Case reports showed that methotrexate (MTX) medication could affect bone metabolism in particular people, resulting in low bone mass, atraumatic stress fractures, and immobilizing bone pain, a condition known as ‘MTX osteopathy.’ However, the clinical characteristics, risk factors, and therapeutic choices for the illness were still unknown. PRISMA guidelines were used to conduct a systematic review. For published cases of MTX osteopathy in patients with rheumatic musculoskeletal disorders (RMD), 2 databases (MEDLINE and Embase) were searched. Data was gathered from the included papers, and descriptive statistical analysis was carried out. Researchers present outcomes from 32 trials, including 80 adult RMD patients who had stress fractures due to MTX osteopathy. Most cases were observed in older women who had long-term RMD, particularly rheumatoid arthritis (72.5%). Stress fractures of the distal tibia (51.3%), calcaneus (35.0%), and proximal tibia (27.5%) were the most common symptoms of MTX osteopathy, which could be mistaken for arthritis in certain cases. Even though most of the patients (58.1%) satisfied the densitometric criteria for osteoporosis, typical osteoporotic fractures (such as vertebral fractures) were uncommon. Bilateral (55.0%), numerous (71.3%), and recurrent fractures were common among the patients (25.0% ). Fractures were more common at low to high MTX dosages (45.0%). It was worth noting that half of the patients (48.8%) did not receive systemic steroid medication for at least 3 years. Low-dose MTX therapy for RMD could cause atraumatic stress fractures in the lower extremity, which could look like arthritis. A pathognomonic form of stress fracture with a band- or meander-shaped appearance along the growth plate characterizes MTX osteopathy.