Tamoxifen and raloxifene slow down the progression of muscular dystrophy Our results show that there are two important advantages of
tamoxifen and raloxifene treatment over steroids, which have limited
benefits for patients with MD. First, the 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," explained Qi Long Lu, MD, PhD, director of the
McColl-Lockwood Laboratory for Muscular Dystrophy Research,
Neuromuscular/ALS Center, Department of Neurology, Atrium Health's
(formerly Carolinas HealthCare System's) Carolinas Medical Center,
Charlotte (NC). The mice used in this study have the identical gene
defects and show almost the same disease manifestation as patients with
MD and are therefore an excellent model for therapeutic evaluation.
Investigators administered tamoxifen (2, 10, or 50 mg/kg), raloxifene
(50 or 100 mg/kg), or saline to mutant mice with dystroglycanopathy, a
form of MD, for up to a year, beginning at three weeks of age.
Raloxifene powder The investigators found several indicators that tamoxifen and
raloxifene delay or even halt disease progression. Within one month,
treatment with either SERM reduced muscle pathology with significant
reduction in the numbers of degenerating fibers. After a year, control
mice showed high variation in fiber size with focal inflammatory
infiltrations, but these dystrophic changes were much less evident after
tamoxifen or raloxifene. A noticeable reduction in collagen
accumulation in limb muscles for all treatment groups vs controls was
observed. Importantly, treatment with SERMs clearly mitigates muscle
damage and enhances functions of both respiratory and cardiac muscles in
addition to the limb muscles. Other benefits were also observed.
Control mice showed progressive muscle degeneration and regeneration in
the diaphragm, accompanied by increasing fibrosis and infiltration, as
well as significant impairment in respiration. Both tamoxifen and
raloxifene eliminated focal infiltration and reduced the extent of
fibrosis in the diaphragm, increased mass, and improved breathing
ability. "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, PhD, a research
scientist at the McColl-Lockwood Laboratory for Muscular Dystrophy
Research, Neuromuscular/ALS Center, Department of Neurology, Atrium
Health's (formerly Carolinas HealthCare System's) Carolinas Medical
Center, Charlotte (NC). These histological changes were accompanied by
functional improvements. For example, SERM treatment improved grip
strength of both forelimb and hindlimb muscles and enhanced running
ability on a treadmill test depending on the dose. Sex-related
differences in the effects of tamoxifen and raloxifene warrant careful
consideration if the drugs are to be administered clinically for MD,
noted the investigators. This is not surprising since SERMs act on
estrogen receptors and interact both as estrogen-receptor agonists and
antagonists. "SERM therapy has great potential to significantly delay or
halt MD progression. 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," noted
Dr. Lu. This together with the detailed analyses of potential side
effects and benefits in male and female populations provide rationale
for early clinical trials. Importantly, the beneficial effects of SERMs
are expected to extend to other forms of MD, beyond the specific mouse
model investigated here.
