How a Common Muscle Relaxant May Influence Bone Formation

A new publication was released by the ENDOTARGET consortium investigating how the commonly prescribed antispastic drugs baclofen and tizanidine influence the behaviour of mesenchymal stem cells and whether they may contribute to the development of heterotopic ossification, which is the abnormal formation of bone in soft tissues. This scientific work was published in March 2026 in the International Journal of Molecular Sciences. The authors of this study are María Crugeiras-Sampedro, Lorena Zas-Veiga, María Piñeiro-Ramil, Andrés Pazos-Pérez, Verónica López-López, Alberto Jorge-Mora, Ana Alonso-Pérez and Rodolfo Gómez.

Baclofen and tizanidine are widely used to treat muscle spasticity after neurological injuries such as spinal cord injury or traumatic brain injury. While these patients are already known to have an increased risk of developing heterotopic ossification, it has remained unclear whether the medication itself might also influence this process. Using laboratory-grown mesenchymal stem cells, the researchers investigated how baclofen and tizanidine affect the balance between fat cell and bone cell formation. Their findings provide new insights into how these commonly used drugs may influence cellular behaviour and highlight the importance of further research into treatment strategies for patients at risk of abnormal bone formation.

Why is this research topic important?

Following severe neurological injuries to the brain or spinal cord, many patients develop spasticity, which is a condition in which muscles become stiff and difficult to control. Baclofen is one of the most frequently prescribed medications to reduce this muscle stiffness and improve mobility, while tizanidine is a widely used drug that is considered a first-line treatment along with baclofen. Next to spasticity, another complication can occur after these injuries: heterotopic ossification (HO). HO is an aberrant tissue repair in which normal regeneration is dysregulated, triggering the formation of bone where it should not be, such as within muscles or other soft tissues surrounding joints. This extra bone can cause inflammation, chronic pain, and progressive loss of joint mobility with a possibility of evolving into ankylosis. Biologically, the abnormal bone formation begins with the differentiation of mesenchymal stem cells (MSCs) into chondrocytes (cartilage cells) or osteoblasts (bone-forming cells), rather than into adipocytes (fat-forming cells). Although spasticity and HO often occur together, scientists have struggled to determine whether the increased risk of HO is caused solely by the injury itself or whether medications used to treat spasticity may also play a role. In patients with traumatic brain injury, large cohort studies have shown that the use of antispastic medications is associated with a higher incidence of HO, highlighting abnormal muscle activity as a contributing factor in this abnormal bone formation. Answering this question is important because baclofen remains one of the most used drugs worldwide. If the drug directly influences the cells involved in bone formation, this information could help physicians make more informed treatment decisions, particularly for patients who are already at high risk of developing HO.

How was the study conducted?

To investigate this question, the researchers used mesenchymal stem cells (MSCs) grown under controlled laboratory conditions. These cells were selected due to their ability to differentiate into cartilage cells (chondrocytes), bone-forming cells (osteoblasts) and fat-forming cells (adipocytes). In the study, MSCs were exposed to the two antispastic drugs, baclofen and tizanidine, after triggering fat-cell formation (adipogenesis) with external molecular signals. This created an ideal situation to observe whether either drug could redirect the cells away from fat formation and towards bone development. MSC differentiation was analysed by the activation (expression) of genes involved in the fat cell formation process (adipogenesis) and bone cell formation process (osteoblastogenesis). To better mimic conditions found after severe injury, the researchers repeated the experiment in the presence of inflammatory molecules. Since inflammation is a key feature following trauma, this allowed the team to investigate whether baclofen behaves differently in an inflamed environment.

What does the analysis show us?

The results revealed clear differences between the two drugs, baclofen and tizanidine.

Baclofen treatment changes gene expression in MSC, but tizanidine does not

The studies showed that under normal laboratory conditions, baclofen significantly reduced the expression of adipogenic marker genes while significantly increasing the expression of osteochondrogenic marker genes. Consistent with these results, the cells had an increased production of SPP1, which is a protein that has previously been linked to HO. In contrast, the treatment with tizanidine had almost no measurable influence on MSC differentiation. Unlike baclofen, it neither reduced adipogenic markers nor substantially increased osteochondrogenic markers.

Baclofen does not affect bone cell formation under inflammation

Although inflammation is present after neurological injury and has been described as a risk factor for HO, excessive inflammation has been associated with the inhibition of bone formation. To investigate this further, the same experiment was repeated with baclofen in the context of a strong and sustained inflammatory environment. Under inflammatory conditions and without any drug addition, the cells showed a significantly enhanced expression of adipogenic marker genes and reduction of osteochondrogenic marker genes. Co-treatment with baclofen led to a significant reduction of the expression of adipogenic marker genes, thus suppressing fat-cell formation. However, baclofen did not increase the expression of osteochondrogenic marker genes.

What can we learn from the study?

In patients, it is almost impossible to distinguish whether HO develops because of the underlying neurological injury, the resulting muscle stiffness, or the medications used for treatment. By studying isolated stem cells under defined laboratory conditions, the researchers were able to investigate the direct effects of baclofen and tizanidine on MSC, independent of spasticity. The findings suggest that baclofen can directly influence MSC fate by triggering pathways associated with bone-cell formation while reducing those associated with fat-cell development. In contrast, tizanidine showed no relevant effect on either the fat-cell formation or the bone-cell formation process. However, it is important to note that the study does not show that baclofen causes HO, nor does it establish a causal relationship between baclofen administration and HO development in patients. Instead, it identifies a previously unrecognised biological effect that needs further investigation in human cells, animal models and clinical studies. Nevertheless, these findings point towards a potential clinical risk associated with baclofen use and provide new knowledge to be considered when selecting which drug to use to manage spasticity in patients at risk of HO.

 

Read full publication here: Baclofen Promotes Osteochondrogenic Commitment of Mesenchymal Stem Cells: Implications for Heterotopic Ossification Risk

 

Glossary

Adipocytes: specialised fat cells that store energy, regulate metabolism, and produce signalling molecules that influence inflammation and tissue function.

Adipogenesis: the process by which stem cells develop into fat cells.

Adipogenetic markers: genes or proteins that indicate whether cells are beginning to develop into fat-forming cells.

Baclofen: a drug commonly used to reduce muscle stiffness (spasticity), particularly after spinal cord or brain injuries.

Gene expression: the process by which a gene is “switched on” so that it produces the molecules needed for a cell to perform specific functions.

Heterotopic ossification (HO): the abnormal formation of bone in soft tissues such as muscles, tendons or connective tissue, where bone normally should not develop.

Inflammation: the body’s natural response to injury or infection. While it helps with healing, prolonged or excessive inflammation can contribute to disease.

Mesenchymal stem cells (MSCs): specialised stem cells that can develop into several types of tissues, including bone, cartilage and fat.

Osteoblasts: specialised bone-forming cells that produce and mineralise the bone matrix, helping to build and repair bone tissue.

Osteochondrogenic differentiation: the process by which stem cells develop into cartilage-forming and bone-forming cells.

Osteochondrogenic markers: genes or proteins that indicate whether cells are beginning to develop into bone-forming cells.

Spasticity: a condition in which muscles become stiff or tight because of damage to the brain or spinal cord, making movement difficult.

SPP1 (Osteopontin): a protein involved in bone formation and tissue remodelling that is often found at increased levels during abnormal bone growth.

Tizanidine: a drug used to treat muscle spasticity that works through a different biological pathway than baclofen.