Baricitinib for the treatment of age-related osteoporosis

Osteoporosis is a common age-related disease that affects millions of people worldwide and is associated with an enormous economic burden. As still only a small number of osteoporotic patients is adequately treated, there is an urgent need to develop new treatment strategies. Proinflammatory cytokines are special proteins produced by various cells in the body in response to the presence of bacteria, viruses, fungi, parasites or tissue damage. They are also involved in immune and inflammatory responses and play an important role in the pathogenesis of osteoporosis. Baricitinib belongs to the group of Janus kinase (JAK) inhibitors, is an anti-inflammatory agent that mediates cytokine signaling and is approved for the treatment of rheumatoid arthritis. From previous preclinical studies it is evident, that in young animals treatment with baricitinib has a positive effect on bone formation; nevertheless, data in a model of age-related osteoporosis are lacking. Based on this gap in research, in our study 60 eight-month-old female SAMP8 mice will be randomly assigned to receive baricitinib or control vehicle. The SAMP8 mouse was selected for this study because it is an established model of age- related osteoporosis. After a treatment period of six weeks, the bones will be examined by micro-CT and histomorphometry. Furthermore, flow cytometry, ELISA analyses, RNA sequencing and integrative data analysis with a systems biology approach will be performed. The main objective of this study is to test the effect of baricitinib on bone microarchitecture by micro-CT. Since it is known from previous studies that baricitinib has a positive effect on new formation of bone in young mice and that bone formation is reduced in age-related osteoporosis, we hypothesize that baricitinib will improve bone properties in our mouse model of age-related osteoporosis (SAMP8). Additional objectives of this study include investigations of bone remodeling and cytokine production by immune cells and transcriptomic analyses. The generated results of this study will demonstrate the role of baricitinib as a bone active compound and provide a clear rationale for the clinical development of baricitinib for osteoporosis treatment in advanced age.

Osteoporosis is a common age-related disease that affects millions of people worldwide and is associated with an enormous economic burden. As still only a small number of osteoporotic patients is adequately treated, there is an urgent need to develop new treatment strategies. Proinflammatory cytokines are special proteins produced by various cells in the body in response to the presence of bacteria, viruses, fungi, parasites or tissue damage. They are also involved in immune and inflammatory responses and play an important role in the pathogenesis of osteoporosis. Baricitinib belongs to the group of Janus kinase (JAK) inhibitors, is an anti-inflammatory agent that mediates cytokine signaling and is approved for the treatment of rheumatoid arthritis. From previous preclinical studies it is evident, that in young animals treatment with baricitinib has a positive effect on bone formation; nevertheless, data in a model of age-related osteoporosis are lacking. In our study we investigated the effects of baricitinib on age-related osteoporosis by using senescence-accelerated mice-prone 8 (SAMP8) mice, a mouse model of accelerated aging, and evaluated the effects of baricitinib by applied it twice daily for six weeks. Bone outcomes were evaluated by high-resolution micro-computed tomography (CT) and static histomorphometry. Intracellular cytokine production by splenocytes was determined via flow cytometry. We demonstrated that baricitinib suppressed the production of key proinflammatory cytokines, potentially resulting in a pronounced attenuation of inflammatory responses. In this context, we specifically examined IL-6, TNF, IL-17, IL-21, and IFN- since these cytokines are not only central drivers of inflammation, but also have a well-documented impact on bone metabolism. The effect of baricitinib on the bone properties of SAMP8 mice was not pronounced. The immune-skeletal crosstalk and/or the anabolic response of osteoblasts to the improved inflammatory milieu following JAK inhibition might be impaired due to age-related alterations. Our data furthermore contributes to deeper insights in the field of inflammaging - a chronic, often initially subclinical, proinflammatory state associated with aging. A hallmark of inflammaging is the sustained overproduction of proinflammatory cytokines, many of which are also bone-resorptive, thereby promoting osteoclast-driven bone loss and contributing to age-related disorders such as RA, and particularly osteoporosis. In our study baricitinib was found to effectively suppress proinflammatory cytokines in a mouse model for age-related osteoporosis. The obtained results were published (Gelles K et al., 2026). Novel insights were furthermore gained by the analysis of the gene expression profile of bone marrow cells derived from mice upon baricitinib treatment; the data are currently under evaluation and will be summarized in an additional publication.