Lumbar degenerative disk disease is a serious health problem for more than 70 million Americans. Repetitive spinal loading is a major factor in the onset of the disease. Treatment options include physiotherapy, pain management, and surgery. Although a well-known correlation exists between excessive or prolonged mechanical loading and degenerative disk disease, the etiology of this process is poorly understood.

New research has shown that mechanical and chemical factors affect nutrition of the disk via diffusion from blood vessels in the endplate. Disruption of the diffusion process, typically resulting from thickening or sclerosis of the endplate, may have a negative impact on overall disk homeostasis.

“I was just beginning my career and an OREF Young Investigator Grant is a wonderful opportunity for faculty and clinician scientists to foster new ideas,” he said. “OREF supports research projects that have enormous potential for improving the field of orthopaedics and what orthopaedists can do in our clinical practices.”

Why nimodipine?
Nimodipine is a dihydropyridine calcium channel blocker originally approved for the treatment of hypertension. It is currently used for prevention of cerebral vasospasm and resultant ischemia following subarachnoid hemorrhage. In one preclinical study, nimodipine was shown to improve the vascularity of the vertebral endplate; in another study, it improved intervertebral disk diffusion.

“This inspired me to conduct an original investigation to see if nimodipine can have a beneficial effect in improving the vasculature or vascularity of the endplate, as well as foster diffusion into the disk to keep it healthy,” said Dr. Lawrence.

Research goals and methodology
Dr. Lawrence defined the following two main goals for his study:

• Demonstrate that cyclic loading-induced chronic intervertebral disk degeneration is mediated by a diffusion pathway.
• Investigate whether nimodipine prevents degenerative changes to the vertebral endplates and the intervertebral disk in a setting of chronic high-frequency loading.

In collaboration with Dr. Eric Ledet, an assistant professor of biomedical engineering at Rensselaer Polytechnic Institute (RPI) in Troy, N.Y., Dr. Lawrence and his research team used a large-animal model to create loading-induced disk degeneration and assess the therapeutic benefits of nimodipine on diffusion and intervertebral disk health. “We used the existing model developed by Dr. Ledet and his lab at RPI,” Dr. Lawrence explained. “We implanted loading devices into live New Zealand white rabbits, which gave us the ability to load a disk at a rate that we could control.”

After 6 months, Dr. Lawrence and his research team used imaging and histologic methods to evaluate the intervertebral disks, endplates, and subchondral bone of the specimens for the extent and mechanism of changes. Intervertebral disk degeneration was quantified by a scoring system that included the following measures:

• disk height loss
• osteophyte formation
• reduced magnetic resonance imaging (MRI) T2 signal intensity
• proteoglycan loss
• fibrosis of the nucleus pulposus
• lamellar disorganization
• matrix homeostasis
• inflammation

Endplate and subchondral bone changes were determined by bony endplate thickness and shape, subchondral bone density, vessel density, endplate cartilage thickness, evidence of endochondral bone formation, and inflammation. Trans-endplate diffusion was quantified by postcontrast enhanced MRI T1 mapping.

Promising results
Standard MRI measurement techniques showed that using nimodipine increased diffusion rates into the disk by about 10 percent. This is a significant clinical result because it shows for the first time that the prognosis of long-term spinal degeneration can be mediated by a pharmacologic intervention that stimulates endplate diffusion.

“Restoration of the vascular supply to the vertebral endplate and maintenance of the diffusion pathway to the disk is a novel approach to both prevention and treatment for degenerative changes to the disk,” said Dr. Lawrence. Based on this work and future research, Dr. Lawrence hopes that at some point, patients will be able to take a tablet, receive an injection, or have a device implanted in the spine to deliver medication to the disk at the onset of symptoms, forestalling what would otherwise be a continuous disease progression. This type of intervention would be especially beneficial to groups at high risk for degenerative disk disease, such as construction workers, laborers, and athletes.

Mark Crawford is a contributing writer for OREF. He can be reached at communications@oref.org