Findings support hereditary link in disk degeneration
Michele C. Battié, PhD; Tapio Videman, MD, PhD; Jaakko Kaprio, MD, PhD; Laura E. Gibbons, PhD; Kevin Gill, MD; Janna Saarela, MD, PhD; and Leena Peltonen, MD, PhD, have received the 2008 Kappa Delta Elizabeth Winston Lanier Award for their manuscript on “The Foundation of a New Paradigm of Disk Degeneration: The Twin Spine Study.”
For much of the last century, disk degeneration was viewed as a result of aging and “wear and tear” from mechanical insults and injuries. Thus, research and prevention focused on mechanical factors as primary causes using an ‘injury model.’ In the last decade, however, that view has changed considerably. Degenerative disk disease is now viewed as being determined in great part by genetic influences, with environmental factors also playing an important role (Fig. 1).
That paradigm shift has occurred largely as a result of several studies, including the Twin Spine Study, a multidisciplinary, multinational research program on the etiology and pathogenesis of disk degeneration. The researchers hope the advances gleaned from their studies and others will provide a new foundation for new hypotheses and more fruitful research to help explain the causes of disk degeneration and their associations with back pain.
“An important lesson for clinicians may be to be more careful when attributing disk changes to occupational exposures and other routine physical demands,” said Dr. Battié, the lead investigator in the study. “Despite extraordinary discordance between identical twin siblings in occupational and leisure time physical loading conditions throughout adulthood, we observed surprisingly little effect on disk degeneration.”
The studies provide evidence that genetics play a critical role in disk troubles, Dr. Battié noted. “The genetic influence can be seen through magnetic resonance imaging (MRI). When viewing the twins’ MRIs, we marveled at the uncanny similarity in the types and locations of degenerative findings (Fig2).” The team also identified the first gene forms associated with disk degeneration.
The Twin Spine Study began in 1991 when collaborators from the United States and Finland conducted a pilot study of 20 pairs of identical twin siblings grossly discordant for cigarette smoking (mean 32 pack-years) to study the effects of smoking on disk degeneration. Since then, the Twin Spine Study has grown to include 300 sets of both identical (MZ) and fraternal (DZ) male twins from the population-based Finnish Twin Cohort. The team now includes collaborators in several disciplines from Canada and the United Kingdom.
Back pain problems are among the most common and costly musculoskeletal conditions facing the developed countries of the world. Unfortunately, prevention and treatment strategies have demonstrated only modest effects. Because the underlying pathology and risk factors are largely unknown, developing rational, effective approaches to prevention and treatment is challenging.
Although the specific underlying pathology is unknown in most cases of back pain, lumbar disk degeneration is a primary suspect and is commonly believed to be responsible for frequent, severe back symptoms, as well as contributing to sciatica and lumbar spinal stenosis, said the authors. Consequently, it is a primary target for diagnostic and therapeutic interventions. “Although the pain mechanisms are unclear and likely to be complex, evidence suggests that the disk plays a role in back symptoms, sciatica, and spinal stenosis but the extent of the role remains unknown,” researchers wrote.
Twin Spine Study
The total sample population included an initial selection of 117 pairs of MZ twins and was based solely on discordance between twin siblings for a specific common behavioral or environmental factor (such as sedentary or heavy occupational physical demands, routine exercise participation, or occupational driving) that was suspected to contribute to spinal degeneration and back symptom complaints. The study also included a random sampling of 30 MZ pairs, stratified by age, and 153 pairs of DZ twins selected using analogous criteria.
Interviews, physical examinations, and clinical testing were performed at a central location. A structured interview was used to obtain data such as demographic information, health history, occupational history, regularly performed leisure time activities/exercise, specific recalled incidents or trauma resulting in acute “back injury,” smoking, and driving history.
Researchers performed MRIs of the lumbar spine on all participants using a set protocol and collected blood samples for DNA extraction.
Old paradigm applied
“We began our research under the paradigm that disk degeneration was primarily the cumulative result of tissue injuries and degradation from trauma and repetitive loading,” said investigators. “Among the factors most commonly suspected of accelerating degenerative changes were various occupational physical loading conditions such as heavy materials handling, postural loading, and vehicular vibration. Yet, findings of studies of suspected physical loading risk factors were often contradictory or equivocal, possible confounding was a major concern, and dose-response relations were unclear.” Also, when researchers began the Twin Spine Study, MRI was just becoming available; most prior epidemiologic or clinical studies had been limited to evaluating disk degeneration through radiographs.
The team conducted a series of studies of identical twins highly discordant for a specific suspected risk factor. For example, among 45 pairs of identical twins—one of whom had substantially more lifetime driving hours than the other—no significant differences could be found in MRI findings of the lumbar disks. “No tendency for greater disk degeneration was seen among drivers.”
Other findings indicated that although physical loading appears to influence disk degeneration, the effect size is very modest, which would help explain the inconsistent results of previous studies. “In fact, we found indications that routine loading may actually have benefits to the disk,” the researchers wrote.
These findings raised questions about the adequacy of an injury model or “wear-and-tear” view of disk degeneration. During the course of these studies, researchers who viewed images of the twins’ spines side-by-side saw a strong resemblance in both the degree of disk degeneration and in the types of findings and spinal levels involved. “Those observations led us to pursue studies of genetic influences,” they wrote.
Genetic link confirmed
These studies and others provided motivation for identifying associated genes. “Disk degeneration and back pain are clearly not synonymous and the association between the two is routinely debated. Yet, if disk degeneration does influence back pain problems, and both have a substantial genetic component, disk degeneration may be one pathway through which genes influence back pain,” they wrote.
To examine whether genetic influences on back pain are mediated through genetic influences on disk degeneration, the team conducted a classic twin study using multivariate quantitative genetic models to estimate the degree to which genetic effects on back pain correlate with genetic effects on disk degeneration.
“A substantial minority (up to one quarter) of the genetic influences on pain was due to the same genetic influences affecting disk height narrowing,” they wrote. “Yet, the substantial portion of genetic influences on pain left unexplained suggests an important role for other genetic influences that may affect pain processing, reporting, or other underlying pathological conditions.”
In contrast, less than 5 percent of the variance in back pain outcomes explained by environmental factors was due to the same environmental factors influencing disk height narrowing, supporting earlier studies that showed negligible or modest effects on disk degeneration of occupational activities associated with back pain complaints. The researchers then asked whether particular environmental physical loading exposures serve primarily to exacerbate symptoms rather than cause the underlying pathology.
“Although little overlap was found between environmental factors influencing pain reporting and disk narrowing, environmental factors do appear to have a substantial role in disk height narrowing as do genetics,” they wrote. This indicates that influential environmental exposures, such as biomechanical forces, may need to be refined or reconceptualized to include hypotheses of interactions with other systems and the pathways through which they may affect lumbar disk degeneration and associated pathology.
The investigation of genetic influences on disk degeneration is still in its infancy, the investigators state. “Future research will aim to clarify the genetics of disk degeneration, identify influential environmental factors, and explore the interplay between the two.” Better phenotype measures will likely be needed.
The team’s research was funded by The National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Finnish Academy, the Finnish Work Environment Fund, the Alberta Heritage Foundation for Medical Research, the Canada Research Chairs Program, and the European Union.
Eileen Norris is a freelance writer specializing in healthcare issues.