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Is methotrexate osteopathy a form of bone idiosyncrasy?
  1. A P Rozin
  1. Bat Galim, Rambam Medical Centre, PO Box 9602, Haifa, Israel
  1. Correspondence to:
    Dr A P Rozin, B Shine Department of Rheumatology, Rambam Medical Centre, PO Box 9602, Haifa 31096, Israel;

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We read the letter about low dose methotrexate (MTX) osteopathy with mixed feelings.1 On the one hand, it is not unusual for a woman to develop insufficiency bone fracture after 25 years of prednisone treatment. Longstanding inflammatory joint disease also affects bone. The patient had an active disease that is associated with osteoclast activation mediated by tumour necrosis factor-osteoprotegerin. However, the authors underestimated other possible factors which might have had an influence on bone density. Menstrual cycle status was not discussed. Results of bone density assessment were not described despite long term steroid treatment. Risk factors such as family history, smoking, diet, and physical activity were not analysed.

Of note, besides pelvic fracture, increased technetium-99m uptake was seen in joint areas with normal standard radiographs. This may be due to active arthritis and enthesopathy. We can draw no conclusions about the duration of the bone scan findings. Data about previous scans are absent. MTX in vitro does not affect the proliferation and further maturation of osteoblasts.2 No adverse effect of low dose MTX (<30 mg/week) on bone formation in RA has been found.3 Studies have shown that low dose MTX treatment did not cause a decrease of bone density and was similar to that of the control groups.4–6 Summarising previous studies we can state that most patients have no increased risk of MTX osteopathy. Osteopathy resulting from high dose MTX treatment in children with malignancy occurs only in 9% of patients.7

On the other hand, however, this young woman developed pelvic spontaneous fracture three months after the onset of MTX treatment. Severe leg pains increased by weight bearing and relieved by rest followed after four months of treatment. Such a rapid occurrence suggests hypersensitivity of the delayed type with targeting to bones. Bone targeted drug idiosyncrasy may also be considered. Very delayed drug induced hypersensitivity affecting fat tissue of the abdomen has been reported previously.8 Other tissues may also be affected. Drug sensitivity tests may be helpful.

High and low dose MTX osteopathy have similar signs and symptoms, including a triad of severe low extremity pain (distal tibia), osteoporosis, and compression bone fractures occurring spontaneously or after minimal trauma. Both may develop even over a short period of time after the onset of MTX treatment.1,9 In both osteoporosis dosage groups scurvy-like lines may be seen onx ray examination, which may be normal at the start. Because the multiple controls receiving the same treatment in both groups do not have signs of such severe osteoporosis, it is assumed that an as yet unknown cause may be responsible.10 We propose hypersensitivity reaction or idiosyncrasy, rapidly affecting bone tissue, may be such causes. There have been comparable reported rates of high and low dose (different by 70–100 fold) MTX osteopathy, independent of cumulative doses,7 pointing to the possible role of idiopathic or hypersensitivity aetiologies (table 1). Bone pain diminished within one month after stopping MTX treatment in both groups, and x ray findings returned to normal 5–7 months later.7,9 Proposed bone hypersensitivity in MTX osteopathy may be compared with hypersensitivity lung or liver disease due to MTX treatment. These serious complications of MTX treatment may follow any cumulative dose of the drug. Recognising the phenomenon of MTX bone idiosyncrasy or hypersensitivity may prevent the unnecessary or harmful proposal that MTX treatment is a risk factor for osteoporosis and should be relatively contraindicated in patients with multiple risk factors for osteoporosis.

Table 1

Publications on high dose and low dose MTX osteopathy since the first report in 1970


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