An Impressive Response to Zoldronic Acid Treatment for Chronic Recurrent Multifocal Osteomyelitis: A Case Report

Abstract

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, non-infectious inflammatory disease with a prevalence of 1 to 2/10⁶, causing multiple lytic bone lesions. There are no established protocols for treating CRMO; thus, current practice is largely empirical. Data on the use of zoledronic acid (ZA) in juvenile CRMO are scarce. A 12-year-old male child with a history of multiple aseptic osteomylitis, affecting the chest wall, right ankle, and wrist, had no fever. Cultures and a bone biopsy ruled out infection or malignancy. The patient’s condition stayed stable while taking naproxen (20 mg/kg/day) and methotrexate (10 mg/week) for 1.5 years until he experienced right elbow pain, swelling, no overlying skin erythema, and a restricted range of motion. The laboratory tests all came back normal, including white blood cell (WBC) count, erythrocyte sedimentation rate, C-reactive protein, and immunoglobin assays. The magnetic resonance imaging showed a focal lesion in the medial humeral condyle with increased signal intensity on T2 and short tau inversion recovery, mild joint effusion, and no cortical break. Thus, intravenous ZA infusion commenced at 0.0125 mg/kg initially, followed by 0.025 mg/kg 3 months later, with a marked improvement in the patient’s clinical symptoms and radiological findings. Non-steroidal anti-inflammatory drugs and methotrexate were initially effective in treating our patient’s condition, but a recurrence necessitated treatment modification. To the best of our knowledge, this case is the first documented instance of the use of ZA in CRMO in Iraq and Arab nations.

Introduction

Chronic recurrent multifocal osteomyelitis (CRMO), which was first described by Giedion in 1972 and is also called chronic non-bacterial osteomyelitis, is a rare, non-infectious inflammatory disease that causes multiple lytic bone lesions and has remissions and flare-ups.^{1 -3} Females outnumber males by a factor of 4 to 1 among the children and adolescents diagnosed with this disorder. Due to its low prevalence (1-2/10⁶), CRMO is still classified as a rare disease. It is likely that the actual prevalence of CRMO is much higher. ⁴ Gradual-onset bone pain is characteristic. Skeletal symptoms can be unifocal or multifocal, and any bone may be affected, with the long bone metaphyses being mostly involved, followed by the vertebral column, pelvis, clavicle, jaw, sternum, and ribs. ⁵ The overlying skin may be inflamed, and arthritis in adjacent and distal joints can be present in up to 80% of cases. ⁶ Lab testing and various imaging tests are part of a lengthy diagnosis process. Although routine inflammation markers are usually within acceptable limits, the imaging may still be unclear, in which case a bone biopsy may be necessary. Bone and hematological malignancies, infectious osteomyelitis, and other systemic disorders all contribute to a differential diagnosis that is frequently challenging to make.^7,8

Case Report

In this report, we present the case of a 12-year-old male child who first attended the rheumatology clinic of Baghdad Teaching Hospital when he was 10 years old, complaining of a 2-month history of right wrist pain and swelling, along with skin redness and no accompanying fever, body skin rash, diarrhea, or preceding upper or lower respiratory infections.

The patient’s condition dates back to when he experienced recurrent right knee swelling at the age of 1.5 years that resolved after a week of non-steroidal anti-inflammatory drug (NSAID) use. These attacks occurred every 5 to 6 months and were associated with fever spikes. Other joints were normal, with no accompanying skin rash or organomegaly. A misdiagnosis of juvenile idiopathic arthritis led to the patient’s initial treatment with prednisolone and methotrexate. This regimen continued until he turned 5 years old, during which he did not experience a flare-up of his condition, prompting the discontinuation of the medication. Subsequently, he experienced 2 abscesses in his right chest wall, which were evacuated and cleared surgically. Two surgeries were necessary to treat another abscess in the right ankle that did not respond to antibiotics and developed into osteomyelitis (according to magnetic resonance imaging [MRI]).

All these incidents occurred following a minor trauma to the area, with no associated fever or constitutional symptoms, and the cultures following the drainage showed no bacterial growth.

Upon physical examination, he was mildly pale, afebrile, and vitally stable; his body mass index (BMI) was 17 (normal for his age); there were 2 scars in the right chest wall and another 2 in the right ankle, measuring 5 to 8 cm; there was a tender, localized swelling of the right wrist, particularly on the radial side, with associated redness of the overlying skin; there was a limitation in his range of motion; there were no scars, bruising, psoriasis plaques, muscle wasting, or deformity, as shown in Figure 1A, and the examination of the adjacent joints was normal.

Figure 1.

(A) Localized right wrist swelling, particularly on the radial side, with associated redness of the overlying skin. (B) After 2 months of treatment with MTX and Naproxen.

The results of the blood tests revealed a white blood cell (WBC) count of 6.9 × 10⁹/L, a hemoglobin level of 10.6 mg/dL, a slightly raised erythrocyte sedimentation rate (ESR) of 19 mm/h, and normal levels of C-reactive protein (CRP) (4.6 mg/L, normal range <10 mg/L). Immunoglobin assays were within normal limits; liver and kidney tests were normal; virology screens and interferon-gamma release assays (IGRAs) were negative; and wrist swab cultures revealed no bacterial growth. A computed tomography (CT) scan of the wrist showed normal alignment and bone density. A bone biopsy revealed no evidence of a bone infection or malignancy. An MRI was scheduled, but the patient initially refused to do it. Therefore, CRMO was strongly suspected in light of the history of previous multiple aseptic osteomylitis, the patient’s symptoms, and the laboratory test results. Naproxen at a dose of 20 mg/kg/day along with a proton pump inhibitor was provided, and methotrexate (10 mg/week) was added after 5 weeks of naproxen because of little improvement, with complete clinical resolution within 2 months as shown in Figure 1B. The patient’s condition remained stable on this regimen for 1.5 years until he experienced right elbow pain and swelling, no overlying skin erythema, and a restricted range of motion. The laboratory tests all came back normal, including WBC, ESR, and CRP. The MRI showed a focal lesion in the medial humeral condyle that had a higher signal intensity on T2. There was bone marrow edema and mild joint effusion, but there was no cortical break (Figure 2).

Figure 2.

(A) MRI of the right elbow before zoledronic acid (ZA) treatment. (B) Complete resolution after ZA treatment.

Therefore, intravenous zoledronic acid (ZA) infusion was added to his therapy at a dose of 0.0125 mg/kg for the first dose and 0.025 mg/kg for the second dose, which was given 3 months following the first dose.

A marked improvement in the patient’s clinical symptoms was noted. The planned maintenance treatment for the patient is 0.05 mg/kg every 6 months.

In conclusion, the case of this 12-year-old male child presented a challenging diagnostic journey marked by recurrent joint swellings and abscess formations, initially misdiagnosed as juvenile idiopathic arthritis. However, with a comprehensive evaluation including detailed clinical history, physical examination, and laboratory investigations, CRMO emerged as the likely diagnosis. This conclusion was supported by the absence of bacterial growth in cultures, normal immunological assays, and characteristic MRI findings. Treatment with naproxen and methotrexate initially, followed by the addition of ZA upon subsequent flare-ups, resulted in significant clinical improvement and stabilization of the patient’s condition over time. This case underscores the importance of considering rare inflammatory conditions like CRMO in the differential diagnosis of recurrent musculoskeletal symptoms, particularly in pediatric patients, to ensure appropriate management and optimal outcomes.

A written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images.

Discussion

Clinical, laboratory, and radiologic evidence all contribute to the CRMO diagnosis. Despite the lack of specificity in laboratory tests, an elevation in the inflammatory index can occasionally be seen in conjunction with leukocytosis.^9,10 In the early stages of disease, a conventional x-ray may be normal as the initial radiological technique in a child with bone pain. Bone metaphyseal changes around growth plates are the earliest radiographic indicators of the disease, but osteolytic and sclerotic lesions typically occur later. ¹¹ When compared with bone scintigraphy, short tau inversion recovery (STIR)-view MRI provides superior accuracy in detecting bone lesions and tissue edema, along with T1- and T2-weighted views. ¹² Although histologic findings are not specific, a biopsy is often required to rule out other potential causes of bone pain, such as infected osteomyelitis or a malignant bone tumor. Some argue that a biopsy might not be necessary if a child exhibits characteristic radiological indications of CRMO or co-morbidities like Crohn’s disease.^8,10,13

We described a 12-year-old boy who experienced recurring non-pyogenic abscess formation events. According to the Jansson et al, ¹⁴ proposed diagnostic criteria for CRMO, our patient met 2 major criteria: a radiologically proven osteolytic and sclerotic bone lesion and a sterile bone biopsy with signs of inflammation. He also met 3 minor criteria: a normal leukocyte count, a mildly elevated ESR, and a period of observation longer than 6 months. In addition, the presence of bone pain and bone marrow edema on STIR MRI, along with more than one afflicted bone and a CRP below 30 mg/dL, demonstrated that the patient met the diagnostic criteria outlined by Roderick et al. ⁵

There are no established protocols for treating CRMO; therefore, current practice is largely empirical. In order to reduce inflammation and pain, nonsteroidal anti-inflammatory medications (NSAIDs) are typically the first line of treatment prescribed for patients with CRMO. Corticosteroids (CS), disease-modifying anti-rheumatic drugs, anti-tumor necrosis factor agents, or bisphosphonates are among the therapy options. ⁸ NSAIDs and methotrexate were initially effective in treating our patient’s condition, but a recurrence necessitated treatment modification. A consensus treatment strategy for patients who are resistant to NSAIDs was recently published by the Childhood Arthritis and Rheumatology Research Alliance (CARRA). One of the agreed-upon regimens called for pamidronate to be given monthly at a dose of 1 mg/kg or ZA to be given every 3 to 6 months after a first dose of 0.0125 to 0.025 mg/kg. Depending on the severity of the condition, an increase in the per-pulse dosage to 0.05 mg/kg/dose (maximum: 4 mg/dose) may be necessary.^15,16 Unfortunately, pamidronate is now unavailable in Iraq due to supply shortages. Therefore, we recommended ZA for the patient who demonstrated a remarkable clinical reaction after the first dose. Data on the use of ZA in pediatric CRMO are scarce.^{16 -18} Bisphosphonates have been shown to provide clinical benefits for conditions other than CRMO. In osteoporosis, for instance, bisphosphonates effectively decrease fracture risk by preventing bone resorption and increasing bone strength. They regulate bone remodeling in Paget’s bone disease. Bisphosphonates are additionally frequently used in malignancies, notably in the management of bone metastases and the prevention of skeletal-related events, as well as treating hypercalcemia of malignancy. These examples demonstrate bisphosphonates’ expanded use in treating bone fragility and inflammation.^19,20 To the best of our knowledge, this case is the first documented instance of the use of ZA in CRMO in Iraq and other Arab nations.

Conclusions

Medical literature rarely documents or analyzes CRMO, an exceptionally uncommon condition. This report aims to enhance awareness and prompt medical professionals and specialists to prioritize the treatment of individuals with this distinctive condition, particularly in developing nations.