Clinical and Radiological Characterization of Patients with Immobilizing and Progressive Stress Fractures in Methotrexate Osteopathy

Abstract

Methotrexate (MTX) is one of the most commonly prescribed drugs for autoimmune rheumatic diseases. As there is no consensus on its negative effects on bone, the purpose of this investigation was to determine the clinical spectrum of patients with stress fractures due to long-term MTX treatment (i.e., MTX osteopathy). We have retrospectively analyzed data from 34 patients with MTX treatment, severe lower extremity pain and immobilization. MRI scans, bone turnover markers, bone mineral density (DXA) and bone microarchitecture (HR-pQCT) were evaluated. Stress fractures were also imaged with cone beam CT. While the time between clinical onset and diagnosis was prolonged (17.4 ± 8.6 months), the stress fractures had a pathognomonic appearance (i.e., band-/meander-shaped, along the growth plate) and were diagnosed in the distal tibia (53%), the calcaneus (53%), around the knee (62%) and at multiple sites (68%). Skeletal deterioration was expressed by osteoporosis (62%) along with dissociation of low bone formation and increased bone resorption. MTX treatment was discontinued in 27/34 patients, and a combined denosumab–teriparatide treatment initiated. Ten patients re-evaluated at follow-up (2.6 ± 1.5 years) had improved clinically in terms of successful remobilization. Taken together, our findings provide the first in-depth skeletal characterization of patients with pathognomonic stress fractures after long-term MTX treatment.

Influence of X-rays and gamma-rays on the mechanical performance of human bone factoring out intraindividual bone structure and composition indices

“…Bone is subjected to different doses of irradiation, ranging from mGy to kGy, in both clinical [ [28] , [29] , [30] ] and research applications [ 2 , 3 , 8 , 9 , 31 ]. Although the risk of radiation to the human body is well documented, the benefits of techniques requiring radiation in clinical imaging outweigh the potential risks.…”

The Effect of Anti-rheumatic Drugs on the Skeleton

“…Over the past 2 years an increasing number of patients on long-term MTX were described who developed multiple, frequently bilateral, insufficiency fractures of calcaneus and/or the metaphysis of distal and proximal tibia and distal femur, so called "MTX osteopathy" [22,23]. Typical MRI findings of methotrexate associated insufficiency fractures are shown in Fig.…”

“…Methotrexate osteopathy was first described in 1970 when five cases of children developed distal femoral and tibial insufficiency fractures whilst receiving prolonged MTX therapy for acute lymphatic leukaemia [24]. To date about 80 cases have been described with this condition [22,23,25]. One of the potential mechanism was thought to be MTX-induced suppression of osteoblast activity [26]; however, this effect was only shown in animal experiments (rats) and to our knowledge low-dose MTX-induced osteoblast suppression has not been replicated in humans.…”

Insuffizienzfraktur der Klavikula nach Implantation einer inversen Schulterendoprothese

“…Die Begleiterkrankungen, konkret der Morbus Parkinson mit erhöhtem Sturzrisiko und die rheumatoide Arthritis, deren erforderliche Therapie sowie das myelodysplastische Syndrom und die konsekutiv langjährig bestehende Osteoporose sollten aus Sicht der Autoren als komplizierende Faktoren beachtet werden. Angesichts der langjährigen antiresorptiven Vorbehandlung in Verbindung mit der für die Knochenregeneration kritischen Glukokortikoid- [ 7 ] und MTX- [ 12 ] Therapie, erscheint pathophysiologisch eine osteoanabole Therapiesequenz zunächst naheliegend, wenngleich die Datenlage dahingehend inkonsistent ist [ 6 ]. Angesichts des Risikos einer Progression des myelodysplastischen Syndroms im Zuge einer forcierten Zellpropagation unter dem Einsatz von Teriparatid sowie des erhöhten Risikos für kardiovaskuläre Endpunkte bei entsprechendem Ausgangsrisiko unter Romosozumab entschieden wir uns gegen einen solchen Behandlungsansatz.…”