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

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.

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.