Statistics from Altmetric.com
We read with some surprise the article by Rudler and colleagues proposing a case of a 36 year old woman with methotrexate (MTX) osteopathy.1 The authors report insufficiency fractures after low dose MTX treatment for three months and further fractures two months later.
They suggest that MTX osteopathy may be more common than expected in patients treated with low dose methotrexate, yet all the evidence suggests the opposite. MTX is now the most commonly prescribed disease modifying antirheumatic drug for rheumatoid arthritis in America and parts of Europe.2,3 We conservatively estimate that 120 000 patients receive low dose MTX in the UK alone, with historically a greater proportion of patients in America receiving the drug. Yet cases of proposed MTX osteopathy with low dose treatment are vanishingly rare (six reported cases in adults). Moreover, recent data suggest that low dose MTX has no effect on bone turnover at all.
In this case only a low dose of MTX was used and is the suggested cause of the fractures. Data from paediatric cases suggest that extremely high doses of MTX (20 g/m2, 80 g/m2, and 135 g/m2) are associated with MTX osteopathy.4 Smaller cumulative doses have been implicated in adults, but in the only other published case with short duration (nine months) the patient received almost fivefold more MTX.5 It is surprising that the authors do not comment on the role of the high doses of prednisolone treatment (estimated cumulative dose of 92 g) or the presence of inflammatory disease over 27 years, both important risk factors for insufficiency fractures.
There is a growing body of evidence to refute the fact that MTX has any clinically significant effect on bone mineral density (BMD) or a significant impact on the osteoblast lineage. Patel et al carried out a prospective study of patients with psoriasis and low dose MTX treatment, and reported no significant change in markers of bone turnover or BMD after 21 months’ follow up.5 Minaur et al found that the proliferation and maturation of cells of the osteoblast lineage were not affected by MTX.6 In a study of 116 patients, no direct association of MTX with BMD loss or bone turnover markers was found, and in a small subset, no impact on bone formation was shown by biopsy.7
There appears to be sufficient evidence to doubt the pathogenic role of MTX in this case. Further information about the treatment of the patient in the study of Rudler et al, her BMD, parathyroid hormone levels, and long term outcome are necessary. Did she receive any treatment at all after her initial fractures? In the last paragraph the authors refer to stress fractures. Are they implying that undue stress or activity contributed to the clinical picture? We believe they should be described as insufficiency fractures. The former are fractures occurring in otherwise normal bones by an abnormally applied mechanical load and the latter are due to abnormal bone.
Currently, it is thought that the possibility of a detrimental impact of MTX on the skeleton, even with concomitant corticosteroids, is low. It is important to emphasise that MTX has had a major impact in improving the health and bones (through corticosteroid sparing) of patients with inflammatory arthritis as well as other inflammatory conditions, which greatly outweighs any possible detrimental effects.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.