Methotrexate continuation increases fracture risk in patients who sustained lower limb insufficiency fractures

Two recent case series and previous case reports have described methotrexate (MTX)-associated insufficiency fractures, so called methotrexate osteopathy (MTXO). Our aim was to assess whether the continuation of MTX after an insufficiency fracture impacts future fracture risk.

Retrospective single-centre case note review of patients who suffered MTXO insufficiency fractures. We assessed the occurrence of subsequent fractures and evaluated fracture healing in patients who either continued or discontinued MTX following the initial fracture.

We identified 33 patients with characteristic MTXO lower limb insufficiency fractures. The mean MTX dose was 20 ± 5.9 mg weekly with average treatment duration of 10.7 ± 6.2 years. MTX was continued in 21 out of 32 patients following the initial insufficiency fracture. Almost all patients (95.2%) who continued methotrexate sustained either further insufficiency (67%) or major osteoporotic (33%) fractures. There were significantly fewer fractures (3 out of 11, 27.3%) in the group that stopped MTX after the initial insufficiency fracture (χ² = (1, N = 32) = 13.4; P < .001). A Kaplan-Meier analysis showed that significantly increased number of patients who continued MTX after the initial insufficiency fracture sustained a further fracture over time when compared to patients who stopped methotrexate (P = .042). Discontinuation of MTX was associated with greater clinical improvement in pain (77.8% vs 36.4%, P = .036) and weight-bearing capacity (71.4% vs 22.7%, P = .030) during fracture healing.

In patients with MTXO insufficiency fractures, continuation of MTX is associated with a high risk of further fracture. It is important to recognise such insufficiency fractures and stop MTX to minimise the future fracture risk.