Statins for Disc Degeneration

Abstract

While only a small percentage of patients with back pain are surgical candidates, conservative therapy (medications, physical therapy, epidural injections, etc.) does not result in adequate analgesia for many patients. As such, there exists a continuing need for the development of novel treatments for back pain. Although the exact pathogenesis is still unclear, disc degeneration likely results from a combination of mechanically-driven and biologically-mediated factors. The extracellular milieu of spinal discs is constantly in flux and balanced by the synthesis, breakdown, and accumulation of matrix macromolecules. Recent insights into this degenerative process have implicated bone morphogenetic protein-2 (BMP-2) as a vital player in this process and in chondrogenesis of the intervertebral disc. Several recent studies have focused on varying BMP expressions in normal and degenerated discs, as well as the use of gene therapy and other mechanisms to up-regulate BMP as a means of initiating chondrogenesis and restoring normal disc morphology. However, much has also been written in the spine fusion literature regarding the adverse effects of BMP-2, including seroma formation, heterotopic ossification, perineural cyst formation, radiculitis, and tumorigenesis. Thus, while BMP may be a promising therapeutic avenue for treating degenerative disc-related diseases, its exogenous application is not without risk. To that end, the recent work of Than et al is especially relevant.1 They took advantage of the fact that simvastatin, an extensively studied and well-tolerated drug, is known to up-regulate expression of BMP-2a. In their investigation, disc injury was induced in 272 Sprague-Dawley rats (3 months old) via 21-gauge needle puncture at the Co5/Co6 and Co7/Co8 levels; Co6/Co7 was left unperturbed to serve as an internal control. Six weeks after stab injury, 2 μL simvastatin at 3 different doses (5, 10, or 15 mg/mL) in either a saline or hydrogel carrier was injected into injured discs using a 31-G (non-disc injuring) needle, as well as control injections of hydrogel, saline and puncture alone. Rats were sacrificed or imaged at predetermined time points from 2 to 24 weeks. Outcome measures assessed were radiologic, histological, and genetic. Radiologically, discs treated with 5 mg/mL simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks post-treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL simvastatin in hydrogel demonstrated improved grades in comparison to discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. Overall, in all outcome measures, degenerated discs treated with simvastatin demonstrated findings consistent with retardation of the degenerative process, or even regeneration of normal disc material. A major limitation of this study is that it remains unknown whether the radiographic/histological/genetic regeneration of the disc correlates with resolution of pain. Also, further elaboration on the dose curve for effect is necessary to reliably attribute benefit to the lower treatment dose. Regardless, the allure of this study is that it provides groundwork for future trials investigating the benefits of statins, a class of drugs in widespread use for other diseases, in the non-operative treatment of degenerative disc disease. As the socioeconomic toll of lumbar disc disorders remains enormous, the continued search for novel treatments remains essential, and in that sense, the work of Than et al brings us one step closer to that goal.Figure 1: Representative histological specimens of rats sacrificed at 24 weeks. A) Normal control. B) Disc treated with 5 mg/mL simvastatin. C) Disc treated with 15 mg/mL simvastatin. Note in A and B the regular appearance of the annulus fibrosus, the intact border of the annulus fibrosus and nucleus pulposus, and the increased cellularity compared to C. (Images at ×4 microscopic power).