 and bone turnover markers differ between males and females. Such biomarkers should be interpreted separately according to sex[9].

However, a thorough elucidation of the cellular and molecular pathways, as described in the pathogenesis section, is required to identify appropriate biomarkers for early diagnosis of RPOH during its initial phase.

EARLY INTERVENTION

As patients with RPOH typically experience severe pain in the affected hip during the initial stage, most are treated with nonsteroidal anti-inflammatory drugs. Some patients with RPOH may receive treatment with alendronate, sodium hydrate, and alfacalcidol. However, these drugs have been reported to have negligible effects on disease progression[88]. These suggest a need for early interventions targeting upstream events, rather than activated osteoclasts, to prevent joint destruction due to RPOH. Based on the hypothetical pathophysiology during the initial phase of RPOH, possible intervention strategies are discussed in this section.

Spinopelvic malalignment, including increased posterior PT, may cause cartilage matrix destruction, leading to DAMP formation via altered mechanical stress concentrations on the femoral head at disease onset. From a biomechanical perspective, incorporating spinopelvic alignment measurements in patients at risk of RPOH is essential to optimize treatment outcomes. As integral components of a comprehensive RPOH management strategy, corrective interventions targeting spinopelvic malalignment should be considered, such as therapeutic exercises, postural adjustments, or surgery.

Based on the possible role of cartilage matrix fragments in hip joint destruction during the initial phase of RPOH, inhibition of DAMP activity driven by such fragments could be a promising therapeutic strategy. A candidate for the key pathways elicited by DAMPs is the NLRP3 inflammasome pathway. Synovial fibroblasts and macrophages in synovial tissues of hip joints affected by RPOH exhibit increased activation of the NLRP3 inflammasome, with the induction of proinflammatory cytokines and osteoclastogenesis[43]. Currently, several experimental inhibitors targeting the NLRP3 inflammasome pathway are available[85,86,89]. These inhibitors exert their effect through distinct mechanisms targeting different proteins within the NLRP3 inflammasome pathway[85,86,89]. The NLRP3 inflammasome has been proposed as a potential pharmacological target for various inflammatory conditions, including systemic lupus erythematosus, gouty arthritis, and multiple sclerosis[90]. Such inflammasome blockers may inhibit inflammation and reduce cartilage breakdown by suppressing MMP-3, MMP-1, and MMP-13 activity during the early stages of RPOH. As NF-κB activates NLRP3[74], NF-κB inhibitors may also serve as effective NLRP3 inflammasome blockers. According to a previous review[89], specific small molecules, including ursolic acid[91], GYY4137[92], and loganin[93], can reduce caspase-1 and MMP protein levels through suppression of IkBα phosphorylation and p65 nuclear translocation.

Another targetable pathway during the initial phase of RPOH is the proinflammatory cytokine cascade. Biological agents that inhibit IL-1β and IL-18 may suppress the NLRP3 inflammasome pathway[94,95]. In addition, JAK inhibitors may downregulate pathological effects through the IL-6/JAK/STAT3 axis, as tofacitinib has been shown to inhibit STAT3 activation in synovial tissues from RPOH-affected hip joints during the early stages[33], as demonstrated in Figure 5. Additionally, tofacitinib has been reported to suppress excessive NLRP3 inflammasome activation[96]. Potential early intervention inhibitors for RPOH, as identified in previous reviews, are summarized in Table 3[85,86,89]. Randomized controlled trials involving candidate drugs should be conducted to evaluate their efficacy in preventing RPOH progression.

Table 3 Potential inhibitors for early intervention to rapidly progressive osteoarthritis of the hip.

Agents	Targets	Mechanism	Human disease/animal model	Ref.
Small molecule inhibitors
MCC950	NLRP3	Block ASC oligomerization and inhibit inflammation. Reduce synovitis and cartilage erosion by inhibiting NLRP3 and caspase-1 activation	Mice	[97-100]
VX-765	Caspase-1	Ameliorate the severity and progression of synovitis	Mice	[101,102]
Disulfiram	GSDMD	Inhibits pyroptosis and inflammatory cytokine release in both canonical and noncanonical inflammasome pathways	Mice	[103]
Degrasyn	NLRP3/	Inhibits pyroptosis of synovial macrophages	Mice	[104]
	GSDMD
CY-09	NLRP3	Inhibits cartilage degradation	Rats	[105]
Icariin	NLRP3/	Inhibits inflammation and pyroptosis	Rats	[106]
	Caspase-1
Ursolic acid	NF-κB/	Inhibits cartilage degradation	Rats	[91]
	NLRP3
GYY4137	NF-κB/	Inhibits pyroptosis of synovial macrophages	Mice	[92]
	NLRP3
Loganin	NF-κB/	Inhibits cartilage degradation	Mice	[93]
	Caspase-1
Disease-modifying anti-rheumatic drugs
Chloroquine	The second signal of NLRP3 activation	Inhibit Ca2+-activated K+ channels, which leads to impaired inflammasome activation in THP-1 macrophages Inhibit NLRP3 inflammasome activation	RA/mice	[107,108]
Anakinra	IL-1β receptor antagonist	Inhibit the NLRP3 inflammasome downstream cytokine, IL-1β	RA	[109]
IL-18 binding protein	IL-18 antagonist	Reduces Th17 cells, with the resultant inhibition of osteoclastogenesis, and induces osteoblasts formation	RA/mice	[110]
Tofacitinib	NLRP3	Restore the balance of γδTreg/γδT17 cells by inhibiting NLRP3 inflammasome	RA/mice	[96]

ASC: Apoptosis-associated speck-like protein containing a caspase recruitment domain; NLRP3: Nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3; GSDMD: Gasdermin D; NF-κb: Nuclear factor-κB; IL: Interleukin; RA: Rheumatoid arthritis.

CONCLUSION

This review highlights two distinct patterns of disease progression during the early stages of RPOH: Chondrolysis, with or without subsequent femoral head destruction, occurring within the first 12 months after onset. Serum MMP-3 Levels and spinopelvic malalignment may be predictive factors for subsequent bone destruction when only joint space narrowing is observed. However, further clarification of the cellular and molecular pathways underlying rapid joint destruction is necessary to identify diagnostic biomarkers and guide targeted therapy during the initial stages of RPOH.

ACKNOWLEDGEMENTS

The authors thank Ms. Yoko Miyake of the Center for Clinical Research and Innovation at Kobe City Medical Center General Hospital for her excellent assistance with the illustrations.