Abstract
We report a case of metachronous stress fractures in the bilateral lower extremities associated with methotrexate (MTX)-induced osteopathy in a 61-year-old woman. She had been treated with low-dose MTX for 4 years for rheumatoid arthritis (RA) and acute lymphoblastic leukemia (ALL). She presented with a 2-month history of right ankle pain and swelling without trauma. Magnetic resonance imaging revealed stress fractures in the distal tibial metaphysis, calcaneus, and talus. The tibial lesion appeared meander-shaped along the growth plates, hypointense on T1-weighted images, with surrounding bone marrow edema hyperintense on fat-suppressed T2-weighted images. The patient received nonweight bearing therapy while continuing low-dose MTX for maintenance of remission in ALL. Twelve months later, pain developed in the contralateral ankle, and MRI demonstrated a stress fracture in the left distal tibial metaphysis. We diagnosed metachronous stress fractures due to MTX-induced osteopathy. Although rare, clinicians and radiologists should be aware of the potential for stress fractures in the lower extremities, particularly the distal tibial metaphysis, in patients receiving low-dose MTX who present with ankle pain.
Keywords: Rheumatoid arthritis, Methotrexate, Osteoporosis, Stress fracture, Magnetic resonance imaging
Introduction
Methotrexate (MTX) is used as an anchor disease-modifying antirheumatic drugs (DMARDs) in treating rheumatoid arthritis (RA) due to its potent efficacy and tolerability [1]. However, MTX suppresses osteoblastic differentiation, resulting in decreased bone formation and thereby increasing the risk of osteopathy [2]. MTX-induced osteopathy refers to pain, osteoporosis, and stress fractures resulting from long-term administration of MTX. The first report of MTX-induced osteopathy was described in children receiving high-dose MTX therapy for acute lymphoblastic leukemia in 1970 [3]. Since then, several case reports have provided evidence that MTX-induced osteopathy observed not only in children receiving oncologic dosages but also in adults using low-dose MTX for RA and psoriasis [[4], [5], [6], [7], [8], [9]].
MTX-induced osteopathy is frequently confused with osteoporosis in clinical practice [10]. Therefore, MTX-induced osteopathy is often overlooked, resulting in continued MTX therapy, which prevents healing and promotes further fractures. Prompt and accurate diagnosis is essential in managing and preventing further fractures. We describe a case of stress fractures in the bilateral lower extremities as a rare side effect of low-dose MTX therapy for RA.
Case report
A 61-year-old female presented with a 2-month history of right ankle pain and swelling. There was no previous history of trauma. She was diagnosed with RA 16 years ago, thymic cancer 9 years ago, and acute lymphatic leukemia (ALL) 18 months ago. MTX had been administered at 4 mg/week for 19 months, then reduced to 2 mg/week for 10 months due to leukopenia as treatment for RA until the diagnosis of ALL. After the diagnosis, 15 mg of MTX was administered intrathecally as consolidation therapy, and 2.5 mg/week was given for 8 months as maintenance therapy. By the time of this visit, she had received a cumulative dose of 475mg of MTX.
The laboratory data at the time of presentation to our institution was summarized in Table 1. Laboratory workup revealed a reduced White Blood Cells (WBC), Red Blood Cells (RBC), Hemoglobin (Hb), total protein (TP), and albumin (Alb). calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), C-Reactive Protein (CRP), and fibroblast growth factor (FGF)-23 were normal limits.
Table 1.
Laboratory data at initial presentation.
| Laboratory test | Result | Reference range |
|---|---|---|
| White blood cells (×10³/µL) | 2.3 | 3.3–8.6 |
| Red blood cells (×106/µL) | 3.12 | 3.86–4.92 |
| Hemoglobin (g/dL) | 10.3 | 11.6–14.8 |
| Platelets (×10³/µL) | 201 | 158–348 |
| Aspartate aminotransferase (AST) (U/L) | 24 | 13–30 |
| Alanine aminotransferase (ALT) (U/L) | 30 | 7–30 |
| Lactate dehydrogenase (LDH) (U/L) | 224 | 124–222 |
| Alkaline phosphatase (ALP) (U/L) | 109 | 38–113 |
| γ-glutamyl transpeptidase (γ-GTP) (U/L) | 22 | 9–32 |
| Total protein (TP) (g/dL) | 5.7 | 6.6–8.1 |
| Albumin (Alb) (g/dL) | 3.7 | 4.1–5.1 |
| Total bilirubin (T-bil) (mg/dL) | 0.5 | 0.4–1.2 |
| Blood urea nitrogen (BUN) (mg/dL) | 12 | 8–20 |
| Creatinine (mg/dL) | 0.52 | 0.46–0.79 |
| Sodium (Na) (mmol/L) | 142 | 138–145 |
| Potassium (K) (mmol/L) | 4.2 | 3.6–4.8 |
| Chloride (Cl) (mmol/L) | 105 | 101–108 |
| Calcium (Ca) (mg/dL) | 9.2 | 8.8–10.1 |
| Phosphorus (P) (mg/dL) | 4 .2 | 2.7–4.6 |
| C-reactive protein (CRP) (mg/dL) | 0.06 | <0.14 |
| Fibroblast growth factor (FGF)-23 (pg/mL) | 30.1 | 19.9–52.9 |
The right ankle radiograph showed osteoporotic change in the distal tibia (Fig. 1). CT demonstrated a meander-shaped sclerosis in the distal tibial metaphysis (Fig. 2). MRI demonstrated stress fractures in the distal tibial metaphysis, calcaneus, and talus with edematous changes in the surrounding soft tissues (Fig. 3). The tibial stress fracture appeared as a meander-shaped lesion along the growth plates. It showed hypointensity on the T1-weighted image (Fig. 3a), with surrounding bone marrow edema demonstrating hyperintensity on the fat-suppressed T2-weighted images (Fig. 3, Fig. 3). There were no vertebral, sacral, femoral neck, or radial fractures, which are commonly seen in ordinary cases of osteoporosis. Considering the patient’s history of low-dose MTX for RA or ALL, MTX-induced osteopathy was suspected.
Fig. 1.
The right ankle anteroposterior radiograph shows osteoporotic change in the distal tibia (arrow).
Fig. 2.
Reconstructed coronal CT of the bilateral ankle demonstrates a meander-shaped sclerosis in the right distal tibial metaphysis (arrows).
Fig. 3.
MRI demonstrates stress fractures in the right distal tibial metaphysis, calcaneus, and talus with edematous changes in the surrounding soft tissues. The distal tibial stress fracture appears as a meander-shaped lesion along the growth plate (arrows). It shows hypointensity on the coronal T1-weighted image (A), with surrounding bone marrow edema demonstrating hyperintensity on the fat-suppressed T2-weighted images (B and C).
The patient was treated with nonweight bearing therapy, while low-dose MTX for maintenance of remission in ALL was continued. Subsequently, the right ankle pain disappeared. The MRI obtained 3 months later demonstrated significant improvement in both the fractures and subcutaneous edema (Fig. 4). However, twelve months later, the patient developed pain in the left ankle, this time on the contralateral side. MRI demonstrated stress fracture in the left distal tibial metaphysis with edematous changes in the surrounding soft tissues (Fig. 5). MTX was discontinued in addition to nonweight bearing therapy, resulting in almost resolution of pain to date. She ultimately received a cumulative dose of 595 mg of MTX. We diagnosed the patient with metachronous stress fractures in MTX-induced osteopathy.
Fig. 4.
Coronal T1-weighted image (A), coronal fat-suppressed T2-weighted image (B), and sagittal fat-suppressed T2-weighted image (C) obtained 3 months later demonstrated significant improvement in the stress fractures in the right distal tibial metaphysis, calcaneus, and talus with edematous changes in the surrounding soft tissues.
Fig. 5.
MRI demonstrates stress fracture in the left distal tibial metaphysis with edematous changes in the surrounding soft tissues. The distal tibial stress fracture appears as a meander-shaped lesion along the growth plate (arrow). It demonstrates hypointensity on the coronal T1-weighted image (A) and hyperintensity on the coronal and sagittal fat-suppressed T2-weighted images (B and C).
Discussion
Stress fractures in MTX-induced osteopathy is characterized by a pathognomonic type of stress fractures with band- or meander-shaped appearance along the growth plate [8]. On magnetic resonance imaging (MRI), the band-like or meander-shaped sclerosis shows low signal intensity on both T1- and T2-weighted images, while the surrounding bone marrow edema demonstrates hyperintensity with an ill-defined border on T2-weighted images [7,8,10]. On radiographs or CT, stress fractures in MTX-induced osteopathy can be described as band- or meander-shaped stress fractures paralleling the former provisional zones of calcification and growth plates. Rolvien et al. [7] reported 4 stages based on the severity of morphological alterations observed on CT: epimetaphyseal osteolysis, followed by confluent microcallus formation, band-like sclerosis, and deformities. However, radiographs may not be invariably helpful for diagnosis, as was the case in the present case. If symptoms persist or the clinical history warrants, MRI should be favored over radiography-based imaging for initial diagnosis. Ruffer et al. [8] suggest MRI-based fracture screening in cases of ‘refractory arthritis’ at the lower extremity because stress fractures at clinically silent locations can be detected.
MTX-induced osteopathy distinctively occurs in the lower extremities as stress fractures, most commonly presenting in the distal tibia (51.3%-53.0%), followed by the calcaneus (10%-35.0%), proximal tibia (27.0%-27.5%), talus (17.5%), and metatarsal bones (13.8%) [6,8].
MTX-induced osteopathy is frequently confused with osteoporosis, whether due to steroid use or other conditions, in clinical practice [10]. However, MTX-induced osteopathy exhibits reduced bone mineral density, though less pronounced than in the case of osteoporosis, and typical osteoporotic fractures including vertebral, sacral, femoral neck, or radial fractures were rarely seen [8,10]. In addition, the stress fractures due to MTX-induced osteopathy can occur without substantial trauma, leading to pain and restricted mobility. When a stress fracture of the distal tibia occurs without a history of trauma, as in the present case, MTX-induced osteopathy should be considered as a possible cause.
Ruffer et al. analyzed previously published cases of MTX-induced osteopathy in patients with RA, including 32 studies describing 80 adult patients and evaluated the clinical characteristics of the disease [8]. They reported that patients frequently suffered from bilateral (55.0%), multiple (71.3%), and recurrent fractures (25.0%). They also reported that the median duration of low-dose MTX therapy at the time of MTX-induced osteopathy occurrence was 6.0 years (range, 0.25–29.0 years), with a median cumulative dose of 2.6 g (range, 0.0975–29.0 g). In our case, the duration of MTX administration until the occurrence of stress fractures in the right extremity was 4 years, with a cumulative dose of 0.475 g, and in the left extremity was 5 years, with a cumulative dose of 0.595 g. These findings are consistent with those of the previous study.
Reported risk factors of MTX-induced osteopathy include prolonged low- to moderate-dose MTX therapy, advanced age, female sex, low bone mineral density or osteoporosis, and the presence of RA, with cases occurring even in the absence of systemic corticosteroid use [8,11]. Prevention strategies emphasize the early recognition of bone pain and characteristic MRI findings, as well as the prompt discontinuation or replacement of MTX when the condition is suspected, since this can lead to symptom improvement and a reduced risk of fractures [12]. Maintaining bone health through calcium and vitamin D supplementation, and in some cases antiosteoporotic agents such as bisphosphonates, as well as conducting regular bone health monitoring and clinical assessment for lower limb pain in long-term MTX users, are recommended to minimize recurrence and optimize patient outcomes [6,10].
In the present case, nonweight-bearing therapy led to temporary improvement in symptoms and MRI findings; however, MTX could not be discontinued because of ongoing treatment for ALL, and new fractures developed in the contralateral lower extremity twelve months later. Discontinuation of MTX remains the primary recommended approach in managing MTX-induced osteopathy. However, new fractures may still occur, and fracture healing may be delayed even after discontinuation of MTX therapy [6]. Rolvien et al. [13] recently reported that, in patients with systemic lupus erythematosus who developed stress fractures after long-term MTX use, discontinuation of methotrexate in combination with individualized and advanced bone-specific therapies proved effective.
In conclusion, stress fractures associated with MTX therapy have characteristic sites and radiological features. Although stress fractures are a rare side effects of low-dose MTX therapy, the potential for stress fractures in the lower extremities, especially distal tibial metaphysis should be considered in patients presenting with ankle pain.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent to publish declaration
Written informed consent was obtained from the patient for publication of this study and accompanying images.
Data availability statement
The datasets supporting the conclusions of this article are available from the corresponding author upon reasonable request.
Patient consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Footnotes
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments: This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets supporting the conclusions of this article are available from the corresponding author upon reasonable request.