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Low dose methotrexate (MTX) is widely used in the treatment of rheumatoid arthritis (RA) and various rheumatic disorders, including juvenile idiopathic arthritis (JIA). MTX is a folate antagonist, and its main adverse effects, which include haematological and hepatic toxicities, are well known. Used in high dosages in paediatric oncology, MTX has been associated with an osteopathy which is characterised by bone pain, osteoporosis, and insufficiency fractures of the legs.1 The occurrence of MTX osteopathy in patients treated with low dose MTX has been reported but is still debated.2–4
A 36 year old woman presented with severe polyarthralgias lasting for the past two months. She had a 27 year history of polyarticular type JIA, and had received prednisone up to 10 mg/day for the past 25 years. She had no history of osteoporotic or insufficiency fractures. Physical examination showed multiple synovitis of hands, wrists, knees, and ankles. Laboratory investigations showed a slight increase of C reactive protein of 20 mg/l, and a strongly positive rheumatoid factor. Low dose oral MTX was started at an initial weekly dose of 7.5 mg (weight 56 kg, height 156 cm, albumin 42 g/l, serum creatinine 60 μmol/l).
In the absence of significant improvement, two months later, the weekly dose of MTX was increased to 10 mg. One month later, while she had a persistent active polyarthritis, and after having received a cumulative dose of 97.5 mg of MTX, she complained of sudden and spontaneous onset of right groin pain that was relieved by rest. Standard radiographs showed a fracture of both inferior and superior right pubic ramus. Serum calcium and 25-hydroxycholecalciferol levels were normal. Pain resolved with rest in a few weeks. Treatment with MTX was maintained.
Two months later, the patient presented with bilateral leg pain increased by weight bearing and relieved by rest. At that time, the received cumulative dose of MTX was 137.5 mg. Standard radiographs were normal but bone scanning with technetium-99m disclosed multiple areas of increased uptake (superior and inferior right pubic ramus, pubic symphysis, left hip, bilateral femoral condyles, right calcaneum) characteristic of multiple new insufficiency fractures (fig 1). MTX osteopathy was suspected and the treatment was discontinued.
MTX osteopathy was initially reported in children with acute leukaemia treated with a high dose of MTX.1 Patients present with severe leg pain, osteopenia, and insufficiency fractures. Several reports have also suggested that the occurrence of spontaneous insufficiency fractures is more common than expected in patients with inflammatory rheumatism treated with low dose MTX.3–6 The effect of MTX on bone mineral density has been rarely studied. In patients with RA, low dose MTX treatment was not associated with increased bone loss in the lumbar spine or the femoral neck at three years.7 However, among the patients who were also receiving prednisone (⩾5 mg/day), MTX use was associated with greater bone loss in the lumbar spine, suggesting that the addition of MTX to prednisone may cause more bone loss than would be expected from corticosteroid treatment alone.7 Recently, Uehara et al have shown in vitro that MTX impairs bone formation by inhibiting the differentiation of osteoblast precursors.8
In patients with inflammatory arthritis receiving corticosteroids, MTX treatment should be considered as an additional risk factor for stress fractures. As far as we know this is the first reported case of MTX osteopathy in a patient with JIA. Rheumatologists should be aware of this complication as it may be easily confused with synovitis. Involvement of the leg articular or periarticular area should raise diagnostic clinical awareness. A bone scan is particularly useful for the diagnosis.3