Scientists in the U.S. have demonstrated that long-term therapy with the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene helps to slow disease progression in a mouse model of one of the most common forms of muscular dystrophy (MD). The study results, reported in the American Journal of Pathology, showed that both male and female mice treated with the drugs for a year demonstrated improved cardiac, respiratory, and skeletal muscle functions, and increased bone density. 

“Our results show that there are two important advantages of tamoxifen and raloxifene treatment over steroids, which have limited benefits for patients with MD,” comments lead researcher Qi-Long Lu, M.D., Ph.D., director of the McColl-Lockwood Laboratory for Muscular Dystrophy Research, Levine Children's Hospital, Carolinas Medical Center, in North Carolina. “First, the selective estrogen receptor modulators (SERMs) improve both histology and function of all muscles; although steroids improve histology, they improve function to a much lesser extent. Second, SERMs enhance bone density, whereas steroids exacerbate osteoporosis and increase the risk for fractures.”

The team reports its findings in a paper entitled “Long-Term Treatment of Tamoxifen and Raloxifene Alleviates Dystrophic Phenotype and Enhances Muscle Functions of FKRP Dystroglycanopathy.”

SERMs are widely used for their anti-inflammatory, antifibrosis, bone loss prevention, and muscle-building effects, which are all features of muscular dystrophies. However, steroids are currently the only treatment available to reduce cycles of inflammation and functional deterioration in patients with muscular dystrophy.

The third most common form of limb-girdle muscular dystrophies is caused by mutations in the Fukutin-related protein gene (FKRP). To see whether SERM treatment could help reduce the pathology and slow disease progression in this form of MD, the McColl-Lockwood Laboratory team tested oral therapy using either the SERM breast cancer drug tamoxifen or raloxifene, which is used to prevent and treat bone loss in postmenopausal women, in the FKRPP448L mutant mouse, which has the same genetic mutation as the human form of this type of the disease. Mice with dystroglycanopathy received either drug for a year, starting at three weeks of age.

The results showed that treatment “significantly ameliorated the disease progression,” the researchers write. “The improvement includes increase in grip force production, extended running time and distance in treadmill test.” Histological analyses confirmed that within a month of starting therapy with either of the SERMs, treated animals demonstrated reduced muscle pathology and fewer numbers of degenerating fibers. After a year of therapy, the mice showed far fewer dystrophic changes in muscle fibers when compared with control mice. There was a parallel reduction in collagen accumulation in limb muscles. And in addition to reducing skeletal muscle damage, SERM therapy also enhanced functioning of both respiratory and cardiac muscles.

Both tamoxifen and raloxifene similarly reduced the extent of fibrotic damage to the diaphragm and resulted in increased diaphragm muscle mass and improved breathing in the treated animals. “Both treatments also improved bone density in the tibia and femur, potentially reducing the risk of fracture, a major threat to patients as MD progresses,” added co-author Bo Wu, Ph.D., a research scientist at the McColl-Lockwood Laboratory.

There were sex-related differences, however. Tamoxifen, but not raloxifene, caused severe adverse effects on male reproductive organs, the researchers note. “The results demonstrate that tamoxifen and raloxifene hold significant potential for treating FKRP-related muscular dystrophy and probably other muscular dystrophies,” they conclude. “Sex-related differential effects of the drugs call for a careful consideration for the drug and dosage selection in male and female patient populations.”

“SERM therapy has great potential to significantly delay or halt MD progression,” Dr. Lu noted. “With the vast amount of safety data available, the selective use of tamoxifen and raloxifene in male and female patients with MD is an attractive and realistic alternative to steroids. The authors suggest that the beneficial effects of SERMs could also extend to other forms of MD.