**5. Rheumatoid disease and methotrexate**

Low-dose MTX is regarded as an effective RA treatment since it reduces joint stiffness, pain, and inflammation while also greatly delaying bone deterioration. It is generally known that generalized osteoporosis can arise in RA per se. Three main causes have been proposed as the mechanism of this osteoporosis [29]:


Since MTX reduces rheumatic inflammation and permits an increase in physical activity, this medication may help with OP brought on by RA. However, MTX has been shown to have a negative impact on bone among RA patients and animal models. Sally et al. described two cases of MTX osteopathy with fractures in rheumatoid arthritis patients getting long-term low-dose MTX treatment. MTX osteopathy has been mentioned in an increasing number of papers [30]. Even though glucocorticoids prefer cancellous bone, MTX-induced bone loss and fractures mostly affected cortical bone. Patients with rheumatic disease who underwent *Non-GCs Drug-Induced Osteoporosis DOI: http://dx.doi.org/10.5772/intechopen.108296*

histological investigation revealed that MTX osteopathy has impaired bone formation, as evidenced by a decreased osteoblast surface and a lower mineral apposition rate. Additionally, May et al. observed that low-dose MTX impairs bone formation and increases bone resorption in both normal and ovariectomized mice, resulting in osteopenia [31, 32]. However, MTX's inhibition of the development of marrow osteoblast precursor cells leaves unclear the particular mechanism by which it reduces bone production. Additionally, MTX significantly reduced ALP activity and prevented calcified nodules from forming in cultures of marrow stromal cells. Given that May et al. found that MTX inhibits matrix mineralization using terminally developed osteoblasts, it is possible that MTX also suppresses mature osteoblasts. The transcription factor Cbfa1 has recently been identified as a key player in osteoblastogenesis. Therefore, a study into how MTX affects osteoprogenitor cells' expression of Cbfa1 may be useful for understanding the molecular basis of MTX osteopathy. Furthermore, bone metabolism is hampered by disease activity [29–34].
