JPED

Introduction

Osteonecrosis (ON), also called avascular necrosis (AVN), is a clinical entity characterized by the death of bone tissue (extensive bone and red medulla necrosis) that results in a collapse of bony architecture, destruction of articular cartilage, with pain, and functional impairment. The etiology remains unclear. The mechanism of AVN development is the compromised vascular supply and progressive ischemia of the subchondral bone. This can be secondary to traumatic events or non-traumatic conditions such as idiopathic ones, chronic alcohol intake, glucocorticoid (GC) use, and rheumatic disorders, especially systemic lupus erythematosus (SLE). Non-traumatic AVN is influenced by various genetic, metabolic, and vascular factors [1,2,3]. GC are a major risk factor for AVN development, impacting endothelial cells, promoting hypercoagulability and fat cell hypertrophy, and inhibiting angiogenesis, thus reducing micro-vessel blood flow and oxygen delivery [4].

AVN typically affects the epiphyses of long bones (e.g. femoral head and condyles, distal tibia, and humeral head), often presenting with multifocal distribution [5]. Treatment approaches for ON vary depending on the severity of the condition. Small, silent lesions can often be managed conservatively, whereas symptomatic or larger weight-bearing lesions typically require surgery. Medications like bisphosphonates and warfarin may help prevent progression. Advanced cases often require grafting or hip replacement. Newer regenerative approaches, such as platelet-rich plasma (PRP) and stem cell therapy, are being explored for early disease [6,7]..

No study has focused on therapeutic effect of these novel approaches on the long-term outcome of children with steroidinduced ON of the femoral head (ONFH). We aim to present our experience in a girl with bilateral ONFH treated with core decompression (CD) associated with injection of autologous bone marrow concentrate (BMC) and PRP comparing our experience with literature evidence available to date.

Combined CD, BMC Transplantation, and PRP treatment in practice

A girl presented to our emergency room was diagnosed with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis at 14 years old, after a twomonth history of migrating arthralgia involving multiple joints. At disease onset, she presented with palpable purpura at lower limb, gastrointestinal complaints with hematochezia, polyarthritis, and renal involvement. The initial diagnostic hypothesis was of Henoch-Schoenlein Purpura with renal and gastrointestinal involvement. However, suddenly, the patient experienced acute dyspnea and desaturation, leading to urgent chest X-ray with bilateral parenchymal haziness and blood examination with decreased hemoglobin levels, elevated D-dimer, and troponins. Therefore, urgent chest computed tomography (CT) with contrast showed findings consistent with hemorrhagic alveolitis, without signs of pulmonary embolism. High titer positivity for antineutrophil cytoplasmic antibodies proteinase-3 (c-ANCA PR3) was later confirmed. The patient started induction therapy with high dose of methylprednisolone by intravenous pulses (1 gr per day for three days) followed by methylprednisolone 2mg/kg/ day.

The diagnostic workup was completed with kidney biopsy that revealed a necrotizing glomerulonephritis. She was treated with rituximab at 375 mg/m2/weekly, interrupted after the second infusion because of a worsening in renal function that let us to switch to oral cyclophosphamide and repeat high doses of methylprednisolone for other 3 pulses. Despite this treatment, the creatinine level kept increasing and she started to present progressive thrombocytopenia. A treatment with complement inhibition (eculizumab) was started obtaining a sudden and sustained remission [8].

6 months later, the patient started complaining increasing hip joint bilateral pain with bilateral limitation in the inward rotation of the hips. Pelvic X-ray was conducted with normal findings. Therefore, pelvic Magnetic Resonance Imaging (MRI) performed one week after the onset of the symptoms, showed bilateral avascular necrosis of the femoral head (left > right) with preserved height and morphology of both femoral heads (Figure 1).

Figure 1 : (a) Hip X-ray at the onset of AVN, revealing no significant bony abnormalities. (b, c) Subsequent coronal Magnetic Resonance Imaging (MRI) performed within days, including STIR (b) and T1-weighted (T1W) (c) sequences, demonstrating diffuse bone marrow edema in both femoral heads, with greater involvement on the left. Notably, the left femoral head exhibits a serpiginous line of hyperintensity, the ‘double line sign’, indicative of subchondral collapse.”

Considering the young age and early stage of ON, after multidisciplinary discussion, she underwent bilateral femoral head decompression surgery and infiltration with PRP, mesenchymal cells, and subchondroplasty. Initially, the bone marrow was reduced from 50 to 6-7 ml through centrifugation to concentrate the cellular component, then combined with platelet-rich plasma (PRP) prepared from umbilical cord blood to promote cellular regeneration. The procedure was completed with the injection of biological bone cement in place according to the subchondroplasty technique. The postoperative course was uneventful. Then she received postoperative hyperbaric therapy. No additional therapy (e.g. bisphosphonate therapy) was administered. Subsequent follow-up included physical therapy to optimize joint function and prevent further complications.

Regular clinical and imaging follow-up have been performed to date showing complete restoration of joint functionality. Three years after the procedure, the girl shows no functional limitation in the hip joints and engages sport activities, and MRI confirmed substantial stability of the condition and stabilization of the cortical profile of the hips (Figure 2).

Figure 2: Radiographic and Magnetic Resonance Imaging (MRI) Follow-up of Bilateral Femoral Head Osteonecrosis. (a) Hip X-ray, approximately 12 months post-surgical intervention, demonstrating preserved femoral head height and morphology despite residual bone structural damage, characterized by areas of resorption and sclerosis, more pronounced on the left side. (b, c, d, e) Sequential coronal MRI images, including STIR and T1-weighted (T1W) sequences, acquired at 16 months (b, d) and 3 years (c, e) post-surgery. These images illustrate progressive improvement in bone marrow signal within the femoral heads, with a notable reduction in bilateral bone marrow edema and stabilization of structural bone changes.

Evidence from Literature

Corticosteroid-induced AVN is a rare, but severe complication in children and adolescents with rheumatologic diseases, such as vasculitis (in this case granulomatosis with polyangiitis) [9-12]. Among patients with AAV a prevalence of 18% was reported [13]. It has also been hypothesized that AVN could arise in the absence corticosteroids use, but the literature review conclude that it should not be listed as an independent cause of AVN [14]. Overall, AVN is a multifactorial disease. In autoimmune disorders, immunologic factors have been implicated for its pathogenesis, such as small vessel vasculitis or other disease-associated features and antiphospholipid antibodies [15]. Conversely, genetic factors play a key-role in AVN pathogenesis with some TIMP4 Single Nucleotide Polymorphism (SNPs) associated with decreased risk of steroid-induced ONFH in the population of northern China [16]. Moreover, Yamazaki et al. reported a Japanese trisomy X female adolescent with childhood-onset SLE complicated by ONFH thus suggesting how also chromosomal abnormalities could increase risk of AVN in rheumatic patients [17].