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.

Keywords: Cone beam CT; Denosumab; MTX osteopathy; Methotrexate; Stress fracture; Teriparatide.

Fig. 1

MRI morphology of stress fractures in MTX osteopathy. Band-like stress fractures in proton density (PD)-weighted fat-suppressed (FS) turbo spin echo (TSE) MRI sequences are seen. a Distal tibia, coronal and sagittal plane of two different patients. b Calcaneus, coronal and sagittal plane of two different patients. c Proximal tibia/distal femur, coronal plane. d Multiple stress fractures were found in 68% of the patients. e Bar graph indicating the regional distribution of stress fractures in n = 34 patients (frequency in % for each skeletal site)

Fig. 2

Clinical characteristics and bone mineral density, turnover and microstructure. a Eighty-eight percent of the affected patients were female. b Prednisone/no prednisone treatment. c Distribution of the different rheumatic diseases. d Age distribution. e, f DXA T-score at the lumbar spine (LS) and total hip. g, h Serum bone-specific alkaline phosphatase (BAP) and osteocalcin levels (both bone formation) and i urinary deoxypyridinoline (DPD) (bone resorption). Gray boxes indicate reference ranges. j Trabecular number (Tb. N), k trabecular thickness (Tb. Th) and l cortical BMD compared to age- and sex-matched reference data [31]

Fig. 3

Cone beam CT (CBCT) imaging. Differentiation and classification of different disease severities based on CBCT imaging a in the distal tibia, b around the knee (distal femur and proximal tibia) and c in the calcaneus

Fig. 4

Biopsy studies (81-year-old woman) in the lateral (nonfractured) tibial plateau. a Anteroposterior radiograph showing the fracture of the medial tibial plateau (red arrow). b Coronal MRI, PD-weighted sequence. c Contact radiography (lateral view) of the resected tibial plateau, a anterior, p posterior. d Histological overview, von Kossa staining in the patient and the control. e–g Quantification of BV/TV, Tb.N and Tb.Th. h Visible osteoclasts on the surface of a trabecula, toluidine blue staining. i, j Osteoblast and osteoclast surface. k Image obtained by backscattered electron imaging with eroded surfaces (asterisks). l BMDD histograms

Fig. 5

Biopsies from different fracture sites reveal interference with fracture healing with chronic callus formation and osteoidosis but an absence of osteonecrosis. a Representative histological images, toluidine blue staining. Left (no. 1): distal tibia (64-year-old woman) showing fracture callus; middle and right (nos. 2, 3): distal tibia and calcaneus (71-year-old woman) with woven bone formation. b Histomorphometric quantification in the individual biopsies nos. 1–3 including osteoid volume per bone volume (OV/BV), osteoblast surface per bone surface (Ob.S/BS) and osteoclast surface per bone surface (Oc.S/BS)

Fig. 6

Follow-up and treatment response. a Subjective clinical course (++ major improvement, + minor improvement, − no improvement in mobility and pain). b MRI, T1-weighted, sagittal sequence. c Individual results for the Timed Up and Go test at follow-up. d Chair rising test (CRT). e–j HR-pQCT at initial presentation and follow-up (distal tibia for all panels). e Trabecular BMD. f Trabecular number. g Cortical BMD. h Cortical thickness. i HR-pQCT image at 0 and 14 months indicating increasing cortical thickness (white arrows). j HR-pQCT changes converted to %-change/1 year