Effects of high-dose methotrexate on bone metabolism: A narrative literature review

Methotrexate (MTX) play an important role in oncology, where it is used in high-dose therapy regimens. However, its associated dose-dependent toxicity, including MTX-osteopathy, poses a serious clinical problem, particularly in pediatric oncology. Even in patients with inflammatory rheumatic diseases receiving low doses, rare cases of MTX-osteopathy have been reported. This review provides an updated discussion of the side effects of high-dose MTX (HD-MTX), with the aim of improving understanding of the pathophysiology underlying its effects on bone, identifying potential supportive treatments, and highlighting new areas of research that could enhance the understanding and management of chemotherapy-related adverse effects. Methodology: A review of the available literature was conducted to analyse the impact of HD-MTX on bone tissue. Results: MTX disrupts bone homeostasis and microarchitecture through a variety of cell-specific mechanisms. These effects trigger a cascade of negative outcomes, including abnormalities in macrometric and structural bone histomorphometric parameters, as well as impaired bone healing. Few studies have evaluated the protective effects of adjunctive therapies, and those that do exist demonstrate only partial protection. This highlights the need for further research to develop more effective strategies to prevent MTX-induced bone toxicity. Conclusions: Available data suggest that the effects of HD-MTX involve multiple mechanisms that disrupt bone homeostasis, including impaired osteoblast function, enhanced osteoclastogenesis, altered osteocyte viability, increased bone marrow adipogenesis, and endothelial damage. These changes lead to reduced bone density, compromised microarchitecture, and impaired healing. This highlights the importance of multi-targeted strategies to prevent MTX-induced bone damage and improve skeletal outcomes.