Methotrexate (MTX) is a folate antagonist with well known side effects, which mainly include haematological and hepatic adverse events, and less frequently lung or bone toxicities. The use of MTX in high doses has been associated with an osteopathy, which is characterised by severe bone pain, osteoporosis, and insufficiency fractures of the legs.¹ We present two patients with rheumatoid arthritis (RA) who developed medial tibial stress syndrome (MTSS) while taking low dose MTX.

The first patient, a 69 year old woman, had a history of RA diagnosed in 2001.² After 1 year’s treatment with MTX (10 mg/week), she reported a 1 month history of severe pain in the medial part of the left tibia. The pain had an acute onset, prevented her from walking, and was relieved by rest. A physical examination disclosed severe tenderness on the anterior and medial part of the lower third of the tibia. A simple x ray examination and bone scanning were normal. Magnetic resonance imaging (MRI) showed a linear abnormal high signal intensity along the medial surface of the tibia on T₂ weighted, fat suppressed, proton density fast spin echo images (fig 1⇓). With the diagnosis of MTSS she was treated with rest for 6 weeks without improvement. In February 2003, MTX was withdrawn because of recurrent oral ulcers. One month later, she still had moderate left tibial pain and treatment was started with alendronate 70 mg/week. Within 1 week she was asymptomatic.

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Figure 1

 Magnetic resonance imaging of distal tibia. Coronal (A) and axial (B) fat suppressed, T₂ weighted, fast spin echo images show hyperintense signal intensity along the medial surface of the tibia corresponding with periosteal oedema (arrows). No cortical or marrow abnormality was demonstrated.

The second patient, a 61 year old woman, was diagnosed with RA² in May 2001. After 27 months’ treatment with MTX (15 mg/week) she developed severe pain in the left tibia that prevented her from walking and was relieved by rest. A physical examination disclosed severe tenderness on the medial part of the tibia, especially on the lower third, with a mild oedema. MRI was compatible with the diagnosis of MTSS and based on the experience of the first patient, MTX was withdrawn and treatment with risedronate 35 mg/week was started. Within 1 week the patient was asymptomatic.

The presence of MTX osteopathy in patients with inflammatory conditions treated with low dose MTX has been reported but is still debated.^3–,⁷ A critical review of published reports suggests that most patients treated with low dose MTX have no increased risk of MTX osteopathy.⁸

MTSS, a common condition of uncertain origin found in athletes, is characterised by pain in the distal posteromedial aspect of the tibia during exercise, with or without increased scintigraphic uptake in the affected region.^9,10 Although the exact cause of MTSS is unclear, changes in bone metabolism are likely to be involved. It has been shown recently that athletes with MTSS have a localised low bone mineral density. MRI is of high diagnostic value in differentiating MTSS and stress fracture. In MTSS MRI can visualise juxta-osseous oedematous and inflammatory reactions, and an increased signal would appear to be characteristic when the band-like image is fixed to the periosteum. The most effective treatment is considered to be rest, and despite appropriate treatment, patients with MTSS are usually symptomatic for a prolonged period. In our patients, the rapid resolution of the clinical syndrome was striking, suggesting that MTX treatment was related to MTSS and that biphosphonate treatment could also accelerate the resolution of the osteopathy.

In summary, we describe two postmenopausal women with RA who developed MTSS while receiving treatment with low dose MTX. Withdrawal of MTX and the addition of biphosphonates were followed by a rapid resolution of symptoms, suggesting a relationship between MTX and MTSS. We suggest that MTSS should be added to the clinical spectrum of MTX osteopathy.