Low-Dose Methotrexate and Bone Health: Pathophysiological and Clinical Perspectives

This narrative review summarizes current evidence on the molecular and cellular effects of low-dose methotrexate (LD-MTX) on bone tissue. In addition, it critically examines the limited and heterogeneous data on LD-MTX-associated osteopathy, a rare and incompletely understood condition that may be underrecognized in clinical practice. Finally, the review highlights key knowledge gaps and outlines future research directions aimed at improving diagnosis, management, and prevention. In total, 451 relevant articles were retrieved, and 71 studies were included in our review. Methotrexate (MTX) has been shown to prevent bone loss associated with inflammatory rheumatic diseases, primarily through its anti-inflammatory properties. However, current evidence highlights a variety of negative effects on bone associated with LD-MTX therapy, including osteoblast dysfunction, increased osteoclastogenesis, and endothelial damage. Collectively, these effects may result in deterioration of microarchitecture, impaired bone healing and insufficiency fractures. Despite the long and successful use of MTX in rheumatology, our knowledge of its effects on bone and awareness of LD-MTX osteopathy remain limited, potentially leading to delayed or missed diagnoses. Recent clinical studies highlight the potential underestimation of this condition and emphasize the need for further research to establish clear diagnostic criteria and treatment guidelines, as well as to achieve a more comprehensive understanding of the complex pathophysiology underlying LD-MTX osteopathy.