Osteoporosis drug alendronate undermines the capacity of immune cells to mount innate memory

Vaccines provide long-lasting protection against an infection by generating memory in T and B cells. Some vaccines also have non-specific immune-boosting effects through memory induction in innate immune cells like monocytes. Mihai Netea’s group from the Department of Internal Medicine described this concept, called trained immunity, in 2011. The tuberculosis vaccine BCG, which has been around for over a century, is the most well-known inducer of trained immunity and can help protect against a variety of infections.

Previous research revealed that the accumulation of mevalonate, an intermediate in cholesterol synthesis, enhances trained immunity. Nitrogen-containing bisphosphonates (N-BPs), drugs often used to treat osteoporosis, block an enzyme that works downstream in the mevalonate pathway. Netea and colleagues hypothesized that N-BPs might boost the effect of BCG by increasing mevalonate levels. They tested this theory in a placebo-controlled study with healthy volunteers, combining BCG vaccination with the N-BP alendronate. Researchers Özlem Bulut and Gizem Kılıç recently published the results of their study in Immunology Letters.

Surprisingly, the research team discovered that the combined use of alendronate and BCG actually reduced the trained immunity response. When participants' immune cells were challenged with bacterial and viral stimuli, those who took alendronate produced less of the cytokine TNFα one month later compared to those who received only BCG or a placebo. Alendronate also counteracted the transcriptional changes induced by BCG, suppressing various inflammatory response pathways.

The researchers emphasize that this study only examined the impact of a single alendronate dose, while N-BPs are typically used long-term. The potential impact of prolonged N-BP use on immunity, including trained immunity, still needs to be investigated. Moreover, the study involved healthy young volunteers, but N-BPs are primarily used by older adults with less robust immune systems. Future research should explore if prolonged N-BP use interferes with the benefits of BCG vaccination and its use as a treatment for bladder cancer, and if it impacts clinical outcomes such as infection rates or cancer progression.

Read the study here: www.sciencedirect.com/science/article/pii/S0165247824000257

Bulut O, Kilic G, Debisarun PA, Röring RJ, Sun S, Kolkman M, van Rijssen E, Ten Oever J, Koenen H, Barreiro L, Domínguez-Andrés J, Netea MG. Alendronate modulates cytokine responses in healthy young individuals after BCG vaccination. Immunology Letters. 2024 Jun 1;267:106851.