Raloxifene injections normalize age-related mechanical sensitization in female and male mice and augment intervertebral disc structure in old female mice

OBJECTIVE: Intervertebral disc (IVD) degeneration (IVDD) is a prevalent contributor to low back pain, yet IVDD-modifying therapeutics are unavailable. Osteoporosis drug raloxifene reduces age- and sex-related IVDD and indications of pain in preclinical and early-stage clinical studies, but the impact of raloxifene on evoked and spontaneous pain-related behavior is unclear. This study evaluated the effects of raloxifene injections on IVD structure and function, and pain-related behavior in 4-month-old and 24-month-old, female and male mice. DESIGN: Raloxifene was injected to 4-month-old and 24-month-old, female and male mice for 4 weeks, 5×/week or 4 days. Mice were assayed for pain by mechanical sensitivity and gait dynamics, neurotransmitter substance P expression, and IVD biomechanical function, function and hydration. RESULTS: Raloxifene injections reduced mechanical sensitivity and IVD substance P in 4-month-old and 24-month-old mice of both sexes with age and sex-differences measured for gait dynamics and IVD morphology. Raloxifene reduced IVDD in 4-month-old and 24-month-old female mice (4-month-old: -44%, p=0.03;24-month-old: -32%, p=0.02), but did not affect male IVDD grade (4-month-old: +7%, p=0.35; 24-month-old: -14%, p=0.34). Similarly, raloxifene increased propel-stance duration in 24-month-old female mice by 4% (p=0.01), but did not affect gait in 24-month-old male mice(-0.4%, p=0.94). Using microMRI, 4 days of raloxifene injections increased IVD hydration from baseline by 4% (p=0.046). CONCLUSIONS: Raloxifene injections significantly reduced IVDD in female mice and reduced mechanical sensitivity to evoked mechanical pain in both male and female mice, suggesting that raloxifene may serve as a therapeutic for painful age-related IVDD.